Thromb Haemostasis
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To investigate the relative importance of direct inhibition of thrombin by complex formation and of inhibition of thrombin generation to the mechanisms by that unfractionated heparin (UH) and recombinant hirudin (rH) exert their anticoagulant effects, thrombin-antithrombin III complex (TAT) and thrombin-hirudin complex (THC) formation was compared with the generation of thrombin and prothrombin fragments 1 + 2 (F 1 + 2). Clotting was initiated by activation of citrated plasma in the absence or presence of UH or rH using partial thromboplastin, ellagic acid and calcium chloride. THC was determined by means of ELISA using specific antibodies to thrombin and rH. ⋯ Using 1200 ng rH/ml or 0.65 U UH/ml to obtain a clotting time of 9 min only a small amount of thrombin could be detected in heparinized plasma, but hirudinized plasma still showed a high peak of thrombin. F 1 + 2 showed essentially the same pattern as thrombin. Prior to the onset of visible clot formation in all experiments using different concentrations of UH about the same values of TAT were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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Randomized Controlled Trial Multicenter Study Comparative Study Clinical Trial
Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis.
Two hundred and four consecutive patients with venographically confirmed deep vein thrombosis (DVT) were randomised either to a low molecular weight heparin, Fragmin, administered subcutaneously (s.c.) once daily as a fixed dose of 200 IU anti-factor Xa/kg or to continuous intravenous infusion of unfractionated heparin (UFH). The UFH dose was adjusted to maintain the activated partial thromboplastin time between 1.5 and 3.0 times the upper limit of the reference value at each centre. Fragmin or UFH was given for a minimum of 5 days until anticoagulation with warfarin, given from day 1, was established (i.e. an Internation Normalised Ratio, of 2.0-3.0). ⋯ Eight documented venous thromboembolic events occurred before the follow-up visit 6 months after randomisation: 5 in patients treated with Fragmin and 3 in those treated with UFH. Six of these events occurred after cessation of warfarin treatment. In conclusion Fragmin given s.c. once daily in a fixed dose adjusted for body weight, is no less effective or safe than a continuous infusion of UFH in the initial treatment of acute DVT.
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A hypothermia-induced hemorrhagic diathesis is associated with cardiopulmonary bypass, major surgery, and multiple trauma, but its pathophysiological basis is not well understood. We examined the hypothesis that hypothermia reversibly inhibits human platelet activation in vitro and in vivo. Platelet activation was studied in normal volunteers by whole blood flow cytometric analysis of modulation of platelet surface GMP-140 and the glycoprotein (GP) Ib-IX complex in: a) shed blood emerging from a standardized in vivo bleeding time wound; b) peripheral blood activated in vitro with either thrombin (in the presence of gly-pro-arg-pro, an inhibitor of fibrin polymerization) or the stable thromboxane (TX) A2 analogue U46619. ⋯ In vitro, hypothermia inhibited both thrombin- and U46619-induced upregulation of GMP-140, downregulation of the GPIb-IX complex, platelet aggregation, and TXB2 generation. These inhibitory effects of hypothermia were all completely reversed by rewarming the blood to 37 degrees C. In vivo, platelet activation was inhibited by hypothermia as shown by 5 independent assays of shed blood: upregulation of GMP-140, downregulation of the GPIb-IX complex, platelet aggregate formation, TXB2 generation, and the bleeding time.(ABSTRACT TRUNCATED AT 250 WORDS)
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Randomized Controlled Trial Comparative Study Clinical Trial
Pharmacokinetics and pharmacodynamics of a low molecular weight heparin (enoxaparin) after subcutaneous injection, comparison with unfractionated heparin--a three way cross over study in human volunteers.
We determined, in volunteers, the plasma levels of heparin above and below the critical chainlength necessary for thrombin inhibition (ACLM and BCLM), from 1 to 24 h after subcutaneous injection of 5000 IU unfractionated heparin (UFH), 40 mg enoxaparin and 1 mg/kg body weight of enoxaparin (LMWH) (n = 12 for each dose). The levels were calculated from the antithrombin- and anti-Xa activities using the specific activities of the materials injected. We also determined the course of thrombin- and of factor Xa generation after triggering the extrinsic system in the same samples. ⋯ When the ACLM and BCLM plasma-levels are plotted against the inhibition of thrombin- and factor Xa generation, it appears that: a) There is a unique dose response relationship between ACLM level and the inhibition of thrombin generation, independent of whether the ACLM is derived from UFH or LMWH. This relationship is not significantly altered by the BCLM appearing after LMWH injection. b) There is a similar unique relationship between ACLM level and the inhibition of factor Xa generation, again independent of BCLM. c) Inhibition of prothrombin activation hardly contributes to the overall effect on thrombin formation and is again independent of the source of ACLM. d) ACLM levels were significantly higher after injection of LMWH than after UFH injection, even though the amounts of ACLM injected with the highest dose of LMWH were smaller than those administered in the UFH injection. We conclude that the only functional difference between LMWH and UFH is the much higher bioavailability of the former.(ABSTRACT TRUNCATED AT 250 WORDS)