Combination therapy for thick submacular hemorrhage_Chinese Journal of Ocular Fundus Diseases

Authors：

Chen Huijin , Feng Xuefeng , Wang Changguan ,  Ma Zhizhong

Department of Ophthalmology, Peking University Third Hospital, Beijing Key Laboratory of Reconstruction, Protection and Rehabilitation of Ocular Nerve Injury, Beijing 100191, China;

Corresponding author：

Ma Zhizhong, Email: puh3_yk@bjmu.edu.cn

Keywords：

Retinal hemorrhage/therapy; Tissue plasminogen activator/therapeutic use; Angiogenesis inhibitors/therapeutic use; Vitrectomy

DOI：

10.3760/cma.j.cn511434-20200204-00036

Video：

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Objective To observe the efficacy and safety of vitrectomy combined with submacular injection of tissue-type plasminogen activator (t-PA), gas filling and anti-VEGF drugs (multiple therapy) for thick submacular hemorrhage.Methods A retrospective case study. From January 2014 to June 2018, 24 patients (24 eyes) with thick submacular hemorrhage who received multiple therapy at the Department of Ophthalmology of Peking University Third Hospital were included in the study. Among them, there were 15 males and 9 females with the average age of 69.05±8.86 years. The average submacular bleeding time was 17.15±10.30 days, the average bleeding area was 13.85±8.63 DD. Seventeen eyes showed hemorrhagic RPE detachment. The international standard visual acuity chart was used to BCVA examination, which was converted to logMAR visual acuity in statistics. The frequency domain OCT was used to measure the height of the foveal elevation. The average logMAR BCVA of the affected eye was 1.37±0.38. The average height of the macular fovea was 824.94±294.38 μm. All eyes underwent 23G or 25G vitrectomy. During the operation, 0.1-0.5 ml t-PA (10 μg/0.1 ml) was injected under the macula. The vitreous cavity was filled with 15% C₃F₈ after gas-liquid exchange in 13 eyes, and 11 eyes were filled with sterilized air. Eleven eyes were injected with anti-VEGF drugs at the end of the operation, and anti-VEGF drugs were given PRN treatment according to the activity of the lesion. The average follow-up time after treatment was 27.90±22.21 months. The absorption of bleeding under the macula, the improvement of vision, the occurrence of rebleeding and treatment-related complications were observed and recorded. The Wilcoxon rank sum test was performed to compare the BCVA and the height of foveal elevation before and after treatment.Results One month after the treatment, the blood in the fovea of all affected eyes was cleared. At the last follow-up, the logMAR BCVA and macular foveal elevation were 0.82±0.28 and 253.88±71.75 μm, respectively. Compared with those before treatment, the difference was statistically significant (Z=－3.727, －3.234; P＜0.001, ＜0.001). The average intravitreal injection of anti-VEGF drugs was 1.08 times. During the operation, a tiny hole was formed in the center of the macula when t-PA was injected under the retina. Two eyes showed mild vitreous hemorrhage early after the operation. During the follow-up period, bleeding recurred in 2 eyes.Conclusions Vitrectomy combined with submacular injection of t-PA, gas filling, and anti-VEGF drugs is an optimal combination for the treatment of thick submacular hemorrhage. It can effectively remove submacular hemorrhage, improve vision, reduce foveal elevation with good safety.

Citation： Chen Huijin, Feng Xuefeng, Wang Changguan, Ma Zhizhong. Combination therapy for thick submacular hemorrhage. Chinese Journal of Ocular Fundus Diseases, 2020, 36(11): 884-889. doi: 10.3760/cma.j.cn511434-20200204-00036 Copy

