Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149871 (deep vein thrombosis)
 12,364 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Native hirudin is a heterogenous polypeptide obtained from the medicinal leech, Hirudo medicinalis. Recent advances in molecular biological techniques have led to the availability of large amounts of hirudin in the recombinant form. Recombinant hirudins (rH) are currently being investigated for potential use in the prophylaxis and treatment of deep venous thrombosis (DVT), in disseminated intravascular coagulation (DIC) and during cardiovascular bypass surgery. In this study, one specific variant of rH with a lysine residue in position 47 (rHV2-Lys 47) was administered in dogs in a multiple dose regimen of 2 mg/kg (i.v. bolus) for three weeks with a dosing interval of one week. After each dose, blood samples were collected at regular time intervals, plasma separated and stored at -4 degrees C. Concentrations of rHV2-Lys 47 in each sample were determined using an enzyme-linked immunosorbent assay (ELISA). Ex vivo antithrombin responses measured included activated partial thromboplastin time (APTT), calcium-thrombin time (Ca++TT-10 NIH units/ml) and a chromogenic anti-IIa assay. It was the purpose of this study to detect any sensitization or desensitization of antithrombin responses when rHV2-Lys 47 is used in a repeated fashion such as would be expected in the prophylaxis of DVT. The results indicated that there was no attenuation in the responses; however, there was a sensitization of response as measured by the Ca++TT (10 NIH units/ml). These findings could have major implications in the clinical use of rH where this drug is expected to be used in a multiple dose regimen.
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PMID:Alteration of pharmacokinetics and pharmacodynamics of recombinant hirudin (rHV2-Lys 47) after repeated intravenous administration in dogs. 846 75

Nuclear medicine procedures and mainly perfusion lung scanning (often associated with ventilation lung scanning), after thirty years still play a major role in the diagnosis of pulmonary embolism. International study groups with accurate statistical methods have shown their efficacy in the diagnosis and follow-up, in reducing the clinical uncertainty, in directing the therapy and in lowering health care costs. The major limitation of nuclear medicine procedures lies in the high percentage of patients for whom intermediate or indeterminate probability is reported. However this percentage is steadily decreasing based on: patient clinical preselection; improved procedures and especially an extensive use of D-SPET with a three-head gamma camera; the combination with other advanced diagnostic imaging procedures (HRCT, fast-CT, MRI); suitable diagnostic algorithms for nuclear medicine procedures which should consider laboratory data (D-dimer, TAT) and the study of deep vein thrombosis; the use of artificial intelligence; the introduction of radiopharmaceuticals which enable direct scanning of the intravasal embolus (as P180 polypeptide) in combination with perfusion scanning which shows the hemodynamic alterations.
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PMID:The role of nuclear medicine in pulmonary embolism. 906 56

Over a century has passed since the anticoagulant properties of hirudin were identified. Our understanding of this unique and promising 65 amino acid polypeptide has grown steadily, allowing clinical experience to be gained. In acute myocardial infarction, hirudin has been associated with a higher incidence of early and sustained TIMI grade 3 flow, a higher rate of infarct-related artery patency at 18-36 hours with a decreased rate of reocclusion, and a lower incidence of in-hospital death and reinfarction as compared with heparin. hirudin has also been associated with a stable level of articoagulation and an acceptable hemorrhagic complication rate when given in carefully chosen doses. In acute coronary syndromes, the initial results indicate that hirudin can improve the resolution of coronary thrombus and reduce the incidence of recurrent ischemic events. Similarly impressive reductions in thrombotic complications and ischemia have been observed in the early balloon angioplasty experience. Promising results have also been seen with hirudin in preventing deep venous thrombosis following orthopedic surgery. The favorable effects of hirudin as compared with heparin in phase II clinical trials have prompted further investigation in two large phase III trials, TIMI 9 and GUSTO 2. It is hoped that these initial results can be confirmed and that hirudin can be proved to be a safe and effective treatment for thrombotic syndromes of the venous and arterial circulatory systems.
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PMID:Hirudin: Its Biology and Clinical Use. 1060 6

