From the National Eye Institute (MA, SY, LJF, RJB, EYC, EDW), National Institutes of Health, Bethesda, Maryland; Retina Group of Washington (MML), Washington, DC; National Heart, Lung, Blood Institute (JP, PS), National Institutes of Health, Bethesda, Maryland; and Walter Reed Army Medical Center (EDW), Washington, DC.
Supported by intramural funding of the National Eye Institute and National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, Maryland.
Dr. Yeh has received support from the Heed Ophthalmic Foundation. The other authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Steven Yeh, MD, Casey Eye Institute, 3375 SW Terwilliger Blvd., Portland, OR 97239.
Aplastic anemia is a rare disease characterized by bone marrow failure with resultant pancytopenia, which may be associated with high mortality if left untreated.1 A bimodal age distribution has been described with a peak onset between 15 and 25 years of age and a smaller peak in patients older than 60 years.2 Aplastic anemia may be an inherited condition, as seen in the autosomal recessive condition Fanconi’s anemia, or an acquired disease following several environmental triggers (eg, B19 parvovirus infection, benzene exposure, or acetazolamide).1
Patients with aplastic anemia are susceptible to malaise and fatigue from severe anemia, hemorrhagic sequelae and bruising due to thrombocytopenia, and infectious complications from neutropenia. Most cases are thought to be due to a T-cell–mediated attack targeting hematopoietic stem and progenitor cells. Current treatment options for aplastic anemia include cyclosporine, horse and rabbit anti-thymocyte globulin, and hematopoietic stem cell transplantation.3,4
Ophthalmic findings associated with aplastic anemia have been reported infrequently, but limited case reports have attributed ophthalmic sequelae to retinal ischemia from severe anemia. Specifically, cotton-wool spots, nerve fiber layer hemorrhages, central retinal vein occlusion, vitreous hemorrhage, neovascular glaucoma, and retinal neovascularization have been described.5–8 Less commonly observed findings have included serous retinal detachment due to aplastic anemia following parvovirus B19 infection,9 optic disc edema,5 and hemorrhagic retinoschisis.10
Herein, we describe the ophthalmic course of three patients with severe aplastic anemia who presented with severe bilateral choroidal ischemia in addition to bilateral vitreous hemorrhages secondary to retinal neovascularization (Table). One patient demonstrated particularly severe retinal findings with bilateral vitreous and submacular hemorrhages with combined rhegmatogenous and tractional detachment prompting surgical management.
Table: Clinical Outcomes of Patients with Aplastic Anemia
A 19-year-old man with a history of aplastic anemia diagnosed in October 2006 presented in March 2007 with blurred vision in both eyes for 10 days. Visual acuities were 20/800 in both eyes. Neovascularization of the iris was not observed. Intraocular pressures were 10 mm Hg in the right eye and 11 mm Hg in the left eye. Dilated funduscopic examination revealed dense vitreous hemorrhages in both eyes. No evidence of retinal detachment was seen on B-scan ultrasound. Laboratory testing revealed hemoglobin of 8.7 g/dL, hematocrit of 24.9%, and platelets of 53,000/μL. Platelet counts varied between 5,000 and 67,000/μL between May and June 2007 with biweekly platelet transfusions and cyclosporine therapy.
In July 2007, visual acuity remained counting fingers in the right eye with a non-clearing vitreous hemorrhage. The patient received a transfusion prior to surgery to a platelet count of 46,000/μL and subsequently underwent pars plana vitrectomy (PPV), membrane peeling, air–fluid exchange, endolaser, and 18% SF6 instillation. Intraoperatively, several large lobular regions of retinal pigment epithelial (RPE) atrophy consistent with choroidal infarction were observed. At 6 months of follow-up, his visual acuity was 20/25 in the right eye. A fluorescein angiogram showed areas of prior choroidal ischemia with lobular RPE atrophy (Fig. 1).
