September 10, 2020

Study suggests marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism

Factor V activity was significantly higher in patients hospitalised with severe coronavirus disease 2019 (COVID-19) than in contemporaneous controls as well as historical controls, and high factor V activity was associated with thromboembolic complications of COVID-19, according to a study published in the American Journal of Hematology.

“In contrast, patients with COVID-19 and a relatively lower factor V activity had a higher mortality and a higher incidence of an abnormally sloped waveform, which is an early predictor of disseminated intravascular coagulation (DIC),” wrote authors led by Jonathan A. Stefely, M.D, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts.

In March 2020, the researchers found that a blood sample from a patient with severe COVID-19 on a ventilator had an unexpected and unusual elevation of factor V activity at 248 IU/dL (reference range 60–150 IU/dL) and the patient developed a saddle pulmonary embolism four days later. The researchers said it was the “highest factor V activity level ever observed” in their high-volume coagulation laboratory.This led them to measure factor V, VIII, and X activity in a cohort of 102 consecutive inpatients with COVID-19. The researchers also analyzed contemporaneous SARS-CoV-2-negative controls (n = 17) and historical pre-pandemic controls (n = 260–478). Further, the cohort of patients with COVID-19 was almost entirely comprised of severe cases based on the observed rate of ventilator use (92%) and ECMO use (7%) at the time of the analyzed coagulation specimen. 

The study found that factor V levels were significantly elevated among patients with COVID-19 (median 150 IU/dL) compared with contemporaneous controls (median 105 IU/dL; P < 0.00001) and historical controls (median 81 IU/dL, P < 1x10–32). Further, 48% of the COVID-19 cohort had factor V levels above the reference range of 60–150 IU/dL and 16% had levels >200 IU/dL, which the authors said was not seen in any of the contemporaneous or historical controls. Meanwhile, a sub-group analysis also demonstrated that factor V was significantly elevated in the COVID-19 patients compared to both the contemporaneous control cases on ventilators (n = 7, median 54 IU/dL, P < 0.05) and the non-ventilated contemporaneous control cases (n = 10, median 107 IU/dL, P < 0.00001). 

“These findings suggest that the elevation of factor V in severe COVID-19 cannot be simply explained by a general state of severe illness or by ventilator use,” the authors wrote. 

Further, the study found 33% of patients with factor V activity well above the reference range had either deep vein thrombosis or a pulmonary embolism, compared with only 13% of patients with lower levels (P = 0.03). Moreover, among patients with COVID-19, the study found that factor V trends toward higher activities in patients who went on to develop deep vein thrombosis or a pulmonary embolism (median 165 IU/dL, n = 23) compared to those that did not develop such conditions (median 145 IU/dL, n = 79) (P = 0.05).

Mortality rates were significantly higher for patients with lower levels of factor V (30% vs 12%; P < 0.05). To investigate if this relationship with mortality could be due to consumption of factor V at the beginning stages of DIC, the researchers also assessed the aPTT waveform slope. They found that a subset of patients with severe COVID-19 showed an abnormal slope at the beginning of the activated partial thromboplastin time (aPTT) waveform, suggesting progression toward DIC, and that factor V was lower in COVID-19 patients with an abnormal waveform slope, compared to COVID-19 patients with a normal slope (median 116 IU/dL versus 158 IU/dL, P = 0.005).

“Thus, an abnormal slope in the aPTT waveform and/or factor V below 150 IU/dL may be early markers of a DIC-like process that appear before routine laboratory tests can diagnose DIC (D-dimer, fibrinogen, platelet count, and PT),” the authors noted.

“Our study reveals factor V perturbations as a previously unrecognized feature of severe COVID-19, adds a mechanistic candidate to ongoing investigations of COVID-19 coagulopathy with potential links to SARS-CoV2 disease biology, and provides a foundation for future studies of COVID-19 coagulopathy diagnosis and biomarkers for guiding anticoagulation therapy in severe COVID-19,” the authors stated.

The authors also pointed out that factor V elevation in COVID-19 could cause misdiagnosis of some patients, because under normal circumstances factor V levels are low in the presence of liver dysfunction or DIC. 

“Thus our findings are important for clinical interpretation of coagulation panels for patients with COVID-19, and could alter management decisions for some patients with suspected liver dysfunction, DIC, or vitamin K deficiency.” they added.

The authors acknowledge that limitations of the study included the lack of mildly symptomatic or asymptomatic COVID-19 cases in the cohort, and the relatively small number of contemporaneous controls. 

SOURCE: American Journal of Hematology
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