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  • Review Article
  • Published:

Inherited risk factors for venous thromboembolism

Nature Reviews Cardiology volume 11, pages 140–156 (2014)Cite this article

Subjects

Key Points

  • Knowledge about the spectrum of genetic abnormalities causing thrombophilia has greatly expanded in the past 20 years

  • These abnormalities increase the risk of venous thromboembolism (VTE) by causing blood hypercoagulability through the impairment of natural anticoagulant pathways or the potentiation of procoagulants

  • VTE risk is higher in carriers of natural anticoagulant deficiencies, homozygous defects, and multiple abnormalities (severe thrombophilia) than in heterozygotes for factor V Leiden and prothrombin 20210A (mild thrombophilia)

  • Family history of VTE is a strong risk factor for VTE regardless of the presence of known VTE susceptibility genes

  • Thrombophilia screening is useful in some instances to inform the optimum duration of secondary prophylaxis in patients who have developed VTE and are at high risk of recurrence

  • Thrombosis-free individuals in risk-enhancing situations (pregnancy, oral contraceptive use, hormone replacement therapy, orthopaedic surgery) do not require thrombophilia screening, except in families with natural anticoagulant deficiencies or history of VTE

Abstract

Venous thromboembolism (VTE) has important heritable components. In the past 20 years, knowledge in this field has greatly increased with the identification of a number of gene variants causing hypercoagulability. The two main mechanisms are loss-of-function of anticoagulant proteins and gain-of-function of procoagulants, the latter owing to increased synthesis or impaired downregulation of a normal protein or, more rarely, to synthesis of a functionally hyperactive molecule. Diagnosis of thrombophilia is useful to determine the causes of VTE, recognizing that this multifactorial disease can also be influenced by various acquired factors including cancer, surgery, trauma, prolonged immobilization, or reproduction-associated risk factors. Diagnosis of inherited thrombophilia rarely affects the acute or long-term management of VTE. However, the risk of recurrent VTE is increased in anticoagulant-deficient patients and in homozygotes for gain-of-function mutations. Screening for inherited thrombophilia in thrombosis-free individuals is indicated only for relatives of a proband who is anticoagulant-deficient or has a family history of VTE. In families with thrombophilia and VTE, primary antithrombotic prophylaxis during risk situations lowers the rate of incident VTE. In this Review, we discuss the main causes of inherited thrombophilia, the associated clinical manifestations, and the implications for antithrombotic prophylaxis in the affected individuals.

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Figure 1: Anticoagulant mechanisms of antithrombin, which mainly inhibits factor IIa and factor Xa, but also factors VIIa, IXa, XIa, and XIIa.
Figure 2: Anticoagulant mechanisms of the protein C–protein S system.

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Authors and Affiliations

  1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via Pace 9, Milan, 20122, Italy

    Ida Martinelli

  2. Institute of Hematology, Catholic University, Largo A. Gemelli 8, Rome, I-00168, Italy

    Valerio De Stefano

  3. Scientific Direction, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 28, Milan, 20122, Italy

    Pier M. Mannucci

Authors
  1. Ida Martinelli
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  2. Valerio De Stefano
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  3. Pier M. Mannucci
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Contributions

All the authors researched data for the article and contributed substantially to the discussion of content. I. Martinelli wrote the first draft of the article; V. De Stefano and P. M. Mannucci contributed to writing subsequent drafts. All the authors reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Pier M. Mannucci.

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The authors declare no competing financial interests.

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Martinelli, I., De Stefano, V. & Mannucci, P. Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 11, 140–156 (2014). https://doi.org/10.1038/nrcardio.2013.211

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