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Chapter 88: Hereditary Thrombophilia

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INTRODUCTION

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  • Risk factors for thromboembolism may be genetic and acquired (Table 88–1).

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

  • Up to 50% 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 88–2).

  • Up to 16% 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 88–1THROMBOPHILIAS AND PREDISPOSING RISK FACTORS FOR VENOUS THROMBOEMBOLISM
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TABLE 88–1 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 88–2FREQUENCY OF THROMBOPHILIAS IN HEALTHY SUBJECTS AND UNSELECTED AND SELECTED PATIENTS WITH VENOUS THROMBOSIS
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TABLE 88–2 FREQUENCY OF THROMBOPHILIAS IN HEALTHY SUBJECTS AND UNSELECTED AND SELECTED PATIENTS WITH VENOUS THROMBOSIS
Type of Thrombophilia Healthy Subjects (% affected) Unselected Subjects (% affected) Selected Subjects (% affected)
Factor V Leiden 5* 19 40
0.05†
Prothrombin G20210A 3* 7 16
0.06†
Protein C deficiency 0.03 4 5
Protein S deficiency 0.18 2 4
Antithrombin deficiency 0.02 2 4

Data are rounded. Unselected patients are from studies that examined consecutive patients with venous thrombosis. Selected patients are from studies that examined those younger than 50 years of age, with a family history of thrombosis; a history of recurrent events; and absence of acquired risk factors, except for pregnancy and use of oral contraceptives.

*All subjects were of European descent.

†All subjects were of African or Asian descent.

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

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HEREDITARY RESISTANCE TO ACTIVATED PROTEIN C

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Etiology and Pathogenesis

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  • Activated protein C (APC) resistance is an abnormally reduced anticoagulant response of a patient’s plasma that, in more than 90% of cases, ...

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