Sickle cell disease: Navigating ocular manifestations in women

Sickle cell disease (SCD) is a serious inherited disorder that affects millions of people of African, Mediterranean, and Middle Eastern descent. Two specialists—Mary Ellen Hoehn, MD, professor of ophthalmology in the Department of Ophthalmology at Hamilton Eye Institute at the University of Tennessee Health Science Center in Memphis, and Adrienne W. Scott, MD, from the Retina Division at Wilmer Eye Institute at Johns Hopkins University School of Medicine in Baltimore, Maryland—discussed the clinical diagnosis, manifestations, and treatment of the disease with an eye toward the contributions of ophthalmologists and optometrists to patient care and with particular emphasis on its effects in women.

Systemic effects of SCD

SCD can damage any major organ as a result of abnormal function of sickle cells and their inability to flow normally through small blood vessels. Complications may include increased infections and fever, leg ulcers or serious sores, bone tissue damage or necrosis, early gallstones, kidney damage and impaired urinary concentrating ability, eye damage, multiple organ failure, acute chest syndrome, and anemia.¹

This chronic inflammatory disorder is due to a mutation affecting red blood cell structure; it causes normally disc-shaped red blood cells to become deformed, sickle-shaped cells in certain circumstances, Hoehn described.

The deformation can result in vaso-occlusion and anemia because the cells cannot transport oxygen efficiently, she noted. The inflammation plays a central role in pain crises, organ damage, and vascular complications such as acute chest syndrome.^2,3

Morbidity remains a significant concern in these patients, as daily life can be severely affected by loss of school and work time.

Cardiopulmonary complications remain the major cause of mortality despite newer therapies and improvements in the lifespan of patients with SCD.³ Inflammation has been identified as a major risk modifier in the pathogenesis of SCD-associated cardiopulmonary complications in recent mechanistic and observational studies, according to Gbotosho and colleagues.³

In addition, the vessels in the brain can become occluded and strokes can occur, Hoehn said, underscoring the seriousness of untreated SCD.

Diagnosis

Most cases of SCD are identified at birth through newborn screening. In the US and its territories, SCD is included in routine screening programs.

“The newborn screening process involves a straightforward blood test with electrophoresis. Individuals who may have the carrier state, or sickle cell trait, may not be aware of their SCD status and may never have systemic complications from that; however, they may have some [minimal] clinical manifestations that may become obvious in adulthood,” Scott said.

A symptom commonly seen in affected babies and adults is yellowing of the sclera; the risk of infection and painful crises resulting from vaso-occlusion and ischemia is higher in affected individuals, Hoehn said.

Although a genetic mutation causes SCD, the specific mutation involved can result in variations in its clinical manifestations.

The common genotypes include hemoglobin SS (HbSS; sickle cell anemia), the most severe and most common form, with 2 inherited SCD genes; HbSC, a milder form, with 1 sickle gene and 1 hemoglobin C gene; and HbS β-thalassemia, with 1 or 2 sickle genes and 1 β-thalassemia gene.⁴

“The symptoms are often heterogeneous,” Scott said. “For example, the patients with the highest rates of retinopathy are those with [certain] SCD [genotypes], which are heterogeneous. The homogeneous mutation, HbSS, accounting for about two-thirds of the disease, typically has more symptoms; pain crises, risk of cerebral infarcts, and breathing or kidney issues can manifest from birth.” Patients are usually protected by maternal hemoglobin until the age of 6 months, after which symptoms can manifest.

The milder HbSC accounts for approximately one-third of cases, and symptoms such as pain crises and other complications may never appear, but these patients seem to manifest more of the severe, sight-threatening sickle cell retinopathy, Scott said.

SCD and the eye

Neglected ocular complications of SCD often stem from lack of early screening, such as proliferative sickle cell retinopathy, which is frequently asymptomatic until advanced stages, leading to irreversible vision loss.⁵

In addition to vaso-occlusion mentioned previously, the conjunctiva and vessels in the optic nerve can be affected. “The classic presentation is the affected vessels in the retina. This can result in hemorrhages and scarring,” Hoehn said.

She noted that when the ends of retinal blood vessels become occluded, the vessels cannot provide necessary nutrients, more occlusion occurs, and the vessels become progressively shorter, resulting in retinal ischemia and accumulation of metabolic waste. This results in growth of abnormal new blood vessels, bleeding, and retinal detachments. “Blindness can be the end point if left untreated,” Hoehn said.

Other complications reported in the literature include orbital bone infarction, hyphema, secondary glaucoma, and sickle cell maculopathy.⁵

“Screening for the ocular complications is important, and it is painless. We are still studying the best screening schedule for children. Most children are screened around 10 years of age, and adults definitely need screening annually and more frequently if they have complications from SCD to prevent blinding complications,” Hoehn said.

