In their letter ‘Clotting factors vs. lipids in the pathogenesis of atherosclerosis: a lost cause for the former’ Girolami et al. address several issues raised by our recent review article ‘The impact of blood coagulability on atherosclerosis and cardiovascular disease’ . First of all, the authors claim that congenital (chronic) hypocoagulability does not protect against atherosclerosis, as demonstrated by several clinical and laboratory observations. As clearly pointed out in our review, the traditional view of congenital hypocoagulability being protective against cardiovascular disease is indeed considered to be controversial, with several studies providing evidence for [2–5] and against [6–10] the hypothesis. It should, however, be noted that, in contrast to the experimental work, hemophilic patients cannot be considered to be ‘null’ for the respective clotting factors, as either they are transfused (and survive nowadays to the stage when they do acquire atherosclerosis), or their disease is mild to moderate, which raises questions about the degree of protection that such deficiencies may offer against a complex process such as atherosclerosis.
Second, although the presence of coagulation factors within atherosclerotic lesions does not imply a causal relationship between the two, there is strong evidence for involvement of the coagulation system in the development and progression of atherosclerotic disease. Wilcox et al. showed the direct synthesis (mRNA expression) of coagulation proteins in the arterial vessel wall by both smooth muscle cells and macrophages [11,12]. As indicated in our review, a second source for coagulation factors may indeed be uptake from the circulation. Besides the presence of coagulation proteins, fibrinogen and fibrin degradation products in atherosclerotic lesions [13–15], it was demonstrated that plaque-derived clotting proteins were functionally active in an in vitro thrombin generation assay , and they were shown to be associated with the stage and severity of atherosclerotic disease . Furthermore, many complex processes involved in the development and progression of atherosclerosis, including angiogenesis, inflammation, and cell proliferation, are regulated by the activation of protease-activated receptors (PARs) on vascular cells. Therefore, by activating PARs, active coagulation proteins may have profound implications for atherogenesis . On the basis of these results, we derive the hypothesis that the coagulation system is a potential contributor to the pathogenesis of atherosclerosis.
Third, Girolami et al. state that anticoagulant therapies are unable to modify the structure and progression of atherosclerotic plaques. This assertion is, however, contradicted by recent animal studies [18–20] that investigated whether modulation of thrombin activity by direct thrombin or factor Xa inhibitors would affect atherosclerotic progression. Kadoglou et al. provided evidence that long-term treatment with dabigatran in addition to a high-fat diet reduced atherosclerotic progression in apolipoprotein E (ApoE)−/− mice, despite the absence of blood lipid changes . Furthermore, dabigatran seemed to promote plaque stability, probably by modifying inflammatory mechanisms. In our own studies, we observed similar inhibitory effects of dabigatran on atherosclerosis in mice with the severe thrombomodulin (TM)pro/pro/ApoE−/− phenotype, also related to anti-inflammatory activity . Moreover, these two studies confirm the results of previous work performed with the thrombin inhibitor melagatran . Although these studies show convincing evidence for anticoagulant-induced atherosclerosis reduction in animals, the effects in patients with pre-existing atherosclerosis have still to be determined.
Fourth, we agree with Girolami et al. in that a clear distinction should be made between atherosclerosis and atherothrombosis. Therefore, throughout the whole review, we used the term atherosclerosis for the development and progression of streaks and plaques within the arterial vessel wall, and arterial thrombosis for pathologic thrombus formation.
Finally, to conclude, there is involvement of more than lipids with regard to the pathogenesis of atherosclerosis, with abundant experimental evidence suggesting clear biological effects of coagulation factors on the progression of atherosclerosis. Future clinical studies are needed to better elucidate the effects of the new oral anticoagulants on atherosclerosis, and cardiovascular disease in humans.