Zwaginga J J, Koomans H A, Sixma J J, Rabelink T J
Department of Nephrology, University Hospital Utrecht, The Netherlands.
J Clin Invest. 1994 Jan;93(1):204-11. doi: 10.1172/JCI116947.
Increased in vitro platelet aggregability and hypercoagulability are generally held to be main determinants in the prethrombotic state in nephrosis. In vivo, however, thrombotic events depend on the dynamic interaction of flowing blood with the vessel wall. The present study confirms that aggregability of platelets of nephrotic patients is significantly increased by mere stirring or by exogenous stimuli as adenosine diphosphate and arachidonic acid. Moreover, the nephrotic patients have high von Willebrand factor and decreased red blood cell deformability, which normally increase platelet-vessel wall interaction. However, perfusion studies under well-defined flow conditions, in which anticoagulated nephrotic blood was exposed to deendothelialized human umbilical artery segments and sprayed collagen, showed normal platelet adhesion and only a modest increase in the deposition of platelet aggregates. This suggests that some factor counteracts platelet-vessel wall interaction under flow conditions in the nephrotic syndrome. When tissue factor associated with endothelial extracellular matrix (ECM) was allowed to generate thrombin, perfusions with nephrotic blood over this ECM resulted in a strong increase in fibrin generation. The capacity of patient blood to form increased amounts of fibrin appeared strongly correlated with the level of hyperfibrinogenemia. Platelet adhesion as well as aggregation in these experiments was even decreased below control values. This suggests that fibrin coverage may block the direct contact between blood platelets and matrix. We therefore also studied the isolated effect of high fibrinogen on platelet-vessel wall interaction by increasing fibrinogen concentrations in normal blood. Modulation of fibrinogen concentrations in normal blood could mimic all the observations in nephrotic blood: platelet aggregation in suspension increased with increasing concentrations of fibrinogen, while platelet adhesion and aggregate formation under flow conditions decreased. In perfusions over tissue factor-rich matrix, fibrin deposition increased. Therefore, our observations indicate that nephrotic hyperaggregability in suspension is not associated with increased platelet vessel wall-interaction under flow conditions. The latter is probably counteracted by high levels of fibrinogen. Our observations further suggest that hyperfibrinogenemia may be a major thrombotic risk factor in nephrosis by inducing more fibrin depositions.
体外血小板聚集性增加和高凝状态通常被认为是肾病血栓前状态的主要决定因素。然而，在体内，血栓形成事件取决于流动血液与血管壁的动态相互作用。本研究证实，仅通过搅拌或外源性刺激如二磷酸腺苷和花生四烯酸，肾病患者血小板的聚集性就会显著增加。此外，肾病患者血管性血友病因子水平较高，红细胞变形性降低，这通常会增加血小板与血管壁的相互作用。然而，在明确的流动条件下进行的灌注研究中，将抗凝的肾病血液暴露于去内皮的人脐动脉段并喷洒胶原蛋白，结果显示血小板黏附正常，血小板聚集体沉积仅适度增加。这表明在肾病综合征的流动条件下，某种因素会抵消血小板与血管壁的相互作用。当与内皮细胞外基质（ECM）相关的组织因子产生凝血酶时，用肾病血液灌注该ECM会导致纤维蛋白生成大幅增加。患者血液形成更多纤维蛋白的能力似乎与高纤维蛋白原血症水平密切相关。在这些实验中，血小板黏附以及聚集甚至低于对照值。这表明纤维蛋白覆盖可能会阻断血小板与基质之间的直接接触。因此，我们还通过增加正常血液中的纤维蛋白原浓度来研究高纤维蛋白原对血小板与血管壁相互作用的单独影响。调节正常血液中的纤维蛋白原浓度可以模拟肾病血液中的所有观察结果：悬浮液中的血小板聚集随着纤维蛋白原浓度的增加而增加，而在流动条件下血小板黏附和聚集体形成减少。在富含组织因子的基质上进行灌注时，纤维蛋白沉积增加。因此，我们的观察结果表明，悬浮液中肾病性高聚集性与流动条件下血小板与血管壁相互作用增加无关。后者可能被高水平的纤维蛋白原抵消。我们的观察结果进一步表明，高纤维蛋白原血症可能通过诱导更多纤维蛋白沉积而成为肾病的主要血栓形成危险因素。
