Management of submacular hemorrhage secondary to age-related macular degeneration with vitrectomy and subretinal tissue plasminogen activator injection: Outcomes and prognostic factors

Abstract

Purpose:

To evaluate the efficacy of pars plana vitrectomy combined with subretinal tissue plasminogen activator injection, pneumatic displacement, and intraoperative intravitreal antivascular endothelial growth factor therapy for treating submacular hemorrhage secondary to polypoidal choroidal vasculopathy or neovascular age-related macular degeneration.

Methods:

This retrospective study enrolled 28 patients who were diagnosed with submacular hemorrhage secondary to polypoidal choroidal vasculopathy or neovascular age-related macular degeneration, all of whom received a minimum follow-up period of 6 months. Key preoperative parameters, such as submacular hemorrhage height and diameter, tissue plasminogen activator dosage, and hemorrhage duration, were documented. Postoperative outcomes evaluated included the degree of submacular hemorrhage displacement, visual acuity changes, incidence of complications, and the requirement for additional intravitreal antivascular endothelial growth factor injections during the follow-up period.

Results:

The mean patient age was 66.71 ± 10.62 years. The mean visual acuity progressively improved from a preoperative logMAR of 1.57 ± 0.64 to 1.26 ± 0.67, 1.15 ± 0.59, 1.14 ± 0.55, and 1.12 ± 0.56 at postoperative months 1, 3, and 6, respectively. Complete hemorrhage displacement was achieved in 85.71% (24/28) of cases. Preoperative hemorrhage duration was significantly negatively correlated with postoperative best-corrected visual acuity at 1 month (r = 0.46; p = 0.013), 3 months (r = 0.42; p = 0.028), 6 months (r = 0.41; p = 0.032), and final follow-up (r = 0.38; p = 0.047).

Conclusions:

Pars plana vitrectomy with tissue plasminogen activator subretinal injection, pneumatic displacement, and intraoperative vitreous antivascular endothelial growth factor injection represents a safe and effective approach for managing submacular hemorrhage secondary to polypoidal choroidal vasculopathy and neovascular age-related macular degeneration. The duration of submacular hemorrhage emerges as the most critical prognostic factor for final visual outcomes. Patients with hemorrhage duration exceeding 14 days demonstrate a significantly reduced likelihood of achieving favorable visual outcomes.

Keywords

submacular hemorrhage (SMH)polypoidal choroidal vasculopathy (PCV)neovascular age-related macular degeneration (nAMD)tissue plasminogen activator (tPA)duration vitrectomy prognostic factors

Introduction

Submacular hemorrhage (SMH) is defined as hematoma accumulation between the neurosensory retina and retinal pigment epithelium (RPE)¹ and can arise from multiple etiologies, with polypoidal choroidal vasculopathy (PCV), neovascular age-related macular degeneration (nAMD), retinal arterial microaneurysm (RAMA), trauma, and high myopia being the most prevalent causes.² The physical separation of the neurosensory retina from the RPE creates a barrier effect that disrupts the normal diffusion of nutrients and metabolites.^3,4 Furthermore, subretinal clot contraction and iron-induced toxicity may cause direct damage to photoreceptor cells, ultimately resulting in extensive macular scarring and poor visual prognosis.⁵

Therefore, timely hemorrhage evacuation is essential for preventing permanent visual impairment. Current therapeutic approaches for SMH encompass pars plana vitrectomy (PPV), macular displacement through pneumatic techniques, pharmacologic fibrinolysis using tissue plasminogen activator (tPA), and antivascular endothelial growth factor (anti-VEGF) therapy for underlying PCV or nAMD.^6–8 These therapeutic approaches can be applied either singly or in combination. However, the optimal therapeutic approach for SMH secondary to PCV or nAMD has not yet been revealed. Current studies have demonstrated that therapeutic approaches for SMH can be broadly classified into two primary strategies: subretinal injection versus intravitreal injection of gas/tPA.^9–12

Several subretinal injection techniques have been documented in the literature. In 2001, Haupert et al.¹³ pioneered the use of PPV combined with subretinal tPA injection for SMH and reported visual improvement in patients with AMD; however, hemorrhage recurred in 27% of treated eyes. Subsequently, Hillenkamp et al.¹⁴ demonstrated that PPV with subretinal tPA injection achieved superior complete displacement of SMH compared to PPV with intravitreal tPA injection in patients with AMD and RAMA. In most patients, function improves because of the absence of direct retinal toxicity associated with subretinal tPA injection. In 2015, Kimura et al.¹⁵ reported that SMH displacement following PPV with subretinal tPA injection enhanced retinal sensitivity and best-corrected visual acuity (BCVA) in AMD patients. A 2024 novel study¹⁶ investigated an innovative surgical technique for SMH displacement utilizing subretinal tPA injection combined with intravitreal ranibizumab and expansile gas injection, without PPV, to evaluate surgical outcomes. The results demonstrated successful hemorrhage displacement away from the fovea in 100% of the included patients (seven cases), with a low incidence of postoperative complications. This innovative minimally invasive surgical approach warrants further investigation and validation through larger clinical studies. Additionally, some investigators have explored intravitreal injection techniques. A 2022 study evaluated 1-year outcomes following single-session intravitreal tPA, ranibizumab, and gas injections for SMH secondary to AMD¹⁷ and revealed that BCVA improvements stabilized by 3 months posttreatment, yet hemorrhage recurrence occurred in 72% of cases. Furthermore, several studies have reported no significant differences between subretinal injection and intravitreal injection approaches in terms of complete displacement rates and SMH recurrence rates.^14,17

