Pronounced Elevation of Factor V in Severe COVID-19 Is Associated with Venous Thromboembolism

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In March 2020, physicians at Massachusetts General Hospital obtained an early blood sample from a patient with severe COVID-19. Testing revealed the highest factor V activity ever observed in the hospital's coagulation laboratory: 248 IU/dL (reference range, 60–150). Four days later, the patient developed a pulmonary embolism.

Because of that finding and multiple publications about coagulopathy in COVID-19, they began testing blood samples from additional critically ill COVID-19 patients. Jonathan A. Stefely, MD, PhD, Bianca B. Christensen, MD, MPH, both clinical fellows in the Department of Pathology at Mass General, and Elizabeth M. Van Cott, MD, director of the Coagulation Laboratory in the Department of Pathology, and colleagues linked high factor V activity with thromboembolic complications of COVID-19. In addition, lower activity was an early predictor of disseminated intravascular coagulation (DIC) and was associated with mortality. The team's report appears in the American Journal of Hematology.

Study Details

Blood samples were collected from 102 COVID-19 patients who were in ICUs at Mass General between March 23 and April 27, 2020, without exclusion criteria. They were compared with samples from 17 contemporaneous controls who tested negative for SARS-CoV-2 and 446 historical controls who were tested prior to the pandemic between April 2016 and February 2020.

Cases with COVID-19 and contemporaneous controls were followed for a median of 78 days (range, 64–99) after the first sample was obtained.

Incidence of Factor V Elevation

• The median factor V value among cases was 150 IU/dL, and 48% had values above the reference range of 60–150 IU/dL
• 16% of cases had factor V levels >200 IU/dL
• Factor V activity was significantly higher in COVID-19 cases than in contemporaneous controls (median 150 vs. 105 IU/dL, P < 1×10−5) or historical controls (median 150 vs. 81 IU/dL, P < 1×10−32)

Factor V and Venous Thromboembolism (VTE)

Among cases, VTE was significantly more likely in those who had factor V activity >150 IU/dL than those with lower levels (33% vs. 13%; P = .03). Similarly, median factor V levels were higher in cases who went on to develop VTE than those who did not (165 vs. 145 IU/dL; P = .05).

Progression Toward DIC and Death

Cases with factor V activity ≤150 IU/dL were more likely to die during the study than those whose values were >150 IU/dL (30% vs. 12%, P < .05).

The relationship with mortality appears to be related to the consumption of factor V at the beginning stages of DIC. As assessed by activated partial thromboplastin time (aPTT) waveform analysis, progression toward a DIC-like state was associated with a decrease in factor V activity, and relatively lower factor V activity was associated with death.

Tips for Clinicians

Factor V activity <150 IU/dL and/or an abnormal slope in the aPTT waveform may be early signs of a DIC-like process that appears before routine laboratory tests can diagnose DIC. aPTT waveform analysis could be discussed via consultation with a facility's local coagulation laboratory.

These findings can also help with the interpretation of coagulation panels for patients with COVID-19 who have liver dysfunction or DIC. Clinicians should take care not to diagnose vitamin K deficiency erroneously in such patients when factors II, VII and X are low and factor V is normal or elevated.

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