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:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombocytopenia is observed with a frequency of up to 2% in patients treated with glycoprotein (GP) IIb/IIIa antagonists. We recently provided evidence that thrombocytopenia is caused by antibody binding to drug-induced conformational changes in GP IIb/IIIa. Here, we report that a murine monoclonal antibody binds to GP IIb/IIIa in an antagonist-dependent manner and activates platelets. Platelet stimulation is associated with a disruption of the phospholipid asymmetry, resulting in the assembly of catalytic active intrinsic Xase and prothrombinase complexes. Further mechanistic studies revealed that this response is (I) mediated in cis, (II) not associated with the formation of prothrombotic microparticles, and (III) requires intact platelet signaling and (IV) is blocked by increases in cAMP. The prothrombotic response is not observed using F(ab')2 fragments and is blocked by incubation of platelets with neutralizing antibodies to the platelet FcgammaRIIa receptor (CD 32).Taken together, these observations suggest that GPIIb/IIIa antagonist-dependent antibody binding to the platelet fibrinogen receptor has the propensity to lead to CD32-mediated platelet activation and accelerated platelet clearance, leading to thrombocytopenia.
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PMID:CD32-dependent platelet activation by a drug-dependent antibody to glycoprotein IIb/IIIa antagonists. 1262 36

Acute peripheral arterial occlusive disease is an important factor affecting the mobility and mortality rate of elderly patients. Catheter-guided arterial thrombolysis in these patients has its limitations: long lysis times, early occlusions, and high restenosis rates. The study investigated whether the use of tirofiban has the same favorable effect as the glycoprotein (GP) IIb/IIIa receptor antagonist abciximab and whether lysis times can be shortened and the disease course positively influenced by these substances. Sixty patients were randomly assigned to 2 groups. Each group received 5 mg recombinant tissue-type (rt-PA) plasminogen activator by slow intra-arterial injection for 10 minutes followed by 5 mg rt-PA per hour and 500 IU heparin per hour IV. After randomization 1 group received a bolus of 0.25 mg abciximab per kg body weight followed by 10 mg per minute IV for 12 hours (heparin was reduced to 250 IU/hr). The other group received a bolus of 0.4 microg tirofiban per kg body weight as well as postinterventional medication with 0.1 microg tirofiban per minute and kg body weight for 24 hours. During medication with GP IIb/IIIa inhibitor, the patients received a reduced heparin dosage for 24 hours. After 24 hours both groups received 200 mg aspirin orally and full heparinization controlled on the basis of the partial thromboplastin time. The following efficacy criteria were analyzed: rehospitalization events, reintervention events, and amputations within 6 months. Secondary endpoints were changes in the Fontaine stage, the crurobrachial index, the distance to claudication, and the duration of local arterial lysis. No significant differences were found between the abciximab and tirofiban groups in terms of the rehospitalization, reintervention, or amputation rates, nor were there any group differences in the total number of events. The secondary parameters, such as the crurobrachial index, distance to claudication, and Fontaine stage, also showed no significant differences between the 2 groups within 6 months. The duration of lysis was significantly shorter in the abciximab group. Major bleeding events did not occur in either group. With regard to the adverse effect rate, there were no significant differences between the 2 groups. Both abciximab and tirofiban can be used successfully in patients with peripheral arterial occlusive disease and arterial thrombosis.
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PMID:Use of abciximab and tirofiban in patients with peripheral arterial occlusive disease and arterial thrombosis. 1267 89