The correlations between SMH size (diameter) and visual outcomes remain inconsistent with previous findings.^13,18,19 Some studies have demonstrated that a smaller hemorrhage area is associated with better final visual outcomes and serves as an important prognostic factor.²⁰ However, Plemel et al.²¹ did not observe a significant correlation between SMH size and final visual acuity (VA). Furthermore, several studies have failed to establish a significant relationship between SMH duration and final VA.²² Furthermore, the previous literature suggests that different research protocols adopt varying treatment approaches and that the average timing of treatment initiation differs. As a result, there is currently no unified conclusion regarding the relationship between treatment duration and final visual outcomes, necessitating further investigation and research.^21,23–26

This study aimed to evaluate the efficacy of a standardized surgical approach comprising PPV, submacular tPA injection, pneumatic displacement (PD) of the SMH, and intraoperative intravitreal anti-VEGF injection in patients with SMH secondary to PCV or nAMD. The secondary objective was to assess the preoperative prognostic factors associated with final visual outcomes in this patient population.

Methods

Participants

This retrospective study reviewed the medical records of 28 consecutive patients with SMH secondary to PCV or nAMD, where all cases involved foveal center involvement. All initial surgical treatments were performed by a single surgeon (D.W.S.) at Zhongshan Torch Development Zone People’s Hospital between June 2021 and December 2024. All patients who underwent PPV with subretinal tPA injection were followed up for 6 months. During this follow-up period, anti-VEGF injections were administered or withheld on the basis of each patient’s clinical condition. This study received approval from the Ethics Committee of Zhongshan Torch Development Zone People’s Hospital (no. 2023B3033) and was conducted in accordance with the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants prior to their inclusion in the study.

The inclusion criteria were thick SMH with a maximum height >200 µm secondary to PCV or nAMD, with lesions measuring two or more disc diameters. The exclusion criteria included (1) underlying causes other than PCV or nAMD, such as retinal macroaneurysm; (2) a follow-up period of <6 months; or (3) a lack of informed consent.

Preoperative examinations included BCVA measured using a 5 m Landolt chart, intraocular pressure measurements, optical coherence tomography (OCT), color fundus photography, slit lamp biomicroscopy, and fundus examination. Medical records were systematically reviewed to collect the following data: patient demographics (age, sex, eye side), clinical characteristics (primary disease, SMH maximum height and diameter, SMH duration, BCVA, anticoagulant medication use, lens status, preoperative vitreous hemorrhage), surgical details (tPA dosage, number of postoperative anti-VEGF injections), and outcomes (SMH displacement, complications, follow-up period). Color fundus photography and OCT findings were also documented.

All patients, except those with preoperative vitreous hemorrhage, underwent both fluorescein angiography and indocyanine green angiography preoperatively and postoperatively. Patients with preoperative vitreous hemorrhage received only postoperative angiographic examinations. For statistical analysis, BCVA was converted to logMAR units. The maximum SMH diameter was evaluated using OCT and is expressed as a ratio relative to the longest optic disc diameter. SMH displacement was categorized as either total or subtotal at the final follow-up visit. Total displacement was defined as the complete absence of subretinal blood within 1500 μm centered on the fovea, whereas subtotal displacement was defined as the absence of hemorrhage under the foveola but with residual blood traces persisting within 1500 μm of the foveal center. The preoperative SMH duration was determined on the basis of the onset of symptoms.

OCT measurement

Spectral-domain OCT measurements were performed using the Spectralis^® system (Heidelberg Engineering, USA). OCT parameters were measured according to the methodology described by Hirashima et al.²⁷ Horizontal OCT scans of the central fovea were utilized for OCT parameter analysis.

Interventions

All surgeries were performed using a standard 25-gauge vitrectomy system (Constellation Vision System; Alcon, USA). Following core vitrectomy, posterior vitreous detachment was induced when necessary, followed by peripheral vitrectomy. Using a 41-gauge flexible cannula (ASJ^® Company, China) and a 1-mL syringe, tPA (Boehringer Ingelheim Pharma GmbH & Co. KG, Germany) was slowly injected into the submacular space. Subsequently, intravitreal filtered air was injected to perform air–fluid exchange, displacing the hemorrhage away from the fovea. After surgical incision closure, 0.1 mL of aflibercept (Vetter Pharma-Fertigung GmbH & Co. KG, Germany; 2.5 µg/0.1 mL) was injected intravitreally during the procedure. The tPA dosage was carefully adjusted on the basis of intraoperative hematoma displacement, primarily guided by the hematoma diameter. Postoperatively, patients were instructed to maintain a prone position for ~5–7 days.

