**3. Pathophysiology**

When ICH occurs, blood leaks into the brain parenchyma, leading to the formation of hema‐ toma, which quickly increases intracranial pressure. The accumulated blood and high intracranial pressure cause immediate primary damage to the brain. This initial injury is followed by secondary damage mainly resulting from inflammatory responses [102, 103]. The exposure of brain parenchyma to blood proteins (e.g., proteases and hemoglobin) and cells (red blood cells and leukocytes) results in activation of microglia, and the secretion of proinflammatory cytokines/chemokines [104, 105], including TNF-α, IL-1β, and MCP1/CCL2. These inflammatory mediators, by forming a concentration gradient, activate and attract more microglia and other inflammatory cells to the injury site [106]. These cells then accumulate around the hematoma, forming a barrier to prevent the spread of injury to other sites. The released pro-inflammatory cytokines/chemokines and possibly activated microglia also act on BMECs, pericytes and astrocytes, leading to compromise of BBB integrity. Through the disrupted BBB, peripheral leukocytes infiltrate into the brain. The infiltrated leukocytes together with activated microglia produce more pro-inflammatory mediators, which induce cell death in the penumbra area [107, 108]. In addition, hemolysis of red blood cells causes iron deposition in the brain parenchyma and subsequent lipid peroxidation [109]. Free radicals generated during lipid peroxidation also lead to cell death and contribute to ICH-induced brain injury [110, 111]. With the progress of disease, microglia and infiltrated leukocytes change their gene expression profile from pro-inflammatory to anti-inflammatory and clear up the dead cells via phagocytosis [110, 112]. The clearance of cell debris finally leads to the resolution of the hematoma and repair of damaged tissue. At this stage, the activated inflam‐ matory cells revert to a resting state again. Due to the limited regenerative ability of neurons, however, most neurological functions cannot be recovered, which explains the high extent of disability after ICH.
