Protection of β2GPI Deficient Mice from Thrombosis Reflects a Defect in PAR3-facilitated Platelet Activation

Area of Science:

• Hematology
• Thrombosis Research
• Coagulation Physiology

Background:

• Antibodies to beta-2 glycoprotein I (β2GPI) are linked to thrombosis in antiphospholipid syndrome.
• The intrinsic role of β2GPI in regulating coagulation pathways in vivo remains unclear.

Approach:

• Generated β2GPI-deficient (Apoh-/-) mice using CRISPR/Cas9.
• Assessed thrombosis propensity in Apoh-/- and wild-type (WT) mice across multiple thrombosis models (carotid artery, cremaster arteriole, inferior vena cava).
• Evaluated tail bleeding times and platelet activation in the presence and absence of exogenous β2GPI.

Key Points:

• Apoh-/- mice showed reduced arterial, venous, and microvascular thrombosis.
• Tail bleeding was prolonged in β2GPI-deficient mice.
• Platelet activation by low thrombin concentrations was impaired, mediated by PAR3, and restored by β2GPI.

Conclusions:

• β2GPI deficiency confers protection against experimental thrombosis in mice.
• β2GPI appears to enhance platelet activation by facilitating thrombin interaction with PAR3, particularly at low thrombin concentrations.