Hemolytic Glaucoma Following Intravitreal Aflibercept Injection for Age-Related Macular Degeneration: A Case Report

Introduction

Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the standard treatment for neovascular age-related macular degeneration (AMD), with major trials showing significant visual improvement and a strong safety profile [1,2]. Although the therapy is generally considered safe, rare cases of anterior chamber hemorrhage have been reported soon after injection [3–5]. These events typically occur within hours to several days, are mild, and resolve without surgical intervention.

Early-onset hyphema can occur, and intraocular pressure (IOP) elevation can arise from hemolytic glaucoma, a secondary open-angle glaucoma caused by obstruction of the trabecular meshwork by hemolyzed erythrocyte debris, free hemoglobin, and hemosiderin-laden macrophages [6–9]. Prolonged intraocular hemorrhage can also lead to the chronic variant known as ghost cell glaucoma [9–11], now recognized as part of a shared posthemorrhagic spectrum rather than a distinct disorder [8].

These complications are reported primarily in eyes with proliferative diabetic retinopathy (PDR), in which vitreous hemorrhage (VH) is common. Xu et al found that approximately 11% of PDR eyes developed ghost cell glaucoma after intravitreal ranibizumab injection [12], and Liu et al noted similar mechanisms in postoperative VH after vitrectomy for PDR [13]. Conversely, neither hemolytic glaucoma nor ghost cell glaucoma has been described after anti-VEGF injection for AMD, in which VH is uncommon.

In this study, we report a rare case of marked IOP elevation associated with hyphema developing several days after intravitreal aflibercept injection for AMD, highlighting that hemolytic glaucoma, although uncommon, can occur following anti-VEGF therapy.

Case Report

A 54-year-old man with a history of epilepsy was referred to our clinic after being diagnosed with exudative AMD in the right eye at a local ophthalmology clinic following concerns of decreased vision. At presentation, best-corrected visual acuity (BCVA) in the right eye was 20/125, and IOP was 18 mmHg. All IOP measurements in this case were obtained using a non-contact tonometer. Slit-lamp examination revealed a cataract with nuclear sclerosis graded as Lens Opacities Classification System III nuclear opacity grade 2, which contributed mildly to visual impairment but still allowed adequate fundus visualization. Fundus examination demonstrated type 2 macular neovascularization with subretinal hemorrhage (Figure 1A). The optic disc was large, with a correspondingly large physiologic cup, but the neuroretinal rim appeared intact without features suggestive of glaucomatous damage. Optical coherence tomography (OCT) confirmed subretinal fluid and subretinal hemorrhage involving the fovea (Figure 1B, 1C).

Intravitreal aflibercept was (2.0 mg/0.05 mL) initiated, with 3 monthly loading injections followed by a treat-and-extend regimen. Each injection was administered using a 30-gauge needle via the superotemporal quadrant, 3.5 to 4.0 mm posterior to the limbus, under topical anesthesia following standard povidone-iodine antisepsis. After the loading phase, BCVA improved to 20/33. Because exudative changes recurred whenever the injection interval was extended, meaningful lengthening was not possible. One year after the initial visit, before the tenth intravitreal aflibercept injection, fundus examination showed resolution of subfoveal hemorrhage with fibrotic change, and OCT confirmed a dry macula (Figure 1D–1F). The injection was uneventful. In addition, spectral-domain OCT obtained during the treatment course demonstrated normal retinal nerve fiber layer and ganglion cell–inner plexiform layer (GCIPL) thickness profiles, without evidence of glaucomatous structural damage (Figure 1G, 1H). Gonioscopy was not performed during the clinical course.

On day 3 after the injection, the patient developed blurred vision, progressing to marked visual loss on day 4. BCVA had declined to hand motion, and IOP was 20 mmHg. Slit-lamp examination revealed a hyphema with a fluid level, and the fundus was not visible (Figure 2A, 2B). Although many erythrocytes were present in the anterior chamber, distinct khaki-colored ghost cells were not identified. Oral carbazochrome sodium sulfonate hydrate (30 mg, 3 times daily) was initiated as conservative therapy. By day 7 after the injection, however, the IOP had risen to 50 mmHg. Medical therapy – including topical and systemic antiglaucoma agents – was considered at that time. However, given the persistent severe visual loss (hand motion), the rapid rise in IOP to 50 mmHg, and concern that medical therapy alone would not promptly eliminate the intraocular source of hemolyzed blood, surgical intervention was prioritized after discussion with the patient.

