Sakharov D V, Rijken D C
Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands.
Thromb Haemost. 2000 Mar;83(3):469-74.
Fibrinolysis initially generates channels in an occluding thombus which results in blood flow through the thrombus. Since the impact of flow along the surface of a thrombus on thrombolysis has not been investigated in detail, we studied in vitro how such a flow affects lysis. Compacted and noncompacted plasma clots were used as model thrombi. With compacted clots, fibrin-specific lysis induced by alteplase in the outer plasma was accelerated about 2-fold by strong flow (arterial shear rate). Non-fibrin-specific lysis induced either by a high concentration of alteplase or by streptokinase was slow, was accompanied by rapid depletion of plasminogen in the outer plasma, and was only slightly accelerated by flow. With noncompacted clots, similar acceleration factors were documented, when mild flow (venous shear rate) was applied. Strong flow further accelerated fibrin-specific lysis, up to 10-fold as compared to lysis without flow, but paradoxically retarded non-fibrin-specific lysis. The data suggest that flow accelerates lysis by enhancing transport of plasminogen from the outer plasma to the surface of the clot. Both opposite effects of the strong flow were mediated by forceful intrusion of the outer plasma into the noncompacted clot due to flow irregularities. In the case of non-fibrin-specific lysis this resulted in the replacement of the plasminogen-containing milieu by plasminogen-depleted outer plasma in certain areas of the clot turning them into virtually unlysable fragments. This flow-enforced "plasminogen steal" may contribute to the relatively high percentage of incomplete thrombolysis (TIMI-2 grade flow) documented in a number of trials for non-fibrin-specific thrombolytic agents. In the case of fibrin-specific lysis, the effect of flow on the speed of fibrinolysis is always beneficial.
纤维蛋白溶解最初会在阻塞性血栓中形成通道，从而使血液流经血栓。由于沿血栓表面的血流对溶栓作用的影响尚未得到详细研究，我们在体外研究了这种血流如何影响溶解过程。将压实和未压实的血浆凝块用作模型血栓。对于压实凝块，强力血流（动脉剪切速率）使阿替普酶在外周血浆中诱导的纤维蛋白特异性溶解加速了约2倍。高浓度阿替普酶或链激酶诱导的非纤维蛋白特异性溶解缓慢，伴有外周血浆中纤溶酶原的快速消耗，且仅略微受血流加速。对于未压实凝块，当施加轻度血流（静脉剪切速率）时，记录到了类似的加速因子。强力血流进一步加速了纤维蛋白特异性溶解，与无血流时的溶解相比加速了10倍，但矛盾的是却延缓了非纤维蛋白特异性溶解。数据表明，血流通过增强纤溶酶原从外周血浆向凝块表面的转运来加速溶解。强力血流的这两种相反作用是由于血流不规则导致外周血浆强力侵入未压实凝块而介导的。在非纤维蛋白特异性溶解的情况下，这导致凝块某些区域中含纤溶酶原的环境被耗尽纤溶酶原的外周血浆所取代，使其变成几乎无法溶解的碎片。这种血流强制的“纤溶酶原窃取”可能导致在许多非纤维蛋白特异性溶栓药物试验中记录的相对较高比例的不完全溶栓（TIMI-2级血流）。在纤维蛋白特异性溶解的情况下，血流对纤维蛋白溶解速度的影响始终是有益的。
