Platelet SR-PSOX/CXCL16 and CXCR6 axis influences thrombotic propensity and prognosis in coronary artery disease

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Dokumentart: Dissertation
Date: 2022-12-07
Source: International journal of molecular sciences vol. 23,19 11066. 21 Sep. 2022
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Rath, Dominik (PD Dr.)
Day of Oral Examination: 2022-11-11
DDC Classifikation: 610 - Medicine and health
Keywords: Coronary heart disease , Thrombocyte
Other Keywords: CXCL16
License: Publishing license including print on demand
Order a printed copy: Print-on-Demand
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Background: CAD has affected 200 million people worldwide, causing more than 9 million deaths and being the leading cause of human death. CAD is classified as CCS and ACS according to different clinical situations. Platelets and chemokines play a vital role in AS which is responsible for the progression of CAD. Platelets express the transmembrane chemokine SR-PSOX/CXCL16, which is a scavenger for the atherogenic mediator ox-LDL, and phosphatidylserine exposed on the surface of apoptotic cells and procoagulant platelets. Proteolytic cleavage of its extracellular domain by metalloprotease ADAM10 generates the soluble-(s) chemokine sCXCL16, which engages CXCR6 on platelets to synergistically propagate degranulation, aggregation, and thrombotic response. Objectives: We assessed the pathophysiological and prognostic association of platelet SR-PSOX/CXCL16-CXCR6 axis in CAD patients. Methods: Platelet surface-associated SR-PSOX/CXCL16 and CXCR6, platelet activation markers CD62P (degranulation from α-granules), and PAC-1 binding (αIIbβ3-integrin activation) were evaluated by flow cytometry in n=240 consecutive patients with symptomatic CAD (CCS n=62; ACS n=178) at baseline upon admission. Blood samples were collected during PCI. sCXCL16 was evaluated by ELISA in serum samples. The course of left ventricular ejection fraction (LVEF) was followed up during intrahospital stay in CAD patients and at 3 years in ACS patients. All patients enrolled in the study were followed up for all-cause death (ACD). Results: Currently, we observed a strong correlation of platelet surface-associated SR-PSOX/CXCL16, and surface-expressed CXCR6 with markers of circulatory (basal) platelet activation i.e. CD62P surface exposure, and PAC-1 binding, which validated an association between platelet SR-PSOX/CXCL16-CXCR6 axis and thrombotic response in CAD patients. Patients with relatively enhanced (1st quartile vs 2nd-4th quartiles) platelet surface-associated SR-PSOX/CXCL16 showed significantly increased aggregation response to collagen assessed by whole blood impedance aggregometry. Platelet SR-PSOX/CXCL16 and CXCR6 expression did not alter with dyslipidemia, triglyceride, total cholesterol, or LDL levels. Patients with higher (>median) plasma HDL levels showed significantly decreased platelet SR-PSOX/CXCL16 and CXCR6 expression. HDL is associated with reduced platelet hyper-reactivity. Serum sCXCL16 showed a stronger positive correlation with deteriorated eGFR, age, and NT-proBNP when compared with platelet SR-PSOX/CXCL16 and CXCR6. Platelet surface-associated SR-PSOX/CXCL16 and CXCR6 were not significantly altered with disease severity in ACS vs CCS patients, in contrast to serum sCXCL16 levels which were significantly elevated in ACS patients confirming previous reports. Although platelet SR-PSOX/CXCL16 and CXCR6 expression did not change significantly with troponin I levels, with hs-CRP, or with diabetes, they corresponded with higher Creatine Kinase-(CK) activity and deteriorated LVEF upon admission and over a 3-year follow-up of LVEF. P2Y12-antagonists did not influence platelet SR-PSOX/CXCL16 or CXCR6 surface expression, but ticagrelor was associated with significantly reduced serum sCXCL16, suggesting an impediment on activated platelet-derived circulatory levels of sCXCL16. Finally, elevated (4th quartile) platelet SR-PSOX/CXCL16 and CXCR6 measured upon admission were significantly associated with ACD. Conclusion: Platelet expression of SR-PSOX/CXCL16 and CXCR6 may be markers of platelet activation and platelet SR-PSOX/CXCL16-CXCR6 axis may influence thrombotic propensity and thereby prognosis specifically for long-term survival in CAD patients.

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