The Plasma Contact System 2.0

Maas, Coen; Oschatz, Chris; Renné, Thomas

doi:10.1055/s-0031-1276586

Cited by 105 publications

(110 citation statements)

References 60 publications

(72 reference statements)

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“…Of note, KNG1 encodes HK, which is known to play an important role in the contact pathway of coagulation. Almost all FXI and 70% to 90% of prekallikrein circulate in blood as a complex with HK, HK enhances FXI activation by FXII, [28][29][30] and severe HK deficiency is usually associated with low FXI levels 31 Thus, it is plausible to conclude that SNPs in KNG1 influence FXI levels by altering levels of HK, which complexes with and stabilizes FXI in plasma. In this regard, the lead SNP in KNG1 (rs710446) causes a nonsynonymous substitution (Ile581Thr) in HK, which is predicted to be benign according to SIFT and PolyPhen software (Craig Venter Institute, Pulyphen Harvard University) but which is suggested to be part of a potential regulatory region (functional-SNP).…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study Identifies KNG1 as a Genetic Determinant of Plasma Factor XI Level and Activated Partial Thromboplastin Time

Sabater‐Lleal

Martinez-Perez

Buil

et al. 2012

ATVB

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Objective-Elevated plasma levels of coagulation factor XI (FXI) are implicated in the pathogenesis of venous thromboembolism and ischemic stroke, and polymorphisms in the F11 gene are associated both with risk of venous thromboembolism and an elevated plasma FXI level. Methods and Results-Here, we report the first hypothesis-free genome-wide genetic analysis of plasma FXI levels.Two genome-wide significant loci were detected in the family-based Genetic Analysis of Idiopathic Thrombophilia 1 cohort: one located in the kininogen 1 gene (KNG1) (rs710446; P=7.98×10) and one located in the structural F11 gene (rs4241824; P=1.16×10 −8 ). Both associations were replicated in a second population-based Swedish cohort. A significant effect on KNG1 mRNA expression was also seen for the 2 most robustly FXI-associated single nucleotide polymorphisms located in KNG1. Furthermore, both KNG1 single nucleotide polymorphisms were associated with activated partial thromboplastin time, suggesting that FXI may be the main mechanistic pathway by which KNG1 and F11 influence activated partial thromboplastin time and risk of thrombosis. Conclusion-These findings contribute to the emerging molecular basis of venous thromboembolism and, more importantly, help in understanding the biological regulation of a phenotype that has proved to have promising therapeutic properties in relation to thrombosis. (Arterioscler Thromb Vasc Biol. 2012;32

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Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study Identifies KNG1 as a Genetic Determinant of Plasma Factor XI Level and Activated Partial Thromboplastin Time

Sabater‐Lleal

Martinez-Perez

Buil

et al. 2012

ATVB

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“…FXII is activated by negatively charged surfaces, and perhaps by platelet-derived polyphosphates, which act as a scaffold on which FXII and cofactors can colocalize [4][5][6]. Activation of FXII and subsequently prekallikrein (PK) can lead to several distinct phenomena, including clot propagation, clot structure, bradykinin formation, complement activation, neutrophil aggregation, and promotion of fibrinolysis through activation of plasminogen [2,[7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Antigen levels of coagulation factor XII, coagulation factor XI and prekallikrein, and the risk of myocardial infarction and ischemic stroke in young women

Siegerink

Rosendaal

Algra

2014

Journal of Thrombosis and Haemostasis

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To cite this article: Siegerink B, Rosendaal FR, Algra A. Antigen levels of coagulation factor XII, coagulation factor XI and prekallikrein, and the risk of myocardial infarction and ischemic stroke, in young women. J Thromb Haemost 2014; 12: 606-13.Summary. Background: High levels of activated proteininhibitor complexes of the intrinsic coagulation proteins are associated with ischemic stroke (IS) but not with myocardial infarction (MI). This study was aimed at determining whether the antigen levels of coagulation factors (factor XII, FXII, and FXI and prekallikrein (PK) are associated with MI and IS, and whether this association is independent of levels of activated protein-inhibitor complexes. Patients and Methods: The RATIO study included young women (< 50 years) with MI (N = 205) and IS (N = 175), and 638 healthy controls. Antigen levels of FXII, FXI and PK were measured and expressed as percentages of of those in pooled normal plasmas. Odds ratios (ORs) and corresponding 99% confidence intervals (CIs) were calculated for high levels (i.e. ≥ 90th percentile of controls) as measures of rate ratios. Results: After adjustment for potential confounders, high levels of FXII antigen were not associated with MI risk or IS risk (OR MI 1.18, 99% CI 0.51-2.74; OR IS 1.03, 9% CI 0.41-2.55). High levels of FXI antigen were slightly associated with an increase in MI risk (OR MI 1.55, 9% CI 0.74-3.21), whereas there was a substantial association with IS risk (OR IS 2.65, 9% CI 1.27-5.56). PK antigen was slightly associated with MI risk but not with IS risk (OR MI 1.54, 9% CI 0.67-3.52; OR IS 0.90, 9% CI 0.35-2.33). All associations remained similar after adjustment for levels of protein-inhibitor complexes. Conclusion: Increased levels of FXI antigen were associated with an increase in IS risk, whereas they showed only a marginal association with MI risk. FXII antigen and PK antigen levels were not substantially associated with MI risk and IS risk.

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“…9 High-molecular-weight kininogen (KNG) is an important constituent of the plasma contact-kinin system which represents a network of serially connected serine proteases. 10 Activation of the contact-kinin system by FXII triggers cleavage of KNG by plasma kallikrein and subsequent release of the proinflammatory peptide hormone bradykinin. The contact-kinin system occupies a central position in the pathophysiology of different neurologic disease models that mimic, for example, multiple sclerosis 11 or traumatic brain injury.…”

Section: Introductionmentioning

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

120

123

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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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The Plasma Contact System 2.0

Cited by 105 publications

References 60 publications

A Genome-Wide Association Study Identifies KNG1 as a Genetic Determinant of Plasma Factor XI Level and Activated Partial Thromboplastin Time

A Genome-Wide Association Study Identifies KNG1 as a Genetic Determinant of Plasma Factor XI Level and Activated Partial Thromboplastin Time

Antigen levels of coagulation factor XII, coagulation factor XI and prekallikrein, and the risk of myocardial infarction and ischemic stroke in young women

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

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