Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation

Abstract

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.

Fig. 1. COVID-19-associated thromboinflammation.

a | In the absence of disease or stressors, platelets and endothelial cells do not directly interact. b | Cardiovascular risk factors such as diabetes mellitus and obesity can induce thrombocytopathy, endotheliopathy, coagulopathy and inflammation, all of which promote cardiovascular disease. c | Coronavirus disease 2019 (COVID-19) through either direct actions on platelets and the endothelium or indirect effects through inflammation and coagulopathy can lead to increased thrombus formation and to emboli and haemorrhage. All these phenotypes have been characterized in blood and autopsy reports from patients with COVID-19. Combination therapies targeting thrombocytopathy, endotheliopathy, inflammation and coagulopathy are needed to reduce morbidity and mortality in patients with COVID-19. A list of drugs or drug classes that might be beneficial for targeting thrombocytopathy, endotheliopathy or both in patients with COVID-19 is provided. All are currently under investigation in this clinical setting. At the top are drugs that predominantly affect platelets (such as aspirin and P2Y purinoceptor 12 (P2Y₁₂) inhibitors), the agents in the middle can affect both, and those at the bottom (complement inhibitors and statins) predominantly target the endothelium. Given the intricate relationship between platelets and the endothelium, the beneficial effects of these drugs on one might improve the other. PDE3, phosphodiesterase 3.

Fig. 2. COVID-19-associated thrombosis.

Imaging examples of thrombotic complications in patients with coronavirus disease 2019 (COVID-19) and with multiple cardiovascular risk factors, including diabetes mellitus, obesity, old age and hypertension. a | CT scan showing pulmonary emboli (arrow) involving the anterobasilar arteries in the left lower lobe of the lung. b | Doppler ultrasound image showing short-segment non-occlusive deep vein thrombus in the right lateral subclavian vein (arrow). c | CT scan showing a 10-mm diameter thrombus in the abdominal aorta (arrow).

Fig. 3. COVID-19-associated thrombocytopathy.

Schematic diagram summarizing the normal physiological platelet response to vessel wall damage, that is, haemostasis (panel a) and the thrombocytopathy associated with coronavirus disease 2019 (COVID-19; panel b). Possible additional inducers of pathological platelet hyperactivation include cardiovascular risk factors such as old age, diabetes mellitus, obesity and hypoxia from lung disease, and immune factors leading to increased intracellular levels of reactive oxygen species (ROS). The consequences of pathological platelet hyperactivation include increased platelet microvesicle and granule release that contribute to increased thrombosis and cytokine storm (local and circulating). Increased platelet activation can result in platelet–leukocyte conjugates (primarily neutrophils) and platelet apoptosis and/or aggregation, which in turn can further lead to increased thrombosis and inflammation. The presence of impaired fibrinolysis and endotheliopathy can contribute to increased thrombosis and can lead to life-threatening thrombosis and thromboembolism. The lungs are the most susceptible organ to thrombosis but these events can occur in many organs, including the heart, kidneys and liver. With platelet hyperactivation, apoptosis and increased thrombus formation, platelet clearance and consumption are higher, leading to thrombocytopenia. Thrombocytopenia occurs only if megakaryocytes are unable to produce sufficient platelets to compensate for the platelet loss. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 4. COVID-19-associated endotheliopathy.

a | The normal resting endothelium is crucial for maintaining vascular homeostasis through production of several anti-inflammatory and antithrombotic factors, including nitric oxide (NO), prostaglandin I₂ (PGI₂; also known as prostacyclin), thrombomodulin, activated protein C, tissue factor pathway inhibitor (TFPI) and antithrombin III (ATIII). b | In disease states, such as obesity and diabetes mellitus, increased oxidative stress with elevated intracellular levels of reactive oxygen species (ROS) can promote the production of pro-inflammatory cytokines (such as IL-1β, IL-6 and TNF), decrease the bioavailability of NO and PGI₂ and induce endothelial cell apoptosis, leading to endothelial damage and dysfunction. Furthermore, the release of pro-inflammatory and prothrombotic factors (such as von Willebrand factor (vWF) and thrombin) can lead to vascular inflammation, platelet aggregation and thrombosis. Simultaneous invasion of the endothelium by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — the virus that causes coronavirus disease 2019 (COVID-19) — via the angiotensin-converting enzyme 2 (ACE2) receptor can exacerbate endothelial dysfunction and damage, further promoting vascular inflammation and thrombosis. The dashed arrows represent complex molecular signalling mechanisms that remain to be defined in the context of COVID-19. TF, tissue factor.