OC 57.2 - Inversed platelet/fibrin ratio in shear-dependent thrombus formation between patients with COVID-19 and sepsis identifies subtherapeutic GPIIb/IIIa blockade as a potential therapeutic target

Tuesday, July 12, 2022

11:00 AM – 11:15 AM

Location: ExCel Center, ICC Capital Suite Room 2-4

Presentation Format: In-Person

Presenting Author(s)

Lukas J. Weiss

Clinical Scientist
University Hospital Wuerzburg
Würzburg, Bayern, Germany

Co-Author(s)

Maria Drayss

Clinician scientist
Institute of Experimental Biomedicine, Chair I, University Hospital Würzburg; Department of Internal Medicine I, University Hospital Wuerzburg
Wuerzburg, Bayern, Germany
MZ

Maximilian Zeitlhöfler

MD student
Institute of Experimental Biomedicine, University Hospital Würzburg
Würzburg, Bayern, Germany
KM

Kristina Mott, MSc

PhD Student
University Hospital Wuerzburg
Würzburg, Bayern, Germany
SF

Stefan Frantz

Professor
Department of Internal Medicine I, University Hospital Würzburg
Würzburg, Bayern, Germany
BN

Bernhard Nieswandt

Professor
Institute of Experimental Biomedicine - Chair I, University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Biomaging, University of Würzburg, Germany
Würzburg, Bayern, Germany
DW

Dirk Weismann

Senior Clinican Scientist
Department of Internal Medicine I, University Hospital Würzburg
Würzburg, Bayern, Germany
HS

Harald Schulze, PhD

Professor
Institute of Experimental Biomedicine I, University Hospital Würzburg, Germany
Würzburg, Bayern, Germany

Background: Thrombotic events are frequent and life-threating complications of COVID-19, but are also observed in patients with bacterial sepsis. Disseminated thrombosis may occur despite strict anticoagulation, suggesting that platelets play a direct, but yet undefined role. Several studies demonstrate altered platelet function in COVID-19, but the impact of platelets in COVID-19 and sepsis remains poorly understood.

Aims: Platelet phenotype and function were comprehensively assessed in over 100 patients with either COVID-19 (non-ECMO, all-ICU, n=23), bacterial infection without sepsis (SOFA-score < 2; n=29), or sepsis/septic shock (SOFA-score ≥2; n=49) at multiple time points during the disease.

Methods: Patients were recruited at the local University Hospital (Ethical vote 94/19). Platelet phenotype and function were studied using flow cytometry (lumino-)aggregometry and whole-mount transmission electron-microscopy. Thrombus formation was investigated using a collagen- and tissue factor-coated flow chamber model at arterial shear rate (1000s-1). Thrombi were imaged by confocal microscopy.

Results: Upon stimulation with ADP or CRP-XL platelets of infection patients without sepsis showed reduced PAC-1 binding and CD62P exposition. In sepsis patients reactivity was even more impaired and highly associated with disease severity (mean normalized geo-MFI PAC-1 infection: 0.56 vs sepsis: 0.25, p< 0.01; ROC-AUC: 0.76, p< 0.001). Intriguingly, platelets of COVID-19 patients were more responsive towards stimulation compared to comparably-ill ICU patients with sepsis. This relative hyper-reactivity was reflected by increased clot-formation in the flow chamber, compared to sepsis patients (mean surface coverage: 36% vs. 19%, p< 0.05). Thrombi of COVID-19 patients were platelet-rich with little fibrin, in contrast to healthy donors or sepsis patients showing increased amount of fibrin and less platelets. Subtherapeutic doses of GPIIb/IIIa blockers eptifibatide or tirofiban, which had minor effect in control blood, sufficiently prevented thrombus formation in COVID-19 samples under arterial flow.

Conclusion(s): Our findings provide evidence that low dose GPIIb/IIIa blockade might act as a powerful therapeutic tool in COVID-19 patients.