Summary
Standard unfractionated heparin is a mixture of mucopolysaccharide chains of various length that may vary from 5000 to 30000 daltons. Heparin is only effective as an anticoagulant in the presence of a plasma protein termed antithrombin III, with which it forms a complex. High- and low-affinity heparin are 2 types that readily bind or do not bind, respectively, to antithrombin III. The pharmacokinetics of unfractionated heparin are compatible with a model based on the combination of a saturable and a linear mechanism. The primary indication for intravenous infusion of conventional heparin is to prevent extension of an established arterial, venous or intracardiac thrombus. The average requirement is 400 U/kg/24h. Subcutaneous administration of 5000U of concentrated unfractionated heparin, administered every 8 or 12 hours, is effective and safe in the prevention of postoperative venous thrombosis and pulmonary embolism in patients at medium thrombotic risk. Adequate prophylaxis is also obtained in patients at high thrombotic risk if 5000U of heparin combined with 0.5mg dihydroergotamine is given subcutaneously 3 times daily, or by monitoring the 3 subcutaneous doses of heparin in order to maintain an adjusted activated partial thromboplastin time (APTT) of around 50 to 70 seconds.
Low molecular weight heparins have been produced by a variety of techniques and their molecular weights range from 3000 to 9000 daltons. These preparations have a ratio of anti-factor Xa activity to anti-factor IIa activity of about 4, while the ratio for unfractionated heparin is 1. After intravenous administration of low molecular weight heparin, the half-life of the anti-factor Xa activity is considerably longer than for unfractionated heparin, while the anti-factor IIa half-lives are similar. In contrast to unfractionated heparin, low molecular weight heparin is completely absorbed after subcutaneous administration and its biological half-life is almost twice as long. In spite of certain differences with regard to the ratio between factor Xa and IIa inhibition, the various low molecular weight preparations show a rather similar absorption pattern. The bioavailability of all low molecular weight heparin fractions is substantially higher than that of unfractionated heparin, which renders their use more simple. Low molecular weight heparins less readily enhance platelet aggregation although there is no evidence that low molecular weight heparins are less antigenic or that they do not interact with platelet IgGFc receptor. A lower bleeding incidence for equivalent antithrombotic efficacy of fractionated heparins when compared to unfractionated heparins has yet to be established in humans.
For prophylaxis of postoperative deep vein thrombosis, one daily subcutaneous injection of low molecular weight heparin results in satisfactory protection with almost no risk of bleeding. For the treatment of deep venous thrombosis, 2 daily injections of low molecular weight heparin are necessary. The presently recommended doses of each low molecular weight heparin differ and are less well established than for standard unfractionated heparin.
After intravenous injection of 100U unfractionated heparin full neutralisation is obtained with 1 mg protamine; the activities of low molecular weight heparins can be neutralised to a lesser extent.
Several of the adverse effects of unfractionated heparin, such as thrombocytopenia and osteoporosis, have also been observed with low molecular weight heparins, but activation of lipoprotein lipase seems to occur to a minor extent with the latter.
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References
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Verstraete, M. Pharmacotherapeutic Aspects of Unfractionated and Low Molecular Weight Heparins. Drugs 40, 498–530 (1990). https://doi.org/10.2165/00003495-199040040-00003
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DOI: https://doi.org/10.2165/00003495-199040040-00003