87: Coagulation Disorders

Bleeding and thrombosis are the 2 extremes of the physiological process of coagulation disorders. Despite major differences in the levels of individual components of the hemostatic system, neonatal coagulation is equal to or somewhat more rapid than that observed in adults. This suggests the existence of a delicately balanced hemostatic system in neonates, with uncommon bleeding or thrombosis in healthy term infants. However, a number of perinatal or neonatal conditions can disrupt this balance and increase the risk for either hemorrhage or thrombus formation. The presence of bleeding in a healthy term or late preterm infant, especially in an infant with a normal platelet count, is strongly suggestive of a congenital bleeding disorder. Hemophilia A and B and von Willebrand disease account for 95–98% of congenital bleeding disorders.

1. The primary phase. The production of the platelet plug. This involves platelet adhesion (to the injured vessel's subendothelium) and their activation mediated by platelet surface glycoprotein (Ib, IIb/IIa) and von Willebrand factor (vWF).

2. The secondary phase. Results in the formation of a cross-linked fibrin clot. Coagulation proteins (factor XII to V) circulating as inactive precursor forms (zymogens) are converted to active forms through limited proteolysis. These activated proteins then further activate other zymogen factors in a chain reaction. Ultimately, the activation of factors V and X leads to cleavage of prothrombin (factor II) to thrombin (factor IIa). Cleavage of fibrinogen (factor I) to fibrin (factor Ia) by thrombin results in the formation of the blood clot.

3. The third phase. Modulates and limits the interactions of activated platelets and the clotting cascade (and Ca⁺²) that give rise to a clot. This includes the removal of activated factors (through the reticuloendothelial system) and the control of activated procoagulants by natural antithrombotic pathways (antithrombin III, protein C, protein S). Furthermore, restoration of vessel patency is triggered by the fibrinolytic pathway that generates plasmin from plasminogen. This is stimulated by tissue plasminogen activator and limited by α₂-antiplasmin and plasminogen activator inhibitor (PAI). Plasmin is a proteolytic enzyme that degrades fibrin into fibrin split products such as d-dimers. Defects in fibrinolytic factors that result in excessive plasmin generation can lead to bleeding.

1. Neonatal platelets are reported to be hypo-reactive; however, this deficiency is balanced by increased vWF activity, resulting in overall normal platelet function.

2. Factor VIII, factor V, fibrinogen, and factor XIII levels are normal at birth.

3. Vitamin K–dependent (factors II, VII, IX, and X) and contact factors (XI and XII) are reduced to about 50% of normal adult values and are further reduced in preterm infants. Similarly, concentrations of the naturally occurring anticoagulants antithrombin, protein C, and protein S are low at birth. As a consequence, both thrombin generation and thrombin inhibition are reduced in the newborn period.

4. Neonatal fibrinolytic activity is intact, despite the decreased concentrations and functional activity of plasminogen. Very low levels of histidine-rich glycoprotein (a physiologic inhibitor of plasminogen binding) and delayed inactivation of neonatal plasmin partially compensate for the reduced plasmin capacity. On the other hand, the increased plasma levels of PAI may explain the high rate of thromboembolic phenomena associated with intravascular devices in newborns. Most coagulation factors reached adult levels by 6 months of life with the exception of protein C levels, which remain low until later in childhood.

Correct interpretation of coagulation tests in the newborn is fraught with difficulties. The following precautions are needed for the appropriate interpretation of neonatal coagulation testing.

1. Gestational and postnatal age reference ranges. Vital to adequately interpret coagulation results in preterm and term neonates (Table 87–1).

2. A free-flowing blood specimen. Needs to be obtained from an atraumatic venipuncture. Samples obtained through intravascular catheters may be contaminated with heparin as it adheres tightly to the walls of the tubing. This sample contamination with trace amounts of heparin will result in a prolonged activated partial thromboplastin time (aPTT) and sometimes prothrombin time (PT), unless heparin is degraded in the specimen. Additionally, small clots can form within the catheter or at the tip, resulting in consumption of clotting factors and alteration of coagulation testing. Difficult venipuncture can hamper sample integrity and lead to platelet clumping that produces a falsely low platelet count.

3. Special sample tubes should be prepared for coagulation testing in infants with a hematocrit >55% or <25%. This allows for a correct amount of anticoagulant to be added to the blood sample (citrate-to-blood ratio of 1:9). Similarly, an insufficient filling of adequately citrated tube (<80%) can produce falsely prolonged coagulation time.

4. A stepwise approach to the neonate with suspected coagulation disorders is key to a correct diagnosis.

   1. Initial screening. Consists of a complete blood count (CBC) with platelets, PT/international normalized ratio (INR), aPTT, and fibrinogen level.

