Acute Diffuse Retinal Hemorrhage Following Intravitreal Conbercept Injection: A Case Report and Mechanistic Analysis

Summary

This case report describes a rare adverse event of acute diffuse retinal hemorrhage in a patient with multiple comorbidities following a series of anti-VEGF treatments. The report explores this adverse event's possible mechanisms, clinical presentation, management, and outcomes.

Abstract

Acute diffuse retinal hemorrhage is a rare but potentially serious complication following intravitreal anti-vascular endothelial growth factor (anti-vascular endothelial growth factor [VEGF]) therapy. Conbercept, a recombinant fusion protein, has been widely used for treating various retinal vascular disorders and has demonstrated both clinical efficacy and safety. Despite its widespread use, isolated reports of acute retinal hemorrhage post-injection have raised concerns. The case report presented here describes an episode of acute diffuse retinal hemorrhage occurring 24 h after the 12^th intravitreal conbercept (IVC) injection in a patient. The patient's significant risk factors included a long-standing history of poorly controlled diabetes mellitus, chronic hypertension, and advanced proliferative diabetic retinopathy (PDR). The patient had undergone pan-retinal photocoagulation in both eyes and received 11 bilateral IVC injections (0.5 mg/0.05 mL per eye) over a 12-month period. This report examines the underlying mechanisms, clinical course, and management, emphasizing the importance of personalized strategies for complex cases.

Introduction

This case report details an episode of acute diffuse retinal hemorrhage occurring 24 h after the 12th intravitreal conbercept (IVC) injection in a patient with refractory PDR. While anti-VEGF agents are a cornerstone in managing PDR, understanding the context of rare hemorrhagic adverse events is critical for risk assessment and patient care^1,2. A review of existing literature establishes that while minor, injection-site hemorrhages are common across all anti-VEGF agents, severe intraocular hemorrhages are infrequent. For widely used agents like ranibizumab and aflibercept, post-injection vitreous hemorrhage in PDR is a recognized complication, often associated with the progression of the underlying disease, persistent neovascularization, or tractional forces. Studies have shown that these agents can effectively treat existing vitreous hemorrhage, reducing the need for vitrectomy.

Conbercept, a novel recombinant fusion protein, has demonstrated a comparable efficacy and safety profile in treating various retinal conditions, including PDR^3,4. Large-scale studies and real-world data generally report a low incidence of severe adverse events, with subconjunctival hemorrhage being one of the more common, yet minor, complications. Studies focusing on Conbercept for PDR with vitreous hemorrhage have found it to be a safe and effective treatment, often in conjunction with panretinal photocoagulation⁴. One prospective randomized controlled trial comparing Conbercept and Ranibizumab as pre-treatment for vitrectomy in PDR patients found no significant differences in intraoperative or postoperative hemorrhagic complications between the two groups⁴.

This case is particularly noteworthy for several reasons. First, the event was a diffuse retinal hemorrhage rather than a more typical vitreous hemorrhage. Second, it occurred after the 12th injection, raising questions about potential cumulative effects or long-term vascular changes in a chronically treated eye. Finally, the patient's high-risk profile-encompassing poorly controlled diabetes, hypertension, and neovascular glaucoma-creates a complex clinical picture where systemic factors likely played a significant role. The presentation of this rare event provides a valuable opportunity to explore potential mechanisms, refine management strategies, and inform consent discussions for high-risk patients undergoing long-term anti-VEGF therapy.

Case Presentation

A 56-year-old woman presented for her 12th intravitreal conbercept injection due to worsening visual acuity (VA) in her right eye. Medical history included a 26-year of type 2 diabetes mellitus with a hemoglobin A1c of 8.9% (1 month before presentation), 5-year uncontrolled hypertension (160/95 mmHg maximum), chronic renal insufficiency, and coronary artery disease. Ocular history included PDR. The patient had undergone pan-retinal photocoagulation in both eyes and received 11 bilateral intravitreal Conbercept (IVC) injections (0.5 mg/0.05 mL per eye) over 12 months.

Diagnosis, Assessment, and Plan

On initial examination, the best-corrected visual acuity (BCVA) was 20/25 in the right eye and hand motion in the left eye. Intraocular pressure (IOP) was 36.3 mmHg in the right and 18.1 mmHg in the left. Slit-lamp examination revealed mild conjunctival hyperemia in the right eye, a clear cornea, a deep and quiet anterior chamber, and a pupil approximately 3 mm in diameter with sluggish light reflex. Neovascularization of the iris (NVI) was observed, with a well-positioned intraocular lens (IOL) and vitreous opacity. The left eye showed no conjunctival hyperemia, a clear cornea, a deep anterior chamber, a pupil approximately 6 mm in diameter with no light reflex, a well-positioned IOL, and vitreous opacity.

