The many faces of the contact pathway and their role in thrombosis

Woodruff, Rebecca S.; Sullenger, Bruce A.; Becker, Richard C.

doi:10.1007/s11239-011-0578-5

Cited by 46 publications

(44 citation statements)

References 139 publications

(158 reference statements)

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“…In contrast to the extrinsic pathway, the intrinsic pathway has low physiological significance, but under pathological conditions, its activation is associated with the formation of circulating clots and thrombi (47). Activation of the intrinsic pathway is triggered in response to damaged vessel wall surfaces, after contact of vessel walls with lipoprotein particles, bacteria, or other pathogens including viruses (33,39).…”

Section: Resultsmentioning

confidence: 99%

Large-Scale Chromatin Immunoprecipitation with Promoter Sequence Microarray Analysis of the Interaction of the NSs Protein of Rift Valley Fever Virus with Regulatory DNA Regions of the Host Genome

Benferhat

Josse

Albaud

et al. 2012

J Virol

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dRift Valley fever virus (RVFV) is a highly pathogenic Phlebovirus that infects humans and ruminants. Initially confined to Africa, RVFV has spread outside Africa and presently represents a high risk to other geographic regions. It is responsible for high fatality rates in sheep and cattle. In humans, RVFV can induce hepatitis, encephalitis, retinitis, or fatal hemorrhagic fever. The nonstructural NSs protein that is the major virulence factor is found in the nuclei of infected cells where it associates with cellular transcription factors and cofactors. In previous work, we have shown that NSs interacts with the promoter region of the beta interferon gene abnormally maintaining the promoter in a repressed state. In this work, we performed a genome-wide analysis of the interactions between NSs and the host genome using a genome-wide chromatin immunoprecipitation combined with promoter sequence microarray, the ChIP-on-chip technique. Several cellular promoter regions were identified as significantly interacting with NSs, and the establishment of NSs interactions with these regions was often found linked to deregulation of expression of the corresponding genes. Among annotated NSs-interacting genes were present not only genes regulating innate immunity and inflammation but also genes regulating cellular pathways that have not yet been identified as targeted by RVFV. Several of these pathways, such as cell adhesion, axonal guidance, development, and coagulation were closely related to RVFV-induced disorders. In particular, we show in this work that NSs targeted and modified the expression of genes coding for coagulation factors, demonstrating for the first time that this hemorrhagic virus impairs the host coagulation cascade at the transcriptional level.

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Section: Resultsmentioning

confidence: 99%

Large-Scale Chromatin Immunoprecipitation with Promoter Sequence Microarray Analysis of the Interaction of the NSs Protein of Rift Valley Fever Virus with Regulatory DNA Regions of the Host Genome

Benferhat

Josse

Albaud

et al. 2012

J Virol

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“…This is in accordance with clinical evidence that elevated levels of FXII(a) positively associate with arterial thrombosis, ischemic stroke, and coronary heart disease. [29][30][31] On the contrary, conflicting evidence exists on whether individuals with partly reduced FXII levels have an increased risk of cardiovascular disease (reviewed in Renné et al 15 and Woodruff et al 16 ). In this regard, the thrombus-destabilizing effect observed under conditions of reduced FXII activity needs more attention.…”

Section: Discussionmentioning

confidence: 99%

“…4,[10][11][12][13] Interestingly, deficiency in FXII in man or mouse is not accompanied by abnormal bleeding. 3,14 On the contrary, individuals with partly reduced FXII levels have an increased risk of cardiovascular disease (reviewed in Renné et al 15 and Woodruff et al 16 ), which indicates that the clinical consequences of (partial) FXII deficiency are more complex than the reported antithrombotic effects of FXII ablation in mice.…”

Section: See Accompanying Editorial On Page 1607mentioning

confidence: 99%

Factor XII Regulates the Pathological Process of Thrombus Formation on Ruptured Plaques

