Fibrinogen Deficiency.

Deficiency of fibrinogen is rare. Bleeding secondary to afibrinogenemia has been reported in newborns after circumcision or as umbilical stump bleeding and soft tissue hemorrhage, with some cases being fatal. Reported replacement therapies have included whole blood, cryoprecipitate, FFP, and fibrinogen concentrates. One fibrinogen concentrate (Haemocomplettan HS, Centeon/Aventis Behring) is available in Europe and North America.

Factor II Deficiency.

Deficiency of prothrombin is very rare. Reported bleeding complications in newborns include gastrointestinal bleeding and ICH. Reviews of adult patients have reported bleeding after invasive events such as circumcision and venipuncture or as soft tissue hematomas. Although FFP can be used as initial therapy, factor II concentrate or prothrombin complex concentrate (PCC) is the preferred replacement product.

Factor V Deficiency.

Bleeding as a result of severe factor V deficiency has been reported in newborns. Clinical manifestations include ICH, subdural hematoma, bleeding from the umbilical stump, gastric hemorrhage, and soft tissue hemorrhage. Replacement therapy includes whole blood and FFP. Although thrombotic complications occur in some patients with factor V deficiency, they have not been reported in newborns.

Factor VII Deficiency.

Severe factor VII deficiency (factor VII level <1%) usually causes significant bleeding equivalent to that seen in patients with severe hemophilia. Patients with factor VII levels greater than 5% generally have mild hemorrhagic episodes. The most commonly reported bleeding complication in newborns with congenital factor VII deficiency is ICH. In a review of 75 patients with factor VII deficiency, ICH was observed in 12 (16%). In 5 (42%) of these 12 patients, ICH occurred in the first week of life, with a fatal outcome. Congenital factor VII deficiency may occur in infants with Dubin-Johnson syndrome or Gilbert syndrome in certain populations. Bleeding episodes secondary to factor VII deficiency can be treated with FFP, PCC, purified factor VIIa concentrates, or, preferably, rFVIIa. Lower doses of rFVIIa (15 to 20 µg/kg) than those used for patients with severe hemophilia and high-titer inhibitors (90 µg/kg) are often sufficient to control bleeding in patients with factor VII deficiency. However, this has not been carefully defined in prospective clinical trials. Moreover, dosing has not been optimized for neonates and infants. Caution should be used in combining treatment with rFVIIa and PPC because thrombotic complications have been reported.

Factor VIII Deficiency.

The severity of factor VIII deficiency is determined by the plasma concentration of factor VIII, with a level of less than 1% being severe, 1% to 5% being moderate, and 5% to 50% being mild. Severe factor VIII deficiency is the most common inherited bleeding disorder of the neonatal period. In addition, a small number of neonates with moderate and mild hemophilia are seen after a hemostatic challenge. Large cohort studies have revealed that approximately 10% of children with hemophilia have clinical symptoms in the neonatal period. In this group of factor VIII–deficient children experiencing bleeding in the neonatal period, approximately 50% of bleeding episodes occur after circumcision, with almost 20% of patients suffering intracranial bleeding; some deaths also occur. In contrast to older infants and children, bleeding into joints is extremely rare in neonates. Severe factor VIII deficiency can, on rare occasion, occur in female infants as a result of homozygosity or compound heterozygosity for an FVIII gene mutation or skewed lyonization. Management of bleeding secondary to factor VIII deficiency is discussed in detail in Chapter 31 .

Factor IX Deficiency.

Classification of the severity of factor IX deficiency is identical to that used for factor VIII deficiency. Diagnosis of milder forms of factor IX deficiency is complicated by physiologic levels of factor IX that can be as low as 0.15 U/mL and, in rare infants, by the potential for concurrent VK deficiency. Bleeding after circumcision and ICH can occur in neonates with factor IX deficiency. Management of bleeding secondary to factor IX deficiency is discussed in detail in Chapter 31 .

Factor X Deficiency.

Severe factor X deficiency can be manifested as bleeding in the newborn period. ICH was present in a high proportion of reported cases, several of which were fatal. Additional sites of bleeding that have been noted include umbilical, gastrointestinal, and intraabdominal sites. Whole blood, FFP, factor X concentrate, and PCC have been used as replacement therapy.

Factor XI Deficiency.

Severe deficiency of factor XI is rare. It is different from other coagulation protein deficiencies in that bleeding symptoms are not necessarily tightly correlated with factor plasma concentrations. Bleeding complications as a result of severe factor XI deficiency were reported in two newborns. One bled after circumcision at the age of 3 days and had a factor XI level of 0.07 U/mL. In another newborn, factor XI deficiency with bilateral subdural hemorrhage was diagnosed prenatally. Either FFP or cryoprecipitate can be used for the treatment of factor XI–deficient patients if factor XI concentrate is not available.

