Sauls D L, Wolberg A S, Hoffman M
Pathology and Laboratory Medicine Service, Durham Veterans Affairs Medical Center, Durham, North Carolina 27705, USA.
J Thromb Haemost. 2003 Feb;1(2):300-6. doi: 10.1046/j.1538-7836.2003.00053.x.
Elevated plasma homocysteine is associated with an increased risk of atherosclerosis and thrombosis. However, the mechanisms by which homocysteine might cause these events are not understood. We hypothesized that hyperhomocysteinemia might lead to modification of fibrinogen in vivo, thereby causing altered fibrin clot structure. New Zealand White rabbits were injected intraperitoneally (i.p.) every 12 h through an indwelling catheter with homocysteine or buffer for 8 weeks. This treatment raised the plasma homocysteine levels to about 30 micro mol L(-1) compared with 13.5 micro mol L(-1) in control rabbits by the end of the treatment period. The fibrinogen levels were 3.2 +/- 0.6 in homocysteine-treated and 2.5 +/- 1.1 mg mL(-1) in control rabbits. The reptilase time was prolonged to 363 +/- 88 for plasma from homocysteine-treated rabbits compared with 194 +/- 48 s for controls (P < 0.01). The thrombin clotting time (TCT) for the homocysteine-treated rabbits was significantly shorter, 7.5 +/- 1.7 compared with 28.6 +/- 18 s for the controls (P < 0.05). The calcium dependence of the thrombin clotting time was also different in homocysteinemic and control plasmas. Clots from plasma or fibrinogen of homocysteinemic rabbits were composed of thinner fibers than control clots. The clots formed from purified fibrinogen from homocysteine-treated rabbits were lyzed more slowly by plasmin than comparable clots from control fibrinogen. Congenital dysfibrinogenemias have been described that are associated with fibrin clots composed of thin, tightly packed fibers that are abnormally resistant to fibrinolysis, and recurrent thrombosis. Our results suggest that elevated plasma homocysteine leads to a similar acquired dysfibrinogenemia. The formation of clots that are abnormally resistant to fibrinolysis could directly contribute to the increased risk of thrombosis in hyperhomocysteinemia.
血浆同型半胱氨酸水平升高与动脉粥样硬化和血栓形成风险增加相关。然而，同型半胱氨酸引发这些事件的机制尚不清楚。我们推测高同型半胱氨酸血症可能导致体内纤维蛋白原发生修饰，从而引起纤维蛋白凝块结构改变。通过留置导管，每12小时给新西兰白兔腹腔注射一次同型半胱氨酸或缓冲液，持续8周。与治疗期结束时对照兔血浆同型半胱氨酸水平13.5微摩尔/升相比，该治疗使血浆同型半胱氨酸水平升高至约30微摩尔/升。同型半胱氨酸处理组兔纤维蛋白原水平为3.2±0.6，对照组为2.5±1.1毫克/毫升。同型半胱氨酸处理组兔血浆的爬虫酶时间延长至363±88秒，而对照组为194±48秒（P<0.01）。同型半胱氨酸处理组兔的凝血酶凝血时间（TCT）显著缩短，为7.5±1.7秒，而对照组为28.6±18秒（P<0.05）。同型半胱氨酸血症血浆和对照血浆中凝血酶凝血时间的钙依赖性也不同。同型半胱氨酸血症兔血浆或纤维蛋白原形成的凝块比对照凝块的纤维更细。同型半胱氨酸处理组兔纯化纤维蛋白原形成的凝块比对照纤维蛋白原形成的类似凝块被纤溶酶溶解得更慢。已有报道称先天性异常纤维蛋白原血症与由细的、紧密排列的纤维组成的纤维蛋白凝块相关，这些纤维对纤维蛋白溶解异常抵抗，并伴有复发性血栓形成。我们的结果表明，血浆同型半胱氨酸水平升高会导致类似的后天性异常纤维蛋白原血症。对纤维蛋白溶解异常抵抗的凝块形成可能直接导致高同型半胱氨酸血症患者血栓形成风险增加。
