Abstract
Direct oral anti-coagulants (DOACs) are employed in clinical practice for the prevention and treatment of recurrent venous thromboembolism and for the prevention of stroke in non-valvular atrial fibrillation. DOACs directly and reversibly inhibit activated factor X or thrombin and can interfere with other pathophysiological processes such as inflammation, lipid metabolism, and bone turnover. We aimed to evaluate the possible effects of DOACs on osteogenesis and angiogenesis. We treated 34 patients affected by cardiovascular disorders with DOACs; biochemical and molecular analyses were performed before and after three months of treatment. Circulating progenitors (CPs; CD34−, CD45−, CD14−, CD73+, CD105+), which share typical bone marrow stem cell (MSCs) features, were harvested from peripheral blood of the study subjects to monitor the expression of osteogenesis-related genes RUNX2 and SPARC. Human umbilical vein endothelial cells (HUVECs) were used to probe angiogenesis-related VEGF, CD31, and CD105 gene expression. We performed co-culture experiments using a commercial human mesenchymal stem cells line (hMSCs) obtained from bone marrow and HUVECs. Clinical parameters related to bone metabolism, coagulation, renal and liver function, and the lipid profile were evaluated. Values of the C-terminal telopeptide type I collagen (CTX) increased after the treatment. We found a significant increase in osteogenesis marker gene expression in CPs after three months of anticoagulant therapy. An increase in the RUNX2 expression determinant alone was detected instead in hMSCs co-cultured with HUVECs in the presence of treated patients’ sera. The VEGF, CD31, and CD105 marker genes appeared to be significantly upregulated in HUVECs co-cultured with hMSCs in the presence of treated patients’ sera. Under these conditions, new vessel formation increased as well. Our results highlight an unexpected influence of DOAC therapy on osteogenic commitment and vascular endothelial function promotion.
Highlights
Direct oral anti-coagulants (DOACs) are direct and selective inhibitors of specific factors of the coagulation cascade [1]
We found a significant increase in osteogenesis marker gene expression in Circulating progenitors (CPs) after three months of anticoagulant therapy
In Human umbilical vein endothelial cells (HUVECs) cultures and animal models, factor Xa appears to be characterized by anti-angiogenic properties, mediated by the activation of PAR-1, and supported by endothelium stabilizing factors secreted by pericytes, fibroblasts, and the smooth muscle cells of the vessel wall
Summary
Direct oral anti-coagulants (DOACs) are direct and selective inhibitors of specific factors of the coagulation cascade [1]. Those currently in use are three activated factor X (AFX) inhibitors, rivaroxaban, apixaban, and edoxaban, and a thrombin inhibitor, dabigatran. DOACs are often referred to as non-vitamin K oral anti-coagulants (NOACs) to emphasize their distinction from vitamin K antagonists (VKAs), whose main exponent is warfarin. The VKA mechanism of action in the coagulation cascade is based on antagonizing vitamin K, an essential cofactor for γ-carboxylation of factors II, VII, IX, and X [2]. DOACs are indicated for the prevention and treatment of recurrent venous thromboembolism (VTE) and for the prevention of stroke and systemic embolization in patients with non-valvular atrial fibrillation (NVAF). Thromboembolic disease can occur both in the arterial and the venous system with different characteristics in terms of the determining factors, thrombus morphology, and associated diseases
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