Factor XIII Deficiency.

Severe factor XIII deficiency is typically manifested at birth as bleeding from the umbilical stump or ICH. Other clinical manifestations of homozygous factor XIII deficiency include delayed wound healing, abnormal scar formation, and recurrent soft tissue hemorrhage with a tendency to form hemorrhagic cysts. ICH occurs even in the absence of trauma in approximately a third of all affected patients. Newborns with heterozygous factor XIII deficiency are not clinically affected.

FFP, cryoprecipitate, or factor XIII concentrates can be used for the treatment of factor XIII–deficient patients. Newborns with known factor XIII deficiency should receive a prophylactic regimen of factor XIII because of the high incidence of ICH. Plasma concentrations of factor XIII greater than 1% are effective, and the very long half-life of factor XIII permits once-per-month therapy. Therefore prophylactic replacement therapy consists of either small doses of FFP (2 to 3 mL/kg) administered every 4 to 6 weeks, cryoprecipitate at a dose of 1 bag/10 to 20 kg of weight every 3 to 6 weeks, or, preferably, factor XIII concentrate at a dose of 10 to 20 U/kg every 4 to 6 weeks, depending on the clinical situation and the preinfusion plasma concentration of factor XIII.

Hereditary Deficiencies of Multiple Coagulation Factors.

Hereditary deficiencies of two or more coagulation proteins have been reported for 16 different combinations of coagulation factors. Combined deficiency of factors V and VIII has been described in patients with mutations in the genes encoding LMAN1 (also called ERGIC-53) and MCFD2. Administration of FFP is usually the initial therapy. Subsequent treatment varies, depending on the specific factors affected.

Epidemiology.

Thrombocytopenia is the most common hemostatic abnormality in newborns admitted to neonatal intensive care units (NICUs). A single prospective cohort study and six retrospective reviews have provided the most reliable information on the occurrence, natural history, mechanisms, and clinical impact of thrombocytopenia in newborns. There is general agreement that thrombocytopenia indicates the presence of an underlying pathologic process; however, the clinical relevance of mild thrombocytopenia is unknown. Thrombocytopenia develops in approximately 22% to 35% of infants and approximately 75% of extremely low birth weight neonates admitted to the NICUs of tertiary hospitals. In some infants the thrombocytopenia is trivial, with platelet counts between 100 and 150 × 10 ⁹ /L. However, in 50% of affected infants, platelet counts decrease to less than 100 × 10 ⁹ /L, and in 20% of infants, platelet counts are lower than 50 × 10 ⁹ /L. What constitutes a safe platelet count in a neonate remains to be rigorously determined, but many neonatal units attempt to keep the platelet count higher than 50 × 10 ⁹ /L, although this figure may vary, depending on the postconceptional age of the infant and comorbid conditions.

Pathogenesis.

Causes of thrombocytopenia in neonates, like those in older children and adults, can be divided into disorders involving increased platelet destruction, decreased platelet production, or sequestration ( Box 5-1 ). Although many of these causes overlap with those seen in older children and adults, several entities are unique to neonates or may occur in the newborn period and are considered in more detail here. Increased platelet destruction is the mechanism responsible for thrombocytopenia in most infants. Characterization of mechanisms responsible for thrombocytopenia is important because they have practical implications in assessing the risk for bleeding and in guiding management.

Increased Platelet Destruction.

Thrombocytopenia secondary to increased platelet destruction can be divided into immune and nonimmune causes.

Immune Thrombocytopenia.

Immune thrombocytopenia is defined as an increased rate of platelet clearance caused by platelet-associated immunoglobulin G (IgG) or complement. It is the most common form of increased platelet destruction in newborns and should always be suspected in otherwise healthy infants with isolated severe thrombocytopenia. Neonatal immune thrombocytopenia can be further broken down into one of three processes: transplacental passage of a maternal antibody directed against a nonshared platelet antigen (termed alloimmune thrombocytopenia or, sometimes, isoimmune thrombo­cytopenia), transplacental passage of a cross-reactive maternal autoimmune-derived antiplatelet antibody, or generation of an autoreactive antiplatelet antibody by the newborn itself (termed autoimmune thrombocytopenia). The second can be distinguished from the other two by examining the mother for a low platelet count. Differentiation of autoimmune thrombocytopenia from alloimmune thrombocytopenia in neonates is critical because the management and severity of these disorders are quite different. Chapter 34 discusses these two forms of immune thrombocytopenia and their management in detail.

Neonatal Alloimmune Thrombocytopenia.

