Platelet-neutrophil interaction in COVID-19 and vaccine-induced thrombotic thrombocytopenia

Abstract

Coronavirus disease 2019 (COVID-19) is known to commonly induce a thrombotic diathesis, particularly in severely affected individuals. So far, this COVID-19-associated coagulopathy (CAC) has been partially explained by hyperactivated platelets as well as by the prothrombotic effects of neutrophil extracellular traps (NETs) released from neutrophils. However, precise insight into the bidirectional relationship between platelets and neutrophils in the pathophysiology of CAC still lags behind. Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare autoimmune disorder caused by auto-antibody formation in response to immunization with adenoviral vector vaccines. VITT is associated with life-threatening thromboembolic events and thus, high fatality rates. Our concept of the thrombophilia observed in VITT is relatively new, hence a better understanding could help in the management of such patients with the potential to also prevent VITT. In this review we aim to summarize the current knowledge on platelet-neutrophil interplay in COVID-19 and VITT.

Elevated NET, Calprotectin, and Neopterin Levels Discriminate between Disease Activity in COVID-19, as Evidenced by Need for Hospitalization among Patients in Northern Italy

“…Additional studies have found that calprotectin and NET levels are raised in vaccineinduced thrombocytopenia and thrombosis (VITT) after vaccination with ChAdOx1 nCoV-19 [23][24][25]. Moreover, recently, we reported increased DNase levels in the ChAdOx1 nCoV-19-vaccinated individuals, as measured via a novel DNase test, which correlated with their previously measured NET values [26].…”

Long COVID: Molecular Mechanisms and Detection Techniques

“…The main characterized interactions occur via P-selectin-PSGL-1, CD40L-CD40, GPIb-Mac-1, and GPIIb-IIIa-SLC44A2 [ 96 ]. P selectin is the main platelet receptor for aggregation in COVID-19 [ 97 ]. Indirectly, both neutrophils and platelets form macrovesicles through membrane budding [ 98 ] and secrete inflammatory mediators such as cytokines and IL-6 [ 99 , 100 ].…”

“…Additionally, a hypofibrinolytic phenotype and increased thrombin generation are described, leading to a hypercoagulable state [ 111 ]. A distinct platelet-neutrophil interaction that mimics an acute infection is seen in long COVID patients [ 97 ]. Increased D-dimer and interleukin-6 levels are also observed in long COVID patients and might be indicative of microvascular thrombosis [ 112 , 113 ].…”

Immune Thrombosis: Exploring the Significance of Immune Complexes and NETosis

“…Platelets can be activated by various stimuli such as immune complexes [16], viruses (e.g., SARS-CoV-2) [73], and vascular injury [74] resulting in either a direct or indirect activation of neutrophils. With the former, activated platelets can bind and activate neutrophils via various corresponding receptors such as P-selectin/PSGL1, GP1bα/Mac-1, αIIβ3/Mac-1, ICAM-2/Mac-1, CD40L/CD40, and GPIIb/IIIa/SLC44A2 [75,76] although P-selectin/PSGL1 has been the most prominent interaction found to be involved in direct platelet-induced NETosis [15,18] (Figure 1). Crosstalk between platelets and neutrophils enhance the thrombotic process as neutrophils become activated and consequently undergo NETosis [15], while NETs in turn can promote platelet activation [77][78][79], further perpetuating the thrombotic condition.…”