Buchanan M R, Brister S J
Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Thromb Res. 2000 Sep 15;99(6):603-12. 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.
对肝素/抗凝血酶III（/AT）抑制作用具有抗性的表面结合凝血酶在血管壁疾病中起关键作用。相比之下，表面结合凝血酶对肝素辅因子II（HCII）的抑制作用以及硫酸皮肤素对其抑制作用的加速作用不具有抗性。然而，硫酸皮肤素在体内预防血栓形成的潜在用途受到其低比活性的限制，这反过来又使得按重量给药时需要过高的剂量。最近，一种新型的HCII激动剂Intimatan已通过对主要由L-艾杜糖醛酸-4-O-硫酸化的N-乙酰-D-半乳糖胺组成的高度纯化硫酸皮肤素进行位点特异性硫酸化合成，在吡喃半乳糖环上产生了一种4,6-O-二硫酸化合物，其分子量更低、溶解度更高且比其母体硫酸皮肤素具有更高的比活性。在本研究中，我们比较了Intimatan与其母体化合物硫酸皮肤素以及肝素在体外和体内影响凝血和抑制表面结合凝血酶的能力，以确定Intimatan在预防体内血栓形成方面是否比其他任何一种化合物都具有更好的潜力。在可比的抗凝血酶浓度下，Intimatan比硫酸皮肤素或肝素更有效地延长活化部分凝血活酶时间（APTT）。这种活性归因于Intimatan在体外对表面结合凝血酶的更具选择性的作用。Intimatan在体内也比肝素更有效地抑制与受损血管壁表面结合的凝血酶，即在对受伤时注射了Intimatan或肝素的兔的受损颈动脉进行测量时。我们得出结论，Intimatan有效地抑制表面结合凝血酶，从而表现出比肝素和硫酸皮肤素更好的抗凝血和抗凝血酶特性。