Statistical analysis

The objective of this study was to evaluate visual outcomes and identify prognostic factors affecting final visual outcomes in patients with SMH secondary to PCV and nAMD. The results are presented as the mean ± standard deviation (SD). VA was measured using the Snellen VA (SVA) chart, and SVA was analyzed using Wilcoxon signed-rank tests preoperatively and at 1, 3, 6, and final months postoperatively. All the SVA results were converted to logMAR values for statistical analysis. For statistical purposes, counting fingers, hand motion, light perception, and no light perception were assigned values of 1.85, 2.3, 2.7, and 3.0 logMAR units, respectively. The significance level was set at 5% (p < 0.05).

Statistical analyses were performed using SPSS v.22.0 software (IBM Corp., USA). For each independent variable, normality was assessed using the Kolmogorov–Smirnov test. Preoperative and postoperative BCVAs were compared using paired samples t tests. Independent groups were evaluated using independent samples t tests. Correlations were assessed using Pearson’s correlation tests. Categorical variables were compared between groups using Fisher’s exact test. The results were considered statistically significant when p < 0.05.

Results

Baseline characteristics and treatment outcomes

This study included 28 eyes from 28 consecutive patients, all of whom presented with SMH secondary to either PCV (n = 16 eyes) or nAMD (n = 12 eyes). The baseline characteristics and treatment outcomes are summarized in Table 1.

Table 1.

Demographics and preoperative/postoperative clinical characteristics.

Parameter	Number
Number of eyes (number of patients)	28 (28)
Mean age (mean ± SD)	66.71 ± 10.62
Gender
Male (n, %)	19 (67.86%)
Female (n, %)	9 (32.14%)
Eye side
Right eye (n, %)	13 (46.43%)
Left eye (n, %)	15 (53.57%)
Primary disease, eyes
PCV (n, %)	16 (57.14%)
nAMD (n, %)	12 (42.86%)
Patients with anticoagulation or antiplatelet therapy (n, %)	7 (25.00%)
Lens status
Phakic (n, %)	20 (71.43%)
Pseudophakic (n, %)	8 (28.57%)
Preoperative VH, eyes (n, %)	12 (42.86%)
SMH duration, days (mean ± SD)	15.21 ± 13.41
SMH (mean ± SD)
Median max. height (μm)	978.25 ± 383.04
Median max. diameter (disc diameter)	5.65 ± 1.61
Subretinal injection of tPA dosage, µg (mean ± SD)	71.07 ± 27.13
BCVA (mean ± SD)
Baseline BCVA (logMAR)	1.57 ± 0.64
Final BCVA (logMAR)	1.12 ± 0.56
Number of anti-VEGF injection after surgery, eyes
0	15 (53.57%)
1	5 (17.86%)
2	4 (14.29%)
3	3 (10.71%)
4	1 (3.57%)
Displacement of SMH
Complete (n, %)	24 (85.71%)
Incomplete (n, %)	4 (14.29%)
Complications, eyes (n, %)
VH	9 (32.14%)
Macular hole	1 (3.57%)
Epiretinal membrane	1 (3.57%)
Secondary glaucoma	1 (3.57%)
Follow-up period, months (mean ± SD)	19.46 ± 11.05

Anti-VEGF: antivascular endothelium growth factor; BCVA: best-corrected visual acuity; nAMD: neovascular age-related macular degeneration; PCV: polypoidal choroidal vasculopathy; SD: standard deviation; SMH: submacular hemorrhage; tPA: tissue plasminogen activator; VH: vitreous hemorrhage.

The mean patient age was 66.71 ± 10.62 years (range: 54–90 years), with 19 male patients (67.86%). The mean duration of hemorrhage prior to surgery was 15.21 ± 13.41 days (range: 2–60 days). At presentation, the mean maximum height and diameter of the hemorrhage were 978.25 ± 383.04 μm (range: 301–1956 μm) and 5.65 ± 1.61 disc diameters (range: 3.50–11.00 disc diameters), respectively.

Preoperative vitreous hemorrhage was present in 12 patients (42.86%). The mean subretinal tPA injection dose was 71.07 ± 27.13 μg (range: 20–100 μg). Complete hemorrhage displacement was achieved in 24 patients (85.71%), whereas subtotal displacement occurred in four patients (14.29%). Fifteen patients did not require postoperative anti-VEGF therapy. The mean follow-up period was 19.46 ± 11.05 months. No perioperative complications were observed in any patient.

The imaging findings from a representative case are shown in Figure 1. A 54-year-old woman with SMH secondary to PCV presented with a hemorrhage duration of 7 days prior to surgery. At initial presentation, the hemorrhage measured 1393 µm in height and 5.4 disc diameters in maximum diameter. Complete displacement of the SMH from the foveal center was achieved. The patient’s BCVA improved from 0.60 logMAR preoperatively to 0.50 logMAR at 6 months postoperatively. Central macular thickness decreased significantly from 1387 µm before surgery to 139 µm at the 6-month follow-up. The patient was monitored for 6 months without any postoperative complications and did not require additional anti-VEGF therapy during the follow-up period.

Figure 1.

