Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An understanding of the coagulation process and the role of platelets is essential to recognizing the shortcomings of older anticoagulant therapies and appreciating the clinical potential of newer forms of antiplatelet and anticoagulant therapy for acute coronary syndromes. The anticoagulant actions of heparin are severely limited by dependence on antithrombin III, neutralization by platelet factor 4, and the resistance of clot-bound thrombin and platelet membrane-bound factor Xa to the heparin-antithrombin III complex. Unlike heparin, the direct thrombin inhibitors (such as hirudin) are active against both circulating and clot-bound thrombin. However, in recent clinical trials they have not resulted in major improvements in patient outcome. Another new class of drugs, the glycoprotein IIb/IIIa receptor antagonists, blocks the final common pathway of platelet aggregation and is capable of preventing platelet accumulation at sites of injury. The net effect is a dramatic reduction in the amount of platelet membrane available to support the process of coagulation. Clinical trials with the glycoprotein IIb/IIIa inhibitors have suggested that this class of agents may be particularly effective in reducing the thrombotic complications associated with coronary interventional procedures and may be useful in the treatment of acute coronary syndromes.
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PMID:Fundamentals of coagulation and glycoprotein IIb/IIIa receptor inhibition. 953 94

An understanding of the coagulation process and the role of platelets is essential to recognizing the shortcomings of older anticoagulant therapies and appreciating the clinical potential of newer forms of antiplatelet and anticoagulant therapy for acute coronary syndromes. The anticoagulant actions of heparin are severely limited by dependence on antithrombin III, neutralization by platelet factor 4, and the resistance of clot-bound thrombin and platelet membrane-bound factor Xa to the heparin-antithrombin III complex. Unlike heparin, the direct thrombin inhibitors (such as hirudin) are active against both circulating and clot-bound thrombin. However, in recent clinical trials they have not resulted in major improvements in patient outcome. Another new class of drugs, the glycoprotein IIb/IIIa receptor antagonists, blocks the final common pathway of platelet aggregation and is capable of preventing platelet accumulation at sites of injury. The net effect is a dramatic reduction in the amount of platelet membrane available to support the process of coagulation. Clinical trials with the glycoprotein IIb/IIIa inhibitors have suggested that this class of agents may be particularly effective in reducing the thrombotic complications associated with coronary interventional procedures and may be useful in the treatment of acute coronary syndromes.
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PMID:Fundamentals of coagulation and glycoprotein IIb/IIIa receptor inhibition. 959 17

Granulocyte colony-stimulating factor (G-CSF) is used in healthy donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. However, some data have recently suggested that G-CSF may induce a hypercoagulable state, prompting us to study prospectively 22 PBSC donors before and after G-CSF 5 microg/kg twice daily. We sought evidence for changes in the following parameters: platelet count, von Willebrand factor antigen (vWF:Ag) and activity (vWF activity), beta-thromboglobulin (beta-TG), platelet factor 4 (PF-4), platelet activation markers (GMP-140 and PAC-1), activated partial thromboplastin time (aPTT), prothrombin time (PT), coagulant factor VIII (FVIII:C), thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), thrombomodulin (TM) and tissue plasminogen activator antigen (tPA:Ag) prior to G-CSF and immediately before leukapheresis. ADP-induced platelet aggregation studies were also performed. G-CSF administration produced only mild discomfort. We found a significant increase in vWF:Ag (from 0.99 +/- 0.32 U/ml to 1.83 +/- 0.69 U/ml; P < 0.001), in vWF activity (from 1.04 +/- 0.34 U/ml to 1.78 +/- 0.50 U/ml; P < 0.001) and in FVIII:C (from 1.12 +/- 0.37 U/ml to 1.73 +/- 0.57 U/ml; P < 0.001) after G-CSF. Of note, four donors with low baseline vWF had a two- to three-fold increase after receiving G-CSF. G-CSF had no impact on the platelet count, beta-TG, PF-4, GMP-140 or PAC-1. The final% of platelet aggregation decreased from 73 +/- 22% to 37 +/- 26% after G-CSF (P < 0.001). We found a significant decrease in aPTT after G-CSF (29.9 +/- 3.1 s to 28.3 +/- 3.3 s; P = 0.004), but the PT was unaffected. In addition, we also observed a significant increase in TAT, F1+2 and TM, but not in tPA:Ag. Our data suggest that G-CSF may possibly induce a hypercoagulable state by increasing levels of FVIII:C and thrombin generation. In contrast to this information, we found reduced platelet aggregation after G-CSF administration. The clinical implications of these findings remain unclear and larger studies are definitely required.
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PMID:A prospective study of G-CSF effects on hemostasis in allogeneic blood stem cell donors. 1037 63

