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Factor IXa and von Willebrand factor modify the inactivation of factor VIII by activated protein C
M E Rick1, N L Esmon, D M Krizek
1Clinical Pathology Department, National Institutes of Health, Bethesda, MD 20892.
Insights
Von Willebrand factor and factor IXa protect factor VIII from inactivation by activated protein C. This additive protective effect may stabilize factor VIII in circulation and during early coagulation stages.
Area of Science:
- Biochemistry
- Hematology
- Molecular Biology
Background:
- Activated protein C (APC) is a key regulator of blood coagulation.
- APC inactivates coagulation factor VIII (FVIII) through proteolytic cleavage.
- Protein S and calcium ions are essential cofactors for APC-mediated FVIII inactivation.
Purpose of the Study:
- To investigate modulators of APC-mediated FVIII inactivation.
- To examine the roles of phospholipids, von Willebrand factor (vWF), and factor IXa (FIXa) in FVIII stability.
Main Methods:
- In vitro assays measuring FVIII inactivation by APC.
- Assessment of modulatory effects of phospholipids, vWF, and FIXa on FVIII inactivation.
- Evaluation of the requirement for FIXa active site in protection.
Main Results:
- Phospholipids and platelets do not protect FVIII from APC inactivation.
- Von Willebrand factor reduces FVIII inactivation by APC by 20-30%.
- Factor IXa provides additional protection to FVIII in the presence of vWF; active site of FIXa is essential for this effect.
Conclusions:
- Von Willebrand factor and factor IXa exhibit an additive protective effect on factor VIII against activated protein C.
- These interactions may play a significant role in stabilizing factor VIII in circulation.
- Understanding these regulatory mechanisms is crucial for managing coagulation disorders.
Abstract:
Activated protein C inactivates factor VIII by proteolytic cleavage of the heavy chain of factor VIII. Protein S and calcium ions are cofactors in this reaction. We have examined the effects of several potential modulators of this reaction, including phospholipids, von Willebrand factor, and factor IXa, all of which bind factor VIII. Our results indicate that neither resting nor stimulated platelets nor phospholipid vesicles protect factor VIII from inactivation by activated protein C in either the presence or the absence of protein S. However, the addition of von Willebrand factor decreases the inactivation of factor VIII by activated protein C by 20% to 30%, and factor IXa, which is known to protect factor VIII from inactivation by activated protein C, confers additional protection with von Willebrand factor. The active site of factor IXa is necessary for the protective effect, because native factor IX and active site-inhibited factor IXa do not protect factor VIII from inactivation. Thus there is an additive protective effect when von Willebrand factor and factor IXa are present with factor VIII, leading to a decrease in the inactivation by activated protein C. These factors may be particularly important in stabilizing factor VIII in the circulation and during the early stages of coagulation.