OVERVIEW: What every practitioner needs to know about congenital thrombophilia

Are you sure your patient has congenital thrombophilia? What are the typical findings for this disease?

The most common signs and symptoms of congenital thrombophilia are related to the anatomic site of a venous thromboembolic event and include hypertension, anemia, thrombocytopenia, and blood in the urine in renal vein thrombosis; irritability, seizure, and/or cranial neuropathies in cerebral sinovenous thrombosis; and circumferential limb swelling with or without discoloration in extremity deep venous thrombosis (DVT). Although pulmonary embolism is rare in neonates, symptoms and signs include tachypnea, unexplained respiratory insufficiency/distress, and unexplained pulmonary hypertension. Catheter-associated arterial thrombosis of the limb or aorta may present with unilateral or bilateral lower extremity discoloration, coolness, and reduced pulses.

What are less common neonatal presentations of congenital thrombophilia?

Other sites for neonatal venous thromboembolism include the portal venous system (presenting with thrombocytopenia and/or typical findings of portal hypertension, including gastroesophageal variceal bleeding). In addition, the rather common renal vein thrombosis can sometimes be complicated by adrenal hemorrhage (secondary to ischemic injury), with associated signs and symptoms of adrenal insufficiency.

Congenital thrombophilia can also be seen with neonatal arterial ischemic stroke, which typically presents with seizure and occasionally with focal neurologic deficits. Albeit rather common in association with central venous catheterization near the heart or in the setting of complex congenital heart disease (particularly postoperatively), the occurrence of intracardiac thrombosis is typically asymptomatic and is found incidentally on echocardiography; however, catheter-associated right atrial thrombosis occasionally presents as catheter malfunction (i.e., failure to infuse or draw back).

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The child or adolescent with an occult history of congenital thrombophilia

Occasionally, diagnostic radiologic imaging in a child or adolescent with acute deep venous thrombosis of the lower limbs may reveal azygous transformation or extensive collateralization in the setting of atretic inferior vena cava, with a remote history of caval catheterization in the neonatal period. Because of a venous low-flow state, such children and adolescents are likely to be at heightened risk for recurrent deep venous thrombosis in the lower venous system and also may manifest signs and symptoms of chronic venous insufficiency, including lower extremity swelling, venous stasis dermatitis, or (in severe cases) venous stasis ulceration.

What other disease/condition shares some of these symptoms?

Some of the signs and symptoms of renal vein thrombosis can also be caused by pyelonephritis; likewise, those of cerebral sinovenous thrombosis can be similar to meningoencephalitis, and those of pulmonary embolism can be similar to pneumonia or bronchopulmonary dysplasia.

What caused this disease to develop at this time?

The neonatal period is one of the peaks of venous thromboembolism in the pediatric age range and is attributable mostly to comorbid conditions such as systemic infection, central venous catheterization, and congenital cardiac disease. The triad of Virchow (venous stasis, endothelial damage, and the hypercoagulable state) is helpful in guiding the clinician to identify permissive risk factors for venous thromboembolism in the neonate.

For example, Ebstein anomaly and hypoplastic left heart syndrome can cause venous stasis in the right and left ventricles, respectively; central venous catheterization can cause focal endothelial injury at the site of the catheter tip and can also cause venous stasis along the length of the catheter from obstruction in blood flow; and chemotherapy in infantile acute lymphocytic leukemia can induce endothelial damage and acquired hypercoagulabilty.

