Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein C, a vitamin K-dependent serine protease zymogen that circulates in plasma, is converted by limited proteolysis to activated protein C (APC) by the thrombin-thrombomodulin complex. APC exerts anticoagulant, antiinflammatory, cytoprotective, and antiapoptotic activities. Recombinant APC therapy reduces mortality in severe sepsis patients. This review summarizes data from clinical observations, from in vitro studies, and from animal models of focal ischemic injury that provide a compelling rationale for clinical trials of APC for ischemic stroke.
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PMID:The promise of protein C. 1646 23

Congestive heart failure (CHF) is associated with marked endothelial dysfunction. We hypothesized that acute and chronic CHF may manifest different degrees of endothelial damage/dysfunction and activation, as reflected by different plasma endothelial markers, such as von Willebrand factor (vWF) and soluble thrombomodulin (both are indexes of endothelial damage/dysfunction) and soluble E-selectin (an index of endothelial activation). Second, we hypothesized a relation between endothelial markers and B-type natriuretic peptide (BNP, an index of cardiac function) in acute and chronic CHF that could be linked to prognosis. To test this hypothesis, we studied 35 patients with acute CHF, 40 patients with chronic CHF, and 32 healthy controls. The patients with CHF were followed up for the combined outcomes of cardiovascular death, nonfatal myocardial infarction, stroke, thromboembolism, and recurrent admissions to the hospital. vWF (p = 0.001), soluble thrombomodulin, E-selectin, and BNP (all p <0.0001) were higher in patients with acute and chronic CHF compared with controls. When the 2 CHF groups were compared, no significant differences were found in vWF or E-selectin (p = NS), but soluble thrombomodulin was significantly elevated in acute CHF (Tukey's post hoc test, p <0.05). Only high vWF was associated with a poorer outcome (log-rank test, p = 0.0188). None of the endothelial indexes correlated with plasma BNP. After a median follow-up of 18 months, only high (median or higher) vWF levels were predictive of adverse outcomes in the patients with CHF (log-rank statistic = 5.52, degree of freedom 1, p = 0.0188). In conclusion, despite similar ejection fractions, patients with acute and chronic CHF have different degrees of endothelial damage/dysfunction and activation, which may be related to differences in pathophysiology. High levels of vWF were associated with a worse short-term outcome. These endothelial markers were unrelated to plasma BNP levels and may imply a different release mechanism.
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PMID:Endothelial activation, dysfunction, and damage in congestive heart failure and the relation to brain natriuretic peptide and outcomes. 1649 Apr 35

Endothelial dysfunction is a key event in cardiovascular disease. Measurement of endothelial dysfunction in vivo presents a major challenge, but has important implications since it may identify the clinical need for therapeutic intervention, specifically in primary prevention. Several biological markers have been used as indicators of endothelial dysfunction. The soluble adhesion molecules sICAM-1 and sVCAM-1 lack specificity and are increased in inflammatory processes. Both markers are increased in coronary artery disease. sICAM-1 level predicts the risk for cardiovascular disease or diabetes mellitus in healthy individuals. sE-selectin is specific for the endothelium and is increased in coronary artery disease and diabetes mellitus. sE-selectin is also associated with diabetic risk. The endothelium-specific marker, soluble thrombomodulin, is associated with severity of coronary artery disease, stroke or peripheral occlusive arterial disease and is not increased in healthy or asymptomatic subjects. Interestingly, thrombomodulin decreases during treatment of hypercholesterolemia or hyperhomocysteinemia. In contrast, von Willebrand factor is the best endothelial biomarker and predicts risk for ischemic heart disease or stroke.
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PMID:Circulating markers of endothelial function in cardiovascular disease. 1653 Jan 77