In the early eighties, following breakthroughs in oligosaccharide chemistry, the total chemical synthesis of pentasaccharides has been achieved, representing the antithrombin binding domain of heparin (the active site). The selective inhibitors of coagulation factor Xa thus obtained represent a new type of antithrombotic drugs. In a further step, based on the knowledge of the mechanism of antithrombin activation by heparin, oligosaccharides (pentadeca- to eicosasaccharides), comprising an antithrombin binding domain prolonged by a thrombin binding domain, were designed and synthesised in the Sanofi group. These compounds inhibit both factor Xa and thrombin, in the presence of antithrombin. Endowed with the full anticoagulant activity of heparin but devoid of undesired non-specific interactions, particularly with platelet factor 4 (PF4), they might represent "the ideal heparin-like antithrombotic".
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PMID:[New antithrombotic oligosaccharides]. 1042 58

Low molecular weight heparins (LMWHs) are obtained from unfractionated heparin by diverse chemical and enzymatic processes and findings with one LMWH cannot be extrapolated to another. Functional assays performed in vitro, evaluating antiprotease activity mediated via antithrombin III, heparin cofactor II interactions, antithrombin III binding, and plasma protein binding, showed wide variations between LMWHs, indicating that compositional differences among the LMWHs have a major impact on function. Evaluation in vitro showed varying potency in United States Pharmacopeia (USP) and anti-Xa assays. LMWHs tested at anti-Xa-adjusted concentrations exhibited varying potencies with anti-IIa, Heptest, and activated partial thromboplastin time (APTT) assays. Evaluation of these assays showed differences between LMWHs and a link with molecular weight. Each LMWH also varied in the in vitro neutralization by platelet factor 4, thrombin, and heparinase. LMWHs also varied in platelet interactions as assessed by whole blood clotting, thromboelastography and P-selectin expression, and in tissue factor pathway inhibitor release in cell culture. It was concluded that compositional variations in LMWHs give each product a unique biochemical profile. This profile, plus varying endogenous interactions and pharmacokinetic profiles may give rise to the clinical differences observed with LMWHs in specific indications.
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PMID:In vitro studies on the biochemistry and pharmacology of low molecular weight heparins. 1054 13

Thrombin, through its procoagulant and prothrombotic actions, plays a central role in the pathogenesis of unstable angina and acute myocardial infarction. Antithrombin therapy with unfractionated heparin has several important disadvantages, such as a variable anticoagulant effect, sensitivity to platelet factor 4, an inability to inhibit clot-bound thrombin, and the potential to cause thrombocytopenia. Alternative approaches have focused on novel anticoagulants, including direct antithrombins (eg, hirudin) and low-molecular-weight heparins (eg, enoxaparin). Direct antithrombins bind tightly to thrombin without requiring the cofactor antithrombin. Low-molecular-weight heparins display enriched anti-factor Xa activity, improved bioavailability, and facilitated administration versus unfractionated heparin. Recent trials demonstrate that direct antithrombins reduce rates of death and myocardial infarction early in patients without ST elevation, but the treatment effect diminishes over time. In contrast, treatment with enoxaparin shows superiority versus unfractionated heparin, and the treatment effect is durable over time. Whether thrombolysis with adjunctive treatment with low-molecular-weight heparins will show efficacy in patients with ST-segment elevation is the subject of ongoing trials.
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PMID:Newer antithrombin agents in acute coronary syndromes. 1057 63

