Abstract
The defective hemostatic process in hemophiliacs overlaps with the underlying physiology contributing to bleeding risk in anticoagulated patients. Hemophiliacs may also develop compensatory changes in fibrinolysis, platelet reactivity, vascular inflammation, and remodeling secondarily. We therefore explored markers for these processes in hemophilia A and B as part of our larger effort to develop translational biomarkers to guide antithrombotic therapy and minimize bleeding risk. Plasmas from hemophilia A patients (11 severe; 1 moderate) and hemophilia B patients (3 severe; 3 mild or moderate), sampled after a treatment washout period, and 7 normal subjects were procured. Markers/assays pursued include: coagulation (F1+2, FPA, TAT, D-dimer), fibrinolysis (PAP, PAI-1, tPA), platelet activation (soluble P-selectin (sP-sel)), vascular inflammation (MCP-1), angiogenesis (VEGF), PT, aPTT, and thrombin generation assay (TGA). Consistent with aPTT prolongation and changes in TGA, both hemophilia groups displayed numerically lower than normal levels of all 4 coagulation markers, with hemophilia A reaching statistical significance for F1+2 and TAT. Hemophilia A also exhibited a significant decrease in PAP and a numerical increase in PAI-1 compared to normal. VEGF and MCP-1 exhibited no appreciable difference. In the combined analysis for hemophilia A and B (“A+B”), PAP displayed a strong positive correlation with F1+2 and a strong negative correlation with PAI-1; A+B exhibited a statistically significant reduction in F1+2, FPA, and TAT, and a non-significant increase in sP-sel and non-significant decrease in PAP, compared to normal. In conclusion, hemophilia A and B plasma samples had significantly reduced markers of in vivo thrombin generation, thrombin activity, and coagulation, and trends evidencing increased platelet activation and decreased fibrinolysis, possibly as compensation. Lack of signal in vascular inflammation or angiogenesis could be due to the (near optimal) hemostatic therapies. Our results illustrate the potential value of biomarkers of in vivo coagulation, fibrinolysis, and platelet activation in translational research on antithrombotic therapies for both their efficacy and bleeding risk.
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