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)

Coagulation and fibrinolysis are crucial in septic shock and inhibition of thrombin may be beneficial in this circumstance. Since porcine endotoxaemia has been found to replicate severe septic shock, a low molecular weight thrombin inhibitor, melagatran, was infused during the first 3 out of 6 h of endotoxaemia in pigs. Plasma creatinine (p <0.01) and urinary output (p <0.05) were less affected in the melagtran + endotoxin group (n=6) as compared to endotoxaemic controls (n=9). The left ventricular stroke work index, systemic vascular resistance index and oxygen extraction were all less affected (p <0.05) by endotoxin during the infusion of melagatran. The plasma concentration of melagatran declined with an apparent plasma half-life of 5 h as soon as the infusion was stopped. APTT, however, continued to increase after the infusion of melagatran had stopped and reached a maximum of 113 s at 5 h (baseline 17 s). APTT in endotoxaemic control pigs reached a maximum of 22 s. Thus, melagatran may counteract some consequences of endotoxaemia.
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PMID:Melagatran, a low molecular weight thrombin inhibitor, counteracts endotoxin-induced haemodynamic and renal dysfunctions in the pig. 986 78

An increased incidence of cerebral thromboembolic events has been reported in young patients with inflammatory bowel disease (IBD). It has been suggested that a hypercoagulable state is associated with clinical activity of the disease, with elevation of factors V, VIII, fibrinogen and platelets and a lowering of anti-thrombin III. We present the case of a 35 y/o male with refractory Crohn's disease who complained of headaches, blurred vision and tonic-clonic seizures. The studies demonstrated an ischemic stroke of the left cerebral hemisphere, without vascular abnormalities. Elevation of factor VIII, platelets, and antithrombin III were found. The symptoms were relieved with medical treatment and the patient has continued in good health after resection of the diseased terminal ileum.
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PMID:Cerebral thrombosis associated with active Crohn's disease. 988 77

Vascular occlusion has a central role in the pathophysiology of sickle cell disease (SCD) and, although there is little evidence that thrombosis alone is responsible, patients with sickle cell disease are known to have an ill-defined but increased thrombotic risk. The most serious complication of this in childhood is stroke which occurs in 7-10% of children and a further 14% have asymptomatic cerebrovascular disease (CVD) on imaging. We have performed a comprehensive profile of coagulation inhibitors and markers of thrombin generation in 96 children (83 nontransfused [NTx] and 13 transfused [Tx]) with steady-state SCD and 18 healthy sibling controls. The levels of protein S (free and total) and heparin cofactor II were reduced in both the NTx and Tx groups compared to controls and protein C and APC resistance ratios were reduced in the NTx group only. Antithrombin levels were not different from controls. Thrombin-antithrombin complexes and prothrombin fragment F1+2 were increased in both patient groups. In the NTx subgroups with or without CVD there were no differences for any of the parameters measured except for lower haemoglobin levels and higher white cell counts in those with asymptomatic CVD. We conclude that children with SCD have a reduction in levels of the majority of the coagulation inhibitors and increased thrombin generation in the steady-state and these are only partially reversed by transfusion. However, these abnormalities do not appear to play a primary role in the development of cerebrovascular disease.
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PMID:Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion. 988 16

We measured the serum levels of macrophage colony-stimulating factor (M-CSF) in 37 patients with an old cerebral infarction who had been surmised to have a damaged vessel wall and who had been in a stable condition for over three months after stroke onset, and those of 41 healthy control subjects. The M-CSF levels in the patients were significantly higher (P < 0.01) than those of the controls at 1320.4 +/- 410.6 unit/ml and 853.9 +/- 180.3 unit/ml, respectively. The plasma levels of von Willebrand factor (vWF) antigen (P < 0.01) and thrombomodulin (TM) (P < 0.05), as well as those of thrombin-antithrombin III (TAT) complex (P < 0.05), prothrombin fragment 1+2 (F1+2) (P < 0.02), D-dimer products of crosslinked fibrin degradation products (D-dimer) (P < 0.01), and plasmin-antiplasmin (PAP) complex (P < 0.05) in the patients were also significantly higher than those in the controls. Significant positive correlations (P < 0.01) were found between these parameters and the M-CSF level, but there was no significant correlation between the M-CSF level and the white blood cell count, serum lipids, or blood pressure. Based on these results, we suggest that an increased M-CSF level indicates vascular damage or a thrombotic state in patients with an old cerebral infarction.
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PMID:Serum macrophage colony-stimulating factor (M-CSF) level is elevated in patients with old cerebral infarction related to vascular damage. 1007 8