More rarely, in the absence of clinical prothrombotic risk factors, severe congenital thrombophilias (e.g., homozygous protein C or antithrombin deficiency) can cause spontaneous venous thromboembolism in utero or in the perinatal period.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The appropriate role and extent of diagnostic thrombophilia testing is greatly debated and is supported more by experience than by high-quality evidence of clinical utility. Comprehensive testing may include protein C activity (chromogenic assay), antithrombin activity (chromogenic assay), free protein S antigen (enzyme-linked immunosorbant assay [ELISA]), homocysteine level, factor VIII activity (one-stage, activated partial thromboplastin time [aPTT]-based clotting assay), activated protein C resistance screen (clotting assay) with reflex testing for the factor V Leiden variant (polymerse chain reaction [PCR]) when positive, prothrombin G20210A variant PCR; lupus anticoagulant (dilute Russell viper venom time); anticardiolipin IgG and IgM (ELISA); β2 glycoprotein I IgG and IgM (ELISA), and homocysteine (mass spectrometry).

In addition, a complete blood count and disseminated intravascular coagulation (DIC) panel (prothrombin time [PT], aPTT, fibrinogen, D-dimer) are helpful in discerning the safety of anticoagulation therapy. Thrombocytopenia, hypofibrinogenemia, or an unexplained prolongation of PT or aPTT may require blood product, fresh frozen plasma, or cryoprecipitate support (as appropriate to the specific abnormality) to maximize the safety of anticoagulation for venous thromboembolism in the neonate. (See also section on treatment, below.)

The D-dimer may also be a useful monitoring tool as a surrogate marker for therapeutic efficacy, as a measure of degree of suppression of coagulation activation and thrombin generation—particularly in the setting of severe thrombophilia states such as protein C, protein S, or antithrombin deficiency.

Would imaging studies be helpful? If so, which ones?

Radiologic imaging is critical to the definitive diagnosis of venous or arterial thromboembolism in the neonate. Appropriate modalities are dependent on the anatomic site of involvement. For deep venous or arterial thrombosis of the limbs, ultrasonography with Doppler (and compression maneuver, in the case of venous thrombosis) is the pragmatic and contemporary gold standard, although historically contrast venography and arteriography were the gold standards.

Compression ultrasonography is also feasible in the neonate with more central involvement, including the inferior vena cava, because of size and compressibility of these structures in the neonate. However, for veins that lie behind bony structures (e.g., portions of the subclavian vein), magnetic resonance venography (MRV) or computed tomography with venography (CTV) of the brain is often required.

Cerebral sinovenous thrombosis is imaged by MRV or CTV of the brain (the latter exposes the neonate to radiation, while the former often requires sedation). Pulmonary embolism is imaged by spiral CT angiogram. Intracardiac thrombosis is diagnosed by echocardiography.

Definitive radiologic diagnosis of renal vein thrombosis is challenging, and typically ultrasonography with Doppler is only suggestive of the diagnosis, based on resistive indices rather than disclosure of intravascular thrombus. Arterial ischemic stroke is optimally imaged by magnetic resonance imaging (MRI) of the brain with diffusion-weighted imaging and MR arteriography of the brain and neck.

Confirming the diagnosis

No clinical decision algorithms for congenital thrombophilia exist that are supported by high-quality evidence. Because the incidence of venous thromboembolism and arterial ischemic stroke remain low in neonates, despite this period being a peak in incidence during the pediatric age range, clinical suspicion for these presentations of congenital thrombophilia is appropriately low in most newborn infants. Diagnostic evaluation (as discussed above) is based on specific signs and symptoms and often includes pursuit of more common diagnoses before investigating for thromboembolism.

If you are able to confirm that the patient has congenital thrombophilia, what treatment should be initiated?

Anticoagulant therapy is the standard of care for neonatal venous thromboemblism, albeit not supported by high-quality evidence given a lack of clinical trials to date in this setting. In arterial thrombosis, antiplatelet therapy (e.g., aspirin, 3-5 mg/kg once-daily) is the mainstay of therapy, although anticoagulation is often used initially during the acute period – and in cases of ischemia – catheter-directed thrombolytic therapy is often considered (particularly in circumstances in which the catheter has not yet been removed).

