Section J: Hematology

BACKGROUND

The initial evaluation of a child with anemia is a common task for general pediatricians or hospitalists. Defined as insufficient red blood cell (RBC) mass for the age of the patient, anemia can develop acutely or insidiously. In children, anemia that develops gradually over several weeks to months may be profound but with little clinical consequence other than obvious pallor. However, if anemia develops acutely, the patient has no time to compensate for decreased oxygen carrying capacity, and symptoms of anemia (ranging from fatigue to cardiovascular collapse) can develop rapidly. Because anemia can result from many disease processes, it is helpful to divide anemia into broad pathophysiologic categories: (1) decreased production of either hemoglobin or RBCs, (2) premature RBC destruction, or (3) blood loss.¹ Fortunately, distinguishing among these processes usually requires only basic, widely available laboratory tests. Once the pathophysiologic category is determined, the differential diagnosis narrows, and the evaluation is much less daunting. This chapter focuses primarily on children with newly recognized anemia for whom the evaluation is often initiated by pediatric hospitalists.

CLINICAL PRESENTATION

Anemia is often discovered incidentally during laboratory screening for other indications in a child who otherwise exhibits no symptoms of anemia.^2-4 Systematic evaluation of febrile hospitalized children demonstrated that a majority may exhibit mild anemia.^5,6 Alternatively, pallor and fatigue, the cardinal symptoms of anemia, may bring the patient to medical attention. Severe anemia, especially when there is a rapid onset, may present with weakness, obtundation, syncope, exertional dyspnea, congestive heart failure, or shock.

The probable causes of anemia can often be predicted by considering the age of the patient and taking a careful history. A directed history should thoroughly review the child’s diet, including the amount and type of milk, red meat, fruits, and vegetables consumed daily, as well as a history of pica. Growth and development, blood loss (i.e. melena, hematemesis, hemoptysis, hematuria), and recent illnesses are also important areas of inquiry. Acute and/or chronic inflammation often are underlying causes of anemia in hospitalized patients. Because many causes of anemia are inherited, the family history is critical and should include questions about transfusions, bleeding, splenectomy, cholelithiasis or cholecystectomy, and prior diagnoses of anemia.

The physical examination should focus on manifestations of anemia and diagnostic clues. Tachycardia, systolic murmur, and pallor suggest a moderate degree of anemia. Severe anemia can be accompanied by symptoms of congestive heart failure and tachypnea, despite children’s typically profound and effective cardiovascular compensatory mechanisms. Jaundice or dark urine suggests intravascular hemolysis and rapidly narrows the differential diagnosis. Similarly, hepatosplenomegaly, a physical sign of great importance in the diagnostic evaluation of an anemic patient, suggests extramedullary hematopoiesis (as in chronic hemolytic anemias) or other diagnoses (e.g. storage diseases, bone marrow infiltration, infections).

The initial laboratory evaluation typically includes a basic panel of hematologic studies, followed by selected studies as directed by the presentation and the history. A complete blood count (CBC) with differential white blood cell count, reticulocyte count, and direct and indirect antiglobulin (Coombs) tests are central for initial classification. RBC indices are usually included in the CBC and provide additional clues to the pathophysiology of the anemia (Table 88-1). Examination of the peripheral blood smear should be performed, with particular attention to RBC morphology and evidence of hemolysis (Table 88-2). Some examples of RBC abnormalities that may be seen on the peripheral smear are provided in Figure 88-1.

Evaluation for occult blood loss should include several stool guaiac tests for subclinical gastrointestinal bleeding. Although less common, trauma-related injuries should also be considered, such as femur fracture with major hematoma, hemothorax, or hemoperitoneum. Outside the special population of very premature infants, it is uncommon for intracranial hemorrhage to account for significant anemia, and unless neurologic symptoms or signs accompany the presentation, cranial imaging is not generally indicated.

Subclinical hematuria usually involves only small amounts of blood in the urine and generally does not result in significant anemia in the absence of some other causative factor. However, blood detected by urinalysis is an important finding and requires attention to both the urine dipstick and microscopic analysis. Blood detected by dipstick without a significant number of RBCs on the microscopic examination indicates the presence of either hemoglobin (suggesting intravascular RBC hemolysis) or myoglobin (due to rhabdomyolysis). Serum concentrations of muscle enzymes (e.g. creatine kinase) or free hemoglobin should help differentiate between myoglobinuria and hemoglobinuria.

Depending on the patient’s age and the history and physical examination findings, further evaluation can be tailored accordingly. Iron-deficiency anemia is a common cause of microcytic anemia, and further evaluation includes a serum iron level, total iron binding capacity, and ferritin. Microcytic anemia with risk factors for plumbism should prompt the measurement of serum lead levels. Clinical concerns for endocrine, renal, or hepatic disease justify the assessment of hepatic transaminases and thyroid and renal function. Hematologic consultation is often useful if initial efforts fail to yield a definitive diagnosis. Further laboratory studies such as hemoglobin electrophoresis (to investigate hemoglobinopathies) and osmotic fragility studies (to rule out spherocytosis) may be indicated. Bone marrow aspiration and biopsy may be useful in the diagnosis of anemias of unclear cause and to rule out diagnoses such as myelodysplastic syndrome, congenital dyserythropoietic anemias, aplastic anemia, and leukemia. Although occasionally presenting with isolated anemia, myelodysplastic syndrome and leukemia usually result in pancytopenia or the appearance of abnormal (e.g. dysplastic or immature) cells in the peripheral blood.

Comparing current RBC indices with those of previous blood examinations may provide important information, such as the rate and timing of onset of the anemia. In addition, whenever possible, specific laboratory studies should be obtained before blood product transfusion so that they reflect the patient’s condition rather than that of the blood donor.

DIFFERENTIAL DIAGNOSIS

Because anemia is associated with various pathophysiologic abnormalities, functional classification simplifies the initial evaluation. One approach divides anemias into those with microcytic, normocytic, or macrocytic erythrocytes based on the mean corpuscular volume (MCV); another considers whether the anemia results from diminished RBC production rather than increased RBC destruction. Table 88-3 unifies both classification schemes for the common anemias encountered by pediatric hospitalists. It is critical to interpret both the hemoglobin and the MCV based on the child’s age, because normal RBC parameters change with age.⁷ Multiple concurrent pathophysiologic processes often complicate even straightforward diagnoses. For example, it can be challenging to evaluate anemia in a patient with chronic renal failure and possible nutritional deficiencies who develops subclinical hemorrhage.

DISORDERS OF RED CELL PRODUCTION: THE RETICULOCYTOPENIC ANEMIAS

This class of disorders is characterized by anemia, generally in the absence of other cytopenias, together with reduced or inappropriately normal reticulocyte counts, and a negative Coombs test, also known as the direct antiglobulin test (DAT).

MICROCYTIC ANEMIA

Iron-Deficiency Anemia

Iron deficiency is the most common cause of anemia in the pediatric population, displaying a bimodal age of distribution affecting mainly toddlers and female adolescents.⁸ Although iron supplementation of infant formula has diminished its incidence, the absence of sufficient iron intake after the depletion of stores deposited in the third trimester commonly results in anemia in older infants and toddlers. Premature infants are also at high risk because of their inability to accumulate sufficient iron stores during the third trimester. Patients with iron-deficiency anemia may also exhibit microscopic stool blood loss from enterocolitis (e.g. cow’s milk protein allergy in toddlers). Although reduced intake is the most common cause of iron-deficiency anemia, malabsorption may also result in iron deficiency and should be suspected in patients with duodenal pathology, as the duodenum is the site of intestinal iron absorption. In toddlers, iron-deficiency anemia is sometimes accompanied by pica, the involuntary ingestion of inert compounds such as dirt, which can result in lead poisoning; this exacerbates iron-deficiency anemia because lead competes with iron for intestinal uptake. In young women, iron deficiency usually results from regular menstrual blood loss. Anemia in this context can be especially severe if associated with a low dietary iron intake.

A nutritional history suggestive of poor iron intake associated with microcytic anemia, a normal to slightly elevated reticulocyte count, an elevated RBC distribution width, and erythroid hypochromasia suggests iron deficiency. Reticulocyte hemoglobin content may be an early indicator of iron deficiency.^9,10 Typical laboratory findings in iron-deficiency anemia are summarized in Table 88-4. Bone marrow examination is rarely required to make this diagnosis. Concurrent causes of microcytic anemia such as α-thalassemia trait can be difficult to diagnose in the context of severe iron deficiency.

A therapeutic trial of oral iron is appropriate for likely iron-deficiency anemia before referral to a hematologist. Mild anemia can be treated with 3 mg elemental iron/kg per day, given once daily. Severe anemia may justify dosing up to 6 mg elemental iron/kg per day, given in divided doses. Although historically associated with the risk of significant side effects, iron may also be administered parenterally, particularly when there is concern for limited absorption or oral intake is insufficient to replenish iron stores. Several parenteral iron formulations, including iron sucrose, ferric gluconate, and ferumoxytol have supplanted high molecular weight iron dextran, which had been associated with anaphylactic reaction.^11-14 Given the gradual development of iron-deficiency anemia, pediatric patients rarely exhibit significant physiologic consequences necessitating RBC transfusion, despite presenting with profoundly low hemoglobin levels. However, diminishing physiologic compensation for severe anemia (e.g. symptoms of impending congestive heart failure) may justify RBC transfusion. In the absence of transfusion, severely anemic children should be observed, given the risk of decompensation in the event of cardiovascular challenge such as a febrile illness, and response to iron supplementation should be documented.

Effective treatment with iron should result in a rising reticulocyte count within 2 to 3 days and an increasing hematocrit within a few weeks. The absence of a response to iron necessitates further evaluation for other causes of anemia. Treatment should be continued for 3 months to replenish iron stores. For toddlers with iron-deficiency anemia caused by excess milk consumption, the intake of all dairy products should be restricted until a rising hematocrit is documented. Small amounts of milk can then be introduced with meals, provided that allergic enterocolitis and occult gastrointestinal bleeding from milk protein allergy have been excluded as diagnostic possibilities.

NORMOCYTIC OR MACROCYTIC ANEMIA

Anemia of Inflammation

Anemia of Acute Infection/Inflammation

Despite surprisingly little literature on this entity, available data suggest that anemia associated with acute infection is common, particularly in very young children, with an incidence second only to iron-deficiency anemia.^15,16 Anemia associated with acute infection/inflammation has been documented in acutely ill children in the outpatient setting,^17,18 and at an even higher frequency in hospitalized patients, with two-thirds to three-quarters of children with at least mild anemia.^5,6 The anemia is normochromic and usually mild and is present in the absence of other cytopenias. Hemoglobin levels are about 1 to 1.5 grams lower than pre- and post-hospitalization values. The anemia resolves after the infection has been treated. Although the precise time course of resolution has not been well documented, it is unlikely to persist longer than 1 month after the resolution of the infection in an otherwise healthy child. The precise mechanism of the development of the anemia of acute infection/inflammation is not known. Acute infection is known to promptly stimulate the release of hepcidin, which significantly impairs the availability of iron for hematopoiesis. However, the decline in hemoglobin occurs too quickly to be explained by lack of iron. No evidence of hemolysis has been detected in children with acute, uncomplicated bacterial infection.⁵ The cause is likely a combination of inhibition of response to endogenous erythropoietin, increased adhesion of red cells to endothelium (sequestration of red cells), and alteration of iron metabolism as shown by hypoferremia, low TIBC, and transferrin saturation with elevated ferritin—effects that are directly or indirectly cytokine mediated.^19-21

Extensive investigation of a mild to moderate anemia in a child without other cytopenias who has an uncomplicated infection is probably not warranted. Although iron deficiency and anemia of acute infection can coexist, serum iron, transferrin, and ferritin may not accurately reflect iron status if measured during or soon after an infection. Definitive investigation of possible underlying iron deficiency should wait for at least 1 month after resolution of the infection.

Anemia of Chronic Inflammation

(also called anemia of chronic disease or anemia of inflammation) produces a mild to moderate normocytic to microcytic anemia. It is associated with infection, inflammatory disorders, and malignancy, and is quite common. For example, about 40% of children with inflammatory bowel disease have anemia of chronic inflammation.²² Anemia of inflammation is due to ineffective hematopoiesis resulting from restricted iron availability along with a slightly decreased erythrocyte life span.²³ Also, erythropoiesis is inhibited by TNF-α and interferons with a blunted response to endogenous erythropoietin. Hepcidin has been identified as the key regulator of this condition in its role as an important mediator between immunity and erythropoiesis.

Anemia of inflammation should be suspected by the presence of mild to moderate anemia with typically normocytic or slightly microcytic RBC in the setting of chronic inflammation, serum iron is low, and ferritin is elevated. Although bone marrow examination is not usually performed to make this diagnosis, when done it shows iron accumulation in macrophages, reflecting a block in the release of iron from the reticuloendothelial system. Although considered a diagnosis of exclusion, an extensive laboratory evaluation of an isolated anemia in a child with chronic inflammation may be of limited utility. However, a careful history may suggest concurrent iron or other nutritional deficiencies. Treatment of the underlying inflammatory condition is required to correct this anemia. In longstanding chronic inflammation which has not responded well to treatment, the use of exogenous erythropoietin with or without parenteral iron has been effective, but this should be undertaken with hematology consultation. Limited response to iron therapy during an episode of inflammation is anticipated.

Transient Erythroblastopenia of Childhood

Transient erythroblastopenia of childhood (TEC) is a relatively common cause of normocytic anemia in young children (aged 6 months to 5 years). Most commonly presenting at age 2 years, TEC is probably an immune-mediated suppression of RBC production that frequently follows mild viral infections (e.g. upper respiratory tract infections), although tests of anti-red cell antibodies (e.g. Coombs tests) are negative as a rule. Although platelets are usually normal in number, there may be associated neutropenia. Hemolysis is not present in TEC; therefore lactate dehydrogenase, bilirubin, haptoglobin, and urinary bilirubin and hemoglobin are within normal limits. TEC should be strongly suspected in the setting of moderate to severe normocytic anemia with an inappropriately low reticulocyte response, although it is worth noting that reticulocytosis may be present if TEC is detected during the recovery phase. TEC must be distinguished from Diamond-Blackfan anemia (pure red cell aplasia), an inherited bone marrow failure syndrome that usually presents in the first year of life. TEC resolves over a period of weeks to months, whereas Diamond-Blackfan anemia persists. Infectious causes of bone marrow suppression should also be considered (e.g. parvovirus B19, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus, human immuno­deficiency virus). Bone marrow examination may be warranted, especially if reticulocytopenia continues for more than a few weeks, repeated blood transfusions are required, or other hematopoietic lineages are affected. Complete recovery usually occurs in 4 to 8 weeks. Transfusion of RBCs is indicated with clinical decompensation as a result of anemia or when the hemoglobin is less than 6 g/dL in the setting of a poor reticulocyte count (<5%). With or without transfusion, patients should be monitored with weekly blood and reticulocyte counts until they recover.

Inherited Bone Marrow Failure Syndromes

If the anemia is chronic, is present from a young age, or is refractory to treatment, one must suspect an inherited cause, especially if the MCV is normal or slightly elevated. Frequently, inherited marrow failure syndromes are accompanied by physical abnormalities (birth defects), necessitating a careful examination for physical stigmata (e.g. short stature, limb abnormalities, cardiac defects, skin pigmentation changes). Some inherited causes of bone marrow suppression are specific to RBCs (e.g. Diamond-Blackfan anemia), whereas others (e.g. Fanconi anemia) affect multiple cell lines, resulting in pancytopenia. Careful attention must be paid to the remainder of the CBC when considering bone marrow failure syndromes. In general, subspecialist consultation is recommended to diagnose and treat these rare patients.

Megaloblastic Anemia

Patients with anemia caused by dietary deficiencies of folic acid or cobalamin (vitamin B₁₂) present with reticulocytopenic macrocytic anemia. The MCV is generally quite elevated (often >100 fL). Other clues to the diagnosis may derive from examination of the peripheral blood smear, most notably hypersegmented neutrophils (>5 nuclear lobes). Folic acid is naturally found in fruits and vegetables and cow’s milk, and deficiency is normally limited to those patients with self-imposed dietary restrictions (e.g. consumption of only unfortified goat’s milk or a diet devoid of fruits and vegetables). Serum or RBC folate levels can be assayed; the latter is less susceptible to short-term fluctuation and more reflective of tissue stores. Vitamin B₁₂ is present in animal products, so a dietary basis for vitamin B₁₂ deficiency is usually limited to strict vegans. Vitamin B₁₂ and folate deficiencies can also result from malabsorption. In contrast to folate, however, vitamin B₁₂ absorption depends on the activity of a gastric-derived cofactor (intrinsic factor); therefore, vitamin B₁₂ deficiency can be due to a lack of intrinsic factor (e.g. pernicious anemia) rather than simple dietary deficiency or malabsorption. It is important to establish that vitamin B₁₂ is the cause of the megaloblastic anemia, because irreversible neuropathy often accompanies vitamin B₁₂ deficiency, making timely diagnosis and treatment critical.

DISORDERS OF RED CELL DESTRUCTION: THE HEMOLYTIC ANEMIAS

Hemolytic anemias result from the accelerated destruction of RBCs and should be suspected when there are signs of hemolysis such as jaundice, hyperbilirubinemia, organomegaly, dark urine, and reticulocytosis. RBCs normally survive for 4 months, so any cause of premature destruction can result in anemia, particularly when bone marrow production fails to keep pace with the destructive process. Hemolytic anemias result from factors either intrinsic or extrinsic to the RBC. In general, intrinsic defects are inherited, whereas extrinsic causes are usually acquired. Inherited hemolytic anemias can be caused by defects in the erythrocyte membrane (e.g. spherocytosis), defects in globin genes (e.g. sickle cell anemia, thalassemia, unstable hemoglobin), or defects in RBC metabolism (e.g. pyruvate kinase deficiency, glucose-6-phosphate dehydrogenase deficiency). A directed family history is critical in the workup of patients with hemolytic anemias since family members will often share a history of anemia or side effects of anemia. The primary causes of extrinsic destruction of RBC in children are immune-mediated; these include autoimmune hemolytic anemia and alloimmune hemolytic anemia (hemolytic disease of the newborn). Microangiopathy can also result in significant anemia; these include typical and atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation.

