last revised September 5, 1998

Stroke in Sickle Cell Disease


 Stroke is a devastating and potentially fatal complication to sickle cell disease. Strokes are difficult to explain on the basis of the central pathological process in sickle cell disease, namely the occlusion of small vessels by deformed sickled cells. The key event in this process is polymerization of the deoxygenated form of the molecule with consequent red cell deformation. Hemoglobin deoxygenation and polymerization occurs in the microcirculation and venous system.

 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).

Mechanism of Stroke in Sickle Cell Disease

 A key point at the onset of this discussion is that the etiology of arterial occlusive stroke in patients with sickle cell disease is unknown. Necropsy evaluations shows little or no abnormality of the vascular endothelium in the occluded vessels (6). The arterial lumen is occluded by a thrombus that includes red cells, platelets and fibrin.

 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).

Consequences of Arterial Occlusive Stroke in Sickle Cell Disease

 The involvement of large arteries commonly produces severe neurological deficits. Occlusion of the middle cerebral artery causes dense hemi-paresis and aphasia if the stroke affects the dominant hemisphere of the brain. Cerebral edema with secondary brain stem compression is often fatal.

Head CT scan of a patient 5 days after an MCA strokeThis 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.

Treatment of Stroke

 Stroke is a life-threatening event for patients with sickle cell disease. Exchange transfusion followed by chronic blood transfusion to maintain the level of HbS at <30% is mandatory. Patients with stroke run a risk of recurrence of about 50% in the absence of chronic transfusion (15).

 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.

Stop Trial

 The multicenter Stroke Prevention (STOP) Trial in Sickle Cell Disease was terminated prematurely in September 1997 because the children randomized to receive prophylactic chronic transfusions had substantially fewer strokes than did the untreated controls. The NHLBI issued a clinical alert suggesting that physicians caring for children with sickle cell disease consider instituting yearly examinations by transcranial doppler. A chronic transfusion regimen would be considered for children in which the blood flow rate in the assessed artery is >190 cm/minute (5).

 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:

  1. Iron Overload

  2. Alloimmunization

  3. Delayed Transfusion Reactions
  4. viral infections, including hepatitis and, much less commonly, HIV

 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.

Transcranial Doppler in Adults with Sickle Cell Disease

 Arterial vaso-occlusive strokes are uncommon in adults with sickle cell disease, but do occur. A natural question is whether adults should be surveyed by transcranial doppler to determine whether some meet the 190 cm/minute arterial blood flow criterion of the pediatric studies. Unfortunately, changes in the thickness of skull bones and problems in geometry make impossible the kind of transcranial doppler assessment done in children. As the technology improves, however, means may arise for the assessment of adults who may be susceptible to arterial occlusive stroke.


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