Thrombosis and Hemostasis Unit, Department of Hematology, Rambam Health Care Campus, Haifa P.O. Box 9602, Israel.
The Rappaport Faculty of Medicine, Technion, Haifa P.O. Box 9602, Israel.
Int J Mol Sci. 2023 Jun 27;24(13):10731. doi: 10.3390/ijms241310731.
The most common clinical presentation of hemophilia A and hemophilia B is bleeding in large joints and striated muscles. It is unclear why bleeding has a predilection to affect joints and muscles. As muscles and joints are involved in intermittent movement, we explored whether this phenomenon could be associated with an impact on factor VIII and IX levels. Purified proteins and a mouse model were assessed using coagulation assays, Western blot analysis and immuno-staining. Movement caused an increase in thrombin activity and a decrease in factor VIII and factor IX activity. The decrease in factor VIII activity was more significant in the presence of thrombin and during movement. Under movement condition, sodium ions appeared to enhance the activity of thrombin that resulted in decreased factor VIII activity. Unlike factor VIII, the reduction in factor IX levels in the movement condition was thrombin-independent. High factor VIII levels were found to protect factor IX from degradation and vice versa. In mice that were in movement, factor VIII and IX levels decreased in the microcirculation of the muscle tissue compared with other tissues and to the muscle tissue at rest. Movement had no effect on von Willebrand factor levels. Movement induces reduction in factor VIII and IX levels. It enables an increase in the binding of sodium ions to thrombin leading to enhanced thrombin activity and augmented degradation of factor VIII. These data suggest a potential mechanism underlying the tendency of hemophilia patients to bleed in muscles and joints.
A 和 B 型血友病最常见的临床表现是大关节和横纹肌出血。目前尚不清楚为什么出血会偏爱影响关节和肌肉。由于肌肉和关节参与间歇性运动，我们探讨了这种现象是否与因子 VIII 和 IX 水平的影响有关。我们使用凝血测定法、Western blot 分析和免疫染色法评估了纯化蛋白和小鼠模型。运动导致凝血酶活性增加，因子 VIII 和因子 IX 活性降低。在存在凝血酶和运动时，因子 VIII 活性的降低更为显著。在运动条件下，钠离子似乎增强了凝血酶的活性，导致因子 VIII 活性降低。与因子 VIII 不同，运动条件下因子 IX 水平的降低与凝血酶无关。高因子 VIII 水平被发现可防止因子 IX 降解，反之亦然。与其他组织相比，在运动的小鼠中，肌肉组织的微血管中的因子 VIII 和 IX 水平下降，而在休息的肌肉组织中则下降。运动对血管性血友病因子水平没有影响。运动导致因子 VIII 和 IX 水平降低。它使钠离子与凝血酶的结合增加，导致凝血酶活性增强和因子 VIII 降解增加。这些数据表明了血友病患者在肌肉和关节中出血的倾向的潜在机制。