Through a series of successive, cascade-like proteinase activation and amplification steps, any vascular injury triggers a rapid burst of alpha-thrombin, a trypsin-like serine proteinase. Thrombin, the main executioner of the coagulation cascade, has procoagulant as well as anticoagulant and antifibrinolytic properties. It exhibits quite diverse physiological functions, but also gives rise to several thrombotic disorders, such as thromboembolism, myocardial infarction, and stroke, thus making it an attractive target for antithrombotic agents. Thrombin interacts specifically with several protein substrates, receptors, cofactors, inhibitors, carbohydrates, and modulators. It cleaves fibrinogen, factors XI (FXI) and FXIII, cofactors V and VIII, and the thrombin receptors; uses thrombomodulin to activate protein C and thrombin-activatable-fibrinolysis inhibitor; is inhibited by heparin cofactor II and antithrombin III with the help of acidic carbohydrates; and its activity/specificity is modulated by sodium ions. A large number of crystal structures of alpha-thrombin in complexes with synthetic polypeptides and protein inhibitors, substrate fragments, cofactors, and carbohydrates have displayed extended recognition sites on the thrombin surface, reflecting the versatility and multifunctional specificity of this remarkable proteinase. These structures essentially show that the thrombin surface can be subdivided into several functional regions, which recognize different chemical moieties. By using different combinations of these surface elements, thrombin can interact with a variety of molecules with high specificity, accounting for its multifunctional properties.
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PMID:The structure of thrombin: a janus-headed proteinase. 1667 63

The anticoagulant protein C system is a dual function cofactor-dependent system. On one hand, it is designed to regulate coagulation, maintain the fluidity of the vasculature and prevent thrombosis. On the other hand, the protein C pathway provides anti-inflammatory and cytoprotective activities. Protein C, a vitamin K-dependent serine protease zymogen that circulates in plasma, is converted by limited proteolysis to activated protein C (APC) by the thrombin-thrombomodulin-endothelial protein C receptor complex on endothelial surfaces. APC and the cofactors of the protein C pathway exert two major distinct types of activities, namely a well-studied anticoagulant activity and a more recently revealed cytoprotective activity due to direct effects on cells. Because of these pleiotropic properties, APC and the protein C pathway components have important roles in the body's host-defense system and provide opportunities for therapeutic treatment of complex and challenging medical disorders, including thrombosis, severe sepsis and stroke.
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PMID:Protein C anticoagulant activity in relation to anti-inflammatory and anti-apoptotic activities. 1672 Mar 21

Several hematologic disorders and hemostatic defects increase risk of ischemic stroke. A common feature of these disorders is the creation of a prothrombotic state, now commonly referred to as "hypercoagulable state." Hematologic diseases such as essential thrombocythemia, polycythemia vera, and thrombotic thrombocytopenic purpura clearly cause stroke. Effective treatment is now available for these disorders. Association of hemostatic defects with stroke risk is still at the investigational stage. Although a number of factors such as soluble thrombomodulin, fibrinogen, factor VIII, von Willebrand factor, and plasminogen activator inhibitor-1 are associated with stroke risk, their predictive values remain unknown. Furthermore, causal relationship has not been established.
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PMID:Hypercoagulable states and strokes. 1682 99

The purpose of this study was to investigate the clinical value of plasma thrombomodulin (PTM) in different diseases or in different severity or complications of diseases, PTM in 979 patients and 60 healthy controls was determined by ELISA method. The results showed that the PTM level in the control group was 20.40 +/- 7.72 microg/L, there was no difference in sex and ages. In chronic primary glomerular disease, the PTM level in chronic renal failure (CRF) group was higher than that in non-CRF group (P < 0.01). PTM level > 70 microg/L was defined as its positive criterion. The sensitivity, specificity and positive predictive value in PTM were 85.7%, 82.4% and 77.8% respectively. The PTM level in septemia group was higher than that in non-septemia group (P < 0.01), the sensitivity, specificity and positive predictive value were 86.6%, 89.5% and 76.5% respectively (> 50 microg/L as its positive criterion). With respect of multiple trauma, the PTM level in multiple organ failare (MOF) group was higher than that in non-MOF group (P < 0.01), while the sensitivity, specificity and positive predictive value were 77.8%, 77.3% and 73.7% respectively (> 40 microg/L as its positive criterion). For systemic lupus erythematosus (SLE), the PTM level in the patients with albuminuria was higher than that in the patients without albuminuria (P < 0.01), and the sensitivity, specificity and positive predictive value were 77.8%, 92.3% and 93.3% respectively (> 35.54 microg/L as its positive criterion). For diabetes, the PTM level in complication group was higher than that in group without complications, the sensitivity, specificity and positive predictive value were 53.4%, 97.1% and 98.6% respectively (> 35.54 microg/L as its positive criterion). The PTM level in microangiopathy group was higher than that in macroangiopathy group (P < 0.01). The sensitivity, specificity and positive predictive value were 71.2%, 97.1% and 97.9% respectively. Acute leukemia (AL) and multiple myeloma (MM) had higher PTM level and PTM level was extremely high when renal failure developed (P < 0.01). As compared the acute stage with the restoration stage in stroke, pre-chemotherapeutics with post-chemotherapeutics in AL and MM, and pre-operation with post-operation in cancer, the PTM level was connected with clinical development. The PTM level in the patients with microangiopathy was higher than that in the patients with macroangiopathy (P < 0.01). The defined PTM level was higher than its normal upper limit as PTM positive criterion in microangiopathy diseases, the sensitivity, specificity and positive predictive value were 77.7%, 71.2% and 75.6% respectively. It is concluded that PTM level is a good criterion in evaluating the microangiopathy, and PTM is also a valuable indicator in prediction or assessment of the severity of diseases, or evaluation of therapeutic effectiveness.
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PMID:Clinical study of plasma thrombomodulin detection. 1749 May 34