(a) Fundus photograph at initial presentation demonstrating submacular hemorrhage measuring 5.5 disc diameter. (b) Fundus photograph 3 days postsurgery showing displacement of most of the submacular hemorrhage to the inferior periphery. (c) Fundus photograph at 6 months postsurgery demonstrating complete resolution of the submacular hemorrhage. (d) SD-OCT at the initial visit revealing dense submacular hemorrhage. (e) SD OCT image 5 days postsurgery demonstrating resolution of the submacular hemorrhage. (f) SD OCT image 6 months postsurgery showing complete resolution of the submacular hemorrhage.

The mean BCVA gradually improved from a preoperative logMAR of 1.57 ± 0.64 to a logMAR of 1.26 ± 0.67, 1.15 ± 0.59, 1.14 ± 0.55, and 1.12 ± 0.56 at postoperative months 1, 3, and 6, respectively. Compared with that at baseline, the improvement in BCVA at all follow-up visits was significant (p < 0.05; Figure 2). Neither age nor sex was correlated with final BCVA. Similarly, no significant correlations were detected between tPA dosage, hemorrhage height and diameter, and postoperative BCVA at months 1, 3, 6, or the final month (p > 0.05 for all).

Figure 2.

Changes in BCVA in logMAR units throughout the study period.

Prognostic factors

The patients were stratified into two groups based on etiology: PCV (n = 16, 57.14%) and nAMD (n = 12, 42.86%; Table 2). No significant differences were observed between the two groups in terms of preoperative characteristics, including age, SMH duration, maximum height and diameter of the SMH, baseline BCVA, or tPA injection dosage (p > 0.05 for all). At postoperative months 1, 3, and 6, as well as at the final follow-up visit, there were no statistically significant differences in BCVA between the groups (p > 0.05 for all).

Table 2.

General characteristics of patients with PCV and nAMD.

	PCV group (n = 16), mean ± SD	nAMD (n = 12), mean ± SD	p value
Age (years)	67.88 ± 10.00	65.17 ± 10.62	0.515
SMH duration (days)	15.88 ± 15.61	14.33 ± 13.41	0.770
SMH median max. height (μm)	1011.88 ± 447.65	933.42 ± 383.04	0.601
SMH median max. diameter (disc diameter)	5.94 ± 1.81	5.27 ± 1.61	0.285
Baseline BCVA (logMAR)	1.44 ± 0.71	1.75 ± 0.64	0.215
Final BCVA (logMAR)	1.09 ± 0.56	1.15 ± 0.55	0.796
tPA injection dosage	74.38 ± 29.20	66.67 ± 24.62	0.467

Independent samples t-test, significant results (p < 0.05) shown in bold.

BCVA: best-corrected visual acuity; nAMD: neovascular age-related macular degeneration; PCV: polypoidal choroidal vasculopathy; SD: standard deviation; SMH: submacular hemorrhage; tPA: tissue plasminogen activator.

A significant negative correlation was observed between preoperative hemorrhage duration and postoperative BCVA at month 1 (r = −0.46; p = 0.013), month 3 (r = −0.42; p = 0.028), month 6 (r = −0.41; p = 0.032), and at the final follow-up (r = −0.38; p = 0.047). Patients were stratified into two groups based on preoperative hemorrhage duration: the early treatment group (duration ⩽14 days; n = 17, 60.71%) and the delayed treatment group (duration >14 days; n = 11, 39.29%; Table 3). BCVA improvement was significantly greater in the early treatment group than in the delayed treatment group at all postoperative time points (p < 0.05 for months 1, 3, and 6; p = 0.009 for the final follow-up).

Table 3.

General characteristics of two groups receiving early surgical intervention (⩽14 days) or delayed surgical intervention (>14 days).

	Early treatment group (n = 17), mean ± SD	Late treatment group (n = 11), mean ± SD	p value
Age (years)	63.71 ± 10.03	71.36 ± 10.22	0.061
SMH duration (days)	7.53 ± 3.37	27.09 ± 14.56	<0.001
SMH median max. height (μm)	878.35 ± 349.74	1132.64 ± 458.51	0.086
SMH median max. diameter (disc diameter)	5.20 ± 1.29	6.35 ± 1.87	0.065
Baseline BCVA (logMAR)	1.39 ± 0.66	1.85 ± 0.53	0.067
Final BCVA (logMAR)	0.91 ± 0.42	1.45 ± 0.60	0.009
tPA injection dosage	67.65 ± 29.05	76.36 ± 24.20	0.417

Independent samples t-test, significant results (p < 0.05) shown in bold.

BCVA: best-corrected visual acuity; SD: standard deviation; SMH: submacular hemorrhage; tPA: tissue plasminogen activator.

The patients were divided into two groups according to the tPA injection dosage used during surgery: low-dose (50 µg; n = 14, 50.00%) and high-dose (100 µg; n = 14, 50.00%; Table 4). The mean maximum SMH diameter significantly differed between the groups (4.87 ± 1.19 disc diameters in the low-dose group versus 6.43 ± 1.64 disc diameters in the high-dose group; p = 0.008). However, there were no significant differences in other preoperative characteristics, including age, SMH duration, maximum SMH height, baseline BCVA, or preoperative VH (p > 0.05 for all) between the two groups. At postoperative months 1, 3, and 6 and at the final month, no statistically significant difference was observed in terms of BCVA between the two groups (p > 0.05 for all).

