Dysregulated autophagic flux is associated with intrinsic platelet dysfunction in heatstroke-induced coagulopathy

Heatstroke progresses from acute thermal injury to multiorgan dysfunction syndrome and heatstroke-induced coagulopathy (HIC). Although consumptive thrombocytopenia is a known hallmark of HIC, whether surviving platelets develop intrinsic qualitative impairments remains unclear. Autophagy maintains platelet mitochondrial quality and energy homeostasis, thereby ensuring appropriate platelet responsiveness to activating stimuli. However, its specific role in heatstroke-induced platelet dysfunction remains unexplored. This study examined the hemodynamic, hemostatic, and molecular consequences of heatstroke, focusing on platelet autophagic flux.

Male Wistar rats were subjected to environmental heat stress (42 °C) until their core temperature reached 41.1 °C. Hemodynamic parameters and multiorgan injury markers were monitored during the experimental period. At 6 h after heat stress, coagulation profiles and platelet functional experiments were assessed using platelet-count-adjusted platelet-rich plasma to differentiate qualitative dysfunction from quantitative depletion. Various platelet autophagy markers were evaluated through Western blotting.

Heatstroke induced acute hyperthermia and compensatory cardiovascular responses, followed by hypotension, tachycardia, multiorgan dysfunction, thrombocytopenia, and prolonged coagulation times. Platelet functions were impaired following heatstroke, as evidenced by reduced platelet aggregation, fibrinogen binding, CD62P (P-selectin) expression, adhesion, and spreading. Furthermore, heatstroke was associated with decreased levels of the autophagy-related proteins Atg7, Beclin1, and LC3B, as well as the mitophagy-associated protein PINK1, accompanied by increased levels of BCL2 and p62.

Multiorgan metabolic catastrophe coincides with substantial count-independent qualitative platelet dysfunction associated with arrested autophagic flux and impaired mitophagy in heatstroke. These findings challenge reliance on platelet count alone for managing HIC and highlight the autophagic machinery as a potential therapeutic target.