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Page 2 of 20 Akinci et al. Vessel Plus 2021;5:56 https://dx.doi.org/10.20517/2574-1209.2021.20

INTRODUCTION
Intracerebral hemorrhage (ICH) is leakage of blood into the brain parenchyma with or without extension of
blood into the ventricles and/or the subarachnoid space, either spontaneously or as a result of trauma.
Chronic arterial hypertension, cerebral amyloid angiopathy, bleeding diathesis (congenital, acquired,
induced by anticoagulants or antithrombotics), tumors, cerebral venous thrombosis, vasculitis, hemorrhagic
transformation of a recent ischemic stroke, vascular malformations, stimulant drugs (cocaine,
[1-4]
amphetamine, and ecstasy) are etiological factors of spontaneous (also known as non-traumatic) ICH . To
date, there have been no generally accepted criteria for the etiologic classification of spontaneous ICH, but
since chronic arterial hypertension and cerebral amyloid angiopathy are the most common etiological
factors, ICH associated with these two factors has been classified as primary ICH, while ICH attributed to
other factors has been considered secondary [1-3,5] . The focus of this review is primary ICH, which is believed
to result from lipohyalinosis and degenerative changes of the small penetrating arteries associated with
hypertension or amyloid angiopathy with the exception of secondary ICH associated with other causes .
[2]
However, albeit at a low rate, patients receiving antiplatelets or anticoagulants were included in the clinical
studies that we will examine in the following sections.

Primary ICH is commonly seen in the basal ganglia, thalamus, cerebral lobes, brain stem (predominantly
pons), and cerebellum . ICH is a multiple-stage dynamic condition including initial extravasation of blood
[2]
into the parenchyma, followed by bleeding around the clot causing hematoma expansion, and edema or
tissue swelling around the hemorrhage caused by pro-osmotic substances released from the acute
hematoma . The subsequent hematoma expansion after initial ictus, which occurs with a highest rate
[1,2]
within the first 3 h from symptom onset and stabilizes within the first 24 h, has been well documented by
repeated brain imaging techniques in many studies and is associated with neurological deterioration, poor
functional outcomes and increased mortality . Previous data indicate that every 1 mL growth in hematoma
[6]
[7]
can increase the risk of death or disability by 7% . The mechanism of hematoma expansion that therapeutic
interventions are focused on, is not yet clearly understood but is likely related to inflammatory cascade
upregulation resulting in imbalance in hemostatic mechanisms and increased expression of matrix
metalloproteinases causing disruption of physical support by the endothelial basement membrane,
stretching and microscopic rupture of surrounding vessels due to the mass effect of the clot, and intracranial
pressure (ICP) causing disruption of venous outflow and subsequent vascular engorgement . In addition to
[1]
these alleged mechanisms, elevated systolic blood pressure (SBP), termed as acute hypertensive response,
has been shown to increase both hematoma expansion and perihematomal edema in acute ICH patients at
the time of hematoma and is a strong, independent predictor of mortality and disability [8-12] . This has led to
the blood pressure (BP) control, which is considered as an important treatment strategy for the prevention
of ICH, also being topics of extensive studies evaluating the reduction of perihematomal edema, prevention
of hematoma expansion and following mortality and disability in acute ICH patients [13,14] .

ACUTE HYPERTENSIVE RESPONSE
Acute hypertensive response is defined as elevation of SBP above normal (≥ 140 mmHg) and premorbid
values that occurs in the first 24 h after symptom onset in patients with ICH . This highly prevalent
[6]
systemic response (which occurs in almost 75% of ICH patients, regardless of prior history of hypertension),
is self-limiting with spontaneous reduction within few days . Chronic hypertension is the most important
[15]
risk factor for spontaneous ICH . Due to higher prevalence on the basis of premorbid hypertension, it can
[16]
be assumed that in at least a proportion of patients, the acute hypertensive response is a reflection of poorly
treated or undetected chronic hypertension, but spontaneous decrease of initial BP over the next few days in
most patients suggests that other mechanisms associated with stroke itself are responsible. Proposed
underlying causes of acute hypertensive response include: