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)

The primary antiphospholipid syndrome is a disorder which is characterized by: arterial and/or venous thrombosis, thrombocytopenia, recurrent fetal loss and high plasma levels of antiphospholipid antibodies. Valvular involvement is associated with arterial thrombosis and the most frequent manifestation is regurgitation. We report the case of a young male with primary antiphospholipid syndrome and previous cerebrovascular thrombosis hospitalized for subacute myocardial infarction. Coronary angiography revealed right and left anterior descendent coronary artery stenosis, the latter being successfully recanalized by direct percutaneous transluminal coronary angioplasty. Transthoracic echocardiography demonstrated aortic valve involvement with predominant regurgitation and transesophageal echocardiography detected valve excrescences on the aortic leaflets. Laboratory study demonstrated thrombocytopenia, prolonged activated partial thromboplastin time and high titers of anticardiolipin antibodies. Oral anticoagulation therapy was started. Thrombotic events have not recurred after three months of follow-up.
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PMID:[Antiphospholipid syndrome with myocardial infarction and aortic valve involvement]. 1108 11

We compared the antithrombotic efficacy of a potent factor Xa inhibitor, FXV673, to heparin and RPR109891, a GPIIb/IIIa antagonist, when used as adjunctive therapy in a canine model of rt-PA-induced coronary thrombolysis. Thrombus formation was induced by electrolytic injury to stenosed coronary artery. After thrombotic occlusion, a 135 min infusion of saline (n=8), FXV673 (10, 30 or 100 microg kg(-1)+1, 3, or 10 microg kg(-1) min(-1), respectively; n=8 per dose), heparin (60 u kg(-1)+0.7 u kg(-1) min(-1), n=8), or RPR109891 (30 microg kg(-1)+0.45 microg kg(-1) min(-1), n=8), was initiated. Aspirin (5 mg kg(-1), i.v.) was administered to all animals. Fifteen minutes after the start of drug infusion, rt-PA was administered (100 microg kg(-1)+20 microg kg(-1) min(-1) for 60 min). The incidence of reperfusion in the high dose FXV673 (8/8, 100%) was significantly greater than that in the heparin group (4/8, 50%), with a trend to faster reperfusion (23+/-5 min for FXV673 versus 41+/-11 min for heparin). Only 2/8 (25%) of the vessels reoccluded in the high dose FXV673 group, compared to 4/4 (100%) and 5/5 (100%) vessels in the heparin and RPR109891 groups, respectively (P<0.05). Throughout the protocol, blood flow was higher in the FXV673 treated group compared to other groups. FXV673 enhanced vessel patency in a dose-dependent manner. Compared to vehicle and heparin groups, the thrombus mass was decreased by 60% in the high dose FXV673. FXV673, heparin and RPR109891 increased the bleeding time by 2.7, 1.7 and 4 fold, and APTT by 2.8, 2.7 and 1.2 fold, respectively. In conclusion, FXV673 is more effective than heparin and at least as effective as RPR109891 when used as an adjunct during rt-PA-induced coronary thrombolysis.
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PMID:Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis. 1148 31

CI-1031 (ZK-807834) is a novel, synthetic factor Xa (FXa) inhibitor with a Ki of 0.11 nM against human FXa. In human plasma in vitro, CI-1031 doubled PT and aPTT at 0.23 and 0.49 microM, respectively. The in vivo antithrombotic effect of CI-1031 was evaluated in a veno-venous shunt model of thrombosis in anesthetized rabbits. After thrombus formation was verified in the first shunts, rabbits received either vehicle or CI-1031 intravenously (bolus injection of 60, 240, or 480 microg/kg followed by an infusion of 2, 8, or 16 microg/kg/min for 140 min, respectively). The second shunts were inserted after 20 min of infusion of CI-1031 or vehicle. CI-1031 dose-dependently prolonged time to occlusion (TTO) in the second shunts (35 +/- 21, 62 +/- 24, and 120 +/- 0 min for the three dose groups, respectively, vs. 10 +/- 1 min for vehicle). Thrombus mass (TM) was reduced in a dose-dependent manner by CI-1031 (42 +/- 7, 27 +/- 6, and 18 +/- 4 mg vs. 50 +/- 4 mg for vehicle). Maximal TM reduction was 70% with an IC(50) of 0.6 microg/ml. Among all the coagulation parameters tested, PT had the best correlation with plasma CI- 1031 concentration (r = 0.97). Ex vivo plasma anti-FXa activity was also well correlated with plasma concentration of CI-1031 and with PT (r = 0.96 and 0.98, respectively). These results indicate that CI-1031, which is currently undergoing clinical evaluation, is an effective antithrombotic compound with a favorable efficacy-to-bleeding ratio. In addition, CI-1031 concentration in plasma can be monitored using PT or anti-Xa assays, thereby providing reliable methods to ensure safe and accurate dose titration of CI-1031.
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PMID:Assessment of ex vivo pharmacodynamic markers during inhibition of thrombosis by CI-1031 (ZK-807834), a novel direct factor Xa inhibitor. 1180 47

