Mathematical modeling to understand the role of bivalent thrombin-fibrin binding during polymerization

Area of Science:

• Biochemistry
• Biophysics
• Mathematical Modeling

Background:

• Thrombin is a key enzyme in blood coagulation, cleaving fibrinogen to form fibrin clots.
• A fibrinogen variant, γA/γ', binds thrombin with high affinity and is linked to cardiovascular diseases.
• The precise role of γA/γ'-thrombin interactions during fibrin polymerization remains unclear.

Purpose of the Study:

• To develop a mathematical model simulating fibrin polymerization, incorporating thrombin, fibrinogen, and fibrin interactions, including the γA/γ' variant.
• To elucidate the biochemical and biophysical roles of fibrin-thrombin interactions during clot formation.

Main Methods:

• Development of a mathematical model to simulate fibrin polymerization dynamics.
• Inclusion of bivalent thrombin-fibrin binding and interactions with the γA/γ' variant.
• Analysis of thrombin localization, residency times, and trapping during polymerization.

Main Results:

• Bivalent thrombin-fibrin binding significantly increases thrombin residency and trapping during polymerization.
• Early polymerization: γ' localizes thrombin, enhancing fibrinogen conversion.
• Late polymerization: Fibrin acts as a sink, removing free thrombin; increased γ' paradoxically decreases trapped thrombin.

Conclusions:

• Fibrin-thrombin interactions play dual roles in polymerization: enhancing clot formation and subsequently trapping thrombin.
• The γA/γ' variant influences thrombin localization and sequestration during fibrin clot formation.
• The model provides insights into the complex regulation of thrombin by fibrin and its variants.