Heatstroke-induced coagulopathy: Biomarkers, mechanistic insights, and patient management

Abstract

Heatstroke is increasingly becoming a significant concern due to global warming. Systemic inflammation and coagulopathy are the two major factors that provoke life-threatening organ dysfunction in heatstroke. Dysregulated thermo-control induces cellular injury, damage-associated molecular patterns release, hyperinflammation, and hypercoagulation with suppressed fibrinolysis to produce heatstroke-induced coagulopathy (HSIC). HSIC can progress to disseminated intravascular coagulation and multiorgan failure if severe enough. Platelet count, D-dimer, soluble thrombomodulin, and inflammation biomarkers such as interleukin-6 and histone H3 are promising markers for HSIC. In exertional heatstroke, the measurement of myoglobin is helpful to anticipate renal dysfunction. However, the optimal cutoff for each biomarker has not been determined. Except for initial cooling and hydration, effective therapy continues to be explored, and the use of antiinflammatory and anticoagulant therapies is under investigation. Despite the rapidly increasing risk, our knowledge is limited, and further study is warranted. In this review, we examine current information and what future efforts are needed to better understand and manage HSIC.

Keywords: Cell death; Coagulation; Endothelial cell; Heatstroke; Inflammation.

Figure 1

Pathophysiology of heatstroke ‘Inflammation’ and ‘coagulation’ are the two major factors that lead to detrimental organ dysfunction in heatstroke. Thermal tissue damage originated damage-associated molecular patterns (DAMPs) stimulates macrophage/monocyte to release cytokines (tumor necrosis factor α [TNFα], interleukin [IL]−1β, IL-6, etc.) via inflammasome production. At the same time, activated macrophages/monocyte express tissue factor (TF) and release microvesicles that initiate coagulation. The inflammatory cytokines activate neutrophils and induce various types of cell death such as apoptosis, necrosis/necroptosis, pyroptosis, and NETosis. Neutrophil extracellular traps (NETs) and adhesive neutrophil damage the endothelial cells and facilitate thrombosis. Extrinsic and intrinsic pathways collaboratively activate coagulation cascades that generate the critical mediator, ‘thrombin.’ Thrombin further activates both inflammation and coagulation and finally leading to the formation of ‘inflammatory thrombus.’ The endothelial damage results in decreased fibrinolysis via plasminogen activator inhibitor 1 (PAI-1) production and increased permeability and loss of natural anticoagulants such as antithrombin (AT) and protein C (PC). Damaged endothelial cell releases von Willebrand factor (VWF) that stimulates platelet aggregation. HO-1: heme oxygenase-1.

Figure 2

Mechanism of acute kidney injury in exertional heatstroke In exertional heatstroke, activated inflammation and coagulation result in the formation of immunothrombus in the glomerulus. Neutrophil extracellular traps (NETs) ejection, activated platelets, damaged endothelial cells in addition to the activated coagulation systems play pivotal roles in thrombus formation. The obstruction of the renal artery leads to the ischemic change of the renal tubular system. Furthermore, myoglobin released from disrupted myocytes provides ferrous oxide (Fe²⁺) and Fe²⁺ is oxidized to ferric oxide (Fe3⁺), and finally generates hydroxyl radical. This oxidative potential is counteracted by physiological antioxidant molecules such as heme oxygenase 1 and hemopexin. However, massive myoglobin release leads to the increase of unquenched reactive oxygen species, and free radicals cause tubular cell injury. It has been suggested that heme and free iron–driven hydroxyl radicals are critical mediators of acute kidney injury in exertional heatstroke.

Figure 3

Classification of coagulopathy Various diseases, including infectious to malignant diseases, accompany coagulopathy. Activated coagulation, inflammation, platelets, and endothelial damage are the main factors that induce thrombosis, and the contribution of each element varies depending on the underlying diseases. The common mechanisms are the initial thrombin generation caused by injuries followed by tissue plasminogen activator (t-PA) release. Plasminogen activator inhibitor 1 (PAI-1) production determines the fibrinolytic levels from hypo- to hyperfibrinolytic status. Heatstroke-induced coagulopathy is a type of hypofibrinolytic coagulopathy that can lead to the decompensated status, namely disseminated intravascular coagulation if severe enough.