Thrombotic events contribute significantly to the morbidity, mortality, and health care costs of patients undergoing major orthopedic surgery. Despite therapy with unfractionated heparin, low-molecular-weight heparin, or warfarin, thrombotic events continue to occur at an unacceptably high rate in populations at risk. The need for improved prophylaxis against venous thromboembolism has resulted in the development of several new antithrombotics, both recently approved and investigational, that target specific steps in the hemostatic pathway. These include direct thrombin inhibitors, agents that inhibit the factor VIIa-tissue factor complex, and selective factor Xa inhibitors. Fondaparinux is the first of the selective factor Xa inhibitors. It was evaluated in the most comprehensive drug development program ever in major orthopedic surgery, culminating in four phase III trials involving more than 7000 enrollees, and is the first agent in its class to be approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. It has been suggested that fondaparinux's superior efficacy may be related to its ability to initiate selective inhibition of factor Xa and its predictable linear pharmacokinetics.
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PMID:Optimizing prophylaxis of venous thromboembolism. 1207 77

FEIBA and Autoplex T have been used to control bleeding in patients with factor VIII or IX inhibitors for over 25 years. The major components of FEIBA are thought to be activated factor X and prothrombin, whereas the main active components in Autoplex T are thought to be activated factors IX and VII. Both products have been found to effectively control approximately 80% of bleeds involving joints and soft tissues. Published experience of their use in surgery is limited. Thrombotic complications have been reported with high dose FEIBA therapy and have led to maximum dosage guidelines for this product.
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PMID:Evidence for the use of activated prothrombin complex concentrates (aPCCs) in the treatment of patients with haemophilia and inhibitors. 1221 39

The antithrombotic effects of direct (ximelagatran and hirudin) and indirect (dalteparin) anticoagulants were compared using a deep venous thrombosis (DVT) treatment model in conscious rats. Thrombus formation was induced in the inferior caval vein by total stasis plus topically applied ferric chloride. After 1-h thrombus maturation, one group of 10 rats were sacrificed and the mean thrombus weight in this group was 27.3 +/- 2.7 mg. This thrombus weight was handled as a reference to which all other results were compared. In all other groups, the total occlusion was removed after 1 h but a partial stasis was retained, permitting some blood flow around the thrombus. Groups of animals received subcutaneous (s.c.) dalteparin (200 IU/kg), s.c. hirudin (0.75 micromol/kg), one of four oral doses of ximelagatran (2.5, 5, 10 or 20 micromol/kg) or s.c. saline (control). After the 3-h treatment, mean thrombus weight in the saline group (26.5 +/- 3.3 mg) did not differ significantly from that of the reference group (27.3 +/- 2.7 mg, see above). Ximelagatran decreased thrombus weight in a dose-dependent manner, with an estimated ID(50) of 15 micromol/kg. Mean thrombus weight with the highest ximelagatran dose (11.1 +/- 1.3 mg) was similar to that with hirudin (13.0 +/- 1.5 mg). The effect of dalteparin on thrombus regression was much less pronounced (20.2 +/- 1.2 mg), compared with ximelagatran and hirudin, even though it was administered at a dose that yielded a similar activated partial thromboplastin time (APTT) prolongation. In conclusion, the results from this DVT treatment model showed that direct thrombin inhibitors ximelagatran and hirudin exhibited superior antithrombotic properties to low molecular weight heparin (LMWH).
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PMID:Effects of ximelagatran, the oral form of melagatran, in the treatment of caval vein thrombosis in conscious rats. 1243 84

