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

Little is known about ischemic stroke occurrence in patients with myasthenia gravis (MG), although antiphospholipid antibodies are detectable in many MG patients. A 47-year-old woman with a 20-year history of generalized MG had an acute onset of right hemiparesis. She had undergone thymectomy 10 years previously and was treated for phlebothrombosis of the lower extremity 3 years previously. Computed tomography (CT) demonstrated an old infarct in the left frontal lobe and a new lesion in the right parietal lobe. Multiple small cortical and subcortical infarcts were demonstrated on fluid attenuated inversion recovery (FLAIR) images. Thrombocytopenia (5.9 x 10(4)/microL), a prolonged activated partial thromboplastin time (aPTT; 50.2 sec), and an elevation of beta 2-IgG-glycoprotein I anticardiolipin antibodies (beta 2-GPIaCL; 55.7 U/mL) were observed. Neurological defects improved significantly over 2 weeks. She then was treated with oral prednisolone (30 mg/day) for 18 months, with resolution of laboratory abnormalities and no new cerebrovascular events or findings on imaging. We believe that our patient's multiple infarcts are caused by antiphospholipid antibodies and recommend glucocorticoid therapy to prevent recurrent of ischemic stroke in similar case.
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PMID:Antiphospholipid syndrome and multiple ischemic strokes in a patient with myasthenia gravis. 1265 72

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

In addition to inhibiting platelet (plt) aggregation abciximab, a glycoprotein (GP) IIb/IIIa antagonist, reduces coagulation in blood or platelet-rich plasma. We assessed the effects of abciximab (10 micro g mL(-1)) on adhesion-dependent procoagulant activity (PCA) of plt upon: (i) collagen to model initial adhesion; or (ii) plasma clot or fibrin to model a preformed thrombus with retained thrombin activity. In a two-stage assay gel-filtered plt (GFP) first adhered on collagen, plasma clot, or fibrin, and plt activation was traced with platelet factor 4 (PF 4) release. Second, PCA was measured on adherent plt (i) by soluble prothrombin fragments (F1 + 2); and (ii) chromogenically by adding defibrinated plasma and thromboplastin. Abciximab inhibited aggregation upon collagen-adherent plt both in the absence and presence of plasma. In contrast, without plasma abciximab enhanced plt deposition to fibrin surfaces depending on thrombin generation and fibrin polymerization. However, abciximab reduced PCA and generation of F1 + 2 on adherent plt surface-independently by 35%, whereas PF 4 release persisted. Also, a GP Ib inhibitor, mAb SZ2, attenuated PCA by 40% alone, and by 65% together with abciximab, leaving 35% of PCA unaltered. Abciximab decreased generation of new thrombin on both collagen- and clot-adherent plt. However, abciximab did not inhibit alpha-granule release, suggesting distinct pathways for PCA and release reaction. Deposition of isolated plt on clots in the presence of abciximab was dependent on thrombin and polymerizing plt-derived fibrin(ogen). Due to local consumption of natural anticoagulants adjacent to a preformed thrombus the antithrombotic effect of abciximab benefits from additional inhibition of thrombin.
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PMID:Abciximab inhibits procoagulant activity but not the release reaction upon collagen- or clot-adherent platelets. 1287 19

To better understand potentially reversible causes of idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, and an apparent association of IIH with polycystic-ovary syndrome (PCOS), we assessed associations of IIH with coagulation disorders and with PCOS in 38 women with well-documented IIH. Fifteen women were found to have PCOS; 14 of them were obese, with a body-mass index (BMI) greater than 30 kg/m(2), and 10 were extremely obese (BMI > or = 40). Factor VIII concentration was high (>150%) in 9 of 38 (24%) IIH cases, compared with 0 of 40 healthy adults controls (P(f) =.0009). Familial aggregation of high concentrations of factor VIII, associated with thrombophilia, was documented in all 5 of the 9 high-level factor VIII probands' families who were sampled. Activated partial thromboplastin time (APTT) was prolonged (> or =31.5 seconds) in 10 of 38 (26%) IIH cases, compared with 1 of 32 (3%) controls (P(f) =.009) and, in 4 of these cases, was accompanied by the lupus anticoagulant. Plasminogen activator inhibitor activity (PAI-Fx) was high (>21.1 U/mL) in 9 of 38 cases (24%), compared with 1 of 40 controls (3%) (P(f) =.006). Lipoprotein A was high (> or =35 mg/dL) in 13 of 37 cases (35%), compared with 5 of 40 controls (13%) (P(f) =.03). IIH cases did not differ (P >.05) from controls for homocysteine, proteins C and S, free S, antithrombin III, ACLAs IgG and IgM, dilute Russell's viper venom time, Factor XI, factor V Leiden G1691A, G20210A prothrombin, C677T MTHFR, plasminogen activator inhibitor 4G/5G, or platelet glycoprotein PL A1A2 mutations. Exogenous estrogens (n = 23), clomiphene (n = 1), or pregnancy (n = 4) accompanied the first appearance of IIH in 28 women. PCOS and coagulation disorders, often augmented by exogenous estrogens or pregnancy, are associated with IIH.
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PMID:Idiopathic intracranial hypertension: associations with coagulation disorders and polycystic-ovary syndrome. 1287 84

