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Chapter 88: Hereditary Thrombophilia

INTRODUCTION

  • 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.

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.

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.

HEREDITARY RESISTANCE TO ACTIVATED PROTEIN C

Etiology and Pathogenesis

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

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