High baseline levels of inflammatory cytokines linked to thrombotic events in patients with COVID-19

In a recent open-access paper published in the Journal of Clinical Medicine, researchers from Iran and Germany show that high baseline levels of inflammatory cytokines measured during admission put patients with coronavirus disease (COVID-19) at increased risk of developing coagulopathy, thrombotic events – and even death.

Cytokine storm and thrombotic events are two principal complications of COVID-19, a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and are more grave and serious in those that have a more serious clinical presentation.

As a result of infection by SARS-CoV-2, innate and adaptive immune responses are triggered. When the innate system (which is the body’s initial barrier) fails, foreign agents’ recognition sites (pathogen-associated molecular pattern – PAMP) are able to provoke the immune system, resulting in the release of more and more cytokines and leading to the phenomenon known as the “cytokine storm.”

The latter is commonly observed among patients with COVID-19, most notably among those that are severely ill and those who succumb to the disease. Moreover, there is a direct correlation between the immune and coagulation systems; hence, it is no wonder that immunological and coagulation disturbances are pervasive in COVID-19.

Because inflammation has a direct effect on coagulation, a group of researchers led by Dr. Fariba Rad from the Yasuj University of Medical Sciences in Iran decided to examine the relationship between these two systems to improve treatment for patients at highest risk.

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Interleukins and coagulation

In this study, 137 consecutive patients that were hospitalized with COVID-19 were included in this study. Baseline levels of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) level were measured at the time of admission with the use of enzyme-linked immunosorbent assay (ELISA).

Furthermore, baseline coagulation parameters (such as prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer, etc.) were assessed as well when patients were hospitalized. Clinical findings, which include the development of thrombosis and the overall clinical outcomes, were recorded prospectively.

Patients were divided into two groups in accordance with their baseline cytokine levels: those with normal cytokine levels and those with increased cytokine levels. The aim was to thoroughly explore the purported link between baseline levels of inflammatory cytokines, coagulation disturbances and disease outcomes in patients affected by COVID-19.

Higher cytokines, higher mortality levels

From 136 patients included in this study, 87 of them had increased cytokine levels (i.e., at least one elevated cytokine) or abnormal coagulation parameters. Among them, 67% presented with only increased inflammatory cytokines, 14% with coagulation abnormalities, and 19.5% with both of these issues.

In short, the researchers found that patients with a high baseline level of inflammatory cytokines may be exposed to more severe coagulation disturbances, thrombotic risks, and potentially fatal consequences. More specifically, the concentration of IL-6 has been shown to be significantly higher in patients with severe COVID-19.

In addition, IL-6 levels in non-survivors were almost two times higher when compared to patients that survived the disease. This study has also demonstrated that mortality rates were overall higher in individuals with elevated baseline cytokines. Therefore, testing for IL-6 and D-dimer can provide an early and rather sensitive/specific predictor of a severe course of the disease.

Is combination treatment a solution?

Since this study clearly implies a direct correlation between inflammatory cytokines and hypercoagulability states, measuring cytokine levels early in the disease course may be a desirable option to prevent severe outcomes of COVID-19.

“It is strongly recommended that all hospitalized patients have their cytokine levels monitored over the course of their illness to enable timely intervention to any emerging hyperinflammatory response”, say the authors of this study. “Patients with hyperinflammation might benefit from concomitant administration of anticoagulants and anti-inflammatories”, they add.

One of such choices may be low molecular weight heparin (LMWH), as it shows both anti-inflammatory and anticoagulation effects. However, the exact effects are still not clear, so there is a need for targeted studies that will further explore this relationship in a clinical setting.

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university – University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.