Factor V Leiden improves in vivo hemostasis in murine hemophilia models

Abstract

To cite this article: Schlachterman A, Schuettrumpf J, Liu J-H, Freguia CF, Toso R, Poncz M, Camire RM, Arruda VR. Factor V Leiden improves in vivo hemostasis in murine hemophilia models. J Thromb Haemost 2005; 3: 2730-7.Summary. The role of factor V Leiden (FVL) as a modifier of the severe hemophilia phenotype is still unclear. We used mice with hemophilia A or B crossed with FVL to elucidate in vivo parameters of hemostasis. Real-time thrombus formation in the microcirculation was monitored by deposition of labeled platelets upon laser-induced endothelial injury using widefield microscopy in living animals. No thrombi formed in hemophilic A or B mice following vascular injuries. However, hemophilic mice, either heterozygous or homozygous for FVL, formed clots at all injured sites. Injection of purified activated FV into hemophilic A or B mice could mimic the in vivo effect of FVL. In contrast to these responses to a laser injury in a microvascular bed, FVL did not provide sustained hemostasis following damage of large vessels in a ferric chloride carotid artery injury model, despite of the improvement of clotting times and high circulating thrombin levels. Together these data provide evidence that FVL has the ability to improve the hemophilia A or B phenotype, but this effect is principally evident at the microcirculation level following a particular vascular injury. Our observations may partly explain the heterogeneous clinical evidence of the beneficial role of FVL in hemophilia.

New insights into the spatiotemporal localization of prothrombinase in vivo

“…27 Therefore, it follows that some or all of the infused FVa localized at the site of the growing hemostatic plug must be functional and complexed with endogenous FXa to generate thrombin. These observations form the basis for our experimental design to use HB mice as a platform to image the constituents of prothrombinase in the developing clot.…”

Thrombus formation reimagined

“…The observation that factor Va corrects the thrombotic defect in the hemophilia B mice proves that it localizes to areas of clotting in this model. 8 The authors…”

Tissue Factor and Thrombosis Models

“…Platelet accumulation (as measured by accumulation of a fluorescent antibody to the ␣ IIb -integrin in platelets) requires thrombin because platelet deposition is abolished or attenuated if thrombin is inhibited with hirudin. 66 Likewise, platelet accumulation is attenuated if laser injury experiments are performed in mice that are deficient in protease-activated receptor (PAR)-4, 85 fVIII, 86 fIX, 86 or fXI. 87 In contrast, platelet accumulation is unaffected by deficiencies in the collagen receptor GPVI, 66 FcR␥, or vWF.…”