   2. Prolonged PT. Reflects decreased plasma concentrations of vitamin K–dependent factors.

   3. Prolonged aPTT. Results from decreased plasma levels of contact factors (V and VIII to XI) as well.

   4. Bleeding neonate who has no laboratory abnormality. Factor XIII and α₂-antiplasmin activity should be assessed.

   5. d-dimers. Elevated as an acute phase reaction in all patients with infection or systemic inflammatory response syndrome (SIRS). A negative d-dimer assay is relatively accurate in ruling out thrombosis.

1. Clinical presentation. Persistent oozing from the umbilical stump, excessive bleeding from peripheral venipuncture/heelstick sites, large caput succedaneum and cephalhematoma or subgaleal hemorrhage occurring without significant birth trauma history, and prolonged bleeding following circumcision are common presentations of neonatal bleeding disorders. The presence of an intracranial hemorrhage in a term or late preterm infant without history of birth trauma should be investigated for possible coagulation defect. Gastrointestinal bleeding must be distinguished from swallowed maternal blood (see DIC). Pulmonary hemorrhages are most frequently hemorrhagic pulmonary edema not associated with specific coagulation anomaly. Similarly, major abdominal organ bleeding such as liver or spleen are more often related to traumatic injury or local lesion (such as teratoma) than any coagulopathy.

2. Maternal, family, and neonatal history. A history of any prior pregnancies and their outcomes can be a clue for disorders such as neonatal alloimmune thrombocytopenia. Maternal medication use can also lead to immune-mediated thrombocytopenia. Parental ethnic background and whether there is consanguinity are significant. However, absence of family history for a bleeding disorder cannot exclude occurrence of severe bleeding disorders. Perinatal complications can result in coagulation activation and disseminated intravascular coagulation (DIC). Although giving vitamin K to neonates is almost a universal routine, it is still important to ascertain that the vitamin K was indeed administered.

3. Physical examination. An otherwise normal neonate with thrombocytopenia is suggestive of alloimmune thrombocytopenia. Skeletal abnormalities such as absence of thumb or radii are important clues for conditions such as thrombocytopenia with absent radii or Fanconi anemia. Cardiac defects may be associated with factor V deficiency. Delayed cord separation and persistent oozing from the umbilical stump is typical for infants with defective fibrinogen production or function and factor XIII deficiency. Acquired consumptive coagulopathy is generally a secondary event in a “sick” acting infant. Bacterial or viral infection and metabolic disorders (such as tyrosinemia) are a few of the conditions that need to be then considered.

Hemophilia A and B are inherited as sex-linked (X chromosome) recessive traits and are characterized by deficiencies of factor VIII or IX. However, one-third of cases will occur in the absence of a positive family history. Factor VIII deficiency is 5 times as common as factor IX deficiency.

Hemophilia A occurs in 1 per 5000 males, and hemophilia B occurs in 1 per 25,000 males; very rare in females.

Deficiency of factor VIII or IX interferes with coagulation cascade.

Male sex, family history of hemophilia or bleeding disorders.

The pattern of hemophilia-associated bleeding differs from that seen in older children. Hemarthroses are rare and many bleeds are iatrogenic in origin (eg, oozing or hematoma following venipuncture or vitamin K IM administration, prolonged bleeding following circumcision). Major bleeding, both intracranial (mostly subdural) and extracranial, is also occasionally seen. Severe factor VIII deficiency (factor VIII activity <1%) is the most common congenital coagulation disorder to present in the neonatal period. A third of cases will present with bleeding manifestations during the first month of life.

Screening coagulation test shows a prolonged aPTT while PT and platelets counts are within normal range. Factor VIII normally approaches adult level at birth, thus a low level reliably diagnoses hemophilia A. On the other hand, the diagnosis of moderate hemophilia B requires testing beyond the neonatal age as factor IX levels are low at birth (≈15%), reaching adult values at 2–6 months.

1. The treatment for hemophilia A or B is recombinant factor VIII or factor IX concentrate, respectively. Fresh frozen plasma should be used only in the instance of acute hemorrhage when confirmatory testing is not yet available.

2. Desmopressin (DDAVP) has been used for mild hemophilia A and for von Willebrand disease type 1 or 2 to increase release of factor VIII and vWF from endothelial stores. The antifibrinolytic agents ε-aminocaproic acid (Amicar) and tranexamic acid can be used in mucocutaneous bleeding to stabilize the fibrin clot and retard fibrinolysis. These agents are contraindicated in hematuria because of concerns about obstruction of urine flow by thrombi.

