Extreme gamma prime fibrinogen levels in covid-19 patients

ABSTRACT

Introduction: COVID-19 disease progression can be accompanied by a 'cytokine storm' that leads to secondary sequelae such as thrombosis and acute respiratory distress syndrome. Several inflammatory cytokines have been associated with COVID-19 disease progression, but have far too much daily intra-individual variability to be useful in tracking the course of the disease. In contrast, we have shown that the inflammatory biomarker γ' fibrinogen (γ' Fbg) has a 6-fold lower coefficient of variability compared to other inflammatory markers such as hs-CRP. The aims of the study were to measure γ' Fbg in serial blood samples from COVID-19 patients at a tertiary care medical center in order to investigate its association with clinical measures of disease progression. Hypothesis: Our hypothesis was that γ' Fbg levels would be elevated in COVID-19 patients compared to historical controls, and that the degree of elevation would be associated with disease severity. Methods: COVID-19 patients at a tertiary care medical center were retrospectively enrolled between 3/16/2020 and 8/1/2020. γ' Fbg was measured using the GammaCoeur ELISA (Gamma Diagnostics, Patent Pending). Results: Our results showed that ten out of the eighteen patients with COVID-19 had the highest levels of γ' Fbg ever recorded. The previous highest γ' Fbg level of 80.3 mg/dL was found in a study of 10,601 participants in the ARIC study. γ' Fbg levels were significantly associated with the need for ECMO and mortality. Conclusions: We found that COVID-19 patients can develop extraordinarily high levels of γ' Fbg. This has several important clinical implications. γ' Fbg contains a high affinity binding site for thrombin that binds to anion-binding exosite II on thrombin and protects it from inactivation by heparin. High levels of γ' Fbg therefore provide a reservoir of heparin-resistant clot-bound thrombin when the γ' Fbg is clotted. These findings have potential clinical implications regarding prophylactic anticoagulation of COVID-19 patients and suggest that heparin prophylaxis may be less effective than using other anticoagulants, particularly direct thrombin inhibitors.