Insufficient hyperfibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Ji, H.-L. J.; Su, Z.; Zhao, R.; Komissarov, A. A.; Yi, G.; Liu, S.-L.; Idell, S.; Matthay, M. A.

Background How aberrant fibrinolysis influences the clinical progression of COVID-19 presents a clinicopathological dilemma challenging intensivists. To investigate whether abnormal fibrinolysis is a culprit or protector or both, we associated elevated plasma D-dimer with clinical variables to identify a panoramic view of the derangements of fibrinolysis that contribute to the pathogenesis of COVID-19 based on studies available in the literature. Methods We performed this systematic review based on both meta-analysis and meta-regression to compute the correlation of D-dimer at admission with clinical features of COVID-19 patients in retrospective studies or case series. We searched the databases until Aug 18, 2020, with no limitations by language. The first hits were screened, data extracted, and analyzed in duplicate. We did the random-effects meta-analyses and meta-regressions (both univariate and multivariate). D-dimer associated clinical variables and potential mechanisms were schematically reasoned and graphed. Findings Our search identified 42 observational, or retrospective, or case series from six countries (n=14,862 patients) with all races and ages from 1 to 98-year-old. The weighted mean difference of D-dimer was 0.97 g/mL (95% CI 0.65, 1.29) between relatively mild (or healthy control) and severely affected groups with significant publication bias. Univariate meta-regression identified 58 of 106 clinical variables were associated with plasma D-dimer levels, including 3 demographics, 5 comorbidies, 22 laboratory tests, 18 organ injury biomarkers, 8 severe complications, and 2 outcomes (discharge and death). Of these, 11 readouts were negatively associated with the level of plasma D-dimer. Further, age and gender were confounding factors for the identified D-dimer associated variables. There were 22 variables independently correlated with the D-dimer level, including respiratory rate, dyspnea plasma K+, glucose, SpO2, BUN, bilirubin, ALT, AST, systolic blood pressure, and CK. We thus propose that "insufficient hyperfibrinolysis (fibrinolysis is accelerated but unable to prevent adverse clinical impact for clinical deterioration COVID-19)" as a peculiar mechanism. Interpretation The findings of this meta-analysis- and meta-regression-based systematic review supports elevated D-dimer as an independent predictor for mortality and severe complications. D-dimer-associated clinical variables draw a landscape integrating the aggregate effects of systemically suppressive and locally (i.e., in the lung) hyperactive derangements of fibrinolysis. D-dimer and associated clinical biomarkers and conceptually parameters could be combined for risk stratification, potentially for tracking thrombolytic therapy or alternative interventions.