Neonatal alloimmune thrombocytopenia (NAIT) is the most common cause of immune-mediated thrombocytopenia in the newborn period, with an estimated incidence of about 1 in 1000 to 5000 live births in white populations. It arises when the mother, who lacks a common platelet antigen, is exposed to the antigen (inherited from the father) on neonatal platelets and generates a neutralizing IgG. This crosses the placenta and mediates premature clearance of fetal and newborn platelets. First-born infants can be affected. Frequently, the thrombocytopenia is severe. It is critical to make the diagnosis because the risk of life-threatening bleeding and central nervous system morbidity is high, estimated at up to 10% to 15% of cases. A useful diagnostic test is to assay the reactivity of the mother’s serum with the father’s platelets. If such samples are not available, it is possible to look for reaction of the mother’s serum with the newborn’s platelets or the presence of antiplatelet antibodies in the newborn’s serum. The most common antigen is HPA-1a (formerly called Pl ^A1 ), although other antigens, such as HPA-3a (formerly called Bak ^a ), HPA-4a (formerly called Pen ^a [more common in Asian populations]), HPA-5a (formerly called Br ^b ), and HPA-5b (formerly called Br ^a ), have been described. Not all cases in which the pregnant mother generates allosensitive antiplatelet antibodies result in neonatal thrombocytopenia.

Treatment of NAIT includes transfusion with washed platelets donated by the mother. Because the mother’s platelets lack the offending antigen, they should have a normal life span. Many blood banks also maintain registries of HPA-1a–negative donors who can be contacted for platelet donation in cases involving antibodies against HPA-1a. If antigen-negative platelets are not available, treatment with intravenous immunoglobulin, 1 g/kg as a single daily bolus for 1 or 2 consecutive days, along with random donor platelets if the patient is bleeding, is effective in reducing the rate of platelet destruction. Endogenous platelet counts typically rise by 36 to 48 hours. The role of corticosteroids in the treatment of infants with NAIT is unclear, and they are typically not used as initial therapy. All infants with NAIT should undergo head ultrasonography or computed tomography to rule out ICH. The natural history of NAIT is gradual resolution of the thrombocytopenia over the first few months of life as the offending antibody is cleared. Close monitoring of the platelet count is indicated for at least the first month of life until the platelet count normalizes. The safety of breastfeeding in the setting of NAIT has not been rigorously studied. One case report suggested that breastfeeding did not significantly worsen the clinical course, even though the breastmilk contained antiplatelet IgG.

Immune Thrombocytopenia Caused by Maternal Antiplatelet Autoantibodies. Maternal autoimmune antiplatelet IgG can cross the placenta and result in increased platelet destruction in the fetus. A common cause is maternal systemic lupus erythematosus. Like NAIT, the thrombocytopenia gradually resolves over the first few months of life as the maternal antibodies are cleared. In severe cases, use of intravenous immunoglobulin in the neonate may help reduce the rate of platelet destruction. Corticosteroids are of no clear utility. Drug-dependent antibodies can result in both maternal and neonatal thrombocytopenia.

Autoimmune Thrombocytopenia.

True autoimmune thrombocytopenia, in which neonates generate an antibody against their own platelets, is very rare in the newborn period. If present, it typically signals an underlying immune dysregulatory disorder. If heparin-induced thrombocytopenia is suspected, heparin therapy should be discontinued immediately and alternative forms of anticoagulation considered if necessary (see Chapter 34 ).

Sepsis and Disseminated Intravascular Coagulation.

A common nonimmune cause of thrombocytopenia in the newborn period is sepsis, with or without DIC. Viral infections (rubella virus, herpesvirus, echovirus, cytomegalovirus, human herpesvirus 6, and human immunodeficiency virus), protozoal infections (Toxoplasma), and bacterial infections cause severe thrombocytopenia. Mechanisms responsible for bacterial sepsis–induced thrombocytopenia are multifactorial and include consumption resulting from DIC, endothelial damage, platelet aggregation caused by binding of bacterial products to platelet membranes, and decreased production as a result of marrow infection. Mechanisms responsible for virus-induced thrombocytopenia include loss of sialic acid from platelet membranes because of viral neuraminidase, intravascular platelet aggregation, and impaired megakaryopoiesis (see later). Congenital rubella causes thrombocytopenia in three quarters of infants, with platelet counts ranging from 20 to 60 × 10 ⁹ /L for the first 4 to 8 weeks of life.

In premature infants, thrombocytopenia often complicates other disorders such as RDS, persistent pulmonary hypertension, necrotizing enterocolitis, and hyperbilirubinemia treated by phototherapy. Activation of coagulation with platelet consumption occurs in RDS, and mechanical ventilation may be an independent factor contributing to thrombocytopenia. It has been suggested that persistent pulmonary hypertension in newborns may be due in part to intrapulmonary platelet aggregation and the release of platelet-derived vasoactive substances such as thromboxane A ₂ . Approximately half of infants with necrotizing enterocolitis are thrombocytopenic, with about 20% having laboratory evidence of DIC.