INHERITED HEMOLYTIC ANEMIAS

Hemoglobinopathies

Many abnormal hemoglobin variants result in premature destruction of the RBC by relative insolubility and precipitation of hemoglobin in the red cell cytoplasm. Hemoglobin precipitation somehow leads to less deformable RBC membranes, resulting in accelerated splenic clearance of the affected cells. Hemoglobin defects can result from either unbalanced expression of α- and β-globin genes (thalassemias) or mutations of the globin genes themselves (e.g. sickle cell, hemoglobin C, hemoglobin E, unstable hemoglobins). Although abnormal RBC morphology is a common finding in hemoglobinopathy, hemoglobin evaluation by electrophoresis, sequencing, and other tests, along with Heinz body testing (which detects hemoglobin precipitation in RBCs), is the preferred method of diagnosing this group of hemolytic anemias. Certain hemoglobin disorders such as α-thalassemia trait are difficult to detect even by electrophoresis. Other than the detection of a small amount of Bart’s hemoglobin at birth, electrophoresis is virtually normal in those with silent α-thalassemia trait and carriers, and these individuals are usually diagnosed by genetics or by sequencing the α-globin loci. Consideration should be paid to children with genetic origins in parts of the world with a high incidence of thalassemia. Sickle cell disease and some thalassemias are diagnosed via standard newborn screening of children in the United States; however, the less common thalassemias may not be detected. In addition, children born in locations without newborn screening may present with undiagnosed sickle cell disease or thalassemia. Owing to its high incidence and special management considerations, sickle cell anemia is discussed separately.

Abnormalities of the Red Blood Cell Membrane

The most common genetic RBC membrane abnormality is hereditary spherocytosis, which is usually inherited dominantly and results from defects in membrane proteins that bridge the actin cytoskeleton and the phospholipid bilayer.²⁴ Defective membrane–protein interactions lead to the loss of small segments of the lipid membrane, resulting in spherocytic red cells that have lost their biconcave discoid shape and have an increased mean corpuscular hemoglobin concentration. Spherocytic cells are less deformable and are cleared rapidly by the spleen, resulting in a much-shortened life span. Patients with hereditary spherocytosis usually have mild chronic hyperbilirubinemia and splenomegaly. Hereditary spherocytosis patients are normally well-compensated but are also susceptible to aplastic crises, worsening anemia with infection and gallstones. The disease is diagnosed by osmotic fragility testing because the cells are unusually sensitive to lysis in hypotonic solutions. Important points for the hospitalist are that the osmotic fragility test may be falsely negative in very young infants, and that infants with hereditary spherocytosis may require transfusions early in the first year of life because of hemolysis and a poor early marrow response. Other membrane abnormalities associated with hemolysis include hereditary elliptocytosis, hereditary pyropoikilocytosis, and hereditary stomatocytosis.

Disorders of Red Blood Cell Metabolism

To survive normally, the RBC must be replete with the enzymes needed for adenosine triphosphate (ATP) generation and reduced nicotinamide adenine dinucleotide phosphate (NADPH) production. Defective enzymes of the hexose monophosphate shunt or Embden-Meyerhof pathway can result in anemia by limiting the RBCs energy or antioxidant capabilities, shortening their life span in the circulation. The most common abnormality is glucose-6-phosphate dehydrogenase (G6PD) deficiency. The enzyme G6PD protects the RBC from oxidative damage. Cells deficient in G6PD are susceptible to injury from oxidant drugs, infection, acidosis, and fava bean ingestion. The most likely presentation of this disorder to a hospitalist would be a boy of Mediterranean or Asian descent who develops acute hemolysis marked by jaundice, dark urine, and anemia. The “A” variant of G6PD, common in African-Americans (1 in 10 males is thought to be affected), is mild and usually does not result in severe hemolysis. G6PD deficiency should be suspected in the setting of prolonged jaundice in the neonatal period after alloimmune hemolysis has been ruled out by a normal Coombs test. Supravital staining for Heinz bodies (to detect precipitated hemoglobin) may be positive. G6PD testing can be performed, although the results may be falsely normal soon after a hemolytic event owing to selective hemolysis of cells with the lowest G6PD levels and increased G6PD levels in abundant reticulocytes. Inheritance of pyruvate kinase deficiency, the second most common enzymopathy, is autosomal recessive. Pyruvate kinase deficiency can result in severe anemia, with reticulocytosis and splenomegaly. In general, the management of patients with enzymopathies is supportive (chronic folic acid supplementation), with an emphasis on the avoidance of known oxidative stressors (e.g. medications, foods, environmental exposure).

Treatment of Inherited Hemolytic Anemias

In general, treatment of inherited hemolytic anemias is dictated by the severity of the anemia, the nature of the defect, and its clinical consequences. Patients with mild anemia can be observed, whereas those with severe anemia may require chronic transfusions or splenectomy. In general, patients with chronic hemolytic anemias require only supportive care (e.g. folic acid supplementation) to facilitate chronic compensatory reticulocytosis. These children generally do well clinically unless an intercurrent illness slows bone marrow production of new RBCs. Parvovirus B19, the causative agent of erythema infectiosum (fifth disease), replicates in RBC precursors and can almost completely shut down erythropoiesis from 1 to 2 weeks, leading to aplastic crisis in children with hemolytic anemias. Often, RBC transfusion is required to maintain homeostasis until erythropoiesis recovers from the infection (typically within 1 month). In general, it is appropriate to involve hematology subspecialists in the diagnosis and long-term management of patients with inherited hemolytic anemias.

ACQUIRED HEMOLYTIC ANEMIAS

Immune-Mediated Hemolytic Anemias

Immune-mediated hemolytic anemias are common causes of acquired anemia in the pediatric population. By definition, antibody is produced against one or more antigens on the surface of RBCs, promoting premature destruction by opsonization and subsequent erythrocyte removal by the reticuloendothelial system or by complement-mediated lysis of RBCs in the bloodstream.^25,26 Antibodies may come from the patient (in which case the process is known as autoimmune hemolytic anemia [AIHA]) or from another source (alloimmune hemolytic anemia), such as occurs in hemolytic disease of the newborn. Unlike hemolytic disease of the newborn, which is invariably caused by transplacental maternal immunoglobulin (IgG) and is a problem only in utero and in the newborn period, AIHA can affect patients of any age and can be caused by either IgM or IgG.

Patients with AIHA often relate a history of previous viral or viral-like illness preceding the development of fatigue and pallor. The presentation of AIHA is usually sudden and may include symptoms of severe anemia. A history of dark urine suggests acute intravascular hemolysis and argues for complement-mediated red cell lysis (see later). Jaundiced sclerae or pruritus suggests hyperbilirubinemia. Mild splenomegaly is occasionally present.

AIHA can result in intravascular or extravascular hemolysis. Intravascular hemolysis is complement mediated and caused by IgM or complement-fixing IgG directed against RBC antigens, resulting in lysis of RBCs directly in the plasma and leading to jaundice or hyperbilirubinemia, elevated lactate dehydrogenase, and low haptoglobin. In contrast, extravascular hemolysis is typically mediated by IgG without complement-fixing characteristics. Extravascular hemolysis may result in little or no increase in lactate dehydrogenase and bilirubin, presumably because RBCs are destroyed in the phagocytic cells of the reticuloendothelial system rather than in the plasma itself. Laboratory evaluation of AIHA reveals a moderate to severe anemia with a brisk reticulocytosis. However, it is important to note that the reticulocyte count may be unexpectedly low if the reactive antibody also results in clearance of young RBCs. Review of the peripheral blood smear may show spherocytosis, polychromasia, and RBC clumping. Urinalysis may show hemoglobinuria in the absence of hematuria. Direct Coombs testing (which tests for antibody bound to the patient’s RBCs) is almost always positive in AIHA. Indirect Coombs testing, which tests for free anti-erythrocyte antibody in the patient’s serum, usually detects alloantibodies but may be positive in AIHA when the antibody titer exceeds antigen binding; this can help define which isotype and RBC antigen are involved. If multiple cell lineages are depressed or Coombs testing is negative, examination of the bone marrow should be considered to rule out leukemia or aplastic anemia. Primary AIHA can be divided into three types based on the nature, thermal reactivity, and amplitude of the implicated antibody.

Warm-Reactive Autoimmune Hemolytic Anemia

In warm-reactive AIHA, antibody (usually IgG) binds RBC antigens at 37°C, resulting in opsonization and removal by the reticuloendothelial system. Warm-reactive IgG typically binds common RBC protein antigens, which explains why blood bank testing often demonstrates a pan-reactive pattern. Warm-reactive AIHA tends to behave in a more chronic fashion than cold agglutinin disease and may warrant a more long-term treatment approach.

Paroxysmal Cold Hemoglobinuria

In paroxysmal cold hemoglobinuria (PCH), complement-fixing IgG autoantibody binds RBCs at low temperatures (usually in the extremities in vivo) and then causes complement-dependent intravascular hemolysis at warm temperatures (in central, warmer parts of the body). PCH sometimes follows infection with Mycoplasma pneumoniae or other atypical organisms. Testing for the cold-reactive (Donath-Landsteiner) antibody of PCH is performed by maintaining freshly drawn venous blood at 37°C until it is intentionally cooled in the laboratory, permitting antibody binding (if the patient’s blood is not kept warm until separation of plasma from RBCs, the antibody may be cleared by binding RBCs in the collection tube, leaving none free to be detected). Erythrocyte–antibody complexes are then warmed, inducing complement activation and hemolysis.

Cold Agglutinin Disease

In cold agglutinin disease, antibody (usually IgM) binds erythrocyte antigens (typically red cell surface polysaccharides) and fixes complement at temperatures below 37°C. In this manner, IgM efficiently results in intravascular hemolysis. Because IgM inefficiently binds antigen at 37°C, unbound antibody can frequently be detected in the plasma. Cold agglutinin AIHA is usually a self-limited process and typically does not respond well to immunosuppressive therapy.

Hemolytic Disease of the Newborn

Although great progress has been made in reducing the incidence of severe hemolytic disease of the newborn caused by Rh incompatibility between parents, hemolytic disease of the newborn caused by ABO mismatch and mismatch related to minor red cell antigen systems still occurs, as does classic hemolytic disease of the newborn, particularly in the later pregnancies of sensitized women. Much of the initial management occurs prenatally or in the NICU—including intrauterine transfusions, and exchange transfusions for hyperbilirubinemia as well as administration of immunoglobulin to slow the immune mediated destruction.

Despite perinatal management, these infants are susceptible to persistent anemia due to the persistence of maternally derived antibodies to their red cells in the infants’ circulation. Hemolysis may continue for several months postnatally. The developing red cells in the bone marrow are also often subject to hemolysis. Infants may require from 1 to 4 transfusions after discharge home from the hospital because of repeated drops in the hemoglobin level. Typically this process declines to a clinically insignificant level within a few weeks, but for some babies this can persist for up to 4 months of age. A careful history is one key to diagnosis, being sure to ask about mother’s Rh status, administration of RhoGam, the performance of prenatal procedures, and prior affected pregnancies. The anemia is normocytic, and some spherocytes can be seen on the smear. The direct antiglobulin test is positive. There may be reticulocytopenia. The decision to transfuse rests on the infant’s response to the anemia, as well as the rate of fall of the hemoglobin and the reticulocyte count.

Microangiopathic Hemolytic Anemia

The hallmark of microangiopathy is the finding of schistocytes (red cell fragments) on peripheral blood smear analysis. Infection and sepsis can result in microangiopathy through uncontrolled fibrinogenesis and consequent physical disruption of RBCs by shearing forces that occur when blood circulates through vessels clogged with fibrin strands. RBC destruction in this setting can be severe and may be accompanied by thrombocytopenia and coagulation factor consumption, resulting in disseminated intravascular coagulation (DIC). These patients are typically quite ill and often have multiorgan pathology in addition to hemolytic anemia.

Microangiopathic anemia also occurs with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS and TTP exist on a continuum and have in common decreased activity of von Willebrand protease (ADAMTS13). HUS is far more common in the pediatric population and typically results from infection with enteric bacteria, classically Escherichia coli 0157:H7, which expresses the Shiga toxin that directly interferes with ADAMTS13.²⁷ Atypical HUS (aHUS) is due to one of several inherited or acquired disorders of the complement system. The complement-inactivating humanized monoclonal antibody eculizumab, which was FDA-approved for the treatment of paroxysmal nocturnal hemoglobinuria, has been used to successfully treat aHUS.^28-30 The clinical syndrome of HUS together with neurologic symptoms suggests TTP^27,31 and justifies prompt treatment with plasma infusion and plasmapheresis and possibly eculizumab.³² Regardless of degree of thrombocytopenia, platelet transfusions are contraindicated. If HUS or TTP is suspected, prompt consultation with hematology and nephrology should be obtained.

Treatment of Acquired Hemolytic Anemias

Treatment of hemolytic anemias due to extrinsic defects is normally directed toward the underlying problem resulting in hemolysis. Severe anemia may justify RBC transfusion, although the underlying pathophysiologic mechanism will likely destroy the newly transfused cells as well as the patient’s own RBCs. Transfusion of other blood products may also be beneficial; however, platelet transfusion should be avoided when TTP is a consideration, given the increased risk of thrombosis.

The appropriate treatment of AIHA depends on the degree of hemolysis and resulting anemia. Children with mild anemia associated with postinfectious antibody development can usually be observed without transfusion. However, children with severe anemia or anemia with physiologic consequences should be promptly transfused with erythrocytes. Determination of the antigenic target of the autoantibody can be helpful in the selection of compatible blood for transfusion. If time permits, blood bank personnel should select the most compatible (or least incompatible) blood available, but emergent transfusion should not be delayed for this purpose.³³ Transfusion in this challenging situation can be facilitated by direct clinician-blood bank interaction. Because incompatible transfused erythrocytes may be rapidly hemolysed, multiple transfusions are often required until more definitive therapy can be instituted. Children with cold-reactive antibodies should avoid cold exposure, and blood should be administered with the use of a blood warmer. AIHA is often responsive to immunosuppression, and systemic corticosteroids are particularly effective for patients with warm-reactive IgG.³⁴

For life-threatening hemolysis, treatment with methylprednisolone (1–2 mg/kg per day intravenously every 6 hours) should be initiated promptly. Response to therapy is characterized by increasingly stable hemoglobin, decreasing reticulocytosis, and diminishing requirement for transfusion. After stabilization, prednisone 1 to 2 mg/kg per day can be substituted for methylprednisolone, and based on response, gradually tapered over several weeks to months. To avoid the side effects of chronic steroid treatment, high-dose therapy should not continue for more than several days, and in the absence of a response, alternative treatments should be considered. Intravenous immunoglobulin has been used to treat AIHA with occasional success, but it should be considered a second-line treatment. Intravenous immunoglobulin may have some efficacy in a limited number of warm-reactive AIHA patients.³⁵ Exchange transfusion or plasmapheresis has limited efficacy in AIHA, although plasmapheresis may be marginally more effective for IgM- than IgG-based disease. Splenectomy may be considered for refractory IgG-dependent chronic extravascular hemolysis. Other immunosuppressive drugs such as cyclophosphamide, 6-mercaptopurine, 6-thioguanine, azathioprine, and cyclosporine A may serve as steroid-sparing agents for children with chronic AIHA. For refractory autoimmune cytopenias there has been increasing use of antibody-mediated immune suppression. For example, rituximab (anti-CD20 monoclonal antibody) has proven effective for a subset of children with chronic or refractory AIHA.³⁶ Treatment with any of these immunosuppressive agents should be in consultation with a hematology or immunology specialist.

ADMISSION CRITERIA

• Severe anemia complicated by physiologic changes.

• Ongoing hemolytic process that requires monitoring and possible transfusion.

• Anemia associated with severe neutropenia or thrombocytopenia.

• Lack of appropriate follow-up.

DISCHARGE CRITERIA

• Absence of physiologic manifestations of anemia.

• No evidence of excessive ongoing hemolysis.

• Reliable outpatient follow-up with a pediatric practitioner to evaluate for a durable response to treatment and for recurrence of anemia. Communication of the inpatient treatment, laboratory values at the time of discharge, and pending laboratory studies is critical for appropriate post-hospital care.

• Follow-up with a hematology or oncology specialist is necessary for children with ongoing hemolysis, unclear diagnoses, bone marrow failure syndromes, or possible neoplastic processes.

CONSULTATION

Hematology or oncology consultation should be obtained in cases of unclear diagnosis, persistent or refractory anemia, requirement for bone marrow examination, concern about bone marrow failure syndromes, possible need for immunosuppressive therapy, or blast forms seen on the peripheral blood smear. Such specialists should also be consulted during the diagnostic workup before transfusion and for the long-term management of patients with chronic or refractory anemia.

Transfusion medicine specialists can be of assistance when there is a need for plasmapheresis or exchange transfusion, there are difficulties in blood crossmatching due to autoantibody production, or a determination of autoantibody specificity is required. They will typically work in conjunction with a pediatric hematologist.

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REFERENCES

BACKGROUND

Sickle cell disease (SCD) is an inherited hemolytic anemia that affects approximately 100,000 persons in the United States, mostly in the African-American population. It is responsible for lifelong medical complications in most affected individuals. Complications of SCD can be divided into those that are acute and those that are the result of the chronic repetitive vaso-occlusion of target organ systems (Table 89-1). This chapter focuses on the acute complications that the hospitalist is likely to encounter.

PATHOPHYSIOLOGY

SCD refers to a group of hemolytic anemias in which hemoglobin S (HbS) is present in either a homozygous state (HbSS) or in a compound heterozygous state, as when combined with hemoglobin C (HbSC) or hemoglobin beta-thalassemia (HbS-beta thalassemia). The HbS mutation is the result of an amino acid substitution (valine is substituted for glutamic acid at position 6) in the beta globin of the hemoglobin heterotetramer. The mutation creates a hydrophobic region that, in the deoxygenated state, facilitates a non-covalent polymerization of HbS molecules into rigid strands. These HbS polymers damage the erythrocyte membrane and change the rheology of the erythrocyte in circulation, causing erythrocyte dehydration hemolytic anemia and vaso-occlusion.

CLINICAL PRESENTATION

The National Institutes of Health recommends that all infants be screened in the neonatal period for SCD¹ and all 50 states and the District of Columbia perform universal screening for SCD.² For this reason, most children with SCD are identified early and medical management is started even before the usual age of presentation. Because the sickle mutation affects beta globin, a component of adult hemoglobin rather than fetal hemoglobin (HbF), affected infants are usually asymptomatic for the first 6 months of life. Anemia and complications from SCD usually present toward the end of the first year of life, after the physiologic switch from fetal to adult hemoglobin.

