Platelet Desialylation Is a Novel Mechanism of Thrombocytopenia during Mechanical Circulatory Assistance

Introduction: Although bleeding associated with thrombocytopenia often complicates mechanical circulatory assistance (MCA), the mechanisms of thrombocytopenia observed in this high shear stress situation remain poorly understood. Recent studies have highlighted that platelet desialylation, a process in which terminal sialic acids are cleaved from glycoconjugates on the platelet surface, leads to accelerate platelet clearance via asialoglycoprotein receptors on hepatocytes and subsequent thrombocytopenia. Moreover, it was demonstrated that platelet receptor GPIba occupancy by plasma protein von Willebrand factor (VWF) under physiological shear stress induces platelet desialylation. As MCA promotes, in the majority of patients, high shear-induced VWF/GPIba interactions, we aimed to investigate whether the thrombocytopenia observed during MCA depends on platelet desialylation.

Methods: The effects of MCA on platelet desialylation were assessed i) in vitro using human whole blood or platelets rich plasma (PRP) and an Impella (Abiomed Europe GmbH, Aachen, Germany) circulatory assistance pump providing flow rate of 5 liters by minute and inserted in a loop and ii) in 11 adult patients requiring arteriovenous extracorporeal membrane oxygenation (ECMO) circulatory assistance. Platelet desialylation was measured by flow cytometry using fluorescent lectin, at baseline and after initiation (5, 30, 60, 120 and 180 minutes and 24 hours for patients) of MCA. The blood platelet count and the immature platelet fraction (IPF), a new parameter that reflects the activity of thrombopoiesis, were also determined in patients at baseline and daily after ECMO initiation.

Results: In vitro, platelet desialylation levels in whole blood and in PRP increased after 5 minutes of circulatory assistance pump compared to baseline (+216%, p<0.05 and +132%, p<0.05, respectively) and the difference persists over time (at 180 minutes: +244%, p<0.05 in whole blood and +292%, p<0.05 in PRP). In all patients, platelet desialylation levels were higher after 5 minutes of ECMO compared to baseline (+197%, p<0.001) and as in vitro, the difference persist over time (at 180 minutes: +187%, p<0.05 and at 24 hours: +223%, p<0.05). In parallel, a decrease of platelet counts and an increase of IPF were observed in all these patients after 2 days under ECMO with a nadir at 4 days for platelet counts (73 G/L, range: 27-119 G/L) and a zenith at 3 days for IPF (13.75%, range: 5.5-22.0%).

Conclusion: The present study is the first to show that MCA increases platelet desialylation within minutes after pump initiation. Thus, thrombocytopenia observed in this context seems dependent on platelet desialylation. Giving these results, further studies evaluating the potential beneficial effects of desialylation inhibitors to prevent or treat MCA associated thrombocytopenia could be valuable.