In most Western countries, people with hemophilia have a life expectancy not different from that of the male population without hemophilia. The optimal schedule for lifelong prophylaxis treatment continues to be controversial and onerous, and the development of inhibitors to factor VIII is still a major unresolved problem.

von Willebrand Disease (vWD) rarely presents during the neonatal period, because healthy neonates have higher plasma concentrations of von Willebrand factor (vWF) activity and an increased proportion of high-molecular-weight vWF multimers compared with adults. The condition is divided into 3 types. Type 3, an autosomal recessive disorder where vWF concentrations are almost absent, is the only type presenting with severe neonatal bleeding.

Isolated factor II, VII, X, VIII, or XIII deficiencies can present in the neonatal period. These rare coagulation deficiencies have an autosomal recessive inheritance (except factor XIII) and present with abnormal coagulation screening tests.

Vitamin K deficiency bleeding in the newborn.

Rare in the United States with routine administration of vitamin K.

Vitamin K, a fat-soluble vitamin, is required for γ-carboxylation of glutamic acid residues on precursors of vitamin K–dependent coagulation proteins (factors II, VII, IX, X, C, and S). Vitamin K exists in 2 forms: vitamin K₁ or phylloquinone (the plant form of the vitamin) and vitamin K₂, a series of compounds synthesized by bacteria and referred to as menaquinones. In contrast to human milk, infant formula contains large amounts of vitamin K (10 vs 65–100 mcg/L). Newborn infants are at risk for vitamin K deficiency because of vitamin K's poor placental transfer, insufficient endogenous production from the intestinal bacterial flora prior to complete colonization of the neonatal colon, and inadequate dietary intake among solely breast-fed infants.

Additional risk factors are liver disease, cholestasis, and maternal short-gut syndrome.

1. Mild vitamin K deficiency. Manifests as an isolated prolongation of PT, with more severe deficiency characterized by prolongation of aPTT. The diagnosis can be confirmed by high serum level of abnormal form of prothrombin (PIVKA-II).

2. Early vitamin K deficiency bleeding (VKDB). Occurs in the first 24 hours among infants born to mothers on oral anticoagulants, anticonvulsants, or anti-tuberculosis therapy and presents generally as serious bleeding such as intracranial hemorrhage (ICH).

3. Classic disease. Presents between days 1 and 7 with gastrointestinal bleeding, ICH, skin bruising, and bleeding following circumcision and tends to occur in infants who did not receive vitamin K at birth and are breast-fed or receiving inadequate overall milk intake. In the absence of vitamin K prophylaxis, the incidence of classic VKDB is 0.25–1.7%.

4. Late VKDB. Presents between 2 and 12 weeks of life. These infants are exclusively breast-fed infants who received none or only one oral dose of vitamin K, or have an associated disease process that interferes with the absorption or supply of vitamin K (intestinal malabsorption defects, cholestatic jaundice, cystic fibrosis, biliary atresia, α₁-antitrypsin deficiency). The majority of cases of late VKDB, whose incidence is 4–7 per 100,000 births, present with ICH.

No routine test is diagnostic. Increased PT with normal platelets and fibrinogen levels are typical.

1. Infants who present with a non–life-threatening bleed only need to be treated with vitamin K₁ given slowly by IV/SQ (no intramuscular [IM] injection) at a dose of 250–300 mcg/kg to restore PT to 30–50% of its normal value within an hour.

2. Treatment of serious bleeding includes fresh frozen plasma (FFP) (20 mL/kg), a prothrombin complex concentrate (50 U/kg), or recombinant factor VIIa (100 mcg/kg).

3. The American Academy of Pediatrics recommends that all infants receive 1 mg of IM vitamin K on the first day of life (0.3 mg for infants <1000 g and 0.5 mg for infants >1000 g but <32 weeks). This single parenteral dose prevents both classic and late VKDB.

4. The safety of IM vitamin K was questioned because of its reported possible association with increased incidence of childhood cancer. Subsequent studies have disproved this risk. Nevertheless, an alternative oral regimen of 2 mg dose at birth followed by a 1 mg dose given weekly for 3 months has been suggested. Its efficacy has not been well established.

Depends on the severity and location of the bleeding.

Disseminated intravascular coagulation (DIC) is the result of excessive and inappropriate activation of the hemostatic system related to exposure of blood to a source of tissue factor. It is a secondary manifestation of an underlying problem such as bacterial or viral infection, asphyxia, or necrosis.

The most common causes of DIC in the newborn are sepsis, severe respiratory distress syndrome, asphyxia, and necrotizing enterocolitis.

Massive thrombin generation with widespread fibrin deposition and consumption of coagulation proteins and platelets leads to multiple organ dysfunction.

