Clinical, biochemical, and molecular evidence of this prothrombotic state and immunothrombotic dysregulation in COVID-19 has been reported, with increased frequency of pulmonary embolism, evidence of platelet-fibrin thrombi in lung tissues, and increased fibrinogen and D-Dimer levels.³Carfora V et al. J Thromb Thrombolysis. doi: 10.1007/s11239-020-02242-0 Recent trials and observational case series have highlighted that COVID-19 positive patients are at an increased risk for thrombotic events.^2,4Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488.
Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397

A recent cohort study performed a histopathological assessment of autopsy cases and a myriad of other assays and tests to demonstrate immunothrombotic dysregulation as a key marker of disease severity in COVID-19.²Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488  The study included 62 patients in 4 cohorts – the control (n=19), COVID-19 ward patients (n=20), COVID-19 intensive care unit (ICU) patients (n=18), and non-COVID-19 pneumonia patients (n=5).²Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488 Patients in the COVID-19 cohorts were confirmed cases from reverse transcriptase-polymerase chain reaction (RT-PCR).²Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488 Reasons for exclusion from the study included severe pre-existing kidney or liver dysfunction, severe autoimmune diseases, immunosuppression, chronic infection, patients requiring extracorporeal membrane oxygenation (ECMO) therapy, and patients receiving antiplatelet medication.²Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488

Histopathological staining of specimens from a deceased patient with RT-PCR-confirmed SARS-CoV-2 infection revealed microvascular clots in the lung that contained platelets, fibrin, and large numbers of granulocytes.² Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488 Immunofluorescence was further used to confirm the presence of neutrophils in the microthrombi, which were embedded in the fibrin clot.² Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488This finding was confirmed in four additional COVID-19 cases.² Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488 These neutrophil-rich depositions were also present in renal and cardiac microvessels, leading to the hypothesis of activated neutrophils and immunogenic platelets driving dysregulated immunothrombosis, and thus contributing to organ injury and a systemic thrombogenic state in COVID-19.² Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488

Results from flow cytometric activation marker analysis and isolation and staining of peripheral blood neutrophils from COVID-19 ICU patients showed the formation of circulating platelet-neutrophil-aggregates correlated linearly with pulmonary disease severity.² Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488 D-Dimer levels were also strongly elevated in COVID-19 patients, with a significant correlation to disease severity, indicating the constant activation of the coagulation cascade in these patients.² Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488 The results of this study indicate that platelets, neutrophils, and the coagulation cascade contribute to disease severity, and COVID-19 patients are at risk for increased thrombotic events due to the procoagulant state.² Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488

A retrospective, observational case series conducted in the Mount Sinai Health System Hospitals across New York City over the peak three weeks of hospitalisation and death from COVID-19 (March 21 to April 12, 2020) also found that over half of emergent large vessel occlusion (ELVO) patients during this period were COVID-19 patients.⁴Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397 A diagnosis of ELVO required vascular imaging confirmation of occlusion, with concomitant acute neurological deficit.⁴Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397

Over the 21-day study period, 45 patients with ELVO were identified, with a mean age of 66, 38% women, and 38% Black. Of these patients, 24 tested positive for SARS-CoV-2.⁴Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397 An exploratory analysis comparing the prevalence and demographic data of ELVO patients during the COVID-19 outbreak to the ELVO patients from the year prior (March/April 2019) found a two-fold increase in the number of ELVO patients during the COVID-19 period.⁴Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397 Over 50% of ELVO patients presenting during this three-week COVID-19 peak tested positive, which was significantly higher than the 19.9% infection rate in the general New York City population.⁴Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397  These patients were younger, more likely to be male, and less likely to be White.⁴Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397 These findings suggest an association between COVID-19 and large-vessel ischaemic stroke.⁴Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397

The data from these two studies point to a prothrombotic state upon infection with SARS-CoV-2 that is correlated with disease severity. Patients presenting with acute ischemic stroke, particularly those without typical cardiovascular risk factors, should be tested for SARS-CoV-2 infection during the pandemic.⁴Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397 Clinicians treating COVID-19 patients should consider prophylactic anticoagulants and vigilant monitoring for thrombotic complications.²Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488