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Chapter 89: Hereditary Thrombophilia

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INTRODUCTION

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  • Risk factors for thromboembolism may be genetic and acquired (Table 89–1).

  • Hereditary thrombophilia is a genetically determined increased risk of thrombosis.

  • Up to 50 percent of patients presenting with a first deep venous thrombosis will have an abnormal laboratory test suggesting a thrombophilic defect, and patients with recurrent thromboses or with a strong family history are even more likely to have laboratory evidence of a thrombophilic state (Table 89–2).

  • Up to 16 percent of patients with thrombophilia have inherited more than one abnormality.

  • These inherited defects also interact frequently with acquired risk factors, such as inactivity, trauma, malignancy, or oral contraceptive use, to lead to clinical thrombosis.

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Table Graphic Jump Location
TABLE 89–1THROMBOPHILIAS AND PREDISPOSING RISK FACTORS FOR VENOUS THROMBOEMBOLISM
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TABLE 89–1 THROMBOPHILIAS AND PREDISPOSING RISK FACTORS FOR VENOUS THROMBOEMBOLISM
Thrombophilias Acquired Predisposing Risk Factors for Venous Thrombosis
Common Increasing age
Factor V Leiden Surgery or trauma
Prothrombin G20210A Prolonged immobilization
Increased factor VIII level* Obesity
Homozygous C677T polymorphism in methylenetetrahydrofolate reductase† Smoking
Malignant neoplasms
Rare Myeloproliferative diseases
Protein C deficiency Superficial vein thrombosis
Protein S deficiency Previous venous thrombosis/Varicose veins
Antithrombin deficiency Pregnancy and puerperium
Very rare Use of female hormones
Dysfibrinogenemia Antiphospholipid antibodies/Lupus anticoagulants
Homozygous homocystinuria Hyperhomocysteinemia
Activated protein C resistance unrelated to factor V Leiden

*Heritability is inferred. No gene alteration has been discerned.

†A questionable thrombophilia that can be associated with hyperhomocysteinemia in patients with deficiencies of folic acid or vitamin B12.

Source: William Hematology, 8th ed, Chap. 131, Table 131–1, p. 2122.

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Table Graphic Jump Location
TABLE 89–2FREQUENCY OF THROMBOPHILIAS IN HEALTHY SUBJECTS AND UNSELECTED AND SELECTED PATIENTS WITH VENOUS THROMBOSIS
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TABLE 89–2 FREQUENCY OF THROMBOPHILIAS IN HEALTHY SUBJECTS AND UNSELECTED AND SELECTED PATIENTS WITH VENOUS THROMBOSIS
Healthy Subjects Unselected Patients Selected Patients
Thrombophilia No. Percent Affected No. Percent Affected No. Percent Affected
Factor V Leiden 16,150* 4.8 1142 18.8 162 40
2192† 0.05
Prothrombin G20210A 11,932* 2.7 2884 7.1 551 16
1811† 0.06
Protein C deficiency 15,070 0.2–0.4 2008 3.7 767 4.8
Protein S deficiency 3788 0.16–0.21 2008 2.3 649 4.3
Antithrombin deficiency 9669 0.02 2008 1.9 649 4.3

*Whites.

†Africans and Orientals.

Adapted with permission from Seligsohn U, Lubetsky A: Genetic susceptibility to venous thrombosis. N Engl J Med Apr 19;344(16):1222-1231, 2001.

Source: William Hematology, 8th ed, Chap.131, Table 131–2, p. 2123.

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HEREDITARY RESISTANCE TO ACTIVATED PROTEIN C (APC)

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Etiology and Pathogenesis

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  • APC resistance is an abnormally reduced anticoagulant response of a patient's plasma that, in more than 90 percent of cases, is caused by a genetic abnormality of factor V (substitution of glutamine for arginine at position 506), which significantly retards inactivation of factor Va by APC. The abnormal factor V is generally referred to as "factor V Leiden."

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