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)

The platelet collagen receptor, glycoprotein (GP)VI, initiates platelet aggregation at low shear stress while GPIb-IX-V, which binds von Willebrand factor, elicits platelet aggregation under high shear conditions. To investigate the possibility that GPIb-IX-V and GPVI are associated on the platelet surface, we first ascertained that aggregation induced by a GPVI-specific agonist, collagen-related peptide, like collagen, is markedly cross-blocked by a GPIb alpha-specific monoclonal antibody, SZ2. Immunoprecipitation of GPIb-IX with anti-GPIb alpha from the 1% (v/v) Triton-soluble fraction of unstimulated platelets and immunoblotting with anti-GPVI demonstrated association between GPIb-IX and GPVI. This association was maintained when platelets were activated by thrombin. Pre-treatment of platelets with methyl-beta-cyclodextrin to disrupt lipid rafts did not affect association in resting platelets under these conditions of detergent lysis. The association is also independent of cytoskeletal attachment, since it was unaffected by treatment with N-ethylmaleimide or DNaseI, which dissociate GPIb-IX from filamin and the actin-containing cytoskeleton, respectively. Finally, the association involves an interaction between the ectodomains of GPIb alpha and GPVI, since soluble fragments of GPIb alpha (glycocalicin) and GPVI are co-precipitated from the platelet supernatant under conditions where GPVI is shed. A contribution of GPIb-IX-V to GPVI-induced platelet responses, and vice versa, therefore warrants further investigation.
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PMID:Glycoprotein VI is associated with GPIb-IX-V on the membrane of resting and activated platelets. 1584 18

Collagens (types I and III) are among the strongest thrombus-forming components of the vascular subendothelium. We compared the thrombogenic effects of four collagen-containing advanced atherosclerotic lesions with those of purified types I and III collagen fibers. Cell-free homogenates from the human plaques effectively promoted platelet adhesion and aggregate formation under high-shear flow conditions, as well as exposure of procoagulant phosphatidylserine (PS) on platelets. With all plaques, blocking of the glycoprotein VI (GPVI) receptor for collagen abolished aggregation and PS exposure. Blocking of platelet ADP receptors resulted in similar, but less complete inhibitory effects. Type I collagen was more potent than type III collagen in inducing aggregation and PS exposure under flow, via stimulation of GPVI and ADP receptors. Type I collagen also more strongly enhanced thrombin generation with platelets and tissue factor, again via GPVI activation and PS exposure. The plaque material enhanced thrombin generation, partly due to the presence of tissue factor and partly via GPVI and ADP receptors. Together, these results indicate that in advanced plaques collagen type I is a major trigger of thrombus formation and PS exposure, acting via GPVI and ADP release, while tissue factor directly enhances coagulation.
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PMID:Contribution of platelet glycoprotein VI to the thrombogenic effect of collagens in fibrous atherosclerotic lesions. 1593 50

Collagen is a unique agonist of platelets, because it acts as an immobilized ligand that only causes platelet activation after stable adhesion. This review addresses the present understanding of how platelet interaction with collagen supports the process of thrombin generation and coagulation. Only some of the collagen-adhered platelets, that is, those showing profound changes in shape and shedding microparticles (resembling apoptotic cells), appear to contribute to the procoagulant activity of platelets. The main signaling receptor for collagen, glycoprotein VI, plays a key role in the platelet procoagulant response during thrombus formation; this is a reason why new anti-glycoprotein-VI antibodies are promising antithrombotic tools.
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PMID:Platelet collagen receptors and coagulation. A characteristic platelet response as possible target for antithrombotic treatment. 1603 67

Clinical trials have shown estrogen replacement therapy (ERT) is associated with adverse arterial vascular events. Arterial thrombosis is initiated by platelet activation, but the in vivo effects of estrogens on platelet function are not well understood. We used a murine model of menopause to examine 3 major ERT regimes and test the hypothesis that ERT affects the intrinsic platelet response to agonists. The 3 ERT regimes studied were: (1) oral conjugated equine estrogen (CEE), (2) oral 17-beta estradiol (E2), and (3) subcutaneously implanted E2 (SQ E2). Paired ovariectomized littermates were treated with these regimes or placebo for 21 days. Two platelet agonists, thrombin and the GPVI-specific agonist collagen-related peptide (COL-RP), were used to evaluate platelet reactivity. Among the 3 regimens, (1) oral CEE enhanced platelet reactivity to COL-RP, (2) oral E2 had no effect on platelet reactivity to COL-RP and (3) SQ E2 increased platelet sensitivity to thrombin but lowered reactivity to COL-RP. Thus, the in vivo effects of estrogen on platelet function are agonist specific and dependent on hormone formulation and mode of delivery. The GPVI collagen receptor likely mediated some of these effects, because the ERT regimens induced changes in platelet surface GPVI expression corresponding to the observed platelet activation.
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PMID:Effects of estrogen replacement therapies on mouse platelet function and glycoprotein VI levels. 1610 41

