Complement activation and endothelial perturbation parallel COVID-19 severity and activity.

BACKGROUND: Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet. OBJECTIVE: To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients. METHODS: In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma. RESULTS: The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels. CONCLUSIONS: Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.

Tocilizumab Effects on Coagulation Factor XIII in Patients with Rheumatoid Arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic auto-immune disease associated with a prothrombotic state. Tocilizumab, an interleukin-6 receptor inhibitor, is highly effective in controlling disease activity and thrombotic risk. Factor XIII (FXIII), involved in thrombotic complications, has been reported to be reduced in RA patients during maintenance treatment with tocilizumab, but no data are available before and after the drug administration. Thus, we investigated the effects of tocilizumab on FXIII, thrombin generation and inflammation in patients with RA naïve for the drug. METHODS: We studied 15 consecutive adult patients with RA at baseline and 4 weeks after the onset of parenteral administration of tocilizumab, measuring disease activity and plasma levels of C-reactive protein (CRP), FXIII, and prothrombin fragments F1+2 by immunoenzymatic methods. Fifteen healthy subjects, sex-and age-matched with patients, served as normal controls for laboratory measurements. RESULTS: At baseline, patients with established RA had a median DAS28 of 4.8 (3.2-8.3) and, compared to healthy controls, had higher plasma levels of CRP (p < 0.0001), FXIII (p = 0.017) and F1+2 (p < 0.0001). Four weeks after starting treatment with tocilizumab, based on the EULAR response criteria, eight patients were classifiable as responders and seven as non-responders. In responders, we observed a statistically significant reduction not only of the values of DAS28 and CRP (p = 0.012 for both), ut also of plasma levels of FXIII (p = 0.05) and F1+2 (p = 0.025). In non-responders, all the studied parameters were unchanged. CONCLUSION: The decrease of FXIII and F1+2 levels after tocilizumab treatment observed only in those patients who responded to the drug indicates that the effect of tocilizumab on the prothrombotic state is linked to the control of inflammation and disease activity and not to a direct effect of the drug, thus contributing to the reduction of the cardiovascular risk.

Hemostasis changes during veno-venous extracorporeal membrane oxygenation for respiratory support in adults.

BACKGROUND: We investigated the coagulation system in patients during extracorporeal membrane oxygenation (ECMO) initiated for respiratory failure and the influence of the ECMO circuit on coagulation tests; we compared different coagulation tests for monitoring unfractionated heparin (UH) therapy; we investigated whether or not coagulation parameters were predictive of bleeding during ECMO. METHODS: Pilot study on twelve consecutive adult patients admitted at our general ICU for acute respiratory failure and placed on ECMO from November 2011 to October 2012. Coagulation tests were performed before ECMO start and daily, including day of circuit change and day of circuit removal. UH was monitored with activated partial thromboplastin time (APTT) ratio, at a therapeutic range of 1.5-2.0. RESULTS: We observed no effect of ECMO circuit on coagulation parameters measured pre- and postlung, but platelet count decreased significantly over time (-82x10(3)/mmc, 95%CI 40-123). APTT showed a correlation with antifactor Xa activity, whereas other global coagulation tests such as activated clotting time, thromboelastography and endogenous thrombin potential did not. Major bleeding occurred in three patients but no difference in any coagulation parameter was observed between them and those who did not bleed. CONCLUSIONS: This pilot study shows that ECMO initiated for respiratory support in adults does not change coagulation parameters. Over time a statistically significant reduction of platelet count was observed, possibly due to consumption within the circuit, consumption microangiopathy or the underlying patients' diseases. Although APTT was appropriate to monitor UH, major bleedings occurred and a lower therapeutic range may be advisable.