Concurrent bacterial or viral infection, asphyxia, or necrosis.

The presence of DIC in a neonate without any evidence of sepsis or history of asphyxia should warrant the evaluation for a capillary hemangioma.

The diagnosis of DIC is made in an ill neonate with thrombocytopenia, prolonged PT and aPTT, reduced fibrinogen, and increased d-dimers.

1. The most important therapeutic intervention is to treat the underlying cause of the DIC.

2. Focus on the acute hematologic management is to support adequate hemostasis to limit hemorrhage. This is usually achieved with platelet transfusions, FFP, or cryoprecipitate, with a goal of maintaining platelets >50,000–100,000/μL, PT <3 seconds above the upper limit of normal, and fibrinogen >100 mg/dL.

3. Anticoagulant therapy is not generally used. The benefit has not proved to outweigh the added risk for hemorrhage.

4. The use of activated protein C is controversial (increased risk of ICH).

5. Recombinant factor VIIa (rFVIIa; 40–300 mcg/kg). This has been used successfully to treat severe bleeding in infants with DIC. In the presence of endothelial damage, rFVIIa binds to exposed tissue factor to activate factor X and thus generate thrombin. The potential for thrombotic complications makes its use limited to life-threatening hemorrhagic situations.

Related to the underlying cause of the DIC.

Vitamin K–dependent factors (II, VII, IX, and X) as well as factor V are synthesized by the liver, and hepatic damage can result in their lower levels. The diagnosis of acute liver disease should include elevated liver enzymes, direct hyperbilirubinemia, and elevated ammonia concentration. A low factor VII associated with low factor V will distinguish between vitamin K deficiency and hepatic dysfunction. A normal factor VIII may differentiate between liver disease and DIC where all clotting factors are depleted. On the other hand, liver disease may trigger DIC and ascites may lead to a loss of all clotting factors.

Systemic anticoagulation with heparin is performed during the duration of extracorporeal membrane oxygenation/extracorporeal life support (ECMO/ECLS) to minimize the potential for clotting within the circuit. Monitoring to prevent bleeding complications is essential. This is done by the activated coagulation time (ACT), a rapid, whole blood point-of-care test. Patients are usually maintained close to a target time of 200 seconds.

Thrombotic complications are more frequent in neonates than in any other pediatric age group. Depending on the type of thrombosis and screening methods used, incidence of 0.5 events per 10,000 live births or 2.4 clinically apparent events (excluding stroke) per 1000 neonatal intensive care unit (NICU) admissions have been reported.

An arterial ischemic stroke (AIS) is a cerebrovascular event occurring between 28 weeks of gestation and 28 days of birth with radiological or pathological evidence of focal arterial infarction of the brain.

The incidence of cerebral arterial occlusion may range from 0.5–1 per 1000 live births. Most occur within the middle cerebral artery of the left hemisphere.

Paradoxical embolism (through the foramen ovale) from the fetal placental circulation is believed to be the most common etiology. Clotting activation originating from the placenta could release thrombin or small fibrin clots into the fetal circulation.

Twin-to-twin transfusion syndrome, fetal heart rate abnormality, and hypoglycemia are independent risk factors.

Approximately 60% of the cases are perinatal AIS and present with symptoms in the first few days of life, chiefly seizures and apnea. AIS is the second most common underlying etiology of neonatal seizures in the full-term newborn. Presumed prenatal stroke, asymptomatic at birth, presents with asymmetrical motor development, hemiplegia, or seizures several months postnatally.

Magnetic resonance imaging (MRI) with diffusion weighted imaging is the most sensitive technique for the early detection of acute cerebral infarction. Magnetic resonance angiography allows for the detection of thrombosed cerebral vessels. Cranial ultrasound has a poor sensitivity for the detection of AIS.

In adults with AIS, recombinant tissue plasminogen activator (rTPA) has shown efficacy in restoring cerebral blood flow when delivered within 3 hours of its onset. In the neonate with AIS, the determination of time of onset is challenging, and there is currently no evidence for the efficacy of any form of anticoagulation treatment.

Many newborns with symptomatic AIS appear clinically normal after recovery from the acute event. On follow-up, one-third will exhibit hemiparesis and another third cognitive abnormalities affecting speech and language.

Arterial thrombosis is classified as catheter related or non-catheter related.

Spontaneous arterial thrombosis is extremely rare. The incidence of catheter (mostly umbilical arterial catheter [UAC])–related thrombosis has been reported as being as high as 30% depending on the method used for diagnosis (such as ultrasound, angiography). The incidence of major clinical symptoms attributable to UAC thrombus is ∼1–5% of catheterized infants.