The pathophysiology of ischemic neuronal cell damage has been studied extensively. Intracellular calcium ions, excitatory amino acids, nitric oxide, oxygen free radicals, proteolysis, apoptosis, and so on play important roles. There are also gene expressions following cerebral ischemia, such as the immediately early gene, heat shock protein, cytokines, adhesion molecule, and growth factor, etc. In vessels of the ischemic brain, activation of platelets, leukocytes, the coagulation cascade, and fibrin generation occur and aggravate the cerebral microcirculatory disturbance. Treatment of acute ischemic stroke must be based on the clinical type (atherothrombotic, lacunar or cardioembolic) and the time after onset. Fibrinolysis by tissue plasminogen activator (intravenous administration) is approved in the USA for patients with cerebral infarction within 3 hours after onset. Efficacy of anticoagulant therapy using heparin was not verified by the International Stroke Trial (IST). In Japan selective anti-thrombin agent (argatroban) is used in patients with atherothrombotic cerebral infarction within 48 hours after onset. Results of IST and Chinese Acute Stroke Trial (CAST) showed aspirin within 48 hours after onset of cerebral infarction reduced recurrence of ischemic stroke during the acute stage and death within 6 months.
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PMID:[Recent advances in pathophysiology and treatment of acute ischemic stroke]. 1034 38

We performed a cross-sectional case-control study among 277 subjects with dementia and 298 control subjects drawn from participants of the Rotterdam Study, a population-based cohort study among subjects aged 55 years or over, and from participants of the Rotterdam Stroke Databank, a hospital-based stroke registry, with the objective to evaluate the association of indicators of coagulability, fibrinogen, prothrombin fragments 1+2, thrombin-antithrombin complex (TAT), and indicators of fibrinolysis, plasmin-inhibitor complex, D-dimer and tissue-type plasminogen activator (t-PA) with dementia. Increased levels of TAT, D-dimer and t-PA activity were associated with an increased risk of dementia. Additional stratified analyses indicated that an increased TAT level was the primary factor related to dementia. The present study provides evidence that predominantly increased thrombin generation is associated with dementia.
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PMID:Coagulation and fibrinolysis markers and risk of dementia. The Dutch Vascular Factors in Dementia Study. 1042 69

Although unfractionated heparin is widely used for thrombin inhibition in the management of unstable coronary artery disease, clinical and experimental evidence suggests that it is suboptimal. Recent pharmaceutical strategies to improve upon unfractionated heparin's efficacy profile have centered on the development of 2 major classifications of thrombin inhibition medications: the naturally occurring leech protein hirudin (and synthetic analogs) and low-molecular-weight (LMW) heparins. In the Organisation to Assess Strategies for Ischaemic Syndromes-2 (OASIS-2) trial, hirudin was demonstrably more effective than heparin in diminishing rates of death, myocardial infarction (MI), and angina at both 72 hours and 7 days after unstable coronary artery disease index events, with risk ratios on the order of 0.8. Similarly, in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) study, the LMW heparin enoxaparin emerged superior to unfractionated heparin in attenuating rates of unstable coronary artery disease at 14 days, 30 days, and 1 year. On the other hand, findings involving other LMW heparins (dalteparin sodium, Fragmin, and fraxaparin) are equivocal. Although the Fragmin During Instability in Coronary Artery Disease (FRISC) study demonstrated statistically significant superiority of this LMW heparin over aspirin/placebo in driving down death/MI/revascularization rates, the Fragmin in Unstable Coronary Artery Disease (FRIC) trial showed no such superiority, but had wide confidence intervals. Similarly, the Fraxaparin Versus Unfractionated Heparin in Acute Coronary Syndromes (FRAXIS) trial with fraxaparin failed to show superiority over unfractionated heparin. The favorable efficacy findings associated with hirudin and enoxaparin regimens, compared with unfractionated heparin, accrued without significant increases in the incidences of life-threatening bleeding events (e.g., hemorrhagic stroke), but did include more frequent lesser bleeding events. In summary, both hirudin and enoxaparin have demonstrated clinically important improvements in outcome compared with standard treatments in unstable coronary artery disease.
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PMID:Implications of the Organization to Assess Strategies for Ischemic Syndromes-2 (OASIS-2) study and the results in the context of other trials. 1050 40