Preoperatively, the fundus remained obscured by hyphema. Intraoperatively, anterior chamber irrigation improved visualization and revealed a mild VH. Although anterior chamber irrigation alone was initially considered, pars plana vitrectomy was performed to remove VH as a potential source of hemolyzed or degenerating erythrocytes contributing to secondary open-angle glaucoma and to prevent recurrent IOP elevation. Because the lens exhibited moderate nuclear sclerosis (grade 2), which was expected to impair intraoperative visualization, phacoemulsification was combined with vitrectomy to secure a clear surgical view. The posterior pole was visible, with mild VH extending temporally to inferiorly (Figure 3A). With temporal scleral indentation, a localized blood clot adherent to the pars plana and vitreous base in the superotemporal-to-inferotemporal quadrant was identified, corresponding to the injection site (Figure 3B). Because posterior vitreous detachment was absent, an artificial posterior vitreous detachment was created, and the hemorrhage was removed as completely as possible. No air or gas tamponade was used.

On postoperative day 1, right eye IOP had decreased to 10 mmHg. Two weeks after surgery, BCVA had improved to 20/20, and the IOP was 20 mmHg. The patient declined further aflibercept treatment and was monitored, without additional injections. During 1 year of follow-up, no recurrence of VH or exudative activity occurred. At the final 1-year follow-up, BCVA was 20/16, and IOP was 18 mmHg, and fundus photography and OCT demonstrated a stable macular appearance without recurrent exudation. GCIPL thickness remained within the normal range, indicating no structural damage related to the transient IOP elevation (Figure 4A–4D). A detailed chronological summary of the clinical course, visual acuity, IOP, and management is provided in Table 1.

Discussion

IOP elevation secondary to injection-related intraocular hemorrhage after intravitreal anti-VEGF therapy for AMD is exceedingly rare. Most reports describe mild, self-limiting hyphema occurring within hours to several days after injection and resolving without surgery [3–5]. By contrast, secondary glaucoma related to intraocular hemorrhage has been reported mainly in eyes with PDR, in which VH is common [12,13]. To the best of our knowledge, however, hemolytic glaucoma has not been documented following anti-VEGF injection for AMD.

The intraocular bleeding observed in the present case likely reflected combined mechanical and fluid-dynamic factors, with the intraoperatively identified VH serving as the primary source. Two mechanisms may explain the VH. First, iatrogenic injury to peripheral retinal or ciliary body vessels in the superotemporal quadrant could have produced localized bleeding at the vitreous base. Even minimal variation in needle angle or depth can injure pars plana vasculature, and, as noted by Ranchod et al, anteriorly directed needle entry can result in hemorrhage extending toward the posterior or anterior chamber rather than remaining confined to the vitreous cavity [3]. Second, transient IOP spikes and fluid-dynamic changes during injection may trigger breakthrough VH from fragile vascular complexes, particularly in eyes with hemorrhagic macular disease [14]. In this case, however, the subretinal hemorrhage associated with choroidal neovascularization had resolved before the tenth injection, making breakthrough VH less likely. The intraoperative finding of a localized clot at the superotemporal vitreous base near the injection site supports iatrogenic vascular injury as the predominant mechanism.

Transient IOP elevation after intravitreal anti-VEGF injection is well documented, typically occurring within minutes of the procedure [15,16]. These short-lived pressure surges cause abrupt IOP and volume shifts that can disrupt the posterior chamber–anterior hyaloid interface [17]. Without posterior vitreous detachment, such disruption could permit anterior migration of erythrocytes from the vitreous base toward the posterior and anterior chambers. Although VH was mild, erythrocytes entering the anterior chamber likely underwent hemolysis, producing hemoglobin and macrophage-mediated debris that obstructed the trabecular meshwork, resulting in acute IOP elevation consistent with hemolytic-type secondary glaucoma. Thus, a small vitreous-base hemorrhage, combined with transient IOP elevation and a fragile anterior hyaloid interface, likely enabled erythrocyte migration into the anterior chamber and led to hemolytic-type secondary glaucoma.