Figure 1. Posterior Pole Photograph of Case 1 (A) and Photograph Superonasal to Optic Nerve of the Right Eye (B) Show Lobular Regions of Retinal Pigment Epithelium Loss with Hypopigmentation and Hyperpigmentation, Consistent with Choroidal Infarction. An Early Venous Phase Fluorescein Angiogram (C) and Late Venous Phase Angiogram (D) Show Hypofluorescence from a Choroidal Vascular Filling Defect and Some Overlying Preretinal Fibrosis Obscuring the Retinal Vessels, Which Appear Tortuous. Posterior Pole (E) and Inferotemporal Photographs of the Left Eye (F) Show Regions of Retinal Pigment Epithelium Loss Consistent with Multiple Lobular Choroidal Infarcts.
The patient subsequently underwent PPV/endolaser with preoperative platelet transfusion to 87,000/μL. At 6 months of follow-up, visual acuity was 20/20 in the left eye. The patient also underwent bone marrow transplant therapy in January 2008 with an improvement in his hematologic parameters to hemoglobin/hematocrit of 12.2 g/dL and 37.1%, platelets of 271,000/μL, and white blood cell count of 3,090/μL with an absolute neutrophil count of 1,700/μL. His ophthalmic examination results were stable at final follow-up with no further vitreous hemorrhage.
A 19-year-old man presented to an emergency department with complaints of acute, bilateral visual loss due to vitreous hemorrhage in both eyes, bleeding gums, and syncope in July 2004. Laboratory evaluation revealed leukopenia with a white blood cell count of 2,500/μL, hemoglobin of 3.3 g/dL, and platelets of 4,000/μL. A bone marrow biopsy showed hypocellular bone marrow with 95% adipose tissue infiltration. The patient was initially treated with blood and platelet transfusions and a course of oral prednisone at a dose of 80 mg for 2 months, but failed to improve his hematologic status. He was subsequently referred in October 2004 when horse anti-thymocyte globulin therapy followed by cyclosporine and sirolimus were initiated.
In October 2004, the patient’s visual acuities were 20/800 in the right eye and 20/80 in the left eye. Ophthalmic examination revealed dense vitreous hemorrhage in both eyes with no ultrasonographic evidence of retinal detachment. The vitreous hemorrhage was observed and resolved over the ensuing 6 months. At 14 months of follow-up, visual acuity improved to 20/20 in both eyes. Diffuse RPE changes involving the posterior pole were seen in both eyes. A fluorescein angiogram showed an area of hypofluorescence within the posterior pole in the right eye, which was consistent with a focal choroidal perfusion defect (Fig. 2). A focal region of hypofluorescence consistent with choroidal hypoperfusion was seen temporal to the fovea in the left eye.
Figure 2. Fundus Photograph of the Right Eye of Case 2 (A) Shows a Large Zone of Retinal Pigment Epithelium Atrophy (white Arrows) Involving the Posterior Pole with Corresponding Hyperfluorescence/window Defect on the Fluorescein Angiogram (B), Consistent with Prior Choroidal Ischemia. A Fundus Photograph of the Left Eye (C) Shows Zonal Retinal Pigment Epithelium Mottling the Surrounding Region of Choroidal Infarction (yellow Arrows) with Choroidal Vascular Non-Filling on the Corresponding Angiogram (D). The Overlying Retinal Vessels Are Perfused and Overlie the Lobular Choroidal Vascular Filling Defect.
The patient’s hematologic parameters responded initially to horse anti-thymocyte globulin followed by cyclosporine and sirolimus. Six months following initiation of this regimen in April 2005, the patient relapsed and underwent peripheral blood stem cell transplant in January 2006 with stabilization of his hematologic parameters. At 44 months of follow-up, visual acuity was 20/20 in both eyes and the ophthalmic examination results remained stable.
A 5-year-old boy was diagnosed as having severe aplastic anemia after presenting to his primary care physician with generalized bruising. Laboratory testing showed hemoglobin of 4 g/dL, platelets less than 10,000/μL, and white blood cell count in the 1,000s. Platelet transfusions were given every 2 weeks and blood transfusions were performed weekly to maintain the hemogoblin around 9 g/dL and platelets around 50,000/μL. Eight weeks following his aplastic anemia diagnosis, the patient developed sudden bilateral visual loss during an episode of severe thrombocytopenia and was referred to our institution. Immunosuppressive therapy was initiated with rabbit anti-thymocyte globulin followed by cyclosporine 125 mg twice a day in December 2007.