To evaluate the role of the coagulation and fibrinolysis abnormalities in the pathogenesis of ischemic stroke of undetermined etiology, we assayed plasma concentration of fibrinopeptide-A and thrombin-antithrombin III complex, both sensitive markers for thrombin activation and fibrin formation, and D-dimer, a marker of plasmin activity and fibrinolysis. Hemostatic markers were measured in 32 patients with acute stroke and 20 patients with chronic stroke, and compared with 21 normal subjects. Fibrinopeptide-A and thrombin-antithrombin III complex levels were not elevated significantly, whereas the D-dimer level was markedly raised in acute (p<0.001) and chronic (p<0.05) phases of ischemic stroke in comparison with the control group. Prolonged elevation of D-dimer concentration suggests that hemostatic abnormalities have a primary role in the pathogenesis of ischemic stroke. The measurement of D-dimer concentration may help to better decide the indications for therapy of the patients with ischemic stroke of undetermined etiology.
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PMID:Hemostatic markers in ischemic stroke of undetermined etiology. 1058 58

Persistent coagulation activity after an acute myocardial infarction may increase the risk of reinfarction. We prospectively investigated the effects on plasma coagulation of a low, fixed dose of warfarin in combination with aspirin after myocardial infarction. We also evaluated the influence of coagulation activity on clinical outcome. Plasma samples from 97 patients, randomised to 1.25 mg of warfarin daily in combination with 75 mg of aspirin or aspirin alone were drawn 4 days, 1 month, and 6 months after myocardial infarction. Patients receiving warfarin had a greater reduction in factor VII coagulation activity (FVII:C) after 6 months: 0.18 vs. 0.06 U/mL,(95% CI, 0.02-0.22), whereas no differences were seen in levels of protein C, protein S, or prothrombin fragment 1+2. In the acute phase, the level of free protein S was lower than after 6 months in both groups: 25.6 vs. 28.8% (95% CI, 4.19--2.35). Cardiovascular mortality, reinfarction, and stroke were evaluated after 4 years (median). In a survival analysis, every 0.1 U/mL increase in the level of FVII:C1 month after myocardial infarction was associated with an 15% increase in risk of cardiovascular events (95% C1, 1.01-1.30). Warfarin at 1.25 mg daily reduces FVII:C but not systemic thrombin generation measured as prothrombin fragment 1 +2. Low levels of the anticoagulant protein S may contribute to a procoagulant state.
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PMID:Changes in levels of factor VII and protein S after acute myocardial infarction: effects of low-dose warfarin. 1058 63

New advances in antithrombotic therapy include direct thrombin inhibitors and low molecular weight heparins and heparinoids. Low molecular weight heparins and heparinoids have improved pharmacologic and pharmacokinetic properties when compared with unfractionated heparin. Low-molecular weight heparins are effective in the prevention of venous thromboembolism in general surgical patients, orthopedic patients, spinal cord injury patients, and general medical patients. At equipotent antithrombotic doses, low molecular weight heparins produce less bleeding. Low molecular weight heparins given in fixed doses subcutaneously have been shown to be as effective or more effective and safer than unfractionated heparin given intravenously with regular monitoring in the treatment of venous thromboembolic disease. Recent studies have demonstrated that low molecular weight heparins are effective in reducing the risk of death and myocardial infarction in patients with unstable angina and are as effective as intravenous heparin when given subcutaneously without monitoring. Preliminary data indicate that low molecular weight heparins may be effective in improving outcomes in patients with ischemic stroke.
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PMID:New Therapeutic Opportunities for Heparins: What Does Low Molecular Weight Heparin Offer? 1060 55


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