After intraocular bleeding, erythrocytes in the vitreous cavity or anterior chamber gradually undergo lysis, releasing hemoglobin and pigmentary degradation products. Once these hemolytic materials enter the anterior chamber, they can obstruct the trabecular meshwork and elevate IOP, inducing hemolytic glaucoma [6,7]. With longer-standing hemorrhage, intact erythrocytes may instead degenerate into rigid, depigmented “ghost cells” containing denatured hemoglobin, which can migrate into the anterior chamber and further impede aqueous outflow [9–11]. These processes form a posthemorrhagic spectrum ranging from hemolytic to ghost cell glaucoma [8]. In the present case, although numerous erythrocytes were present in the anterior chamber, distinct khaki-colored ghost cells were not observed, suggesting that IOP elevation occurred during an earlier hemolytic phase before erythrocyte transformation – consistent with the short interval between hemorrhage onset and surgery. Collectively, these findings indicate that a small vitreous-base hemorrhage, followed by hemolysis and anterior migration of blood components, led to trabecular meshwork obstruction and acute IOP elevation. However, gonioscopy was not performed either at baseline or at the time of intraocular hemorrhage. Acute-phase gonioscopy was not feasible because the dense anterior chamber hemorrhage obscured angle structures, preventing meaningful assessment. The absence of baseline and acute-phase angle evaluation represents a limitation in fully excluding other mechanisms of secondary glaucoma. Despite this limitation, other causes of secondary open-angle glaucoma, such as angle recession or inflammatory glaucoma, were considered less likely given the absence of ocular trauma, uveitic signs, or sustained anterior segment inflammation, together with the acute temporal association with intraocular hemorrhage and the rapid normalization of IOP after surgical removal of hemorrhagic material. The overall clinical course and imaging findings remained consistent with hemolysis-related trabecular meshwork obstruction. In addition, IOP measurements were obtained using non-contact tonometry, which may be less reliable in the presence of corneal edema. However, given the magnitude of pressure elevation and its rapid normalization after surgical removal of hemorrhagic material, a true pathological increase in IOP was considered most likely. A schematic summary of this proposed mechanism is shown in Figure 5.

Management of secondary glaucoma after intraocular hemorrhage depends on IOP elevation severity and the bleeding source. Mild cases may respond to medical therapy and observation, whereas persistent or marked elevation requires surgery to remove the intraocular reservoir of hemolyzed blood [8]. In our patient, the IOP remained within the normal range (20 mmHg) on day 4 after the intravitreal injection, although visual acuity had decreased due to hyphema. Therefore, only oral carbazochrome sodium sulfonate hydrate was initiated as conservative therapy at that time. However, the IOP rose sharply to 50 mmHg on day 7 after the injection. Although the use of antiglaucoma medications, including topical agents and oral carbonic anhydrase inhibitors, was considered, the patient’s visual acuity had already deteriorated to hand motion, and the patient strongly preferred early surgical treatment. Anterior chamber irrigation was performed first, which allowed partial visualization of the fundus and revealed mild vitreous hemorrhage. Although the anterior chamber was the primary site of obstruction, we judged that anterior chamber irrigation alone would provide only temporary IOP control because the residual vitreous hemorrhage could continue supplying hemolyzed erythrocytes into the anterior chamber, leading to recurrent pressure elevation. Therefore, pars plana vitrectomy was performed to definitively remove the posterior segment source of hemolyzed blood and prevent recurrent hemolytic trabecular obstruction.

In addition, the lens exhibited grade 2 nuclear sclerosis, which was expected to compromise intraoperative visualization during vitrectomy. Consequently, phacoemulsification was combined with vitrectomy primarily to secure a clear operative view and facilitate complete removal of vitreous hemorrhage, rather than for visual rehabilitation. Previous studies have shown that combined phaco-vitrectomy can achieve comparable safety and visual outcomes while reducing overall treatment burden, compared with sequential surgery [18]. Moreover, cataract progression after pars plana vitrectomy is well recognized in phakic patients over 50 years of age, even when the crystalline lens is preserved, with nuclear sclerosis progressing more rapidly in older patients [19]. Accordingly, combined phacoemulsification and vitrectomy is commonly selected in appropriate cases in Japan, where the universal health insurance system may also reduce the financial burden of a single combined procedure, compared with staged surgeries. In the present case, combined surgery was selected primarily based on intraoperative visualization requirements and the need for definitive management of vitreous hemorrhage, while healthcare system considerations may have provided an additional practical advantage.

This combined approach successfully normalized IOP and prevented recurrence. Although anterior chamber irrigation alone could have offered temporary IOP control, the choice of surgical approach – irrigation alone versus combined vitrectomy – should be individualized based on the extent of hemorrhage, IOP dynamics, visual function, and patient preference. The present case highlights the need for further clinical experience to better define optimal management strategies for secondary glaucoma following intraocular hemorrhage.

This case underscores that even limited hemorrhage after intravitreal injection can cause substantial IOP elevation through hemolytic mechanisms. Prompt recognition and timely intervention are crucial to preventing irreversible glaucomatous damage. Further accumulation of similar cases may help clarify the pathophysiology of hemolytic glaucoma following anti-VEGF therapy for AMD and aid in establishing optimal management strategies.

Conclusions

This case shows that hemolytic glaucoma can occur even after intravitreal anti-VEGF injection in eyes with age-related macular degeneration, a scenario in which intraocular bleeding is uncommon. Although it is rare, clinicians should remain vigilant for postinjection IOP elevation. Careful anterior segment assessment and timely surgery when medical therapy fails can result in favorable visual and pressure outcomes. Greater awareness of this potential complication may help refine monitoring strategies after anti-VEGF injections, particularly when visual symptoms or anterior chamber changes arise in the days following treatment.