Anticoagulant protein S in COVID-19: low activity, and associated with outcome

Abstract

Introduction: COVID-19 disease was associated with both thrombo-embolic events and in-situ thrombi formation in small vessels. Antiphospholipidic antibodies were found in some studies.Aim: Assessment of protein S activity in patients with COVID-19 as a cause this prothrombotic state, and of the association of protein S activity with worse outcome.Methods: All patients admitted for COVID-19 disease in a university hospital between 15th of May and 15th of July 2020 were prospectively enrolled into this cohort study. Patients treated with antivitamin K anticoagulants and with liver disease were excluded. All patients had protein S activity determined at admission. The main outcome was survival, secondary outcomes were clinical severity and lung damage.Results: 91 patients were included, of which 21 (23.3%) died. Protein S activity was decreased in 65% of the patients. Death was associated with lower activity of protein S (median 42% vs. 58%, p<0.001), and the association remained after adjustment for age, inflammation markers and ALAT. There was a dose-response relationship between protein S activity and clinical severity (Kendall_tau coefficient = -0.320, p < 0.001; Jonckheere-Terpstra for trend: p<0.001) or pulmonary damage on CT scan (Kendall_tau coefficient = -0.290, p<0.001; Jonckheere-Terpstra for trend: p<0.001). High neutrophil count was also independently associated with death (p=0.002).Conclusion: Protein S activity was lower in COVID-19 patients, and its level was associated with survival and disease severity, suggesting that it may have a role in the thrombotic manifestations of the disease.

The SARS-CoV-2 SSHHPS Recognized by the Papain-like Protease

“…Factor V synergistically stimulates PROS1 activity. 57 Stoichitoiu et al ( 55 ) showed a correlation between PROS1 activity and clinical severity and lung damage. 55 All three studies showed that PROS1 activity (free Protein S) was below the normal range in COVID-19 patients.…”

“… 51 , 52 Blood clots have been reported in cases of COVID-19 and SARS; however, data for the few cases of MERS are scarce. 53 Lemke et al , 54 Zhang et al , 59 and Stoichitoiu et al ( 55 ) have postulated that depletion of Protein S may be related to the observed hypercoagulability of the blood. Lemke et al ( 54 ) and Stoichitoiu et al ( 55 ) also proposed that PROS1 deficiency may play a role in the immune hyper-reactions observed in humans with COVID-19 since PROS1 is involved in the activation of immunosuppressive TAM (Tyro3, Axl, and Mer) receptors that prevent hyperinflammation and lung injury.…”

The Impact of SARS-CoV-2 Infection on Blood Coagulation and Fibrinolytic Pathways: A Review of Prothrombotic Changes Caused by COVID-19

“…A study investigating the effect of baseline protein S activity of 91 patients, with survival as the main outcome, revealed protein S activity to be reduced in 65% of the patients; death was associated with lower activity of protein S (median 42 vs. 58%, p < 0.001). 94 Another study showed a significant decrease in protein S activity of patients compared with the control group. 91 Two other studies reported protein S activity slightly below the normal range.…”

The enzymes in COVID-19: A review

“…Its influence on coagulation is palpable since protein S deficiencies are related to elevated thrombotic risk [ 83 ]. Clinical data revealed low activity of protein S in COVID-19 patients, suggesting this may contribute to coagulopathy in COVID-19 [ 84 , 85 ]. Also, backing this suggestion, SARS-CoV-2 papain-like protein cleaves a sequence within protein S, and this cut may result in impaired protein S function or secretion in the course of the viral infection [ 5 ].…”