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.
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.
The coagulation cascade, showing the steps of the intrinsic pathway (measured by the PTT) and the extrinsic pathway (measured by the PT).
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).
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).
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.
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.
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.
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.
Algorhythm of partial list of differential diagnoses to consider when coagulation tests are abnormal.
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.
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.
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 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.
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.
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.
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
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.
TABLE 92-1Factor Replacement Goals in Hemophilia ||Download (.pdf) TABLE 92-1 Factor Replacement Goals in Hemophilia
|Type of Bleeding ||Replacement Goal (%) ||Replacement Dose Factor VIII (IU/kg/day) ||Replacement Dose Factor IX (IU/kg) ||Duration (days) |
|Hemarthrosis ||40–60 ||20–30 ||40–60 ||1–3 |
|Intramuscular hematoma ||General: 40 ||General: 20 ||General: 40 ||General: 1–2 |
| ||Iliopsoas: 30–100 ||Iliopsoas: 15–50 ||Iliopsoas: 30–100 ||Iliopsoas: 100% for 3 days, then 30% for 7 days |
|CNS, life threatening ||100 ||50 ||100 ||14 days, trough >50%, then 30% for at least 7 days |
|Oral, dental extraction ||40–60 ||20–30 ||40–60 ||1 day, then aminocaproic acid for 5–7 days |
|Surgery ||100 ||50 ||100 ||100% for 1 day, 50% for 5–7 days, 30% for 5–7 days |
|Gl bleeding ||100 ||50 ||100 ||Continue 1–2 days after stool clears of blood |
|Compartment syndrome ||100 ||50 ||100 ||Days to weeks |
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.
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
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 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.
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.
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
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 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.
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.
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
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
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).
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.
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.
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.
TABLE 92-2Inherited Thrombotic Risk Factors ||Download (.pdf) TABLE 92-2 Inherited Thrombotic Risk Factors
|Genetic Risk Factor ||Prevalence in General Population (%) ||Relative Risk for the First Venous Thromboembolic Event |
|Factor V R506Q (factor V Leiden) ||3–7 ||3–5 |
|Prothrombin G20210A ||1–4 ||2–3 |
|Protein C ||0.2 ||4–6 |
|Protein S deficiency ||0.1 ||1–10 |
|Antithrombin deficiency ||0.02 ||5–10 |
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.
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.
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
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 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.
TABLE 92-3Guidelines for the Initiation, Monitoring, and Adjustment of Unfractionated Heparin ||Download (.pdf) TABLE 92-3 Guidelines for the Initiation, Monitoring, and Adjustment of Unfractionated Heparin
|Initiate therapy with a 75 units/kg bolus over 10 min |
|Initial maintenance dose: |
| 1 yr or younger: 28 units/kg/hr |
| Older than 1 yr: 20 units/kg/hr |
|Obtain first aPTT 4 hr later, and adjust dosage as follows: |
|aPTT (sec) ||Heparin (U/mL) ||Bolus (U/kg) ||Hold ||Rate ||Recheck |
|<40 ||0–0.15 ||50 ||− ||+20% ||4 hr |
|40–50 ||0.16–0.2 ||0 ||− ||+20% ||4 hr |
|51–59 ||0.21–0.29 ||0 ||− ||+10% ||4 hr |
|60–90 ||0.3–0.5 ||0 ||− ||− ||24 hr |
|91–110 ||0.51–0.7 ||0 ||− ||−10% ||4 hr |
|111–150 ||0.71–1 ||0 ||30 min ||−10% ||4 hr |
|>150 ||>1 ||0 ||60 min ||−15% ||4 hr |
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 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
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.
The diagnosis of a bleeding disorder relies on:
Personal and family history of abnormal bleeding or clotting
Appropriate screening laboratory tests which may include CBC, PFA, PT, PTT, fibrinogen
Hemophilia is an X-linked congenital deficiency in the production of factor VIII (hemophilia A) or factor IX (hemophilia B). It presents with bleeding episodes of various severity, typically deep bleeds of joints or muscles. Hemophilia can be treated with factor replacement or, for mild factor VIII deficiency, DDAVP. For hemarthrosis the supportive therapy is equally important: Rest, Ice, Compression bandages, Elevation of the limb.
Von Willebrand disease is a disorder resulting from decreased levels or activity of vWFct. DDAVP, vWFct concentrates, and antifibrinolytic drugs are the mainstays of treatment.
The incidence of venous thromboembolism in children is on the rise as a result of more complex medical interventions, better imaging modalities, and increased awareness. Unfractionated heparin, LMWH, and warfarin are the main treatment options for management of venous thromboembolism.
DIC is a severe systemic disorder commonly seen in critically ill patients. Central to its management is treatment of the underlying cause, with blood products or platelet support as needed.
Gene therapy holds promise for patients with hemophilia because clinical impact can be realized by only partial replacement of the missing coagulation factor. The preliminary results of hemophilia B gene therapy trials are encouraging, though more questions have to be answered before this treatment will translate into clinical care.
New factor VIII and IX concentrate with prolonged half-life are in clinical trials. It is expected that these new medications will significantly change the treatment strategies in hemophilia.
New anticoagulants that directly inhibit thrombin or activated factor X are currently in use in adults. Argatroban is a direct antithrombin agent approved for use in the anticoagulation of children with heparin-induced thrombocytopenia.
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