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<p>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, <i>n</i> = 618,205; hypothermia, <i>n</i> = 623,671; coagulopathy, <i>n</i> = 3,268,220), we assessed causal relationships using rigorous instrumental variables (<i>P</i> &lt; 5 × 10<sup>− 5</sup>, <i>F</i>-statistics &gt; 10) and sensitivity analyses (MR-Egger, weighted median, MR-PRESSO). Results demonstrated genetic independence: acidosis showed null effects on coagulopathy (<i>OR</i> = 0.987, <i>95%CI =</i> 0.957–1.018, <i>P</i> = 0.408) or DIC (<i>OR</i> = 0.983, <i>95%CI =</i> 0.852–1.134, <i>P</i> = 0.815), while hypothermia exhibited no coagulopathy association (<i>OR</i> = 0.984, <i>95%CI =</i> 0.963–1.005, <i>P</i> = 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月30日

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  • Ren Jing,
  • Yanli Hou,
  • Nan Wu,
  • Shijian Yi

摘要

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.