Despite newborn screening and early identification, cases of previously undiagnosed SCD presenting with a medical complication do occur, and the clinician is advised to consider SCD in the differential of patients with non-immune hemolytic anemia. Although affected patients typically have moderate or severe anemia with hemoglobin values ranging from 7 to 9 g/dL, they generally are not overly symptomatic (e.g. weakness, fatigue) since the anemia is chronic and physiologically compensated. As the result of a markedly shortened red cell survival time, bone marrow production of new erythrocytes is brisk, as indicated by chronically elevated reticulocyte counts (usually 10% to 20%). Patients will often be slightly icteric due to chronic hemolysis, and may have splenomegaly and skull bone deformities due to extramedullary hematopoiesis.

HEALTH MAINTENANCE

Infants diagnosed by newborn screening should be referred to pediatric hematologists for confirmation of the diagnosis, parental education, genetic counseling, and long-term follow-up. Routine health maintenance visits to a pediatric hematologist are scheduled for every 3 months in the first 2 years of life, then every 6 months until 4 to 5 years of age, and annually thereafter. More frequent visits may be required for patients with increased educational needs, accumulated complications, and therapeutic monitoring (e.g. hydroxyurea and/or chronic transfusion therapy). “Well visits” allow the practitioner to obtain baseline clinical, laboratory, and radiological data that is important in the event of an acute complication and affords the opportunity for education and anticipatory guidance.

COMPLICATIONS AND MANAGEMENT

Acute and chronic complications are an important part of the management of SCD (Table 89-1). Although the hematologist manages conditions associated with chronic disease, the generalist may need to consider these complications and their impact when called upon to evaluate children with SCD. The discussion below focuses on the acute complications.

FEVER

Patients with SCD develop impaired spleen function in the first year of life and are functionally asplenic by 2 years of age. They are therefore at risk for invasive and overwhelming infections. Prior to the introduction of routine vaccination in many countries, encapsulated bacteria (e.g. Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis) were a significant threat.^3,4 Though less frequent now, pneumococcus remains a common cause of sepsis. Antibiotic prophylaxis should be initiated when the diagnosis of SCD is made (Table 89-2). Children with SCD should receive a complete routine immunization schedule, including Haemophilus influenzae type b series (Hib), pneumococcal conjugate vaccine (Prevnar [PCV13]) series, and a pneumococcal polysaccharide vaccine (Pneumovax [PPV23]) at age 2 with a booster 3 to 5 years later, to decrease the risk of bacteremia. Influenza vaccine should be administered to all sickle cell patients annually and the meningococcal polysaccharide vaccine should be administered to patients 2 years of age and older.⁴

Even with antibiotic prophylaxis and complete immunizations, all sickle cell patients should be considered high-risk for bacteremia and overwhelming sepsis. Prompt evaluation and empiric treatment of febrile SCD patients is necessary to reduce both mortality and morbidity of sepsis. Children with an obvious source of infection (e.g. otitis, gastroenteritis) should still receive full evaluation and appropriate empiric treatment until bacteremia has been excluded. The key to the proper management of febrile SCD patients (or any asplenic patient) involves rapid triage and assessment with administration of empiric parenteral antibiotics within 1 hour of presentation. The focused history, physical examination, and laboratory evaluation, including blood cultures, should be done promptly. If the patient has a central line or implanted port, blood cultures must be drawn off this line. Additional peripherally obtained cultures are not necessary. A chest radiograph is recommended for most patients, especially those with tachypnea, cough, hypoxemia, or thoracic pain, and considered for history of asthma or recurrent acute chest syndrome (ACS). Urinalysis and urine culture are recommended for all males <6 months and females <2 years. Throat culture with rapid antigen testing for group A β-hemolytic streptococci, analysis (including cell count, glucose, protein, and Gram stain) and culture of the cerebrospinal fluid, stool cultures, respiratory viral panels, and other studies should be obtained as clinically indicated.

All febrile patients with SCD require empiric parenteral antibiotic coverage for at least 24 hours. Ceftriaxone, given at 50 mg/kg IV/IM (maximum 2 grams/day), is the mainstay of empiric therapy.^5,6 Other third-generation cephalosporins may be used to complete coverage for the first 24 hours depending upon institutional guidelines or formulary. For patients allergic to cephalosporins, other broad-spectrum possibilities include clindamycin, and quinolones (e.g. levofloxacin). Vancomycin is usually reserved for those with signs of meningitis, a history of pneumococcal sepsis, or toxic appearance. Vancomycin should also be considered in areas with high local prevalence of resistant organisms^7,8 or if a central venous line is present. If a central venous line is present, antibiotics should be administered via this route. If a new infiltrate is identified on chest radiograph, a macrolide antibiotic should be added to the previously mentioned empiric antibiotics because of the high incidence of pneumonia caused by atypical organisms in this setting.⁹

Admission to hospital should be considered if there is any indication of possible complications or if high-risk features are present^10-12 (Table 89-3). If none of these features are present, one may consider discharge from the acute care setting if the patient is stable 1 hour after receiving empiric antibiotics.¹³ Patients should be counseled to return immediately for persistent fever longer than 48 hours, or worsening symptoms—especially respiratory decline, dehydration, lethargy, or pain. Clear instructions should also be given for follow-up in 24 hours with primary care physician, emergency department, or by phone so that pending cultures will be tracked.

CEREBROVASCULAR ACCIDENT

Vaso-occlusive stroke represents one of the most important causes of disability in the sickle cell population. Sickle cell patients are at increased risk of stroke starting in the late school-age period. Primary stroke affects approximately 10% of HbSS sickle cell patients before the end of their second decade of life.¹⁴ Risk factors for primary stroke include previous transient ischemic attack, low baseline hemoglobin, preceding acute chest syndrome, hypertension, and abnormal transcranial Doppler ultrasound (TCD) screen. TCD is a reliable screening test to identify patients with HbSS and HbS-beta thalassemia at highest risk of stroke. If the TCD is abnormal, these patients are prescribed chronic monthly transfusion therapy, with a goal of suppressing endogenous erythropoiesis and maintaining the sickle hemoglobin at less than 30% as measured by hemoglobin electrophoresis. This has been demonstrated to reduce the risk of recurrent stroke¹⁵ and to reduce the risk of primary stroke in those children with elevated TCD velocities.^16,17

Any acute neurological findings such as weakness, altered consciousness, seizure, or language/speech disturbance must prompt immediate evaluation for cerebral ischemia. The majority of childhood stroke in SCD is caused by a nonhemorrhagic vaso-occlusion, although infection, tumor, intoxication, and thromboembolic disease should be considered. Obtaining or reviewing neuroimaging should not delay the initiation of transfusion therapy, especially if symptoms have persisted for more than 24 hours. Computerized tomography (CT) findings may be normal in early ischemia. Highly sensitive MRI diffusion and T2-weighted-Fluid-Attenuated Inversion Recovery (FLAIR)-weighted images remain abnormal for several days after significant cerebral ischemia and MRA will often reveal static intracranial arterial vasculopathy.

Initial stabilization should include fluid hydration with crystalloid while samples for cross-matching are sent in preparation for red blood cell exchange transfusion. Correction of dehydration plus maintenance hydration alone may quickly reverse symptomatology, though should not be so aggressive as to risk the formation of cerebral edema. The goal of exchange transfusion is to reduce the proportion of sickle hemoglobin to below 30%. Exchange transfusion may be achieved through manual exchange techniques; however, simple transfusion may be a temporizing measure until adequate cross-matched blood and personnel are present to perform the exchange. Patients should be monitored for metabolic or electrolyte disturbances, such as hypocalcemia or hyperkalemia, arising from large transfusion, with prompt treatment as necessary. Automated exchange transfusion by erythrocytapheresis is the preferred method of treatment; however this requires specialized equipment, trained personnel, and central access in most children. Consultation with an experienced pediatric hematologist is important.

Other symptoms or signs should also be investigated and treated, such as EEG and anti-epileptics for seizure activity, and antipyretics for fever. Treatments with tissue–plasminogen activator (tPA), antiplatelet agents, and hypothermia have not been studied adequately in childhood and are generally not indicated in the acute setting.

Patients with recurrent neurological events should undergo further evaluation by MRA for moyamoya disease, a cerebrovascular disorder marked by progressive stenosis of cerebral arteries leading to development of a poorly defined network of fragile collateral vessels. Patients with significant cerebral vasculopathy have increased risk of recurrent stroke despite chronic transfusion therapy.¹⁸ Cohorts of patients with SCD and moyamoya have been treated with pial synangiosis or encephalo-duro-arteriosynangiosis (EDAS) with good outcomes.^19,20 In one series of 12 patients, EDAS resulted in a decrease from 16 strokes in 26.3 patient-years to no strokes in 38.3 patient-years.²⁰

ACUTE CHEST SYNDROME

ACS is a leading cause of morbidity and mortality in children with SCD.²¹ It is an acute illness characterized by fever, respiratory symptoms (one or more of tachypnea, cough, wheeze, or hypoxemia relative to baseline) and a new infiltrate on chest radiograph. Risk factors for the development of ACS include low HbF, elevated steady-state WBC counts,^9,22 comorbid asthma,²³ preceding vaso-occlusive pain crisis, and general anesthesia. The underlying pathophysiology is unclear, though infection, infarction, and pulmonary fat embolism have been implicated.⁹ Infectious agents most often identified are Chlamydia,²³ Mycoplasma,²⁴ and viruses with children showing a seasonal variation of presentation.²¹ Inadequately treated vaso-occlusive pain involving the sternum, ribs, trunk, or abdomen may lead to splinting respirations, decreased tidal volume, and the development of atelectasis, ventilation/perfusion mismatching, hypoxemia, and progression to ACS. ACS is the most common complication of surgery and anesthesia in patients with SCD,²⁵ likely related to high risk of cold exposure, hypoxia, acidosis, atelectasis, and psychological stress in the perioperative period. Use of incentive spirometry has been shown to decrease incidence of ACS in patients hospitalized with vaso-occlusive crisis²⁶ and should be used routinely in the care of all hospitalized sickle cell patients.

Initial treatment of patients with ACS should include supplemental oxygen if patients are hypoxemic (PaO2 <75 mmHg or oxygen saturation <95%) or are below their known baseline. Control of chest pain with frequent incentive spirometry (5–10 times/hour) and avoidance of oversedation with analgesics are key to minimizing hypoventilation.²⁶ Arterial blood gas (ABG) measurement of the partial pressure of arterial oxygen (PaO2) and calculation of the alveolar to arterial (A-a) oxygen gradient [A-a gradient = PAO2 – PaO2 where PAO2 = (FiO2 (Patmos – 47)) – (PaCO2 / 0.8)] can serve as a guide for severity and treatment intensification but are not recommended routinely. Increasing A-a gradient indicates worsening V/Q mismatch [Normal A-a gradient = (Age + 10)/4]. Judicious fluid replacement should correct deficits but should not exceed 100% maintenance as rapid or excessive hydration may contribute to pulmonary edema, effusions and respiratory distress. Fever should be investigated with blood cultures prior to the institution of empiric broad-spectrum antibiotic (e.g. ceftriaxone), as well as a macrolide (e.g. azithromycin) for atypical bacterial pathogens. Bronchodilators should be used aggressively in patients with history of asthma or clinical evidence of wheezing, and bear consideration in any patient if worsening clinically. Systemic corticosteroids have been shown to hasten recovery from ACS but are also associated with rehospitalization from “rebound” vaso-occlusive crisis²⁷ and generally require a taper if used. Systemic corticosteroids should be strongly considered in the setting of comorbid asthma, as patients with asthma are more likely to require readmission without standard asthma therapies.²⁸

Red blood cell transfusion is the mainstay of therapy for ACS^9,29 although there are no randomized controlled trials comparing it to supportive care. Simple transfusion should be considered early in the presentation or progression in an attempt to abort progressive hypoxemia.³⁰ Various triggers for simple transfusion have been suggested including >5% drop in SaO2 from baseline or PaO2 < 70 mmHg. If simple transfusion is not effective in aborting the progression of respiratory symptoms, or if anemia is too mild to allow for simple transfusion, exchange transfusion must be considered. Corticosteroids and inhaled nitric oxide (NO) are other adjuvant therapies but lack proven benefit. If mechanical ventilation is required, frequent therapeutic bronchoscopy with aggressive suction removal of tenacious plastic bronchial casts^31,32 is often indicated, and inhaled mucolytics³³ can be considered. Crabtree et al. report their successful use of a clinical respiratory score and clinical practice guideline in reducing the length of hospital admission in patients with ACS.³⁰

VASO-OCCLUSIVE PAIN

Acute vaso-occlusive [bone] pain crises (VOC) are the central clinical manifestation of SCD and are characterized by their recurrent, excruciating, and often unpredictable nature. As HbF wanes in the first year of life, the proportion of HbS increases, and patients with SCD become vulnerable to VOC pain episodes. Often, the first manifestation of VOC pain seen in infants and young children is secondary to infarction of the small bones of the hands and feet leading to painful swelling referred to as dactylitis, or “hand-foot” syndrome. In later ages, VOC pain of the long bones (humerus, tibia, and femur particularly), vertebrae, ribs, and sternum are more common. There is often associated warmth, swelling, and decreased range of motion of adjacent joints. Chronic or recurrent VOC may lead to osteonecrosis, with the femoral head and humeral head most commonly affected.

Acute VOC pain requires urgent attention. Episodes can be mild and transient or intense and of several weeks’ duration. VOC pain is the leading cause of acute care visits and admissions to hospital for patients with SCD.³⁴ Parental education and an effective outpatient pain management plan are critically important in the prevention and initial management of VOC pain. Rapid assessment and treatment can halt progression of VOC to life-threatening events such as ACS or stroke. Ineffective treatment is most often a result of inadequate provider knowledge of SCD, poor pain assessment skills, unfamiliarity or discomfort with the use of opioid analgesics, and poor understanding of concepts of opioid tolerance, dependence, and addiction.

The assessment of sickle cell pain must include standardized assessment tools, such as visual analog scale, Wong-Baker Faces scale, that facilitate frequent repeated subjective patient report of pain. Care must be taken during the assessment to look for comorbid processes that may complicate the pain (e.g. pneumonia, cholelithiasis, splenic sequestration, and appendicitis).

The mainstay of medical therapy for acute VOC pain is pharmacologic therapy. Treatment of mild/moderate pain begins with nonsteroidal anti-inflammatory (NSAID) agents either orally (e.g. ibuprofen) or parenterally (e.g. ketorolac). If these agents have been initiated at home and/or the pain is more severe, clinicians should not hesitate to use parenteral opioid medications. Loading doses equivalent to 0.1 mg/kg morphine are recommended, and reassessment of pain and level of sedation should be performed at the anticipated peak effect of the chosen opioid and frequently thereafter. If there is inadequate analgesic effect, repeated doses (0.025–0.05 mg/kg morphine equivalent) should be administered approximately every 30 to 60 minutes, with frequent reassessment until pain reduction to at least 50% of initial score is achieved without excessive sedation. Patient-controlled anesthesia (PCA) plays an important role in pain management of the older child and adolescent.^35,36

In addition to diligent pharmacologic therapy, the initial management of pain crisis also includes attention to non-pharmacologic and psychosocial interventions. Important supportive measures include heating pads, massage, distraction with art or music by Child Life specialists, and ensuring adequate oral and/or parenteral hydration. Correction of fluid deficits with normal saline should be followed by total fluid hydration not exceeding 150% maintenance. Due to sickle-associated hyposthenuria, initial maintenance fluid choice should be relatively hypotonic (i.e. 5% dextrose + 1/2 normal saline + 20 mEq KCl/L) and adjusted for chemistry results. Based on age and cognitive-developmental stage, progressive muscle relaxation, meditation, guided imagery, or self-hypnosis may prove helpful. In addition, attention should be given to the elimination/diminution of psychosocial stressors that may potentiate pain perception (i.e. supporting and educating family members to avoid dysfunctional family interactions).

Discharge may be considered when consistent analgesia is achieved, and if needed, parenteral opioids can be converted to oral formulations. Optimal outpatient pain management often involves use of long-acting controlled-release opioids (e.g. morphine sulfate controlled-release capsules, methadone) with short-acting immediate-release preparations (e.g. morphine sulfate, oxycodone) for breakthrough pain.

ACUTE SPLENIC SEQUESTRATION

Acute splenic sequestration is a significant cause of mortality in children with SCD.³⁷ With this event, the hypoxic environment of the spleen promotes acute sickling and trapping of erythrocytes leading to acute anemia and hypovolemia, manifest by weakness, pallor, tachycardia, tachypnea, and abdominal distention. This acute hypovolemic state can progress to shock. Peak incidence of ASS occurs between 6 months and 5 years of age,^38,39 though has been described in early infancy^40,41 and adulthood.⁴² Recurrent acute splenic sequestration occurs in approximately half of those who survive the first event, and subsequent mortality may be as high as 20%.³⁸ Acute splenic sequestration occurs most commonly in homozygous SCD (HbSS) but also occurs in HbSC and HbS-beta thalassemia, often at a later age. Acute splenic sequestration which occurs prior to age 1 should be managed more aggressively than those which occur later, as younger age of onset predicts risk of recurrence.⁴²

The definition of acute splenic sequestration is a drop of 2 g/dL in steady-state hemoglobin, evidence of compensatory marrow response (accentuated reticulocytosis above baseline) and an acutely enlarging spleen. The splenomegaly may be massive such that the splenic tip may be found in the right lower quadrant. Parents should be educated in the technique of palpating the spleen in their infant and instructed to seek medical attention if it becomes enlarged.

Acute treatment of acute splenic sequestration is focused on the emergent correction of hypovolemia with crystalloid and/or erythrocyte transfusion. Improvement of circulating volume is often accompanied by release from the spleen of sequestered sickle erythrocytes leading to an increase in hemoglobin higher than predicted by the volume of transfused erythrocytes alone. One must take into account this autotransfusion phenomenon when planning the transfusion volume so as to not to risk hyperviscosity associated with hemoglobin >10 g/dL. The rate of recurrent sequestration is high in children, and although observation may be recommended in adults,⁴³ children should be considered for short-term serial transfusion⁴⁴ or laparoscopic splenectomy once symptoms of the acute episode have waned. Laparoscopic splenectomy is the treatment of choice in the child requiring transfusion support during the acute episode, persistent hypersplenism (splenomegaly associated with premature/inappropriate clearance of blood elements from the circulation resulting in new or accentuated anemia, leukopenia, and/or thrombocytopenia), or who has suffered multiple episodes of sequestration. Post-splenectomy antibiotic prophylaxis should continue at least 2 years postoperatively and likely indefinitely.⁴⁵

PRIAPISM

Priapism is defined as a sustained, painful, and unwanted erection usually unrelated to sexual activity.^46,47 It should be treated as a medical emergency because of the subsequent high incidence of erectile dysfunction and impotence in affected males if not treated promptly. Priapism may be subclassified as prolonged or stuttering. Prolonged priapism refers to an episode lasting greater than 4 hours and stuttering refers to recurrent episodes lasting minutes to less than 3 hours duration, though may herald a prolonged event.