Most animal models of venous thrombosis involve acute thrombosis with hypercoagulability in small rodents. To better replicate human disease, we developed two models in the pig, a species similar to humans in size and in vascular and coagulation reactivity. One model involves de-endothelialisation with 50% or 80% stenosis and the other replacement of a venous segment by a Gore-Tex vascular prosthesis. Both models were tested with and without acute induced hypercoagulability (thromboplastin infusion). Thrombi obtained without thromboplastin infusion were composed of a multilayered platelet and a fibrin meshwork structure similar to that usually found in humans. With thromboplastin infusion, the thrombi were homogeneous fibrin structures imprisoning red blood cells. The high incidence of thrombosis obtained with the 80% stenosis model would be useful for studying anticoagulant treatments, whereas the low incidence with 50% stenosis would be useful for evaluating procoagulant effects of conditions or treatments. These new models shed further light on the development of venous thrombi under conditions similar to those seen in humans and may prove useful for investigating anticoagulant and procoagulant effects.
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PMID:In vivo pig models of venous thrombosis mimicking human disease. 1257 4

Thrombus on the atherosclerotic plaque is mainly responsible for acute coronary syndromes. Antithrombin therapy continues to be the mainstay of the therapy defeating thrombus. Up-to-date antithrombin therapy consists of vitamin K antagonists, unfractionated and low molecular heparins, direct thrombin inhibitors and selective inhibitors of factor Xa. Today, none of these drugs is effective enough in every aspect. The need for new antithrombin drugs, as well as the need for new antiplatelet drugs which can be safely and effectively used together with other antithrombin drugs, persists.
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PMID:[Antithrombotics (Antithrombin therapy)]. 1661 71

Synergism between low-molecular-weight heparin and low doses of unfractionated heparin (UH) enhancing anti-factor Xa activity and the release of tissue factor pathway inhibitor was observed. The aim of this study was to verify whether this association is effective in preventing experimental venous thrombosis. Seventy rats were allocated into 7 groups: the control group treated with distilled water, the H(350) group treated with UH 350 IU/kg, the E(2) group treated with enoxaparin 2 mg/kg, the H(175) group treated with UH 175 IU/kg, the E(1) group treated with enoxaparin 1 mg/kg, the H(175) + E(1) group treated with UH 175 IU/kg plus enoxaparin 1 mg/kg, and the H(100) + E(0.5) group treated with UH 100 IU/kg plus enoxaparin 0.5 mg/kg. Forty minutes after subcutaneous injection, thrombosis was induced in vena cava. Three hours later, if present, thrombi were withdrawn and weighed. Bleeding time, activated partial thromboplastin time, thrombin time (TT), and anti-factor Xa were measured at the beginning and end of the experiment. Forty-eight other animals were treated, but without inducing thrombus, and tests were performed 40 min after injection. Thrombus developed in 90.9% of control animals, 20% of the H(350) group, 22.2% of the E(2) group, 10% of the H(175) + E(1) group, and 30% of the H(100) + E(0.5) group; there was a difference between group C and the other groups. Only in the H(350) and H(175) + E(1) groups were TT and activated partial thromboplastin time prolonged in relation to control at the end of the experiment. Forty minutes after injection, TT was prolonged in the H(350) and H(175) + E(1) groups. In conclusion, combinations of low doses of low-molecular-weight heparin and low doses of UH were as effective as high doses of each one used alone in preventing thrombus development in rat vena cava.
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PMID:Combinations of low doses of unfractionated heparin and of low-molecular-weight heparin prevent experimental venous thrombosis. 1677 37

Cardiovascular disease is the leading cause for mortality and morbidity in the western world. Arterial thrombosis has multiple origins and may present with different clinical presentations such as acute coronary syndromes, stroke, and peripheral embolization. Furthermore, thrombotic complications may occur during percutaneous interventions. The underlying causes range from atherosclerosis with plaque rupture or erosion, embolization, stasis and hypercoagulable states. Thrombotic complications lead to activation of the intrinsic coagulation system and to platelet aggregation. Despite the development of effective platelet inhibitors, there is still the need for an optimal anticoagulation regimen. While unfractionated heparin is the most commonly used antithrombotic agent, which has major inherent limitations. Direct thrombin inhibitors and anti factor Xa agents are agents which may overcome the limitation of unfractionated heparin. The potential advantages of these new compounds are discussed on the basis of available clinical data in patients with coronary artery disease.
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PMID:Thrombin inhibitors and anti-factor Xa agents in the treatment of arterial occlusion. 1707 89


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