Factor XI deficiency in animal models

Renné, Thomas; Oschatz, Chris; Seifert, Sabine; Müller, Felicitas; Antović, Jovan P.; Karlman, Mattias; Benz, P.

doi:10.1111/j.1538-7836.2009.03393.x

Cited by 52 publications

(48 citation statements)

References 59 publications

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“…Gene-targeted mice lacking the capacity to produce FXI are healthy and fertile and do not display increased bleeding tendencies in response to tail tip amputation or large surgical procedures (12,32). However, both FXI-deficient mice and primates treated with FXI-blocking antibodies are significantly protected against experimentally induced thrombosis (12,32). Together, these observations suggest that FXI is not critical for normal hemostasis but may contribute to thrombosis.…”

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“…Humans with a severe FXI deficiency rarely bleed spontaneously but often exhibit moderate injury-related bleeding tendencies, particularly in tissues with high levels of fibrinolytic activity (35). Gene-targeted mice lacking the capacity to produce FXI are healthy and fertile and do not display increased bleeding tendencies in response to tail tip amputation or large surgical procedures (12,32). However, both FXI-deficient mice and primates treated with FXI-blocking antibodies are significantly protected against experimentally induced thrombosis (12,32).…”

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“…One key component of the intrinsic pathway is activated FXI (FXIa), a protease produced by the liver that circulates in plasma as an inactive homodimer (32). The FXI zymogen can be activated by FXIIa, thrombin, or FXIa (11,13,26,42).…”

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Factor XI-Deficient Mice Display Reduced Inflammation, Coagulopathy, and Bacterial Growth during Listeriosis

et al. 2012

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In mice infected sublethally with Listeria monocytogenes, fibrin is deposited at low levels within hepatic tissue, where it functions protectively by limiting bacterial growth and suppressing hemorrhagic pathology. Here we demonstrate that mice infected with lethal doses of L. monocytogenes produce higher levels of fibrin and display evidence of systemic coagulopathy (i.e., thrombocytopenia, fibrinogen depletion, and elevated levels of thrombin-antithrombin complexes). When the hepatic bacterial burden exceeds 1 ؋ 10 6 CFU, levels of hepatic fibrin correlate with the bacterial burden, which also correlates with levels of hepatic mRNA encoding the hemostatic enzyme factor XI (FXI). Gene-targeted FXI-deficient mice show significantly improved survival upon challenge with high doses of L. monocytogenes and also display reduced levels of hepatic fibrin, decreased evidence of coagulopathy, and diminished cytokine production (interleukin-6 [IL-6] and IL-10). While fibrin limits the bacterial burden during sublethal listeriosis in wild-type mice, FXI-deficient mice display a significantly improved capacity to restrain the bacterial burden during lethal listeriosis despite their reduced fibrin levels. They also show less evidence of hepatic necrosis. In conjunction with suboptimal antibiotic therapy, FXI-specific monoclonal antibody 14E11 improves survival when administered therapeutically to wild-type mice challenged with high doses of L. monocytogenes. Together, these findings demonstrate the utility of murine listeriosis as a model for dissecting qualitative differences between protective and pathological host responses and reveal novel roles for FXI in exacerbating inflammation and pathogen burden during a lethal bacterial infection.

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Factor XI-Deficient Mice Display Reduced Inflammation, Coagulopathy, and Bacterial Growth during Listeriosis

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“…Third, the degree of neuroprotection caused by KNG depletion is remarkable and exceeds that observed in other reports of cerebral ischemia in animals deficient in members of the kallikrein-kinin system. 4,32 This is probably because of the central role of KNG in multiple processes, including thrombosis, vascular permeability, and inflammation. 33 Finally, although severe deficiencies of FXI may be associated with bleeding in humans, there is no such association of bleeding with KNG deficiency.…”

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confidence: 99%

Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Langhauser¹,

Göb²,

Kraft³

et al. 2012

Blood

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Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. Highmolecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng Ϫ/Ϫ mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng Ϫ/Ϫ mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases. (Blood. 2012;120(19): 4082-4092) IntroductionThe pathology of ischemic stroke is complex and involves a myriad of distinct molecular pathways and cellular interactions. Among these, progressive thrombus formation in the cerebral microvasculature is a key process that can cause secondary infarct growth despite successful recanalization of larger proximal brain vessels both under experimental conditions as well as in humans. 1,2 We recently identified the intrinsic coagulation cascade as a novel and safe antithrombotic target for the prevention and treatment of acute ischemic stroke. 3 Genetic depletion or pharmacologic blockade of coagulation factor XII (FXII), the origin of the intrinsic pathway, markedly reduced intracerebral thrombus formation and infarct growth in mice without increasing the risk of bleeding complications. 4,5 Clot formation was also significantly reduced in several in vitro models of thrombosis after FXII inhibition. 5 Current pathophysiologic concepts also emphasize the importance of inflammatory mechanisms in stroke. 6 The cerebral endothelium is activated early during the course of an ischemic event, leading to the up-regulation of cell adhesion molecules and successive trafficking of inflammatory cells (neutrophils, macrophages, T cells) from the blood stream into the brain parenchyma. Those cells attracted from the periphery in concert with resident cell populations (endothelial cells, microglia) secrete an array of soluble immune mediators such as cytokines and chemokines that perpetuate the inflammatory response to cause direct or indirect ti...

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“…3 The role of FXI in hemostasis and thrombosis has been extensively studied in animal models. 4,5 In contrast to patients with hereditary FXI deficiency, FXI-null mice do not bleed excessively when challenged by surgical procedures. FXI-null mice have not been systematically analyzed by injury to tissues with high fibrinolytic activity, so it is not known whether the protease is required for normal hemostasis in mice in some situations.…”

Section: Safe(r) Anticoagulation ------------------------------------mentioning

confidence: 99%

Safe(r) anticoagulation

Renné

2010

Blood

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Factor XI deficiency in animal models

Cited by 52 publications

References 59 publications

Factor XI-Deficient Mice Display Reduced Inflammation, Coagulopathy, and Bacterial Growth during Listeriosis

Factor XI-Deficient Mice Display Reduced Inflammation, Coagulopathy, and Bacterial Growth during Listeriosis

Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Safe(r) anticoagulation

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