Visual acuities were bare light perception in the right eye and hand motions in the left eye. Dense, bilateral vitreous hemorrhage precluded a view of the retina. B-scan ultrasound showed large, serous macular detachments with probable subretinal blood and no evidence of a posterior vitreous detachment in both eyes. Platelets at that time were 75,000/μL. Medical therapy with rabbit anti-thymocyte globulin and cyclosporine and routine platelet and blood transfusions were continued.
One month later, ophthalmic examination results were unchanged. On B-scan ultrasound, a partial temporal posterior vitreous detachment in the right eye and a complete posterior vitreous detachment in the left eye were seen. Stable submacular hemorrhagic detachments were also noted. Platelets were 86,000/μL at this time. Because of concern for amblyopia in the setting of dense non-clearing vitreous hemorrhage in both eyes, the patient underwent PPV, membrane peeling, air–fluid exchange, endolaser, and 20% SF6 instillation in the left eye. A dense submacular hemorrhage, neovascularization of the disc, and neovascularization elsewhere were observed intraoperatively. A tractional retinal detachment was also seen nasally. Multiple zonal areas of RPE atrophy, consistent with choroidal infarction, were also seen. One month following surgery, visual acuity improved to 20/80 in the left eye with minimal resolving vitreous hemorrhage inferiorly and regression of neovascularization of the disc.
One month following this procedure, the patient underwent PPV, membrane peeling, endolaser, and 20% SF6 instillation in the right eye for the non-clearing vitreous hemorrhage and submacular hemorrhage in the right eye after platelet transfusion to 104,000/μL. Intraoperatively, zonal regions of RPE atrophy consistent with choroidal ischemia, neovascularization of the disc, neovascularization elsewhere, and a large submacular hemorrhage with overlying severe fibrosis and vitreous traction were observed. In addition, the peripheral retina was severely atrophic and thinned, likely from chronic retinal ischemia.
One week postoperatively, visual acuity was hand motions but subsequently declined to no light perception 3 weeks following surgery. A recurrent vitreous hemorrhage prevented adequate retinal examination. A repeat B-scan ultrasound was concerning for a retinal detachment and a repeat PPV was performed. At this time, a severely contracted, fibrotic, total retinal detachment with a closed funnel anteriorly and posteriorly was noted. Attempts to attach the retina following PPV and 360° retinectomy were unsuccessful due to the dense anterior and posterior proliferative vitreoretinopathy formation.
At 13 months of follow-up, the patient’s visual acuities were no light perception in the right eye and 20/80 in the left eye. The patient continues to be monitored closely for the development of recurrent vitreous hemorrhage, but the retinal status has remained stable.
Posterior segment findings previously reported in aplastic anemia include vitreous hemorrhage, intra-retinal hemorrhages, retinal neovascularization, central retinal vein occlusion, cotton-wool spots, cystoid macular edema, optic disc edema, and serous retinal detachment.5,6,8,9,11 Mansour et al. previously described 18 patients with aplastic anemia in whom nerve fiber layer or preretinal hemorrhages were the most common ophthalmic findings. Vitreous hemorrhage was found in 13% of patients in their series. They recommended evaluation of blood profiles for patients with these complications; our data support this recommendation because 2 of 3 patients developed vitreous hemorrhage within 2 months of their aplastic anemia diagnosis.
The three patients described in our series demonstrated greater severity of ocular ischemic complications than those cases previously observed and may reflect the severe degree of anemia and thrombocytopenia at various times during their clinical course. The documented hemoglobin nadirs for these patients were 3.3, 4, and 7.5 g/dL and the documented platelet nadirs for these patients were 4,000, 5,000, and 9,000/μL. One prior study suggested that ischemia may jeopardize retinal endothelial cell integrity; concomitant vessel wall dilation and increased blood flow (ie, high cardiac output state seen with severe anemia) may then lead to the extravasation of red blood cells through endothelial tight junctions.5
In our series, retinal neovascularization was observed in cases 1 and 3 and likely resulted in the vitreous hemorrhage observed. Vitreous hemorrhage due to retinal ischemia and its resultant retinal neovascular complications has been documented in other conditions of severe anemia, including sickle cell anemia,12 but choroidal ischemia was the more notable finding in our series and was observed in all eyes. This complication has not been reported previously in association with aplastic anemia.
