Elevated factor V activity and antigen levels in patients with Covid‐19 are related to disease severity and 30‐day mortality

approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. Oncotargets. 2011;2:518-524. 5. Wang L, Shalek AK, Lawrence M, et al. Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL. Blood. 2014;124(7): 1089-1098. 6. Khan MW, Saadalla A, Ewida AH, et al. The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. Cancer Immunol Immunother. 2018;67(1): 13-23.

Elevated factor V activity and antigen levels in patients with Covid-19 are related to disease severity and 30-day mortality To the Editor: We were very interested to read the recent manuscript by Stefely and coworkers who reported markedly increased factor V (FV) activity levels in critically ill patients with Covid-19. 1 In this report, high FV activity levels were shown to be associated with thrombotic events, whereas declining levels were associated with poor outcome. A paper by Voicu and coworkers confirmed elevated FV activity levels in critically ill Covid-19 patients. 2 We have recently reported on the hemostatic profile of a Covid-19 patient cohort. 3 These patients had much milder disease in comparison to the cohort studied by Stefely. We were interested in investigating if elevated FV activity levels also occur in patients with milder disease. In addition, we wondered if the increase in FV activity reflects an increase in FV protein (antigen) level or whether these unusually elevated FV activity levels could be explained by an increase in specific activity rather than an increase in FV antigen. Patient characteristics have been described previously. 3 In short, we included consecutive patients with Covid-19 in a single hospital in Sweden, and drew blood within 7 days of hospital admission. We measured FV activity using an automated coagulation analyzer (STACompact 3, Stago, Breda, the Netherlands) and FV antigen using a commercially available enzyme-linked immunosorbent assay (Stago, Breda, The Netherlands) in platelet poor plasma of 97 patients with Covid-19 and 28 healthy controls. Both FV activity and antigen were higher in Covid-19 patients compared to controls, although the difference in antigen levels did not reach statistical significance (P = .072). Patients on medium or intensive care units had higher FV antigen levels compared to patients on general wards ( Table 1). The FV activity levels were similar when patients were stratified according to their level of respiratory support, but FV antigen levels were higher in those patients with a higher level of respiratory support, although this difference did not reach statistical significance ( Table 1). The FV activity and antigen levels were lower in those patients that died within 30 days of admission ( Table 1). The specific FV activity (ie, the FV activity to antigen ratio) was similar between patients and controls, although patients admitted to higher levels of care had decreased specific activity (healthy controls vs high care patients P = .013). The correlation (performed by simple linear regression) between FV antigen and activity was less pronounced in patients (r 2 = 0.10, P < .001) compared to controls (r 2 = 0.20, P = .028).
Our data confirm and extend data by Stefely and coworkers. Hospitalized patients with Covid-19 have elevated FV activity levels, with more pronounced increases in patients receiving higher levels of care. Nevertheless, our data show that even those patients admitted to general wards and patients that do not require respiratory support have elevated FV activity levels. Interestingly, we find decreased FV activity levels in the first week of admission in patients that died within 30 days of admission, which is also in line with the observation of Stefely and coworkers that declining FV activity levels appear associated with a poor prognosis. No thrombotic events occurred in our cohort during a 30-day follow up, and we were therefore unable to confirm the finding by Stefely of elevated FV activity levels as a risk factor for Covid-19-associated venous thrombosis.
Elevated levels of FV activity were in part related to increased FV antigen, although the correlation between FV activity and antigen was modest in both patients and controls. Besides fibrinogen, FV is the only liver-derived coagulation factor that shows elevated levels in Covid-19 patients, and the reason for this selective FV increase remains unclear. Part T A B L E 1 Factor V activity and antigen levels in Covid-19 patients related to severity of disease and mortality   Macroscopic examination ruled out acute myocardial infarction, pulmonary thromboembolism and stroke. The most striking feature was that during the organ dissection there was hardly any blood within the blood vessels, as seen in cases of complete exsanguination.
There was no blood in the gastro-intestinal tract. For this reason, forensic pathology was consulted. There were no findings suggesting external or internal blood vessel trauma or puncture or hematoma.
The respective weights of liver and spleen were 3.35 and 0.49 lb, ruling out massive acute splenic and/or hepatic sequestration of blood as the cause of the almost empty vascular bed. The weight of the lungs was normal. Microscopic findings of the liver and spleen revealed red cell entrapment ( Figure 1A,B) without red cell entrapment in the lungs ( Figure 1C). Examination of a lumbar vertebra revealed massive entrapment of sickled red blood cells ( Figure 1D). Based on these findings it seems that circulatory arrest occurred largely due to acute blood sequestration in the bone marrow.
A bone marrow sequestration crisis has not, to our knowledge, been previously described. Normal bone marrow histology shows at E100 CORRESPONDENCE