CD39 polymorphism enables lung thrombosis in sickle cell disease

Area of Science:

• Hematology
• Vascular Biology
• Genetics

Background:

• Sickle cell disease (SCD) involves hemolysis and platelet activation, yet lung thrombosis risk varies among patients.
• Adenosine diphosphate (ADP) released during hemolysis promotes thrombosis via platelet activation.
• The mechanism protecting against lung thrombosis in SCD remains unclear.

Purpose of the Study:

• To investigate the role of extracellular vesicles (EVs) and CD39 in preventing ADP-induced lung thrombosis in sickle cell disease.
• To explore the impact of CD39 genetic variations on lung thrombosis risk in SCD patients.

Main Methods:

• Real-time in vivo lung microscopy in humanized SCD mice.
• Analysis of platelet aggregation and CD39+ extracellular vesicles in blood samples from SCD patients and controls.
• Association study of CD39 polymorphism rs3176891 with lung thrombosis incidence.

Main Results:

• Humanized SCD mice showed protection from ADP-induced lung thrombosis, mediated by CD39 on lung endothelial EVs degrading ADP.
• SCD patients with higher levels of CD39+ EVs exhibited impaired ADP-induced platelet aggregation.
• The CD39 rs3176891G allele was associated with fewer CD39+ EVs and higher platelet aggregation in SCD patients, correlating with lung thrombosis incidence.

Conclusions:

• A novel mechanism involving CD39-expressing EVs protects against lung thrombosis in SCD by clearing ADP.
• CD39 polymorphisms can compromise this protective mechanism, elevating lung thrombosis risk in susceptible SCD patients.