Kuijpers

Meijden

Feijge

et al. 2014

ATVB

117

100

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A therothrombosis, characterized by atherosclerotic lesion disruption with superimposed thrombus formation, is the major cause of acute coronary syndromes and cardiovascular death. Predominantly, platelet-rich (white) thrombi are formed at the ruptured area, because platelet recruitment preferentially occurs at regions of high shear rate and disturbed flow, whereas maximal fibrin generation occurs in regions of low flow.1 Activated platelets support the tissue factor (TF) pathway of blood coagulation by binding various (anti)coagulation factors.2 There is emerging evidence that platelets also support the intrinsic coagulation pathway mediated by factors XII (FXII) and XI (FXI), for example, by releasing polyphosphates, although the exact mechanism is still unclear.3-5 Better understanding of these multifaceted roles of platelets in coagulation stimulation can lead to new approaches to selectively inhibit the pathways most relevant in atherothrombosis. See accompanying editorial on page 1607Collagen type I is not only the most potent platelet activating component in atherosclerotic plaques by binding and activating the glycoprotein VI receptor, 6-8 but has also has been shown to bind to and activate FXII. 9 Several mouse studies using nonatherosclerotic vessels point to a consolidating role of the FXII pathway in arterial thrombus formation and thrombus stabilization, as concluded from experiments with genetic ablation or pharmacological inhibition of FXII.4,10-13 Interestingly, deficiency in FXII in man or mouse is not accompanied by abnormal bleeding.3,14 On the contrary, individuals with partly reduced FXII levels have an increased risk of cardiovascular disease (reviewed in Renné et al 15 and Woodruff et al 16 ), which indicates that the clinical consequences of (partial) FXII deficiency are more complex than the reported antithrombotic effects of FXII ablation in mice.To date, no experimental data exist on a role of the intrinsic coagulation pathway in pathological thrombus formation after atherosclerotic plaque rupture. A recent report studying plaque-induced thrombin generation in vitro suggested that the intrinsic FXII pathway may not play a key role in this process, such in contrast to a predominant role for plaque-derived TF triggering the extrinsic pathway. 8 In the present article, we therefore compared the roles of both the extrinsic and intrinsic coagulation pathways in thrombus formation on atherosclerotic plaques in vivo and ex vivo. Objective-Atherothrombosis is the main cause of myocardial infarction and ischemic stroke. Although the extrinsic (tissue factor-factor VIIa [FVIIa]) pathway is considered as a major trigger of coagulation in atherothrombosis, the role of the intrinsic coagulation pathway via coagulation FXII herein is unknown. Here, we studied the roles of the extrinsic and intrinsic coagulation pathways in thrombus formation on atherosclerotic plaques both in vivo and ex vivo. Approach and Results-Plaque rupture after ultrasound treatment evoked immediate formation of subocclu...

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“…Patients with hereditary deficiencies of prekallikrein, high-molecular-weight kininogen or factor XII do not have bleeding problems while deficiency of factor XI leads to a moderate bleeding diathesis [16]. However recent evidence suggests that the intrinsic pathway may play a role in pathological thrombosis, fibrinolysis and angiogenesis [18].…”

Section: Overview Of Haemostasismentioning

confidence: 99%

Emerging Anticoagulants

Kennedy¹,

Gargoum²,

Kennedy³

et al. 2012

curr med chem

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Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.

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The many faces of the contact pathway and their role in thrombosis

Cited by 46 publications

References 139 publications

Large-Scale Chromatin Immunoprecipitation with Promoter Sequence Microarray Analysis of the Interaction of the NSs Protein of Rift Valley Fever Virus with Regulatory DNA Regions of the Host Genome

Large-Scale Chromatin Immunoprecipitation with Promoter Sequence Microarray Analysis of the Interaction of the NSs Protein of Rift Valley Fever Virus with Regulatory DNA Regions of the Host Genome

Factor XII Regulates the Pathological Process of Thrombus Formation on Ruptured Plaques

Emerging Anticoagulants

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