Risk of thrombosis with SARS-CoV-2 infection

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HEPATITIS C VIRUS

Medical writer: Kirsty LEE | Last updated: 27th August 2020 | In: Cardiovascular, COVID-19, Critical Care Medicine, Infectious Disease, Internal Medicine, SARS-CoV2

Article Keywords

2019-nCoV, ARDS, COVID-19, D-Dimer, ELVO, fibrinogen, hypoxia, immunothrombosis, ischaemic stroke, neutrophils, pneumonia, RT-PCR, thrombosis

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) in late 2019 has led to a global pandemic.¹ Infection with SARS-CoV-2 causes coronavirus disease 2019 (COVID-19), which presents most severely with interstitial pneumonia that progresses to acute respiratory distress syndrome (ARDS) and multi-organ failure.¹ Non-pulmonary organ damage has emerged as a predictor of mortality.² However, the underlying mechanisms of COVID-19 tissue injury are currently not sufficiently understood. Current evidence indicates a prothrombotic state in COVID-19 patients that could contribute to an increased mortality rate.^1,2 Immunothrombosis is a process that under certain inflammatory conditions, is the cumulative impact of neutrophils, platelets, and the coagulation cascade to contain invading pathogens, that can aggravate tissue damage by triggering vessel occlusion and hypoxia.²

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.³ Recent trials and observational case series have highlighted that COVID-19 positive patients are at an increased risk for thrombotic events.^2,4

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-19.² 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).² Patients in the COVID-19 cohorts were confirmed cases from reverse transcriptase-polymerase chain reaction (RT-PCR).² 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.²

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 Immunofluorescence was further used to confirm the presence of neutrophils in the microthrombi, which were embedded in the fibrin clot.²This finding was confirmed in four additional COVID-19 cases.² 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

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 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 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

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.⁴ A diagnosis of ELVO required vascular imaging confirmation of occlusion, with concomitant acute neurological deficit.⁴

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-2.⁴ 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.⁴ 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.⁴ These patients were younger, more likely to be male, and less likely to be White.⁴ These findings suggest an association between COVID-19 and large-vessel ischaemic stroke.⁴

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.⁴ Clinicians treating COVID-19 patients should consider prophylactic anticoagulants and vigilant monitoring for thrombotic complications.²

Reference

Hajra A et al. Drugs. doi: 10.1007/s40265-020-01377-x

Nicolai L et al. Circulation. doi: 10.1161/CIRCULATIONAHA.120.048488

Carfora V et al. J Thromb Thrombolysis. doi: 10.1007/s11239-020-02242-0

Majidi Shahram et al. Stroke. doi: 10.1161/STROKEAHA.120.030397

Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).