Al-Jafar and colleagues also noted that the “degree of ocular complications is not necessarily based on the severity of the systemic disease. Both the anterior and posterior segments in the eye can be compromised due to the pathological processes of SCD. However, ocular manifestations in the retina are considered the most important in terms of frequency and visual impairment. Eye complications could be one of the silent systemic SCD complications. Hence, periodic ophthalmic examination should be added to the prophylactic and treatment protocols.”⁵

Systemic SCD therapy

Several promising systemic therapies exist for patients with SCD. Hydroxyurea is the first FDA-approved treatment for SCD shown to increase the production of fetal hemoglobin (HbF), which is the main protein that carries oxygen to the fetus, and reduce hemolysis. Findings from prior cohort studies suggest that systemic management of SCD with hydroxyurea can affect the development and progression of retinopathy.⁶ In a retrospective cohort study, Mian et al⁷ showed that patients with SCD treated with hydroxyurea who had lower HbF were significantly more likely to develop retinopathy. However, if HbF levels were above 15%, the odds of developing retinopathy decreased by 50%.

In 2019, the FDA approved voxelotor (Oxbryta; Pfizer Inc), an oral direct antisickling agent that significantly increased hemoglobin levels compared with placebo in the HOPE trial (NCT03036813).⁸ However, this medication was withdrawn from the market in September 2024 after higher rates of vaso-occlusive crises (VOC) in patients taking voxelotor were noted in postmarketing clinical trials.

Crizanlizumab, a P-selectin antibody that blocks adhesion of blood cells to vascular endothelial cells, was also approved in 2019 after findings from a randomized trial showed it reduced the frequency of VOC for patients with SCD.⁹ However, the STAND trial (NCT03814746), which was another placebo-controlled trial comparing crizanlizumab and placebo, did not find any significant difference in pain crises.¹⁰ The European Union subsequently revoked its initial marketing authorization, and crizanlizumab use in the US remains limited.

L-glutamine, an amino acid known to have greater uptake in sickle cells, was approved by the FDA in 2017 for SCD treatment. It is theorized that L-glutamine reduces oxidative stress, thereby reducing red cell sickling, resulting in a statistically significant decrease in pain crises and hospitalizations in phase 3 clinical trials.¹¹ Although some of these therapies have shown promise for treating systemic SCD, the impact on sickle cell retinopathy is unknown and warrants further study.

Hoehn and colleagues investigated the efficacy of hydroxyurea and chronic transfusions (CTXNs) to reduce sickle cell retinopathy.¹² The background for these treatments is that hydroxyurea increases HbF, thus reducing ischemia, and CTXNs reduce strokes in children with abnormally high intracranial vessel velocities. The investigators hypothesized that the 2 treatments may decrease the risk of development and slow progression of retinopathy.

In their recent large, longitudinal cohort study, the investigators reported that pediatric and adolescent patients with SCD treated with hydroxyurea therapy were “29% less likely to demonstrate sickle cell retinopathy.”¹² Patients receiving CTXNs were 68% less likely to develop SCR. They concluded that “these therapies are associated with a smaller number of patients demonstrating SCR.”

In very severe cases, bone marrow transplantation and, more recently, gene therapy are used. For the latter, the patient’s cells are genetically modified and returned to the body after the bone marrow is ablated (clustered regularly interspaced short palindromic repeats; CRISPR); bone marrow transplantation and use of CRISPR can lead to cures, Hoehn noted.

Both exagamglogene autotemcel (exa-cel; Casgevy; Vertex Pharmaceuticals Inc) and lovotibeglogene autotemcel (lovo-cel; Lyfgenia; bluebird bio Inc) are autologous hematopoietic stem cell–based gene therapies.^13-15 In December 2023, under priority review and fast track designation, each therapy received FDA approval for individuals 12 years or older with SCD who experience recurrent VOC.¹³ Additionally, in January 2024, exa-cel received FDA approval for individuals 12 years or older who have transfusion-dependent β-thalassemia.¹⁶

These 2 genetic therapies represent potentially curative treatments for SCD. Exa-cel works by reactivating HbF using CRISPR-Cas9 gene editing in hematopoietic stem and progenitor cells, thus increasing HbF levels. Lovo-cel is administered via autologous hematopoietic stem cell transplantation and works by encoding a modified β-globin gene that increases production of an antisickling hemoglobin. Although both therapies are highly effective in reducing VOC, those receiving these therapies must first undergo a myeloablative conditioning regimen, which is associated with severe adverse effects. Additionally, these therapies do not appear to reverse pre-existing damage caused by chronic systemic vaso-occlusion, and their very high cost has limited their use.^17,18

Specifically, Scott described the treatment of retinopathy as challenging.

