Thrombophilia by definition represents acquired and/or genetic conditions which predispose patients to both venous and arterial thromboembolic events.  Thrombosis is the most common cause of death worldwide.  On the arterial side, myocardial infarction and stroke result in significant morbidity and mortality.  Venous thromboembolic (VTE) events most commonly involve the deep veins of the lower extremity with potential complications of pulmonary emboli. Pregnancy is a hypercoagulable state, and thromboembolism is the leading cause of antepartum and postpartum maternal mortality.

Recent attention has focused on certain inherited thrombophilic factors that may predispose to arterial and/or venous thromboses and their possible association with pregnancy complications, including early pregnancy loss. These include a group of mostly autosomal dominant, inherited gene mutations leading to a hypercoagulable state, such as Factor V Leiden G1691A, Factor II or Prothrombin G20210A, and, deficiencies in Protein S, Protein C, and Antithrombin can lead to a hypercoagulable state.  With the identification of genetic risk factors, there has been synergistic amplification of thrombotic risk when one has an abnormal gene (e.g., Factor V Leiden) plus environmental issues (e.g., pregnancy). Current understanding indicates that a combination of risk factors, including multiple inherited thrombophilic defects associated with secondary hypercoagulable states (such as pregnancy and antiphospholipid sybndrome) can be associated with adverse pregnancy outcome.



In this diagram of the coagulation pathway, the critical role of Factor V activation (FVa) and Factor VIII activation (FVIIIa) can be demonstrated in the formation of thrombin and ultimately a clot. Factor V Leiden is simply a mutation in Factor V that limits the inactivation of Factor V, thus it continues to function in the coagulation pathway. Protein C must be activated by free Protein S to form the Activated Protein C complex (APC) which is critical in the inactivation of Factor V. Thus, a deficiency of Protein C or a deficiency of Protein S leads to a hypercoagulable condition because Factor V is not inactivated.

Since hypercoagulability with inherited thrombophilias has been well established, screening of pregnant women with a personal history of VTE has been generally well accepted in practice, with the purpose of providing thromboembolic prophylaxis if needed.  This practice is supported by the most recent guidelines, and its acceptance confirmed in our survey findings of physicians’ practices.  Screening in the presence of a family history of VTE has also historically been accepted.




 Thrombophilia                                              Inheritance                                  Prevalence              Risk of DVT



Factor V Leiden G1691A Mutation           Autosomal dominant                      2-15%                         3-8x


Factor II G20210A Mutation                      Autosomal dominant                      2-3%                            3x
(Prothrombin Mutation)


MTHFR C677T Mutation                           Autosomal recessive                       11%                              2.5-4x


Antithrombin Deficiency                           Autosomal dominant                      0.02%                          25-50x


Protein C Deficiency                                  Autosomal dominant                   0.2-0.3%                        10-15x


Protein S Deficiency                                  Autosomal dominant                    0.1-0.2%                         2x




A larger controversy has existed in the recent past around the utility of screening for inherited thrombophilias in women with a history of adverse pregnancy outcome or loss.  Several strong arguments exist against screening in this population.  Perhaps most importantly, only weak associations have been found between hypercoagulability and pregnancy outcomes, and no causative relationship has been established..  Even more, many inherited thrombophilias are common in the general population, and most of these women have normal pregnancy outcomes.  From the standpoint of thromboembolism prevention, some argue that inherited genetic aberrations in clotting proteins are less likely to be significant in the absence of a thromboembolic event history, and that screening this population is akin to screening the general population, which has shown to be cost-ineffective..  Due to these positions, current recommendations are against screening women with recurrent pregnancy loss unless they have a personal history or strong family history of thrombosis..