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)

We have previously described Kunitz-type serine proteinase inhibitors purified from Bauhinia seeds. Human plasma kallikrein shows different susceptibility to those inhibitors. In this communication, we describe the interaction of human plasma kallikrein with fluorogenic and non-fluorogenic peptides based on the Bauhinia inhibitors' reactive site. The hydrolysis of the substrate based on the B. variegata inhibitor reactive site sequence, Abz-VVISALPRSVFIQ-EDDnp (Km 1.42 microM, kcat 0.06 s(-1), and kcat/Km 4.23 x 10(4) M(-1) s(-1)), is more favorable than that of Abz-VMIAALPRTMFIQ-EDDnp, related to the B. ungulata sequence (Km 0.43 microM, kcat 0.00017 s(-1), and kcat/Km 3.9 x 10(2) M(-1) s(-1)). Human plasma kallikrein does not hydrolyze the substrates Abz-RPGLPVRFESPL-EDDnp and Abz-FESPLRINIIKE-EDDnp based on the B. bauhinioides inhibitor reactive site sequence, the most effective inhibitor of the enzyme. These peptides are competitive inhibitors with Ki values in the nM range. The synthetic peptide containing 19 amino acids based on the B. bauhinioides inhibitor reactive site (RPGLPVRFESPL) is poorly cleaved by kallikrein. The given substrates are highly specific for trypsin and chymotrypsin hydrolysis. Other serine proteinases such as factor Xa, factor XII, thrombin and plasmin do not hydrolyze B. bauhinioides inhibitor related substrates.
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PMID:Synthetic peptides and fluorogenic substrates related to the reactive site sequence of Kunitz-type inhibitors isolated from Bauhinia: interaction with human plasma kallikrein. 1125 60

Eighty percent of patients with diabetes mellitus die a thrombotic death. Seventy-five percent of these deaths is due to cardiovascular complications, and the remainder is due to cerebrovascular events and peripheral vascular complications. Vascular endothelium, the primary defense against thrombosis, is abnormal in diabetes. Endothelial abnormalities undoubtedly play a role in the enhanced activation of platelets and clotting factors seen in diabetes. Coagulation activation markers, such as prothrombin activation fragment 1+2 and thrombin-anti-thrombin complexes, are elevated in diabetes. The plasma levels of many clotting factors including fibrinogen, factor VII, factor VIII, factor XI, factor XII, kallikrein, and von Willebrand factor are elevated in diabetes. Conversely, the level of the anticoagulant protein C (PC) is decreased. The fibrinolytic system, the primary means of removing clots, is relatively inhibited in diabetes due to abnormal clot structures that are more resistant to degradation and an increase in plasminogen activator inhibitor type 1 (PAI-1). Increased circulating platelet aggregates, increased platelet aggregation in response to platelet agonists, increased platelet contractile force (PCF), and the presence of higher plasma levels of platelet release products, such as beta-thromboglobulin, platelet factor 4, and thromboxane B(2), demonstrate platelet hyperactivity in diabetes. This constellation of findings supports the clinical observation that diabetes is a hypercoagulable state. This article briefly reviews the published evidence for this conclusion and the putative roles played by hyperglycemia and hyperinsulinemia in its development.
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PMID:Diabetes mellitus: a hypercoagulable state. 1125 26

The lipolysis of triglyceride-rich lipoproteins may provide a surface that supports the activation of factor XII (FXII) with subsequent activation of factor VII (FVII). Plasma levels of activated FVII (FVIIa) but not activated FXII (FXIIa) are increased in the post-prandial state when there is a transient increase in triglyceride levels. We compared plasma levels of FXIIa antigen in control subjects (n = 33) and in patients with chronically elevated lipids (primary hyperlipidaemia, n = 49), with FVIIa and markers of thrombin generation. Results are given as median (first and third quartiles). Plasma levels of FXIIa [2.34 (1.68-3.32) ng/ml versus 1.53 (0.93-1.86) ng/ml, P = 0.0002], FVIIa [3.02 (2.15-4.64) ng/ml versus 2.20 (1.66-2.56) ng/ml, P = 0.0004], thrombin-antithrombin complexes [3.08 (2.16-5.54) microg/I versus 2.13 (1.46-2.84) microg/l, P = 0.005] and prothrombin fragment 1 + 2 (Pro F1 + 2) [1.28 (1.08-1.50) nmol/l versus 0.92 (0.65-1.08) nmol/l, P = 0.0001] were increased compared with controls irrespective of the type of hyperlipidaemia. In hyperlipdaemic subjects, levels of Pro F1 + 2 were correlated with FVIIa (r = 0.56, P = 0.0002) and FXIIa (r = 0.31, P = 0.03). These results suggest increased activation of both FVII and FXII in hyperlipidaemic subjects, which correlates with increased thrombin generation. Given the lack of correlation between levels of FXIIa and FVIIa, it remains to be established whether the increase in FXIIa is responsible for increased FVIIa activity in this subject group.
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PMID:Plasma levels of factor XIIa and factor VIIa are increased but not related in primary hyperlipidaemia. 1141 32

