[每周一问]NO.31-anesthesia and warfarin(part 2)
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1.How quickly does warfarin work?
2.Does warfarin always lead to anticoagulation?
1.华法林起效时间如何（最短时间）?
2.华法林是否自始自终表现为抗凝作用?
参考答案（请战友指正)
1华.法林起效时间如何（最短时间）?
凝血因子VII和蛋白C在血浆中半衰期很短，只有6-8h。服药后24-36小时凝血因子VII水平下降使初期凝血酶原时间延长。Heit等认为，只有在凝血因子VII降至正常值55%时才开始出现凝血酶原时间延长。然而华法林的治疗效应主要是减少凝血因子II和X，这两个凝血因子的半衰期分别为36-48和72-96小时。因此，即使国际标准化值水平在治疗范围，华法林真正的抗凝时间达不到4-6天。相反，如果停止华法林，凝血因子II和X恢复至正常水平速度很慢，因此国际标准化值下降至正常范围，可能是由于因子VII水平的增加的结果，但凝血系统不一定回复到正常水平。迄今为止，未见到近期停用华法林后出血风险性的研究报道。
2.华法林是否自始自终表现为抗凝作用?
如上所述，华法林可影响维生素K，蛋白C是维生素K依赖性蛋白。与凝血因子相反，蛋白C是凝血抑制蛋白。由于蛋白C的半衰期很短，理论上蛋白C减少可能导致应用华法林后最初几天，凝血功能一过性增高。最常见的预防此种潜在并发症的治疗方案是开始应用华法林的同时静脉或皮下应用肝素治疗。
治疗剂量华法林常减少正常的蛋白C水平约20%左右（此水平可导致明显的凝血）。Smirnov等假设血栓形成必须其他凝血因子的参与调节，通过研究激活蛋白C的抗凝效应，得出结论认为，蛋白C水平很低时，激活蛋白C效能增加大约50%。因此当蛋白C水平下降导致蛋白C激活系统受损害时，激活蛋白C的抗凝功能将抵消蛋白C水平的下降导致的凝血效应。这使得在应用华法林治疗早期使患者至少部分的避免了由于蛋白C水平下降导致的凝血危险。
英文参考答案
1.How quickly does warfarin work?
Factors VII and protein C have the shortest plasma half-lives of 6-8 h. As a result, initial increases in prothrombin time reflect the decline in factor VII, which can be witnessed in 24-36 hrs. Heit et al. (1) noted that a prolongation in PT occurred when factor VII was reduced to 55% of normal. However, the principle therapeutic effect of warfarin is derived from the reduction of Factors II and X, which have half lives of 36-48 and 72-96 hrs respectively (2). As a consequence, although the INR may enter the therapeutic range, true antithrombotic anticoagulation is not adequate for 4-6 days. Conversely, should warfarin be discontinued, factors II and X are the slowest to return. Thus a drop into the normal INR range may be due to primarily an increase in factor VII and may not ensure the return to a normal coagulation profile (2). To date, no studies have examined the risk of procedure-related bleeding with recent discontinuation of warfarin.
2.Does warfarin always lead to anticoagulation?
As mentioned above, protein C is a vitamin K dependent protein which is affected by warfarin. However, in contrast to the clotting factors, Protein C is a a clot inhibitor protein. As a consequence, and due to its short half life, a reduction in Protein C formation during the first few days of warfarin use can result in a theoretical increase in clotting! The most common therapeutic solution to avoid this potential complication is to start warfarin concurrently with intravenous or subcutaneous heparin.
Acknowledging that warfarin therapy often reduced protein C levels to 20% of normal (a level associated with significant clot formation), Smirnov et al. (3) hypothesized that thrombosis must be modulated by other factors. By studying activated protein C (APC) anticoagulant activity, the authors noted that when protein C levels were low, the effectiveness of APC would increase approximately 5-fold. Thus, while the protein C activation system could be impaired by a quantitative reduction in protein C levels, a qualitiative increase in the APC anticoagulant function offset that reduction. This allows patients during the early stages of warfarin therapy to be at least partially protected from the thrombotic risk of reduced protein C levels.
References:
1.Heit JA, Plumhoff EA, Thompson CK, et al. Monitoring oral anticoagulant therapy: Prothrombin time/INR versus factor II activity/native prothrombin antigen. Thromb Haemost 1993;69:2080A.
2.Enneking FK, Benson H. Oral anticoagulants and regional anesthesia: a perspective. Reg Anesth Pain Med 1998;23: Suppl 2: 140-5.
3.Smirnov MD, Safa O, Esmon NL, Esmon CT. Inhibition of activated protein C anticoagulant activity by prothrombin. Blood 1999 Dec 1;94(11):3839-46
作者: 风雨同
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