Τόμος 6 (1992) – Τεύχος 1 – Άρθρο 1 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Διεθνής Έκδοση – Volume 6 (1992) – Issue 1 – Article 1 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-International Edition

Title

Unfractionated and low molecular weight heparins in the prophylaxis and therapy of venous thromboembolism an overreview
Authors Charalampos T. Plessas¹ and Stavros T. Plessas²

1. PHARMAKON Press Information Services, Athens, Greece

2. Professor of Physiology, Nursing Department, University of Athens, Athens, Greece

Citation Plessas, C.T., Plessas, S.T.: Unfractionated and low molecular weight heparins in the prophylaxis and therapy of venous thromboembolism an overreview, Epitheorese Klin. Farmakol. Farmakokinet. 6(1): 5-58 (1992)
Publication Date 1992-04
Full Text Language English
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Keywords Hemostasis, blood coagulation, intrinsic and extrinsic pathways, clotting factors, tissue factor, antithrombin III, fibrinolysis, chemistry of heparins, unfractionated heparin, low molecular weight heparins, Fraxiparine, Enoxaparin, Fragmin, Logiparin, Sandoparine, Fluxum, Pharmacology, Pharmacokinetics, clinical uses of heparins in the prevention of thromboembolism, treatment of venous thromboembolism, use of heparins in hemodialysis, adverse effects of heparins.
Other Terms review article
Summary Hemostasis is a physiological process permitting the cessation of blood loss from an injured vessel; it leads to the thrombin formation resulting in the fibrin clot production. Thrombosis is a pathological form of hemostasis leading in the formation of an intravascular thrombus which occludes a blood vessel. Blood coagulation is a complex phenomenon which is induced by the intrinsic and extrinsic pathways and involves a series of zymogen activation reactions. At each reaction a precursor or zymogen protein (prekallikrein, XII, XI, IX, X, VII and II) is converted to an active protease or activated zymogen by cleavage of one or more peptide bonds in the zymogen molecule. Other components involved in the coagulation cascade include non-enzymic protein cofactors (factors V and VIII, tissue factor and high molecular weight kininogen) and calcium ions. Theoretically, factor X generation may represent a crucial step in the coagulation and thrombin causes an important feedback activation of the coagulation. Several naturally occurring substances, such as antithrombin III (AT-III), heparan sulfate proteoglycans, the protein C/protein S/thrombomodulin system, are inhibitors or modulators of blood coagulation. AT-III plays an important protective role in inhibiting the activation of coagulation; its complex with heparin is a powerful and rapid inhibitor of thrombin and other factors ( XIIa, XIa, IXa and Xa). Fibrinolysis represents a major defence mechanism against fibrin deposition; fibrin is broken down by plasmin formed from plasminogen. The fibrinolytic system includes (a) the plasminogen, (b) the plasminogen activators (tissue and urokinase type ), and (c) the plasminogen activator inhibitors.Unfractionated heparin (UFH) is a heterogeneous mixture of sulfated polysaccharide chains of the glucosamine family, with a molecular weight varying from 30,000 to 100,000 daltons; its biosynthesis occurs in mast cells from a precursor macromolecule. UFH exerts its anti-coagulant action via AT-III, after the binding of AT-III to a specific site of heparin; this specific binding site is a pentasaccharide, with a glucosamine residue in its centre. The binding of UFH to AT-III results in a major increase in the inhibition of coagulation factors by the AT-III. The anti-Xa activity of heparin is amplified by small oligosaccharides, but only octadecasaccharides and larger fragments can activate AT-III against thrombin. Low-molecular-weight heparins (LMWHs), prepared by various techniques, consist of 18-20 monosaccharides on average, with molecular weights averaging 4,0-6,000 daltons, but ranging from 2,000 to 8,0 daltons. The LMWHs have an anti-Xa/anti-IIa activity ratio of about 4, while this ratio for UFH is 1. UFH and LMWHs are all effective in inhibiting thrombosis; the antithrombotic activity correlates with the ability to catalyze thrombin inhibition in contact-activated plasma. Other actions of heparins include a fibrinolytic effect, the interaction with endohelium, an effect on vessel wall permeability and a lipolytic effect on plasma lipids. LMWHs are readily absorbed after s.c. injection, with a bioavailability ranging from 87 to 98%, against 25% for UFH. The biological half-life of LMWHs is almost twice as long as that of UFH. Heparins do not cross the placenta and they do not produce untoward effects in the fetus or newborn when administered to the mother during pregnancy.Clinical trials have demonstrated that LMWHs are highly effective in the prophylaxis of venous thrombosis in orthopedic surgery, where they appear to be more effective than UFH and they do not produce excessive bleeding. LMWHs have also been shown to be either more than or as effective as low-dose UFH in patients undergoing general surgery. Some studies also suggest that LMWHs are effective in the treatment of venous thrombosis, but larger studies are required. A subcutaneous administration of 5,0 U UFH, given every 8 or 12 hours, is effective and safe in the prevention of post-operative deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients at medium thrombotic risk; in patients at high risk, this dosage regimen must be combined with 0.3 mg dihydroergotamine or monitored – adjusted in order to maintain the APTT between 60 and 70 seconds. A daily subcutaneous injection of LMWHs provides satisfactory protection against post-operative thromboembolism, without bleeding risk, while two daily injections are recommended in the treatment of recent deep veneous thrombosis.The most common side effects of heparins is hemorrhage. Other complications include thrombocytopenia with or without thrombosis, osteoporosis, hypersensitivity reactions, skin necrosis, hypoaldosteronism and alopecia.
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