Hoffman Maureane
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27705, USA.
Blood Rev. 2003 Sep;17 Suppl 1:S1-5. doi: 10.1016/s0268-960x(03)90000-2.
Our cell-based model of haemostasis replaces the traditional 'cascade' hypothesis, and proposes that coagulation takes place on different cell surfaces in three overlapping steps: initiation, amplification, and propagation. In highlighting the importance of cellular control during coagulation, the cell-based model allows a more thorough understanding of how haemostasis works in vivo, and sheds light on the pathophysiological mechanisms behind certain coagulation disorders. For instance, this model proposes that haemophilia involves a failure of platelet-surface FXa generation, leading to a lack of platelet-surface thrombin production. Our data suggest that high-dose FVIIa is able to bind weakly to activated platelets, independently of tissue factor, in order to generate sufficient amounts of FXa to support a burst bf thrombin generation in the absence of FIXa/FVIIIa. The considerable success of high-dose recombinant FVIIa (rFVIIa; NovoSeven, Novo Nordisk, Copenhagen, Denmark) as a therapy for patients with haemophilia and inhibitors has led to its use in a growing number of alternative indications. We believe that even in the presence of the FIXa/FVIIIa complex, rFVIIa may be able to enhance both FXa and FIXa levels on the surface of activated platelets, thus increasing the production of thrombin.
我们基于细胞的止血模型取代了传统的“级联”假说，并提出凝血在不同细胞表面以三个重叠步骤发生：启动、放大和传播。基于细胞的模型强调了凝血过程中细胞控制的重要性，使人们能够更全面地了解体内止血的工作原理，并揭示某些凝血障碍背后的病理生理机制。例如，该模型提出血友病涉及血小板表面FXa生成失败，导致血小板表面凝血酶生成不足。我们的数据表明，高剂量FVIIa能够独立于组织因子与活化血小板弱结合，以便在缺乏FIXa/FVIIIa的情况下产生足够量的FXa以支持凝血酶生成爆发。高剂量重组FVIIa（rFVIIa；NovoSeven，丹麦哥本哈根诺和诺德公司）作为血友病和抑制剂患者的治疗方法取得了相当大的成功，这导致其在越来越多的替代适应症中得到应用。我们认为，即使在存在FIXa/FVIIIa复合物的情况下，rFVIIa也可能能够提高活化血小板表面的FXa和FIXa水平，从而增加凝血酶的产生。
