Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage

Table 1

The time phase and pathophysiology of PHE.

Time phases	Time points	Events	Main reasons	Mechanisms	PHE classification	References
Hyperacute	Within a few hours	Clot retraction and mass effect	(i) Increase in the interstitial osmotic pressure.; (ii) Oligemic and metabolic changes.	(i) Transendothelial Na^+ gradient.; (ii) Extracellular accumulation of neurotoxins (e.g., glutamate).	Cytotoxic or ionic edema	[14, 22–25, 90]
Acute	First 2 days	Coagulation cascade	Activation of thrombin and fibrinogens.	(i) Increase in inflammatory mediators (e.g., TNF-α, IL-1β, IL-6, IL-12, and ICAMs).; (ii) Activation of complement mediators (e.g., C3a and C5a).; (iii) Increased expression of matrix metalloproteinases (e.g., MMP-9) and aquaporins (e.g., AQP4).; (iv) Inflammatory cell infiltration.; (v) Free radical generation.	BBB breakdown and vasogenic edema	[14, 16, 22, 32, 33, 35, 37–40, 43, 44, 47, 48, 51, 52]
Delayed	≥3 days	Erythrocyte lysis	Hemoglobin and its degradation products (e.g., heme, ferric iron, and carbon monoxide).	Increase in the response to oxidative stress and the inflammatory response.	BBB breakdown and vasogenic edema	[2, 14, 22, 57–72]

Abbreviations: PHE: perihematomal edema; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; IL-6: interleukin-6; IL-12: interleukin-12; ICAM: intercellular cell adhesion molecules; MMP-9: matrix metalloproteinase-9; AQP4: aquaporin 4; BBB: blood-brain barrier.