Inherited thrombophilia and pregnancy complications

The research presented in this thesis addresses several aspects of the association between inherited thrombophilia and pregnancy complications. Antithrombotic therapy is prescribed to women with recurrent miscarriage and antiphospholipid syndrome to increase their chance of live birth in a subsequent pregnancy. Whether women with recurrent miscarriage and inherited thrombophilia also benefit from this therapy is unknown. In Part I of this thesis, we provide an overview of what is currently known on the use of antithrombotic therapy for this indication, we review the available evidence and we present two studies in which this therapy is evaluated. In recent studies, variants in the promoter of the Annexin A5 gene have been proposed as a form of thrombophilia. Annexin A5, formerly called placental anticoagulant protein, is a protein with anticoagulant properties, which forms a two-dimensional shield on phospholipid bilayers such as cell membranes, preventing coagulation reactions to occur. A reduction of Annexin A5 levels may be the mechanism by which thrombosis and pregnancy loss occur in the antiphospholipid syndrome. Another hypothesis is that Annexin A5 gene variants lead to reduced Annexin A5 mRNA levels and protein levels, thereby resulting in a form of thrombophilia. In part II of this thesis we investigate whether gene variants in the Annexin A5 gene are associated with deep vein thrombosis (DVT), pre-eclampsia, or recurrent miscarriage. We observed that the prevalence of single nucleotide polymorphisms (SNPs) and of common haplotypes was similar between DVT patients and controls. In a second study, Annexin A5 mRNA expression levels in placental tissue were not associated with pre-eclampsia risk and neither individual SNPs, nor any of the common haplotypes were associated with an increased risk of pre-eclampsia. Finally, we investigated the association of the Annexin A5 haplotypes with recurrent miscarriage in Dutch women and showed that haplotypes were not associated with recurrent miscarriage when compared to the reference haplotype