The protein C system and venous thromboembolism in reproduction: Pathophysiology, epidemiology and diagnosis

In this thesis we examine blood coagulation and venous thromboembolism in their relation to reproduction.
The first part covers the versatile effects of the protein C system, a crucial regulatory mechanism in coagulation, on reproduction. We find that carriers of the most common mutation affecting the system, factor V Leiden, have beneficial traits beside the negative effects on pregnancy and thrombosis risk. This might explain the mutation’s high prevalence. Examples of the beneficial traits with relation to reproduction are identified in both sexes. Female carriers reach pregnancy after a shorter time of trying to conceive. Male carriers have a higher sperm count. Several potential causes for the latter finding are explored, including genetic linkage, a direct effect of the mutation on spermatogenesis in mice, and increased protein C activation. The role of thrombomodulin, a pivotal coenzyme in the protein C system, is investigated using tissue-selective or temporally controlled thrombomodulin gene knockout and genetic supplementation in mice. Thrombomodulin is found to be crucial in embryonic development, pregnancy and adult physiology, with protein C activation being the critical function.
In the second part of the thesis we present three studies on the diagnosis of venous thromboembolism, using available data from the literature. Pulmonary embolism can be safely excluded during pregnancy with both computed tomography pulmonary angiography and lung scintigraphy, though evidence is of poor quality. The diagnostic challenges of pregnancy related deep venous thrombosis are investigated. Finally, sex-differences are ruled out in the diagnostic performance of pre-imaging algorithms for pulmonary embolism.