Acute anticoagulation conventionally uses unfractionated heparin (UFH), administered in term neonates as an initial bolus dose of 75-100 U/kg intravenously, followed by continuous infusion at a starting dose of approximately 28 U/kg/hr (adjusted to achieve an anti–factor Xa activity level of 0.35-0.7 U/mL, measured 6-8 hours after initiation of the infusion).

When bleeding risk is clinically determined to be low, subsequent anticoagulant therapy in the term neonate typically uses low-molecular-weight heparin (LMWH), most commonly enoxaparin, at a starting dose of 1.5-1.7 mg/kg subcutaneously every 12 hours (adjusted to achieve an anti–factor Xa activity level of 0.5-1.0 U/mL, measured at 4 hours after the first or second dose).

While preterm neonates typically require higher per-kg doses of UFH and LMWH to achieve goal anti-factor Xa activity levels, the increased risk of intracranial hemorrhage in pre-term neonates may in fact warrant lower initial doses than the term neonate, with close observation and gradual titration toward goal levels.

Warfarin is rarely feasible in infants. Conventional duration of therapy is 3 months for neonatal venous thromboembolism occurring in the setting of an identifiable transient clinical trigger and in the absence of severe congenital thrombophilia (e.g., homozygous protein C, protein S, or antithrombin deficiency); however, current guidelines suggest giving consideration to a shortened duration of anticoagulation, such as 6 weeks. The question of duration of anticoagulation for provoked venous thromboembolism in neonates and older children is currently being studied via the multi-national Kids-DOTT trial (NCT NCT00687882).

In neonatal arterial ischemic stroke occurring perinatally, most often no antithrombotic therapy is warranted (in the absence of severe congenital thrombophilia or congenital cardiac disease). In arterial ischemic stroke occurring in the late neonatal period, aspirin is often used (at doses of 4 mg/kg orally once daily) in the absence of congenital cardiac disease, and anticoagulation is often used when the evaluation is suggestive of a cardioembolic cause.

Oral direct factor IIa and factor Xa inhibitors have been approved for venous thromboembolism treatment in adults and are presently under study in pediatric clinical trials.

What are the adverse effects associated with each treatment option?

Bleeding is the most common adverse effect of anticoagulation or antiplatelet therapy. UFH is also associated (rarely) with heparin-induced thrombocytopenia, which confers a high risk of progressive/recurrent thrombosis due to potent coagulation activation. Long-term use of UFH is also associated with osteoporosis. LMWH has also been associated with heparin-induced thrombocytopenia, but less commonly than UFH.

Allergic responses are rare. Aspirin (used for some instances of arterial ischemic stroke) is also associated with bleeding risk. Allergic responses to aspirin may occur. In addition, active influenza poses a theoretical risk for Reye syndrome (characterized by liver failure), and for this reason annual influenza vaccine injections are advised while the patient is taking aspirin chronically – although this syndrome was historically associated with much higher doses of aspirin than is presently used (3-5 mg/kg once-daily) for arterial ischemic stroke or other arterial thrombosis.

What are the possible outcomes of congenital thrombophilia?

Outcomes of neonatal venous or arterial thromboembolism in part depend on the anatomic site of involvement. Outcomes of limb DVT include pulmonary embolism, death (often due to either underlying disease or fatal pulmonary embolism), recurrent thrombosis, clinically significant hemorrhage related to anticoagulant therapy, and the post-thrombotic syndrome (PTS). PTS is a syndrome of chronic venous insufficiency after DVT of the limb.

Arterial thrombosis of the limb may occasionally result in gangrene of the limb or distal portions thereof, necessitating amputation; alternatively, it may result rarely in reduced growth of a limb, causing limb length and size discrepancy.

The risk of recurrent venous thromboembolism is approximately 10% at 2 years, with most recurrent events occurring within the first 6 months. Risk of recurrence is higher in children with unprovoked/spontaneous first events or severe underlying thrombophilia states (e.g., homozygous protein C, protein S, or antithrombin deficiency) and lower among children without severe thrombophilia in whom the first event was associated with a transient clinical risk factor (such as a central venous catheter in a child with bacteremia).

