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)

When a blood vessel is injured, control of bleeding starts with the rapid adhesion of circulating platelets to the site of damage. Within seconds, the adhered platelets are activated, secrete the contents of storage organelles, spread out over the damaged area and recruit more platelets to the developing thrombus. However, if this same process occurs in a diseased, sclerotic or occluded vessel, the resulting platelet thrombus may break away and block the coronary artery, causing a heart attack, or restrict blood supply to the brain, causing a stroke. The glycoprotein (GP) Ib-IX-V complex, a member of the leucine-rich protein family, is a constitutive platelet membrane receptor for von Willebrand Factor (vWF), a multimeric adhesive glycoprotein found in the matrix underlying the endothelial cell lining of the blood vessel wall and in the plasma. Binding of vWF to the GP. Ib-IX-V complex regulates adhesion of platelets to the subendothelium at high shear flow, and initiates signal transduction leading to platelet activation. The GP Ib-IX-V complex also constitutes a binding site for alpha-thrombin, an interaction that facilitates thrombin-dependent platelet activation. This review will focus on recent detailed analysis of the GP Ib-IX-V complex and vWF that has identified discrete amino acid sequences that mediate their interaction. An anionic/sulfated tyrosine sequence of the GP Ib alpha-chain that is critical for binding of the GP Ib-IX-V complex to both vWF and alpha-thrombin is analogous to sulfated anionic amino acid sequences mediating interactions of other adhesive proteins, including P-selectin binding to PSGL-1 and Factor VIII binding to vWF.
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PMID:Molecular mechanisms of platelet adhesion and activation. 907 44

Nitric oxide (NO) is known to be an important endogenous modulator of leukocyte-endothelial cell interactions within the microcirculation. We examined leukocyte rolling and adhesion under baseline conditions and following thrombin (0.25 U/ml) superfusion in the mesentery of wild-type, inducible NOS (iNOS)-deficient (-/-), neuronal NOS (nNOS) -/-, and endothelial cell NOS (ecNOS) -/- mice to further our understanding of NO and leukocyte function. Baseline leukocyte rolling (cells/min) was significantly elevated in both the nNOS -/- (30.0 +/- 4.0) and ecNOS -/- mice (67.0 +/- 12.0) compared with wild-type mice (11.0 +/- 1.4). In addition, baseline leukocyte adherence (cells/100 micrometers of vessel) was also significantly elevated in the nNOS -/- (5.2 +/- 1.0) and ecNOS -/- (13.0 +/- 1.3) compared with wild-type animals (1.3 +/- 0.5). Deficiency of iNOS had no effect on baseline leukocyte rolling or adhesion in the mesentery. Baseline surface expression of P-selectin was observed in 68.0 +/- 9.0% of intestinal venules in ecNOS -/- mice compared with 10.0 +/- 2.0% in wild-type mice. Additional studies demonstrated that administration of an anti-P-selectin monoclonal antibody (RB40. 34) or the soluble P-selectin ligand, PSGL-1, completely inhibited the increased rolling and firm adhesion response in nNOS -/- and ecNOS -/- mice. Transmigration of neutrophils into the peritoneum following thioglycollate injection was also significantly augmented in nNOS -/- and ecNOS -/- mice. These studies clearly indicate the NO derived from both nNOS and ecNOS is critical in the regulation of leukocyte-endothelial cell interactions.
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PMID:Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice. 1036 74

The mechanism of healing or rejection of implant materials is unknown, but the process always starts at the contact with coagulating blood. Here, the initial reactions of clean (hydrophilic) and alkylated (hydrophobic) titanium with blood were investigated by short-term exposure to human blood and detection of polymorphonuclear leukocyte (PMNL) surface antigens with an immunofluorescence technique. The fluorescence intensity was quantitated by computer-aided image analysis. Antibodies specific to CD11b, CD16, CD18, CD62L, and CD162 were used to block PMNL adhesion. The respiratory burst of adhering cells was stimulated with opsonized zymosan and measured by chemiluminiscence. The thrombin dependence of PMNL reactions was studied by using hirudin, a specific thrombin inhibitor. The expression of CD62L decreased with increasing exposure time, and the rate of decrease was faster at the hydrophilic surface. At the hydrophilic surface, the CD16 exposure was high after 8 minutes of blood contact, and it decreased with time. At the hydrophobic surface, a peak in CD16 expression was seen after 32 minutes of blood exposure. At the hydrophobic surface, the expression of CD11b increased slowly with increasing blood exposure time, whereas at the hydrophilic surface, a peak of CD11b expression was seen after 32 minutes of blood exposure. The expression of CD11b and that of CD16 were found to be thrombin dependent. At the hydrophilic surface, adhesion of PMNLs was blocked by CD16 antibodies, whereas adhesion to the hydrophobic surface was blocked by anti-CD162. Mixing blood with antibodies to CD11b, CD18, and CD62L amplified the adhesion of PMNLs to the hydrophilic surface.
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PMID:Polymorphonuclear leukocytes in coagulating whole blood recognize hydrophilic and hydrophobic titanium surfaces by different adhesion receptors and show different patterns of receptor expression. 1128 25