To evaluate the therapeutic effects of the HELP system (heparin-induced extracorporeal low-density lipoprotein-apolipoprotein(a)-fibrinogen precipitation) in patients with acute ischemic stroke and probe into its possible mechanism, 10 patients with acute ischemic stroke were included in this study and received the HELP therapy in addition to low molecular weight dextran, salvia miltiorrhiza and aspirin. Matched with gender, age, European Stroke Scale (ESS) and fibrinogen, 20 patients with cerebral infarction treated with low molecular heparin were chosen as controls during the same period. We compared the efficacy and prognosis between the two groups. In order to clarify the effects of HELP treatment on endothelial function, human umbilical vein endothelial cells (HUVEC) were cultured with the serum of pre- and post-HELP therapy and control patients, then endothelial permeability and biomarkers of endothelial dysfunction or activation in the supernatant of incubated HUVEC, such as soluble thrombomodulin (sTM), soluble intracellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1), were tested. Twenty-one days after treatment, ESS scores in the HELP group (70.4 +/- 23.06) were higher than those in control group (60.7 +/- 18.94), but there was no statistical significance (P > 0.05). In the HELP group, total efficacy rate reached 60% with ESS score (6 cases of recovery and efficacy, 4 cases of inefficacy), while it was 40% in control group (8 cases of recovery and efficacy, 12 cases of inefficacy), but unfortunately there was no significant difference between both groups using the chi(2)-test (P > 0.05). Interestingly, with the activities of daily living (ADL) score, the efficacy rate in the HELP group (60%) was markedly higher than that in the control group (20%) (P < 0.05). Furthermore, Pearson correlation analysis showed that the therapeutic window (the time from the patient's onset to receiving the therapy) was correlated to final ADL scores (P = 0.044) and the mean therapeutic window was 14.08 +/- 3.41 h in patients who achieved efficacy criteria. After therapy, no difference was found in hemorheology, fibrinogen, blood lipid, oxidized low-density lipoprotein (oxLDL) or C-reactive protein (CRP) in the control group, while there was a significant decrease in the HELP group immediately after treatment (P < 0.01). But the hospital stay time was similar between the HELP group and the controls (23.11 +/- 10.65 vs. 21.53 +/- 8.73 days; P > 0.05) and 21 days later, the dimension of the largest cross-sectioned infarction area by CT scan did not significantly change for the two groups' of patients (P > 0.05). When cultured with the patient's serum after HELP therapy, the concentration of sTM, sICAM-1, and MCP-1 in the supernatant of cultured HUVEC remained unchanged at 24 h (P > 0.05), while it was remarkably higher when HUVEC was cultured with the serum of the controls and patients before HELP therapy (P < 0.01), except for sTM. The endothelial permeability was also improved after the HELP treatment. With the effects of improving hemorheology, decreasing acute phase reactive proteins such as CRP and fibrinogen, ameliorating endothelial cell function, HELP system may be a novel therapy for acute ischemic stroke.
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PMID:Effects of HELP therapy on acute ischemic stroke and vascular endothelial cell function. 1749 97