Table 4.

General characteristics of two groups according to tPA injection dosage: low-dose (⩽50 µg) or high-dose (>50 µg).

	Low-dose group (n = 14), mean ± SD	High-dose group (n = 14), mean ± SD	p value
Age (years)	68.57 ± 12.52	64.86 ± 8.37	0.365
SMH duration (days)	11.50 ± 6.64	18.93 ± 17.31	0.146
SMH median max. height (μm)	984.21 ± 260.08	972.29 ± 486.84	0.936
SMH median max. diameter (disc diameter)	4.87 ± 1.19	6.43 ± 1.64	0.008
Baseline BCVA (logMAR)	1.54 ± 0.60	1.60 ± 0.70	0.830
Final BCVA (logMAR)	1.00 ± 0.44	1.23 ± 0.64	0.284
tPA injection dosage	46.43 ± 9.29	95.71 ± 11.58	<0.001

Independent samples t-test, significant results (p < 0.05) shown in bold.

BCVA: best-corrected visual acuity; SD: standard deviation; SMH: submacular hemorrhage; tPA: tissue plasminogen activator.

Discussion

SMH secondary to PCV or nAMD is associated with poor visual outcomes, predominantly due to retinal damage with multiple underlying disease processes that can lead to severe vision loss if left untreated.²⁸ Currently, advances in pharmacological therapies, particularly the utilization of tPA for hematoma clearance and standardized anti-VEGF drug administration intraoperatively and postoperatively, have substantially enhanced treatment success rates.^8,29 Similarly, vitrectomy-based therapeutic regimens represent a cornerstone treatment modality for SMH management. PPV combined with subretinal tPA injection, air tamponade, and with or without anti-VEGF agent injection has become increasingly employed. In 2015, a prospective case series study¹⁵ revealed the utilization of PPV with subretinal injection of 4000 IU tPA followed by fluid/air exchange, with anti-VEGF drugs administered when indicated for exudative changes. In all 15 patients, the surgical intervention successfully achieved displacement of the SMH from the macular region. Sharma et al.³⁰ reported that combined PPV with subretinal injection of air and tPA (125 mg/mL), partial fluid–air exchange with gas tamponade, and comprehensive anti-VEGF therapy (administered preoperatively, intraoperatively, and postoperatively) resulted in effective SMH displacement. Among the 24 patients evaluated, subretinal air injection concurrent with tPA administration during PPV exhibited remarkable efficacy, consistently displacing the SMH from the foveal region toward the peripheral retina, thereby yielding significant improvements in VA and retinal thickness. Furthermore, the findings of this study suggest that this surgical approach may also prove therapeutically beneficial for select cases of sub-RPE hemorrhage. In 2017, this surgical technique incorporated PPV combined with subretinal injection of tPA (4000 IU) and fluid–air exchange, followed by anti-VEGF agent administration.³¹ In a cohort of 11 consecutively treated PCV patients, this method successfully displaced the SMH and enhanced retinal sensitivity. Furthermore, a three-dimensional (3D) head-up display system has been implemented in PPV surgery.³² Eighteen eyes with SMH (10 due to PCV/five due to RAM/two due to traumatic retinopathy/one due to nAMD) were treated using 3D-assisted PPV with subretinal tPA injection, which safely and effectively eliminated the SMH and improved visual outcomes. In 2024, a real-world comparative study³³ revealed that compared with PD, PPV combined with subretinal injection of tPA, anti-VEGF agents, and air exhibited superior efficacy in displacing SMH while maintaining a comparable safety profile. This surgical approach should be considered for patients with severe SMH characterized by thick and extensive hemorrhage or as a rescue secondary intervention when initial treatments fail to achieve adequate outcomes.

In this study, we evaluated the efficacy of a standardized surgical protocol comprising vitrectomy, submacular tPA injection, PD of the SMH, and intraoperative intravitreal anti-VEGF injection for blood displacement in patients with SMH secondary to PCV or nAMD. Additionally, we investigated preoperative prognostic factors associated with final visual outcomes. Total or subtotal hemorrhage displacement was achieved in all patients at the final follow-up. Notably, the complete SMH displacement rate exceeded 85%, indicating exceptional efficacy. The results revealed statistically significant improvements in the mean BCVA at all follow-up visits. The duration of SMH emerged as the most crucial prognostic factor influencing final BCVA. However, hemorrhage height and diameter were not significant outcome predictors. Furthermore, preoperative clinical characteristics and postoperative BCVA did not differ significantly between the two distinct etiologies (PCV versus nAMD).

In our study, all patients demonstrated significant BCVA improvement at postoperative visits, with VA gains remaining stable throughout the follow-up period. Previous research has reported comparable outcomes: Sharma et al.³⁰ documented a BCVA reduction in logMAR from 1.95 at baseline to 0.85 at a mean follow-up of 12.5 months, whereas Wu et al.³⁴ reported improvement from 1.85 to 0.98 at 3 months posttreatment. Ogata et al.,³⁵ who investigated subretinal air injection, reported a BCVA improvement of 0.3 logMAR, which is consistent with our findings. Similarly, Chang et al.⁹ conducted a study on SMH secondary to AMD (n = 101) and reported that 82% of eyes achieved at least one line of VA improvement, with 19.6% gaining three lines or more. However, their study did not identify a significant correlation between preoperative hemorrhage duration and final BCVA.