Considerable data now support the hypothesis that platelets actively regulate the propagation of coagulation by (1) expressing specific, high-affinity receptors for coagulation proteases, zymogens, and cofactors; (2) protecting the bound coagulation enzymes from inactivation/inhibition; (3) restricting coagulant activity to the site of vascular injury; and (4) amplifying the initiating stimulus to lead to explosive thrombin generation. Thrombin generation is sustained at the site of vascular injury by the recruitment of circulating monocytes and neutrophils to the growing thrombus via the interaction of PSGL-1, which is constitutively expressed by leukocytes, with P-selectin, which is expressed by activated platelets. Unique among cells, monocytes can provide the appropriate membrane surface for the assembly and function of all the coagulation complexes required for tissue factor-initiated thrombin production. More studies are required to further delineate the roles of neutrophils and lymphocytes in the procoagulant response. This review will discuss the recent investigations and controversies regarding the various mechanisms by which platelets and leukocytes function in, and regulate, thrombin generation.
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PMID:Platelets, leukocytes, and coagulation. 1160 60

High plasma levels of soluble P-selectin are associated with thrombotic disorders and may predict future cardiovascular events. Mice with high levels of soluble P-selectin have more microparticles in their plasma than do normal mice. Here we show that chimeras of P-selectin and immunoglobulin (P-sel-Ig) induced formation of procoagulant microparticles in human blood through P-selectin glycoprotein ligand-1 (PSGL-1; encoded by the Psgl1 gene, officially known as Selpl). In addition, Psgl1-/- mice produced fewer microparticles after P-sel-Ig infusion and did not spontaneously increase their microparticle count in old age as do wild-type mice. Injected microparticles specifically bound to thrombi and thus could be involved in thrombin generation at sites of injury. Infusion of P-sel-Ig into hemophilia A mice produced a 20-fold increase over control immunoglobulin in microparticles containing tissue factor. This significantly improved the kinetics of fibrin formation in the hemophilia A mice and normalized their tail-bleeding time. P-sel-Ig treatment could become a new approach to sustained control of bleeding in hemophilia.
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PMID:Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. 1289 56

This study was undertaken to systematically investigate the binding kinetics of platelet recruitment by monocytes relative to neutrophils in bulk suspensions subjected to shear as well as the molecular requirements of leukocyte-platelet binding. Hydrodynamic shear-induced collisions augment the proportion of monocytes with adherent platelets more drastically than that of neutrophils with bound platelets. These heterotypic interactions are further potentiated by platelet activation with thrombin or to a lesser extent by monocyte stimulation with N-formyl-methionyl-leucyl-phenylalanine (fMLP). Monocyte-platelet heteroaggregation increases with increasing shear rate and shear exposure time. Platelet P-selectin binding to monocyte P-selectin-glycoprotein-ligand-1 is solely responsible for maximal platelet adhesion to unstimulated monocytes in shear flow. However, the enhanced platelet binding to fMLP-treated monocytes involves a sequential two-step process, wherein P-selectin-PSGL-1 interactions are stabilized by CD18-integrin involvement. Blocking platelet alpha(IIb)beta(3) or monocyte beta(1)-integrin function had no effect. This study underscores the preferential recruitment of platelets by monocytes relative to neutrophils in shear flow, and demonstrates that the shear environment of the vasculature coupled to the state of cell activation modulates the dynamics and molecular constituents mediating monocyte-platelet adhesion.
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PMID:Preferential binding of platelets to monocytes over neutrophils under flow. 1572 13