Heparin-induced thrombocytopenia (HIT) is a transient hypercoagulability state initiated, paradoxically, by the anticoagulant, heparin. It is characterized by antibody-induced activation of platelets, leading to thrombin generation. Many patients with HIT develop thrombosis; even when heparin is stopped because of "isolated HIT" detected during routine platelet count monitoring, 25-50% of patients subsequently develop symptomatic thrombosis. Thus, an alternative anticoagulant should be substituted for heparin when HIT is strongly suspected. Two direct thrombin inhibitors (DTIs), lepirudin and argatroban, have been studied for prevention and treatment of thrombosis in HIT patients. Lepirudin is a polypeptide that binds irreversibly to the fibrin-binding and catalytic sites on thrombin (bivalent inhibitor). In contrast, argatroban is a synthetic, small-molecule DTI that binds reversibly to the catalytic site alone (univalent inhibitor). Results of historically controlled clinical trials suggest both agents are effective for preventing and treating thrombosis in HIT. However, these agents have not been compared directly, and important differences in study design limit conclusions from indirect comparison. For example, lepirudin was given for 12-14 days (mean) in treatment studies of thrombosis complicating HIT, whereas argatroban was given only for 6-7 days, a difference that could explain apparent lower thrombosis rates (and greater bleeding) with lepirudin. Recently, the transition from DTI therapy to oral anticoagulation in patients with deep venous thrombosis (DVT) complicating HIT has been identified as a risk period for coumarin-induced venous limb gangrene. Thus, the DTI should be given alone during acute HIT, with oral anticoagulants deferred until substantial resolution of the thrombocytopenia has occurred.
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PMID:Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban. 1289 20

NAPc2, an anticoagulant protein from the hematophagous nematode Ancylostoma caninum evaluated in phase-II/IIa clinical trials, inhibits the extrinsic blood coagulation pathway by a two step mechanism, initially interacting with the hitherto uncharacterized factor Xa exosite involved in macromolecular recognition and subsequently inhibiting factor VIIa (K(i)=8.4 pM) of the factor VIIa/tissue factor complex. NAPc2 is highly flexible, becoming partially ordered and undergoing significant structural changes in the C terminus upon binding to the factor Xa exosite. In the crystal structure of the ternary factor Xa/NAPc2/selectide complex, the binding interface consists of an intermolecular antiparallel beta-sheet formed by the segment of the polypeptide chain consisting of residues 74-80 of NAPc2 with the residues 86-93 of factor Xa that is additional maintained by contacts between the short helical segment (residues 67-73) and a turn (residues 26-29) of NAPc2 with the short C-terminal helix of factor Xa (residues 233-243). This exosite is physiologically highly relevant for the recognition and inhibition of factor X/Xa by macromolecular substrates and provides a structural motif for the development of a new class of inhibitors for the treatment of deep vein thrombosis and angioplasty.
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PMID:Intermolecular interactions and characterization of the novel factor Xa exosite involved in macromolecular recognition and inhibition: crystal structure of human Gla-domainless factor Xa complexed with the anticoagulant protein NAPc2 from the hematophagous nematode Ancylostoma caninum. 1717 31

Conversion of fibrinogen to fibrin plays an essential role in hemostasis and results in stabilization of the fibrin clot. Fibrinogen consists of three pairs of non-identical polypeptide chains, encoded by different genes (fibrinogen alpha [FGA], fibrinogen beta [FGB] and fibrinogen gamma [FGG]). A functional single nucleotide polymorphism (SNP) in the 3' untranslated region of the FGG gene (FGG 10034C>T, rs2066865) has been associated with deep venous thrombosis and myocardial infarction. Aim of the present study was to analyze the role of this polymorphism in peripheral arterial disease (PAD). The study was designed as case-control study including 891 patients with documented PAD and 777 control subjects. FGG genotypes were determined by exonuclease (TaqMan) assays. FGG genotype frequencies were not significantly different between PAD patients (CC: 57.3%, CT: 36.7%, TT: 5.8%) and control subjects (CC: 60.9%, CT: 33.5%, TT 5.6%; p=0.35). In a multivariate logistic regression analysis including age, sex, smoking, diabetes, arterial hypertension and hypercholesterolemia, the FGG 10034 T variant was not significantly associated with the presence of PAD (Odds ratio 1.07, 95% confidence interval 0.84 - 1.37; p = 0.60). The FGG 10034C>T polymorphism was furthermore not associated with age at onset of PAD. We conclude that the thrombophilic FGG 10034 T gene variant does not contribute to the genetic susceptibility to PAD.
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PMID:The fibrinogen gamma 10034C>T polymorphism is not associated with Peripheral Arterial Disease. 2070 68