More Than Meets the Eye Cerebrovascular Disease in Sickle Cell Disease Is About More Than Sickling

Abstract

A 56-year-old male with a known history of sickle cell disease (SCD) with HbSC and progressive deafness presented to the hospital with increased left-sided weakness accompanied by worsening confusion for the past 5 days. He experienced a multiorgan crisis requiring plasmapheresis 10 years prior.

He had lived independently until moving in with his brother because of progressive cognitive problems.

On presentation, he appeared mildly confused, with mild bilateral proximal weakness, and scored a 3 on the National Institutes of Health Stroke Scale.

Laboratories

Hemoglobin was 12.9, and peripheral blood smear showed occasional sickle cells. Serum electrophoresis demonstrated 52% hemoglobin S (HbS) and 44.7% hemoglobin C (HbC).

Imaging

Magnetic resonance imaging (MRI) brain revealed multifocal punctate areas of restricted diffusion of acute infarction affecting the deep white matter and the cortex. These were superimposed on diffuse volume loss and multifocal areas of old lacunar infarction (Figure 1). Computer topographic angiography showed severe stenosis in the right superior division of the middle cerebral artery and moderate stenosis in the distal aspect of bilateral anterior, middle, and posterior cerebral arteries (Figure 2). His transesophageal echocardiogram was normal, and transcranial Doppler (TCD) showed no evidence of vasospasm or elevated velocities.

Figure 1.

Axial diffusion-weighted imaging showing multiple areas of restricted diffusion consistent with multifocal acute ischemia.

Figure 2.

Computed tomographic angiogram showing multifocal stenosis in different vascular territories most pronounced in the left internal carotid artery terminus.

Clinical Course

He appeared stable with no obvious changes on clinical examination. The hematology team was consulted, but they did not think he was a candidate for exchange transfusion given his normal HgB, normal MCV, few peripheral sickle cells, and most importantly, because of compound heterozygosity with HbC. Given the uncertainty of stroke pathogenesis and lack of treatment consensus, repeat brain imaging was performed demonstrating new punctate areas of restricted diffusion (Figure 3). Updated TCDs remained stable.

Figure 3.

Axial diffusion-weighted imaging (DWI; left) at initial presentation demonstrating scattered restricted diffusion consistent with acute ischemia. Axial DWI (right) obtained 1 wk later illustrates new areas of restricted diffusion in the left lentiform nuclei.

Considering his progressive injury, further hematologic opinion was pursued and partial RBC exchange transfusion initiated. After 2 rounds of exchange transfusion, repeat electrophoresis showed HbC decreased to 27% and HbS to 32.9%. He was discharged to a skilled nursing facility.

Unfortunately, 3 months later, the patient passed away because of urosepsis. His serum electrophoresis showed an HbS of 37%.

Discussion

SCD is an inherited hemoglobinopathy where there is a qualitative disorder in either the α or the β globin chain. HbS is the most important inherited hemoglobinopathy in the United States followed by HbC. β-Globin gene can be homozygous (HbSS), commonly referred to as sickle cell anemia , or heterozygous sickle cell trait, HbSC and HbS-thalassemia. Stroke is a major complication of SCD and most frequently seen in HbSS in up to 25% in these patients followed by the thalassemias and HbC.^1,2 Understanding the mechanism of stroke is crucial to prevent their recurrence. Several risk factors increase the likelihood of strokes in patients with SCD, including cerebral vasculopathy, elevated TCD velocities, anemia, leukocytosis, evidence of silent infarcts, and traditional cardiovascular risk factors.²

Our patient’s presentation of a progressive cognitive decline is consistent with the severe leukoaraiosis seen on MRI. The lateralizing findings on his neurological examination corresponded to his acute multifocal strokes. The presentation of multifocal recurrent strokes within 2 weeks of maximal medical management did not fit the typical pattern observed in intracranial atherosclerosis. Although his leukoaraiosis could be partially attributed to his one known vascular risk factor (hypertension), his symptom progression and history of HbSC suggested the alternative pathogenesis of symptomatic SCD.

Underlying pathogenesis of cerebrovascular disease in SCD involves both large vessel as well as penetrating (small) artery disease. Small-vessel infarction in SCD is thought to involve immature red cell congestion at the postcapillary venules. This causes backward propagation, delayed transit and, ultimately, more red cell sickling.³ Large artery vasculopathy seen in SCD is not clearly understood although proposed hypotheses include a mechanical response because of a mixture of oxygenated and deoxygenated, polymerized clumped red cells, platelets, white blood cells, and thrombin. Both large-vessel vasculopathy and small-vessel occlusion have been attributed to abnormal adherence to the endothelium, reperfusion injury, promotion of a hypercoagulable state, hemolysis, and impaired vasomotor tone.⁴ Silent infarcts often contribute to the progressive cognitive decline that affect patients with SCD.

