Major bleeding complications appear to be common among critically ill patients with pneumonia from the COVID-19 virus who are administered anticoagulants for thromboprophylaxis, according to the results of a new study published in the Journal of Thrombosis and Thrombolysis.

The findings highlighted the need to carefully monitor inflammatory biomarkers and anticoagulant dosage as the high thrombotic risk period, which is characterized by early hyperinflammation and endothelial dysfunction, in order to avoid bleeding events.

The investigators conducted a retrospective chart review of all adult patients with COVID-19 pneumonia who required mechanical ventilation and were admitted to their institution’s intensive care unit (ICU) between March 20, 2020 and April 14, 2020.


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They examined major bleeding and thrombotic events, along with their relationships with inflammation and thromboprophylaxis, and assessed anticoagulation status and coagulation test findings.

The study included 56 consecutive ICU patients with COVID-19 (71% male), who had a median age of 60 years (IQR, 53–69) and increased body mass index (median, 27 kg/m2; IQR, 24–31).

Overall, 16 patients (29%) had thrombotic events, while 10 patients (18%) experienced major bleeding. These events exhibited biphasic patterns. Thrombotic events occurring earlier than bleeding events at a median of 9 days (IQR, 3-11) following ICU admission vs at a median of 17 days (IQR, 14-23; P =.005).

Fibrinogen concentration and d-dimers followed the same biphasic pattern. Both fibrinogen concentration (median, 7 g/l; IQR, 6-7.6) and d-dimers (median, 1401 ng/ml; IQR, 1056-2122) were elevated in all patients upon ICU admission and continued to increase to peaks of 8.5 g/l (IQR, 7.4-9.3) for fibrinogen on day 5 (IQR, 2-9), indicative of severe inflammatory syndrome (>8 g/l) and 5908 ng/ml (IQR, 3544-9380) on day 6 (IQR, 3-8), indicative of the hypercoagulable state (>3000 ng/ml).

The investigators found that fibrinogen concentration always decreased a median of 4 days prior to bleeding (IQR, 3–5), with d-dimers following the same trend.

In patients receiving therapeutic anticoagulation, overdose occurred in more patients after fibrinogen was decreasing (78%) than while it was increasing (22%; P <.05).  Anticoagulant overdose occurred at a median of 7.5 days (IQR, 3.5–9.25) after the fibrinogen peak. All patients who had bleeding events were still being treated with anticoagulants on the day of bleeding, and for 60% of the patients who had bleeding events, anticoagulation was overdosed on the day of or the day before bleeding.

“Bleeding is likely to occur later during ICU stay when inflammation is decreasing and

exposes [the patient] to supra-therapeutic levels of anticoagulation,” the study authors wrote. “Intensivists may modulate thromboprophylaxis strategy according to inflammatory biomarkers, especially fibrinogen. Moreover, when fibrinogen decreases repeatedly, anti-Xa activity should be controlled to adapt heparin dosing.”

More research is needed to determine the end of the COVID-19 high thrombotic risk period and the appropriate dosing of thromboprophylaxis over the course of disease.

Disclosures: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Godier A, Clausse D, Meslin S, et al. Major bleeding complications in critically ill patients with COVID-19 pneumonia. J Thromb Thrombolysis. Published online March 1, 2021. doi:10.1007/s11239-021-02403-9