Congenital clotting factor deficiency and cardiovascular disease: protected by nature?

Abstract

Since the introduction of clotting factor concentrates, life expectancy of patients with hemophilia (PWH) has increased and now approaches that of the general population. Consequently, aging PWH are increasingly confronted with age-related comorbidities, including ischemic cardiovascular disease. Interestingly, studies reported a reduced occurrence of non-fatal and fatal IHD in PWH as compared with the general population. As coagulation plays an important role in atherogenesis via inflammation, we compared carotid and femoral intima-media thickness and coronary artery calcification between men with and without hemophilia. No evidence for a protective effect of congenital factor VIII deficiency on the extent of atherosclerosis was found. An alternative, and plausible, explanation would be that the hypocoagulable state of PWH has a protective effect on thrombus formation. Another possibility could be that plaque ruptures occur less often in PWH. The risk of plaque rupture mainly depends on plaque composition and is influenced by inflammation. On the other hand, intraplaque hemorrhage is an important determinant of plaque vulnerability and PWH might be more prone to intraplaque hemorrhage resulting in more plaque destabilization than in men without hemophilia. In conclusion, the protective effect of congenital clotting factor deficiencies on IHD is most likely mediated by effects on both atherothrombosis and atherosclerotic plaque phenotype and needs further investigation. Treatment of IHD in PWH is complex, because of the delicate equilibrium between bleeding and thrombosis. We developed a guideline based on both experience from hemophilia specialists and existing guidelines on treatment of IHD in non-hemophilic patients. In a case series of PWH who underwent cardiac catheterization/intervention and were treated with antithrombotic drugs, while (partially) correcting the clotting factor deficiency, we show that treatment according to the guideline is feasible and safe. Documentation and evaluation of future patients is needed to keep improving treatment. The process of hemostasis is dependent on the interplay between platelets, coagulation, the vessel wall, and blood rheology. The balance between the determinants of hemostasis results in the hemostasis integral. As no clinical trials exist, we cannot depend on epidemiological data and knowledge to assess the effects of antithrombotic drugs in combination with clotting factor substitution on the hemostasis integral in PWH with IHD. Current tests use either platelet poor plasma for coagulation assays or platelets devoid of plasmatic components and are mostly performed under static conditions. A global hemostasis test, which integrates the different determinants of hemostasis does not yet exist. We developed a disposable microfluidic device, in which sodium-citrate anticoagulated blood and a calcium solution enter a static mixer and pass a certain repeating geometry by flowing through it. Then, the recalcified blood is lead to a parallel-plate perfusion channel where it flows over a thrombogenic surface. Platelet aggregation and fibrin formation can be visualized. This device creates new possibilities to study the hemostasis integral, could help us understand hemostatic processes in PWH better and might result in optimization of dosages of both antithrombotic drugs and clotting factor concentrates.