Major bleeding during oral anticoagulant therapy associated with factor V activation by factor Xa

Figures

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  FIGURE 1. Marked differences in TIX‐5 sensitivity of the thrombin generation lag time in plasma of healthy individuals. Thrombin generation was initiated with 5 pM tissue factor in plasma of 60 healthy individuals in the absence or presence of 4 μM TIX‐5. Representative curves are shown of healthy individuals in the category men (n = 15; A), women without (w/o) oral contraceptives (OC) use (n = 15; B), or women with OC use (n = 15; C). D, Lag times of thrombin generation in the absence or presence of TIX‐5 or (E) expressed as TIX‐5 sensitivity by the lag time + TIX‐5/lag time + vehicle ratio with the vehicle condition set at 100% per category. F, TIX‐5 effect on the thrombin generation parameters lag time, endogenous thrombin potential (ETP), and velocity index in plasma of all 60 healthy individuals shown as TIX‐5/vehicle ratio, with the vehicle conditions set at 100%. All data are depicted as median ± 95% confidence interval. Statistical significance: **P < 0.01, ***P < 0.005, ****P < 0.001

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  FIGURE 2. Substantial prolongation of the thrombin generation (TG) lag time by TIX‐5 in plasma of vitamin K antagonist (VKA)‐treated patients with major bleeding. Thrombin generation was initiated with 20 pM tissue factor in the absence or presence of 4 μM TIX‐5 in plasma of patients on VKA therapy without (controls, n = 538) or with major bleeding (cases, n = 263). A, Representative TG curves for normal human pooled plasma (NHP) and individual patients on VKAs. B, Vehicle lag time of all patients on VKA without or with major bleeding were plotted against the TIX‐5 sensitivity of the lag time of TG of these patients. C, The lag time and (D) endogenous thrombin potential (ETP) of TG in the absence or presence of TIX‐5 in plasmas of controls and cases. Data are depicted as median ± 95% confidence interval. Statistical significance: *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001

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  FIGURE 3. Association of γ′‐fibrinogen and tissue factor pathway inhibitor (TFPI⍺) levels with major bleeding and TIX‐5 sensitivity in cases and controls on vitamin K antagonist (VKA) therapy. Plasma levels of γ′‐fibrinogen (A) or TFPI⍺ (C) were determined in VKA patients without (n = 538; controls) and with major bleeding (n = 263; cases). The data are depicted as median ± 95% confidence interval. The TIX‐5 sensitivity (lag time + TIX‐5/lag time + vehicle ratio) was plotted versus the plasma levels of γ′‐fibrinogen (B) or TFPI⍺ (D) in all cases and controls combined. Correlations were analyzed by linear regression analysis. Statistical significance: **P < 0.01, ***P < 0.005, ****P < 0.001

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  FIGURE 4. Ablation of TIX‐5 mediated lag time prolongation by FV‐short like FV‐810 is modulated by tissue factor pathway inhibitor (TFPIα). Thrombin generation was initiated with 5 pM tissue factor in normal human pooled plasma (NHP) in the absence or presence of 4 μM TIX‐5 and with 1 nM FV‐810 as indicated. A, Thrombograms representing NHP (black), NHP + FV810 (blue), NHP + FV810 + 1 nM TFPIα (red), or NHP + FV810 + 2 nM TFPIα. B, Lag times of thrombin generation in the absence (filled) or presence (striped) of TIX‐5 depicted as mean (n = 2), and (C) the TIX‐5 sensitivity (lag time + TIX‐5/lag time + vehicle ratio) of the curves in (A)

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  FIGURE 5. Schematic representation of the observed associated risk of major bleeding during vitamin K antagonist (VKA) therapy with processes and regulators of the pathway to thrombin. A, Factor FXa (Xa) and thrombin (IIa) activate FV (V) to FVa (Va) during the initiation phase of prothrombin (II) activation to thrombin. B, The quick activation of FV by thrombin (IIa) is inhibited by γ′‐fibrinogen, increasing the contribution of FXa‐mediated activation of FV. Tissue factor pathway inhibitor (TFPIα) inhibits FXa, FV activation, FV‐short, and FV activation intermediates (latter two not indicated for clarity). Greater dependence of thrombin generation on FXa‐mediated FV activation, and higher TFPIα and γ′‐fibrinogen levels are associated with major bleeding during VKA therapy