The choroidal vasculature in the region of the macula provides the highest rate of blood flow of any tissue in the body and is responsible for the metabolic needs of the RPE and outer retinal layers. Normally, oxygenation provided by the high-flow choroidal vascular system greatly exceeds the metabolic demands of the retina; however, in conditions of severe ischemia (eg, ophthalmic artery occlusion with carotid artery disease and malignant hypertension), choroidal infarction with secondary RPE disruption and photoreceptor injury may occur. These findings have also been previously reported in association with disseminated intravascular coagulation.13 It is not clear whether the choroidal ischemia directly contributed to the development of vitreous hemorrhage in these patients; however, vascular endothelial growth factor is up-regulated in RPE cell lines under hypoxic conditions14 and may have contributed to the development of retinal neovascularization in some cases.
Several reports have described vitreous hemorrhage in association with thrombocytopenia that was amenable to vitrectomy in some cases.15–19 Carraro et al. reported that approximately 40% of patients with both thrombocytopenia and anemia demonstrated some form of retinopathy, and the presence of fundus lesions was correlated with the degree of anemia (Hgb < 8 g/dL) and thrombocytopenia (platelets < 50,000 μL).19 Both of these factors may have played a role in the retinopathy observed in this series.
Successful anatomic outcomes were achieved in three of four eyes that underwent pars plana vitrectomy in our series of patients. However, the youngest patient in our series demonstrated the most severe disease and presented with tractional retinal detachments and massive subretinal hemorrhages in both eyes. Although vitrectomy was successful in improving vision in one of his eyes, an irreparable anterior or posterior closed-closed retinal detachment developed following attempted repair in his opposite eye.
This case series highlights the severe choroidal ischemia and posterior segment complications that may occur with severe aplastic anemia. All patients received platelet transfusions prior to surgery and in the postoperative period in our attempts to maintain platelets above 75,000/μL. Despite this goal, these levels were difficult to maintain because both of the patients who underwent vitrectomy surgery required frequent (ie, biweekly) platelet transfusions. Preoperative and postoperative blood transfusions were also required. All three patients required immunosuppressive therapy with or without hematopoietic stem cell transplant for long-term stabilization of the platelet and hemoglobin levels.
Based on this retrospective case series, we would recommend aggressive stabilization of hematologic parameters prior to undertaking vitrectomy in this setting. Expert medical care to optimize the patients’ hematologic parameters is advisable in the perioperative time period because severe anemia and thrombocytopenia may place patients at risk for recurrent vitreous hemorrhage, choroidal ischemia, and further visual compromise.
- Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108:2509–2519. doi:10.1182/blood-2006-03-010777 [CrossRef]
- Brodsky RA, Jones RJ. Aplastic anaemia. Lancet. 2005;365:1647–1656. doi:10.1016/S0140-6736(05)66515-4 [CrossRef]
- Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol. 2006;133:622–627. doi:10.1111/j.1365-2141.2006.06098.x [CrossRef]
- Young NS, Scheinberg P, Calado RT. Aplastic anemia. Curr Opin Hematol. 2008;15:162–168. doi:10.1097/MOH.0b013e3282fa7470 [CrossRef]
- Mansour AM, Salti HI, Han DP, et al. Ocular findings in aplastic anemia. Ophthalmologica. 2000;214:399–402. doi:10.1159/000027532 [CrossRef]
- Yahia SB, Touffahi SA, Zeghidi H, Zaouali S, Khairallah M. Ocular neovascularization in a patient with Fanconi anemia. Can J Ophthalmol. 2006;41:778–779. doi:10.3129/I06-078 [CrossRef]
- Chan WM, Liu DT, Tham CC, Wu RM, Lam DS. Bilateral subhyaloid haemorrhage in aplastic anaemia. Br J Haematol. 2003;123:757. doi:10.1046/j.1365-2141.2003.04531.x [CrossRef]
- Bahar I, Weinberger D, Kramer M, Axer-Siegel R. Retinal vasculopathy in Fanconi anemia: a case report. Retina. 2005;25:799–800. doi:10.1097/00006982-200509000-00023 [CrossRef]
- Suzuki J, Goto H, Usui M, Sakai J. Serous retinal detachment in a patient with aplastic anemia associated with parvovirus B19 infection. Graefes Arch Clin Exp Ophthalmol. 2007;245:324–326. doi:10.1007/s00417-006-0315-5 [CrossRef]
- Wong VG, Bodey GP. Hemorrhagic retinoschisis due to aplastic anemia. Arch Ophthalmol. 1968;80:433–435.
