Stroke in patients with sickle cell disease involves large vessels in the arterial circulation (1). The internal carotid artery and the middle cerebral arteries are affected with particular frequency, with devastating consequences. Other vessels commonly compromised are the anterior cerebral and basilar arteries. Blockade of these large arteries by deformed red cells is implausible.
Transcranial doppler studies of children show that high blood flow velocity through these vessels is associated with higher probabilities of arterial occlusive stroke (2, 3). Children with flow rates of >190 cm/minute through the internal carotid artery are at great risk of stroke. The Stroke Prevention (STOP) Trial was designed to determine whether prophylactic transfusions could prevent arterial-occlusive stroke in children in whom the flow rate through the assessed arteries equaled or exceeded 200 cm/sec (4). Those randomized to receive chronic transfusion had significantly fewer strokes than did those observed without transfusion during the study. The results were so convincing that the trial was terminated prematurely and a clinical alert was issued by the National Heart, Lung, and Blood Institute (5).
Red cell adherence to the endothelium mediated by von Willebrand's protein my be important in arterial occlusive stroke in sickle cell disease. Von Willebrand's protein enhances adherence of sickle red cells to endothelial cells (7). This fact concurs with the observation that high rates of blood flow (which produce high linear sheer stress) through the major cerebral arteries correlates with the risk of stroke (2,3).
The membranes of sickle red cells are strikingly abnormal. For instance, the ratio of membrane phospholipids and cholesterol is abnormal in sickle cell disease (8), (9). As a result, sickle red cell membranes have pro-coagulant activity(10). Therefore, a cascade could occur in which von Willebrand's protein promotes sickle red cell/endothelial cell adhesion, which then is a nidus for thrombus formation.
This hypothetical series of events in arterial occlusive stroke would explain the benefit derived from exchange transfusion and subsequent chronic transfusion in patients with arterial occlusive stroke. Removing the abnormal sickle red cells would interrupt this cascade of events in thrombus formation. The prediction that flows from this model is that stopping chronic transfusion would return the risk of stroke to its previous level. This is, in fact, observed (11).
|This is head CT scan was performed five days after a 37 y.o. man with hemoglobin SC disease suffered a stroke due to occlusion of the right middle cerebral artery. The image shows swelling of brain tissue with displacement of the ventricles. The patient expired the next day due to compression of his brainstem.|
The median age at which patients with sickle cell disease suffer stroke is five years (12). Patients who survive strokes show disturbed learning profiles and psychoemotional problems. Children perform poorly in school relative to their peers. Stroke impairs intellectual development (13).
Neovascularization occurs in the areas of the brain that are left underperfused by the stroke. The network of small, delicate vessels that appear as cloud-like puffs on an arteriogram are called "moyamoya." The name derives from a disorder described most often in people of Japanese ancestry in which a similar network of vessels develops idiopathically (14).
The network of vessels in moyamoya have a propensity to rupture. Hemorrhage produces additional neurological deficits. The problem frequently is complicated by pre-existing defalcations from the earlier arterial occlusive stroke. Bleeds from moyamoya can be extremely debilitating and even fatal in patients with sickle cell disease.
Another late complication of arterial occlusive stroke in patients with sickle cell disease is aneurysm in the contralateral circulation. Neural tissue in the region of the brain whose blood flow is compromised by the stroke often remains viable due to blood flow up the contralateral circulation and between the cerebral hemispheres by the Circle of Willis. Aneurysms can develop due to the increase in blood flow rate and arterial wall pressure. Bleeds from these sources are catastrophic and frequently fatal.
The duration of chronic transfusion needed to prevent recurrent stroke is undefined. Cessation of chronic transfusion after as long as five years was associated with a high incidence of recurrent stroke in some studies (16). Clearly, most children do not continue indefinitely with chronic transfusion after a stroke. Many adults with sickle cell disease have a history of stroke in childhood. Very few of these adults continue receive chronic transfusions, however. At some point, often during the transition between pediatric and adult care facilities, chronic transfusions are terminated. One report highlights an experience in which chronic transfusions were stopped in several adults without deleterious consequences (17). Clearly, more data are needed to address this critical question.
The STOP trial is a major step forward in the treatment of patients with sickle cell disease. The prospect of long-term chronic transfusion therapy creates new potential problems for patients with sickle cell disease. Complications of chronic transfusion include:
Iron overload is a substantial problem. Chronic transfusion regimens initiated on the basis of transcranial doppler evaluation would convert children clinically from sickle cell disease to thalassemia major. Chronic transfusion therapy would not only prevent strokes, but would suppress many of the other clinical problems of sickle cell disease, including recurrent vaso-occlusive pain. The major challenge faced by these children would then be transfusional iron overload. The problems of compliance with or intolerance of Desferal® loom as major difficulties in managing these children.