Augmented Degradation of Factors VIII and IX in the Intermittent Movement State

• Published in: International journal of molecular sciences Vol. 24; no. 13; p. 10731
• Main Authors: Cohen, Haim, Keren-Politansky, Anat, Crispel, Yonatan, Yanovich, Chen, Asayag, Keren, Nadir, Yona
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27-06-2023; MDPI
• Subjects: Analysis; Animals; Anticoagulants; Binding sites; Bleeding; Blood coagulation factors; Coagulation; Coagulation factors; Degradation; factor IX; Factor IX - metabolism; Factor IX deficiency; factor VIII; Factor VIII - metabolism; Hemophilia; Hemophilia A - metabolism; Hemorrhage; Hemostatics; Mice; Molecular weight; movement; Muscles; Photographic industry; Plasma; Proteins; Sodium; Thrombin; Von Willebrand factor; Japan; Germany; factor IX; thrombin; factor VIII; movement
• ISSN: 1422-0067; 1661-6596; 1422-0067
• 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.