Anticoagulant and Antithrombin Effects of Intimatan, a Heparin Cofactor II Agonist

• Published in: Thrombosis research Vol. 99; no. 6; pp. 603 - 612
• Main Authors: Buchanan, Michael R, Brister, Stephanie J
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Ltd 15.09.2000; Elsevier Science
• Subjects: Animals; Anticoagulants - pharmacology; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Carotid Artery Injuries - metabolism; Dermatan Sulfate - analogs & derivatives; Dermatan Sulfate - pharmacology; Dermatan sulphate; Dose-Response Relationship, Drug; Factor Xa - drug effects; Factor Xa Inhibitors; Female; Heparin; Heparin - pharmacology; Heparin Cofactor II - agonists; Intimatan; Male; Medical sciences; Partial Thromboplastin Time; Pharmacology. Drug treatments; Rabbits; Sodium Chloride - pharmacology; Surface-bound thrombin; Thrombin - antagonists & inhibitors; Thrombin - drug effects; HCII, heparin cofactor II; Intimatan; USP, United States Pharmacopoeia; MW, molecular weight; kDa, kilodalton; Dermatan sulphate; Surface-bound thrombin; U, unit; AT, antithrombin III; ELISA, enzyme linked immuno assay; Heparin; Hg, mercury; APTT, activated partial thromboplastin time; Blood coagulation; Agonist; Rabbit; Anticoagulant; Lagomorpha; In vitro; Biological activity; In vivo; Vertebrata; Chemotherapy; Mammalia; Thrombin(drug); Heparin cofactor; Animal; Inhibitor; Mechanism of action; Comparative study
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/S0049-3848(00)00276-0

Surface-bound thrombin, which is resistant to inhibition by heparin/antithrombin III (/AT), plays a key role in vessel wall disease. In contrast, surface-bound thrombin is not resistant to inhibition by heparin cofactor II (HCII) and its acceleration of its inhibitory effect by dermatan sulfate. However, the potential use of dermatan sulfate to prevent thrombus formation in vivo is limited by its low specific activity, which in turn, necessitates excessively high doses when given on a gravimetric basis. Recently, a novel HCII agonist, Intimatan, has been synthesized by site-specific sulphation of highly purified dermatan sulfate comprising primarily of L-iduronic acid-4-O-sulphated N-acetyl- d-galactosamine, yielding a 4,6-O-disulphate compound on the galactopyranose ring with a lower molecular weight, higher solubility, and specific activity than its parent, dermatan sulfate. In this study, we compared the abilities of Intimatan with its parent compound, dermatan sulfate, and with heparin to affect coagulation and to inhibit surface-bound thrombin both in vitro and in vivo, to determine if Intimatan demonstrates a better potential than either other compound in preventing thrombus formation in vivo. Intimatan prolonged the activated partial thromboplastin time (APTT) more effectively than either dermatan sulfate or heparin at comparable antithrombin concentrations. This activity was attributed to the more selective action of Intimatan against surface-bound thrombin in vitro. Intimatan also inhibited thrombin bound to an injured vessel wall surface in vivo more effectively than heparin, i.e., when measured in injured carotid arteries of rabbits injected with Intimatan or with heparin at the time of injury. We conclude that Intimatan effectively inhibits surface-bound thrombin, thereby exhibiting better anticoagulant and antithrombin properties than heparin and dermatan sulfate.