Erythrocyte-derived microvesicles amplify systemic inflammation by thrombin-dependent activation of complement.

Area of Science:

• Hematology
• Immunology
• Transfusion Medicine

Background:

• Transfusion of aged blood is linked to increased complications in critically ill patients.
• Erythrocytes release increasing numbers of microvesicles (RBC-MV) during storage.

Purpose of the Study:

• To investigate if RBC-MV mediate deleterious effects associated with aged blood transfusions.
• To elucidate the mechanism of RBC-MV-induced inflammation.

Main Methods:

• Established a murine transfusion model using purified RBC-MV from aged erythrocytes.
• Assessed the effects of RBC-MV on lipopolysaccharide-induced inflammation in mice.
• Investigated RBC-MV complement activation pathways in vitro and in vivo.
• Utilized C5aR-deficient mice and phosphatidylserine-expressing liposomes.

Main Results:

• RBC-MV aggravated lipopolysaccharide-induced pulmonary leukocyte sequestration and leukopenia.
• RBC-MV increased plasma proinflammatory cytokines in a C5aR-dependent manner.
• RBC-MV activated complement via C3 fragment binding, independent of classical, lectin, or alternative pathways.
• Thrombin generation inhibition blocked complement activation and reversed RBC-MV proinflammatory effects.
• Phosphatidylserine expression on RBC-MV was mechanistically involved.

Conclusions:

• RBC-MV mediate transfusion-related inflammation through a novel thrombin-dependent complement activation pathway.
• RBC-MV are potential mediators of transfusion-related morbidity.
• Findings may extend to other inflammatory conditions involving microvesicle release, such as sickle cell disease and thrombotic microangiopathy.