A Human Pharmacological Study Comparing Conventional Heparin and a Low Molecular Weight Heparin Fragment
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The pharmacokinetics of a heparin fragment of low molecular weight (LMWH) of 4000-5000 D and unfractioned standard heparin (UFH) have been studied after i.v. injections of different doses and infusions in 8 humans. The heparin activity was significantly higher and the effect on APTT lower after LMWH fragment as compared to UFH in the same doses. The half-life of heparin activity was about 1 hr for UFH and about 2 hr for LMWH. LMWH was found to be eliminated according to first order kinetics and there were no signs of dose dependency.Keywords:
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An unexpectedly high rate of adverse events and deaths were reported from November 2007 to April 2008 in patients exposed to heparin. Investigations on the quality of heparin revealed an oversulfated chondroitin sulfate (OSCS) contaminant in the heparin. Several reports on the chemical structure and limited biologic actions of OSCS have recently become available. However, no data are available on its anticoagulant and antiprotease effects. Moreover, its interaction with heparin, resulting in the modulation of heparin's anticoagulant activity, is not reported. The isolated contaminant from recalled batches of heparin and several semisynthetic OSCSs were profiled for their in vitro anticoagulant effects. The contaminant and OSCSs both exhibited measurable anticoagulant activity and produced supra-additive effects in the presence of heparin. In addition, in animal models of thrombosis and bleeding, the contaminated heparin produced stronger anticoagulant and bleeding effects than heparin. Thus, in addition to the reported biological actions, the heparin contaminant exerts measurable anticoagulant effects and interacts with heparin to produce supra-additive effects. These studies suggest that the contamination of heparin with OSCS was based on a rational design and prior knowledge of molecular and anticoagulant profiles. These studies also indicate that the OSCS contaminant may itself be heterogeneous and its molecular and biological profiles may vary in different recalled heparins.
Chondroitin
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Protamine sulfate
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The anticoagulant activity of heparin dissolved in intravenous solutions was measured by two different methods of heparin assay. Both procedures showed markedly reduced anticoagulant activity within four hours after the addition of heparin to the solutions. When measured according to the procedure of Yin, heparin in the intravenous solutions fully regained its lost anticoagulant activity after 24 hours at room temperature. When measured by the thrombin time, however, the heparin anticoagulant activity reamained reduced. The source of heparin, from either the lung or intestine, does not explain the reduction in anticoagulant activity. Although its cause is unknown, the erratic behaviour of heparin in intravenous solutions stresses the importance of a laboratory monitor of heparin therapy.
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Severe heparin-induced thrombocytopaenia associated with thromboembolism is a well known complication, although the exact pathogenic mechanism remains unclear. It sets the problem of whether to continue heparin therapy because standard heparin must be withdrawn. Heparin is a mucopolysaccharide composed of fractions of different molecular weights. The fractions with high molecular weights have been held responsible for these severe thrombocytopenias and so, the use of low molecular weight heparin has been suggested. The authors used subcutaneous low molecular weight heparin (CY 216 Choay Institute) at empirical doses of 350 to 1 500 units/kg/24 hour in six cases of severe heparin-induced thrombocytopaenia. Platelet counts rapidly returned to normal (4 days on average) in 5 cases. Thrombocytopaenia persisted with low molecular weight heparin in 1 case. The study of platelet aggregation was positive with low molecular weight heparin in this case and the platelet count returned to normal when the treatment was withdrawn. The authors conclude that, although low molecular weight heparin is useful in severe heparin-induced thrombocytopaenia, its efficacy remains modest. Not only may platelet aggregation persist with low molecular weight heparin which rekindles the debate as to its pathogenic mechanism, but also low molecular weight heparin may have a slight antithrombin effect which limits its use in patients at high risk of thromboembolism, imposing treatment with fast acting vitamin K antagonists.
Heparin-Induced Thrombocytopenia
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The pharmacokinetics of a heparin fragment of low molecular weight (LMWH) of 4000-5000 D and unfractioned standard heparin (UFH) have been studied after i.v. injections of different doses and infusions in 8 humans. The heparin activity was significantly higher and the effect on APTT lower after LMWH fragment as compared to UFH in the same doses. The half-life of heparin activity was about 1 hr for UFH and about 2 hr for LMWH. LMWH was found to be eliminated according to first order kinetics and there were no signs of dose dependency.
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Heparin-induced thrombocytopenia is very uncommon with low-molecular-weight heparin, especially when given for prophylaxis of venous thromboembolism. In two of the four published cases, with thrombotic complications, thrombocytopenia may have been related to cross-reactivity between unfractionated heparin and low-molecular-weight heparin. We report one patient who received low-molecular-weight heparin for prophylaxis against venous thromboembolism without any previous injection of unfractionated heparin, and experienced thrombocytopenia with thrombotic complications. Heparin-induced thrombocytopenia was confirmed by several laboratory assays. This observation emphasizes the need for platelet count monitoring during low-molecular-weight heparin therapy.
Heparin-Induced Thrombocytopenia
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Ex vivo
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Heparin-induced thrombocytopenia with thrombosis occurs in one out of about 2,000 patients on heparin treatment for five days. The new thrombosis is often arterial and may carry a grave prognosis. If thrombocytopenia develops during heparin treatment, heparin must be discontinued immediately. Alternative antihrombotic medication should be considered. Organs is probably the best alternative. Vascular surgery can be considered. In order to reduce the risk of experiencing this serious complication, oral anticoagulation should be initiated rapidly after heparin therapy is started. Compared with standard heparin, low molecular weight heparin probably involves less risk of the patient developing thrombocytopenia and thrombosis.
Heparin-Induced Thrombocytopenia
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From my previous report it is supposed that the anticoagulant action of the peanut extract is skin to that of heparin. So I prepared heparin from dog's livers after the method originated by Charles-Scott, and investigated on this action to blood coagulation, comparing with those of the extract of the peanut. The results may be summarized as follows: 1) Heparin did not interfere with the presence of Ca-ion, inhibited the blood coagulation acting as antiprothrombin as well as as antithrombin. 2) The anticoagulant actiom of heparin was markedly inhibited by the addition of fresh serum, but recovered its action to a certain extent 24 hours after the adition, and again diminished gradually with the lapse of time. 3) It may be concluded that the anticoagulant substance contained in the peanut extract is akin to heparin.
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