Arterial thrombosis usually involves the aorta and tends to mimic congenital heart disease (such as coarctation). Iatrogenic arterial thrombosis is mainly related to complications from indwelling catheters.

Presence of UACs and peripheral arterial catheters.

Findings suggestive of an acute thrombosis include line dysfunction, extremity blanching and/or cyanosis, decreased pulse, and persistent thrombocytopenia.

Ultrasound Doppler is the method more frequently used in sick preterm infants, although contrast angiography may be more accurate when feasible.

1. Suspicion or confirmation of an arterial thrombosis. Warrants prompt removal of the catheter unless local instillation of TPA into the thrombus is contemplated.

2. Recommendations for UAC-related thrombosis. Treat with heparin. rTPA thrombolysis may be attempted for life-, limb-, or organ-threatening conditions (see Management).

Most symptomatology attributed to thrombus formation will resolve with prompt removal of the catheter.

Purpura fulminans (PF) is a rare syndrome of diffuse intravascular thrombosis and hemorrhagic infarction of the skin that is rapidly progressive and often fatal.

The incidence of severe protein C deficiency is 1 per 1,000,000 live births.

Based on severe genetic (or acquired) protein C and/or protein S deficiency. Acquired PF may result from conditions triggering acute reduction of protein C activity such as bacterial infection.

Protein C deficiency.

Extensive venous and arterial thrombosis with ecchymosis is present soon after delivery and can result in skin necrosis.

Laboratory tests yield results consistent with DIC (thrombocytopenia, hypofibrinogenemia, and increased PT and aPTT) and show no measurable protein C or S.

Early treatment is paramount for successful outcome and consists of FFP, protein C concentrate, or activated protein C and lifelong anticoagulation.

Purpura fulminans is associated with a high mortality rate.

Cerebral sinovenous thrombosis (CSVT) typically involves the thrombosis of cerebral veins or the dural sinus with cerebral parenchymal lesions or central nervous system (CNS) dysfunction.

The incidence of CSVT has been reported as 0.4 per thousand live births.

Thrombophilic factors (Table 87–2) may play a role in perinatal stroke. The superior and lateral sinuses are the most frequently involved vessels, and up to 30% of cases have venous infarction with subsequent hemorrhage.

Often associated with perinatal asphyxia, coagulopathy, maternal diabetes, and infection.

The symptoms of cerebral sinovenous thrombosis are those of a perinatal stroke and include seizures, apnea, and lethargy.

Diagnosis of CSVT is best made through diffusion MRI and MR venography.

Heparin anticoagulation is indicated only when there is evidence of thrombus propagation, multiple emboli, or a severe prothrombotic state, but is contraindicated in the presence of intracerebral hemorrhage.

Based on extent of cerebral defect.

Thrombus in a major vein in the upper or lower extremity with or without central extension.

The true incidence of neonatal deep vein thrombosis (DVT) is difficult to determine and many central venous lines (CVLs) related to venous thrombosis are clinically “silent.” Thrombosis and infection have been reported to occur in 2–22% of neonates with indwelling CVLs with a higher incidence reported in studies applying regular ultrasound screening.

Infants are at increased risk of thrombosis, with indwelling catheters further increasing the risk of venous thrombosis.

Nearly one-third of cases are associated with systemic infection, while prematurity is also correlated with higher prevalence of DVT. Other risk factors may include polycythemia, dehydration, repair of congenital heart disease, and hypoxia and parenteral nutrition.

Upper or lower venous DVT in neonates may present as swelling and discoloration of the associated limb, swelling of the face and head, chylothorax, and superior vena cava syndrome. Thrombocytopenia may be present.

Doppler ultrasound is the technique most frequently used for confirmation of neonatal DVT, although a venogram might be a more sensitive diagnostic method.

1. Suspicion or confirmation of a venous thrombus. This warrants prompt catheter removal. However, due to the risk for emboli, delaying CVL removal until 3 to 5 days after the start of anticoagulant therapy may be considered (controversial).

2. Anticoagulation and thrombolytic treatment is equally controversial. The decision needs to take into account the degree of threat to limbs or vital organs.

3. Role of thrombophilia screening in neonatal DVT. In light of its poor yield and the low risk and predictability of DVT recurrences, this remains controversial as well.

Short-term morbidities include pulmonary embolism and neonatal stroke from emboli or brain hemorrhagic infarction.

Thrombosis of the superior vena cava (SVC) with extension into the right atrium.

Right atrial thrombosis (RAT) accounts for 6% of all neonatal thromboses.

Despite early administration of aspirin, this has become a common complication in infants undergoing repair of complex congenital heart disease. There is a strong association of the location of the catheter tip in the right atrium and the development of RAT.

