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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated platelets are implicated in the development of premature arterial vascular diseases, in particular ischemic stroke. Since elevated cytosolic [Ca(2+)](i) is an integrative marker of platelet activation, we determined the generation of Ca(2+) signal in stimulated platelets from 26 young patients recuperating from stroke, 20 patients with symptomatic peripheral arterial disease, and 56 healthy volunteers. Even in the presence of aspirin, the platelets from various individuals showed highly different thrombin-induced Ca(2+) responses. On average, the thrombin-induced Ca(2+) response was increased for platelets from either patient group in comparison to the controls (P <0.04). Relatively more stroke patients had high-responsive platelets (27%, 7/26) than patients with peripheral arterial disease (10%, 2/20) or healthy subjects (4%, 2/56). The average prothrombinase activities of platelets from patients and controls were similar, but 3 out of 6 patients with increased thrombin-induced Ca(2+) responses also exhibited high prothrombinase activity. In a follow-up study, the subject-dependent thrombin-induced Ca(2+) response was found to correlate strongly with the platelet response to protease-activated receptor 1 (PAR1) agonist (r = 0.91), but was not linked to the Pl(A1/2) polymorphism. It is concluded that a significant part of young patients with stroke have platelets with hyperactivity toward thrombin, which is not normalised by aspirin treatment. Furthermore, the subject-dependent variation in thrombin-induced signalling is likely to involve PAR1-mediated platelet activation.
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PMID:Thrombin-induced hyperactivity of platelets of young stroke patients: involvement of thrombin receptors in the subject-dependent variability in Ca2+ signal generation. 1252 41

Serine proteases play an important role in thrombogenesis, the process that leads to blood clotting and conditions such as heart attack, stroke and other cardiovascular disorders. In the coagulation network, the activation of various serine proteases facilitates the formation of the serine protease Factor Xa, which plays a central role in the process of coagulation and platelet activation. Factor Xa is an essential component of the prothrombinase complex, from which thrombin is formed, which then directly leads to fibrin clot formation. Thus, the inhibition of Factor Xa and its generation is an important strategy in the development of new antithrombotic drugs.
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PMID:Factor Xa inhibitors: today and beyond. 1273 28

Coronary heart disease (CHD) is the leading cause of mortality and morbidity in the United States. Currently, there are approximately 12 million Americans with CHD, which is most frequently caused by atherosclerosis. The thrombotic complications of atherosclerosis, such as acute coronary syndrome and ischemic stroke, can be fatal and those who survive such events have a far greater risk of future cardiovascular events. This huge medical need cries out for improved novel anticoagulants, antiplatelet agents, and profibrinolytic agents. These agents will successfully respond to the medical need by providing safe, effective, and easily administered treatments that have little, if any, drug and food interactions and that require minimal monitoring. The currently approved antiplatelet agent, clopidogrel, has satisfied some of these requirements and has played a large role in expanding the antithrombotic market over the past few years. New antithrombotics approaching the marketplace, such as the prodrug thrombin inhibitor ximelagatran, have promise in expanding the antithrombotic market further. Over the past two decades, the pharmaceutical industry has mounted a huge effort to develop antithrombotics that function by inhibiting key enzymes positioned at "higher" levels of the coagulation system. Direct inhibitors of factor Xa, which may provide a better safety and efficacy profile than currently available agents, appear to be the next major class of antithrombotic agents poised to take the pharmaceutical industry one step closer to delivering the ideal antithrombotic agent. This review focuses on recent innovations in the discovery and development of potent parenteral and oral direct factor Xa inhibitors.
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PMID:Recent advances in the discovery and development of direct coagulation factor Xa inhibitors. 1452 95