1.	Stanescu-Segall D, Balta F, Jackson TL. Submacular hemorrhage in neovascular age-related macular degeneration: a synthesis of the literature[J]. Surv Ophthalmol, 2016, 61(1): 18-32. DOI: 10.1016/j.survophthal.2015.04.004.
2.	Cho JH, Ryoo NK, Cho KH, et al. Incidence rate of massive submacular hemorrhage and its risk factors in polypoidal choroidal vasculopathy[J]. Am J Ophthalmol, 2016, 169: 79-88. DOI: 10.1016/j.ajo.2016.06.014.
3.	Scupola A, Coscas G, Soubrane G, et al. Natural history of macular subretinal hemorrhage in age-related macular degeneration[J]. Ophthalmologica, 1999, 213(2): 97-102. DOI: 10.1159/000027400.
4.	Glatt H, Machemer R. Experimental subretinal hemorrhage in rabbits[J]. Am J Ophthalmol, 1982, 94(6): 762-773. DOI: 10.1016/0002-9394(82)90301-4.
5.	Vander JF, Federman JL, Greven C, et al. Surgical removal of massive subretinal hemorrhage associated with age-related macular degeneration[J]. Ophthalmology, 1991, 98(1): 23-27. DOI: 10.1016/s0161-6420(91)32348-0.
6.	Machemer R, Steinhorst UH. Retinal separation, retinotomy, and macular relocation: Ⅱ. A surgical approach for age-related macular degeneration?[J]. Graefe's Arch Clin Exp Ophthalmol, 1993, 231(11): 635-641. DOI: 10.1007/BF00921957.
7.	Joussen AM, Heussen FM, Joeres S, et al. Autologous translocation of the choroid and retinal pigment epithelium in age-related macular degeneration[J]. Am J Ophthalmol, 2006, 142(1): 17-30. DOI: 10.1016/j.ajo.2006.01.090.
8.	Ma Z, Han L, Wang C, et al. Autologous transplantation of retinal pigment epithelium-Bruch's membrane complex for hemorrhagic age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2009, 50(6): 2975-2781. DOI: 10.1167/iovs.08-2573.
9.	van Zeeburg EJ, van Meurs JC. Literature review of recombinant tissue plasminogen activator used for recent-onset submacular hemorrhage displacement in age-related macular degeneration[J]. Ophthalmologica, 2013, 229(1): 1-14. DOI: 10.1159/000343066.
10.	Gopalakrishan M, Giridhar A, Bhat S, et al. Pneumatic displacement of submacular hemorrhage: safety, efficacy, and patient selection[J]. Retina, 2007, 27(3): 329-334. DOI: 10.1097/01.iae.0000231544.43093.40.
11.	Shienbaum G, Garcia Filho CA, Flynn HW Jr, et al. Management of submacular hemorrhage secondary to neovascular age-related macular degeneration with anti-vascular endothelial growth factor monotherapy[J]. Am J Ophthalmol, 2013, 155(6): 1009-1013. DOI: 10.1016/j.ajo.2013.01.012.
12.	Kim JH, Chang YS, Kim JW, et al. Intravitreal anti-vascular endothelial growth factor for submacular hemorrhage from choroidal neovascularization[J]. Ophthalmology, 2014, 121(4): 926-935. DOI: 10.1016/j.ophtha.2013.11.004.
13.	Hattenbach LO, Klais C, Koch FH, et al. Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions[J]. Ophthalmology, 2001, 108(8): 1485-1492. DOI: 10.1016/s0161-6420(01)00648-0.
14.	Olivier S, Chow DR, Packo KH, et al. Subretinal recombinant tissue plasminogen activator injection and pneumatic displacement of thick submacular hemorrhage in age-related macular degeneration[J]. Ophthalmology, 2004, 111(6): 1201-1208. DOI: 10.1016/j.ophtha.2003.10.020.
15.	Treumer F, Klatt C, Roider J, et al. Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related macular degeneration with submacular haemorrhage[J]. Br J Ophthalmol, 2010, 94(1): 48-53. DOI: 10.1136/bjo.2009.164707.
16.	Meyer CH, Scholl HP, Eter N, et al. Combined treatment of acute subretinal haemorrhages with intravitreal recombined tissue plasminogen activator, expansile gas and bevacizumab: a retrospective pilot study[J]. Acta Ophthalmol, 2008, 86(5): 490-494. DOI: 10.1111/j.1600-0420.2007.01125.x.
17.	Kitagawa Y, Shimada H, Mori R, et al. Intravitreal tissue plasminogen activator, ranibizumab, and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy[J]. Ophthalmology, 2016, 123(6): 1278-1286. DOI: 10.1016/j.ophtha.2016.01.035.
18.	Sharma S, Kumar JB, Kim JE, et al. Pneumatic displacement of submacular hemorrhage with subretinal air and tissue plasminogen activator: initial United States experience[J]. Ophthalmol Retina, 2018, 2(3): 180-186. DOI: 10.1016/j.oret.2017.07.012.