The most important is an indwelling CVL. Other associated risk factors include prematurity, administration of parenteral nutrition (PN), sepsis, and congenital heart disease.

More than half of the cases are asymptomatic and are detected incidentally during echocardiography performed for other reasons such as investigation for a persistent infection focus. The remaining cases may present with respiratory distress, new heart murmur, heart failure symptoms, or tachyarrhythmia.

The diagnostic method of choice for RAT is echocardiography. Documentation of the size, mobility, and shape of the thrombus, as well as the concomitant cardiac function are essential in helping to decide on treatment and predict outcome.

1. Asymptomatic and hemodynamically stable infants with small, immobile RATs may need no treatment except close echocardiography follow-up.

2. For symptomatic patient or RATs that are large, mobile, pedunculated, or snake shaped, treatment should include systemic anticoagulation therapy.

3. Thrombolytic therapy or surgical embolectomy may be indicated in life-threatening conditions.

Thrombolytic therapy in preterm infant with infective endocarditis carries a high risk for intracranial hemorrhage.

It is most common cause of non–catheter-associated thrombosis and usually presents in the first week of life.

Renal vein thrombosis (RVT) accounts for up to 10% of venous thromboses in newborns.

Unilateral left-sided RVTs are the most common.

Risk factors for the development of RVT include perinatal asphyxia, dehydration, maternal diabetes, and male sex.

The classic clinical triad of RVT includes hematuria, palpable abdominal mass, and thrombocytopenia. Other features include hypertension, proteinuria, and renal impairment. Patients with thrombus extension and caval occlusion may also develop bilateral lower limb edema.

The diagnosis of RVT is usually made via ultrasound (US) with Doppler. Ultrasonographic features of RVT include enlarged, echogenic kidneys with attenuation or loss of corticomedullary differentiation. Color flow Doppler shows absence of flow in the main or arcuate renal veins.

The treatment for RVT is controversial. Renal outcomes appear to be similar between supportive treatment and anticoagulation therapy. Similar proportions of affected kidneys that received supportive care or received anticoagulation became atrophic on follow-up. Possible exceptions to exclusive supportive treatment may include the following:

1. Low molecular weight heparin (LMWH) therapy for unilateral renal vein thrombosis with inferior vena cava extension for 6 weeks to 3 months. (See Complications.)

2. Bilateral RVT with caval extension may warrant thrombolytic therapy. (See Pharmacology.)

Acute complications of RVT include adrenal hemorrhage, extension of the clot into the inferior vena cava (IVC), renal failure, hypertension, and death. Chronically, cortical or segmental infarction of the affected kidney and/or hypertension is common.

Thrombus in the portal vein usually associated with umbilical vein catheterization.

The incidence of portal vein thrombosis (PVT) has been reported as 3.6 per 1000 NICU admissions. The incidence of PVT in neonates associated with the insertion of umbilical venous catheters (UVCs) varies between 1 and 43% depending on imaging protocols.

Hypercoagulability of the newborn coupled with UVC entering the liver in an area of relatively low flow.

Risk factors include umbilical infection as well as position of the tip of UVC. The UVC tip should be kept outside the low flow portal venous system and placed at the level of inferior vena cava/right atrium, or below the level of the umbilical-portal confluence. Its position needs to be ascertained by imaging.

Most thromboses in the portal venous system are clinically silent and spontaneously resolved within a short period of time after catheter removal.

Large studies have shown that PVT can usually be detected by ultrasound within the first week of a UVC insertion.

Use of anticoagulation is controversial (see Prognosis). For dosing see Management.

Long-term outcome of neonatal PVT and whether anticoagulation has any benefit in the outcome is unknown. Left lobe atrophy and portal hypertension are the most important sequelae. PVT is the major cause of extrahepatic portal hypertension in children, and a history of neonatal umbilical venous catheterization is frequently found among those children.

Thrombophilia is a term used to describe known inherited or congenital blood coagulation disorders that may predispose to thrombosis.

Rare.

Conditions that predispose to thrombophilia are noted in Table 87–2. Despite a high prevalence of multiple thrombophilic gene mutations, the majority of neonates with these traits do not develop thrombosis.

Central venous and arterial catheters constitute the greatest acquired risk for the development of thromboembolic events (TEs) in neonates in addition to those noted in Table 87–2.

Thrombophilia should be considered in any neonate who presents with thrombotic events or extensive thrombosis in the absence of identifiable environmental risk factors (intravascular catheter, neonatal sepsis, or shock).

The evaluation of a neonate with a significant TE for a prothrombotic disorder is controversial.

See below.

Neonates with multiple traits of thrombophilia and symptomatic thrombosis are at an increased risk for thrombus recurrence, although those usually occur in the setting of other comorbidities, such as infection, surgery, or trauma.

