Excessively activated plasminogen in human plasma cleaves VWF multimers and reduces collagen-binding activity

Area of Science:

• Biochemistry
• Hematology
• Physiology

Background:

• Plasmin (Pm) is a serine protease primarily known for its role in fibrinolysis.
• Potential functions of plasmin beyond fibrin clot dissolution in blood require further investigation.
• Understanding plasmin's interaction with von Willebrand factor (VWF) is crucial for evaluating its role in primary hemostasis.

Purpose of the Study:

• To investigate the effects of plasmin on primary hemostasis.
• To evaluate the cleavage of von Willebrand factor multimers (VWFMs) by streptokinase-activated plasminogen (Pg).
• To assess the impact of VWFMs cleavage on their binding ability to collagen.

Main Methods:

• Analysis of VWFMs cleavage in human plasma by streptokinase-activated plasminogen (Pg) and ADAMTS13.
• Comparison of VWFMs cleavage under static conditions (urea buffer dialysis) versus dynamic conditions (vortex-based shear stress).
• Assessment of VWFMs binding capacity to collagen after enzymatic digestion.

Main Results:

• Both SK-activated Pg and ADAMTS13 cleaved VWFMs in a conformation-dependent manner under static conditions.
• Under shear stress, SK-activated Pg cleaved VWFMs, whereas ADAMTS13 did not, indicating shear-dependent exposure of cleavage sites.
• Cleavage by SK-activated Pg significantly reduced VWFMs' binding ability to collagen.

Conclusions:

• Streptokinase-activated plasmin degrades VWFMs and impairs their collagen-binding function, thereby affecting primary hemostasis.
• The findings suggest that excessive plasminogen activation may lead to impaired primary and secondary hemostasis due to VWF degradation.
• This highlights a potential mechanism by which plasmin can influence hemostatic balance beyond its fibrinolytic activity.