The Characterization of Mice with a Targeted Combined Deficiency of Protein C and Factor XI

Chan, Janice; Ganopolsky, Jorge G.; Cornelissen, Ivo; Suckow, Mark A.; Sandoval-Cooper, Mayra J.; Brown, Erica C.; Noria, Francisco; Gailani, David; Rosen, Elliot D.; Ploplis, Victoria A.

doi:10.1016/s0002-9440(10)63989-2

Cited by 38 publications

(37 citation statements)

References 29 publications

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“…In addition, increased tissue fibrin levels (data not shown) and multiple foci of myocardial fibrosis ( Figure 4d) were apparent in 8-week-old TMLox mice, indicating thrombosis of cardiac blood vessels. Of note, no thrombus formation was observed in cardiac atria, which has been described in factor V Leiden mice (26) and mice deficient in PC (27)(28)(29). Fibrin deposition, as determined by immunohistochemistry and Western blot analysis, was minimal in the brain of TMLox mice, whereas tissue fibrin levels in the lung and heart were increased (at age 3 and 8 weeks; data not shown).…”

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confidence: 50%

Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis

et al. 2001

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The thrombomodulin (TM) gene was ablated in mice in a cell type-restricted manner from vascular endothelium by Cre-recombinase-mediated excision controlled by the endothelial cell lineage-specific Tie2 promoter. Forty percent of mutant (TMLox-) mice display a distinct lethal embryonic phenotype not observed in completely TM-deficient embryos. The remaining 60% of TMLox mice survive beyond birth, but invariably succumb to a severe hypercoagulable state and massive thrombosis after 3 weeks, terminating in a lethal consumptive coagulopathy. The progression of thrombosis was age-and sex-dependent. Disruption of the TM/protein C pathway was not associated with a latent proinflammatory state. Disease onset and progression could be prevented by warfarin anticoagulation. These results show that in mice, loss of endothelial cell TM function causes spontaneous and fatal thrombosis in the arterial and venous circulation, resulting from unfettered activation of the coagulation system. The combination of complete disease penetrance, uniform disease onset at young age, large vessel thrombosis of the extremities and multiple organ systems, and consumptive coagulopathy as the disease end-point provides a unique mouse model of human thrombotic disease.

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confidence: 50%

Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis

et al. 2001

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Section: Genetic Manipulation Of Fxi In Micementioning

confidence: 64%

“…Mice deficient in both protein C and FXI were partially protected in that they did not die until much later in life. 36 These data further validate FXI as a therapeutic target in a model in which fibrin formation is activated in a physiological manner.Overall, studies with FXI-null mice are consistent with the tolerable hemostatic defect of hemophilia C. They also strongly support FXI as a therapeutic target for preventing occlusive thrombosis in response to severe vessel injury. The question of whether efficacy could be obtained with a more proportionate and incomplete inhibition of FXI or FXIa requires the evaluation of selective pharmacological tools.…”

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confidence: 64%

Inhibition of Factor XIa as a New Approach to Anticoagulation

Schumacher

Luettgen

Quan

et al. 2010

ATVB

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Abstract-The dose-limiting issue with available anticoagulant therapies is bleeding. Is there an approach that could provide antithrombotic protection with reduced bleeding? One hypothesis is that targeting proteases upstream from the common pathway provides a reduction in thrombin sufficient to impede occlusive thrombosis yet allows enough thrombin generation to support hemostasis. The impairment of intrinsic coagulation by selective inhibition of factor XI (FXI) leaves the extrinsic and common pathways of coagulation intact, making FXI a drug target. This concept is supported by the observation that human deficiency in FXI results in a mild bleeding disorder compared with other coagulation factor deficiencies, and that elevated levels of FXI are a risk factor for thromboembolic disease. Moreover, FXI knockout mice have reduced thrombosis with little effect on hemostasis. The results from genetic models have been supported by studies using neutralizing antibodies, peptide inhibitors, and small-molecule inhibitors. These agents impede thrombosis without affecting bleeding time in a variety of experimental animals, including primates. Together, these data strongly support FXIa inhibition as a viable method to increase the ratio of benefit to risk in an antithrombotic drug. (Arterioscler Thromb Vasc Biol. 2010;30:388-392.)Key Words: intrinsic pathway Ⅲ coagulation Ⅲ factor XI Ⅲ thrombosis The Need for Improved Anticoagulant TherapyHemostasis is an adaptive process that maintains blood in a fluid state and preserves vasculature integrity. Thrombosis is a maladaptive process of vascular occlusion and remains a primary cause of cardiovascular morbidity and mortality. Antithrombotic therapy is effective for the prevention and treatment of thromboembolic disease. However, the established oral anticoagulant warfarin has numerous limitations, including lack of reversibility, a steep dose response, food and multiple drug-drug interactions, need for monitoring, and a narrow therapeutic index. The availability of newer oral anticoagulants, such as direct and selective inhibitors of factor Xa (FXa) and thrombin, has overcome many of these liabilities; however, dose-dependent bleeding continues to be observed. 1,2 An overlap of antithrombotic benefit and a disruption of hemostasis are not unexpected given that both processes involve interactions between the vessel wall, platelets, blood coagulation, and fibrinolysis. Improving the risk to benefit ratio remains a viable goal for antithrombotic drug See accompanying article on page 369discovery. This requires selecting a molecular target that defines a difference between hemostasis and thrombosis. Selecting such a target derives from the detailed study of human physiology and animal models. A good example is the inhibition of blood coagulation FXIa as a novel mechanism for preventing and treating thromboembolic diseases. Role of FXIa in Blood CoagulationBlood coagulation is the coordinated activation of plasma proteases, their cofactors, and platelets. The end product is the pr...

