Meta-analysis of coagulation disbalances in COVID-19: 41 studies and 17601 patients

Len, P.; Iskakova, G.; Sautbayeva, Z.; Kussanova, A.; Tauekelova, A. T.; Sugralimova, M. M.; Dautbayeva, A. S.; Abdiyeva, M. M.; Ponomarev, E. D.; Bekbossynova, M. S.; Barteneva, N. S.

Introduction. Coagulation parameters are important determinants for COVID-19 infection. We conducted meta-analysis to assess the early hemostatic parameters in retrospective studies in association with severity of infection. Methods. Ovid, PubMed, Web of Sciences, and Google Scholar were searched for research articles that addressed clinical characteristics of COVID-19 patients and disease severity. Results were filtered using exclusion and inclusion criteria and then pooled into a meta-analysis to estimate the standardized mean difference with 95% CI for each of five coagulation parameters (D-dimers, fibrinogen, prothrombin time, platelets count, activated partial thromboplastin time). Two authors independently extracted data and assessed study quality. To explore the heterogeneity and robustness of our fundings, sensitivity and subgroup analyses were conducted. Publication bias was assessed with contour-enhanced funnel plots and Egger test by linear regression. Results. Overall, 41 original studies (17601 patients) on SARS-CoV2 were included. For the two groups of patients, stratified by severity, we identified that D-dimers, fibrinogen, activated partial thromboplastin time, and prothrombin time were significantly higher in the severe group (SMD 0.6985 with 95%CI [0.5155; 0.8815]); SMD 0.661with 95%CI [0.3387; 0.9833]; SMD 0.2683 with 95%CI [0.1357; 0.4009]; SMD 0.284 with 95%CI [0.1472; 0.4208]). In contrast, PLT was significantly lower in patients with more severe cases of COVID-19 (SMD -0.1684 with 95%CI [-0.2826; -0.0542]). Neither the analysis by the leave-one-out method nor the influence diagnostic have identified studies that solely cause significant change in the effect size estimates. Subgroup analysis showed no significant difference between articles originated from different countries but revealed that severity assessment criteria might have influence over estimated effect sizes for platelets and D-dimers. Contour-enhanced funnel plots and the Egger test for D-dimers and fibrinogen revealed significant asymmetry that might be a sign of publication bias. Conclusions. The standard coagulation laboratory parameters with exception of platelets counts are significantly elevated in patients with severe COVID-19. However, fibrinolysis shutdown requires evaluation outside conventional coagulation tests and analysis of additional specific markers related to clotting formation and PLT characteristics. We hypothesize that a proportion and parameters of immature reticulated platelets may serve as additional biomarkers for prediction of adverse events.