The relationship between SMH duration and visual outcomes remains controversial in the literature. In our study, we identified a significant negative correlation between preoperative hemorrhage duration and postoperative BCVA. Hattenbach et al.³⁶ emphasized the critical importance of early intervention, demonstrating that eyes with SMH persisting for <14 days and receiving prompt treatment achieved optimal visual outcomes when the initial clinical presentation exceeded 21 days, when no improvement in visual prognosis was expected, or when a poor visual outcome was anticipated. Similarly, a recent study identified surgical timing as the most crucial determinant of final BCVA.²³ Notably, compared to patients with longer durations, patients with an SMH duration of <10 days had significantly better BCVA outcomes. Furthermore, this study revealed that shorter SMH duration correlated with higher rates of total displacement. However, Kimura et al.³¹ reported no significant correlation between preoperative SMH duration and postoperative BCVA. In their study, the mean SMH duration was 10.25 ± 2.9 days (12/13 eyes), and preoperative SMH height did not significantly affect postoperative BCVA at either 1 or 3 months postsurgery. Nevertheless, eyes with SMH <300 μm demonstrated significant BCVA improvements as early as 1 month postoperatively, suggesting earlier visual recovery in these cases. In 2022, Ogata et al.³⁵ reported that the mean time for SMH displacement following surgery was 11.1 ± 6.3 days, excluding one eye that experienced SMH recurrence within 3 months postprocedure. The authors reported that none of the analyzed preoperative factors were significantly associated with the postoperative duration required for SMH displacement, although this may be partially attributable to the approximate rather than exact nature of the time measurements.

The correlation between SMH size (diameter) and visual outcomes remains controversial in the literature. In our study, hemorrhage diameter was not a significant predictor of postoperative VA. Hattenbach et al.³⁶ reported that SMH size was not significantly associated with postoperative visual improvements in eyes with hemorrhage duration ⩽14 days. However, Sandhu et al.³¹ noted that eyes with SMH sizes ⩽5.5 disc diameters tended to achieve better visual outcomes. In 2020, a study³⁷ classified SMH size into three groups: small (⩾1–<4 disc diameters), medium (⩾4 disc diameters within the temporal arcade), and large (⩾4 disc diameters exceeding the temporal arcade). The findings demonstrated that visual outcomes correlate with SMH size. The study compared three treatment modalities: anti-VEGF monotherapy, PD with anti-VEGF, and PPV with subretinal tPA and gas tamponade. As SMH size increases, treatment approaches require more comprehensive and aggressive management. With respect to the small-sized group, all three treatment modalities resulted in gradual BCVA improvement with high rates of hemorrhage regression or displacement (>75%). However, in patients with larger SMH, invasive techniques, including PD or surgical intervention, demonstrated greater advantages compared with anti-VEGF monotherapy.

In our study, tPA dosage was primarily determined by SMH diameter. Final VA was not significantly correlated with tPA dosage. These findings are likely attributable to the multifactorial nature of visual outcomes, which are particularly influenced by preoperative VA and SMH duration. Nevertheless, our study revealed a total SMH displacement rate exceeding 85% without retinal toxicity, including retinal detachment. Hesse et al.³⁸ reported that pars plana intravitreal injection of 50 or 100 µg tPA in 11 AMD patients yielded a complete displacement rate of 81% (35 out of 43 eyes). This displacement rate closely aligns with our study findings. However, Avci et al.²³ reported a complete displacement rate of only 53% (16 out of 30) in 30 nAMD patients treated with PPV combined with intravitreal 5% C3F8 gas and subretinal tPA injection (25–50 µg). This discrepancy may be partially attributed to the relatively lower tPA dosage. However, retinal toxicity may occur when tPA doses exceed 100 µg.³⁹

In contrast to previous studies employing multiple techniques or procedures performed by various surgeons,^40,41 our investigation utilized a standardized approach with a single experienced surgeon performing all operations using identical techniques, thereby ensuring technical uniformity. This design maintains surgical quality consistency, although validation through studies involving multiple surgeons is warranted. However, several limitations should be acknowledged in our research. While patients were consecutively enrolled during a defined period, no formal sample size calculation was conducted. The study featured a relatively small cohort and employed a retrospective design. Additionally, the follow-up period for surgical outcomes was comparatively brief. Consequently, large-scale investigations with extended follow-up durations are essential to thoroughly evaluate the efficacy of this surgical protocol.

Conclusion

The results of this study demonstrate that PPV with subretinal tPA injection, PD, and intraoperative intravitreal anti-VEGF administration represents a safe and effective technique for displacing SMH secondary to PCV and nAMD. Additionally, SMH duration emerges as the most critical prognostic factor influencing final VA, with patients experiencing hemorrhage durations exceeding 14 days demonstrating reduced likelihood of achieving favorable outcomes. Nevertheless, further investigations are warranted to elucidate prognostic factors affecting both functional and anatomical outcomes.

