Differential roles of factors IX and XI in murine placenta and hemostasis under conditions of low tissue factor

Abstract

The intrinsic tenase complex (FIXa-FVIIIa) of the intrinsic coagulation pathway and, to a lesser extent, thrombin-mediated activation of FXI, are necessary to amplify tissue factor (TF)-FVIIa–initiated thrombin generation. In this study, we determined the contribution of murine FIX and FXI to TF-dependent thrombin generation in vitro. We further investigated TF-dependent FIX activation in mice and the contribution of this pathway to hemostasis. Thrombin generation was decreased in FIX- but not in FXI-deficient mouse plasma. Furthermore, injection of TF increased levels of FIXa-antithrombin complexes in both wild-type and FXI−/− mice. Genetic studies were used to determine the effect of complete deficiencies of either FIX or FXI on the survival of mice expressing low levels of TF. Low-TF;FIX−/y male mice were born at the expected frequency, but none survived to wean. In contrast, low-TF;FXI−/− mice were generated at the expected frequency at wean and had a 6-month survival equivalent to that of low-TF mice. Surprisingly, a deficiency of FXI, but not FIX, exacerbated the size of blood pools in low-TF placentas and led to acute hemorrhage and death of some pregnant dams. Our data indicate that FIX, but not FXI, is essential for survival of low-TF mice after birth. This finding suggests that TF-FVIIa–mediated activation of FIX plays a critical role in murine hemostasis. In contrast, FXI deficiency, but not FIX deficiency, exacerbated blood pooling in low-TF placentas, indicating a tissue-specific requirement for FXI in the murine placenta under conditions of low TF.

Description of the first mutation in the human tissue factor gene associated with a bleeding tendency

“…20 These low TF mice survive to wean at close to the expected frequency but exhibit spontaneous fatal hemorrhages later in life. 21,22 Low TF mice demonstrate a mildly prolonged bleeding in the tail transection and saphenous laser injury models. 23,24 It is notable that mice expressing very low levels of FVII have a similar phenotype to low TF mice.…”

“…Importantly, TF‐null mice can be rescued by the expression of a low level (~1%) of human TF from a human TF minigene 20 . These low TF mice survive to wean at close to the expected frequency but exhibit spontaneous fatal hemorrhages later in life 21,22 . Low TF mice demonstrate a mildly prolonged bleeding in the tail transection and saphenous laser injury models 23,24 .…”

Role of Factor XIa and Plasma Kallikrein in Arterial and Venous Thrombosis

“…70 Interestingly, a recent study showed that FXI, but not FIX deficiency in mice with low levels of TF is associated with increased blood pool size in the placenta, suggesting a tissue-specific role for FXI in mice. 71 Postnatal survival of low TF mice was however dependent on FIX levels. 71 Similar antithrombotic effects of FXI deficiency could be shown in a FeCl 3 -induced vena cava thrombosis mouse model.…”

“…71 Postnatal survival of low TF mice was however dependent on FIX levels. 71 Similar antithrombotic effects of FXI deficiency could be shown in a FeCl 3 -induced vena cava thrombosis mouse model. 72 Likewise, the role of FXI in development of thrombosis has been studied in higher species.…”

Unraveling the role of factor XI and plasma prekallikrein in coagulation

“…70 Interestingly, a recent study showed that FXI, but not FIX deficiency in mice with low levels of TF is associated with increased blood pool size in the placenta, suggesting a tissue-specific role for FXI in mice. 71 Postnatal survival of low TF mice was however dependent on FIX levels. 71 Similar antithrombotic effects of FXI deficiency could be shown in a FeCl3-induced vena cava thrombosis mouse model.…”