NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis.

Immunothrombosis - immune-mediated activation of coagulation - is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as in severe Coronavirus Disease 2019 (COVID-19). The NACHT-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines of the interleukin (IL)-1 family, IL-1ß and IL-18, and induces pyroptotic cell death. Activation of the NLRP3 inflammasome pathway also promotes immunothrombotic programs including release of neutrophil extracellular traps and tissue factor by leukocytes, and prothrombotic responses by platelets and the vascular endothelium. NLRP3 inflammasome activation occurs in patients with COVID-19 pneumonia. In preclinical models, NLRP3 inflammasome pathway blockade restrains COVID-19-like hyperinflammation and pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety and efficacy, and is approved for the treatment of hypoxemic COVID-19 patients with early signs of hyperinflammation. The non-selective NLRP3 inhibitor colchicine reduced hospitalization and death in a subgroup of COVID-19 outpatients, but is not approved for the treatment of COVID-19. Additional COVID-19 trials testing NLRP3 inflammasome pathway blockers are inconclusive or ongoing. We herein outline the contribution of immunothrombosis to COVID-19-associated coagulopathy, and review preclinical and clinical evidence suggesting an engagement of the NLRP3 inflammasome pathway in the immunothrombotic pathogenesis of COVID-19. We also summarize current efforts to target the NLRP3 inflammasome pathway in COVID-19, and discuss challenges, unmet gaps and the therapeutic potential that inflammasome-targeted strategies may provide for inflammation-driven thrombotic disorders including COVID-19.

A case report of multisite arterial thrombosis in a patient with coronavirus disease 2019 (COVID-19).

BACKGROUND: A systemic coagulation dysfunction has been associated with COVID-19. In this case report, we describe a COVID-19-positive patient with multisite arterial thrombosis, presenting with acute limb ischaemia and concomitant ST-elevation myocardial infarction and oligo-symptomatic lung disease. CASE SUMMARY: An 83-year-old lady with history of hypertension and chronic kidney disease presented to the Emergency Department with acute-onset left leg pain, pulselessness, and partial loss of motor function. Acute limb ischaemia was diagnosed. At the same time, a routine ECG showed ST-segment elevation, diagnostic for inferior myocardial infarction. On admission, a nasopharyngeal swab was performed to assess the presence of SARS-CoV-2, as per hospital protocol during the current COVID-19 pandemic. A total-body CT angiography was performed to investigate the cause of acute limb ischaemia and to rule out aortic dissection; the examination showed a total occlusion of the left common iliac artery and a non-obstructive thrombosis of a subsegmental pulmonary artery branch in the right basal lobe. Lung CT scan confirmed a typical pattern of interstitial COVID-19 pneumonia. Coronary angiography showed a thrombotic occlusion of the proximal segment of the right coronary artery. Percutaneous coronary intervention was performed, with manual thrombectomy, followed by deployment of two stents. The patient was subsequently transferred to the operating room, where a Fogarty thrombectomy was performed. The patient was then admitted to the COVID area of our hospital. Seven hours later, the swab returned positive for COVID-19. DISCUSSION: COVID-19 can have an atypical presentation with thrombosis at multiple sites.