Cerebral Microbleeds and Thrombolysis

Abstract

Using intravenous thrombolysis in a stroke patient with cerebral microbleeds represents one of the most challenging clinical decisions in acute stroke neurology. In this setting, the implications of coexisting ischemic and hemorrhagic cerebrovascular disease(mixed cerebrovascular disease) 1 must be confronted and urgently addressed. The clinical consequences of intervening or not intervening are profound.What exactly are the consequences? The greatest concern, of course, is the risk of thrombolysis-induced intracerebral hemorrhage. This risk is explored in this issue of JAMA Neurology. In the study by Tsivgoulis et al, 2 the presence of cerebral microbleeds was associated with substantial increased risk of symptomatic intracerebral hemorrhage. Among patients with any number of cerebral microbleeds, risk for symptomatic intracerebral hemorrhage increased more than 2-fold. Among patients with the highest number of microbleeds (more than 10), the risk increased 7-to 12-fold, and likelihood of symptomatic intracerebral hemorrhage increased 18-to 31-fold. This increased risk of symptomatic intracerebral hemorrhage with mixed cerebrovascular disease will certainly give any clinician pause before using tissue plasminogen activator (tPA). Does presence of cerebral microbleeds represent a relative contraindication for tPA? An absolute contraindication for tPA? How does the contraindication depend on the number of microbleeds present? At one level, hemorrhagic risk of thrombolysis in acute stroke is reasonably well understood. Activation of plasmin shifts the hemostatic balance toward fibrinolysis, with resultant mitigation of thrombus generation necessary to maintain vascular integrity. The vasculature is left relatively unprotected to the threat of ischemic injury to vessel integrity, and hemorrhage becomes more likely. At amore subtle level, the proteolytic consequences of plasmin activation include the well-described activation of matrix metalloproteinases, which further enhance ischemic injury to the vasculature. 3 Therefore, hemorrhage in the setting of plasmin activation is no mystery.

Cerebral Microbleeds, Hypertension, and Intracerebral Hemorrhage in Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

“…Moreover, CMB increases with age for all locations in a general population (21), and age may be compounded by important vascular comorbidities for development of CMB (22, 23). Both CADASIL and hypertension have important effects on arteriolar function, with both processes targeting vascular smooth muscle cells (5). …”

“…We recently proposed a “two site” model of CMB and ICH, in which the specific vascular sites for development of CMB and ICH are different (5). In both CADASIL and hypertension, (arteriolar) smooth muscle cells and blood–brain barrier are targeted; the former has been suggested as site for ICH and the latter a site for CMB (5). While the findings of the current study are consistent with this model, further mechanistic investigations are needed to confirm the observation.…”

“…CMB are well-defined MRI-demonstrable brain lesions consisting of tiny perivascular hemosiderin deposits, detectable using T2*-weighted gradient echo or susceptibility-weighted imaging (SWI) (4). CMB are associated with hypertension, cerebral amyloid angiopathy (CAA), and chronic kidney disease (5). CMB are also associated with intracerebral hemorrhage (ICH), which accounts for 20–30% of stroke in Asian countries such as Korea and Japan (6).…”

Cerebral Microbleeds in a Stroke Prevention Clinic

“…Some studies have reported more extensive vascular calcification in both intracranial and extracranial arteries (internal carotid and coronary arteries) in patients with cerebral small vessel disease, including those with CMB [15][16][17]. Vascular calcification could disrupt the ability of brain arterioles to compensate for changes in systemic blood pressure, leading to a rise in the intraluminal pressure within the microvasculature and subsequent erythrocyte extravasation contributing to microhemorrhage formation [9,[18][19][20]. The potential mechanisms relating vascular calcification and CMBs are complex and further studies are needed to gain a better understanding.…”

“…In the current study, we investigated stroke events and the progression of CMB in patients who were initially evaluated and managed in a stroke clinic. We attempted to identify biomarkers for progression of CMB, using a recently proposed conceptual framework in which CMB development is associated with arterial abnormalities related to dysfunctional regulation of cerebral blood flow [9]. We therefore analyzed clinical outcomes and intracranial calcification in patients with CMB.…”