Heparin: A Review of its Pharmacology and Therapeutic Use in Horses

Abstract

Heparin is used clinically in horses to treat hemostatic abnormalities associated with severe gastrointestinal disease, septicemia, and endotoxemia. The primary anticoagulant effect of heparin is through the suppression of thrombin-dependent amplification of the coagulation cascade, and inhibition of thrombin-mediated conversion of fibrinogen to fibrin. Heparin may be of benefit in preventing the complications associated with hypercoagulable states such as jugular vein thrombosis, laminitis, and organ failure. Heparin may also be beneficial in the prevention of intraabdominal adhesions after gastrointestinal surgery, and in amelioration of hernodynamic abnormalities associated with endotoxic shock. Because a sequential rise in serum unique compound with anticoagulant activity was ac-A cidentally discovered in 19 16 by McClean, a medical student, while he was attempting to identify a procoagulant in the liver.' The substance was named heparin because of its abundance in hepatic tissue.' In 1939, Brinkhous discovered that a plasma cofactor was necessary for the anticoagulant activity of h e~a r i n .~ Abildgaard named the cofactor antithrombin 111 (AT 111), and the specific mechanism of action of this cofactor was elucidated shortly thereafter. [4][5][6] Heparin is composed of a family of straight-chain, highly sulfated, anionic polysaccharides, specifically glycosaminoglycuronan sulfate esters, with molecular weights varying from 4,000 to 40,000 d.7-9 The structural unit of this complex molecule is a two hexose sugar that, in 8 to 15 repeating disaccharide subunits, forms a polymer of differing length^.^.' The structure of heparin is markedly heterogenous and varies with respect to the sequence and ratio of the different hexose units, the extent and type of sulfation, and the extent of N-a~etylation.~ The heterogeneity of heparin is not an artifact of preparation, but occurs because of the randomness of the biosynthetic process. lo Endogenous heparin is produced within mast cells of the lung, liver, and intestine.' ' Commercially-available heparin is derived from the mast cells of porcine intestinal mucosa and bovine lung."A small and distinct fraction of the heparin molecule is responsible for its anticoagulant effect. l 3 The active site of the heparin molecule contains a unique glucosamine unit with a specific pentasaccharide ~equence.'~.'~ This distinct fraction of the heparin molecule binds to AT 111, an endog-

Thromboelastometric evaluation of horses submitted to experimental thrombosis and jugular thrombectomy

“…In relation to the use of heparin as an anticoagulant in allopathic therapy or as a postoperative co-adjuvant after vascular surgeries, there is consensus on the importance of its laboratory monitoring with reagents of aPTT (more sensitive to the inhibitory effects of heparin on thrombin, the factors Xa and IXa) and the platelet count, being that the absence of thrombocytopenia at D16 and an increase not greater than 1.5 to 2.5 times (in seconds) of aPTT, in both groups, demonstrated that the lowest heparin dose utilized (150 UI/Kg, SC) is safe (Moore & Hinchcliff 1994, Dornbusch, 2005, Borghesan 2010). …”

“…In this case, its effect is related to agglutination of erythrocytes (Mahaffey & Moore 1986, Moore & Hinchcliff 1994, resulting in phagocytosis by macrophages and reduction in globular volume. In our study, hematocrit presented a considerable reduction between D9 and D16 and D19.…”

Avaliação da tromboflebite jugular experimental em equinos tratados com heparina

“…Os valores numéricos de TTPA, TP, volume globular e contagem total de plaquetas foram submetidos à análise estatística pelo teste paramétrico para variável 11 Omnipaque -Sanifi Winthrop Farmacêutica Ltda. 12 Scalp 21G -Abbot.…”

“…A heparina catalisa a reação de inibição realizada pela AT III, acelerando o processo. A trombina (fator II ativado) e o fator X ativado são as enzimas da coagulação mais sensíveis à inativação pelo complexo formado pela heparina e a AT III [1,8,11], sendo que mecanismos secundários para a expressão do efeito anticoagulante da heparina têm sido descritos [10,11,12,13].…”

“…A inativação da heparina é feita através de fagócitos mononucleares, células endoteliais vasculares e proteínas plasmáticas, sendo este um mecanismo saturável [8,9,11]. A heparina também é metabolizada por enzimas hepáticas chamadas heparinases e parcialmente eliminada na forma íntegra pelo sistema renal [2,9].…”