A synthetic selective inhibitor of factor Xa, the pentasaccharide SR90107A/Org31540 is in clinical development for the prophylaxis of postsurgical deep vein thrombosis. Another synthetic pentasaccharide with even more sustained inhibition of factor Xa, SanOrg34006, has also been developed. Both of these agents were tested in comparison to unfractionated heparin and a low molecular weight heparin (enoxaparin) for their relative platelet activation potential in heparin-induced thrombocytopenia assays. Sera from patients (n = 30) with heparin-induced thrombocytopenia were pooled and validated for heparin-dependent aggregation responses. Using heparin-platelet factor 4 Sepharose columns, antibodies to heparin-platelet factor 4 were purified from the same pool. The effects of heparin, enoxaparin, SR90107A/Org31540, and San-Org34006 were evaluated in a platelet aggregation assay using platelet donors (n = 10). At comparable concentrations, heparin and enoxaparin consistently produced platelet activation, whereas both pentasaccharides failed to produce a response at a concentration up to 100 micrograms/mL (approximately 50 microM). Similarly, in the 14C-serotonin release and flow cytometric assays, heparin and enoxaparin produced positive responses (n = 30), whereas the two pentasaccharides consistently failed to produce any effect. These observations suggest that the two pentasaccharides with highly selective anti-Xa activity are devoid of generating antiheparin-platelet factor 4 antibody, do not produce heparin-induced thrombocytopenic responses and may inhibit active heparin-induced thrombocytopenia antibody platelet activation.
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PMID:Synthetic pentasaccharides do not cause platelet activation by antiheparin-platelet factor 4 antibodies. 1072 24

Thromboelastography (TEG) has been used increasingly as an intraoperative hemostasis monitoring device. Low-molecular-weight heparins are given increasingly to reduce the development of antibodies against the heparin-platelet factor 4 complex, and heparinoids are given to patients who have developed the antibody. We studied the effect of unfractionated heparin, a low-molecular-weight heparin (enoxaparin sodium [Lovenox]), and a heparinoid (danaparoid sodium [Orgaran]) on blood clotting assayed with TEG (TEG clotting) in vitro and the efficacy of protamine sulfate and heparinase for reversing the effect. Heparin, enoxaparin, and danaparoid all caused a dose-dependent inhibition of TEG clotting of normal blood. Concentrations of enoxaparin and danaparoid that totally inhibited TEG clotting only minimally prolonged the activated partial thromboplastin time. While inhibition of TEG clotting by heparin and enoxaparin was reversed by protamine sulfate and heparinase, inhibition by danaparoid was reversed only by heparinase. Abnormal TEG clotting was observed in patients receiving enoxaparin whose plasma level of the drug was more than 0.1 antiXa U/mL. However, the degree of TEG abnormality did not always coincide with plasma levels of the drug.
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PMID:Effects of unfractionated heparin, low-molecular-weight heparin, and heparinoid on thromboelastographic assay of blood coagulation. 1080 Apr 6