The primary event in the pathogenesis of sickle cell anemia is the polymerization of the sickle cell (HbS) mainly in the deoxygenated state of the erythrocyte. Thus, the sickle cell obstructs the vessels and shortens the erythrocyte’s life span, leading to diffuse vasculopathy and tissue damage in various organs.⁵

Downstream hypoxia, however, is not the same phenomenon that occurs in HbSC patients. Heterozygosity with HbS or HbC traits are associated with a less severe phenotype and therefore generally considered benign.

However, the combination of these 2 relatively benign conditions (HbSC) result in significant clinical and physiological abnormalities that are distinct from HbSS. HbC enhances the formation of intracellular polymer of HbS by dehydrating the cell. Moreover, a slower rate of hemolysis and longer erythrocyte half-life in HbSC result in a higher hemoglobin level and MCHC-generating hyperviscosity.⁵

The clinical manifestations seen in HbSC disease are generally milder than HbSS and occur later in life. Nonetheless, retinitis proliferans, osteonecrosis, and acute chest syndrome often have a higher incidence in HbSC disease than in HbSS. Ischemic stroke rates are 2% to 3% and are higher than the general population.⁶ Increased blood viscosity compromising the blood oxygen delivery to the terminal arteries in the cochlea is a possible explanation of the patient’s progressive hearing loss.⁵ It could be argued that a similar mechanism explains central nervous system ischemic insult although this remains to be established.

Given the uncertainty of pathogenesis, many questions remain on how to treat, or better yet, prevent the ischemic complications seen in SCD. Initially, the hematology team did not think that our patient was a candidate for exchange transfusion or phlebotomy based on lack of anemia (HGB>10). However, the proportion of HbS rather than absolute blood counts is more relevant. The role for exchange transfusion in the prevention of stroke is clearly established in pediatric population with SCD. When TCD velocities >200 cm/s are demonstrated on 2 repeated studies, children should undergo exchange transfusion. More than a 10-fold reduction in recurrent stroke is observed if HbS concentration is maintained <30% of their total hemoglobin. Prophylactic transfusions are supported until the age of 16 years.⁷ Discontinuation of exchange transfusions has been associated with an increased incidence of strokes, creating controversy on when (if ever) to stop prophylactic transfusions. Chronic transfusion therapy must be weighed against the risks of blood borne pathogens, alloimmunization, and hemosiderosis.

The appropriate primary and secondary stroke prevention strategies in adults with SCD have not been widely studied. A TCD velocity criterion is still lacking in adults. Adult studies concluded that TCD velocities in adults were lower than in children with SCD, and velocity criterion used in children cannot be used to stratify stroke risk in adults.⁸

The American Heart Association and American Stroke Association recently recommended treating all SCD patients with intravenous alteplase after reviewing new evidence for the first time this year.⁹ Otherwise, the initial acute management of strokes in adults remains blood transfusion if MRI shows evidence of acute stroke. If the Hgb <10 g/dL, simple blood transfusion is performed followed by exchange transfusion.¹⁰ If Hgb >10 g/dL, a partial or complete exchange transfusion can be offered.

Specific management recommendations of HbSC disease do not exist. Many physicians think that HbSC disease is a mild form of SCD without any significant clinical consequence as occurred in our case. However, HbSC disease is a unique disease entity from sickle cell anemia. Management of HbSC disease is under investigation. Some preliminary data suggest rehydrating HbS to decrease polymerization, as well as the effects of oral magnesium supplementation to optimize the K-Cl transport system.⁶

Secondary prevention of stroke includes repeat MRI brain in 30 days to assess for recurrent strokes and if there is evidence of new infarcts, initiation of monthly exchange or simple transfusions. Guidelines for the long-term use of partial RBC exchanges and the subsequent use of hydroxyurea have not been determined in this disease. Simple therapeutic phlebotomy to target the Hgb to 9.5 to 10.0 g/dL has also been used successfully in the prevention of multisystem organ damage in HbSC disease. However, management of HbSC disease is currently based on treatment of sickle cell anemia with a goal to reduce HbS to <30%. Annual MRI scans are reasonable in patients with no obvious clinical changes. Aggressive treatment of all cardiovascular risk factors is warranted in all patients with SCD; however, it is important to note that antiplatelet therapy in patients with SCD is generally contraindicated because of the increased risk of hemorrhagic strokes. The goal of therapy is to either reduce polymerization of HbS or hyperviscosity.

TEACHING POINTS.

• Patients with sickle cell disease and acute ischemic stroke symptoms who are otherwise lytic candidates should receive alteplase.

• Exchange transfusions in the acute phase to achieve hemoglobin S <30% followed by prophylactic simple transfusions are reasonable secondary prevention measures.

• Other vascular risk factors should be managed aggressively, and routine follow-ups should be performed in patients with sickle cell disease to rule out any silent infarctions that could also trigger transfusions because this might prevent long-term cognitive decline.

• HbSC disease should not be considered a benign entity or a mild form of sickle cell anemia but as a separate hemoglobinopathy disorder with its own pathogenesis and presentation.