Device‐induced platelet dysfunction in mechanically assisted circulation increases the risks of thrombosis and bleeding

Abstract

Thrombotic and bleeding complications are the major obstacles for expanding mechanical circulatory support (MCS) beyond the current use. While providing the needed hemodynamic support, those devices can induce damage to blood, particularly to platelets. In this study, we investigated device‐induced alteration of three major platelet surface receptors, von Willebrand factor (VWF) and associated hemostatic functions relevant to thrombosis and bleeding. Fresh human whole blood was circulated in an extracorporeal circuit with a clinical rotary blood pump (CentriMag, Abbott, Chicago, IL, USA) under the clinically relevant operating condition for 4 hours. Blood samples were examined every hour for glycoprotein (GP) IIb/IIIa activation and receptor loss of GPVI and GPIbα on the platelet surface with flow cytometry. Soluble P‐selectin in hourly collected blood samples was measured by enzyme linked immunosorbent assay to characterize platelet activation. Adhesion of device‐injured platelets to fibrinogen, collagen, and VWF was quantified with fluorescent microscopy. Device‐induced damage to VWF was characterized with western blotting. The CentriMag blood pump induced progressive platelet activation with blood circulating time. Particularly, GPIIb/IIIa activation increased from 1.1% (Base) to 11% (4 hours) and soluble P‐selectin concentration increased from 14.1 ng/mL (Base) to 26.5 ng/mL (4 hours). Those device‐activated platelets exhibited increased adhesion capacity to fibrinogen. Concurrently, the CentriMag blood pump caused progressive platelet receptor loss (GPVI and GPIbα) with blood circulating time. Specifically, MFI of the GPVI and GPIbα receptors decreased by 17.2% and 16.1% for the 4‐hours sample compared to the baseline samples, respectively. The device‐injured platelets exhibited reduced adhesion capacities to collagen and VWF. The high molecular weight multimers (HMWM) of VWF in the blood disappeared within the first hour of the circulation. Thereafter the multimeric patterns of VWF were stable. The change in the VWF multimeric pattern was different from the progressive structural and functional changes of platelets with the circulation time. This study suggested that the CentriMag blood pump could induce two opposite effects on platelets and associated hemostatic functions under a clinically relevant operating condition. The device‐altered hemostatic function may contribute to thrombosis and bleeding simultaneously as occurring in patients supported by a rotary blood pump. Device‐induced damage of platelets may be an important cause for bleeding in patients supported with rotary blood pump MCS systems relative to device‐induced loss of HMWM‐VWF.

Platelet Function During Extracorporeal Membrane Oxygenation in Adult Patients

“…This suggests that activated platelets in ECMO patients express a larger quantity of bound fibrinogen on their surface, than healthy platelets do. This finding is consistent with studies reporting an increased expression of the activated fibrinogen receptor, GPIIb/IIIa, on platelets exposed to high shear stress, as in the ECMO circuit (51, 52). As high shear stress activates the platelets, a sequence of signaling events is triggered, resulting in the activation of the glycoprotein receptor GPIIb/IIIa, which then mediates platelet aggregation and thrombus formation (53).…”

Device-Induced Hemostatic Disorders in Mechanically Assisted Circulation

“… 91 In simulated LVAD systems, our in-vitro studies demonstrated that high shear stress induced platelet activation, increased the platelet adhesion on fibrinogen, reduced platelet adhesion capacity with VWF and collagen, and reduced both ristocetin- and collagen-induced platelet aggregation. 67 , 92 Some clinical studies also showed severely impaired ristocetin-induced platelet aggregation, which may contribute to an increased tendency of bleeding in the LVAD patients. 93 , 94 However, high shear rates (≥10,000/s) can cause vWF-mediated activation-independent platelet adhesion and aggregation, followed by stable aggregation in LVADs.…”

Flow Dynamics and Mixing in Extracorporeal Support: A Study of the Return Cannula

“…Cerebral bleedings and thromboembolism are the most common severe complications leading to death in 80–85% of the cases (Dalton et al, 2015 ; Fletcher-Sandersjöö et al, 2017 ). These complications are associated with blood component damage/activation with subsequent increased risks of hemolysis, thrombosis, and emboli (Chen et al, 2019b ). Thrombus has been observed in tubing connectors, cannulae, in the artificial lung, as well as in the blood pumps (Fraser et al, 2012 ; Fujiwara et al, 2017 ; Hastings et al, 2017 ).…”