Priapism is reported to have affected as many as 75% to 89% of males with SCD by the time they reach 20 years of age.^48,49 It may occur in patients as young as 3 years old. Lack of awareness of this sickle-related complication and embarrassment to discuss an acute event represent significant hurdles to appropriate care.

The precise pathophysiology of priapism associated with SCD is unclear, though it may result from a low-flow ischemic state. It is assumed that relative hypoxia in the turgid corpus cavernosa leads to enhanced sickling and obstruction of venous outflow through the dorsal penile vein.^4,48 Recurrent or prolonged priapism can result in corpus cavernosal fibrosis and erectile dysfunction, the incidence of which may be correlated to the duration of priapic events.⁵⁰ Venous stasis leads to further oxygen extraction, acidosis, and a vicious cycle of sickling and inflammation, which if not stopped can lead to penile fibrosis and erectile dysfunction. Triggers for priapism include prolonged sexual arousal/intercourse, fever, cold exposure, nocturnal tumescence (REM sleep), full bladder, dehydration, alcohol, cocaine, and testosterone.^4,48,51,52

The goals of management are pain relief, detumescence, and preservation of erectile function. Effective treatment of early priapism includes increased fluid intake, urination, oral pain medications, warm baths, gentle exercise, and oral pseudoephedrine.^46,48,49,53 The patient should seek urgent medical attention if priapism is accompanied by inability to void, unusually severe pain, or no improvement with home treatment within 2 hours.

Emergency care should include prompt institution of supportive medical therapy (i.e. intravenous fluids, analgesia, oxygen) and catheterization if there is inability to void. Ice packs should never be used in SCD, despite their use in non-sickle priapism. Urgent urology consultation is required for adjunctive corporeal aspiration with possible injection of vasoactive medications^49,54 if medical therapy is ineffective in the first 3 to 4 hours of presentation. After conscious sedation and local anesthesia, the urologist can perform irrigation of the corpus cavernosa with a dilute epinephrine or phenylepherine solution while aspirating until detumescence is achieved. This procedure may need to be repeated with application of firm pressure for 5 minutes after each irrigation/aspiration. If this fails to produce consistent detumescence, exchange transfusion has been shown to be effective in small series.^55,56 If sustained detumescence is not achieved, surgical shunting between the corpus cavernosa and draining veins may be indicated. Complications of priapism and its surgical treatment include infection, stricture, fistula, and high risk of impotence. Long-term management of patients with recurrent priapism requires collaboration between hematologists and urologists. The mainstay of chronic medical therapy is pseudoephedrine.⁴⁹ Increasingly, anti-androgenic agents such as ketoconazole⁵⁷ and finasteride⁵⁸ have shown promise in reducing the frequency of episodes in small series of patients with SCD or idiopathic ischemic priapism.

TRANSIENT APLASTIC CRISIS

In hemolytic anemias, due to the shortened erythrocyte lifespan, there is compensatory increased bone marrow erythropoietic rate and peripheral reticulocytosis. Transient suppression of the marrow’s response can lead to a rapid and severe decline in hemoglobin, the magnitude of which depends on the underlying rate of hemolysis and the duration of the suppression. Transient aplastic crises (TAC) often have an infectious etiology, as evidenced by preceding viral symptoms. Other family members with an underlying hemolytic anemia may be affected within days of one another. Typical presentation includes symptoms of exacerbated anemia (e.g. fatigue, dyspnea, and tachycardia) and a relative reticulocytopenia and anemia compared to baseline values. Suppression of erythropoiesis is typically 7 to 10 days, and the convalescent phase is marked by a brisk reticulocytosis with gradual return to baseline hemoglobin levels.

The great majority of aplastic crises in SCD are related to infection with human parvovirus B19,⁵⁹ though other viruses have been implicated. Parvovirus B19 has direct cytolytic effect on erythroid progenitors in the bone marrow, though it may affect several cell lines. (Diagnostic elevated parvovirus B19 IgM titers usually occur within 1 to 2 weeks of the acute infection and are followed by seroconversion to IgG and the slapped-cheek appearance of erythema infectiosum, or fifth disease.) Recurrent parvovirus B19 infection is rare in the immunocompetent host, suggesting exposure provides long-term immunity. Approximately one-third of school age children and three-quarters of adults in the general population are sero-positive,⁶⁰ many without any history of clinical infection or erythroid suppression.⁶¹ TAC often recovers spontaneously, although some patients may require hospitalization and erythrocyte transfusion to bridge their anemia until baseline erythropoiesis returns.

CHOLELITHIASIS AND CHOLECYSTITIS

Any patient with a chronic hemolytic anemia is at risk of developing gallstones because of precipitation of excess bilirubin derived from the catabolism of heme released by prematurely senescent red blood cells.⁶² Approximately one-third of patients with SCD will develop cholelithiasis by adulthood. Cholelithiasis is responsible for considerable morbidity including recurrent abdominal pain mimicking vaso-occlusive painful events, cholecystitis, and choledocholithiasis with the possible complication of pancreatitis. To avoid these clinical consequences, elective cholecystectomy is often recommended^63,64 even for those with asymptomatic cholelithiasis⁶⁵ or biliary sludge;⁶⁶ however, controversy exists for these indications, as a more conservative approach with serial ultrasound is advocated by some.⁶⁷ Cholecystectomy has become the most common elective surgical procedure performed in the United States for patients with SCD,⁶⁸ and the laparoscopic approach has become the favored method for children.⁶⁵

ADMISSION CRITERIA

Admission to hospital is required for many of the acute complications of SCD outlined, especially if outpatient management is complex or follow-up is not assured. Fever with complicated or high-risk features, new neurological symptoms, and features of acute chest syndrome or VOC pain not controlled by an outpatient pain management plan are absolute indications for admission.

DISCHARGE CRITERIA

Discharge may be considered when the acute complication has been diagnosed and managed. Completion of treatment or transition to continued outpatient treatment should be in place. This would include institution of any preventative therapies or follow-up necessary for possible recurrence. Further details are provided in the subsections above.

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REFERENCES

BACKGROUND

NEUTROPENIA

Neutrophils are the cellular elements of the blood, which provide a large portion of anti-bacterial immunity to the body. The risk of sepsis, fungal infections, and mucositis correlates with the severity of neutropenia.¹ Neutrophils phagocytize bacteria opsonized by either immunoglobulin or complement and kill them by means of enzymatic and oxidative mechanisms. Because neutrophils play such an important role in the killing of bacteria and fungi, neutropenic patients may succumb to severe infections caused by either. Immunity is preserved until neutrophil counts are profoundly suppressed. As with red blood cells or platelets, the absolute number of circulating neutrophils is determined by rate of production in the marrow as well as circulating half-life. Therefore absolute neutrophil count (ANC) will be influenced by processes that affect production or maturation of neutrophils in the marrow as well as conditions that shorten neutrophil survival in the periphery. Since the life span of a circulating neutrophil is on the order of hours rather than days, ANC can be an early indication of hematopoietic activity in the marrow compartment. However, there are actually two distinct populations of neutrophils in the circulation—one free in the blood and the other associated with the endothelial surface of blood vessels. Glucocorticoid steroids such as prednisone or dexamethasone have a demarginating effect on neutrophils, resulting in higher ANCs in blood samples, especially in the first hours-to-days of taking such medications. Therefore neutrophil counts can be influenced by the rate of demargination of endothelial-associated cells into the circulation.

Normal neutrophil levels vary between individuals of different races and ages; however, an ANC below 1000 cells/μL represents neutropenia. ANC, determined by total white blood cell count in the CBC as well as the percentage of cells of the neutrophilic lineage in the differential, is calculated as follows:

Thus the ANC for a person whose CBC shows a WBC of 10,000 cells/μL and a differential of 50% neutrophils, 30% lymphocytes, 10% monocytes, and 10% band forms would calculate to 6000 cells/μL. Conventionally, neutropenia is classified by the absolute number of circulating neutrophils (ANC) and is usually classified as: mild (1000–1500 cells/μL), moderate (500–1000 cells/μL), severe (<500 cells/μL), or very severe (<200 cells/μL). Generally, neutrophil counts below 1000 are abnormal and warrant further investigation.

ISOLATED NEUTROPENIA

Neutropenia, whether isolated or as part of a broader clinical scenario, may be caused by a number of different underlying conditions (Table 90-1). The epidemiology, presenting symptoms, risk of infection, clinical course, and management differ depending on the etiology. The diagnostic approach to the neutropenic patient depends on clinical context and should be guided by whether neutropenia is accompanied by other hematologic imbalances (Table 90-2). “Isolated neutropenia” implies that every other aspect of the CBC (differential, hemoglobin/hematocrit, mean corpuscular volume [MCV], and platelet count) is normal for age. Congenital forms such as Kostmann disease, cyclic neutropenia, and Shwachman-Diamond syndrome generally result in lifelong neutropenia with frequent, severe bacterial infections.² Acquired causes of neutropenia may be temporary or more long-lasting. In many cases, no identifiable diagnosis can be made at the onset, and the cause of neutropenia can only be made retrospectively or with the clarity of time.

PANCYTOPENIA

Pancytopenia is defined as inadequate numbers of more than one element of the CBC. Strictly speaking, “pancytopenia” refers to simultaneous insufficiency of all three cell lines (white blood cells, red blood cells, and platelets), with “bicytopenia” more appropriately describing patients with two lines affected instead of three. However, as their differential diagnosis, workup, and management are similar, we will simply use the more inclusive and widely-used term of pancytopenia. Pancytopenia often reflects serious pathology in the bone marrow, and many patients who eventually develop pancytopenia first present either with a single cytopenia or with partial pancytopenia. For this reason, patients with any cytopenia should be carefully followed over time, and should be referred for hematology consultation if laboratory abnormalities persist, worsen, or are accompanied by worrisome clinical findings.³ Some cases of pancytopenia may resolve, particularly if associated with viral infection or autoimmunity; however, pancytopenia in many patients will persist and worsen over time. Presenting symptoms of marrow failure depend upon the cell line(s) affected. Anemia is suspected by pallor, lethargy, and easy fatigability. Easy bruising and bleeding or the appearance of petechiae suggests thrombocytopenia. Signs/symptoms of neutropenia are discussed above.

It is important to determine if pancytopenia is caused by defective production or by peripheral destructive processes. Most of the time, destructive processes sufficiently robust enough to cause pancytopenia will be clinically evident (e.g. severe sepsis, burns, thrombotic thrombocytopenic purpura [TTP], disseminated intravascular coagulation). Red cell indices can be especially useful in distinguishing between problems of production versus destruction. Laboratory evidence of defective hematopoiesis includes a low reticulocyte count, low or normal markers of hemolysis (lactate dehydrogenase [LDH], free serum hemoglobin, bilirubin, and haptoglobin), and the absence of autoantibodies (e.g. negative Coombs testing). For this section, we focus on pancytopenia caused by marrow failure thought to be due to injury to hematopoietic stem cells themselves or marrow abnormalities that interfere with normal hematopoiesis. Bone marrow failure syndromes can be challenging to diagnose, as many share similar symptoms and signs such as pallor, petechiae, and purpurae.⁴ The differential for marrow failure is extensive (Table 90-1), but it is critical to assess children appropriately because of profound prognostic and management implications that accompany certain diagnoses.

Though marrow failure can be due to inherited causes, most cases occur in previously well children without a recognizable genetic problem, and are therefore acquired rather than inherited. Nonetheless, a detailed history including extended family medical history is imperative to rule out major causes of bone marrow failure. Physical examination should focus on signs of malignancy (especially lymphadenopathy and organomegaly), dysmorphic features, short stature, and pigmentary findings or congenital abnormalities.⁵ Certain environmental agents such as toxins, radiation, and chemicals are clearly associated with acquired bone marrow failure; however, etiologic agents are identified only in a handful of cases, and most cases of acquired bone marrow failure in children are idiopathic.⁶

PATHOPHYSIOLOGY

Disorders of formed blood elements can be due to inherited genetic deficiencies or they can be acquired. In general, inherited causes are associated with progressive bone marrow failure, while acquired cases may either be temporary (e.g. drug- or virus-induced marrow suppression or immune-mediated cytopenias) or more permanent (e.g. aplastic anemia). In fact, the underlying cause for many cases of pediatric cytopenia is often never identified, and the clinician must determine how aggressively patients should be managed based on symptoms, duration, and degree of cytopenia.

CLINICAL PRESENTATION

Neutropenia can present as a laboratory abnormality in an asymptomatic child, as part of a broader disease process, or with severe, unusual, or frequent bacterial infections. One can get a good idea of the underlying etiology of neutropenia based on the frequency and severity of infections coincident with the abnormal neutrophil count. In general, children with mild or moderate neutropenia have only a minimally increased risk of infection while those with severe neutropenia have a significantly increased risk of infection.⁷ Certain causes of neutropenia (e.g. benign neutropenia of childhood) can present with profound neutropenia yet have little clinical consequence, presumably because the patient can summon neutrophils if needed to fight off infection. The most common types of infections seen in neutropenic patients are otitis media, skin infections (cellulitis and abscesses), gingivitis, pneumonia, and bacteremia or sepsis.⁸ The bacteria most commonly isolated are Staphylococcus aureus, Pseudomonas species, Escherichia coli, other enteric species, Streptococcus pyogenes, and Streptococcus pneumoniae. Fungal infections such as candidiasis or aspergillosis occur particularly if duration of neutropenia is long or in the setting of concomitant corticosteroid or immunosuppressant use. Increased susceptibility to viral pathogens is not characteristic, probably because antiviral immunity is mainly carried out by lymphocytes rather than neutrophils. In addition to infections, symptoms that suggest pathologic neutropenia include fever, oral ulcers or stomatitis, frequent paronychiae, and delayed separation of the umbilical cord in infants.

DIFFERENTIAL DIAGNOSIS

Cytopenias can result from a variety of causes (Table 90-1). We mention only the more common causes of neutropenia and pancytopenia, and refer the reader to more comprehensive reviews on the topic.^4,9-13

BENIGN NEUTROPENIA OF CHILDHOOD

Benign neutropenia of childhood is characterized by neutropenia lasting at least 6 months without identifiable etiology and without apparent association of severe neutropenia-associated infection. Once the most common causes of pediatric neutropenia, it is now thought that many prior cases of benign neutropenia of childhood may actually have been autoimmune in nature, the diagnosis confounded by problems with antineutrophil antibody testing. In fact, it is possible that unrecognized autoantibodies may still be responsible for many cases of “benign neutropenia of childhood.” The low infectious risk and self-resolving nature of benign neutropenia of childhood mimic that of primary autoimmune neutropenia. Not every child with clinical features of benign neutropenia will demonstrate (or even be tested for) the presence of antineutrophil antibodies; therefore some practitioners still make a distinction between benign neutropenia of childhood and autoimmune neutropenia. It affects mainly toddlers and preschoolers, and rarely affects those under 1 year or older school-age children and adolescents. Definitive diagnosis of benign neutropenia of childhood implies resolution of the neutropenia over time, and affected children should be carefully followed until neutrophil counts normalize. Bone marrow examination is usually not indicated unless some other CBC abnormality or worrying clinical feature (e.g. organomegaly, serious infection) develops. If tested, the marrow will usually demonstrate adequate cellularity and myeloid maturation with a reduction in the number of mature neutrophils. It is likely that because of adequate bone marrow reserves, children with benign neutropenia of childhood are usually able to resist serious infections that plague children with congenital neutropenias. Chronic benign neutropenia usually lasts no more than 2 to 3 years and has an excellent prognosis.

NEUTROPENIA SECONDARY TO INFECTION

Neutropenia occasionally accompanies a number of childhood infections (Table 90-1), often apparently independent of the severity of infection. Mechanisms of neutropenia may include suppression of granulopoiesis, interference with neutrophil maturation, immune-mediated clearance, or premature destruction of mature neutrophils.^14-16 Infections do not typically cause severe neutropenia. Viruses known to cause neutropenia include parvovirus B19, Epstein-Barr virus [EBV], human immunodeficiency virus [HIV], measles, human herpesvirus 6 [HHV-6], varicella, rubella, and hepatitis viruses.^17-25 Bacterial infections associated with neutropenia include typhoid fever, tularemia, and brucellosis.²⁶ Sepsis, particularly in neonates, can result in neutropenia. Infection with the tic-born rickettsial organism that causes ehrlichiosis predictably causes a leucopenia and neutropenia that is often associated with thrombocytopenia.²⁷

IMMUNE-MEDIATED NEUTROPENIA

Immune-mediated neutropenias, humorally mediated by antineutrophil antibodies, can be classified as primary, secondary, or alloimmune, depending on clinical context. Definitive diagnosis is made by the identification of antineutrophil antibodies; however, testing for such antibodies is challenging because repeated testing may be required for detection. The lack of positive antibody testing does not necessarily rule out the diagnosis. Immune-mediated neutropenia is mediated mostly by premature destruction of mature granulocytes. Bone marrow biopsy, which is not a necessary part of the diagnostic evaluation if antibodies are identified, typically shows hypercellularity with normal neutrophil maturation but a decreased number of mature myeloid cells presumably due to antibody-mediated clearance of neutrophils.

PRIMARY AUTOIMMUNE NEUTROPENIA

Primary autoimmune neutropenia, with an incidence of 1 in 100,000, usually occurs in young children between 5 and 15 months of age. To be diagnosed with autoimmune neutropenia, children must have neutropenia, evidence of antineutrophil antibodies, and not have an underlying autoimmune disease. Neutrophil counts may drop below 500 cells/μL but often increase during periods of infection. Risk of infection is moderate. In one large series of patients with primary autoimmune neutropenia, 12% developed severe bacterial infections such as sepsis, pneumonia, or meningitis;²⁸ therefore fevers should be managed conservatively in affected patients. Almost all patients with primary autoimmune neutropenia will undergo spontaneous remission within 7 to 24 months of diagnosis. Because neutropenia is transient and the infection risk is only moderate, specific treatment of neutropenia is not required. When treatment of neutropenia is required, as for severe infection or surgery, granulocyte-colony stimulating factor (G-CSF), steroids, and intravenous immunoglobulin (IVIG) have all been used with moderate degrees of success.²⁹ Prophylaxis with sulfamethoxazole and trimethoprim may decrease the frequency of infections without significant side effects.³⁰

SECONDARY AUTOIMMUNE NEUTROPENIA

Secondary autoimmune neutropenia can be seen in association with a number of chronic conditions and therefore can last longer than primary autoimmune neutropenia. Leading comorbid conditions include rheumatologic conditions such as systemic lupus erythematous, Sjögren syndrome, and scleroderma, malignancies, and certain immunodeficiency states such as common variable immunodeficiency.