Footnotes

ORCID iD

Ming-ming Li

Author contributions

Ming-ming Li and Ding-wang Su: substantial contributions to the conception or design of the work, the acquisition, analysis, and interpretation of data for the work. Drafting the work or revising it critically for important intellectual content. Final approval of the version to be published. Ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Huang Zhang and Zhi-min Cen: substantial contributions to the conception or design of the work and interpretation of the data. Final approval of the version to be published. Ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Zhongshan Science and Technology Bureau Research Funding for the Social Welfare and Basic Research Project, China (no. 2023B3033).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

Tennant

Borrillo

Regillo

CD.

Management of submacular hemorrhage. Ophthalmol Clin North Am 2002; 15(4): 445–452.

Sheu

SJ.

Intravitreal tissue plasminogen activator and pneumatic displacement of submacular hemorrhage secondary to retinal artery macroaneurysm. J Ocul Pharmacol Ther 2005; 21(1): 62–67.

Scupola

Coscas

Soubrane

, et al. Natural history of macular subretinal hemorrhage in age-related macular degeneration. Ophthalmologica 1999; 213(2): 97–102.

Bressler

Childs

, et al. Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: ophthalmic findings: SST report no. 13. Ophthalmology 2004; 111(11): 1993–2006.

Stanescu-Segall

Balta

Jackson

TL.

Submacular hemorrhage in neovascular age-related macular degeneration: a synthesis of the literature. Surv Ophthalmol 2016; 61(1): 18–32.

Cho

Koh

Kim

, et al. Anti-vascular endothelial growth factor monotherapy in the treatment of submacular hemorrhage secondary to polypoidal choroidal vasculopathy. Am J Ophthalmol 2013; 156(3): 524–531.

Kunavisarut

Thithuan

Patikulsila

, et al. Submacular hemorrhage: visual outcomes and prognostic factors. Asia Pac J Ophthalmol 2018; 7(2): 109–113.

Iglicki

Zur

New Approaches in the management of submacular hemorrhages. Ophthalmologica 2024; 247(5–6): 275–276.

Chang

Garg

Maturi

, et al. Management of thick submacular hemorrhage with subretinal tissue plasminogen activator and pneumatic displacement for age-related macular degeneration. Am J Ophthalmol 2014; 157(6): 1250–1257.

10.

Kadonosono

Arakawa

Yamane

, et al. Displacement of submacular hemorrhages in age-related macular degeneration with subretinal tissue plasminogen activator and air. Ophthalmology 2015; 122(1): 123–128.

11.

Mizutani

Yasukawa

Ito

, et al. Pneumatic displacement of submacular hemorrhage with or without tissue plasminogen activator. Graefes Arch Clin Exp Ophthalmol 2011; 249(8): 1153–1157.

12.

Shin

Lee

Byeon

SH.

Anti-vascular endothelial growth factor with or without pneumatic displacement for submacular hemorrhage. Am J Ophthalmol 2015; 159(5): 904–914.

13.

Haupert

McCuen

Jaffe

, et al. Pars plana vitrectomy, subretinal injection of tissue plasminogen activator, and fluid-gas exchange for displacement of thick submacular hemorrhage in age-related macular degeneration. Am J Ophthalmol 2001; 131(2): 208–215.

14.

Hillenkamp

Surguch

Framme

, et al. Management of submacular hemorrhage with intravitreal versus subretinal injection of recombinant tissue plasminogen activator. Graefes Arch Clin Exp Ophthalmol 2010; 248(1): 5–11.

15.

Kimura

Morizane

Hosokawa

, et al. Submacular hemorrhage in polypoidal choroidal vasculopathy treated by vitrectomy and subretinal tissue plasminogen activator. Am J Ophthalmol 2015; 159(4): 683–689.

16.

Hui

Tsang

Mohamed

, et al. Subretinal tissue plasminogen activator without vitrectomy for submacular hemorrhage displacement using Nano-vitreoretinal gateway device: a pilot report. Retin Cases Brief Rep 2024; 18(1): 1–4.

17.

Kitagawa

Shimada

Mori

, et al. One-year outcome of intravitreal tissue plasminogen activator, ranibizumab, and gas injections for submacular hemorrhage in polypoidal choroidal vasculopathy. J Clin Med 2022; 11(8): 2175.

18.

Juncal

Hanout

Altomare

, et al. Surgical management of submacular hemorrhage: experience at an academic Canadian centre. Can J Ophthalmol 2018; 53(4): 408–414.

19.

Singh

Patel

Sears

JE.

Management of subretinal macular haemorrhage by direct administration of tissue plasminogen activator. Br J Ophthalmol 2006; 90(4): 429–431.

20.

Gonzalez-Lopez

McGowan

Chapman

, et al. Vitrectomy with subretinal tissue plasminogen activator and ranibizumab for submacular haemorrhages secondary to age-related macular degeneration: retrospective case series of 45 consecutive cases. Eye 2016; 30(7): 929–935.

21.

Plemel

Lapere

Rudnisky

, et al. Vitrectomy with subretinal tissue plasminogen activator and gas tamponade for subfoveal hemorrhage: prognostic factors and clinical outcomes. Retina 2019; 39(1): 172–179.

