Potential role of platelets in COVID‐19: Implications for thrombosis

Abstract

Coronavirus disease 2019 (COVID-19) has already caused severe health and economic burdens worldwide and, as of May 15, 2020, has claimed 60 300 total deaths in the United States. 1 COVID-19 presents with various symptoms which include increased inflammatory cytokines, dysregulated coagulation parameters, increased D-dimer, increased microthrombi and reduced platelet count. 2 In COVID-19 patients, disseminated intravascular coagulation and reduced platelet count are associated with poor prognosis and increased risk of mortality. 2-4 These clinical observations suggest that platelets may serve important functions during COVID-19 progression. To understand how the incidence of microthrombosis and reduced platelet count may occur during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, it is necessary to look at the potential active versus reactive roles of platelets during progression of SARS-CoV-2 infection. The first stage of infection involves viral replication in epithelial cells of the respiratory tract. SARS-CoV-2 is a single-stranded RNA virus classified as β-coronavirus. It is an upper respiratory virus that, similarly to influenza, becomes problematic when it reaches the lower lung epithelial cells. These cells comprise the lining of the alveolar sacs and are located in very close proximity to the capillary endothelial cells. This proximity established by both cell types is instrumental to gas exchange. In the capillary, platelets are essential in mediating endothelial integrity by performing their hemostatic function. 5 During infection with respiratory viruses, however, the integrity of infected epithelial and endothelial cells becomes compromised, leading to increased permeability that may allow virus to crossover into the circulation. Limited presence of SARS-CoV2 RNA in blood has been reported in some patients. 6 Of note, viral RNA tested by quantitative polymerase chain reaction (qPCR) does not indicate presence of infectious virus in blood. qPCR can amplify fragmented RNA while plaque assays are appropriate for determination of infectious virus. Due to their abundance, platelets may be the first blood component to internalize viral particles and induce a response once the pathogen reaches circulation. For example, although viremia (infectious virus in blood) is considered rare, platelets from influenza-infected patients have been found to contain influenza particles. 7

COVID-19 vasculitis and novel vasculitis mimics

“…As such, it is noteworthy that viral RNAaemia is more common in patients on ventilation than in patients not on ventilation. 4 , 47 Systemic venous thrombosis in patients with severe COVID-19 and cardiac pathology attests to such a potential mechanism, 44 as does prostatic venous plexus thrombosis reported in post-mortem samples. 48 When the existing recognised vasculitides and systemic thrombosis are taken into account, we believe that a novel vasculitis mimic that afflicts the systemic arterial tree might underscore much of the systemic vascular pathology in COVID-19 ( table 1 ).…”

Is there a role for the ACE2 receptor in SARS‐CoV‐2 interactions with platelets?

“…While these findings certainly deserve confirmation in future studies, currently available evidence would indicate that interactions between SARS‐CoV‐2 and platelets are unlikely to occur only through CD26. In addition to direct virus interaction with megakaryocytes and platelets, it is possible SARS‐CoV‐2 virus released into extracellular vesicles from infected white blood cells or endothelial cells can be internalized by platelets, resulting in SARS‐CoV‐2 virus positive platelets through indirect uptake of viral particles contained inside extracellular vesicles 45‐48 …”

The role of platelets in sepsis

“…The contribution of platelets to the immune response to bacterial, malaria, and viral infection has been extensively reviewed elsewhere 40,41,42 . Platelets also have an emerging role in the immune response during coronavirus disease 2019 (COVID‐19), reviewed in Koupenova 43 . An overview of potential platelet interactions in inflammation and sepsis is shown in Figure 3 and discussed below.…”