Leslie J. Raffini, J. Paul Scott
Numerous inherited risk factors for thrombosis have been identified, but the majority of individuals who inherit one of these risk factors do not necessarily develop thrombosis during childhood. Identification of inherited risk factors that could be identified in the laboratory initially led to widespread testing of both children and adults with thrombosis. The clinical utility of performing such tests has been scrutinized, and it is important to understand the potential benefits and limitations of testing.
Table 505.1 lists the most common inherited thrombophilias and their prevalence in the general population. The inherited defects with the best understood pathogenic link include the factor V Leiden mutation, the prothrombin gene mutation, and deficiencies of protein C, protein S, and antithrombin III (AT III). Elevated levels of factor VIII (FVIII) and homocysteine are associated with thrombosis, but these thrombophilias are less well characterized and not necessarily genetically determined. Although additional alterations in coagulation have been associated with thrombotic risk, including elevated concentrations of factors IX and XI, heparin cofactor II deficiency, elevated lipoprotein (a), and dysfibrinogenemia, none has gained widespread acceptance in routine testing of children for inherited thrombophilia. In general, the prothrombotic tendency conferred by these defects is either a result of an increased procoagulant effect (prothrombin gene mutation, elevated FVIII, hyperhomocysteinemia) or a decreased anticoagulant effect (factor V Leiden mutation, deficiency of protein C, protein S, or AT III).
Table 505.1
Common Inherited Thrombophilias and Accompanying Diagnostic Laboratory Studies
| THROMBOPHILIA | PREVALENCE IN WHITE POPULATION (%) | ODDS RATIO FOR FIRST EPISODE VTE IN CHILDHOOD* | LABORATORY STUDIES |
|---|---|---|---|
| Factor V Leiden mutation | DNA-based PCR assay (or screen with activated protein C resistance) | ||
| Heterozygote | 3-7 | 3.8 | |
| Homozygote | 0.06-0.25 | 80-100 | |
| Prothrombin 20210 mutation | DNA-based PCR assay | ||
| Heterozygote | 1-3 | 2.6 | |
| Homozygote | — | — | |
| Antithrombin III deficiency | 0.02-0.04 | 9.4 | Antithrombin activity via chromogenic or clotting assay |
| Protein S deficiency | 0.03-0.13 | 5.8 | Protein S activity via assay or immunologic assay of free and total protein S antigen |
| Protein C deficiency | 0.2 | 7.7 | Protein C activity via chromogenic or clotting assay |
| Hyperhomocysteinemia | — | — | Fasting homocysteine |
| Elevated factor VIII | — | — | Factor VIII activity via 1-stage clotting or chromogenic assay |
* Data from Young G, Albisetti M, Bonduel M, et al: Impact of inherited thrombophilia on venous thromboembolism in children, Circulation 118:1373–1382, 2008.
PCR, Polymerase chain reaction; VTE, venous thromboembolism.
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. This defect is also known as activated protein C resistance . Approximately 5% of the U.S. white population is heterozygous for this mutation; it is less prevalent in other ethnic groups. Individuals who are heterozygous have a 5-7–fold increased risk of venous thrombosis, whereas 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 1:3,500 for those taking oral contraceptives. For young women who are heterozygous for the factor V Leiden mutation and are taking OCs, this baseline annual risk is increased 20-30–fold (relative risk) to approximately to 1:500 women.
The prothrombin 20210 gene mutation is a G-to-A transition in the 3′ untranslated region of the gene that results in increased levels of prothrombin messenger RNA. 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 III , the natural anticoagulant proteins, are less common than the 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 III, protein C, or protein S may present with purpura fulminans . This rare 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, 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 III concentrates are also available and have been demonstrated to be effective.
Both venous and arterial thromboses are common in young patients with homocystinuria, an inborn error of metabolism caused by 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 is not indicated because these polymorphisms are common and by themselves 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. Although 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.
Although interpretation of genetic studies (factor V Leiden and prothrombin gene mutations) is fairly straightforward, several challenges in interpretation of thrombophilia studies are unique to pediatric patients. Neonates have decreased concentrations of protein C, protein S, and AT III that increase rapidly over the 1st 6 mo of life; protein C concentrations remain below adult levels throughout much of childhood. It is important to use pediatric normal ranges when evaluating these values and recognize that often the normal range overlaps with heterozygous defects and that retesting may be required, particularly in young children. Several nongenetic factors may also influence the results of inherited thrombophilia testing, including acute thrombosis, infection, inflammation, hepatic dysfunction, nephrotic syndrome, medication, and vitamin K deficiency. In some patients the hereditary nature may be confirmed by testing the parents.
Thrombophilia testing is often considered during childhood in 2 situations: a child who develops thrombosis and a child who has relatives with thrombosis or thrombophilia. Thrombophilia testing rarely influences the acute management of a child with a thrombotic event. The majority of children who develop thrombosis have multiple, coexistent acquired risk factors (see Table 506.1 in Chapter 506 ); inherited thrombophilia is uncommon in this scenario, and testing is generally not warranted. However, inherited thrombophilia is more common in an otherwise healthy child or adolescent who develops a blood clot or in a child who develops unusual or recurrent thrombosis. Thrombophilia testing may be useful in these situations, because it may help explain why the child developed a blood clot. In some cases, identification of strong or combined defects may alter the duration of therapy. However, current treatment recommendations do not differ based on the presence or absence of an inherited thrombophilia.
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 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 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.