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Key Points

  • Disease summary:

    • The term thrombophilia refers to an inherited or acquired predisposition to thromboembolism.

    • Inherited thrombophilias include deficiencies of the three natural anticoagulant proteins antithrombin (AT), protein C (PC), and protein S (PS), and specific mutations in the genes for factor V (factor V Leiden) and prothrombin (prothrombin 20210G>A).

    • Inherited thrombophilias increase the risk for a first venous thromboembolism (VTE) 2- to 20-fold but are not major risk factors for arterial thromboembolism.

    • Although the risks vary, inherited thrombophilias are not strongly predictive of recurrent VTE after an initial episode.

    • The clinical expression of an inherited thrombophilia reflects a complex interplay between genetic and acquired risk factors.

  • Hereditary basis:

    • Deficiencies of the three natural anticoagulant proteins AT, PC, and PS are typically inherited as autosomal dominant traits. However, rare homozygous or compound heterozygous patients have been reported and they have a much more severe phenotype.

    • Mutations in the factor V Leiden and prothrombin 20210G>A predispose to thrombophilia both in the heterozygous and homozygous states but the latter tends to confer higher risk (see later).

  • Differential diagnosis:

    • The differential diagnosis of VTE includes multiple inherited and acquired thrombophilic disorders.

    • Because these disorders are clinically indistinguishable, laboratory testing is required for diagnosis in each case.

    • Acquired thrombophilias include antiphospholipid antibodies, high levels of several clotting factors (factors VIII, IX, XI), myeloproliferative disorders and paroxysmal nocturnal hemoglobinuria (PNH).

    • Homozygosity and compound heterozygosity for two common polymorphisms in the 5,10-methylenetetrahydofolate reductase (MTHFR) gene (C677T, A1298C) predispose to mild hyperhomocysteinemia. MTHFR polymorphisms do not increase the risk for VTE independent of homocysteine levels and genetic testing is not recommended.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria

At least one of the following (Fig. 18-1)

Figure 18-1

Algorithm for diagnostic testing for thrombophilia.

  • Identification of factor V Leiden or prothrombin 20210G>A mutation

  • Abnormal activated PC (APC) resistance assay confirmed by a genetic test for factor V Leiden

  • Low AT activity

  • Low PC activity

  • Low free PS antigen (and/or PS activity)

The diagnosis of AT, PC, or PS deficiency also requires

  • Exclusion of acquired causes of a deficiency

  • Repeat testing on a separate sample to confirm a low protein level

  • Demonstration of a deficiency in family members in difficult cases

Thrombophilia testing should include tests for inherited and acquired disorders (Table 18-1):

Table 18-1Genetic Differential Diagnosis

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