Thrombin generation is associated with extracellular vesicle and leukocyte lipid membranes in acute coronary syndrome
Authors: Protty Majd B , Tyrrell Victoria J , Allen-Redpath Keith , Soyama Shin , Hajeyah Ali A , Costa Daniela , Choudhury Anirban , Mitra Rito , Yaqoob Parveen , Jenkins P Vince , Yousef Zaheer , Collins Peter W , O’Donnell Valerie B 
Published: May 2023

Background

Acute coronary syndrome (ACS) is caused by arterial thrombosis and is associated with sustained activation of coagulation. Clotting requires interactions of coagulation factors with aminophospholipids (aPL): phosphatidylserine (PS) and phosphatidylethanolamine (PE) on membrane surfaces. The aPL composition of circulating membranes in coronary disease has not been characterized. Furthermore, the contribution of external-facing aPL to elevated thrombotic risk in ACS is unknown.

Methods and results

Thrombin generation was measured on platelet, leukocyte and extracellular vesicles (EV) from patients with ACS (n = 24), stable coronary artery disease (CAD, n = 18), risk factor positive (RF, n = 23) and healthy controls (HC, n = 24). The aPL composition on the surface of EV, platelets and leukocytes was determined using lipidomics. Leukocytes, platelets and EV externalized PE- and PS-containing fatty acids ranging from C16:0-20:4. These included both diacyl and plasmalogen forms, with significant increases stimulated by agonist activation. Thrombin generation on the surface of EV and leukocytes was higher in ACS than HC. Also, thrombin generation was higher for EV from CAD and RF, than HC. EV counts were higher in CAD and ACS compared with HC. Thrombin generation correlated positively with plasma EV counts and membrane surface area.

Conclusion

The aPL membrane of EV and leukocytes may contribute to the activation of coagulation in CAD and ACS. Targeting EV formation/clearance and the aPL surface of EV and leukocyte membranes represents a novel anti-thrombotic target in CAD and ACS.

Condensed abstract

Acute coronary syndrome (ACS) is associated with sustained activation of coagulation, requiring procoagulant aminophospholipids (aPL). However, the aPL composition of circulating membranes and their contribution to thrombotic risk in ACS is undetermined. Lipidomics demonstrated that leukocytes, platelets and extracellular vesicles (EV) externalized aPL-containing fatty acids ranging from C16:0-20:4. Thrombin generation on the surface of EV and leukocytes was higher in ACS patients than healthy controls (HC). EV counts were higher in ACS compared with HC and correlated positively with thrombin generation. In summary, aPL in the outer membranes of EV and leukocytes may contribute to elevated thrombotic risk in ACS.

Highlights

What is new?

The aPL profile of platelets, leukocytes and EV in patients with ACS, CAD, RF and HC is defined for the first-time using lipidomics.

Thrombin generation on the surface of unstimulated leukocytes, is elevated in patients with ACS compared with HC.

Thrombin generation on the surface of EV is elevated in patients with ACS, CAD and RF compared with HC.

EV counts in patients with ACS/CAD/RF were elevated compared with HC and correlate positively with thrombin generation.

Clinical Perspective

What are the clinical implications?

The membranes of EV and leukocytes may contribute to the activation of coagulation in ACS.

The aPL in EV and leukocyte membranes represent a novel target for reducing thrombotic risk in ACS.

Targeting EV formation/clearance could reduce thrombotic risk in CAD and ACS.