Thrombolysis vs. bleeding from hemostatic sites by a prourokinase mutant compared with tissue plasminogen activator
Thrombolysis vs. bleeding from hemostatic sites by a prourokinase mutant compared with tissue plasminogen activator
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DOI：
10.1111/j.1538-7836.2006.01993.x
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发表时间：
2006-07-01
影响因子：
10.4
通讯作者：
Badylak, S. F.
中科院分区：
文献类型：
--
作者：
Gurewich, V.;Pannell, R.;Badylak, S. F.
背景：尿激酶原（proUK）的一个单位点突变体（M5）被开发出来，使proUK不易于在血浆中自发激活。这是一个严重损害临床试验中proUK的问题，因为它排除了治疗浓度的proUK介导的纤维蛋白溶解。方法与结果：完成剂量探索研究后，12只患有股动脉血栓形成的麻醉犬在60分钟内静脉输注M5（2.0 mg kg（-1））或组织纤溶酶原激活剂（t-PA）（1.4 mg kg（-1））（20%以推注方式给药）。造成两对标准化损伤，并在给药前完成止血。通过测量从这些部位吸收的血液中的血红蛋白来定量失血。在90分钟时评价溶栓，两种激活剂均有效。1只t-PA犬发生再血栓形成。发现的主要差异是，t-PA组的失血量（平均值与40 mL相似）是M5组（平均值与4 mL相似）的10倍（P = 0.026），并且发生在更多部位（平均值2.7 vs. 1.2）。假设该效应与t-PA和M5激活纤溶酶原的机制差异相关，其中后者是由降解而非完整（止血）纤维蛋白促进的。此外，双链M5被血浆Cl灭活剂有效灭活，这是一种特殊的性质，有助于抑制其非特异性蛋白水解作用。结论：与t-PA相比，M5血管内溶栓的止血部位出血明显较少。这归因于通过突变将纤维蛋白溶解的proUK范例保持在治疗浓度。
Background: A single site mutant (M5) of prourokinase (proUK) was developed to make proUK less vulnerable to spontaneous activation in plasma. This was a problem that seriously compromised proUK in clinical trials, as it precluded proUK-mediated fibrinolysis at therapeutic concentrations. Methods and results: After completing dose-finding studies, 12 anesthetized dogs with femoral artery thrombosis were given either M5 (2.0 mg kg(-1)) or tissue plasminogen activator (t-PA) (1.4 mg kg(-1)) by i.v. infusion over 60 min (20% administered as a bolus). Two pairs of standardized injuries were inflicted at which hemostasis was completed prior to drug administration. Blood loss was quantified by measuring the hemoglobin in blood absorbed from these sites. Thrombolysis was evaluated at 90 min and was comparably effective by both activators. Rethrombosis developed in one t-PA dog. The principal difference found was that blood loss was 10-fold higher with t-PA (mean similar to 40 mL) than with M5 (mean similar to 4 mL) (P = 0.026) and occurred at more multiple sites (mean 2.7 vs. 1.2). This effect was postulated to be related to differences in the mechanism of plasminogen activation by t-PA and M5 in which the latter is promoted by degraded rather than intact (hemostatic) fibrin. In addition, two-chain M5 was efficiently inactivated by plasma Cl inactivator, an exceptional property which helped contain its non-specific proteolytic effect. Conclusions: Intravascular thrombolysis by M5 was accompanied by significantly less bleeding from hemostatic sites than by t-PA. This was attributed to the proUK paradigm of fibrinolysis being retained at therapeutic concentrations by the mutation.