Exchange Transfusion, Hyperbilirubinemia, and Phototherapy.

Intrauterine and exchange transfusions cause thrombocytopenia by a dilutional effect that depends on the amount of blood transfused. After exchange transfusion, platelet counts increase within 3 days and reach preexchange levels by about 7 days. Both hyperbilirubinemia and phototherapy are associated with mild thrombocytopenia in newborn humans and shortened platelet survival in rabbits.

Hypoxia and Placental Insufficiency.

Acute asphyxia is a consistent cause of DIC and thrombocytopenia. Chronic hypoxia is associated with placental dysfunction, intrauterine growth retardation, and significant thrombocytopenia.

Vascular Malformations.

Certain types of large vascular malformations are associated with Kasabach-Merritt syndrome, in which a local consumptive coagulopathy occurs as a result of abnormal endothelium. This causes hypofibrinogenemia, elevated levels of fibrinogen-fibrin degradation products, microangiopathic fragmentation of red cells, and thrombocytopenia (see Chapter 34 ). The thrombocytopenia can be severe, with platelet counts lower than 50 × 10 ⁹ /L. Approximately 50% of affected infants experience systemic bleeding during the first month of life. Sometimes the vascular malformations are not apparent on physical examination and require imaging studies to detect.

Thrombosis and Familial Thrombotic Thrombocytopenic Purpura.

Thrombocytopenia is loosely associated with thromboembolic complications and polycythemia in infants with hematocrit values greater than 70%. However, thrombocytopenia may also indicate the presence of other concurrent disease processes. Infants with a familial form of hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura have a microangiopathic hemolytic anemia in association with transient neurologic or renal abnormalities (see Chapter 34 ).

Decreased Platelet Production.

Thrombocytopenia secondary to decreased platelet production is rare and accounts for less than 5% of thrombocytopenic infants. Causes include viral infections, drug-induced thrombocytopenia, congenital leukemia, Down syndrome transient myeloproliferative disorder (DS-TMD), neuroblastoma, histiocytosis, osteopetrosis, congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia with absent radius syndrome (TAR), other inherited genetic platelet disorders, and bone marrow failure syndromes.

Disorders with Small Platelets

Disorders with Normal-Size Platelets

Disorders with Large Platelets

Clinical Impact of Neonatal Thrombocytopenia.

Clinically important bleeding is less likely to occur in patients with consumptive platelet disorders than in those with production defects. The bleeding risk is increased in patients who have both thrombocytopenia and a defect in platelet function. Selection of a platelet count at which one should intervene, though a simplistic response, provides a guideline for therapy. A platelet count less than 50 × 10 ⁹ /L places some otherwise healthy full-term newborns at risk for serious ICH. The importance of “moderate” thrombocytopenia (platelet counts between 50 and 100 × 10 ⁹ /L) in sick premature infants has been a subject of controversy. A randomized, controlled trial assessed the potential benefits of platelet concentrate transfusions in 154 premature thrombocytopenic infants during the first 72 hours of life. Treated infants received platelet concentrates to maintain platelet counts higher than 150 × 10 ⁹ /L. No beneficial effect on the incidence or extension of ICH was shown in this study, which was designed to detect an effect of 25% or greater. However, infants who received transfusions had shortened bleeding times and required significantly less blood product support. A retrospective study of 53 neonates with severe thrombocytopenia treated at a single NICU showed no significant difference in major hemorrhage in those transfused to maintain a platelet count greater than 30 × 10 ⁹ /L versus greater than 50 × 10 ⁹ /L.

Treatment.

Management of thrombocytopenic infants depends in part on the underlying disorder. If an infant is bleeding, a trial of platelet concentrates (10 to 20 mL/kg) is indicated. The increased platelet count usually shortens the bleeding time and is frequently clinically effective. Autoimmune and alloimmune thrombocytopenia typically does not respond to random donor platelet concentrates and requires additional specific forms of therapy.

Thrombocytosis in the Newborn.

Elevated platelet counts are frequently observed in premature infants at approximately 4 to 6 weeks after birth. There are no clinical manifestations of neonatal thrombocytosis, and therapeutic intervention is not indicated.

Phototherapy.

When platelets are exposed to a broad-spectrum blue fluorescent light in vitro, aggregation is decreased and microscopic alterations in granules and external membranes occur.

Medications

Maternal Diabetes.

