Elevation of plasma FIXa activity in association with reductions in TFPI-α and PS is a potential mechanism for systemic hypercoagulability and resistance to APC in premenopausal females on hormonal contraception.
These new approaches include replacement therapy with porcine factor VIII concentrate (currently approved for use in acquired hemophilia patients), bispecific antibodies to simulate the biologic function of factor VIII (already in use in some jurisdictions), pegylated forms of activated factor VII, and strategies targeting the natural anticoagulants TFPI and antithrombin, which create a hypercoagulable phenotype to counterbalance the hypocoagulability imposed by hemophilia.
Tissue factor pathway inhibitor (TFPI) antibodies, which have been reported in patients with antiphospholipid syndrome (APS), may impair TFPI activity and contribute to hypercoagulability, but their role in APS and in thrombosis remains undefined.
Other biomarkers reviewed, which did not consistently demonstrate significant associations with VTE included prothrombin fragments F1 + 2, factor VIII, protein C, protein S, von Willebrand antigen and activity, antithrombin, thrombin antithrombin complex, antiphospholopid antibody, plasminogen activator inhibitor, tissue factor pathway inhibitor and several variants associated with known hypercoagulable states (factor V Leiden, prothrombin gene variant, methylenetetrahydrofolate reductase variant).
Although it is difficult to speculate on the factors that might modify bleeding severity in patients with hemophilia, recent observations indicate that other coagulation proteins, such as tissue factor pathway inhibitor or polymorphisms in coagulation factor genes and genetic defects associated with hypercoagulability may account for the variability in clinical phenotype among patients with hemophilia.
Thrombin generation assays sensitive to the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S revealed similar hypercoagulable states in type I and type III protein S-deficient plasma.
Thrombin generation assays sensitive to the APC- and TFPI-cofactor activities of protein S revealed similar hypercoagulable states in type I and type III protein S-deficient plasma.
These results indicate that the TFPI -33T->C and -399C->T polymorphisms are significantly associated with venous thrombosis in the presence of other risk factors, especially APS, and may be clinically relevant in patients who are prone to hypercoagulability.