A missense mutation in lectin domain of thrombomodulin causing functional deficiency.

Thrombomodulin (TM) functions in coagulation, fibrinolysis and inflammation by its cofactor activity for protein C, thrombin-activatable fibrinolysis inhibitor (TAFI) activation and high mobility group box 1 (HMGB1) degradation induced by thrombin. It has been widely reported that mutations in TM are related to thromboembolic diseases but hardly in lectin domain. Here we report our findings about the functional deficiencies in TM caused by substitution of aspartate with tyrosine at residue 126. Three patients suffering from recurrent thromboembolic diseases were identified with this mutation and their plasma soluble TM levels were decreased. Transfected cells expressing wild-type TM or the variant and corresponding proteins were used to examine TM functions in vitro. The cofactor activity of the mutant for protein C, TAFI activation was reduced to approximately 50% and 60% respectively. Loss in anti-inflammation due to weakened HMGB1 degradation was also observed. And the study with thrombosis models of mice suggested the decreased inhibition of thrombus development of the mutant. Together the results showed deleterious changes on TM function caused by this mutation, which may explain the thrombophilia tendency of the patients. This work provided supportive evidence that mutation in lectin domain of TM might be related to thrombotic diseases and may help us better understand the physiological roles of TM.

Safety and efficacy of convalescent plasma therapy in severely and critically ill patients with COVID-19: a systematic review with meta-analysis.

BACKGROUND: The rapidly evolving coronavirus disease 2019 (COVID-19) has resulted in more than 24 million infections and 821 thousand deaths. However, a vaccine or specific drug is absent up to this date and more attention has been focused on the use of convalescent plasma (CP). Several articles have described the CP treatment for patients with SARS-CoV-2 infection. But a comprehensive systematic review with meta-analysis about the safety and efficacy of CP transfusion in SARS-CoV-2-infected patients has not been published. We conducted this study for a better understanding of the therapeutic significance of CP for patients with COVID-19. RESULTS: A fixed-effect model (I2=0.0%) was used on the 9 articles for quantitative analysis showing that the mortality of patients with COVID-19 treated with or without CP was statistically significant (RR=0.57 [0.44-0.74]). Subgroup analysis showed that the severely ill patients benefited more from CP than the critically ill patients. Our study concluded that clinical improvement in severe COVID-19 cases were obvious. Adverse events were few and the effect of convalescent plasma on reducing viral load was apparent. CONCLUSIONS: Convalescent plasma therapy appears safe for COVID-19, and plasma treated patients have marked reductions in their serum viral loads and most are virus negative after transfusion. Patients with severe COVID-19 benefit more from the convalescent plasma transfusion than critical patients, and patients treated in early stage are more likely to survive. METHODS: We reviewed the scientific literature from four databases published from December 8, 2019 to August 20, 2020. Statistical analyses were performed with STATA (version 15.1; Stata Corporation, College Station, TX, USA). The frequency with 95% confidence intervals (CI) was assessed using fixed effect model in analyzing the overall mortality and p <0.05 was considered statistically significant.