ALLOIMMUNE NEUTROPENIA

Alloimmune neutropenia occurs because of passive transfer of antineutrophil antibodies to the patient. It can occur following transfusions with blood products³¹ or from intrauterine transfer of maternal IgG directed against paternally-derived neutrophil antigens to neonates (neonatal alloimmune neutropenia). Like Rh disease, alloimmune neonatal neutropenia usually affects the infants of multiparous women, because maternal humoral response to paternal neutrophil antigens strengthens with each subsequent pregnancy. Neonatal neutropenia is typically severe and can last for several weeks. Fortunately, infections tend to be mild, with skin infections being the most common type.³² Specific treatment of neutropenia is usually not required, but if necessary neutrophil counts can be increased with G-CSF, glucocorticoids, or IVIG.

DRUG-INDUCED NEUTROPENIA

Medications that inhibit cell division predictably cause cytopenias by stunting marrow hematopoiesis, which requires enormous proliferation of blood cell precursors. In fact, neutropenia is such an expected side effect of chemotherapy that many cancer patients are routinely placed on G-CSF to limit the duration and intensity of neutropenia.³³ Other drugs, however, may cause neutropenia by alternative, sometimes ill-defined means. Certain medications are well known to cause neutropenia (Table 90-1). Drug-induced neutropenia typically occurs 1 to 2 weeks after initiation of an offending agent and is treated by removal of the drug. Once the responsible medication has been discontinued, neutrophil levels typically return to normal over the next 1 to 2 weeks. Children with drug-induced neutropenia are at high risk of infection.^34,35 When treatment of neutropenia is required for severe infection or surgery, G-CSF, steroids, and IVIG have all been used with moderate success.^36,37

APLASTIC ANEMIA

“Aplastic anemia” is a descriptive term referring pancytopenia resulting from a long-lasting, often permanent failure of hematopoiesis due to marrow pathology. The natural history of untreated aplastic anemia in most cases is an inexorable and progressive decline in marrow function, with patients succumbing to marrow failure and infection.³⁸ “Idiopathic” aplastic anemia is the type most commonly diagnosed, in the absence of known exposure to marrow toxins (“secondary aplastic anemia”) or genetic marrow failure syndromes such as Fanconi anemia (“inherited aplastic anemia”). In fact, identifying a cause for aplasia is quite unusual, and the great majority of pediatric cases are “idiopathic.”³⁹ It is critical to rule out inherited causes of aplastic anemia because of key medical and genetic implications that accompany their diagnoses. All children with aplastic anemia must be evaluated with a thorough medical history (including in-depth family medical and environmental exposure history), physical examination (especially focused on features suggestive of an inherited syndrome), and extensive laboratory evaluation including bone marrow examination and tests for known marrow failure syndromes.⁴⁰ As a rule, the bone marrow will look too “empty” on biopsy, with normal hematopoietic elements replaced by fat.

Aplastic anemia occurs in roughly 1 in 500,000 children annually, roughly 25 times less frequent than acute leukemia. Prognosis and treatment are guided by the degree of pancytopenia. Thus, “severe aplastic anemia” features at least two of the following: ANC <500/μL, platelet count <20,000/μL, and/or an absolute reticulocyte count of ≤40 × 10⁹/L. If the ANC falls below 200/μL, then the patient is diagnosed with “very severe aplastic anemia.”^6,41 Milder forms of aplastic anemia exist with less profound cytopenias, and in general can be managed less intensively; however, pancytopenia may worsen over time. Prognosis for aplastic anemia has improved over the past several decades. Whereas less than 10% of patients survived before the 1960s, now improved supportive care and advances in hematopoietic stem cell transplantation have resulted in overall survival rates of over 70% for aplastic patients treated in appropriate pediatric institutions. Management includes judicious blood product support, infectious disease prophylaxis, and therapies aimed at restoring marrow hematopoiesis. If an appropriate HLA-matched donor can be identified, outcomes are best with timely hematopoietic stem cell transplantation. If transplantation must be delayed, then most centers will offer immunosuppressive therapy incorporating antithymocyte globulin, cyclosporine, and corticosteroids. This approach benefits many patients and reduces their transfusion requirement, but relapses occur in many patients, and immunosuppressive therapy does little to curb risk for myelodysplastic syndrome (MDS) and leukemia in aplastic anemia patients over time. In general, because of the complexity of their medical issues, children with aplastic anemia are probably best treated by experienced pediatric hematology/oncology or bone marrow failure teams.⁴²

INHERITED NEUTROPENIA AND MARROW FAILURE SYNDROMES

There are inherited forms of neutropenia and marrow failure that are beyond the scope of this chapter. In general these present with signs of hematopoietic deficiency, manifesting with easy bruising, anemia symptoms, or severe infections. Patients affected by these syndromes are best managed by hematology or marrow failure specialists. For more information, please refer to the many excellent reviews on this topic.^4,13,43-48

DIAGNOSTIC EVALUATION

When evaluating the patient with cytopenia, the history should include questions about a personal history of fevers, mouth sores, and infections, as well as a thorough family history focusing on blood disorders, transfusions, infections, or untimely childhood deaths (Table 90-2).⁴⁹ Consideration should be given to recent and remote medication and toxic exposure history. Physical examination should pay particular attention to the presence of oral lesions, lymph nodes, organomegaly, height/weight, skin, teeth, nails, and subtle signs of infection. Laboratory evaluation will vary depending on the most likely etiology (Figure 90-1). If immune mechanisms are suspected, testing for antineutrophil antibodies should be considered. A bone marrow aspirate and biopsy should be obtained if neutropenia is long-lasting or whenever more than one hematologic cell line is decreased to rule out dangerous diagnoses such as aplastic anemia, leukemia, or myelodysplasia. If neutropenia is associated with fevers, tests for infections known to be associated with neutropenia should be considered. Consultation with a pediatric hematologist is indicated whenever neutropenia is persistent, whenever multiple abnormalities are found in the CBC, when clinical evidence suggests marrow failure or lymphoproliferative diseases, or when there is a personal or family history of severe or recurrent neutropenia-related infections (Figure 90-1).

MANAGEMENT

Management of a child with neutropenia or pancytopenia will be dictated by clinical circumstance, severity of cytopenias, and underlying pathology. In general, self-resolving cytopenias are managed supportively, whereas marrow failure syndromes must be approached more aggressively. There are excellent reviews that cover treatment suggestions for most of the conditions listed in this chapter,^47,50-53 thus we include a figure presenting overarching treatment themes relevant to the universal care of patients with cytopenias (Figure 90-2). In general, therapy is aimed at normalization of blood counts, antimicrobial prophylaxis, and monitoring for known complications. If there is the possibility of a lymphoproliferative disorder such as acute leukemia, it is critical to rule out malignancy (with a bone marrow examination) prior to starting glucocorticoid medications that might partially treat leukemia and contribute to eventual poorer outcome. It is recommended that hematology consultation be considered prior to blood product transfusions because transfusions may jeopardize interpretation of various diagnostic tests (e.g. serologic testing for infectious agents) and they carry a risk of sensitization to HLA antigens that might endanger stem cell engraftment if the patient requires stem cell transplantation in the future. In general, transfusions should be used judiciously (e.g. to treat symptoms rather than a “number”), and all blood products should be leukocyte-depleted, CMV negative, and irradiated (Table 90-3). Digital rectal examination and any other manipulation of the rectum such as rectal temperatures and suppositories should be avoided in neutropenic children because of the risk of physically introducing bacteria during the procedure and inadvertently raising infectious risk.

ADMISSION AND DISCHARGE CRITERIA

In general, neutropenic patients or patients with pancytopenia may be managed as outpatients provided they are well (show no signs of infection) and are afebrile. Fever in a neutropenic patient is a medical emergency since overwhelming bacterial sepsis and death can rapidly develop in the absence of adequate neutrophils. Therefore it is standard to admit neutropenic patients who are febrile, to obtain appropriate infectious workup (including a blood culture) and to administer broad-spectrum antibiotic coverage until cultures prove negative (typically 24–36 h) and symptoms resolve (e.g. afebrile for 24 h).^35,54-55 In almost every case, patients with cytopenias should be followed closely upon discharge. Neutropenia in the absence of fever does not generally require admission to the hospital.

CONSULTATION

Formal hematologic consultation is recommended for children with any of the following:

• Prolonged cytopenias or cytopenias of unclear etiology

• Pancytopenia or particularly severe level of single cytopenia

• Clinical features suggestive of marrow failure or lymphoproliferative syndromes (low reticulocyte count, immature cells on differential, high MCV, high LDH, high uric acid, splenomegaly, lymphadenopathy, weight loss, night sweats, fevers, etc.)

• Family history of cytopenias

• Before starting a child on steroids, immunosuppressive therapy, or hematopoietic growth factors (e.g. G-CSF)

• When marrow examination is being considered

PREVENTION

Most cases of neutropenia or pancytopenia in children occur in the absence of identifiable environmental or infectious risk factors; however, agents known to promote bone marrow suppression should be avoided in children at risk (Table 90-1).

REFERENCES

BACKGROUND

Thrombocytopenia, usually defined as an absolute platelet count less than 150,000/mm³, is a common cause of bleeding in pediatric patients. A low platelet count can be the result of increased platelet destruction, reduced production, consumption, or sequestration (Table 91-1), and considering these distinctions will help in formulating a differential diagnosis. Formation of a platelet plug is vital to hemostasis. Regardless of the cause, when platelet numbers are decreased, there can be petechiae, bruising, or bleeding. The body has a remarkable capacity to maintain hemostasis despite low platelet numbers, so symptoms may not become evident until the platelet count is quite low—usually below 50,000/mm³. Patients with moderately decreased platelet counts may be asymptomatic, with the thrombocytopenia being noted incidentally. This chapter focuses on the major causes of thrombocytopenia and their evaluation and management.

IMMUNE-MEDIATED THROMBOCYTOPENIA

THROMBOCYTOPENIC PURPURA

Clinical Presentation

The annual incidence of immune or idiopathic thrombocytopenic purpura (ITP) in children is about 50 per million, and it most commonly affects children between 2 and 6 years of age. The clinical definition of ITP was recently standardized to include peripheral blood platelet count less than 100 × 10⁹/L in the absence of other conditions associated with thrombocytopenia.¹ Immune thrombocytopenia is an autoimmune condition caused by antiplatelet antibodies, which leads to a drastically shortened platelet survival time due to platelet opsonization and enhanced clearance.² Primary ITP is the most common form (“typical ITP”), whereas secondary ITP can be ascribed to a secondary condition, such as administration of a live vaccine, viral infection, systemic lupus erythematosus, or human immunodeficiency virus.² A common presentation of primary ITP is an otherwise healthy child with the sudden onset of petechiae or bruising, or both, often with an antecedent febrile illness. As a general rule, thrombocytopenia is profound and typically the only abnormal finding in the complete blood count (CBC).

Differential Diagnosis

Since the age distribution and presenting symptoms of ITP can be very similar to that of acute leukemia, there is often some anxiety around the diagnostic workup for acute thrombocytopenia. In most cases, the history, physical examination, and review of the CBC parameters and peripheral blood smear can be used to differentiate ITP from acute leukemia or aplastic anemia (Table 91-2). One also needs to consider other causes of “secondary immune thrombocytopenia,” including drugs, infections, malignancy, and autoimmune disorders (Table 91-3). Systemic lupus erythematosus, rheumatoid arthritis, and human immunodeficiency virus infection, as well as other inflammatory diseases, must be considered in the differential diagnosis for children presenting with thrombocytopenia, especially teenagers. A number of congenital conditions may also cause thrombocytopenia, such as thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, von Willebrand disease (type IIB), and congenital amegakaryocytic thrombocytopenia.³

Diagnostic Evaluation

The diagnosis of ITP is one of exclusion and is often apparent from a reliable and thorough history and physical. A CBC demonstrates a normal number of white blood cells and a relatively normal hematocrit. The platelet count is typically extremely low, often less than 10,000/mm³ and frequently as low as 1000/mm³. Other important laboratory tests include Rh blood group typing and a direct antiglobulin test to determine eligibility for anti-Rh₀D therapy and to rule out Evans syndrome, which is concurrent autoimmune cytopenia of more than one blood cell line. The peripheral blood film should be examined by an experienced hematologist or technician to ensure no blasts are present. Any aberrations in the history, physical examination, or laboratory findings warrant a bone marrow examination to rule out acute leukemia or aplastic anemia as a cause of thrombocytopenia, especially if steroids are being considered as treatment.

Management

Many physicians opt for close observation alone for a child with ITP who is not bleeding acutely and does not have evidence of significant blood loss, although many care providers and families of patients with ITP feel much more comfortable treating the thrombocytopenia rather than waiting for spontaneous resolution. Therapies may raise the platelet count, but most do not shorten the duration of the disease state. In general, physicians tend to treat ITP under the following circumstances: when the patient has active bleeding, when the platelet count is below 10,000/mm³, or when the patient is prone to trauma (e.g. toddlers or athletically active patients). Treatment of ITP includes corticosteroids, intravenous immunoglobulin (IVIG), anti-Rh₀D therapy (WinRho), rituximab (anti-CD20 monoclonal antibody treatment), and splenectomy (Table 91-4).³ Corticosteroids are the most cost-effective therapy and are easiest to administer, though they are associated with significant potential side effects, especially with long-term use. Before steroids are given, the clinician must be reassured that the child does not have acute leukemia, as steroids can induce a temporary remission in acute lymphoblastic leukemia and thus make the ultimate diagnosis and treatment more difficult. For ITP, a short course of steroids usually causes a rise in the platelet count in a few days, which is thought to mainly be a result of interference with splenic uptake of antibody-coated platelets. In most children steroids can be tapered quickly, and most will not relapse. In some patients, however, another course of steroids or a slower taper may be needed. The treatment that results in the most rapid rise in the platelet count is IVIG;^3,4 however IVIG is very expensive and generally involves hospitalizing the patient for the 8- to 12-hour infusion. In addition, many children experience headaches after the infusion, probably related to the increased protein load, and this often leads to imaging studies (e.g. CT scanning) to evaluate for possible intracranial hemorrhage. The use of anti-Rh₀D has increasingly gained popularity as a treatment option for ITP, but it is useful only in patients with an Rh-positive blood type. Administration of anti-Rh₀D causes a rise in platelet count with a predictable decline in hemoglobin, perhaps related to saturation of the reticuloendothelial system by opsonized red blood cells, although the precise mechanism remains unknown. Very rarely, a patient with ITP has a concomitant immune-mediated hemolytic anemia at presentation, a constellation of autoimmune processes known as Evans syndrome. In this setting, addition of more anti–red blood cell antibody to the system would exacerbate the hemolytic anemia. Therefore before using anti-Rh₀D the clinician must verify that the Coombs test (direct and indirect antiglobulin tests) is negative. After any of these treatments, the development of new petechiae/purpura should slow, and the platelet count typically rises over the next several days. In general, the platelet count should be measured 2 to 3 days after treatment and then again in 1 week if stable.

Second-line therapies for chronic ITP (defined as persistence of thrombocytopenia for at least 6 months) include cyclosporin A, azathioprine, cyclophosphamide, and thrombopoietic agents.⁵ An important therapy for chronic ITP is rituximab, a monoclonal antibody that targets plasma cells, the source of the antiplatelet antibodies causative of ITP. Rituximab has been used successfully in adults with ITP,^6,7 and there are cohort studies and case reports of its use in children.⁸ Side effects include fevers, chills, rigors, and rarely hypotension and bronchospasm. Importantly, treatment with rituximab will cause hypogammaglobulinemia that can last up to a year or more. Therefore fevers during this period may require evaluation and prophylactic antibiotics and IVIG. Despite these drawbacks, rituximab has become a valuable tool in the treatment of chronic refractory ITP. Recombinant thrombopoietin (TPO) and TPO receptor antagonists have also emerged as potential therapies for chronic ITP.⁸

In addition to the above treatment modalities, there are agents that help prevent bleeding in patients with ITP. Aminocaproic acid (ε-aminocaproic, Amicar) acts as an inhibitor of fibrinolysis and is often useful as adjuvant therapy in a patient with wet purpura or epistaxis because it can help prevent bleeding until the platelet count rises. Before aminocaproic acid is given, the patient’s urine must be examined, because hematuria and the risk for urinary obstruction by blood clots in the setting of inhibition of fibrinolysis are considered contraindications to the use of ε-aminocaproic acid.

In the face of any immune-mediated thrombocytopenia, platelet transfusions will raise the count only briefly at best and are reserved for children with acute life- or limb-threatening bleeding. Similarly, contrary to practice in adults, splenectomy is generally reserved as an option of last resort for children with chronic ITP, only after other therapies aimed at interrupting immune destruction of platelets have been exhausted. Although removing the spleen does little to affect the generation of antiplatelet antibodies, the procedure removes the main site of platelet destruction in ITP and often results in a rise in platelet counts, which can improve quality of life significantly. Patients will occasionally relapse after first-line therapy for ITP. Such relapses should not be confused with chronic ITP, which is a prolonged, protracted disease course. Acute ITP is self-limited and lasts a few weeks to a few months. Children with acute ITP may require several courses of therapy to maintain their platelet counts until the disease remits. Patients with chronic ITP will often still respond to standard therapies for ITP but with only a transient and short-lived response. Their disease does not resolve spontaneously and may require more aggressive intervention (rituximab, splenectomy). For more than 75% of pediatric patients, ITP is a disease with an abrupt onset and a quick and permanent resolution. In the remaining 25% of cases, however, the disease becomes chronic, defined as persistence of thrombocytopenia for 6 months or longer, with or without treatment. The incidence of protracted ITP increases with age and is highest in adolescents.

Admission and Discharge Criteria

Most children with acute ITP can be managed safely at home. Despite extremely low platelet counts, children with ITP have less than a 1% incidence of intracranial hemorrhage, and these cases are often complicated by trauma or the use of antiplatelet medications such as aspirin or nonsteroidal anti-inflammatory drugs.^9-11 Although many families feel reassured by spending a night or two in the hospital, the artificial environment (e.g. high beds, hard floors) of the inpatient unit may actually predispose toddlers to falls or accidents. Some centers recommend helmets for children between the ages of 1 and 5 years. Children with active bleeding, other comorbidities, or a clinical picture not completely consistent with ITP should be considered for hospital admission for additional evaluation.

