Necrotic platelets provide a procoagulant surface during thrombosis.

Area of Science:

• Hematology
• Cell Biology
• Thrombosis Research

Background:

• Platelets play a critical role in hemostasis and thrombosis.
• A procoagulant subpopulation of platelets is essential for thrombin burst and clot stability.
• The precise identity and formation mechanism of these procoagulant platelets have remained unclear.

Purpose of the Study:

• To identify and characterize the procoagulant platelet subpopulation.
• To investigate the mechanism of formation of these platelets.
• To explore potential therapeutic targets for pathological thrombosis.

Main Methods:

• Utilized 4-[N-(S-glutathionylacetyl)amino]phenylarsonous acid (GSAO) as a cell death marker for platelet labeling.
• Assessed platelet procoagulant potential by GSAO labeling and P-selectin exposure.
• Investigated platelet formation in murine thrombosis models with genetic manipulation (cyclophilin D deletion).
• Analyzed human platelets from subjects on aspirin therapy.

Main Results:

• GSAO labeling identified a distinct platelet subpopulation with high procoagulant potential.
• These GSAO(+) platelets are formed via regulated necrosis involving cyclophilin D.
• GSAO(+) platelets were found in occluding thrombi and support fibrin formation.
• Procoagulant platelets form despite aspirin therapy but can be attenuated by inhibiting the necrosis pathway.

Conclusions:

• The major procoagulant platelet subpopulation involved in fibrin formation arises from regulated necrosis.
• Cyclophilin D is a key mediator in the formation of these procoagulant platelets.
• Targeting the necrosis pathway offers a potential therapeutic strategy for thrombosis, independent of initial platelet activation.