“It can be quite heterogeneous. We can see evidence of retinal changes with the hemoglobin mutation causing retinal ischemia and new neovascularization, which is a precursor to vision-threatening sickle cell retinopathy with vitreous hemorrhages or retinal detachments. These are the sequelae of advanced sickle cell proliferative retinopathy,” she said.

In these patients, laser is the successful gold-standard treatment as in patients with proliferative diabetic retinopathy. In other cases, anti-VEGF therapy, an off-label use of these drugs, can be beneficial for sickle cell retinopathy. Scott uses anti-VEGF in combination as an adjunctive therapy to scatter laser.

Vitrectomy may be necessary in patients with vitreous hemorrhages, or surgery may be necessary for retinal detachment repair.

The treatments are often successful, but although surgeries can help stabilize the disease, they often cannot improve vision, Scott said. She advised using a combination of close monitoring, laser treatment, and anti-VEGF therapy, with surgery as a last resort in the event of unsuccessful medical intervention.

Sex-based differences in SCD

Although no sexual predilection is apparent for SCD, females may have less severe disease manifestations compared with males. Some studies have reported that girls and women have different complications than boys and men with SCD.

“Perhaps one reason for more severe disease or earlier presentation is that some types of sickle cell retinopathy can be more advanced or progress more if there is a higher load of sickle cells; patients with a higher hematocrit value tend to have a higher load of sickle cells. Men tend to have higher hematocrit levels than women and carry a heavier volume of blood,” Scott noted.

One investigation observed differences in sex-based clinical outcomes in a study that included 2124 participants (56% female).¹⁹ The authors reported, “The majority had the Hb SS SCD genotype. Females had worse reports of pain severity (mean (SD) T-score 51.6 (9.6) vs 49.3 (10), P < .001), more VOC episodes (P = .01), and a higher occurrence of three or more hospital admissions in the past year (30.9% vs 25.5%, P = .03). Multivariable analysis showed that males had higher odds of acute chest syndrome (odds ratio (OR) 1.4, P = .002), cardiovascular (odds ratio [OR] 1.70, P < .001) and musculoskeletal (OR 1.33, P = .0034) complications, and lower odds of depression (OR 0.77, P = .0381). Females had higher HbF levels with and without hydroxyurea use (9.6% vs 8.5%, P = .03 and 3% vs 2.2%, P = .0005, respectively).”

Women’s health and SCD

SCD varies among individuals, but women and girls may experience unique complications.^20,21 These include the following:

1. Delayed puberty: Girls with sickle cell anemia may start their menstrual cycles approximately 2 years later than girls who are not affected, whereas those with milder types of SCD may have less delay.²¹
2. More pain crises before and during periods: Many women experience more pain crises just before and during their periods, which may result from changes in hormone levels.²² Hormonal treatment, such as progesterone injections, may help.²¹
3. Heavy periods: Many women with SCD do not have heavy periods; however, for those who do, heavy bleeding may increase the risk of iron-deficiency anemia. Physicians often prescribe birth control pills to lessen heavy menstrual bleeding.²¹
4. Birth control: Not all birth control pills are appropriate for women with SCD due to a higher risk of stroke. Patients are advised to discuss progesterone-only birth control. Birth control with progesterone combined with estrogen may increase the risk of stroke.
5. Fertility challenges: Patients are advised to discuss the risk of premature ovarian insufficiency or diminished ovarian reserve due to microinfarction of the ovaries.²³

A message for eye care clinicians

Scott sends a message to ophthalmologists and optometrists.

“SCD is a unique disease in that the patients are highly heterogeneous; ie, there are those with no evidence of retinopathy and others who are systemically affected by their sickle cell mutation and can have severe retinopathy. Careful patient monitoring is extremely important over time,” she said.

One caveat from Scott is that ophthalmologists and optometrists should be alert to the potential presentation of SCD, despite their practices being in areas where there are few patients in the ethnic groups who are generally affected.

“With mobilization and global migration, it is common for individuals who carry the SCD gene or the trait to mate with individuals and thereby perpetuate their SCD gene,” Scott said. “It is important for physicians to be familiar with the disease and the possible manifestations of retinopathy. It is not possible to tell whom a carrier is based on phenotype.

“A good history and a dilated retinal examination are important; imaging the retinal periphery is important because retinopathy is not diagnosed based on visual acuity,” Scott concluded.

Mary Ellen Hoehn, MD

E: [email protected]

Hoehn is from the Department of Ophthalmology at Hamilton Eye Institute at the University of Tennessee Health Science Center in Memphis. She has no financial interest in this subject matter.

Adrienne W. Scott, MD

E: [email protected]

Scott is from the Wilmer Eye Institute at Johns Hopkins University School of Medicine in Baltimore, Maryland. She has no financial interest in this subject matter.

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