The optimal treatment modality for neonates with thrombosis is controversial. Information on treatment of neonatal thrombosis is limited to case reports and small case series. Dosing information is often extrapolated from children or adult data. Available options include observation, anticoagulation, thrombolytic therapy, and surgical thrombectomy. Treatment should be limited to clinically significant thrombosis with the goal of preventing clot expansion or embolism.

1. Pharmacology

   1. UFH is a heterogeneous mixture of negatively charged glycosaminoglycans with a molecular weight ranging from 5000 to 30,000 kDa. The anticoagulant properties are via conformational change in antithrombin (AT), converting it to a more efficient (1000-fold) inhibitor of factors IIa, IXa, Xa, XIa, and XIIa.

   2. The anticoagulant activity of heparin is variable because of the differential clearance of the various sizes of heparin moieties, as well as its propensity to bind to other positively charged noncoagulation proteins, as well as to platelets and endothelial surfaces.

   3. The most important anticoagulant actions of heparin are the potentiation of AT inhibition of thrombin (IIa) and factor Xa.

2. Dosage. See Table 87–3.

   1. The half-life of UFH, secondary to increased clearance, is short in neonates. Infants with the most significant thromboses demonstrate the highest clearance.

   2. The efficacy of UFH might be decreased in neonates because of the physiologically low antithrombin plasma concentration. Antithrombin supplementation with FFP is sometimes suggested.

   3. Neonates require continuous intravenous therapy. Higher doses than those used in older patients are required to achieve therapeutic adult aPTT levels. Anticoagulation is recommended for 10–14 days.

3. Monitoring

   1. The goal for anticoagulation is to maintain aPTT at 1.5–2 times the upper limit of age values. When feasible, anti–factor Xa level monitoring is preferable with its level kept at 0.3–0.7 U/mL.

   2. Following the initial dose, anti–factor Xa or aPTT level are assessed 4 or 6 hours later, respectively, and once daily thereafter. If the level of anticoagulation is below or above target values, the test is repeated 4–6 hours after appropriate dose adjustment. In general, a 10% rate adjustment is made when levels are inappropriate. An additional 50 U/kg may be given if aPTT is <50 seconds.

   3. A CBC, platelet count, and coagulation screening (including aPTT, PT, and fibrinogen) should be performed before starting UFH therapy. Platelet count and fibrinogen levels should be repeated daily for 2–3 days once therapeutic levels are achieved and twice weekly thereafter.

4. Complications

   1. The most important adverse effect from heparin therapy is bleeding. A 2% risk has been reported in term infants, and the risk is higher among preterm infants.

   2. Accidental overdose of UFH is a major safety issue. This occurs when an inappropriately diluted, supposedly low-dose UFH is used to flush a vascular access device.

   3. Heparin-induced thrombocytopenia (HIT) rarely occurs in neonates.

   4. Treatment of hemorrhage

      1. Usually, due to the UFH's short half-life, it only requires cessation of the infusion.

      2. If bleeding continues following cessation of the infusion. A full coagulation assessment should be performed and hemostatic deficiencies replaced as indicated.

      3. Protamine. One milligram of protamine will neutralize 100 U of UFH. The amount to be administered is according to the time elapsed since the last heparin injection. A full neutralizing amount is to be given if that time was <30 minutes. This dose is reduced by 50% for every hour past the last time heparin had been given. A repeat aPTT is required 15 minutes later.

5. Advantages over LMWH

   1. Because of its short half-life, it can be used as the first-line agent in patients whose anticoagulation may need to be stopped rapidly.

   2. Antidote (protamine sulfate) is available.

   3. At doses below 100 U/kg, its elimination is unaffected by renal dysfunction.

1. Pharmacology

   1. LMWH is a glycosaminoglycan of smaller molecular weight (2000–8000 kDa) than UFH. As such it lacks a binding site for thrombin.

   2. Primary action of LMWH. To potentiate the antithrombin inhibition of factor Xa with little effect on the antithrombin inhibition of thrombin. Consequently, aPTT is unaffected at therapeutic LMWH doses.

2. Dosage of LMWH (enoxaparin)

   1. Dosing recommendations for enoxaparin. 1.7 mg/kg every 12 hours in term neonates and 2.0 mg/kg every 12 hours in preterm neonates.

   2. LMWH can be administered by subcutaneous injection. Frequent needle pricks can be minimized with the use of an extremely low dead space subcutaneous catheter (Insuflon TM). Local bruising, induration, and leakage occur in 10% of neonates.