Consultation

The physician seeing a child with acute thrombocytopenia should seek consultation with a pediatric hematologist, even if the presentation is “classic.” In addition to the nuances of making the correct diagnosis and choosing the most appropriate therapy, the child will also need follow-up with a hematologist, and establishing this relationship early is beneficial.

Special Considerations

Children with platelet counts less than 50,000/mm³ should refrain from any high-impact activities, including contact sports and situations in which they are at risk for falls and injuries. The lower limit is controversial, but most physicians let their patients participate in sports once their platelet count reaches 75,000/mm³ and usually when it is above 100,000/mm³.

NEONATAL THROMBOCYTOPENIA

Clinical Presentation

Neonatal thrombocytopenia is a relatively common, potentially devastating disorder that necessitates prompt intervention once diagnosed. The prevalence in full-term neonates is less than 5% but increases with decreasing gestational age.¹² Unlike older children with very low platelet counts who are at only small risk of intracranial bleeding, the incidence of intracranial hemorrhage in preterm neonates with thrombocytopenia is higher than 20%.¹² Therefore if diagnosed in utero, cesarean section is often recommended to avoid head trauma during vaginal delivery. A fetus can be exposed to antiplatelet antibodies in two main ways. First, a mother with ITP can pass her antiplatelet antibodies to her child, as evidenced by low platelet counts in both the mother and baby. Neonatal alloimmune thrombocytopenia (NAIT) is a more serious disorder that occurs when the mother’s immune system recognizes paternal antigens on fetal platelets and makes immunoglobulin G (IgG) that crosses the placenta and binds to fetal platelets, thereby hastening their destruction. It is similar to Rh disease of the newborn, which targets red blood cells, but unlike Rh disease, antigenic exposure can occur early in gestation and lead to an affected offspring with the first pregnancy. Generalized petechiae can develop within minutes of birth. Intracranial hemorrhage can occur, sometimes in utero, and result in fetal demise.

Differential Diagnosis

The timing of onset can often be a strong clue to the cause of thrombocytopenia. When occurring after 72 hours or in the setting of clinical instability, the cause of low platelets is more likely to be infection (cytomegalovirus [CMV], toxoplasma, rubella), metabolic (e.g. organic acidemias), or inherited (e.g. congenital amegakaryocytic thrombocytopenia).¹² Early thrombocytopenia increases the likelihood of NAIT or ITP, in addition to thrombocytopenia secondary to hypoxia, asphyxia, disseminated intravascular coagulation, or Group B streptococcus infection.

Diagnostic Evaluation

The diagnosis of NAIT can often be made by carefully considering the history, physical examination, and laboratory findings. Unexplained severe thrombocytopenia in the first 48 hours of life has a high likelihood of being due to NAIT. Unlike neonatal ITP secondary to maternal ITP, the mother’s platelet count should be normal in NAIT. If a bone marrow study is performed, there should be increased numbers of megakaryocytes, as would be expected when the cause is increased destruction of platelets. Diagnosis can be confirmed by demonstrating serologically that the mother possesses antibodies to paternal human platelet antigens.

Management

Thrombocytopenia is usually self-limited but therapy depends on the platelet count and neonate’s clinical condition. All neonates with suspected NAIT should be evaluated by head ultrasound for intracerebral hemorrhage (ICH). Neonates should promptly receive human platelet antigen–negative platelets when the platelet count is less than 30 × 10⁹/L for those with no sign of ICH, and 50 × 10⁹/L for neonates with ICH.^12,13 Fortunately, a source of these antigen-negative platelets exists in the mother of the child. Importantly, the mother’s platelets should be washed before transfusion (to remove plasma containing maternal antibodies) and irradiated (to eliminate the risk for transfusion-associated graft-versus-host disease). If maternal platelets are not available, the blood bank may be able to obtain platelets lacking the platelet antibody. Random donor platelets may be used, but the benefit will probably be very short lived, and they should be reserved for cases of life-threatening bleeding. Intravenous gamma globulin and steroids are good options to maintain adequate platelet counts until resolution of the process (typically several weeks). Once an infant is diagnosed with NAIT, every effort should be made to determine the platelet genotypes of the mother and father, because this will be important for both verifying the diagnosis of NAIT and for genetic counseling and obstetric care in future pregnancies.

Consultation

All neonates with thrombocytopenia should be seen by a pediatric hematologist. Additionally, because future pregnancies may again result in NAIT, high-risk obstetric care is essential.

THROMBOCYTOPENIA SECONDARY TO CONSUMPTION

Several different states can cause thrombocytopenia by removing platelets from the circulating pool, including disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and Kasabach-Merritt syndrome (KMS).

DISSEMINATED INTRAVASCULAR COAGULATION

DIC is generally a consequence of overwhelming sepsis or other systemic illness that results in an imbalance between the clot promotion and clot lysis systems in the body.^14,15 Its presence always represents another underlying problem (e.g. infection, malignancy, major trauma). Activation of the coagulation system leads to a depletion of clotting factors, and platelets are consumed and activated by both thrombin and the underlying process. Screening tests for DIC may include the prothrombin time (PT), partial thromboplastin time (PTT), platelet count, fibrinogen level, and D-dimer level. In DIC, the PT and PTT are usually high, and the platelet count and fibrinogen level are usually low. Treatment of DIC-induced thrombocytopenia is supportive while treating the underlying disease process. It may be helpful to replace clotting factors with fresh frozen plasma and cryoprecipitate or replace platelets, but the consumptive process will continue until the underlying problem is corrected. In addition, there is a risk for volume overload because isotonic products such as fresh frozen plasma are infused in significant amounts.

HEMOLYTIC UREMIC SYNDROME

Thrombocytopenia in HUS occurs as a result of platelet aggregates becoming trapped in small vessels. Caused by a prothrombotic state induced by endothelial cell injury and inhibition of the ADAMTS13 metalloproteinase, platelets become inappropriately activated in HUS and are depleted from the circulation.

THROMBOTIC THROMBOCYTOPENIC PURPURA

Thrombotic thrombocytopenic purpura is less common than HUS in children, has a much higher mortality rate, and can have a remitting/relapsing course. As with HUS, a microangiopathic hemolytic anemia is seen, but unlike HUS, there is no association with microorganisms. Instead, most TTP occurs because of deficient ADAMTS13, a metalloprotease responsible for the cleavage of von Willebrand factor into smaller pieces.^16,17 This leads to platelet clumping and red blood cell destruction. Treatment of TTP is aggressive daily exchange plasmapheresis with cryoprecipitate-poor plasma.¹⁸ As with HUS, platelet transfusions may exacerbate the disease and should be used only in patients with life-threatening bleeding.

KASABACH-MERRITT SYNDROME

KMS, characterized by consumptive coagulopathy and thrombocytopenia, can develop in infants with large vascular tumors.¹⁹ This condition is rare (affecting only 0.3% of infants with hemangiomas) but has a very high mortality rate (30%–40%). Although the precise mechanism is not known, KMS is thought to arise secondary to platelet trapping by the vascular endothelium. This causes platelet activation and subsequent consumption of clotting factors. The profound thrombocytopenia (sometimes less than 20,000/mm³) along with the coagulopathy leads to a very high risk for devastating bleeding. Therapy for KMS is aimed first at correcting the bleeding diathesis, which may involve product replacement or systemic treatment with steroids, interferon alpha, or vincristine. Once the patient is stabilized, the focus of treatment can be shifted to management of the lesion. Surgical therapy can be attempted for small cutaneous lesions, but this is not always feasible. Other local therapies include vascular embolization, laser therapy, and radiotherapy.

HYPERSPLENISM

Many conditions (e.g. liver disease, infection, malignancy) are associated with an enlarged spleen. As the spleen enlarges, there is greater opportunity for blood cells to be damaged and for platelets to be sequestered. This is purely a physical phenomenon, and splenectomy is often helpful in cases of protracted, chronic thrombocytopenia. Of course, removing the spleen of a young patient carries a significant risk, especially infection with encapsulated organisms. Therefore splenectomy is only rarely offered as a primary treatment option.

THROMBOCYOTOPENIA CAUSED BY DECREASED PRODUCTION

Decreased bone marrow production of platelets is a predictable iatrogenic consequence of treatment with cytotoxic drugs that suppress hematopoiesis of all bone marrow elements. In addition to many chemotherapeutic agents, other drugs that can cause thrombocytopenia include ibuprofen, ranitidine, vancomycin (and other antibiotics), and phenytoin.

Thrombocytopenia can also be a prominent feature of bone marrow failure syndromes such as Fanconi anemia, but generally more than one blood cell line will be affected in such cases. The syndrome of thrombocytopenia–absent radii (TAR) presents with signs of thrombocytopenia in infants with upper limb abnormalities. Fortunately, patients with TAR syndrome need only supportive care in the first few years of life, including platelet transfusions, because the thrombocytopenia frequently improves with age. Wiskott-Aldrich syndrome is an X-linked disorder consisting of the triad of atopic dermatitis, immune dysfunction, and thrombocytopenia. Effective treatment of Wiskott-Aldrich syndrome requires stem cell transplantation. Finally, there are rare types of bone marrow failure specific to platelet precursor stem cells, most notably amegakaryocytic thrombocytopenia, that also require stem cell transplantation. One clue to decreased bone marrow production in a child with a low platelet count is the presence of tiny platelets on the blood smear and low mean platelet volume on the complete blood count.

PLATELET DYSFUNCTION

Although there are bleeding disorders that result from disorders of platelet function, they are very rare. A bleeding patient with a normal platelet count is much more likely to have another disorder responsible for the bleeding (e.g. coagulopathy). One of the most common causes of platelet dysfunction (“functional thrombocytopenia”) is uremia. In this scenario, dialysis may actually be more effective than platelet transfusion. Of course, consultation with a specialist is necessary in such settings. Other disorders of platelet function are much more unusual and usually involve congenital defects in platelet adhesion (Bernard-Soulier syndrome), platelet aggregation (Glanzmann thrombasthenia), or platelet secretion (gray platelet syndrome). These disorders can be difficult to diagnose, and patients require the care of a hematologist.

REFERENCES

DISORDERS OF COAGULATION

Blood leaks or vascular occlusions may compromise blood delivery with potentially fatal consequences. The role of the hemostatic system is to maintain blood fluidity and to stop leaks once the vessel wall is damaged. It is a dynamic system maintained by a balance of factors that promote and factors that inhibit clotting. Disruption of this equilibrium leads to either bleeding or thrombotic complications.

PATHOPHYSIOLOGY

The intact vascular endothelium provides a smooth surface that promotes the blood flow and inhibits coagulation. When the endothelial surface is disrupted, blood comes in contact with the subendothelial matrix, which activates the hemostatic system. The first step of the hemostatic process—formation of the platelet plug—consists of adherence of platelets to the margins of the injured vessel, followed by their activation and release of pro-coagulant substances. During this process, von Willebrand factor (vWFct) acts as a bridging protein between platelets and the vascular wall. The next step is the coagulation cascademis, a carefully regulated series of pro-coagulant events initiated by tissue factor released from the subendothelial matrix. Tissue factor along with factor VII activates factor X, which together with factor V forms the prothrombinase complex, which subsequently activates factor II (prothrombin) to generate thrombin. Thrombin is the enzyme that converts fibrinogen to fibrin. Fibrin polymerizes and crosslinks with the help of factor XIII to form a strong mesh that traps red cells, white cells, and more platelets to form the final clot. This pathway, known as the “extrinsic” pathway, feeds an auto-amplification loop to recruit the “intrinsic” coagulation cascade to further clot formation (Figure 92-1). To do so, thrombin activates factors IX and VIII, which in turn activate factor X to increase thrombin production several thousand-fold. The goal of the coagulation cascade is formation of a fibrin-based clot able to achieve hemostasis but to limit coagulation to interfere with normal blood flow. Once enough fibrin is generated, the coagulation cascade is terminated by anticoagulant factors including tissue factor pathway inhibitor (TFPI), activated protein C, and antithrombin. The fibrin clot will persist for a variable amount of time, allowing for the repair of the vascular wall before the clot is broken down by the fibrinolytic system. The main fibrinolytic enzyme is the plasmin, which in turn is kept in check by the inhibitory action of antiplasmin. Thus the coagulation cascade is a finely tuned system consisting of amplification steps limited by important checks to maintain the appropriate balance between clot formation and clot dissolution.

CLINICAL PRESENTATION

The main issues to consider in the clinical presentation of a patient with a suspected bleeding disorder are to determine whether the bleeding episodes are prolonged or unexpected, identify the pattern of bleeding, and clarify whether there are family members with similar manifestations.

Magnitude of the Bleed in Relation to the Causative Factor

Intense trauma will always cause vascular injury and bleeding. Patients with hemostatic defects have bleeds that are spontaneous or disproportionate to the inciting event, last longer than expected, or are recurrent. Inquire about hemostatic challenges such as surgeries, deliveries, dental extractions, intense traumatic events, or activities likely to involve trauma (contact sports).

Bleeding Pattern

Mucocutaneous bleeds manifested by purpurae, epistaxis, gastrointestinal (GI) bleeding, and menorrhagia suggest a defect of primary hemostasis involving platelets (i.e. diminished number or function), von Willebrand factor, or the vessel wall (e.g. inflammation, collagen defect). Deep-seated bleeds, on the other hand, such as muscular hematomas or hemarthroses, suggest a coagulopathy, most commonly caused by a deficit of factors VIII, IX, or XI. Generalized bleeding combining the two patterns is encountered in consumptive coagulopathies such as disseminated intravascular coagulation (DIC).

Family History

The majority of pediatric bleeding disorders are inherited. Hemophilia A and B have an X-linked pattern of inheritance (and therefore affect males predominantly), while von Willebrand disease (vWD) has an autosomal dominant inheritance with variable expressivity and penetrance.

DIAGNOSIS AND EVALUATION

Complete Blood Count

The number of circulating platelets is normally far greater than what is minimally needed for effective hemostasis. In fact, only when the platelet count is less than 50,000 to 70,000/fl does bleeding tendency increase. Severe thrombocytopenia, with platelet counts below 10,000 to 20,000/fl, puts the patient at risk for serious bleeds with minimal or no trauma. The approach to thrombocytopenia is discussed in Chapter 91, Thrombocytopenia.

Platelet Function Assay

The platelet function assay (PFA) simulates platelet adhesion in vitro by measuring response to collagen/epinephrine and collagen/ADP stimuli. The PFA is fairly sensitive for detecting vWD and severe platelet functional defects such as Glantzman thrombasthenia or Bernard Soulier disease. PFA sensitivity is lower for platelet secretion defects and storage pool defects. The PFA has high negative predictive value but poor specificity, since PFA closure times can be artifactually prolonged by anemia, thrombocytopenia, or various medications such as nonsteroidal anti-inflammatory drugs.

Platelet Aggregation Studies

Platelet aggregation studies evaluate platelet clumping in response to various agonists. The testing is relatively complex, time consuming, and requires large quantities of blood, making it impractical for young infants. A normal platelet aggregation study will exclude most qualitative platelet defects and all but the mildest forms of vWD.

Prothrombin Time

The prothrombin time (PT) is influenced by the activity of factors II, VII, IX, X, and fibrinogen. It thus explores the extrinsic and common coagulation pathways. It is commonly reported as the international normalized ratio (INR), in order to give comparable results across different laboratories. Isolated PT prolongation is suggestive of factor VII deficiency, which may be inherited or secondary to liver failure. An algorithm for the interpretation of coagulation test abnormalities is presented in Figure 92-2.

Activated Thromboplastin Time

The activated thromboplastin time (aPTT) evaluates the activities of coagulation factors of the intrinsic and common pathway: II, V, X, VIII, IX, XI, XII, prekallikrein, and bradykinin. It is important to note, however, that in general, levels of any given factor must decrease below 40% before PTT prolongation is noted. Furthermore, PTT is longer in the newborn and during infancy due to low levels of factor IX compared to the adult. Deficiency of factors VIII, IX, and XI may result in a clinically evident bleeding disorder, whereas deficiencies of factor XII, bradikinin, or prekallikrein are not associated with bleeding despite prolonging the aPTT.

Thrombin Time

The thrombin time measures the amount of time needed for conversion of fibrinogen to polymerized fibrin after addition of thrombin. It is prolonged in quantitative or qualitative fibrinogen abnormalities, as might be reflected by prolongation of both PT and aPTT, or if the specimen contains heparin.

Mixing Studies

Abnormal coagulation studies can be due to true deficiency of one or more clotting factors or to antibodies against clotting factors. To distinguish between these possibilities, mixing studies can be helpful. Mixing studies involve combining the patient’s plasma in equal proportion with normal plasma and determining the effect of the patient’s plasma on the PT and aPTT immediately and after 1 to 2 hours. If the patient’s prolonged PT or aPTT corrects after mixing with normal plasma, it suggests that the patient has a clotting factor deficiency (corrected by levels in the normal plasma); if, however, the test does not correct, it suggests the presence of an inhibitor such as lupus anticoagulant or an antiphospholipid antibody in the patient’s blood that interferes with the coagulation profile of normal plasma. Curiously, however, the presence of an inhibitor may not be clinically associated with a bleeding diathesis, despite influencing in vitro coagulation tests. In fact, lupus anticoagulants and antiphospholipid antibodies are more associated with thrombosis than with bleeding.

D-Dimers

D-dimers are the products of degradation of cross-linked fibrin, and their presence in the blood indicates the presence of a thrombus. An elevated D-dimer may be present in various conditions involving inflammation and activation of coagulation, including deep venous thrombosis (DVT) and pulmonary embolization. A normal D-dimer has a strong negative predictive value for venous thromboembolism in adults. In pediatrics, the negative predictive value of the D-dimer is weaker, as 13% to 40% of children with pulmonary embolization may have a normal D-dimer.

SPECIAL CONSIDERATIONS

Hemophilia

The term hemophilia refers to a group of bleeding disorders characterized by deep-seated bleeds (hematomas, hemarthroses) due to congenital deficiencies in factors VIII (hemophilia A), IX (hemophilia B), or XI (hemophilia C). Factor XI deficiency is uncommon in the general population, and the bleeding manifestations are generally milder.