The reactivity of platelets from diabetic mothers and their infants is increased, as demonstrated by enhanced thromboxane B ₂ production, enhanced platelet aggregation, and a lower threshold to many aggregating agents. The enhanced platelet function in diabetes is associated with increased synthesis of a prostaglandin E–like substance that crosses the placenta and affects the fetus. Despite these in vitro findings, the evidence linking enhanced platelet reactivity to clinically significant thromboembolism in newborns of diabetic mothers is weak.

Diet.

Alterations in the diet of mothers or infants during the postnatal period can affect newborn platelet function. Increases in the ratio of polyunsaturated fatty acids to saturated fatty acids in the diet of mothers who breastfeed their infants result in increases in the concentration of linoleic acid and enhanced thromboxane B ₂ production. Infants receiving a diet deficient in essential fatty acids may exhibit arachidonic acid depletion and platelet dysfunction. Vitamin E functions as an antioxidant and as an inhibitor of platelet aggregation/release in humans. Instances of vitamin E–deficient infants with increased platelet aggregation that reversed after vitamin E supplementation have been reported.

Amniotic Fluid.

Amniotic fluid contains procoagulant activity that enhances the generation of thromboxane A ₂ by platelets. Infants in whom perinatal aspiration syndrome develops have pulmonary hypertension with platelet thrombi in the pulmonary microcirculation. The exact mechanism or mechanisms leading to persistent pulmonary hypertension in these infants is unknown.

Nitric Oxide.

Nitric oxide prevents adhesion of platelets to endothelial cells and inhibits ADP-induced aggregation of cord platelets in a manner similar to that in adults.

Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) permits transfer of oxygen into blood across a semipermeable membrane and is currently used for infants with life-threatening severe respiratory insufficiency. Underlying respiratory disorders include meconium aspiration syndrome, severe RDS, congenital diaphragmatic hernia, persistent pulmonary hypertension, and sepsis. Hemorrhage, particularly ICH, is one of the most serious complications of this technique. Hardart and Fackler reported an overall incidence of new ICH of about 10% in infants included in the Extracorporeal Life Support Organization Registry (N = 4550) from 1992 through 1995. Of 1398 evaluable premature infants (born at <37 weeks’ EGA) reported to the registry between 1992 and 2000, ICH developed in 13%. Similar to that found with cardiopulmonary bypass, the increased risk of bleeding during ECMO is due mostly to the use of heparin in combination with other hemostatic defects, including significantly decreased plasma concentrations of coagulation factors and platelet dysfunction secondary to chronic activation. Other recognized contributing factors include prolonged hypoxia, ischemia, general anesthesia, acidosis, sepsis, and treatment with epinephrine. In premature infants, the risk for ICH with ECMO correlates inversely with postconceptional age. Although anticoagulation is required for ECMO, the optimal use of heparin has never been tested in clinical trials.

Clinical Findings.

The classic clinical manifestation of homozygous protein C/protein S deficiency consists of cerebral or ophthalmic damage (or both) in utero, purpura fulminans within hours or days of birth, and, on rare occasion, large-vessel thrombosis. Purpura fulminans is an acute, lethal syndrome of DIC characterized by rapidly progressive hemorrhagic necrosis of the skin secondary to dermal vascular thrombosis. The skin lesions start as small, ecchymotic sites that increase in radial fashion, become purplish black with bullae, and then turn necrotic and gangrenous. The lesions develop mainly on the extremities but can occur on the buttocks, abdomen, scrotum, and scalp. They also occur at pressure points, at sites of previous puncture, and at previously affected sites. Moreover, affected infants have severe DIC with hemorrhagic complications. Large-vessel arterial thromboses have been described in a neonate with homozygous AT deficiency.

Diagnosis.

The diagnosis of homozygous protein C/protein S deficiency in infants is based on the appropriate clinical picture, a protein C/protein S level that is usually undetectable, a heterozygous state in the parents, and, ideally, identification of the molecular defect. The presence of very low levels of protein C/protein S in the absence of clinical manifestations and a family history cannot be considered diagnostic, because physiologic plasma levels can be as low as 0.12 U/mL. Molecular diagnosis is available for identified families (see Chapter 33 ).

Initial Treatment.

The diagnosis of homozygous protein C/protein S deficiency is usually unanticipated and made at the time of clinical evaluation. Although numerous forms of initial therapy have been used, 10 to 20 mL/kg of FFP every 6 to 12 hours is usually the form of therapy that is most readily available. Plasma levels of protein C achieved with these doses of FFP vary from 15% to 32% at 30 minutes after the infusion and from 4% to 10% at 12 hours. Plasma levels of protein S (which was entirely bound to C4b) were 23% at 2 hours and 14% at 24 hours, with an approximate half-life of 36 hours.