A 36-yr-old pregnant woman with blood coagulation factor XII deficiency was scheduled to undergo cesarean section. Preoperative blood coagulation scan revealed prolonged activated partial thrombin time of 105.6 s (control, 30.3 s), and a decrease in factor XII level of 3% (normal; 70-120%). Other examinations such as prothrombin time, platelet count and bleeding time were within normal limits. But she reported no history of bleeding. Before the operation, we discussed with obstetricians whether fresh frozen plasma (FFP) should be administered, or not. According to a report, a patient with factor XII deficiency can undergo major surgery without plasma replacement therapy. But another study showed that 15-30% of the factor XII activity was needed for hemostasis. We, therefore, administered 4 units of fresh frozen plasma before the operation. The operation was performed with general anesthesia uneventfully. Generally, a patient with factor XII deficiency has no clinical bleeding problems and unnecessary FFP administration may cause infection. Therefore it is not necessary to administer FFP to this patient.
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PMID:[Anesthetic management of a patient with blood coagulation factor XII deficiency]. 1142 74

We have investigated the effect of simulated saturation diving on the activation of intrinsic and extrinsic coagulation pathways. Thirty-one male divers divided into two groups were tested in decompression habitat LSH-200. The first group of 16 divers was subjected to hyperbaric exposure at pressure of 180 kPa with air as a breathing mixture, and the second group of 15 divers, exposed to a pressure of 400 kPa with a heliox breathing mixture (helium-oxygen mixture: pO2, 40 kPa; pN2, 40 kPa; pHe, 420 kPa). The concentrations of tissue factor, tissue factor pathway inhibitor, factors XII, X, VII, and I, prothrombin fragment F1 + 2, and thrombin-antithrombin complex as well as platelet count, prothrombin time, activated partial thromboplastin time, plasmin-antiplasmin complex (PAP) and D-dimers were measured. We did not detect activation of the extrinsic coagulation pathway after decompression. There was a statistically significant decrease in platelet counts and factor I, XII and X concentrations after air-diving, and a potent and statistically significant increase of PAP concentration in both groups of divers. We suggest that saturated air or heliox diving followed by decompression have little if any effect on thrombin generation. Saturated air diving, however, may induce a decrease in platelet count and factor XII concentration. The observed elevation of PAP concentrations in both groups of divers suggests possible activation of fibrinolysis. The exact effect of diving and decompression on fibrinolytic system has to be further investigated.
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PMID:Changes in the extrinsic and intrinsic coagulation pathways in humans after decompression following saturation diving. 1146 10

The mechanism by which thrombin is generated on a polymer surface in an extracorporeal circuit is not yet fully understood. To address this question we have developed an in vitro chamber model in which whole blood containing heparin (1 IU/mL) comes in contact with a commonly used biomaterial, polyvinyl chloride (PVC). Incubation of blood in the chamber for 60 minutes at 37 degrees C resulted in the binding of platelets to the material surface and the generation of thrombin-antithrombin complexes. Corn trypsin inhibitor, a specific inhibitor of factor XIIa, inhibited this thrombin-antithrombin complex generation in blood in contact with PVC, which is not considered an efficient activator of factor XII. The addition of the glycoprotein IIb/IIIa inhibitor Ro44-9883 abrogated platelet binding and aggregation and resulted in decreased generation of thrombin-antithrombin complexes. Thrombin-antithrombin generation was also negligible in platelet-rich plasma but could be partially restored in the presence of erythrocytes. Taken together, these data are compatible with a model in which thrombin generation is triggered by factor XII. The response to contact with PVC appears to begin with a low-grade generation of thrombin that involves both erythrocytes and leukocytes and that activates platelets, followed by the activation of a platelet-dependent amplification loop that produces most of the thrombin.
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PMID:Contact between a polymer and whole blood: sequence of events leading to thrombin generation. 1147 81