Platelets are important mediators of thrombosis in both healthy and diseased vessels. When platelets become activated by various soluble agonists or by adhesion to subendothelium under high shear, they release adenosine-5'-diphosphate that acts in a positive feedback mechanism on two different G-protein coupled receptors (P2Y(12), P2Y(1)) on platelets. This released adenosine-5'-diphosphate, acting through P2Y(12), is critical for sustained aggregation and stabilization of thrombi. P2Y(12) is the target of antithrombotic drugs (ticlopidine, clopidogrel), whereas the role of P2Y(1) in thrombosis remains to be fully established. Recent studies using either inhibitors of key components of signaling pathways or genetically engineered mice have contributed to our understanding of the signaling mechanisms in platelets mediated by adenosine-5'-diphosphate through the P2Y(12) receptor. Studies of patients with defective adenosine-5'-diphosphate mediated aggregation, as well as P2Y(12)-null mice, have revealed the importance of this receptor in mediating platelet activation and aggregation. Recent clinical trials using approved P2Y(12) blockers have extended the use of these drugs to additional patient populations. Recent data demonstrating the role of P2Y(12) in mediating platelet adhesion to thrombogenic surfaces (collagen, von Willebrand factor) provide further rationale as to the clinical efficacy of P2Y(12) blockers. P2Y(12) antagonists in combination with anticoagulants (thrombin inhibitors, factor Xa inhibitors) act synergistically in inhibiting thrombus formation (similar to aspirin) ex vivo. These findings suggest the potential for combination therapies (P2Y(12) antagonists with inhibitors of GPIIb-IIIa, thrombin or Factor Xa, etc.) to provide additional clinical benefit to patients with various cardiovascular diseases, especially those who may be aspirin-resistant.
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PMID:Scientific and therapeutic insights into the role of the platelet P2Y12 receptor in thrombosis. 1291 86

Many new antithrombotic and antiplatelet drugs have been developed that have markedly improved prophylaxis and treatment of thrombotic diseases. Clopidogrel, a potent new antiplatelet compound, is the first clinical alternative to aspirin for long-term oral treatment and prevention of arterial thrombosis. Another new, exciting category of antiplatelet compounds is the GPIIb/IIIa-antagonists, the first antiintegrins in clinical use and the most potent inhibitors of platelet aggregation. Low molecular weight heparins (LMWHs) are the quantitatively dominating group of new antithrombotics, which has replaced unfractionated heparin for the prophylaxis and treatment of venous thromboembolism. Current clinical evidence suggests that LMWHs might replace unfractionated heparin for the treatment and prophylaxis of atherothrombotic complications in acute coronary syndromes in the near future. Fondaparinux is the first synthetic pentasaccharide and a selective inhibitor of factor Xa with exciting clinical data; it could become an alternative LMWH for prophylaxis of arterial and venous thromboembolism in high-risk patients. The field of oral thrombin inhibitors is still dominated by the coumarins. However, much effort is being undertaken to develop new orally active drugs from which ximelagatran is currently the leading compound with a predicted better safety and efficacy profile. Alternatively, inhibitors of factor VIIa might be of interest as well. Open questions include, in particular, the possible individualization of drug therapy in dependence on the kind of disturbed platelet function or blood hypercoagulability, respectively.
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PMID:Antithrombotic drugs in vascular medicine: a historical perspective. 1519 72

Circulating procoagulant microparticles (MP) were measured as markers of vascular damage and prothrombotic risk in patients undergoing ST-segment myocardial infarction (STEMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) and additional GPIIb-IIIa antagonists. Cells possibly more responsive to GPIIb-IIIa (alpha(IIb)beta(3)) antagonists were evidenced through MP phenotypes by comparison with healthy volunteers (HV) and STEMI patients treated by PTCA without GPIIb-IIIa antagonist (CP). In 50 STEMI patients, blood samples were collected at day 1 and day 6. Circulating procoagulant MP were captured on annexin V and quantified by prothrombinase assay as nanomolar phosphatidylserine equivalents (nm PhtdSer). Platelet activation by thrombin was confirmed through independent measurement of soluble GPV (sGPV). With respect to HV, procoagulant MP levels were high in patients with STEMI or unstable angina, platelet-derived MP and elevated sGPV testifying to significant platelet activation. A substantial release of endothelial-derived MP was evidenced simultaneously. In abciximab-treated patients, procoagulant MP, mainly of platelet origin, decreased precociously at day 1 (4.2 +/- 0.6 vs. CP 15.5 +/- 2.1 nm PhtdSer; P = 0.001) together with sGPV (36 +/- 3 vs. CP 58 +/- 8 ng mL(-1); P = 0.02). Leukocyte-derived MP decreased at day 6 (0.12 +/- 0.04 vs. CP 0.56 +/- 0.12 nm PhtdSer; P = 0.01) suggesting a possible effect on underlying inflammatory status. In patients presenting cardiovascular events at 6-month follow-up, procoagulant MP levels at day 1 could be indicative of a worsened outcome. MP could constitute a relevant parameter for the follow-up of STEMI patients treated by GPIIb-IIIa antagonists.
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PMID:Circulating procoagulant microparticles and soluble GPV in myocardial infarction treated by primary percutaneous transluminal coronary angioplasty. A possible role for GPIIb-IIIa antagonists. 1521 95

