Factor XI/ADAMTS13 complexes are quantitatively insignificant in human plasma

Reportedly, complexes between factor XI and ADAMTS13 are detected with a commercial ADAMTS13/FXI ELISA kit in plasma and are decreased in thrombotic thrombocytopenic purpura (TTP). Using this kit, control and TTP patient plasma contained varying amounts of signal (25-670% of a reference plasma) but no signal was observed for mixtures of recombinant enzymes, suggesting little interaction. ADAMTS13/FXI complexes were undetectable by immunoprecipitation or gel filtration chromatography in control plasma or mixtures of recombinant proteins. These results suggest that ADAMTS13/FXI complexes are insignificant in plasma and unlikely to affect the function of either protein during normal hemostasis or in TTP

Defective thrombus formation in mice lacking coagulation factor XII

Blood coagulation is thought to be initiated by plasma protease factor VIIa in complex with the membrane protein tissue factor. In contrast, coagulation factor XII (FXII)–mediated fibrin formation is not believed to play an important role for coagulation in vivo. We used FXII-deficient mice to study the contributions of FXII to thrombus formation in vivo. Intravital fluorescence microscopy and blood flow measurements in three distinct arterial beds revealed a severe defect in the formation and stabilization of platelet-rich occlusive thrombi. Although FXII-deficient mice do not experience spontaneous or excessive injury-related bleeding, they are protected against collagen- and epinephrine-induced thromboembolism. Infusion of human FXII into FXII-null mice restored injury-induced thrombus formation. These unexpected findings change the long-standing concept that the FXII-induced intrinsic coagulation pathway is not important for clotting in vivo. The results establish FXII as essential for thrombus formation, and identify FXII as a novel target for antithrombotic therapy

Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases

Protective Roles for Fibrin, Tissue Factor, Plasminogen Activator Inhibitor-1, and Thrombin Activatable Fibrinolysis Inhibitor, but Not Factor XI, during Defense against the Gram-Negative Bacterium Yersinia enterocolitica

Septic infections dysregulate hemostatic pathways, prompting coagulopathy. Nevertheless, anticoagulant therapies typically fail to protect humans from septic pathology. The data reported here may help to explain this discrepancy by demonstrating critical protective roles for coagulation leading to fibrin deposition during host defense against the gram-negative bacterium Yersinia enterocolitica. After intraperitoneal inoculation with Y. enterocolitica, fibrinogen-deficient mice display impaired cytokine and chemokine production in the peritoneal cavity and suppressed neutrophil recruitment. Moreover, both gene-targeted fibrinogen-deficient mice and wild type mice treated with the anticoagulant coumadin display increased hepatic bacterial burden and mortality following either intraperitoneal or intravenous inoculation with Y. enterocolitica. Mice with low tissue factor (TF) activity succumb to yersiniosis with a phenotype similar to fibrin(ogen)-deficient mice, whereas factor XI (FXI)-deficient mice show wild type levels of resistance. Mice deficient in plasminogen activator inhibitor-1 (PAI-1) or thrombin activatable fibrinolysis inhibitor (TAFI) display modest phenotypes, but mice deficient in both PAI-1 and TAFI succumb to yersiniosis with a phenotype resembling fibrin(ogen)-deficient mice. These findings demonstrate critical protective roles for the TF-dependent extrinsic coagulation pathway during host defense against bacteria and caution that therapeutics targeting major thrombin-generating or anti-fibrinolytic pathways may disrupt fibrin-mediated host defense during gram-negative sepsis

Fibrin Facilitates Both Innate and T Cell-Mediated Defense against Yersinia pestis

The gram-negative bacterium Yersinia pestis causes plague, a rapidly progressing and often fatal disease. The formation of fibrin at sites of Y. pestis infection supports innate host defense against plague, perhaps by providing a non-diffusible spatial cue that promotes the accumulation of inflammatory cells expressing fibrin-binding integrins. This report demonstrates that fibrin is an essential component of T cell-mediated defense against plague but can be dispensable for antibody-mediated defense. Genetic or pharmacologic depletion of fibrin abrogated innate and T cell-mediated defense in mice challenged intranasally with Y. pestis. The fibrin-deficient mice displayed reduced survival, increased bacterial burden, and exacerbated hemorrhagic pathology. They also showed fewer neutrophils within infected lung tissue and reduced neutrophil viability at sites of liver infection. Depletion of neutrophils from wild type mice weakened T cell-mediated defense against plague. The data suggest that T cells combat plague in conjunction with neutrophils, which require help from fibrin in order to withstand Y. pestis encounters and effectively clear bacteria