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Akinci et al. Vessel Plus 2021;5:56 https://dx.doi.org/10.20517/2574-1209.2021.20 Page 3 of 20

(1) Transient or permanent damage to the widely distributed areas responsible for BP regulation including
prefrontal cortex, insula, amygdala, hypothalamus, cingulate cortex, and brainstem (particularly
[6]
ventrolateral medulla and nucleus tractus solitarius) .

(2) Autonomic dysregulation caused by increased sympathetic activity due to subsequent release of renin
and vasoconstriction of arterioles results from direct damage to inhibitory or modulatory brain regions, or
indirect effects of decreased parasympathetic activity leading to reduced baroreceptor sensitivity and
ultimately significant BP variability .
[6]

(3) Raised ICP (especially with brainstem compression) due to acutely increased intracranial volume and
reduced intracranial compliance (Cushing’s reflex) .
[17]

(4) Raised levels of circulating catecholamines and inflammatory cytokines due to stress related to
hospitalization, white coat hypertension, pain, urinary retention, and concominant infection .
[17]
This phenomenon is not specific to ICH, but is associated with all stroke subtypes most likely with
differences in underlying pathophysiology, but among stroke subtypes the prevalence of severe
hypertension is higher in acute ICH patients (in one study, the proportion of patients with initial SBP ≥ 140
[15]
mmHg was 67% in ischemic stroke patients vs. 75% in ICH patients) . This difference is not only
significant in prevalence but also in severity. The Oxford Vascular Study showed that despite similar rates of
chronic hypertension history, the difference between the mean first SBP after stroke onset and the most
recent pre-stroke reading was markedly greater in ICH patients than in ischemic stroke patients (mean 43.5
mmHg vs. mean 17.9 mmHg) and acute-phase SBP was much closer to the usual long-term premorbid
[18]
values in major ischemic stroke patients .

High diastolic blood pressure (DBP) (≥ 90 mmHg) has also been documented in patients with acute ICH
(found to occur in 23.6% of patients admitted with ICH). However, as the available data do not indicate a
clear association between DBP and hematoma expansion, SBP is preferably used to describe the acute
hypertensive response [15,19] .

MECHANISMS UNDERLYING ACUTE HYPERTENSIVE RESPONSE RELATED INJURY
How does acute hypertensive response increase the hematoma expansion? Probably one of the most
probable explanation is that higher systemic BP causes a predisposition to continued intraparenchymal
bleeding and perihematomal edema by transmitting higher hydrostatic pressure to damaged small arteries.
Furthermore, the fact that treatment with hemostatic agents such as intravenous (IV) recombinant activated
Factor VII (rfVIIa) reduces the hematoma expansion rate suggests that there may be additional interaction
between high SBP and the hemostatic system . It has been shown that the renin angiotensin system (RAS),
[20]
which is a peptide hormone system involved in BP regulation and blood volume homeostasis in the
circulation with increased activity in the hypertensive state, acts as a local paracrine system in the brain .
[21]
The systemic and tissue RAS activity increases in hypertensive state . Angiotensin II (Ang II), a powerful
[22]
vasoconstrictor regulated by RAS that increases BP and cerebral blood flow (CBF), increases venous
thrombus formation and exert prothrombotic activity in an experimental model of arterial thrombosis,
possibly due to the fibrinolysis inhibition [22,23] . Despite the increased level of Ang II with prothrombotic
effect, the question of how the hematoma size increases in patients with hypertensive ICH is waiting to be
answered. Increased BP and increased CBF due to the effect of Ang II may impede the hemostasis . Ang
[12]
II-mediated oxidative stress and activation of matrix metalloproteases in the cerebral vessels in the
hemorrhage area may also contribute to hematoma expansion [24,25] .