Glanzmann's thrombasthenia is an inherited hemorrhagic disorder characterized by a severe reduction in, or absence of, platelet aggregation in response to multiple physiologic agonists due to qualitative or quantitative abnormalities of platelet glycoprotein IIb-IIIa. Glanzmann's thrombasthenia is characterized by potentially major mucocutaneous bleeding and prolonged bleeding time. Platelet counts, platelet morphology, prothrombin, and activated thromboplastin times are all within normal ranges in patients with Glanzmann's thrombasthenia. Pregnancy and delivery are rare in Glanzmann thrombasthenia patients and have been associated with immediate postpartum hemorrhage. We describe the peripartum management of a 31-year-old primipara with Glanzmann's thrombasthenia who underwent spontaneous vaginal delivery. Four units of single-donor platelets, two units of packed red blood cells, 36 microg/kg recombinant human coagulation Factor VIIa (rFVIIa) were given during peripartum management.
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PMID:The use of recombinant factor VIla in a primigravida with Glanzmann's thrombasthenia during delivery. 1549 26

The safety of glycoprotein (GP) IIb/IIIa inhibitors has been well documented in clinical trials. Although these trials have included a broad patient population, the strict enrollment criteria may have resulted in exclusion of patients at a higher risk of bleeding complications. The authors conducted a retrospective chart review of 1020 consecutive patients who received GP IIb/IIIa inhibitors and underwent percutaneous coronary intervention in a large community hospital. They used Thrombolysis in Myocardial Infarction (TIMI) criteria to define major or minor bleeding complications. Bleeding complications developed in 214 (21%) patients, with major bleeding in 89 (9%). Univariate predictors of bleeding were older age, lower body weight, elevated serum creatinine, higher activated partial thromboplastin time (aPTT) level, history of diabetes mellitus (DM), peripheral vascular disease (PVD), congestive heart failure (CHF), and emergency procedure for acute myocardial infarction (AMI). Multivariate predictors of major bleeding were PVD (20% in bleeding group vs 11% in nonbleeders, odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.2-2.6, P < .004), age (68 +/- 2 years, 95% CI = 66-70 in bleeding group vs 63 +/- 13 years, 95% CI = 61.2-63 in nonbleeders, P < .001), and higher aPTT level (66 +/- 27 seconds, 95% CI = 63-70 in bleeding group vs 53 +/- 28 seconds, 95% CI = 51-56 in nonbleeders, P < .001). The risk of bleeding in the large community hospital setting may be higher than in randomized clinical trials. This increased risk is associated with higher hospitalization costs. Recognition of predictors of bleeding should further enhance the safety of these antiplatelet agents.
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PMID:Glycoprotein IIb/IIIa receptor antagonists and risk of bleeding: a single-center experience in 1020 patients. 1549 51

Thrombosis and neointima formation limit the efficacy of coronary angioplasty. Factor Xa inhibitors and GPIIb/IIIa antagonists have shown to be effective on acute thrombosis and late neointima formation, however, their combined effects remain to be elucidated. Vascular injury was induced by FeCl(3) in the carotid artery in mice. For thrombosis studies, the test drug was orally administered 1 hour before vascular injury. For neointima studies, the test drug was orally administered 1 hour before and twice daily for 1 week after vascular injury, and then histological analysis was performed 3 weeks after vascular injury. YM466 inhibited thrombotic occlusion at 30 mg/kg with prolongation of prothrombin time (PT), and tail transection bleeding time (BT) was affected at 100 mg/kg. YM466 also inhibited neointima formation at 10 mg/kg. YM128 inhibited thrombotic occlusion and neointima formation at 10 and 30 mg/kg, respectively, with inhibition of platelet aggregation and prolongation of BT. In contrast, the combination of 10 mg/kg YM466 and 3 mg/kg YM128 inhibited thrombotic occlusion and neointima formation without affecting PT, platelet aggregation and BT. Concomitant inhibition of factor Xa and GPIIb/IIIa may provide a safer and more effective therapeutic regimen for treatment of coronary angioplasty.
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PMID:Combined effects of a factor Xa inhibitor YM466 and a GPIIb/IIIa antagonist YM128 on thrombosis and neointima formation in mice. 1558 27