Protein Z (PZ) is a single chain vitamin-K-dependent glycoprotein synthesized by the liver. Studies in vivo and in vitro suggest that PZ plays an important role in inhibiting coagulation as it serves as cofactor for the inactivation of factor Xa by forming a complex with the plasma PZ-dependent protease inhibitor. Recently, conflicting findings on plasma PZ levels in patients with ischemic stroke have been published. Aim of our study was to investigate the role of PZ in acute coronary syndromes (ACS). PZ plasma levels were determined in 223 (189 M; 34 F) patients with ACS referring to the Coronary Intensive Therapy Unit of University of Florence and in 265 (219 M; 46 F) healthy subjects. Patients under oral anticoagulation treatment as well as subjects with positivity for antiphospholipid antibodies were excluded. None had liver or kidney dysfunction. The mean PZ plasma level was lower in patients (1508 +/- 730 ng/mL) than in controls (1728 +/- 594 ng/mL) (p < 0.0001). PZ levels below the 5th percentile (565 ng/mL) of normal values distribution in control subjects were found in 15.7% of patients and in 4.9% of controls (p <0.0001). At multivariate analysis, PZ levels below 565 ng/mL were associated with ACS (OR=3.3; 99%CI 1.1-9.7; p = 0.004). The contemporary presence of low PZ levels and smoking habit leads to an increased risk of ACS (OR=9.5; 99%CI 2.4-37.2; p < 0.0001). In conclusion, our results suggest a possible role of PZ in the occurrence of arterial thrombosis.
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PMID:Low protein Z plasma levels are independently associated with acute coronary syndromes. 1465 53

We illustrate a strategy for developing an antithrombotic agent based on the low-molecular-weight heparin (LMWH) tinzaparin experience. After anti-factor Xa and IIa activity pharmacokinetic characterization in healthy volunteers, clinical studies first explored the doses and then confirmed thrombosis prevention effects in postoperative (general and hip or knee replacement surgery) settings as compared with placebo and active treatments. This experience and additional dose-finding assessments led to large clinical studies verifying the effectiveness of tinzaparin in the treatment of deep vein thrombosis and acute pulmonary embolism. Subgroup analyses from these studies and preclinical experiments suggested a role for tinzaparin in patients with malignancy who are at high risk for thromboembolic complications. Challenging patient populations and other thrombotic disorders spawned interest in tinzaparin studies in the obese, the hemodialysis, the stroke, peripheral angioplasty, and the pregnant patient as well as in children with thromboembolic disorders. New therapeutic challenges were addressed with a bridging study for patients requiring interruption of oral anticoagulant therapy, a study of patients undergoing cardioversion for atrial fibrillation, and outpatient venous thromboembolism treatment studies. Efficient antithrombotic development programs not only build on traditional indications but elaborate on new therapeutic hypotheses generated from clinical studies, new therapeutic areas, and on-going basic science research programs.
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PMID:Extending the role of antithrombotic agents: an example based on the low-molecular-weight heparin, tinzaparin. 1508 61

Traditional anticoagulants have drawbacks that make them complex to manage, limit their usefulness, and increase the possibility of adverse events. New anticoagulants are being developed that directly target a single coagulation factor. The agents have improved pharmacokinetics and pharmacodynamics and may not need coagulation monitoring. In addition, many are available orally. Agents that target factor Xa or factor IIa are the most advanced in development and of greatest interest. Fondaparinux and idraparinux are parenteral, specific, indirect, factor Xa inhibitors that have a mechanism of action similar to that of heparin. Idraparinux has a prolonged half-life and is dosed once weekly. Razaxaban is a small-molecule, oral, direct FXa inhibitor with demonstrated efficacy in orthopedic surgery for primary prevention of venous thromboembolism. Other oral Xa inhibitors are entering clinical trials. Ximelagatran is an oral factor IIa or thrombin inhibitor with documented efficacy for primary prevention of venous thromboembolism in orthopedic surgery, for the acute and chronic treatment of deep venous thrombosis and stroke prevention in atrial fibrillation. Other oral IIa inhibitors are entering clinical trials. Many of these agents will have a profound effect on the treatment of venous thromboembolism potentially resulting in reduced costs, improved patient satisfaction with treatment, and greater use of selected indications.
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PMID:New anticoagulants and their potential impact on the treatment of thromboembolic disease. 1534 3