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“…The progress of thrombosis was observed with an epiilluminiscence microscope (BX10; Olympus), which was equipped with a digital camera (Cooke 1600; Cooke Corporation). A series of brief videos were recorded using Camware software (Cooke Corporation) at different time points (1,3,5,7,10,15,20,30, and 40 minutes) after carotid artery injury. The size of the thrombus was estimated by measurement of the fluorescence intensity of thrombus inside the vessel based on the image acquired from the recorded video with NIH ImageJ software after background correction.…”

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confidence: 99%

The kunitz protease inhibitor domain of protease nexin-2 inhibits factor XIa and murine carotid artery and middle cerebral artery thrombosis

Navaneetham

et al. 2012

Blood

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Coagulation factor XI (FXI) plays an important part in both venous and arterial thrombosis, rendering FXIa a potential target for the development of antithrombotic therapy. The kunitz protease inhibitor (KPI) domain of protease nexin-2 (PN2) is a potent, highly specific inhibitor of FXIa, suggesting its possible role in the inhibition of FXI-dependent thrombosis in vivo. Therefore, we examined the effect of PN2KPI on thrombosis in the murine carotid artery and the middle cerebral artery. Intravenous administration of PN2KPI prolonged the clotting time of both human and murine plasma, and PN2KPI inhibited FXIa activity in both human and murine plasma in vitro. The intravenous administration of PN2KPI into WT mice dramatically decreased the progress of FeCl 3 -induced thrombus formation in the carotid artery. After a similar initial rate of thrombus formation with and without PN2KPI treatment, the propagation of thrombus formation after 10 minutes and the amount of thrombus formed were significantly decreased in mice treated with PN2KPI injection compared with untreated mice. In the middle cerebral artery occlusion model, the volume and fraction of ischemic brain tissue were significantly decreased in PN2KPI-treated compared with untreated mice. Thus, inhibition of FXIa by PN2KPI is a promising approach to antithrombotic therapy. (Blood. 2012;120(3):671-677) IntroductionCoagulation factor XI (FXI) has an essential role both in maintaining normal hemostasis and in the pathogenesis of thrombosis. 1 Because deficiencies of factor XII (FXII), prekallikrein, and high M r kininogen are not associated with hemostatic abnormalities but FXI deficiency produces relatively mild, posttraumatic bleeding complications in ϳ 50% of affected individuals, 2-4 the more relevant pathway for activation of plasma FXI might be via feedback activation by thrombin or possibly autoactivation by FXIa. 5,6 High levels of FXI constitute a risk factor for deep venous thrombosis (DVT) 7 and cardiovascular disease in women. 8 Although inherited FXI deficiency confers no protection against acute myocardial infarction (AMI), 9 a large clinical study showed that the risk of DVT in the 10% of individuals in a population with the highest levels of FXI was Ͼ 2-fold greater than that for the remaining 90% of the population, supporting the conclusion that elevated FXI levels constitute an important risk factor for venous thrombosis. 7,8,10 There is also a reduced incidence of ischemic stroke in patients with severe FXI deficiency. 11 One study followed 600 patients with a first episode of venous thromboembolism and found an increased risk of recurrence, especially among those with increased levels of thrombin-activatable fibrinolysis inhibitor (TAFI) and FXI, 12 whereas another study showed that increased levels of TAFI, but not FXI, increased the risk of venous thromboembolism in patients with FV Leiden carrier status. 10 These studies are consistent with the results of studies demonstrating increased rabbit jugular vein thrombolysis by FXI Ab neutrali...

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The Characterization of Mice with a Targeted Combined Deficiency of Protein C and Factor XI

Cited by 38 publications

References 29 publications

Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis

Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis

Inhibition of Factor XIa as a New Approach to Anticoagulation

The kunitz protease inhibitor domain of protease nexin-2 inhibits factor XIa and murine carotid artery and middle cerebral artery thrombosis

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