Hereditary Predisposition to Thrombosis

Chapter 472 Hereditary Predisposition to Thrombosis

Pediatricians are frequently asked to evaluate children for inherited risk factors for thrombosis with symptomatic thrombosis or asymptomatic children who have relatives affected with either thrombosis or thrombophilia. The clinical utility of thrombophilia testing is debated, both in adults and children.

Thrombophilia testing rarely influences the acute management of a child with a thrombotic event. The association between inherited thrombophilia and pediatric thrombosis varies based on the clinical scenario: children with unprovoked thrombotic events have a high prevalence of inherited defects, while the role of thrombophilic defects in children with catheter-related thrombotic events is questionable. Although some thrombophilic defects are associated with a higher risk of recurrent venous thromboembolism in children, how to use these results to guide the duration of therapy has not been determined. Prospective longitudinal analyses of such patients to determine outcome and response to treatment as well as the impact of known thrombophilic states on these outcomes are clearly needed.

The decision to perform thrombophilia testing in an otherwise healthy child with a family history of thrombosis or thrombophilia should be carefully considered, weighing the potential advantages and limitations of such an approach. Given that the absolute risk of thrombosis in children is extremely low (0.07/100,000), it is unlikely that an inherited thrombophilia will have any impact on clinical decision-making for a young child. The risk of thrombosis increases with age, so that identification of a thrombophilic defect in an adolescent may guide thromboprophylaxis in high-risk situations (lower extremity casting or prolonged immobility), inform the discussion about estrogen-based contraceptives, and may promote lifestyle modification to avoid behavioral prothrombotic risk factors (sedentary lifestyle, dehydration, obesity, and smoking). Limitations of such testing include the cost as well as the potential for causing unnecessary anxiety or false reassurance.

The most common inherited thrombophilias are listed in Table 472-1. The inherited defects in which the pathogenic link is best understood include the factor V Leiden mutation, the prothrombin gene mutation, and deficiencies of protein C, protein S, and antithrombin (AT). Elevated levels of factor VIII, lipoprotein (a), and homocysteine are associated with thrombosis, though these are less well characterized and not necessarily genetically determined. Although there are additional alterations in coagulation that have been associated with thrombotic risk, including elevated concentrations of factors IX and XI, heparin cofactor II deficiency, and dysfibrinogenemia, none has gained widespread acceptance in routine testing of children for inherited thrombophilia.

Table 472-1 INHERITED THROMBOTIC DISORDERS

AD, autosomal dominant; APC, activated protein C; AR, autosomal recessive; AT, antithrombin; PAI-1, plasminogen activator inhibitor-1; TM, thrombomodulin; TPA, tissue plasminogen activator.

From Robetorye RS, Rodgers GM: Update on selected inherited venous thrombic disorders, Am J Hematol 68:256–268, 2001.

Modified with permission from Rodgers GM, Chandler WL: Laboratory and clinical aspects of inherited thrombotic disorders, Am J Hematol 41:113–122, 1992. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

The factor V Leiden mutation is the result of a single nucleotide change at nucleotide 1765 within the factor V gene. This mutation causes factor Va to become resistant to inactivation by activated protein C and is the most common inherited risk factor for thrombosis. Approximately 5% of the U.S. white population is heterozygous for this mutation, and it is less prevalent in other ethnic groups. Individuals who are heterozygous have a 5- to 7-fold increase in risk of venous thrombosis, while homozygotes have a relative risk of 80-100. The baseline annual risk of thrombosis for young women of reproductive age is 1 per 12,500 and increases to 1 per 3,500 for those on oral contraceptives. For young women who are heterozygous for the factor V Leiden mutation and are taking oral contraceptives, this baseline annual risk is increased 20- to 30-fold (relative risk) to approximately to 1 per 500 women.

The prothrombin 20210 gene mutation is a G to A transition in the 3′ untranslated region of the gene that results in elevated levels of prothrombin. This variant is present in approximately 2% of U.S. whites. It is a weaker risk factor for venous thrombosis than factor V Leiden, with a relative risk of 2-3.

Deficiencies of protein C, protein S, and AT, the natural anticoagulant proteins, are more rare than the common genetic mutations described previously but are associated with a stronger risk of thrombosis. Although heterozygous deficiencies do not often present during childhood, homozygous defects may result in significant symptoms in infancy. Neonates with homozygous deficiencies of AT, protein C, or protein S may present with purpura fulminans. This condition is characterized by rapidly spreading purpuric skin lesions resulting from thromboses of the small dermal vessels followed by bleeding into the skin. In addition, these infants may also develop cerebral thrombosis, ophthalmic thrombosis, disseminated intravascular coagulation (DIC), and large vessel thrombosis. An infant with purpuric skin lesions of unknown cause should receive initial replacement with fresh frozen plasma. Definitive diagnosis can be difficult in the sick premature neonate who may have undetectable levels of these factors but not have a true genetic deficiency. Protein C and AT concentrates are also available and have been demonstrated to be effective.

Neonates have decreased concentrations of protein C, protein S, and AT that increase rapidly over the first 6 mo of life; protein C concentrations remain below adult levels throughout much of childhood. Multiple acquired conditions may affect plasma concentrations of these anticoagulants. Patients with single ventricle congenital heart disease and hepatic dysfunction may have decreased concentrations of all 3 anticoagulants; vitamin K deficiency and warfarin result in a reduction of the vitamin K–dependent factors, including protein C and protein S; nephrotic syndrome, severe burns, and asparaginase all disproportionately decrease AT; and protein S may be decreased during pregnancy and in the presence of antiphospholipid antibodies.

Both venous and arterial thromboses are common in young patients with homocystinuria, an inborn error of metabolism due to deficiency of cystathione β-synthase. In this very rare condition, plasma levels of homocysteine exceed 100 µmol/L. Much more common are mild to moderate elevations of homocysteine, which may be acquired or associated with a polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. Although moderate elevations of homocysteine have been associated with both venous and arterial thrombotic events, testing for polymorphisms in the MTHFR gene are not indicated, because these polymorphisms are not associated with venous thromboembolism. The pathogenic mechanisms for thrombosis in homocystinemia are not well understood.

Increased plasma concentrations of factor VIII (>150 IU/dL) appear to be regulated by both genetic and environmental factors and are associated with an increased risk of thrombosis. While there is a strong component of heritability contributing to factor VIII levels, the molecular mechanisms responsible for elevated factor VIII are not well understood. Factor VIII is also considered to be an acute phase reactant, and may increase transiently during periods of inflammation.

Lipoprotein (a) [Lp(a)] is a low-density lipoprotein particle that has been linked to atherothrombosis in adults, with elevated levels associated with premature myocardial infarction and stroke. Levels of Lp(a) >30 mg/dL have been demonstrated to be an independent risk factor for stroke and venous thrombosis in children in small studies. Lp(a) has a structure that is similar to plasminogen and it is postulated that elevated levels may inhibit fibrinolysis, though this has not been proven.

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