Elevated factor VIII enhances thrombin generation in the presence of factor VIII-deficiency, factor XI-deficiency or fondaparinux.
BACKGROUND: Increased levels of factor VIII occur as a response to vascular injury and/or inflammation, and may increase thrombotic risks. In contrast, factor VIII deficiency poses a major hemostatic challenge. The role of factor VIII in modulating hemostasis/thrombosis was investigated in plasma models of hypocoagulable and hypercoagulable state using thrombin generation (TG) assay. METHODS: TG was performed in undiluted/diluted control, FVIII-deficient, FVIII-deficient with low antithrombin (AT activity, ~59%), and factor XI-deficient plasma samples using relipidated tissue factor (TF, 2 pM) or dilute Actin as activators. The impact of elevated FVIII on TG was simulated by adding Humate-P (0 to 3 U/ml) to the above plasma samples. In fondaparinux (1 μg/ml) treated plasma with normal or lower AT activity effects of Humate-P vs. 60 nM of recombinant activated factor VII (rFVIIa) were also evaluated. RESULTS: Humate-P increased TG concentration dependently in undiluted and diluted control plasma with TF activation. With Actin activation, only the concentration dependent shortening of lag time, but no change in peak thrombin was observed. In FVIII-deficient, FVIII-deficient with low AT, and FXI-deficient samples, 3 U/ml of Humate-P increased TG, and decreased its onset with either activator. The reduced peak thrombin due to fondaparinux was reversed with Humate-P (3 U/ml) more than with rFVIIa. Elevated FVIII levels seem to favor intrinsic tenase formation and antagonize fondaparinux because anti-FIXa aptamer added to fondaparinux effectively attenuated TG. CONCLUSION: Elevated FVIII supports the propagation of TG via intrinsic tenase formation under low TF condition, factor XI deficiency or in the presence of fondaparinux.
Szlam, F; Sreeram, G; Solomon, C; Levy, JH; Molinaro, RJ; Tanaka, KA
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