Not Only Lungs: COVID-19 Hits Platelets as Well

Dario Bongiovanni; Melissa Klug; Marco Valgimigli; Isabell Bernlochner


Eur Heart J. 2022;43(22):2092-2093. 

Despite the worldwide diffusion of SARS-CoV-2 infection, still little is known concerning the mechanism leading to multi-organ damage in coronavirus disease 2019 (COVID-19). It is now clear that the coronavirus does not only affect the pulmonary system but causes damage to several other organs.[1] From the very beginning of the pandemic outbreak, severe arterial and venous thromboembolic events have been reported in patients with COVID-19.[2] Pulmonary embolism, as well as myocardial infarction and stroke, have been observed not only in severe COVID-19 but also in young patients with mild disease. However, the pathophysiological mechanisms leading to thromboembolic events are not completely understood. Several studies described a hypercoagulable state during SARS-CoV-2 infection with abnormal coagulation parameters and increased cardiovascular events.[3,4] These results suggested that COVID-19 could dysregulate the vascular homeostasis, particularly in high-risk patients, and the definition of COVID-19 changed rapidly from an acute respiratory syndrome to a systemic disease with severe implications on the vascular system.

It is now clear that the COVID-19-induced coagulopathy is a common condition, which mostly remains subclinical and its features are still under investigation. In particular, thrombocytes may play a key role in the multi-organ damage induced by SARS-CoV-2 infection leading to thrombus formation and disseminated ischaemia. In fact, a recent study described in severe SARS-CoV-2 infection, the presence of microvascular thrombi in many organs containing neutrophils highlighting a link between COVID-19-induced thrombo-immune dysregulation and the thromboembolic events. Several groups reported alterations in platelet transcriptome and proteome as well as an increased platelet reactivity in COVID-19.[5,6] We recently described with mass cytometry, a hyperactivated phenotype in platelets following SARS-CoV-2 infection. Compared with healthy controls, thrombocytes of mild symptomatic COVID-19 patients expressed higher levels of important transmembrane adhesion proteins and receptors. Of note, we noticed this prothrombotic upregulation in patients not requiring intensive care treatment and not incurring in thromboembolic events.[7] The severe dysregulation of important transmembrane proteins, which control platelet activity, might be detrimental, particularly in patients at high cardiovascular risk and it could contribute to the coagulopathy observed in COVID-19.

It has been speculated that the observed platelet activation could result from a direct effect of the SARS-CoV-2 virus on thrombocytes. However, while a direct association of SARS-CoV-2 RNA with platelets has been reported,[6] a viral transfection into thrombocytes still needs to be demonstrated. Interestingly, a recent investigation showed that the viral spike protein S stimulates human platelets to release prothrombotic factors and induces the formation of platelet–leucocyte aggregate even in the absence of the virus.[8] A direct effect on platelets by the spike protein could partially explain the observed platelet activation in COVID-19. Conversely, investigating healthy donors undergoing SARS-CoV-2 vaccination and consequently spike protein expression, we did not detect any significant alteration of platelet reactivity and of the expression of the most important platelet adhesion proteins and receptors.[9] Thus, the hyperactivated platelet phenotype observed in platelets in symptomatic mild COVID-19 patients[7] was not reproducible after vaccine-induced viral spike protein S overexpression.[9] Nevertheless, these data need to be further validated in different settings and the mechanism leading to platelet activation through SARS-CoV-2 infection remains largely unclear.

Currently, numerous clinical trials worldwide are testing different antithrombotic therapies in symptomatic COVID-19 patients. However, it is still not certain whether these strategies will be able to reduce the cardiovascular complications following SARS-CoV-2 infection. Two years after the beginning of the pandemic, the pathophysiology of COVID-19 still remains to be fully explained. In this context, the anucleated platelets, the smallest cells in our blood, may play an important role in severely ill patients (Figure 1) and they could be the key to successfully reduce the cardiovascular burden of COVID-19 disease.

Figure 1.

Platelet dysregulation and activation is an important feature of COVID-19-induced coagulopathy. The figure was created with Biorender.