Genetic independence of the trauma lethal triad: endelian randomization evidence against germline causality in acidosis, hypothermia, and coagulopathy

Abstract

The lethal triad of acidosis, hypothermia, and coagulopathy synergistically elevates trauma, yet their genetic interdependence remains unestablished. Through bidirectional Mendelian randomization (MR) leveraging European-ancestry GWAS (acidosis, n = 618,205; hypothermia, n = 623,671; coagulopathy, n = 3,268,220), we assessed causal relationships using rigorous instrumental variables (P < 5 × 10^− 5, F-statistics > 10) and sensitivity analyses (MR-Egger, weighted median, MR-PRESSO). Results demonstrated genetic independence: acidosis showed null effects on coagulopathy (OR = 0.987, 95%CI = 0.957–1.018, P = 0.408) or DIC (OR = 0.983, 95%CI = 0.852–1.134, P = 0.815), while hypothermia exhibited no coagulopathy association (OR = 0.984, 95%CI = 0.963–1.005, P = 0.138). These findings contrast with clinical triad synergism mediated by pH-dependent enzyme inhibition and fibrinogen degradation. Trauma-induced coagulopathy instead arises from protein C activation and fibrinolysis hyperactivation—acute processes independent of germline variants but linked toendothelial glycocalyx shedding. Our results refute genetic predisposition as a unifying mechanism, prioritizing modifiable triggers (hemorrhage control, balanced resuscitation) as therapeutic targets.

Keywords

Lethal triad / Trauma-induced coagulopathy / Acidosis / Hypothermia / Mendelian randomization

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Funding

Youth Science Foundation of Foundation and Applied Basic Research Fund Project of Guangdong Province(2023A1515110149)

Shenzhen Science and Technology Program(JCYJ20240813144035045)

RIGHTS & PERMISSIONS

Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare

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