The role of collagens and collagen receptors was investigated in stimulating platelet-dependent thrombin generation. Fibrillar type-I collagens, including collagen from human heart, were most potent in enhancing thrombin generation, in a way dependent on exposure of phosphatidylserine (PS) at the platelet surface. Soluble, non-fibrillar type-I collagen required pre-activation of integrin alpha2beta1 with Mn2+ for enhancement of thrombin generation. With all preparations, blocking of glycoprotein VI (GPVI) with 9O12 antibody abrogated the collagen-enhanced thrombin generation, regardless of the alpha2beta 1 activation state. Blockade of alpha2beta1 alone or antagonism of autocrine thromboxane A2 and ADP were less effective. Blockade of alphaIIbbeta3 with abciximab suppressed thrombin generation in platelet-rich plasma, but this did not abolish the enhancing effect of collagens. The high activity of type-I fibrillar collagens in stimulating GPVI-dependent procoagulant activity was confirmed in whole-blood flow studies, showing that these collagens induced relatively high expression of PS. Together, these results indicate that: i) fibrillar type-I collagen greatly enhances thrombin generation, ii) GPVI-induced platelet activation is principally responsible for the procoagulant activity of fibrillar and non-fibrillar collagens, iii) alpha2beta1 and signaling via autocrine mediators facilitate and amplify this GPVI activity, and iv) alphaIIbbeta3 is not directly involved in the collagen effect.
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PMID:Fibrillar type I collagens enhance platelet-dependent thrombin generation via glycoprotein VI with direct support of alpha2beta1 but not alphaIIbbeta3 integrin. 1611 93

Gab2, a recently identified docking protein, contains a pleckstrin homology domain and potential binding sites for SH2 and SH3 domain-containing proteins. Gab2 has been shown to support growth, differentiation, and function in a number of haematopoietic cells, although its role in platelets remains to be determined. Here we report that cross-linking of the collagen receptor GPVI by the snake venom toxin convulxin stimulates tyrosine phosphorylation of Gab2. Furthermore, platelet aggregation induced by submaximal concentrations of convulxin is attenuated in the absence of Gab2, although recovery is seen with higher concentrations of the toxin. Consistent with this, tyrosine phosphorylation of Fc receptor gamma-chain, Syk, Btk, and phospholipase Cgamma2 by convulxin is reduced in the absence of Gab2. In comparison, the G protein-coupled receptor agonist, thrombin, does not induce phosphorylation of Gab2 and aggregation is unaltered in the absence of the toxin. These findings provide evidence for a functional role of Gab2 in supporting platelet activation by GPVI.
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PMID:Docking protein Gab2 positively regulates glycoprotein VI-mediated platelet activation. 1619 16

Adaptor proteins play a pivotal role in the regulation of signal transduction events elicited after the engagement of cell surface receptors. Platelets exhibit a number of integral membrane receptors capable of initiating a cellular response. These include collagen receptors, von Willebrand factor receptors, the fibrinogen receptor, and a number of G-protein coupled receptors, such as those for thrombin and ADP. The primary function of platelet receptors is the translation of externally applied signals into appropriate responses leading to platelet activation being a prerequisite for normal hemostasis. Multitude of signalling pathways described in platelets is based on the interaction of compounds of many different categories, such as transmembrane receptors, protein kinases, protein phoshatases, G-proteins, transmembrane and cytosolic adaptor proteins, phosphoinositides, cyclic AMP or GMP. Adaptor proteins lack intrinsic effector function, but contain distinct molecular domains, which mediate protein-protein and protein-lipid interactions. These molecules thus serve as a scaffolding, around which effectors and their substrates are assembled into three-dimensional signaling complexes. Adaptor proteins integrate receptor-mediated signals at intracellular levels and couple signaling receptors to cytosolic signaling pathways. While the function of adaptor proteins is well established in immune cells, the knowledge about their role in platelet activation is still at the onset Over the last decade numerous adaptor proteins have been identified in platelets and shown to be involved in accurate assembly of intracellular signaling complexes. Collagen-induced platelet intracellular signaling through GPVI resembles the functional response of B- and T-cell antigen receptors and is the best described in the literature. This review focuses on the structure and functional role of the most extensively studied adaptor proteins during platelet activation induced by physiological agonists.
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PMID:[Adaptor proteins of blood platelets]. 1638 Nov 75