The risk of clinically significant bleeding averages 2% in children receiving a conventional 3- to 6-month course of therapeutic anticoagulation (e.g., 3 months for a first provoked venous thromboembolism, and 6 months for a first unprovoked venous thromboembolism). PTS occurs in approximately 25% of children after limb venous thromboembolism, and typically consists of intermittent swelling and discomfort of the affected limb with prolonged use/activity but in severe cases may involve venous stasis dermatitis and ulceration.

In special circumstances (site-specific), such as renal vein thrombosis, long-term outcomes other than recurrent thrombosis/pulmonary embolism can include chronic hypertension and renal insufficiency (particularly in the setting of bilateral involvement). Outcomes of cerebral sinovenous thrombosis can include intracranial hypertension and associated visual loss, as well as focal neurologic deficits in select circumstances. In portal vein thrombosis, outcomes can include portal hypertension and associated gastroesophageal variceal bleeding.

Therapeutic anticoagulation is the current standard of care, as discussed above. Risk of clinically significant bleeding is believed to be outweighed by the risk of recurrent venous thromboembolism (including pulmonary embolism) during the first several weeks to months after acute venous thromboembolism in most neonates. By contrast, by 3 months after an acute venous thromboembolism episode that was associated with a transient clinical trigger in children without severe thrombophilia, the risk of bleeding may be higher than the risk of recurrent venous thromboembolism, and hence the conventional duration of anticoagulant therapy is 3 months in this most common scenario of neonatal venous thromboembolism.

What causes this disease and how frequent is it?

Causes of neonatal venous thromboembolism are discussed above. These causes can be conceptualized in the triad of Virchow: venous stasis, endothelial damage, and the hypercoagulable state. Examples include venous stasis from impaired venous return in some congenital cardiac diseases, endothelial damage from central venous catheterization, and hypercoagulable state from acquired anticoagulant deficiency in sepsis.

Bimodal peaks in the incidence of venous thromboembolism in pediatrics occur in the neonatal and adolescent periods. Overall incidence of venous thromboembolism in neonates is approximately 1 in 10,000.

What complications might you expect from the disease or treatment of the disease?

Bleeding complications and long-term outcomes of neonatal venous thromboembolism are discussed above.

Are additional laboratory studies available; even some that are not widely available?

Thrombin generation assay (not widely available) or other global coagulation assays evaluating overall coagulative or fibrinolytic function may ultimately provide a more rational approach to a panel of individual tests and may disclose thrombophilia not identified by individual tests; however, the role for such assays has not yet been substantiated.

How can congenital thrombophilia be prevented?

Given the risk of bleeding with anticoagulation (to which neonates may be particularly vulnerable, particularly preterm neonates) and given the low incidence of the disease, safe and effective primary prevention strategies have not been developed. Early diagnosis of venous thromboembolism or arterial ischemic stroke may prevent adverse long-term outcomes, but prevention of incident venous thromboembolism or arterial ischemic stroke remains elusive. Central venous catheters should be removed as soon as they are no longer necessary for the care of the neonate.

What is the evidence?

Management options and standards of care are principally derived from consensus-based recommendations (e.g., American College of Chest Physicians).

Monagle, P, Chan, AK, Goldenberg, NA. “American College of Chest Physicians. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines”. Chest. vol. 141. 2012. pp. e737S-801S.

Ongoing controversies regarding etiology, diagnosis, treatment

Key questions remain regarding anticoagulation agent types, duration of anticoagulation and the role for acute thrombolytic therapy in neonates with venous thromboembolism.

Goldenberg, NA, Takemoto, CM, Yee, DL. “Improving evidence on anticoagulant therapies for venous thromboembolism in children: key challenges and opportunities”. Blood. vol. 126. 2015. pp. 2541-7.