Abstract Number: OC 01.4
Meeting: ISTH 2021 Congress
Background: Sepsis is the most severe course of infection and early diagnosis is beneficial for patient survival. There is no pathognomonic symptom for sepsis and its diagnosis is based on an increased sequential organ failure assessment (SOFA) score by ≥ 2 points. Thrombocytopenia is an integral part of the SOFA-score reflecting sepsis-associated hemorrhagic diathesis. In animal sepsis models the platelet collagen receptor GPVI and its signaling cascade are known to play a pivotal role, rather than a drop in platelet count alone. The role of GPVI in human sepsis, however, remains poorly understood.
Aims: We comprehensively assessed GPVI reactivity in septic and non-septic (SOFA-score < 2) infection patients at disease onset.
Methods: Platelet function was determined in 35 infection patients (25 septic, 10 non-septic) by flow cytometry, light transmission aggregometry and immunoblot using the GPVI agonists collagen-related peptide (CRP-XL) or convulxin.
Results: At admission day, 23/25 sepsis patients showed abrogated GPVI reactivity upon CRP-XL stimulation preceding thrombocytopenia in 15 cases. GPVI dysfunction occurred in virtually all patients, independent of therapy, focus of infection or identified pathogen (14/25 Gram-negative, 8/25 Gram-positive). This dysfunction was not inducible in platelets of healthy donors by co-incubation with patient bacterial-isolates or antibiotics. GPVI expression on sepsis platelets was reduced, correlating with increased GPVI ectodomain plasma levels, suggesting increased receptor shedding. Tyrosine phosphorylation of GPVI downstream mediators Syk or LAT could not be induced upon stimulation. CRP-XL dose escalation or convulxin stimulation partially restored platelet activation in sepsis patients, most likely due to receptor clustering. In contrast, GPVI function in non-septic infection patients was only partly reduced, in opposite to sepsis patients, suggesting the identified defect is rather specific for the systemic dysregulation in sepsis and could be used as early biomarker.
Conclusions: Detection of reduced platelet reactivity towards GPVI agonists can improve reliable identification of patients with sepsis at disease onset.
To cite this abstract in AMA style:Weiss LJ, Manukjan G, Weigel M, Winter N, Kredel M, Nieswandt B, Weismann D, Schulze H. Acquired Platelet GPVI Signaling Deficiency Occurs Early in Patients with Gram-Positive or Gram-negative Sepsis [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/acquired-platelet-gpvi-signaling-deficiency-occurs-early-in-patients-with-gram-positive-or-gram-negative-sepsis/. Accessed February 20, 2024.
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