Crosstalk between inflammation and coagulation in severe COVID-19 infections

In a special session at this year's virtual meeting, member of the ISTH COVID-19 Task Force Prof. Roberta Gualtierotti (University of Milan, Italy) highlighted haemostatic changes in patients with severe COVID‐19 [1].

Transmission of the novel coronavirus occurs via direct contact or respiratory droplets. The virus enters by binding to the ACE2 receptor expressed on bronchial and alveolar epithelial cells, endothelial cells, and monocytes in the lung. “Evidence speaks in favour of the role of endothelial cells in severe COVID-19, both as culprits and victims of the inflammatory state and consequent coagulopathy,” Prof. Gualtierotti explained.

While most infections lead to mild-to-moderate respiratory symptoms, about 5% of the patients progress to a more severe and systemic disease with acute lung injury, eventually leading to acute respiratory distress syndrome, shock, and multiple organ dysfunction associated with a peculiar coagulopathy and an increased mortality risk [2]. Among hospitalised patients with severe COVID-19-associated pneumonia, respiratory failure with hypoxia is frequent. Moreover, evidence suggest that patients with 1 or more pre-existing risk factors such as obesity, diabetes, and dyslipidaemia may be more at risk of developing severe COVID-19.

In severe COVID-19, inflammation is caused by immune dysregulation. Prof. Gualtierotti emphasised that “severe COVID-19 is characterised by hyperinflammation, triggering a series of pathogenic mechanisms that further amplify the inflammatory state and activate coagulation and other systems, and by a [COVID-19-associated] peculiar coagulopathy. Hypercoagulability leads to a prothrombotic state.” She pointed out "that a bidirectional crosstalk does exist between inflammation and coagulation.” Severe COVID-19 is a paradigm of this crosstalk. Coagulation activation induces microvascular thrombosis - a phylogenetically preserved mechanism that, in the end, is an attempt by the body to prevent the spreading of pathogens. “However, when uncontrolled, this may lead to multiple organ dysfunction,” she warned.

Previous studies have reported a cumulative incidence of venous thromboembolism in severe COVID-19 of about 30% at 21 days of follow-up in patients hospitalised in different intensive care units with COVID-19, despite routine thrombosis prophylaxis [1]. Prof. Gualtierotti presented data from Milan, demonstrating a slightly higher incidence of venous thromboembolism (31.6% at 21 days) but this analysis included not only ICU but also intermediate care patients [3].

While many patients with severe COVID-19 experience coagulopathies that may resemble other systemic coagulopathies associated with severe infections and systemic inflammation, e.g. disseminated intravascular coagulation (DIC) and consumption coagulopathy, none of these fully fit the description of COVID-19-associated coagulopathy. DIC is rarely seen in severe COVID‐19 infection other than pre-terminal multiple organ failure. In case of COVID-19, fibrinogen is not reduced but increased. Thrombotic microangiopathy is an expression of microvascular involvement and the development of fibrin and microthrombi. In COVID-19, haemolysis and thrombocytopenia are not typical features. In secondary hemophagocytic lymphohistiocytosis, fibrin formation is caused by survival of histiocytes and failure of normal cytotoxic cells to abandon the triggering antigen. Sepsis is associated with DIC and cytokine storm is an umbrella term, including a variety of inflammatory aetiologies with overwhelming systemic inflammation, leading to hemodynamic instability, multiple organ dysfunction, and death. "However, none of these terms fully describes COVID-19-associated coagulopathy,” Prof. Gualtierotti concluded.

1. 
   
   1. Gualtierotti R. COVID19.02. ISTH 2020 Virtual Congress, 12-14 July.
   2. Wu Z, McGoogan JM. JAMA 2020;323:1239-1242.
   3. Martinelli I, et al. 2020. Submitted for publication.

Posted on 8 September, 202020 February, 2024