A protein C concentrate (Ceprotin) received approval by the Food and Drug Administration in 2007 for use in treating congenital protein C deficiency. A second plasma-derived concentrate (Protexel) is also available in Europe. Recommended initial doses for acute thrombotic episodes and short-term prophylaxis in patients with severe protein C deficiency are 100 to 120 IU/kg in neonates, with subsequent doses of 60 to 80 IU/kg every 6 hours and maintenance doses of 45 to 60 IU/kg thereafter every 6 to 12 hours. However, dosing should be adjusted to maintain trough protein C activity of 50%. After resolution of the acute event, the patient should continue on a dose to maintain the trough protein C activity level above 25% for the duration of treatment. Replacement therapy should be continued until all the clinical lesions resolve, which usually takes place at 6 to 8 weeks. In addition to the clinical course, plasma D-dimer concentrations may be useful for monitoring the effectiveness of protein C replacement.

Long-Term Therapy.

Modalities used for the long-term management of infants with homozygous protein C/protein S deficiency include oral anticoagulation therapy, replacement therapy with either FFP or protein C concentrate, or liver transplantation. When oral anticoagulation therapy is initiated, replacement therapy should be continued until the international normalized ratio (INR) is at a therapeutic value so that skin necrosis can be avoided. The therapeutic range for the INR can be individualized to some extent but is usually between 2.5 and 3.5. Risks associated with oral anticoagulation therapy include bleeding with high INR values and recurrent purpuric lesions with low INR values. Frequent monitoring of INR values is required if these complications are to be avoided. Bone development should also be monitored because the long-term effect of warfarin use on the bones of young infants is unknown. Long-term use of low–molecular-weight heparin (LMWH) could be considered, but it also has the potential for osteopenia. Moreover, it is expensive and requires twice-daily subcutaneous injections.

Treatment.

Treatment consists of supportive therapy alone, anticoagulation with heparin, thrombolytic therapy, and replacement with specific factor concentrates. Removal or treatment of the secondary acquired insult is important. For AT deficiency, AT concentrates were administered to four infants as either boluses or continuous infusions. Boluses of 52 and 104 U/kg of AT concentrate increased AT levels from 0.10 U/mL to 0.75 and 1.48 U/mL, respectively, at 1 hour. At 24 hours, levels of AT had decreased to approximately 0.20 U/mL. A continuous infusion of AT concentrate at a rate of 2.1 U/kg/hr maintained a plasma level of 0.40 to 0.50 U/mL.

Diagnosis.

Contrast-enhanced angiography is considered the reference test for the diagnosis of arterial thrombosis. Noninvasive techniques such as Doppler ultrasound offer advantages, but their sensitivity and specificity are unknown. A review of 20 neonates with aortic thrombosis treated in one institution revealed that ultrasound failed to identify thrombi in four patients, three of whom had complete aortic obstruction.

Sequelae.

The sequelae of catheter-related thrombosis can be immediate or long term. Acute symptoms reflect the location of the catheter and include renal hypertension, intestinal necrosis, and peripheral gangrene. The long-term side effects of symptomatic and asymptomatic thrombosis of major vessels have not been studied but are probably significant.

Prophylaxis with Heparin.

A low-dose continuous heparin infusion (3 to 5 U/hr) is commonly used to maintain catheter patency. The effectiveness of heparin was assessed in seven studies focusing on three outcomes: patency, local thrombus, and ICH. Patency, which is probably linked to the presence of local thrombus, is prolonged with the use of low-dose heparin. Local thrombosis was assessed by ultrasound in two randomized studies. The evidence linking low-dose heparin prophylaxis to ICH in newborns is weak. One study had a sample size of only 15 per arm ; another case-control study had a broad odds ratio that ranged from 1.4 to 11 ; and a third study was a retrospective association analysis that may be confounded by other variables. A randomized study involving 113 premature infants using a 1-U/hr continuous heparin infusion showed no difference in ICH. Thus the magnitude of risk for ICH is uncertain. Heparin is used in at least three quarters of American nurseries.

Clinical Findings and Etiology.

The initial symptoms and clinical findings are different in neonates and older patients and are influenced by the extent and rapidity of thrombus formation. Neonates generally have a flank mass, hematuria, proteinuria, thrombocytopenia, and impaired function of the involved kidney. Clinical findings suggesting acute inferior vena cava thrombosis include cold, cyanotic, and edematous lower extremities. RVT results from pathologic states characterized by reduced renal blood flow, increased blood viscosity, hyperosmolality, or hypercoagulability.

Coagulation Abnormalities.

The most common coagulation abnormality in RVT is thrombocytopenia, which is usually mild, with average values of 100 × 10 ⁹ /L. Thus RVT should be considered in the differential diagnosis of thrombocytopenia in neonates. Coagulation may be prolonged and levels of fibrinogen-fibrin degradation products increased. Children with RVT are often evaluated for a congenital prothrombotic disorder, although the significance of thrombophilic markers in this disease is unknown.