Transmittance waveforms are generated during clot formation on photo-optical coagulation analyzers. We previously showed that 61.5% of patients with antiphospholipid antibodies (APLA) exhibited a negative deflection in the pre-coagulation phase of the prothrombin time (PT slope 1). The current studies investigated the 'molecular basis' of this abnormal parameter. We found that the negative PT slope 1 is IgG-mediated and is not dependent on the presence of fibrinogen or thrombin activity. We also found that IgG from most of the patients required a specific thromboplastin and the presence of prothrombin or beta(2)-glycoprotein I beta(2) GPI) to produce an abnormal IgG wave-form assay. In addition, the abnormal IgG waveform required cofactor binding to phospholipids when beta(2) GPI was the cofactor, and annexin V could partially block this interaction. In conclusion, these results showed that the interactions of IgG with phospholipids via beta(2) GPI or prothrombin constitute the core mechanisms of the abnormal waveforms.
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PMID:Prothrombin and beta 2-glycoprotein I frequently contribute to antiphospholipid antibody interactions with phospholipids and the generation of abnormal waveform profiles in coagulation assays. 1288 68

In the blood coagulation cascade, human antithrombin III (hAT III) acts as an inhibitor of serine proteases such as thrombin and factor Xa, and this anticoagulatory glycoprotein requires the binding of heparin for its activation. In this study, we synthesized the polypeptides corresponding to the proposed heparin-binding sites including the (41-49), (286-301) and (123-139) regions of hAT III, and examined their interactions with heparin by means of physicochemical and biochemical methods. All the synthetic peptides had a high affinity toward heparin, evidenced by the fact that they were eluted from a heparin-agarose column at the high salt concentration range of 520-700 mM. In addition, hAT III (123-139) attenuated the effect of heparin on the activation of hAT III, whereas other HBPs did not, suggesting that only hAT III (123-139) could interact with the active site of heparin. On the basis of these results, we prepared novel hAT III (123-139)-related derivatives as potent heparin antagonist candidates, and examined the influence of several modifications on their activity in vitro. The results provided new findings about the structure-activity relationship of hAT III (123-139), and led us to the successful development of a potent antagonist for heparin.
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PMID:Human antithrombin III-derived heparin-binding peptide, a novel heparin antagonist. 1451 65

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

Our specific aim was to assess associations of thrombophilia, hypofibrinolysis, and polycystic ovary syndrome (PCOS) with recurrent pregnancy loss (RPL) (>/=3 consecutive pregnancy losses < 20 weeks gestation). Prospective studies were performed in 33 Caucasian women referred for diagnosis and treatment of PCOS who were subsequently found to have RPL and in 16 Caucasian women referred for diagnosis and treatment of RPL, who did not have PCOS. Cases (PCOS-RPL, RPL without PCOS) were compared with controls (116 healthy Caucasian females) for the G1691A Factor V Leiden, G20210A prothrombin, C677T methylenetetrahydrofolate reductase (MTHFR), plasminogen activator inhibitor 4G/5G, and platelet glycoprotein PL A1A2 gene mutations. Cases were compared with controls (44 healthy adult Caucasian females) for serologic coagulation tests including homocysteine, proteins C, S, free S, antithrombin III, anticardiolipin antibodies IgG and IgM, dilute Russel's viper venom time, activated partial thromboplastin time, Factor VIII, Factor XI, lipoprotein (Lp)(a), and plasminogen activator inhibitor activity (PAI-Fx). The 33 Caucasian women with PCOS subsequently found to have RPL were 10% of a cohort of 322 Caucasian women who had >/= 1 previous pregnancy and had been referred for diagnosis and therapy of PCOS over a 4.3-year period. The Factor V Leiden G1691 mutation was present in 6 of 33 women (18%) with PCOS-RPL and in 3 of 16 women with RPL without PCOS (19%) versus 2 of 116 (1.7%) female controls, Fisher's P (p(f)) =.0016, p(f) =.013. The 33 PCOS-RPL cases also differed from the 44 female controls for high PAI-Fx (>21.1 U/mL), 38% versus 8%, p(f) =. 004. The thrombophilic G1691A Factor V Leiden mutation is associated with RPL in women with and without PCOS; hypofibrinolysis (high PAI-Fx) is also associated with RPL in women with PCOS.
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PMID:Polycystic ovary syndrome, the G1691A factor V Leiden mutation, and plasminogen activator inhibitor activity: associations with recurrent pregnancy loss. 1466 68

Cyclosporine (CyA) has been implicated to increase cardiovascular morbidity and mortality after renal transplantation. Impairment of the fibrinolytic system is one factor involved in the development of thrombotic complications. The aim of this study was to compare hematological and hemostatic parameters among patients on CyA, azathioprine, and prednisone (n = 31) versus CyA and steroids (n = 14). Using commercially available kits we evaluated thrombin activity as thrombin-antithrombin complexes (TAT), prothrombin fragments (1 + 2), thrombin activatable fibrinolysis inhibitor-(TAFI), TAFI activator, thrombomodulin (TM)-a marker for endothelial cell injury,-plasmin generation (plasmin-antiplasmin complex PAP), a glycoprotein linking coagulation and fibrinolysis. We observed that patients not treated with azathioprine displayed longer prothrombin times and activated partial thromboplastin times; higher fibrinogen, platelet counts and fibrinolytic activity index (FAI); shorter euglobulin clot lysis time; as well as lower thrombin generation markers namely, prothrombin fragments 1 + 2 and thrombin-antithrombin complexes. Although patients in the non-AZA group tended to have been engrafted for a longer time (P =.086), the groups did not differ with regard to age, BMI, erythrocyte count, hematocrit, leukocyte count, creatinine clearance, alanine and asparagine aminotransferase activities mean arterial blood pressure, fibrinogen, TAFI, thrombomodulin, or plasmin-antiplasmin complexes. These findings suggest that kidney transplant recipients on triple therapy are at greater risk of cardiovascular disease than those without azathioprine treatment, despite the lower fibrinolytic activity.
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PMID:Some aspects of hemostasis in kidney transplant recipients maintained on cyclosporine, azathioprine, and prednisone in comparison to patients treated with cyclosporine and prednisone. 1469 44


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