The objective of this study was to examine the pharmacokinetics of intravenous dalteparin (Fragmin, Pharmacia-Upjohn, Peapack, NJ) and to assess the accuracy of standard coagulation-based monitoring techniques as an estimate of drug concentration with which to guide dosing. Knowledge of the kinetic behavior of low-molecular-weight heparins (LMWHs) and the possible utility of coagulation times for monitoring may aid in the development of safe and effective dosing algorithms for percutaneous coronary interventions. Twenty normal volunteers were treated at 2-week intervals with each of three intravenous dalteparin doses. Measurement of anti-IIa, anti-Xa, activated partial thromboplastin time (aPTT), activated clotting time (ACT), and low-range ACT was performed at baseline and at seven additional time points over 8 hours. The half-life of intravenous dalteparin is 77 minutes with slight dose-related variation. The aPTT, LR-ACT, and standard ACT are prolonged after dalteparin administration with the increase closely correlated to anti-Xa activity (aPTT, r = 0.85; LR-ACT, r = 0.79). Classification of anticoagulation intensity range using aPTT or LR-ACT in comparison to anti-Xa activity (0.5-0.99, 1.0-1.49, 1.5-2, >2) displays a level of agreement (kappa: aPTT = 0.69, LR-ACT = 0.59) that is comparable to values reported for coagulation time guidance of unfractionated heparin administration. Standard coagulation times are sensitive to the anticoagulant effect of dalteparin with a degree of correlation that suggests their utility for estimating drug concentration during high dose therapy. Trials establishing a relationship between monitoring and clinical efficacy, and the risk/reward of different treatment ranges alone or in combination with GPIIb/IIIa inhibitors and clopidogrel, are necessary.
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PMID:High-dose intravenous dalteparin can be monitored effectively using standard coagulation times. 1582 19

The existence of an association between idiopathic intracranial hypertension (IIH) and coagulation disorders in men was assessed prospectively. Microthrombi, associated with thrombophilia-hypofibrinolysis, occlude arachnoid sinus villi, thus reducing resorption of cerebrospinal fluid, leading to IIH. Ten consecutively referred men with IIH, nine whites, one African American, median age 36 years, were 2 to 1 matched by age and race by healthy male controls. Polymerase chain reaction assays were done for four thrombophilic and one hypofibrinolytic gene mutations: G1691A factor V Leiden, G20210A prothrombin, C677T MTHFR, platelet glycoprotein IIb/IIIa (PL A1/A2), and 4G/5G polymorphism of the plasminogen activator inhibitor (PAI-1) gene promoter. Coagulation measures in plasma included dilute Russel's viper venom time (dRVVT), activated partial thromboplastin time (aPTT), the lupus anticoagulant, factor VIII, factor XI, plasminogen activator inhibitor activity (PAI-Fx), protein C antigenic, protein S total (antigenic), protein S free (antigenic), antithrombin III (functional), and resistance to activated protein C (RAPC). Tests performed on serum included anticardiolipin antibodies, homocysteine, and Lp(a). The body mass index was 40 kg/m(2) or greater (extremely obese) in two men, 30 to 40 kg/m(2) (obese) in three, and was 25 to 30 kg/m(2) in five (overweight). Cases differed from controls for inherited 4G4G homozygosity of the PAI-1 gene, four of 10 (40%) vs. one of 20 (5%), Fisher's p [p(f)]= .031, and for high levels (>21.1 U/mL) of the hypofibrinolytic PAI-1 gene product, PAI-Fx, 5 of 10 (50%) vs. one of 18 (6%), p(f) = .013. Thrombophilic factor VIII was high (> or = 150%) in three of 10 (30%) cases vs. zero of 16 (0%) controls, p(f)=. 046. The thrombophilic lupus anticoagulant was present in two of 10 (20%) cases vs. zero of 32 (0%) controls, p(f) = .052. Heritable hypofibrinolysis and heritable and acquired thrombophilia appear, speculatively, to be treatable etiologies of IIH in men. Understanding contributions of hypofibrinolysis and thrombophilia to the development of IIH should facilitate development of novel new approaches to treat this often-disabling neurologic disorder.
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PMID:Idiopathic intracranial hypertension: associations with thrombophilia and hypofibrinolysis in men. 1624 70


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