Diagnosis and Treatment.

Ultrasound is the radiographic test of choice for the diagnosis of RVT because of ease of testing and sensitivity to an enlarged kidney. Treatment options include supportive care, anticoagulation, and thrombolytic therapy. The use of anticoagulants and thrombolytic agents is controversial. Evidence-based guidelines have recently been published. Either supportive care with serial radiographic monitoring or heparin therapy with therapeutic doses for 6 weeks to 3 months should be considered for unilateral RVT in the absence of uremia and extension into the inferior vena cava. Heparin therapy with therapeutic doses for 6 weeks to 3 months is recommended for unilateral RVT that extends into the inferior vena cava or for bilateral RVT because of the risk of pulmonary embolism and complete renal failure. Thrombolytic therapy should be considered in the presence of bilateral RVT and renal failure. Thrombectomy, though a common therapeutic choice in the past, is rarely indicated.

Outcome.

RVT has changed from a frequently lethal complication to one that is now associated with nearly 100% survival. However, there are considerable long-term renal sequelae, with approximately 70% of affected kidneys having irreversible atrophy, approximately 20% of children having hypertension, and approximately 3% of children having chronic renal failure.

Age-Dependent Features.

Although the benefits of heparin therapy in newborns are probably similar to those in adults, the relative risk that major bleeding will occur with its use may be increased. Infants with thromboses that are extending or infants whose organ or limb viability is threatened by thrombosis may benefit from heparin therapy.

Heparin’s anticoagulant activities are mediated primarily through acceleration of inhibition of thrombin and factor Xa by AT. Although dosing for heparin therapy in newborns differs from that in adults, optimal dosing cannot be predicted. Several observations suggest that the heparin requirements of neonates are decreased in comparison to those of adults. First, the capacity of plasma from healthy newborns to generate thrombin is both delayed and decreased in comparison to that of adult plasma, but similar to that of plasma from adults receiving therapeutic amounts of heparin. Second, at heparin concentrations in the therapeutic range, the capacity of plasma from healthy newborns to generate thrombin is barely measurable. Third, the amount of clot-bound thrombin is decreased in newborns because low plasma concentrations of prothrombin probably reduce heparin requirements. Observations suggesting higher heparin requirements include the following: (1) clearance of heparin is accelerated in newborns, and (2) plasma concentrations of AT are decreased to levels frequently less than 0.40 in premature infants, which may limit heparin’s antithrombotic activities.

Therapeutic Range and Dose.

Therapeutic ranges reflect the optimal risk-benefit ratio of anticoagulant therapy with regard to recurrent thrombotic events and bleeding complications. In the absence of clinical trials in newborns, one approach is to use heparin in doses that achieve the lower therapeutic range for adults (see Chapter 33 ).

General guidelines for initial dosing and subsequent dose adjustment of unfractionated heparin in full-term and premature neonates have been published. Average doses of heparin required in newborns are bolus doses of 25 to 100 U/kg, depending on gestational age, and average maintenance doses of 15 to 28 U/kg/hr, again depending on gestational age. Adjustments are made most reliably with heparin assays, with a target-level anti-Xa range of 0.35 to 0.70 U/mL. Because of the short half-life of unfractionated heparin, simple discontinuation of the infusion is typically sufficient to reverse anticoagulation in the event of hemorrhage. For more rapid reversal, protamine sulfate can be used to neutralize heparin in vivo. However, anaphylactoid reactions with hypotension and bradycardia have been associated with protamine use in children and adults, and protamine should therefore be used with caution.

The use of LMWH offers significant therapeutic advantages over unfractionated heparin, and there is now considerable experience using these preparations in newborns. Potential advantages include more predictable pharmacokinetics, the need for less frequent monitoring than with unfractionated heparin, ease of administration, decreased bleeding, and possibly a lower incidence of heparin-induced thrombocytopenia. Full-term and moderately preterm (28 to 36 weeks EGA) infants metabolize heparin at considerably faster rates than older children and adults do and typically require higher doses to maintain the same levels. Very premature infants (<28 weeks) have similar pharmacokinetic parameters for heparin as do older children and adults. General guidelines for initial therapeutic dosing and subsequent sliding-scale dose adjustments of LMWH in neonates of different gestational ages have been published. Typically, higher doses of LMWH are required in neonates compared with adults to achieve the same anti-Xa levels. Traditional doses of enoxaparin in full-term neonates for full anticoagulation are 1.5 mg/kg given subcutaneously every 12 hours, but they can be as high as 2 mg/kg given subcutaneously every 12 hours in preterm neonates. Levels should be monitored with anti-Xa heparin assays on samples drawn via fresh venipuncture 4 to 6 hours after the subcutaneous dose is given to achieve levels of 0.5 to 1 U/mL for full therapeutic dosing. Levels should be checked every two to four doses for the first week of therapy, then once a week for a month, and then monthly if the infant is stable. Infants who do not respond appropriately to heparin therapy, despite adequate levels, may benefit from infusions of AT concentrate, even if the levels are close to the normal physiologic range for their age. Intramuscular and arterial puncture and the use of antiplatelet medications should be avoided in newborns receiving heparin therapy, and platelet counts should be monitored periodically.