- Lilley ER, Bruggers CS, Pollock SC. Papilledema in a patient with aplastic anemia. Arch Ophthalmol. 1990;108:1674–1675.
- Goldberg MF. Retinal neovascularization in sickle cell retinopathy. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol. 1977;83: OP409–OP431.
- Kinyoun JL, Kalina RE. Visual loss from choroidal ischemia. Am J Ophthalmol. 1986;101:650–656.
- Ikeda Y, Yonemitsu Y, Onimaru M, et al. The regulation of vascular endothelial growth factors (VEGF-A, -C, and -D) expression in the retinal pigment epithelium. Exp Eye Res. 2006;83:1031–1040. doi:10.1016/j.exer.2006.05.007 [CrossRef]
- Ohnishi A, Kaneko M, Hori S, Teramura M, Kato S. Vitrectomy for vitreous bleeding and tractional retinal detachment in a case of Evans syndrome. Jpn J Ophthalmol. 2000;44:177–179. doi:10.1016/S0021-5155(99)00186-0 [CrossRef]
- Simon J, Sood S, Yoon MK, et al. Vitrectomy for dense vitreous hemorrhage in infancy. J Pediatr Ophthalmol Strabismus. 2005;42:18–22.
- Ackerman J, Goldstein M, Kanarek I. Spontaneous massive vitreous hemorrhage secondary to thrombocytopenia. Ophthalmic Surg. 1980;11:636–637.
- Okuda A, Inoue M, Shinoda K, Tsubota K. Massive bilateral vitreoretinal hemorrhage in patient with chronic refractory idiopathic thrombocytopenic purpura. Graefes Arch Clin Exp Ophthalmol. 2005;243:1190–1193. doi:10.1007/s00417-005-1183-0 [CrossRef]
- Carraro MC, Rossetti L, Gerli GC. Prevalence of retinopathy in patients with anemia or thrombocytopenia. Eur J Haematol. 2001;67:238–244. doi:10.1034/j.1600-0609.2001.00539.x [CrossRef]
Clinical Outcomes of Patients with Aplastic Anemia
|Case||Age at Diagnosis (Y)||Gender||Eye||Initial VA||Final VA||Ophthalmic Findings||Intervention||Total Follow-up (Mo)|
|1||19||M||OD||20/800||20/25||NCVH, NVE, NVD, choroidal ischemia||PPV/MP/AFx/EL/SF6||15|
|OS||20/800||20/20||NCVH, NVE, NVD, choroidal ischemia||PPV/MP/AFx/EL/SF6|
|2||19||M||OD||20/800||20/20||VH, choroidal ischemia||Observation||44|
|OS||20/80||20/20||VH, choroidal ischemia||Observation|
|3||5||M||OD||BLP||NLP||NCVH, NVD, NVE, submacular hemorrhage with overlying fibrosis and traction, peripheral retinal thinning with multiple retinal tears, choroidal ischemia||PPV/MP/AFx/EL/SF6||15|
|OS||HM||20/80||NCVH, NVD, NVE, submacular hemorrhage, nasal TRD, choroidal ischemia, peripheral retinal thinning||PPV/MP/AFx/EL/SF6|