Acquired Platelet GPVI Dysfunction As Possible Predictor for Early Sepsis Diagnosis and Poor Outcome

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.3609-3609
• Main Authors: Weiss, Lukas J, Manukjan, Georgi, Nagler, Nils, Kredel, Markus, Lam, Thien-Tri, Nieswandt, Bernhard, Weismann, Dirk, Schulze, Harald
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-131088

Introduction: Sepsis is a major contributor to the global disease burden with estimated 20 million cases per year. With every hour prior to begin of therapy mortality increases by over 7%. Hence, early diagnosis is indispensable for patient survival, though it is hampered by the lack of known pathognomonic symptoms. Sepsis diagnosis is set according to an increase of the sequential organ failure assessment (SOFA) score, reflecting organ dysfunction. Severe symptoms comprising dysfunctional hemostasis are disseminated intravascular coagulation and formation of massive edema due to loss of vascular integrity. Functional hemostasis and maintenance of vascular integrity depends particularly on the platelet surface receptor glycoprotein (GP)VI that dimerizes upon activation and transduces its signals via the associated immunoreceptor tyrosine activation motif (ITAM) of the Fc-gamma chain. Sepsis-associated thrombocytopenia has been extensively investigated and low platelet counts are implemented in the SOFA score.Platelet function during sepsis, however, remains ill-defined with few reports using ADP or thrombin receptor activating peptide (TRAP) and overall conflicting results. Objectives: We assessed platelet function in patients with sepsis III criteria in a single center study at three times during disease: (I) intensive care unit (ICU) admission day; (II) day five to seven at ICU; (III) day of ICU discharge. Methods: Fifteen patients were recruited from the ICU of the University Hospital Würzburg, Germany (m:f ratio 9:6; median age 70; mortality: 40%). Platelets in whole blood were stimulated with ADP, TRAP, or the GPVI agonist collagen-related peptide (CRP). Activation was detected flow cytometrically by P-selectin (CD62P) exposure and integrin GPIIb/IIIa activation (PAC-1 binding). Results were correlated with light transmission aggregometry (LTA) and immunoblotting of phospho-Syk and -LAT. Co-incubation experiments were performed with plasma, whole blood or patient-borne bacterial isolates comprising Gram-negative (E. coli, K. pneumoniae) or Gram-positive (E. faecalis) strains. Results: Platelet function was markedly reduced in all patients assessed by flow cytometry and LTA despite overall unaltered receptor expression. The defect was most prominent after GPVI stimulation with CRP(Mean Geo-MFI ± SD; Control: 9356 ± 3460; Sepsis: 1438 ± 2090; p