Fundus examination of the right eye revealed scattered retinal hemorrhages, hard exudates, and microaneurysms (Figure 1A). In the left eye, extensive neovascular membranes were observed over the optic disc and macular area, leading to tractional retinal detachment. Optical coherence tomography (OCT) demonstrated multiple intraretinal hyperreflective lesions with shadowing in the right eye (Figure 1B).

The patient was diagnosed with bilateral proliferative diabetic retinopathy (PDR) complicated by neovascular glaucoma (NVG). The treatment plan included administering the twelfth intravitreal injection of conbercept in the right eye.

Protocol

​This study adhered to established medical ethics and was conducted under a standard clinical protocol approved by the Ethics Committee of Chongqing University Three Gorges Hospital (Approval No. 2025046). Written informed consent was obtained from the patient prior to participation.

1. Pre-surgical steps

1. Preoperatively, the patient presented with an elevated intraocular pressure of 36.3 mmHg in the right eye. This was successfully reduced to 19.2 mmHg following the administration of topical (timolol-dorzolamide) and systemic (oral acetazolamide) hypotensive agents.
2. At the time of the injection, the patient's blood pressure was maintained at 138/86 mmHg.
3. Immediately prior to the procedure, ocular antisepsis was performed by instilling 5% povidone-iodine into the conjunctival sac.
4. A sterile drape was applied, and an eyelid speculum was inserted to ensure adequate exposure and maintain aseptic conditions.

2. Surgical procedure

1. The patient was placed in a supine position.
2. Under topical anesthesia, an intravitreal injection of conbercept (0.5 mg/0.05 mL) was administered into the inferotemporal quadrant of the right eye, 3.5 mm posterior to the limbus, using a 30-G needle.
3. The injection was delivered slowly over a 5-s period to minimize the risk of transient intraocular pressure (IOP) spikes and mechanical stress.
4. Immediately following the injection, ophthalmoscopy was performed to confirm perfusion of the central retinal artery and to ensure the absence of retinal tears or detachment.
5. The procedure was completed without any immediate complications.

3. Postoperative management

1. Following the procedure, the patient was instructed to monitor for visual symptoms and return for a follow-up examination within 24 h. In line with updated clinical guidelines, no antibiotics were prescribed.
2. Initially, the patient was asymptomatic and reported no ocular discomfort in the right eye.
3. At the follow-up appointment on postoperative day 1, the patient complained of a significant decline in vision.
4. The examination confirmed that the BCVA in the right eye had decreased to 20/200. A fundus examination revealed confluent circular hemorrhages extending from the posterior pole to the mid-peripheral retina (Figure 2A).
5. Furthermore, OCT showed retinal edema with intraretinal fluid accumulation, indicated by a central subfield thickness of 613 µm OD (Figure 2B).
6. An empirically guided management plan was immediately initiated, which included the following interventions: Carbazochrome Sodium Sulfonate for Injection was administered at a dosage of 60 mg/day to reduce capillary permeability.
7. The patient was prescribed Hexue Mingmu Pian, a traditional Chinese medicine formulation to facilitate the resorption of the fundus hemorrhage.
8. Strict blood pressure control was continued with a target systolic pressure of less than 130 mmHg. IOP-lowering therapy with Brinzolamide eye drops was maintained.

Results

At 1 month follow-up, the patient reported a subjective improvement in vision. This was consistent with objective findings, as the best-corrected visual acuity (BCVA) had improved to 20/40. The fundus examination revealed a partial resolution of the hemorrhagic lesions and reduced macular edema (Figure 3A). Correspondingly, optical coherence tomography (OCT) demonstrated improved macular architecture, with the central subfield thickness having decreased to 452 µm (Figure...

Discussion

Acute diffuse retinal hemorrhage following intravitreal conbercept injection is a rare but potentially sight-threatening complication, often observed in eyes with advanced proliferative diabetic retinopathy (PDR) and systemic comorbidities^5,6,7,8,9. The pathogenesis of this diffuse retinal hemorrhage is likely multifactorial, stemming from the potent pharmacod...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Brinzolamide eye drops	Alcon-Couvreur	HJ20140976
Carbazochrome SodiumSulfonate for Injection	Jiangsu Wuzhong Group	H20044326
Conbercept Ophthalmic Injection	Chengdu Kanghong Pharmaceutical Group	202204b11
Fundus camera	CarlZeiss Meditec,Inc	CLARAS 500
Hexue Mingmu Pian	Xi'an Beilin Pharmaceutical Co., Ltd	Z20025067
Non-contact tonometer	TOPCON	CT-800A
Optical Coherence Tomography	Heidelberg Engineering	SpectraLisOCT
Refractometer	TOPCON	KR-800