Fibrillar collagens are among the most potent activators of platelets and play an important role in the initiation of thrombosis. The glycoprotein VI (GPVI)/FcRgamma-chain complex is a central collagen receptor and inhibitors of GPVI produce a major defect in arterial thrombogenesis. In this study we have examined arterial thrombus formation in mice lacking the GPVI/FcRgamma-chain complex (FcRgamma(-/-)). Using 3 distinct arterial thrombosis models involving deep vascular injury, we demonstrate that deficiency of GPVI/FcRgamma is not associated with a major defect in arterial thrombus formation. In contrast, with milder vascular injury deficiency of GPVI/FcRgamma was associated with a 30% reduction in thrombus growth. Analysis of FcRgamma(-/-) platelets in vitro, using thrombin-dependent and -independent thrombosis models, demonstrated a major role for thrombin in overcoming the thrombosis defect associated with GPVI/FcRgamma deficiency. Inhibition of thrombin in vivo produced a much greater defect in thrombus formation in mice lacking GPVI/FcRgamma compared with normal controls. Similarly, thrombin inhibition produced a marked prolongation in bleeding time in FcRgamma(-/-) mice relative to wild-type mice. Our studies define an important role for thrombin in overcoming the hemostatic and thrombotic defect associated with GPVI/FcRgamma deficiency. Moreover, they raise the interesting possibility that the full antithrombotic potential of GPVI receptor antagonists may only be realized through the concurrent administration of anticoagulant agents.
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PMID:Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRgamma deficiency. 1639 Oct 10

A kinetic Monte Carlo simulation was developed using the deterministic reaction network developed by the Mann laboratory for tissue-factor (TF)-initiated blood coagulation. The model predicted thrombin dynamics in recalcified whole blood (3-fold diluted) pretreated with convulxin (platelet GPVI activator) and picomolar levels of TF (0-14 pM). The model did not accurately predict coagulation times at low TF (0-0.7 pM). The simulation revealed that approximately 0.2 pM TF was the critical concentration to cause 50% of reactions containing 3-fold diluted whole blood to reach a clotting threshold of 0.05 U/ml thrombin by 1 h. Simulations of 1 nl of blood (5 pM TF) revealed small stochastic variations in thrombin initiation time, while 16.6 pl simulations were highly stochastic at this level of TF (50 molecules/16.6 pl). Further experiment and simulation will require evaluation of mechanisms of coagulation kinetics at subpicomolar levels of TF.
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PMID:Stochastic modeling of blood coagulation initiation. 1643 10

The gray platelet syndrome (GPS) is a rare inherited disorder of the megakaryocyte (MK) lineage. Thrombocytopenia and enlarged platelets are associated with a specific absence of alpha-granules and their contents. GPS patients exhibit much heterogeneity both in bleeding severity and in their response to platelet function testing. A unique feature is that proteins endogenously synthesised by megakaryocytes (MK) or endocytosed by MK or platelets fail to enter into the secretable storage pools that characterise alpha-granules of normal platelets. Although the molecular basis of the disease is unknown, evidence suggests that alpha-granules simply fail to mature during MK differentiation. One result is a continued leakage of growth factors and cytokines into the marrow causing myelofibrosis. While for some patients platelet function may be only moderately affected, for others thrombin and/or collagen-induced platelet aggregation is markedly modified and an acquired lack of the GPVI collagen receptor has been reported. In this review, we document the clinical and molecular heterogeneity in GPS, a unique disease of the biogenesis of platelet alpha-granules and of the storage of growth factors and secretable proteins.
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PMID:The gray platelet syndrome: clinical spectrum of the disease. 1644 92


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