The genetic background of complex diseases is proposed to consist of several low-penetrance risk loci. Addressing this complexity likely requires both large sample size and simultaneous analysis of different predisposing variants. We investigated the role of four thrombosis genes: coagulation factor V (F5), intercellular adhesion molecule 1 (ICAM1), protein C (PROC), and thrombomodulin (THBD) in cardiovascular diseases. Single allelic gene variants and their pair-wise combinations were analyzed in two independently sampled population cohorts from Finland. From among 14,140 FINRISK participants (FINRISK-92, n = 5,999 and FINRISK-97, n = 8,141), we selected for genotyping a sample of 2,222, including 528 incident cardiovascular disease (CVD) cases and random subcohorts totaling 786. To cover all known common haplotypes (>10%), 54 single nucleotide polymorphisms (SNPs) were genotyped. Classification-tree analysis identified 11 SNPs that were further analyzed in Cox's proportional hazard model as single variants and pair-wise combinations. Multiple testing was controlled by use of two independent cohorts and with false-discovery rate. Several CVD risk variants were identified: In women, the combination of F5 rs7542281 x THBD rs1042580, together with three single F5 SNPs, was associated with CVD events. Among men, PROC rs1041296, when combined with either ICAM1 rs5030341 or F5 rs2269648, was associated with total mortality. As a single variant, PROC rs1401296, together with the F5 Leiden mutation, was associated with ischemic stroke events. Our strategy to combine the classification-tree analysis with more traditional genetic models was successful in identifying SNPs-acting either in combination or as single variants--predisposing to CVD, and produced consistent results in two independent cohorts. These results suggest that variants in these four thrombosis genes contribute to arterial cardiovascular events at population level.
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PMID:Combined effects of thrombosis pathway gene variants predict cardiovascular events. 1767

Atrial fibrillation (AF) is said to be an epidemic, affecting 1%-1.5% of the population in the developed world. The clinical significance of AF lies predominantly in a 5-fold increased risk of stroke. Strokes associated with AF are usually more severe and confer increased risk of morbidity, mortality, and poor functional outcome. Despite the advent of promising experimental therapies for selected patients with acute stroke, pharmacological primary prevention remains the best approach to reducing the burden of stroke. New antithrombotic drugs include both parenteral agents (e.g. a long-acting factor Xa inhibitor idraparinux) and oral anticoagulants, such as oral factor Xa inhibitors and direct oral thrombin inhibitors (ximelagatran, dabigatran). Ximelagatran had shown significant potential as a possible replacement to warfarin therapy, but has been withdrawn because of potential liver toxicity. Its congener dabigatran appears to have a better safety profile and has recently entered a phase III randomized clinical trial in AF. Oral factor Xa inhibitors (rivaroxaban, apixaban, YM150) inhibit factor Xa directly, without antithrombin III mediation, and may prove to be more potent and safe. Selective inhibitors of specific coagulation factors involved in the initiation and propagation of the coagulation cascade (factor IXa, factor VIIa, circulating tissue factor) are at an early stage of development. Additional new agents with hypothetical, although not yet proven, anticoagulation benefits include nematode anticoagulant peptide (NAPc2), protein C derivatives, and soluble thrombomodulin. A battery of novel mechanical approaches for the prevention of cardioembolic stroke has recently been evaluated, including various models of percutaneous left atrial appendage occluders which block the connection between the left atrium and the left atrial appendage, minimally invasive surgical isolation of the left atrial appendage, and implantation of the carotid filtering devices which divert large emboli from the internal to the external carotid artery, preventing the embolic material from reaching intracranial circulation. Despite recent advances and promising new approaches, prevention of recurrent AF may be one of the best protections against AF-related stroke and may reduce the prevalence of stroke by almost 25%. Improved pharmacological and nonpharmacological rhythm control strategies for AF as well as primary prevention of AF with 'upstream' therapy and risk factor modification are likely to produce a larger effect on the reduction of stroke rates in the general population than will specific interventions.
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PMID:Stroke in atrial fibrillation: update on pathophysiology, new antithrombotic therapies, and evolution of procedures and devices. 1770 79


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