1. P-selectin is involved, with P-selectin glycoprotein (GP)-ligand-1 (PSGL-1), in platelet/leukocyte interactions during thrombo-inflammatory reactions; it also stabilizes platelet aggregates. Its antagonism accelerates thrombolysis and enhances the anti-aggregatory effects of GPIIb-IIIa inhibitors. This study was designed to investigate the mechanisms of P-selectin-mediated platelet aggregation. 2. In freshly isolated human platelets, P-selectin translocation after thrombin stimulation increased rapidly to 48, 72, and 86% positive platelets after 60, 120, and 300 s, respectively. Platelet aggregation at 60 s post-stimulation averaged 46.7 +/- 1.9% and its extent followed closely the kinetics of P-selectin translocation. 3. Pre-treatment of platelets with P-selectin antagonists, a recombinant PSGL-1 (rPSGL-Ig) or a blocking monoclonal antibody, significantly delayed platelet aggregation in a dose-dependent manner. At 100 microg ml(-1) of rPSGL-Ig, platelet aggregation was completely inhibited up to 60 s post-stimulation and increased thereafter to reach maximal aggregation at 5 min. The second phase of platelet aggregation, in the presence of rPSGL-Ig, was completely prevented by the addition of a GPIIb-IIIa antagonist (Reopro) at 60 s, whereas its addition in the absence of rPSGL-Ig was without any significant effect. 4. Combination of rPSGL-Ig with Reopro or with an inhibitor of Pi3K (LY294002), which reduces GPIIb-IIIa activation, showed to be more effective in inhibiting platelet aggregation, in comparison to the effects observed individually. 5. rPSGL-Ig blocks P-selectin, whereas Reopro and LY294002 block GPIIb-IIIa and its activation, respectively, without a major effect on the percentage of platelets expressing P-selectin. 6. In summary, platelet P-selectin participates with GPIIb-IIIa in the initiation of platelet aggregation. Its inhibition, with rPSGL-Ig, delays the aggregation process and increases the anti-aggregatory potency of Reopro. Thus, combination of P-selectin and GPIIb-IIIa antagonism may constitute a promising therapeutic option in the management of thrombotic disorders.
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PMID:Recombinant P-selectin glycoprotein-ligand-1 delays thrombin-induced platelet aggregation: a new role for P-selectin in early aggregation. 1663 57

Sepsis and trauma lead to a sustained activation of monocytes and endothelium. In the vascular compartment, stimulated cells release microparticles. Circulating MP provide an additional procoagulant phospholipid surface enabling the assembly of the clotting enzymes complexes and thrombin generation. Their procoagulant properties rely on the exposition of phosphatidylserine, made accessible after cell stimulation and on the possible presence of tissue factor, the main cellular initiator of blood coagulation. Microparticles constitute the main reservoir of blood-borne tissue factor activity. At sites of endothelium injury, enhanced release or recruitment of procoagulant MP through P-selectin-PSGL-1 pathway could concentrate TF activity above a threshold allowing blood coagulation to be triggered. Converging evidences from experimental or clinical data highlight a role for MP harboring tissue factor in the initiation of disseminated intravascular coagulopathy. In these settings, the pharmacological modulation of MP levels or biological functions through activated protein C or factor VIIa allows challenging issues.
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PMID:[Microparticles during sepsis and trauma. A link between inflammation and thrombotic processes]. 1692 90

We assessed the effect of the intercellular mediator of inflammation, platelet activating factor (PAF), on platelet function. The interaction between PAF and the platelet agonists ADP, thrombin and convulxin was analyzed in vitro in whole blood with the use of flow cytometry and was further characterized with the use of receptor antagonists to PAF (ABT-491), P2Y1 (MRS-2179), and P2Y12 (cangrelor) as well as a monoclonal anti-PSGL-1 antibody (anti-CD162). Low concentrations of PAF (0.1 nM) synergistically augmented platelet activation induced by other agonists (P < 0.01). Augmentation by PAF was receptor mediated and did not require platelet-leukocyte interaction. With >99% inhibition of P2Y receptor-mediated platelet activation, greater than additive activation was still observed with the combination of ADP plus PAF. Accordingly, PAF synergistically augments platelet activation in response to ADP and thrombin, and the extent of inhibition exerted by P2Y receptor antagonists is decreased in the presence of PAF.
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PMID:The influence of platelet activating factor on the effects of platelet agonists and antiplatelet agents in vitro. 1857 70

The popular concept of TF serving predominantly as a hemostatic envelope encapsulating the vascular bed, has recently been challenged by the observation that blood of healthy individuals may form TF-induced thrombus under conditions entailing shear stress and activated platelets, corroborating the notion of blood borne TF. Accordingly, small amounts of TF activity is detected in calcium ionophore-stimulated monocytes, whereas it is questionable whether neutrophils and eosinophils express TF. Still there are contradicting reports on TF synthesis and expression in activated platelets, but when using a very sensitive and specific assay for TF activity measurements, we fail to detect TF activity associated with platelets activated with various agonists. However, activated platelets may play a role in decrypting monocyte TF activity in a process entailing transfer of TF to activated platelets in a P-selectin-PSGL-1 reaction whereby inactive TF (encrypted) becomes active through the availability of clusters of phosphatidylserine. Microparticles from plasma of healthy subjects possess weak TF-like activity which is not inactivated by anti-TF antibody. Endothelial cells are well documented to synthesize TF by several agonists in vitro. In contrast, there is little evidence that these cells are capable of synthesizing TF in vivo, and a recent report fails to show that TF on the endothelium may play any role in thrombin generation in a murine endotoxemia model. It may be concluded that monocytes are the only blood cells that synthesize and express TF and which may be the only source for TF-induced thrombosis when the endothelium is intact.
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PMID:Tissue factor expression in blood cells. 2014 15


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