Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vivo mouse models have indicated that the intrinsic coagulation pathway, initiated by factor XII, contributes to thrombus formation in response to major vascular damage. Here, we show that fibrillar type I collagen provoked a dose-dependent shortening of the clotting time of human plasma via activation of factor XII. This activation was mediated by factor XII binding to collagen. Factor XII activation also contributed to the stimulating effect of collagen on thrombin generation in plasma, and increased the effect of platelets via glycoprotein VI activation. Furthermore, in flow-dependent thrombus formation under coagulant conditions, collagen promoted the appearance of phosphatidylserine-exposing platelets and the formation of fibrin. Defective glycoprotein VI signaling (with platelets deficient in LAT or phospholipase Cgamma2) delayed and suppressed phosphatidylserine exposure and thrombus formation. Markedly, these processes were also suppressed by absence of factor XII or XI, whereas blocking of tissue factor/factor VIIa was of little effect. Together, these results point to a dual role of collagen in thrombus formation: stimulation of glycoprotein VI signaling via LAT and PLCgamma2 to form procoagulant platelets; and activation of factor XII to stimulate thrombin generation and potentiate the formation of platelet-fibrin thrombi.
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PMID:Dual role of collagen in factor XII-dependent thrombus formation. 1962 16

Early evidence has already shown that activated platelets play a role in the intrinsic pathway of coagulation, but the mechanism remained unclear. The finding that the dense granules of platelets contain polyphosphate (polyP), which has procoagulant effects, resolved this missing link between activated platelets and coagulation. PolyP secreted from platelets leads via activation of Factor XII to in vivo thrombin and fibrin formation. The relative importance of polyP in the process and stages of thrombus formation will require further investigation. In addition to its role in coagulation, polyP-induced Factor XII activation mediates the release of the inflammatory mediator bradykinin by activating the kallikrein-kinin system. This results in vascular leakage and edema formation in vivo. Together, polyP release from platelets has a physiological role in the thrombus-forming process, as well as in inflammatory reactions.
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PMID:Polyphosphates: a link between platelet activation, intrinsic coagulation and inflammation? 2000 7

Cancer is an established risk factor for venous thromboembolism (VTE) and VTE is the second leading cause of death in patients with cancer. The incidence of cancer-related thrombosis is rising and is associated with worse outcomes. Despite our growing understanding on tumor-driven procoagulant mechanisms including cancer-released procoagulant proteases, expression of tissue factor on cancer cells and derived microvesicles, as well as alterations in the extracellular matrix of the cancer cell milieu, anticoagulation therapy in cancer patients has remained challenging. This review comments on a newly discovered cancer-associated procoagulant pathway. Experimental VTE models in mice and studies on patient cancer material revealed that prostate cancer cells and associated exosomes display the inorganic polymer polyphosphate on their plasma membrane. Polyphosphate activates blood coagulation factor XII and initiates thrombus formation via the intrinsic pathway of coagulation. Pharmacologic inhibition of factor XII activity protects mice from VTE and reduces thrombin coagulant activity in plasma of prostate cancer patients. Factor XII inhibitors provide thrombo-protection without impairing hemostatic mechanisms and thus, unlike currently used anticoagulants, do not increase bleeding risk. Interference with the polyphosphate/factor XII pathway may provide the novel opportunity for safe anticoagulation therapy in patients with malignancies.
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PMID:The polyphosphate/factor XII pathway in cancer-associated thrombosis: novel perspectives for safe anticoagulation in patients with malignancies. 2720 22

Contact between biomedical materials and blood often initiates undesirable pro-coagulant and pro-inflammatory processes. On negatively charged materials, blood coagulation is known to be triggered through autoactivation of Factor XII, while activation on cationic surfaces follows a distinct and so far enigmatic mechanism. Because Factor VII activating protease (FSAP) is known to be activated on positively and on negatively charged macromolecules in plasma, we have investigated its interaction with charged biomaterials and its consequences for coagulation. Several activation processes in blood and plasma were characterized after contact with material surfaces with varied charge. FSAP was found to be exclusively activated by the positively charged surfaces polyethylenimine (PEI) and poly-l-lysine (PLL), not by the negatively charged glass or self-assembled monolayer with carboxyl group termination (SAM-COOH), as well as uncharged (Teflon AF) surfaces. Whole blood incubation on PEI showed that this activation was concomitant with coagulation as determined by thrombin and fibrin formation, which was high for glass (F1+2, 138 nM) and PEI (F1+2, 44 nM) but low for Teflon AF (F1+2, 3.3 nM) and SAM COOH (F1+2, 5.8 nM). Contact phase inhibitor diminished coagulation to background levels for all surfaces except PEI (F1+2: ^PEI 43 to 25 nM; glass, 58 to 1.5 nM) indicating that coagulation activation is not dependent on FXII activation on the PEI surface. A decisive role of endogenous FSAP for coagulation however was confirmed with the use of FSAP inhibitory antibodies which showed no influence on Teflon AF, glass and SAM COOH but diminished F1+2 on PEI to less than 50%. We propose that FSAP activation could be a novel mechanism of surface-driven coagulation. An inhibition of this protease might improve hemocompatibility of cationic surfaces and therefore facilitate the application of polycationic surfaces in blood.
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PMID:A Positively Charged Surface Triggers Coagulation Activation Through Factor VII Activating Protease (FSAP). 2909 93

