Cerebrovascular disease associated with sickle cell pulmonary hypertension

Abstract

In patients with sickle cell disease, anemia is a recognized risk factor for stroke, death, and the development of pulmonary hypertension. We have proposed that hemolytic anemia results in endothelial dysfunction and vascular instability and can ultimately lead to a proliferative vasculopathy leading to pulmonary hypertension. Consistent with this mechanism of disease, we now report a case series of six patients with obliterative central nervous system vasculopathy who also have pulmonary hypertension and high hemolytic rate. These patients, identified in the course of a prospective screening study for pulmonary hypertension, presented with neurological symptoms prompting neuroimaging studies. Compared to 164 other patients of similar age in the screened population, those with newly diagnosed or clinically active cerebrovascular disease have significantly lower hemoglobin levels and higher levels of lactate dehydrogenase. A review of the literature suggests that many clinical, epidemiological, and physiological features of the arteriopathy of pulmonary hypertension closely overlap with those of stroke in sickle cell disease, both known to involve proliferative vascular intimal and smooth muscle hypertrophy and thrombosis. These cases suggest that cerebrovascular disease and pulmonary hypertension in sickle cell disease share common mechanisms, in particular, reduced nitric oxide bioactivity associated with particularly high-grade hemolysis. Clinicians should suspect occult cerebrovascular disease in sickle cell patients with pulmonary hypertension.

Fig. 1

Watershed infarcts due to cerebrovascular disease in the circle of Willis. Chronic infarcts in the left frontal and left parietal watershed regions are identified in patient 1 on axial FLAIR MRI (arrowheads, a). High-grade focal stenosis of the M1 segment of the left MCA is present on MRA (long arrow – b). A moya–moya type pattern is developing in the territory of the left PCA (short arrow, b).

Fig. 2

Early subacute infarct at the level of the centrum semiovale on axial MRI images performed 16 h after ictus in patient 2. Hyperintense lesion on DWI (arrow, a) suggests acute to subacute infarct, which is confirmed by the restricted diffusion (hypointensity) on the computed ADC map (arrow, b). Hyperintensity on FLAIR indicates subacute to chronic infarct (arrow, c). Other foci of hyperintensity on FLAIR suggest chronic infarcts in the watershed areas of the centrum semiovale (arrowheads). MRA demonstrates high grade stenosis at the left MCA trifurcation (thin white arrow, d) with attenuation of distal MCA branches. Prominence of the distal left PCA branches (black arrows, d) indicates the development of collateral circulation.

Fig. 3

Chronic watershed infarcts resulting from nearly complete occlusion of the cervical internal carotid arteries at the carotid bifurcation. Axial FLAIR MRI from patient 3 demonstrates (a) right frontal cortical infarct and bilateral, left greater than right, chronic infarcts in the white matter of the centrum semiovale at the boundary of the anterior and middle cerebral artery territories. Volume rendered 3D TOF MRA of the intracranial vasculature (b, inferior projection; c, left lateral projection) shows complete absence of flow-related enhancement in the intracranial carotid arteries (asterisk). Note the large vertebrobasilar system and, in particular, the marked enlargement of the posterior communicating arteries that supply collateral flow to the anterior circulation (white arrows). An angiographic “string sign” is seen in the cervical ICA just above the carotid bifurcation (d, left anterior oblique projection of 2D time of flight MRA).