Anticoagulation therapy with unfractionated heparin, low-molecular-weight heparins and oral vitamin K antagonists is currently the mainstay of treatment and prevention of thromboembolic disorders (such as deep vein thrombosis, pulmonary embolism and stroke prevention in patients with atrial fibrillation). Although these therapies have proven benefits, they also have important limitations that result in their underuse in routine clinical practice. Consequently, many patients identified by guidelines as requiring anticoagulant therapy receive no or inadequate treatment. Heparins require parenteral administration and pose the risk of heparin-induced thrombocytopenia. Vitamin K antagonists have a narrow separation of antithrombotic and haemorrhagic effects and numerous food and drug-drug interactions, and require frequent coagulation monitoring and dose adjustment to ensure effective antithrombotic protection while minimizing the risk of bleeding complications. In response to these limitations, several new anticoagulants have recently been developed, including selective factor Xa inhibitors such as fondaparinux and ximelagatran, the first oral agent in the new class of direct thrombin inhibitors and the first new oral anticoagulant for almost 60 years. Ximelagatran possesses many of the properties of an ideal agent for anticoagulation therapy. With its oral formulation, consistent and predictable pharmacological profile and no coagulation monitoring, ximelagatran has the potential to increase the use and duration of anticoagulation treatment in thromboembolic disorders and to reduce the burden associated with long-term management.
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PMID:Current issues in anticoagulation. 1581 98

The Kunitz-type proteinase inhibitor, tissue factor pathway inhibitor (TFPI), is the only endogenous inhibitor of the tissue factor (TF)-mediated coagulation pathway that plays a dominant role in normal haemostasis. TFPI exerts its action by binding to factor Xa (FXa) forming a TFPI-FXa complex that then, in a second step, binds and effectively inhibits the TF-factor VIIa (FVIIa) complex. Both full-length TFPI and chemically modified forms (e.g., truncated, glycosylated or phosphorylated TFPI variants) exert various pharmacological effects. The anticoagulant and antiplatelet actions of TFPI, its potency in inhibiting thrombin and FXa generation, as well as its favourable antithrombotic effectiveness seen in different animal models of venous and arterial thrombosis make this inhibitor a promising agent that could be potentially useful in several clinical indications. The inhibitory action of TFPI is accelerated by heparin. Heparin, as well as low molecular weight heparin (LMWH) derivatives, release TFPI from the vascular endothelium, an effect which seems to contribute mainly to the antithrombotic effectiveness of these drugs. The clinical relevance of TFPI is still undefined. Based on the beneficial actions in animal studies, as well as on the results obtained in first clinical investigations, TFPI is expected to be effective in the treatment of various diseases, such as disseminated intravascular coagulation, sepsis, coronary syndromes, stroke and acute respiratory distress syndrome (ARD). Further clinical trials should clarify the role of TFPI and more importantly define its potential usefulness as a prophylactic and/or therapeutic agent.
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PMID:Recombinant TFPI and variants: potential implications in the treatment of cardiovascular disorders. 1599 20

Fondaparinux sodium (Arixtra; GlaxoSmithKline) is the first of a new class of antithrombotic agents. It is a chemically synthesised pentasaccharide mimicking the site of heparin that binds to antithrombin. It is purely a factor Xa inhibitor and an inhibitor of thrombin generation that requires binding to antithrombin. Fondaparinux sodium differs from heparin, low-molecular-weight heparin and heparinoids, and cannot be used interchangeably. It has been approved in the US and Europe for the prophylaxis of venous thrombosis after orthopaedic surgery by a fixed dose of 2.5 mg/day without monitoring. Using this pentasaccharide as a backbone, other structures have been synthesised. Idraparinux sodium (Sanofi-Aventis) differs structurally from fondaparinux sodium as it has additional methyl groups, a long half-life, and once-weekly administration. Both drugs are being developed as antithrombotics for venous and arterial thrombosis, acute coronary syndrome, stroke and as adjuncts to thrombolytic therapy.
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PMID:Short- and long-acting synthetic pentasaccharides as antithrombotic agents. 1602 74

Atrial fibrillation (AF) is the most potent common risk factor for ischemic stroke. The number of Americans with nonvalvular AF is expected to increase markedly over the next several decades, making AF-related stroke an important public health concern. Given the individual and societal burden associated with AF-related stroke, efforts to identify and implement efficacious and acceptably safe therapeutic stroke prevention strategies are paramount. This article reviews the existing randomized trial evidence supporting the efficacy of oral vitamin K antagonists (ie, warfarin) or aspirin for preventing thromboembolism in AF, as well as completed and ongoing studies exploring novel antithrombotic agents including the oral direct thrombin inhibitor, ximelagatran, other antiplatelet agents (eg, clopidogrel), factor Xa inhibitors, and other pharmacological agents and additional therapeutic approaches such as mechanical devices and surgical procedures to obliterate the left atrial appendage.
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PMID:Antithrombotic therapy for stroke prevention in atrial fibrillation. 1625 51


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