Ventricular Assist Devices and Extracorporeal Membrane Oxygenation Devices Are Associated with Loss of Platelet Receptors

Aim

Ventricular assist devices (VADs) and extracorporeal membrane oxygenation devices (ECMO) are associated with bleeding, not fully explained by anticoagulant or anti-platelet therapy. Acquired von Willebrand syndrome (AVWS) may contribute to bleeding in patients with these devices. We investigated the relationship between AVWS and platelet dysfunction, through the loss of von Willebrand factor (VWF) receptor, GPIb (of the GPIb-IX-V complex) and the major collagen receptor, GPVI. GPIb and GPVI are crucial for platelet function at arterial shear rates and we have shown that metalloproteolytic shedding of GPVI is triggered on exposure of platelets to high shear (Al-Tamimi et al. Blood, 2012).

Methods

A pilot analysis was performed in 21 VADs patients (0.5-30 months post-implant) and 13 ECMO patients (1-9 days post-implant). All patients were in receipt of at least one anticoagulant and/or one anti-platelet therapy. Platelet counts, coagulation tests and VWF analyses including VWF multimers were performed. Levels of platelet surface and shed receptors were measured by flow cytometry-based assays or ELISA developed in-house. The in-house assays are unaffected by routine therapeutics used in these patients. Data were analysed by non-parametric Wilcoxon-Mann-Whitney test. The National Cancer Institute (NCI) bleeding score was used and VADs patients were grouped into major (NCI ≥3) or non-major (NCI<3) bleeding.

Results

We demonstrated loss of high molecular weight VWF multimers in most VADs patients (19 of 21) and 60% of the ECMO patients (6 of 10, VWF multimer analysis was not performed in 3 patients), consistent with AVWS. In VADs patients, platelet receptor shedding was demonstrated by significantly elevated plasma soluble GPVI levels (p=0.025), and reduction in surface GPVI (p=0.0003) and GPIb levels (p=0.0008) compared to healthy donors (Table 1). Similarly, ECMO patients demonstrated significantly elevated plasma soluble GPVI levels (p=0.0002), and reduction in surface GPVI (p=0.001) and GPIb levels (p=0.001) compared to healthy donors (Table 1). Five patients with VADs (24%) had major bleeding however platelet receptor levels were not analysed prior to the bleeding event.

Conclusion

We linked AVWS for the first time with loss of platelet adhesion receptors in patients with VADs or ECMO. Loss of platelet surface receptors GPIb or GPVI may impact platelet adhesion/activation and limit thrombus formation under pathologic shear conditions. Further investigation will elucidate mechanisms of platelet receptor loss and assess whether temporal changes in platelet receptor levels are associated with bleeding outcomes in these patients.