Thrombolytic drugs do not only stimulate the plasmin system but also induce thrombin activation additionally to the preexisting hypercoagulative state in patients with acute myocardial infarction. Testing the in vitro-derived hypothesis of a plasmin-mediated activation of the contact phase of the coagulation leading to the procoagulant effect, several thrombolytic regimen have been evaluated. Paradoxical thrombin activation (referred to as "thrombolytic paradox") was related to absence of fibrin specificity. Highly fibrin-specific drugs like tenecteplase did not cause additional thrombin activation, while non-fibrin-specific drugs like streptokinase caused a marked additional activation of the contact phase and of thrombin. It could be shown that the thrombolytic paradox was related to the extent of systemic plasmin activation confirming the hypothesis of a plasmin-mediated factor XII/kallikrein system activation as cause of the thrombolytic paradox.
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PMID:The thrombolytic paradox. 1156 69

We have analyzed the influence of plasma lipoproteins on the activation of the contact pathway of blood coagulation in platelet-rich plasma (PRP). The formation of thrombin in PRP incubated in vitro was abolished by the factor XIIa antagonist corn trypsin inhibitor and by severe factor XII deficiency, indicating mediation by the contact system. Addition of VLDL to the PRP shortened the lag period and increased the generation of thrombin. There was no effect of HDL and LDL. In whole blood, VLDL accelerated the rate of fibrin formation, the procoagulant effect being prevented by factor XII deficiency and by corn trypsin inhibitor. The thrombin formation in the PRP was strongly increased by microemulsions of the VLDL lipids while it was reduced by the aqueous phase of the particles. Separation of the VLDL lipids indicated the phospholipid component as the major activating principle. Vesicles supplemented with all VLDL phospholipids but lacking specifically the fraction containing phosphatidylethanolamine (PE) prolonged the lag time. The PE containing fraction alone as well as vesicles enriched with egg PE shortened the lag period. In summary, VLDL stimulates the contact pathway of blood coagulation, ethanolamine phospholipids being the most active components of the particles.
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PMID:Phosphatidylethanolamine participates in the stimulation of the contact system of coagulation by very-low-density lipoproteins. 1159 47

Twelve patients undergoing cementless hip joint arthroplasty were retransfused with unwashed drainage blood collected postoperatively. Global coagulation parameters, coagulation factors (factor V:C, factor VIII:C, activated factor XII, and factor XIII) and markers of thrombin generation (F1+2 Fibrin split products, thrombin-antithrombin complexes), fibrin generation (fibrinogen and fibrin degradation products), and fibrinolysis (D-dimers, thrombin degradation products, plasminogen) were determined. High levels of factor XIIa, thrombin and fibrin generation markers, and markers of fibrinolysis were present in the shed blood. After retransfusion (mean, 433 mL), increased levels of these markers together with decreased values for factor XIII and plasminogen were indicative of renewed clot formation and fibrinolysis in the circulation. These changes were highly significant compared with preretransfusion values. The unwashed drainage blood contained high levels of procoagulation material and induced an activation of the plasma coagulation pathway with renewed clot formation and fibrinolysis in the patients.
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PMID:Activation of plasma coagulation by retransfusion of unwashed drainage blood after hip joint arthroplasty: a prospective study. 1160 99

We reported previously that mast cell tryptase is a growth factor for dog tracheal smooth muscle cells. The goals of our current experiments were to determine if tryptase also is mitogenic in cultured human airway smooth muscle cells, to compare its strength as a growth factor with that of other mitogenic serine proteases, and to determine whether its proteolytic actions are required for mitogenesis. Highly purified preparations of human lung beta-tryptase (1-30 nM) caused dose-dependent increases in DNA synthesis in human airway smooth muscle cells. Maximum tryptase-induced increases in DNA synthesis far exceeded those occurring in response to coagulation cascade proteases, such as thrombin, factor Xa, or factor XII, or to other mast cell proteases, such as chymase or mastin. Irreversibly abolishing tryptase's catalytic activity did not alter its effects on increases in DNA synthesis. We conclude that beta-tryptase is a potent mitogenic serine protease in cultured human airway smooth muscle cells. However, its growth stimulatory effects in these cells occur predominantly via nonproteolytic actions.
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PMID:Tryptase's potent mitogenic effects in human airway smooth muscle cells are via nonproteolytic actions. 1179 23


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