22.

Sandhu

Manvikar

Steel

DH.

Displacement of submacular hemorrhage associated with age-related macular degeneration using vitrectomy and submacular tPA injection followed by intravitreal ranibizumab. Clin Ophthalmol 2010; 4: 637–642.

23.

Avci

Mavi

Cinar

, et al. Subretinal coapplication of tissue plasminogen activator and bevacizumab with concurrent pneumatic displacement for submacular hemorrhages secondary to neovascular age-related macular degeneration. Turk J Ophthalmol 2021; 51(1): 38–44.

24.

Guthoff

Meigen

, et al. Intravitreous injection of bevacizumab, tissue plasminogen activator, and gas in the treatment of submacular hemorrhage in age-related macular degeneration. Retina 2011; 31(1): 36–40.

25.

Kumar

Roy

Bansal

, et al. Modified approach in management of submacular hemorrhage secondary to wet age-related macular degeneration. Asia Pac J Ophthalmol 2016; 5(2): 143–146.

26.

Meyer

Scholl

Eter

, et al. Combined treatment of acute subretinal haemorrhages with intravitreal recombined tissue plasminogen activator, expansile gas and bevacizumab: a retrospective pilot study. Acta Ophthalmol 2008; 86(5): 490–494.

27.

Hirashima

Moriya

Bun

, et al. Optical coherence tomography findings and surgical outcomes of tissue plasminogen activator-assisted vitrectomy for submacular hemorrhage secondary to age-related macular degeneration. Retina 2015; 35(10): 1969–1978.

28.

Jackson

Bunce

Desai

, et al. Vitrectomy, subretinal Tissue plasminogen activator and Intravitreal Gas for submacular haemorrhage secondary to Exudative Age-Related macular degeneration (TIGER): study protocol for a phase 3, pan-European, two-group, non-commercial, active-control, observer-masked, superiority, randomised controlled surgical trial. Trials 2022; 23(1): 99.

29.

Iglicki

Khoury

Donato

, et al. Comparison of subretinal aflibercept vs ranibizumab vs bevacizumab in the context of PPV, pneumatic displacement with subretinal air and subretinal tPA in naive submacular haemorrhage secondary to nAMD. “The Submarine Study”. Eye 2024; 38(2): 292–296.

30.

Sharma

Kumar

Kim

, et al. Pneumatic displacement of submacular hemorrhage with subretinal air and tissue plasminogen activator: initial United States experience. Ophthalmol Retina 2018; 2(3): 180–186.

31.

Kimura

Morizane

Matoba

, et al. Retinal sensitivity after displacement of submacular hemorrhage due to polypoidal choroidal vasculopathy: effectiveness and safety of subretinal tissue plasminogen activator. Jpn J Ophthalmol 2017; 61(6): 472–478.

32.

Zhao

Wang

, et al. Three-dimensional heads-up system assisted pars plana vitrectomy and subretinal recombinant tissue plasminogen activator injection for submacular hemorrhage. Eye Vis 2023; 10(1): 8.

33.

Szeto

Tsang

Mohamed

, et al. Displacement of submacular hemorrhage using subretinal cocktail injection versus pneumatic displacement: a real-world comparative study. Ophthalmologica 2024; 247(2): 118–132.

34.

Yan

Zhang

, et al. Visual recovery and prognosis in the treatment of submacular hemorrhage due to polypoidal choroidal vasculopathy and retinal arterial macroaneurysm: a retrospective study. Int J Clin Pract 2023; 2023: 3880297.

35.

Ogata

Nakata

, et al. Displacement of submacular hemorrhage secondary to age-related macular degeneration with subretinal injection of air and tissue plasminogen activator. Sci Rep 2022; 12(1): 22139.

36.

Hattenbach

Klais

Koch

, et al. Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions. Ophthalmology 2001; 108(8): 1485–1492.

37.

Jeong

Park

Sagong

Management of a submacular hemorrhage secondary to age-related macular degeneration: a comparison of three treatment modalities. J Clin Med 2020; 9(10): 3088.

38.

Hesse

Schmidt

Kroll

Management of acute submacular hemorrhage using recombinant tissue plasminogen activator and gas. Graefes Arch Clin Exp Ophthalmol 1999; 237(4): 273–277.

39.

Irvine

Johnson

Hernandez

, et al. Retinal toxicity of human tissue plasminogen activator in vitrectomized rabbit eyes. Arch Ophthalmol 1991; 109(5): 718–722.

40.

Sniatecki

Ho-Yen

Clarke

, et al. Treatment of submacular hemorrhage with tissue plasminogen activator and pneumatic displacement in age-related macular degeneration. Eur J Ophthalmol 2021; 31(2): 643–648.

41.

Ozkaya

Erdogan

Tarakcioglu

HN.

Submacular hemorrhage secondary to age-related macular degeneration managed with vitrectomy, subretinal injection of tissue plasminogen activator, hemorrhage displacement with liquid perfluorocarbon, gas tamponade, and face-down positioning. Saudi J Ophthalmol 2018; 32(4): 269–274.