Uncoupling of platelet granule release and integrin activation suggests GPIIb/IIIa as a therapeutic target in COVID-19

Abstract

Thromboembolic events are frequent and life-threating complications of COVID 19, but are also observed in patients with sepsis. Disseminated thrombosis can occur despite anticoagulation, suggesting that platelets play a direct, but yet incompletely understood role. Several studies demonstrated altered platelet function in COVID 19 with in part controversial findings, while underlying disease-specific mechanisms remain ill-defined. We performed a comprehensive cohort study with 111 patients, comprising 37 with COVID-19, 46 with sepsis, and 28 with infection, compared to controls. Platelet phenotype and function were assessed under static and flow conditions, revealing unexpected disease-specific differences. From hospital admission on, platelets in COVID-19 failed to activate integrin GPIIb/IIIa in response to multiple agonists. Dense granule release was markedly impaired due to virtually missing granules, also demonstrated by whole mount electron microscopy. In contrast, alpha-granule marker CD62P exposure was only mildly affected, revealing a subpopulation of PAC-1-/CD62P+ platelets, independently confirmed by automated clustering. This uncoupling of alpha-granule release was not observed in sepsis patients, despite a similar disease severity. We found overall unaltered thrombus formation in COVID 19 and sepsis samples under venous shear rates, which was dependent on the presence of tissue factor. Unexpectedly, under arterial shear rates thrombus formation was virtually abrogated in sepsis, while we detected overall normal-sized and stable thrombi in blood from COVID-19 patients. These thrombi were susceptible to subthreshold levels of GPIIb/IIIa blockers eptifibatide or tirofiban that had only a minor effect in control blood. We provide evidence that low dose GPIIb/IIIa blockade could be a therapeutic approach in COVID-19.

Ontogenesis of functional platelet subpopulations from preterm and term neonates to adulthood: The PLINIUS study

“…Immunoreceptors are important mediators of platelet function beyond hemostasis, including the separation of blood and lymphatic vessels (C-type lectin receptor 2; CLEC-2), maintenance of vascular integrity under inflammatory conditions (GPVI), and immune defense (FcγRIIa), as shown in mice and humans. 3 , 23 , 24 , 25 , 26 GPVI and CLEC-2 expression increased gradually from extremely preterm neonates (I) to adults (VI) ( Figure 6 A-B). The levels correlated with FSC, suggesting that receptor density remained unaltered overall during platelet maturation (CLEC-2: r = 0.54; P < .0001; GPVI: r = 0.68; P < .0001) ( Figure 6 C-D).…”

The homophilic CD84 receptor is upregulated on platelets in COVID-19 and sepsis

“…1 G). We repeated this experiment with platelets from COVID-19 patients and observed a similar extent of CCCP-induced CD84 shedding as in healthy controls, but not for TRAP-6, which could in part be explained by COVID-19-based hyporesponsiveness [8] ( Fig. 1 H).…”

Decreased Platelet Aggregation in Patients with Decompensated Liver Cirrhosis and TIPS Implantation

“…In line with this, impaired GPIIb/IIIa activation and reduced platelet aggregation have been shown in patients with alcoholic liver cirrhosis in response to stimulation in vitro [ 27 ]. Dysfunctional GPIIb/IIIa responses have been recently described for COVID-19 and sepsis [ 28 , 29 , 30 ]. However, except for one diagnosed dual hepatitis B/C virus infection, the patients included in this study had no other suspected or proven infection.…”