The incidence of hemophilia is about 1:5000 males; about 85% have factor VIII deficiency and 15% have factor IX deficiency. Inheritance for both factor VIII and factor IX deficiency is X-linked; therefore males are affected and females are generally asymptomatic carriers. About one-third of factor VIII mutations are spontaneous, thus there may be no family history of a bleeding disorder.

Clinical Presentation

The clinical manifestations of hemophilia A and B correlate with factor VIII or IX activity and levels. Individuals with a factor activity of <1% are deemed severe; they may develop joint bleeds and hematomas during routine daily activities with no or minimal trauma. Patients who have factor levels between 1% and 5% (moderate severity) develop joint bleeds with mild to moderate trauma and have significant bleeds with surgical or dental procedures. Subjects who have factor levels between 5% and 30% have a mild clinical course, they rarely bleed, only with moderate to severe trauma or with surgical or dental procedures.

Musculoskeletal bleeds are common in severe hemophilia. Hemarthroses typically affect the large joints (ankles, knees, elbows) and usually start when the infant starts to crawl and walk and continue throughout childhood. In the absence of factor replacement therapy, a patient may have several joint bleeds per month. The first sign of a hemarthrosis is pain, especially with weight bearing or moving of the joint, followed by enlargement of the joint, warmth, and reduction in the range of motion. Repeated or persistent joint bleeds lead to synovial proliferation, damage of the cartilage, and ultimately to chronic hemophilic arthropathy manifested through pain, repeat bleeds, and limitation of range of motion.

Muscle bleeds are also common in hemophilia. They present with pain, point tenderness, swelling, and ecchymosis of the overlying skin. Large muscle bleeds, occurring in locations where the muscle is surrounded by a tight fascia such as the forearm or the lower leg may increase the pressure in that compartment and compromise the blood circulation in what is referred to as compartment syndrome. The clinical presentation of compartment syndrome includes changes in the color and temperature of the skin, paresthesia, weakness, and decreased pulse amplitude. Iliopsoas muscle bleeds are sometimes subtle, presenting with vague abdominal pain, and pain with the flexion of the thigh or antalgic position, with the affected leg flexed on the abdomen and internally rotated. Sometimes the symptoms may mimic a hip hemarthrosis; a hip ultrasound may be a useful test to differentiate between the two. Ileopsoas bleeds may result in significant blood loss and may lead to hemorrhagic shock. Bleeding in hemophilia may be life threatening if it occurs in the vicinity of the airway, if it is intracranial, or if it is large enough to cause exsanguination.

Treatment

The treatment of an acute bleed includes:

• Correcting the coagulopathy with clotting factor replacement and antifibrinolytic therapy

• Decreasing the blood flow to the site of bleeding and reducing local inflammation through limb elevation, pressure, and ice packs

• Rest of the affected joint or muscle until the pain subsides

• Pain management

Timely intervention and effective management are essential for the treatment of acute bleeds in hemophiliacs. The primary goal is to correct the clotting activity as soon as possible, even before the full evaluation of the patient is complete, and a pediatric hematologist familiar with the case should be involved early in the decision-making process. Clotting factor concentrates are either plasma derived or artificially produced by recombinant technology. Risk of transmitting a severe infection such as HIV or hepatitis through the use of clotting factor concentrates is extremely low, with no documented transmissions for decades. The dose of factor concentrate and the length of therapy are based on the type of hemophilia, baseline factor activity, and severity of the bleed (Table 92-1). For factor VIII concentrates, 1 IU/kg raises the factor activity by 2% and the half-life is approximately 12 hours. Regarding factor IX concentrates, 1 IU/kg raises factor activity by 1% (0.7% to 0.8% for recombinant factor IX [Benefix]) and the half-life is approximately 18 hours.

The main risk of using factor concentrates is the development of inhibitors, which are antibodies triggered by exposure to the factor. Since inhibitors bind to and inactivate the relevant coagulation factor, their presence complicates management of hemophilia. The amount of inhibitors present in the serum is calculated by Bethesda units (BUs), with 1 BU defined as the amount of inhibitor needed to inactivate 50% of the relevant factor. If the inhibitor titer is low the patient can be treated with larger amounts of factor (VIII or IX) to overwhelm the inhibitors. If, however, the inhibitor titer is high (more than 5 BUs), then giving the patient enough factor to overwhelm his/her inhibitory antibodies becomes impractical. In such cases, bleeding is best treated by administering a factor or mixture of factors that bypasses factor VIII or IX in the coagulation cascade, such as activated factor VII (Novo-Seven) or the prothrombin complex concentrate (FEIBA). Long-term therapy for high titer inhibitors is immune tolerance induction, with the goal of eliminating the inhibitor by making the immune system tolerant to factor infusions.¹

Oral and nasal bleeds may benefit from the use of antifibrinolytic medication (aminocaproic acid or tranexamic acid). In mild hemophilia (basal factor levels >5%) desmopressin acetate (DDAVP) administered intravenously or intranasally may transiently increase factor VIII levels and be sufficient to stop a mild or moderate bleed without the use of factor concentrates. Arthrocentesis is generally avoided except for symptom relief in a hemarthrosis with a tensed effusion. A muscle bleed that evolves toward a compartment syndrome may require surgical decompression either through evacuation of the hematoma or incision of the fascia, obviously with adequate coagulation factor coverage.

Prevention

Bleed prevention is critically important in the management of hemophilia. Preventative treatment has two components: (1) lifestyle choices that decrease risk of trauma and bleeding, and (2) prophylactic factor infusion with the goal of maintaining factor activities of at least 1% at all times. Prophylactic therapy is demonstrated to be superior to on-demand therapy for maintaining joint functionality.²

New Developments in the Treatment of Hemophilia

Long-acting clotting factors

One of the main drawbacks of current hemophilia prophylactic therapy is the need for intravenous factor infusions two to three times a week. There are several new clotting factors in development designed to extend the half-life of factor VIII or IX by coupling them to different residues such as polyethylene-glycol, Fc IgG fragments, or albumin. With the advent of these new drugs one may expect lots of changes in hemophilia care, including new tests to assess factor activity, new prophylactic schedules, more personalized treatment based on individual pharmacokinetic characteristics, and possibly new side effects of the therapy.³

Gene therapy

Hemophilia seems an ideal target for gene therapy since it is caused by a single gene defect and restoration of only minimal levels of the missing protein would impact clinical outcome. Nathwani et al⁴ reported the first successful long-term expression of factor IX, to therapeutic levels, in six patients with hemophilia B, by introducing the factor IX gene in hepatic cells by means of a viral vector. The translation of this formidable feat in clinical practice is still years away, but the prospect of cure for hemophilia now seems to be within reach.⁵

Von Willebrand Disease

Von Willebrand factor (vWFct) is a multimeric glycoprotein that facilitates the adherence of the platelets to the injured endothelium. vWFct also serves as carrier for the circulating factor VIII. vWD is caused by a quantitative or qualitative defect of vWFct. The most common form, type 1 vWD, is characterized by low levels of functional vWFct. Type 2 vWDs are caused by functional abnormalities of vWFct, while type 3 vWD represents the complete absence of vWFct.

Clinical Presentation

vWD is manifested by mucocutaneous bleeds: petechiae and ecchymoses, epistaxis, menorrhagia, unexplained hematochezia, as well as prolonged bleeding following trauma, surgery, dental extractions, and childbirth.

Diagnosis and Evaluation

The initial tests used in the diagnosis of vWD include VWFct activity by the ristocetin cofactor assay, vWFct antigen, and factor VIII activity. The vWFct multimeric analysis is helpful in differentiating between the different type 2 subtypes.

The vWFct level may be increased by acute inflammation, exercise, pregnancy or estrogen therapy. The level may be falsely low if the blood was not rapidly processed. Blood type O individuals have physiologically low levels of vWFct compared to the other blood types.

The diagnosis of vWD is based on the presence of abnormal bleeding manifestations, a vWFct activity less than 30%, and a family history of vWD or of abnormal bleeding.⁶

Treatment

The main goal of therapy is to elevate levels of vWFct at the time of bleeding or in preparation for a procedure. Desmopressin acetate (DDAVP) administered intranasal or intravenous stimulates the release of vWFct from the endothelial cell stores. The treatment is usually effective in type 1 vWD, may be useful in certain subtypes of type 2 vWD and is ineffective for type 3. The response is not always predictable, especially for the intranasal preparation. A trial of DDAVP should be performed in a non-bleeding state in order to assess the magnitude as well as the duration of the response. Response to DDAVP decreases after 2 to 3 daily doses, as the endothelial reserves are depleted. DDAVP may cause free water retention and hyponatremia. Estrogen-containing oral contraceptive pills elevate vWFct levels and may be effective in controlling menorrhagia for some women. Von Willebrand and factor VIII concentrates are typically used in more severe forms of vWD, for treatment of bleeds, or perioperatively, with dosing based on vWFct/ristocetin cofactor units (typically 20–60 U/kg every 8–24 hrs depending on indication). Antifibrinolitic therapy with either aminocaproic acid or tranexamic acid may be useful for menorrhagia, gingivorhagia, and epistaxis.

Prevention

Prevention of bleeds in vWD includes lifestyle changes aimed at avoiding significant trauma, use of estrogen-containing oral contraceptive pills for women with menorrhagia, and avoidance of medications with antiplatelet or anticoagulant effect.

Platelet Functional Disorders

Inherited platelet functional disorders are relatively uncommon. They may be due to a defect in the membrane receptor glycoproteins (glycoprotein Ib IX for Bernard Soulier and glycoprotein IIb IIIa for Glanzmann thrombasthenia) disorders of platelets storage granules, defects in secretion, or signal transduction. Inherited platelet functional disorders present with mucocutaneous bleeding and prolonged bleeding with trauma and surgery.

Diagnosis

The CBC evaluates the platelet number, size (mean platelet volume; MVP) and appearance on the peripheral smear. Bernard Soulier syndrome may present with mild thrombocytopenia with large platelets, whereas in Wiskott-Aldridge syndrome the platelets are smaller than normal. Platelet aggregation studies offer functional platelet information regarding the response to different agonists. The absence of surface glycoprotein receptors characteristic for Bernard Soulier or Glantzman thrombastenia may be diagnosed using flow cytometric assays. Electron microscopy examination of the platelets may be useful in diagnosing disorders such as gray platelet syndrome, where most of the platelets do not have alpha granules.

Treatment

Platelet transfusion should be used for severe bleeds; however, repeated use of platelet transfusion may lead to the formation of antibodies against platelet-associated proteins (e.g. to the glycoptotein II b IIIa in Glantzman thrombastenia) and accelerated clearance of transfused platelets. For such situations there are case reports of successful off-label use of activated factor VII (Novo Seven). DDAVP may shorten bleeding time and reduce bleeding in certain cases. Antifibrinolytic medications similarly may be useful epistaxis, gingivorgagia, and menorrhagia.

Acquired Platelet Functional Defects

Renal insufficiency

Patients with renal insufficiency and uremia may exhibit platelet dysfunction and clinical bleeding. The mechanism is not quite understood but it is probably a dialyzable substance that alters the platelet vessel–wall interaction. The treatment includes dialysis, DDAVP, cryoprecipitate.⁷

Medications

Aspirin and other nonsteroidal anti-inflammatory drugs interfere with the cyclooxygenase, the first enzyme in the prostaglandin synthesis pathway, which is needed for platelet activation, and inhibit platelet function. In otherwise healthy individuals this impairment has little clinical significance; however, it may precipitate bleeding if the patients have other hemostatic defects (hemophilia, vWD, uremia, thrombocytopenia).

DISORDERS OF THROMBOSIS

The incidence of venous thrombosis in children is much lower than in the adult population, approximately 34 to 58 cases per 10,000 hospital admissions⁸ or 49 cases per 100,000 children.⁹ Arterial thrombosis is even less common at 0.05 to 0.6 cases per 10,000 children/year. Arterial thrombosis is not discussed in this chapter, as pediatric stroke is discussed elsewhere.

PATHOPHYSIOLOGY

The mechanisms of venous thrombosis described in the nineteenth century by the German physician Rudolf Virchow are still valid today: venous stasis, endothelial damage, and hypercoagulability. Most risk factors for venous thromboembolism act through one of these mechanisms.

DIFFERENTIAL DIAGNOSIS

The incidence of venous thromboembolism among children is highest in the first year of life, declines during childhood, and then increases again in adolescence. The differential diagnosis of thrombosis should focus on identifying a predisposing condition or precipitating event. Thromboembolic episodes occurring in infancy are often related to congenital heart disease, use of central venous lines, invasive procedures, infection, acidosis, and hypovolemia. In older children and adolescents venous thromboembolism occurs as a result of trauma, surgery, indwelling venous catheters, cancer and cancer chemotherapy, chronic inflammatory conditions, obesity, prolonged immobility, infection, use of oral contraceptive pills, presence of antiphospholipid antibodies, or inherited hypercoagulable condition. Evaluation for inherited hypercoagulable risk factors is especially warranted in adolescents, in patients with a prior personal or family history of venous thromboembolism (including DVT, stroke, or myocardial infarction), or in cases wherein the cause of the thrombotic event is not apparent. Inherited hypercoagulability traits may be separated into those that are uncommon but confer a high risk of thrombosis (e.g. protein C deficiency, protein S deficiency, and antithrombin deficiency) and those that are relatively prevalent but increase risk of thrombosis only moderately (e.g. factor V Leiden, prothrombin gene mutation, hyperhomocystenemia, and elevated factor VIII). Identification of thrombophilic traits is especially critical in informing the patient of their personal risk, to facilitate appropriate lifestyle choices aimed at lowering thrombotic risk (Table 92-2). With rare exceptions, the results do not influence the management of the acute thrombosis in the intensity or duration of therapy.

CLINICAL PRESENTATION

DVT presents with pain, edema, plethora, as well as manifestations related to the location of the thrombus (superior vena cava syndrome, collateral superficial circulation, signs of increased intracranial pressure). Thrombi occurring in the deep venous system, especially in the proximal veins of the extremities, may embolize in the pulmonary circulation. Clinical manifestations of pulmonary embolization include chest pain, shortness of breath, hypoxia, cough, hemoptysis, anxiety, and tachycardia. Pulmonary embolism is a life-threatening complication of DVT and requires urgent treatment. Depending on the size of the embolus and the progression of thrombosis in the pulmonary arteries, pulmonary embolization may be lethal.

DIAGNOSIS AND EVALUATION

Venography is the gold standard for the diagnosis of DVT; however, the technique is impractical in many children and is rarely used. Instead, compression Duplex ultrasound is the most commonly used imaging technique. It is very sensitive for the DVT in the lower or upper extremity but is less useful for evaluation of intrathoracic and pelvic veins. CT venography and the magnetic resonance imaging/magnetic resonance venography (MRI/MRV) have proven utility in adults and are commonly used in pediatrics. The diagnosis of pulmonary embolization can be made most accurately using pulmonary angiography; however, this is an invasive procedure, is not available in some centers, and requires general anesthesia in children. Ventilation/perfusion (V/Q) scintigraphy is considered safe and sensitive, but specificity is lower when used in patients with congenital heart disease or those with right-to-left shunts. In many centers, helical CT pulmonary angiography has become the imaging modality of choice in adults and children.^10,11 Magnetic resonance pulmonary angiography is an alternative that offers sensitive evaluation of the pulmonary circulation without exposing the patient to radiation, and it uses a contrast material (gadolinium) less likely to cause allergic reactions than CT contrast. Though the sensitivity and specificity of MR pulmonary angiography are above 95%, the procedure is long and frequently requires anesthesia in young children. Many clinical probability scores used in adults have not been validated in children. The D-dimer test, for example, has high negative predictive value in adults with pulmonary embolism (PE), but is less useful in children.¹² Echocardiogram is used in assessing right ventricular function and possible pulmonary hypertension as well as in visualization of intracardiac or large vessel thrombi.

TREATMENT

The treatment of venous thromboembolism includes pharmacologic interventions (anticoagulants, thrombolytic agents) and vascular procedures (placement of inferior vena cava filters or surgical removal of the clot). The reader is referred to guidelines of the American College of Chest Physicians for more information regarding the treatment of pediatric thrombosis.¹³

Anticoagulants

The goal of anticoagulation therapy is to prevent clot progression and embolization, to facilitate resolution of the thrombus, and to prevent recurrence. The duration of anticoagulation varies with the clinical circumstances and management should be done in consultation with an experienced pediatric hematologist. In general, patients with secondary or provoked thrombosis wherein a causative factor can be identified and removed would benefit from at least 3 months of anticoagulation. Idiopathic or unprovoked thrombosis should be treated with anticoagulants for 6 months or more. If an unprovoked thrombosis recurs after the initial treatment or if the causative factor cannot be removed, there should be strong consideration for long-term, even lifelong, anticoagulation. Primary prophylaxis with an anticoagulant may considered for patients with inherited prothrombotic traits who have a transiently increased thrombotic risk (e.g. surgery, immobilization, pregnancy) until that risk factor is removed. Treatment decisions should ideally be made with the help of an experienced pediatric hematologist.

Heparin

Heparin enhances the activity of antithrombin, thereby inhibiting thrombin activity and activated factor X. The main advantages are the rapid onset of action, the short half-life (1.5 hrs), and the ability to reverse the anticoagulant effect with protamine. The disadvantages are the need for a continuous intravenous infusion, unpredictable clinical response, and the need for frequent monitoring. The main risks are bleeding, heparin-induced thrombocytopenia, and potential risk of osteoporosis with prolonged use. For a recommended dose algorithm, refer to Table 92-3. The anticoagulant activity may be measured by aPTT or anti-activated factor X activity (anti-Xa). The goal of anticoagulation is an aPTT 1.5 to 2.5 times above the baseline, or an anti-Xa activity of 0.35 to 0.7 U/mL. Since the goal varies with the clinical situation and the therapeutic window is relatively narrow, a consultation with a hematologist is typically indicated.

Low Molecular Weight Heparins

The most commonly used low molecular-weight heparin (LMWH) in pediatrics is Enoxaparin, and like unfractionated heparin, its anticoagulant action depends on amplifying the activity of antithrombin. It differs from unfractionated heparins, however, in that LMWH inhibits activated factor X more than it inhibits thrombin. Nonetheless, LMWH has become the heparin of choice for many pediatric thrombophilia patients because of its ease of use and ability to be used in the outpatient setting. The treatment dose is 1 mg/kg sq every 12 hours, with a larger dose in newborns and young infants. Anticoagulant activity is monitored by measuring anti-Xa activity. The therapeutic range is 0.5 to 1 IU/mL for most patients, and the prophylactic range is 0.1 to 0.3 U/mL.¹⁴ Other advantages of LMWH are its predictable response, less frequent monitoring, and lower risk of heparin-induced thrombocytopenia. Disadvantages of LMWH include its higher cost and partial reversability with protamine.

