To study the impact of maternal thrombophilia on pregnancy outcomes, the authors carried out a series of elegant and complicated breeding experiments utilizing multiple mouse strains engineered with genetic defects in the protein C pathway. They found that mothers homozygous for factor V Leiden or for a thrombomodulin point mutation with severe inability to activate protein C showed consistent, severe fetal loss only when the offspring were homozygous for the thrombomodulin mutation, or heterozygous for both the thrombomodulin mutation and the Leiden mutation, or homozygous for a mutation in the endothelial protein C receptor (EPCR) gene. EPCR serves as a binding site for protein C and facilitates its activation by the thrombin/thrombomodulin complex. The mice did not have spontaneous systemic thrombi, but the placentas were markedly abnormal, showing a defect at the maternal-fetal interface with abnormal development of the labyrinth layer and severely diminished fetal and maternal vessel in-growth. No placental thrombi or infarcts were seen. Interestingly, deficiency of tissue factor pathway inhibitor in these models was associated with severe systemic thrombosis, but not fetal loss. Surprisingly, if the pregnant mice were depleted of platelets before the tenth day of gestation (normal gestation for mice is ~22 days), or if the mice were genetically null for the platelet thrombin receptor PAR4, the phenotype of fetal loss was rescued.
In Brief
Multiple case-controlled, epidemiologic studies have shown an association between genetic thrombophilias ― particularly factor V Leiden ― and recurrent pregnancy loss. Many obstetricians routinely screen high-risk women with recurrent, spontaneous abortions for thrombophilia based on these studies and on data suggesting improved outcomes with anti-coagulation therapy. This study provides important new insights into the problem by 1) confirming that (at least in mice) the factor V Leiden mutation does indeed cause fetal loss and 2) showing that the risk and timing of the loss is clearly dependent on the genotype of both the mother and the fetus. Homozygosity for the mutation in the mothers was associated with earlier fetal loss than heterozygosity, and penetrance of the phenotype of fetal loss was dramatically enhanced if the fetus had a genetic defect in the protein C pathway. Rescue of the phenotype by depleting the mothers of platelets or by preventing thrombin-dependent platelet activation, along with the pathologic data showing abnormal development of the maternal-fetal interface but no systemic or placental thrombosis, leads to the following model: The placental trophoblast (which is of fetal origin) constitutively expresses tissue factor and generates small amounts of thrombin that is "balanced" by robust expression of the protein C activating system (thrombomodulin and EPCR). Maternal resistance to activated protein C (for example, factor V Leiden) coupled with fetal inability to generate sufficient protein C could lead to inappropriate thrombin generation at the maternal-fetal interface resulting in inappropriate platelet activation and faulty placental development. These studies suggest that investigators should include examination of paternal or fetal genetics in future studies assessing the role of thrombophilia in recurrent fetal loss. In addition, they suggest that efficacy of heparin in preventing early fetal loss may be due to prevention of thrombin-induced platelet activation rather than protection from placental thrombosis, and that early therapeutic intervention is likely to be critical to allow normal placental development.
Competing Interests
Dr. Silverstein indicated no relevant conflicts of interest.