The aim of the study was the comparison of the influence of fresh frozen plasma (FFP) (Freiburg, Germany) and Biseko, Biotest Pharma GmbH (Dreieich, Germany), as a plasma substitute (a standardized, virus inactivated human serum protein solution) on the coagulation factors, inhibitors, proteins, and complement factors in the plasma of autoimmune disease patients following membrane plasma separation. Patients (n = 24) with autoimmune disease were randomized to receive either FFP or Biseko for membrane plasma separation therapy. During each plasma exchange, 100% of the plasma volume was replaced by the respective substitute. Plasma exchange volume was performed once daily for 3 days. Target test parameters of the coagulation system were fibrinogen, fibrinopeptide A, factor VIII (FVIIIC), von Willebrand factor antigen (vWFAg), partial thromboplastin time (PTT), thromboplastin time (Quick value), and antithrombin (AT III). The immunoglobulins were IgG, IgA, and IgM and C-reactive protein (CRP). The thrombocytes were platelet factor 4 (PF4), and complement factors were C3 and C4. Biseko was well tolerated with 1 mild adverse drug reaction (ADR) (n = 1) while FFP gave rise to ADR on 7 occasions (n = 4). Statistically significant differences in the 2 groups were observed for fibrinogen, PTT, Quick value, and AT III. From the clinical point of view, all fluctuations and differences in parameter levels remained clinically silent. The differences had no clinical consequences. Reflecting on a potential decrease in the risk of infections in comparison to FFP therapy and the lower rate of adverse drug reactions, it is possible to postulate an advantage of Biseko for plasma exchange therapy.
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PMID:Comparison of fresh frozen plasma with a standardized serum protein solution following therapeutic plasma exchange in patients with autoimmune disease: a prospective controlled clinical trial. 1111 13

Heparinomimetic mannopentaose phosphate sulfate (PI-88) (Progen Industries Ltd. Brisbane, Australia), currently developed as an anticoagulant and antiproliferative agent, mainly is composed of a pentomannan. However, tetrasaccharide and disaccharide components are also present. The molecular profile and the anticoagulant potency of PI-88 are investigated in this study. Gel permeation chromatography and polyacrylamide gel electrophoresis analyses were carried out to determine the molecular profile and separation of components of PI-88, respectively. Potentiation of antithrombin III (ATIII) and heparin cofactor-II (HC-II) activity were measured using chromogenic substrate assay. In order to determine anticoagulant and antiprotease effects of PI-88, various global anticoagulant tests, such as the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), Hep-test (Haemachem Inc., St. Louis), ecarin clotting time (ECT), activated clotting time (ACT), and thromboelastography (TEG) were used. Anti-Xa and anti-IIa activities also were measured. The effect of PI-88 on the release of tissue factor pathway inhibitor (TFPI) was performed in nonhuman primates who received PI-88 and in endothelial cell culture systems. The relative susceptibility of PI-88 to heparinase I, protamine sulfate (PS), and platelet factor 4 (PF4) also was evaluated. The high-performance liquid chromatography profiles of PI-88 showed that its average molecular weight is approximately 2300 Da. Separation and gradient electrophoretic patterns of PI-88 showed that it is composed of five different fractions. This agent activates HC-II through inhibiting the thrombin generation but not inhibiting ATIII. Although PI-88 produced a concentration-dependent prolongation of all of the clotting tests, ECT gave the best correlation in the dose-response curve (ECT, r2 = 0.94; TT, r2 = 0.84; APTT, r2 = 0.69). Heparinomimetic mannopentaose phosphate sulfate (PI-88) exhibited marked inhibition of FIIa, but not of FXa. Heparinase I failed to produce significant neutralization of PI-88 in all the assays used, whereas PS and PF4 partially neutralized the effects of this compound. Heparinomimetic mannopentaose phosphate sulfate (PI-88) produced fivefold increase in the TFPI levels at 15 minutes after intravenous (IV) injection to primates. The incubation of PI-88 in endothelial cell culture system also showed a strong effect on TFPI release. These results suggest that PI-88 exhibited strong antithrombotic and anticoagulant activity in addition to its known antiproliferative properties. Because of the molecular characteristics and the dual nature of the pharmacologic action of PI-88, this agent represents an attractive pharmacologic agent for the control of thrombotic and proliferative disorders.
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PMID:Anticoagulant and antiprotease profiles of a novel natural heparinomimetic mannopentaose phosphate sulfate (PI-88). 1129 91


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