Vitamin K Antagonists

Vitamin K plays an essential role in the carboxylation of coagulation factors II, VII, IX, and X. Since vitamin K–mediated carboxylation is required for the function of these proteins, inhibiting this step is an effective way to achieve anticoagulation. The vitamin K antagonist available in the United States is warfarin, and its anticoagulant activity is monitored by PT/INR. The INR therapeutic range is generally 2 to 3 (dictated by clinical circumstance), and may be higher for certain patients (e.g. prosthetic heart valves). The typical dose of warfarin is 0.1 mg/kg administered orally, and steady-state levels are achieved 5 to 7 days after the start of the treatment. Warfarin cannot be used in newborns and young infants because of their delicate vitamin K balance and the absence of a liquid warfarin formulation. The main adverse effect is bleeding. The activity of warfarin can be reversed with vitamin K, or in an emergent situation with fresh frozen plasma or off-label use of activated factor VII (Novoseven). Importantly, the anticoagulant proteins C and S are also vitamin K-dependent factors, and thrombotic risk is paradoxically increased when first starting warfarin (due to the inhibition of protein C and S), requiring clinical “bridging” with heparin until the appropriate INR is achieved.

Newer Anticoagulant Drugs

There are several new anticoagulant drugs currently in use in adults targeting the thrombin or activated factor X. Since the pediatric data is limited, one should consider using them only in consultation with hematologists and typically for extreme situations such as heparin-induced thrombocytopenia or when warfarin is contraindicated.¹⁵ The only drug approved for pediatric use is the direct thrombin inhibitor argatroban. Its pharmacokinetics are more predictable than that of heparin and does not cause heparin-induced thrombocytopenia. Argatoban is administered intravenously, has hepatic excretion, and its anticoagulant effect can be monitored using the aPTT. There is no accepted antidote to revert argatroban’s anticoagulant activity. Thrombolytic therapy has been used more extensively in adults; pediatric experience is limited. The agent of choice in children is tissue–plasminogen activator (tPA). This intervention is, for now, reserved for limb- or life-threatening thrombosis and should only be performed under the supervision of a hematologist familiar with this therapy.¹⁶

Inferior vena cava filters have been used extensively in adults to reduce the risk of pulmonary embolization. Pediatric experience is limited; they have been used for children with a weight greater than 10 kg who have a high risk of pulmonary embolization and have a contraindication for anticoagulation.¹⁷ Thrombectomy is the mechanical removal of the clot, either through open surgical procedure or through percutaneous catheterization. It has been used mostly for life-threatening intracardiac or large vessel thrombosis or for IVC thrombosis associated with Wilms tumor, at the time of nephrectomy

SPECIAL CONSIDERATIONS

Central Venous Catheter Thrombosis

Central venous catheter thrombosis has become more prevalent as more and more children have indwelling central venous catheters placed for prolonged intravenous therapies. A clot may occur inside the lumen, around the catheter in a sleeve disposition, or it may attach to the vessel wall. The mural clots may occlude the vein and pose a risk for embolization. Often the occlusion is gradual, allowing for development of collateral venous circulation that helps the catheter-associated thrombosis to remain clinically silent. Prevalence of central catheter–associated DVT varies from 5% to 50% depending on whether they are symptomatic or identified by venography.¹⁸ Treatment decisions are influenced by the presence of signs and symptoms of obstruction and the ongoing need for vascular access. If the line is no longer needed and or the patient is symptomatic, the catheter should be removed, preferably after 3 to 5 days of anticoagulation. If the line is needed one may consider anticoagulation at therapeutic levels for 3 months, followed by prophylactic doses until the line may be removed.

Disseminated Intravascular Coagulation

DIC is a microangiopathic and consumptive hematologic process triggered by a variety of clinical conditions including trauma, tissue injury, sepsis, acidosis, and hypotension. Increased expression of tissue factor on the endothelial cells and monocytes activates the coagulation cascade to result in widespread formation of intravascular thrombi and end-organ failure and consumptive coagulopathy.¹⁹ Laboratory abnormalities include thrombocytopenia, increased PT and PTT, decreased fibrinogen, presence of schistocytes on peripheral blood smear, and elevation of D-dimers. The most important part of treatment is to address and manage the underlying cause of DIC and provide hemodynamic and respiratory support as needed. Correction of consumptive coagulopathy is accomplished with infusions of fresh frozen plasma and platelet transfusion.

REFERENCES

INTRODUCTION

The primary goal of transfusion medicine is to provide the safest blood transfusions possible for patients who need them. In the pediatric patient population, red blood cell (RBC) transfusions comprise the majority of transfusions (58.5%), followed by platelet and plasma transfusions (26% and 15.4%, respectively).¹

While pediatric patients received 2.6% of the 15 million red cell units and 2.3% of the 4.5 million plasma units transfused annually, the most recent available National Blood Collection and Utilization Survey reports that there was a 7.6% increase in RBC transfusions in the pediatric population, which is in contrast to the declining trends identified in the adult patient population.¹ In addition, the overall trends for platelet transfusions indicate an increase, as well as for other blood derivatives, such as intravenous immunoglobulin (IVIG).

Recognition of the clinical benefits of hemotherapy should help guide the clinician in the decision to transfuse. These benefits must be weighed against adverse events associated with transfusion, including infections, as well as cost. A British report indicated that the most common error (80% of errors) in pediatrics is transfusion of the incorrect blood component.² In this report, a blood component was considered to be incorrect if it did not meet special requirements, if there was an administrative error, or when there was a laboratory error. Examples included not transfusing a cytomegalovirus (CMV)-negative or irradiated unit when required by hospital policy, transfusing one twin with an RBC unit intended for the other, or not considering maternal anti-erythrocyte antibodies when selecting an RBC unit for a neonate. An understanding of pediatric-specific issues may help minimize such problems.

CLINICAL CONSIDERATIONS

Transfusional requirements and parameters may differ between children and adults, especially in neonates and young children. Most studies focus on adults with extrapolation of these data and guidelines to children. Children have slightly higher blood volume per kilogram (of ideal body weight) than adults. Term neonates have 85 mL/kg, while preterm neonates have 100 mL/kg. Children up to pre-adolescence have 75 to 85 mL/kg and adolescents have 70 to 75 mL/kg. Neonates are at risk for anemia due to phlebotomy and a poor erythropoietic response. Neonatal organ functions are not fully developed and may lead to metabolic and electrolyte imbalances following transfusion. Small-volume and slow-rate transfusions may prevent such problems. With more rapid transfusions, particular attention should be given to hypocalcemia due to citrate present in blood components as well as hyperkalemia. Neonates, especially premature infants, are also at risk for hypothermia and its attendant problems, such as acidosis and hypoxia.³ The use of blood warmers may be useful for more rapid transfusions in susceptible neonates.

In most instances, medical consent should be obtained from the parents and/or legal guardians of all children requiring blood transfusions.⁴ Institution-specific policies may also require obtaining assent from certain minors who have some decision-making capacity. The exception is when blood transfusion is deemed immediately life-saving and a parent/legal guardian is unable to provide consent. The patient should be examined prior to transfusion. This provides a baseline for assessing patients for any transfusion reactions.

BLOOD COMPONENTS AND DERIVATIVES

Whole blood transfusion is rarely performed, and is not available in most institutions.⁵ However, blood banks can prepare reconstituted whole blood by mixing RBCs with plasma. Reconstituted whole blood is usually used for neonatal exchange transfusions for hyperbilirubinemia or severe anemia.

Specific blood components are transfused depending on therapeutic goals. Blood components can be divided into the traditional whole blood components (i.e. packed red blood cells, platelets, granulocytes, plasma, and cryoprecipitate) as well as derivatives (i.e. intravenous immunoglobulin, factor concentrates). Blood is considered a biological product, with manufacturing regulated by the US Food and Drug Administration. Each blood component must be collected and stored under specific conditions, which limits their shelf life.

PACKED RED BLOOD CELLS

There are two ways of determining the dose for packed red blood cell (pRBC) transfusion. The standard dose is 10 to 15 mL/kg body weight. At this dose, RBC transfusion is expected to increase the hemoglobin by 2 to 3 g/dL.⁶ The following formula can be used to estimate the volume of pRBCs needed to increase the hemoglobin by a desired amount:

Packed red blood cell transfusions are performed to increase oxygen carrying capacity,^8,9 with the ultimate goal of adequate tissue oxygenation.¹⁰

Patients with acute blood loss can have impaired oxygenation due to both intravascular fluid loss with resultant cardiac output compromise and oxygen carrying capacity loss (i.e. loss of RBC mass). In severe blood loss, the primary consideration should be volume resuscitation, usually with crystalloid, to avoid cardiovascular collapse. The clinical presentation should guide the amount of pRBCs to transfuse. In infants less than 4 months of age, acute anemia can result in signs such as tachypnea and tachycardia. Transfusion rates are relatively rapid in order to correct volume loss and counteract volume loss.

In contrast, patients suffering from chronic anemia may have compensated by increasing oxygen extraction and cardiac output. Such patients include those with hemoglobinopathies and other intrinsic erythrocyte disorders. In addition, patients with nutritional deficiency (e.g. iron, vitamin B, or folate deficiency) or intoxication (e.g. lead poisoning) can also present with chronic anemia. In these cases, the etiology of the anemia should be corrected. Transfusions should be reserved until symptomatic anemia is present or there is imminent risk of decompensation. Red cell transfusions should be carried out slowly (rate of 1–2 mL/kg/hr) because these patients are at risk for cardiopulmonary overload.

In emergencies, there may be insufficient time to type, screen, and/or cross-match blood. The patient should be given blood group O, Rh-negative red cells and AB plasma while the blood bank completes the workup.

Preoperative blood transfusions may be indicated because of the dangers of general anesthesia in the setting of very low hemoglobin values. In adults and children, RBC transfusion is generally indicated before anesthesia when the hemoglobin is below 6 to 8 g/dL.¹¹ Children with congenital cardiac disease are often transfused at higher triggers to achieve a hemoglobin concentration of up to 13 g/dL.³ Clinical judgment should be used, taking into consideration the patient’s overall health, hemodynamics, and nature of the procedure^12-14 when deciding to provide preoperative transfusions.

Most patients with sickle cell disease do not require regular transfusions; however, some patients receive chronic transfusions to decrease recurrent sickle pain crises, acute chest syndrome, or stroke.^15,16 Chronic red cell therapy may be offered as simple transfusions or as exchange transfusions, and its goal generally is to maintain hemoglobin S at <30% to 50% while keeping the hematocrit close to 30% to avoid hyperviscosity.¹⁶ Preoperatively, maintaining the hemoglobin of sickle cell patients at 10 g/dL, irrespective of hemoglobin S fraction, is associated with a 50% reduction in transfusion-associated complications. This strategy has the same clinical outcomes as a more aggressive transfusion strategy to keep the hemoglobin S fraction to <30%.¹⁷ The 10-g/dL hemoglobin threshold for preoperative transfusion was also shown to decrease the occurrence of perioperative acute chest syndrome in low- and moderate-risk surgeries when compared with a preoperative hemoglobin below 10 g/dL.¹⁸

In patients with autoimmune hemolytic anemia, transfusion of compatible blood is difficult because of anti–red blood cell antibodies present against universal red cell antigens that confound cross-matching. In an otherwise healthy child in whom anemia has developed slowly, without cardiovascular disease or hypoperfusion, a hemoglobin >4 g/dL appears sufficient for oxygenation.¹⁹ If the patient does require transfusion, the RBCs will often be incompatible and the patient should be monitored closely for transfusion reactions (Table 93-1).

Additional considerations for red cell transfusions should be made when dealing with premature and low-birth-weight neonates. RBC transfusion should be considered in newborns, preterm, and low-birth-weight infants when there is shock or >10% blood volume loss or when the degree of anemia leads to growth failure, spells, or other clinical complication.²⁰ Hemoglobin should be maintained at 13 g/dL (~45% hematocrit) in such patients with cardiovascular disease (including congenital heart disease) and 8 to 10 g/dL (~30% hematocrit) in patients with tachypnea, tachycardia, or recurrent apnea.^3,20 While the Premature Infants in Need of Transfusion (PINT) study showed that in very low birth weight (VLBW) infants (<1000 g), a low-threshold hemoglobin sliding scale trigger was not any worse than liberal transfusion, other studies and a subsequent review of the PINT data suggested that a higher hemoglobin level in VLBW infants may improve neurocognitive development and leads to decreased costs of care related to neurologic function.^21-23

PLATELETS

Platelets are prepared from whole collections or from an apheresis platelet collection. One whole blood–derived platelet is a sufficient dose for most patients up to 10 to 15 kg. Larger patients can receive pools of whole blood–derived platelets in which the pool size is proportional to the size of the patient. One apheresis platelet is usually an adequate dose for most adult patients, and aliquots can be prepared for smaller pediatric patients. Platelets must be kept at 20 to 24^°C with gentle agitation. Platelets only have a 5-day shelf life. The standard dose is ~5 mL/kg. At this dose, the platelet count should increase 50,000/μL.⁶

Platelet transfusions are indicated in patients who are bleeding due to thrombocytopenia or platelet dysfunction. Thrombocytopenia may be due to decreased production or increased clearance/consumption of platelets. Platelet dysfunction may be due to congenital causes (e.g. Bernard-Soulier syndrome) or an acquired dysfunction (e.g. uremic thrombocytopathy). In general, transfused platelets will be more lasting and beneficial when the underlying reason for thrombocytopenia is one of defective production. In cases of increased platelet clearance, for example in primary autoimmune thrombocytopenia (ITP) or consumptive coagulopathy, platelet transfusions are generally reserved for life- or limb-threatening bleeding. In such cases, definitive therapy involves correction of the underlying pathology.

Prophylactic platelet transfusions in non-bleeding, thrombocytopenic patients may also be considered if they are at risk for bleeding. There is no particular platelet count known at which bleeding will occur. In at-risk patients, however, it has been shown that hemorrhage is more frequent and more severe, the lower the platelet count.²⁴ Though there are limited data on platelet count thresholds for prophylactic transfusions in pediatric patients, the American Society for Clinical Oncology guidelines²⁵ have nonetheless been extended to the pediatric population.²⁶ A general transfusion guideline for prophylactic platelet transfusion includes a platelet count of <10,000/μL and <50,000/μL prior to an invasive procedure. Institutional guidelines should be followed.

Pediatric patients are generally transfused with ABO-compatible platelets whenever possible.¹⁸ Because platelets have ABO antigens, incompatibility results in slightly diminished half-life; however, this is not usually clinically significant.^16,27 Conversely, anti-A antibodies present in the plasma of platelets from group O and B blood donors can causes clinically significant hemolysis of patient A or AB erythrocytes. This rare complication appears to be more prevalent in pediatric patients, and the risk may be mitigated by blood bank policies preventing transfusions of platelets with high titers of incompatible anti-A antibodies.²⁸

Current methods for preparation of platelet units by apheresis or from pooled whole blood results in less than 0.007 mL or 0.5 mL of contaminating RBCs, respectively.²⁹ The risk of RhD alloimmunization in RhD-negative individuals is low following transfusion with either RhD-positive pooled³⁰ or single donor^31,32 platelet units. RhD allosensitization appears to be dose dependent, but doses as low as 0.03 mL have resulted in RhD allosensitization.³³ Consequently, anti-RhD immunoglobulin may be offered to RhD-negative females with child bearing potential within 72 hours of receiving RhD-positive platelets, but institutional policies may vary.

Occasionally, patients will exhibit unresponsiveness to platelet transfusions (i.e. platelet refractoriness) by failing to increase their platelet count after transfusion. There are many causes of refractoriness and up to a quarter of those are due to anti-human leukocyte antigen (HLA) alloantibodies.³⁴ A platelet count taken 10 to 60 minutes after platelet transfusion is helpful in documenting unresponsiveness. Platelet-refractory patients may benefit from transfusion of HLA-matched or HLA-compatible platelets when the etiology is due to HLA alloantibodies.^35-37

PLASMA

Several different types of plasma products are available. The distinguishing feature is the time between collection and a certain storage condition, and how long after thawing the plasma can be used. This determines the stability of coagulation factors. The most commonly used product is fresh frozen plasma (FFP). FFP is plasma that is frozen within 8 hours of collection. Prior to transfusion, FFP is thawed at 37^°C and can be kept refrigerated for up to 24 hours. Other plasma products can be frozen up to 24 hours following collection and/or kept refrigerated for up to 5 days following thawing. The standard dose for plasma transfusion is 10 to 15 mL/kg with an expected 15% to 20% increase in factor levels.⁶

Plasma transfusion is indicated for multiple plasma factor replacement or as an alternative for single factor replacement when a purified or recombinant factor is not available.^30,38 Patients with liver disease, vitamin K deficiency, or treatment with vitamin K antagonists (e.g. warfarin) may cause multiple coagulation factor deficiency. In addition, patients undergoing massive transfusion should also receive plasma transfusions³⁹ for dilutional coagulopathy as well as disseminated intravascular coagulation (DIC). Plasma should be used judiciously, since unwarranted plasma transfusions increase risk of transfusion reactions. The recommended dose of FFP is 10 to 20 mL/kg body weight for pediatric patients,³⁸ but must be used cautiously to avoid fluid overload.

CRYOPRECIPITATE

Cryoprecipitate is the precipitated component of plasma that forms when previously frozen plasma is thawed at 4^°C. It contains fibrinogen, von Willebrand factor, factor VIII, and factor XIII. There is also fibronectin present but in general cryoprecipitate should only be used for fibrinogen replacement. Purified and safer forms of all the other factors in cryoprecipitate are preferred, because cryoprecipitate does not undergo additional pathogen inactivation. The standard dose is 1 to 2 units/10 kg body weight with an expected 60 to 100 mg/dL rise in fibrinogen.⁶

Cryoprecipitate is used in the setting of hypo- or dysfibrogenemic states. It can also be administered to correct factor XIII deficiency if a concentrate is unavailable. Cryoprecipitate does not contain all the coagulation factors present in plasma and should not be used to correct multifactor coagulation factor deficiencies. It should be used in bleeding patients to replace fibrinogen (when the fibrinogen level is <100 mg/dL) or if the patient has dysfunctional fibrinogen, and in conjunction with plasma and platelets in DIC.³⁸ When purified or recombinant factor VIII, VWF, or factor XIII is not available, cryoprecipitate may also be used to replete these factors.^30,38