The need to improve blood biocompatibility of medical devices is urgent. As soon as blood encounters a biomaterial implant, proteins adsorb on its surfaces, often leading to several complications such as thrombosis and failure of the device. Therefore, controlling protein adsorption plays a major role in developing hemocompatible materials. In this study, the interaction of key blood plasma proteins with superhemophobic titania nanotube substrates and the blood clotting responses was investigated. The substrate stability was evaluated and fibrinogen adsorption and thrombin formation from plasma were assessed using ELISA. Whole blood clotting kinetics was also investigated, and Factor XII activation on the substrates was characterized by an in vitro plasma coagulation time assay. The results show that superhemophobic titania nanotubes are stable and considerably decrease surface protein adsorption/Factor XII activation as well as delay the whole blood clotting, and thus can be a promising approach for designing blood contacting medical devices.
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PMID:Interaction of blood plasma proteins with superhemophobic titania nanotube surfaces. 3127 63

Hageman factor (factor XII) has a key role in activation of intrinsic coagulation system gauged by activated partial thromboplastin time (aPPT). Hageman factor deficiency is more often an autosomal recessive condition, but an autosomal dominant inheritance is also reported. This condition in its own is not known to cause bleeding complications rather is associated with paradoxical fatal thromboembolic complications. Exact prevalence of this condition is not known, as under normal conditions they are asymptomatic. In literature, a prevalence of 2.3% has been reported in one study on 300 patients presenting with complications. Homozygous patients has non-detectable levels of factor XII, while heterozygous individuals has variable levels ranging from 20-60%. Hageman factor is a pro-coagulation protein initiating intrinsic pathway. Intrinsic pathway is activated either by direct contact with a negative charged surface or by proteolytic activation on the endothelial cells via prekallikerin/kallikerin system. Factor XII as an integral part of this system leads to factor XI activation resulting in production of thrombin orchestrated by intrinsic system. In addition, there is concomitant activation of complement components C3 and C5 via C1-estrase activation. Patients with this condition are known to have spontaneous thromboembolic complications although less common but are prone to life threatening complications under provocating circumstances. The aim of this case report is to study the relation of factor XII deficiency and isolated raised activated partial thromboplastin time (aPPT) and how it can be prevented. We are presenting a Saudi female patient, 29 years of age who presented to accident and emergency room (A&E room) of our hospital with sudden severe breathlessness and chest pain.
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PMID:Factor XII (Hageman Factor) Deficiency: a rare harbinger of life threatening complications. 3138 54

In the past several years, a number of C1q binding surface proteins or receptors have been described. This is not of course surprising considering the complexity of the C1q molecule and its ability to bind to a wide range of cellular and plasma proteins via both its collagen-like [cC1q] region and its heterotrimeric globular heads [gC1q] each of which in turn is capable of binding a specific ligand. However, while each of these "receptor" molecules undoubtedly plays a specific function within its restricted microenvironment, and therefore merits full attention, this review nonetheless, will singularly focus on the structure and function of gC1qR-a multi-functional and multi-compartmental protein, which plays an important role in inflammation, infection, and cancer. Although first identified as a receptor for C1q, gC1qR has been shown to bind to a plethora of proteins found in plasma, on the cell surface and on pathogenic microorganisms. The plasma proteins that bind to gC1qR are mostly blood coagulation proteins and include high molecular weight kininogen [HK], Factor XII [Hageman factor], fibrinogen, thrombin [FII], and multimeric vitronectin. This suggests that gC1qR can play an important role in modulating not only of fibrin formation, particularly at local sites of immune injury and/or inflammation, but by activating the kinin/kallikrein system, it is also able to generate, bradykinin, a powerful vasoactive peptide that is largely responsible for the swelling seen in angioedema. Another important function of gC1qR is in cancer, where it has been shown to play a role in tumor cell survival, growth and metastatic invasion by interacting with critical molecules in the tumor cell microenvironment including those of the complement system and kinin system. Finally, by virtue of its ability to interact with a growing list of pathogen-associated molecules, including bacterial and viral ligands, gC1qR is becoming recognized as an important pathogen recognition receptor [PRR]. Given the numerous roles it plays in a growing list of disease settings, gC1qR has now become a potential target for the development of monoclonal antibody-based and/or small molecule-based therapies.
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PMID:The C1q Receptors: Focus on gC1qR/p33 (C1qBP, p32, HABP-1)¹. 3174 53

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cause of vascular death after heart attack and stroke. Anticoagulation therapy is the cornerstone of VTE treatment. Despite such therapy, up to 50% of patients with DVT develop postthrombotic syndrome, and up to 4% of patients with PE develop chronic thromboembolic pulmonary hypertension. Therefore, better therapies are needed. Although direct oral anticoagulants are more convenient and safer than warfarin for VTE treatment, bleeding remains the major side effect, particularly in cancer patients. Factor XII and factor XI have emerged as targets for new anticoagulants that may be safer. To reduce the complications of VTE, attenuation of thrombin activatable fibrinolysis inhibitor activity is under investigation in PE patients to enhance endogenous fibrinolysis, whereas blockade of leukocyte interaction with the vessel wall is being studied to reduce the inflammation that contributes to postthrombotic syndrome in DVT patients. Focusing on these novel antithrombotic strategies, this article explains why safer anticoagulants are needed, provides the rationale for factor XII and XI as targets for such agents, reviews the data on the factor XII- and factor XI-directed anticoagulants under development, describes novel therapies to enhance fibrinolysis and decrease inflammation in PE and DVT patients, respectively, and offers insights into the opportunities for these novel VTE therapies.
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PMID:Novel antithrombotic strategies for treatment of venous thromboembolism. 3191 85


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