Like unfractionated heparin, LMWH can be reversed with the use of protamine, with dosing dependent on the last dose of LMWH given. As discussed earlier, protamine must be given slowly, and caution must be exercised to avoid potential hypersensitivity reactions. Repeat doses of protamine may be required to reverse the effects of LMWH because the half-life of protamine is relatively shorter than that of LMWH.

Close monitoring of the thrombus with objective means such as ultrasound is recommended. The duration of heparin therapy required for the treatment of thromboembolic complications is uncertain. One approach is to treat the infant for 10 to 14 days with heparin alone. If there is subsequent extension of the thrombus in the absence of anticoagulation therapy, treatment with oral anticoagulants may be considered.

Adverse Effects.

There are two clinically important adverse effects of heparin therapy: hemorrhage, including ICH, and heparin-induced thrombocytopenia. In the absence of an alternative cause, thrombocytopenic patients should be evaluated for heparin-induced thrombocytopenia and treated with alternative therapies.

Age-Dependent Features.

Oral anticoagulation therapy in children is discussed in Chapter 33 , and only specific issues related to newborns are discussed in this section. The oral anticoagulant warfarin works by reducing functional plasma levels of the VK-dependent proteins. At birth, levels of the VK-dependent proteins are similar to those found in adults receiving therapeutic amounts of warfarin for deep venous thrombosis/pulmonary embolism. In addition, stores of VK are low, and a small number of newborns have evidence of functional VK deficiency. These features significantly increase the sensitivity of newborns to warfarin and potentially their risk for bleeding. Oral anticoagulant therapy should be avoided when possible during the first month of life. Unfortunately, a small number of infants require extended anticoagulation therapy, and heparin cannot be used for extended periods because of the risk of osteopenia.

Indications, Therapeutic Range, and Dose.

The optimal therapeutic INR range is unknown for newborns and almost certainly differs from that for adults. Recommendations for oral anticoagulation therapy in adults can be used as a guideline for determining the lowest effective dose, which to some extent can be individualized. Maintenance doses for warfarin are age dependent, with infants requiring the highest doses (0.32 mg/kg).

Adverse Effects.

Close monitoring of oral anticoagulation in newborns is required if both hemorrhagic and recurrent thrombotic complications are to be prevented. Unfortunately, these infants often have poor venous access, as well as complicated medical problems. Weekly or biweekly INR measurements and frequent dose adjustments are required. Doses are affected by diet, medications, and intercurrent illnesses. Breastfed infants are very sensitive to oral anticoagulants because of low concentrations of VK in breastmilk. Daily supplementation of breastfed infants with small amounts of commercial formulas reduces their sensitivity to oral anticoagulants and the risk of sudden increases in INR values. In contrast to breastfed infants, infants receiving commercial formulas or total parenteral nutrition are resistant to oral anticoagulants because of VK supplementation. Reducing or removing VK supplementation in infants receiving total parenteral nutrition significantly decreases the dose requirements. Most infants requiring oral anticoagulants also require other medications on an intermittent and long-term basis. The effects of dosage changes and the introduction of new medications must be closely supervised.

Age-Dependent Features.

The activity of thrombolytic agents depends on endogenous concentrations of plasminogen, which are physiologically decreased at birth. Low plasminogen levels result in impairment of the capacity to generate plasmin and a decrease in the capacity to thrombolyse fibrin clots. In addition, fetal glycoforms of plasminogen are less efficiently converted to plasmin by tPA than is adult plasminogen. Thus neonates have an overall reduced capacity to respond to tPA in comparison with adults. If an infant’s condition does not respond to thrombolytic therapy, replacement of plasminogen should be considered.

Indications, Therapeutic Range, and Dose.

Infants in whom serious thrombotic complications develop, as defined by organ or limb impairment, may benefit from thrombolytic therapy. The clinical objective is removal of the clot as quickly and safely as possible. Surgical removal of a clot in a major vessel can be curative; however, it is technically difficult and poses a considerable life-threatening risk to infants, who are often premature. In the absence of contraindications, the use of thrombolytic agents in these infants is a preferred approach (see Chapter 33 ).