3. Monitoring. See Table 87–4.

   1. LMWH works largely by inhibiting factor Xa, thus dosing must be titrated to anti–factor Xa activity and not to the aPTT.

   2. The goal of treatment is to maintain an anti–factor Xa level of 0.5–1.0 U/mL.

   3. Levels should be obtained 4 hours after the second dose and then weekly.

4. Advantage over UFH. Low molecular weight heparin (specifically, enoxaparin) has become an increasingly popular alternative to UFH following studies in adults that demonstrated at least comparable efficacy and safety.

   1. Pharmacokinetics of LMWH are more predictable, making the need for monitoring less frequent.

   2. Lesser risk of bleeding complications.

   3. LMWH is given subcutaneously, which eliminates the requirement for intravenous access.

   4. LMWH has a lesser risk of heparin-induced thrombocytopenia as well a reduced risk of osteoporosis that is associated with long-term use of UFH.

The goal of thrombolytic therapy is to degrade fibrin and dissolve the fibrin clot. Systemic thrombolytic therapy should be strongly considered for clots that have a high risk of morbidity and mortality. The rate of vascular patency following anticoagulant therapy in older children has been reported at 50%; following thrombolysis, it is >90%.

1. Pharmacology

   1. Recombinant tPA, which facilitates conversion of plasminogen to plasmin to enhance degradation of fibrin, fibrinogen, and factors V and VII; it is the most commonly used agent.

   2. Systemic tPA is effective when administered within 2 weeks of symptomatic clot onset and is only partially effective beyond 2 weeks.

   3. Direct instillation of potent thrombolytic agents into clots via an infusion catheter has been shown to result in significant increases in vessel patency rates in adults. It also carries the potential advantage of less exposure to the bleeding risks of systemic thrombolysis.

2. Dosage. Based on a limited number of studies, the following protocol is proposed:

   1. Systemic low doses. Starting dose of 0.06 mg/kg/h with possible escalation up to 0.24 mg/kg/h over the next 48–96 hours.

   2. Alternatively use one of the following local treatments:

      1. Bolus. Initial dose of 0.5 mg/kg for 15 minutes to be followed by 0.1–0.4 mg/kg/h for a maximal period of 72 hours

      2. Single dose. 0.7 mg/kg over 30–60 minutes

   3. Repeat echocardiogram/Doppler every 6–8 hours to assess the presence of the clot to guide the escalation of thrombolytic treatment or its cessation.

   4. Heparin. Because thrombolysis does not inhibit clot propagation or directly affect hypercoagulability, simultaneous treatment with low-dose UFH (5–10 U/kg/h) or LMWH (0.5 mg/kg bid) is recommended.

   5. Plasminogen supplementation. Prolonged thrombolytic therapy is likely to exhaust the low plasminogen neonatal supplies more readily than in adults. With thrombolytic therapy lasting over 24 hours, consideration should be given to either monitoring plasminogen concentrations or empiric infusion of FFP (10–20 mL/kg) to optimize thrombolysis.

   6. Fibrinogen. Fibrinogen concentration decreases by 25–50% in response to systemic thrombolytic therapy. If fibrinogen concentrations are <100 mg/mL, dose reductions of the thrombolytic agent and infusion of replacement therapy in the form of cryoprecipitate or fresh frozen plasma should be considered.

   7. Platelet counts. Need to be maintained over 50,000.

   8. d-dimer and fibrinogen degradation product (FDP) plasma concentrations are expected to increase as a response to effective thrombolytic action.

   9. Daily head sonograms.

   10. Avoid IM injections and urinary catheterizations.

3. Exclusion criteria for tissue plasminogen activator (TPA) thrombolysis

   1. Major surgery or CNS bleeding within 10 days

   2. Major asphyxial event within 7 days (usually birth asphyxia)

   3. An invasive procedure within 72 hours

   4. Seizures within 48 hours

4. Adverse effects

   1. Bleeding complications have been reported in nearly two-thirds of pediatric patients; half of those patients required replacement blood transfusions.

   2. Most frequently, bleeding is at sites of invasive procedures. Gastrointestinal, pulmonary, and intraventricular hemorrhages are reported in about 1% of term infants and 14% of preterm infants.

   3. The frequency and severity of bleeding may be dose and duration (<6 hours) dependent.

   4. Concurrent low-dose heparin treatment and FFP (10 mL/kg) given a half hour before each TPA infusion may lessen those bleeding risks.

The small size of neonatal blood vessels, the rarity of thrombosis in neonates, and the severity of illness in neonates with thrombosis preclude the use of surgical thrombectomy in the majority of neonates. However, with the use of microsurgical techniques combined with thrombolytic regimens, thrombectomy has been successfully used in neonates in isolated cases.