19.	徐惠娟, 杨正林. 抗血管内皮生长因子药物治疗渗出型老年性黄斑变性的局限性研究现状[J]. 中华眼底病杂志, 2020, 36(2): 156-161. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.017.Xu HJ, Yang ZL. The limitation of anti-vascular endothelial growth factor treatment for wet age-related macular degeneration[J]. Chin J Ocul Fundus Dis, 2020, 36(2): 156-161. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.017.
20.	Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration[J]. N Engl J Med, 2006, 355(14): 1419-1431. DOI: 10.1056/NEJMoa054481.
21.	Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular a ge-related macular degeneration[J]. N Engl J Med, 2006, 355(14): 1432-1444. DOI: 10.1056/NEJMoa062655.
22.	de Jong JH, van Zeeburg EJ, Cereda MG, et al. Intravitreal versus subretinal administration of recombinant tissue plasminogen activator combined with gas for acute submacular hemorrhages due to age-related macular degeneration: an exploratory prospective study[J]. Retina, 2016, 36(5): 914-925. DOI: 10.1097/IAE.0000000000000954.
23.	Hillenkamp J, Surguch V, Framme C, et al. Management of submacular hemorrhage with intravitreal versus subretinal injection of recombinant tissue plasminogen activator[J]. Graefe's Arch Clin Exp Ophthalmol, 2010, 248(1): 5-11. DOI: 10.1007/s00417-009-1158-7.
24.	Fassbender JM, Sherman MP, Barr CC, et al. Tissue plasminogen activator for subfoveal hemorrhage due to age-related macular degeneration: comparison of 3 treatment modalities[J]. Retina, 2016, 36(10): 1860-1865. DOI: 10.1097/IAE.0000000000001030.
25.	Shin JY, Lee JM, Byeon SH. Anti-vascular endothelial growth factor with or without pneumatic displacement for submacular hemorrhage[J]. Am J Ophthalmol, 2015, 159(5): 904-914. DOI: 10.1016/j.ajo.2015.01.024.
26.	Kamei M, Misono K, Lewis H. A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits[J]. Am J Ophthalmol, 1999, 128(6): 739-746. DOI: 10.1016/s0002-9394(99)00239-1.
27.	Maggio E, Polito A, Guerriero M, et al. Vitreomacular adhesion and the risk of neovascular age-related macular degeneration[J]. Ophthalmology, 2017, 124(5): 657-666. DOI: 10.1016/j.ophtha.2017.01.018.
28.	陶继伟, 陈亦棋, 毛剑波, 等. 玻璃体黄斑粘连与渗出型老年性黄斑变性相关性的meta分析[J]. 中华眼底病杂志, 2017, 33(6): 626-630. DOI: 10.3760/cma.j.issn.1005-1015.2017.06.017.Tao JW, Chen YQ, Mao JB, et al. The correlation between the vitreomacular adhesion and exudative age-related macular degenerationa meta-analysis[J]. Chin J Ocul Fundus Dis, 2017, 33(6): 626-630. DOI: 10.3760/cma.j.issn.1005-1015.2017.06.017.
29.	Benner JD, Morse LS, Toth CA, et al. Evaluation of a commercial recombinant tissue-type plasminogen activator preparation in the subretinal space of the cat[J]. Arch Ophthalmol, 1991, 109(12): 1731-1736. DOI: 10.1001/archopht.1991.01080120115039.
30.	Kadonosono K, Arakawa A, Yamane S, et al. Displacement of submacular hemorrhages in age-related macular degeneration with subretinal tissue plasminogen activator and air[J]. Ophthalmology, 2015, 122(1): 123-128. DOI: 10.1016/j.ophtha.2014.07.027.
31.	姚一民, 马景学, 柴艳霞, 等. 玻璃体腔注射t-PA和SF₆治疗外伤性黄斑部视网膜下出血的临床研究[J]. 眼外伤职业眼病杂志, 2010, 31(1): 51-53. DOI: 10.3760/cma.j.issn.2095-1477.2010.03.004.Yao YM, Ma JX, Cai YX, et al. Intravitreous injection of t-PA and GAS of SF₆ to treat traumatic hemorrhage of submacular[J]. Chin J Ocul Traum Occupat Eye Dis, 2010, 31(1): 51-53. DOI: 10.3760/cma.j.issn.2095-1477.2010.03.004.
32.	张霜, 张杰, 徐鑫彦, 等. 组织型纤溶酶原激活剂、雷珠单抗联合C₃F₈治疗息肉样脉络膜血管病变并发早期黄斑下出血的疗效观察[J]. 中华眼底病杂志, 2018, 34(5): 448-452. DOI: 10.3760/cma.j.issn.1005-1015.2018.05.007.Zhang S, Zhang J, Xu XY, et al. The efficacy of intravitreal injection of tissue plasminogen activator, ranibizumab and C₃F₈ in the treatment of early submacular hemorrhage induce to polypoid choroid vasculopathy[J]. Chin J Ocul Fundus Dis, 2018, 34(5): 448-452. DOI: 10.3760/cma.j.issn.1005-1015.2018.05.007.

1. Stanescu-Segall D, Balta F, Jackson TL. Submacular hemorrhage in neovascular age-related macular degeneration: a synthesis of the literature[J]. Surv Ophthalmol, 2016, 61(1): 18-32. DOI: 10.1016/j.survophthal.2015.04.004.
2. Cho JH, Ryoo NK, Cho KH, et al. Incidence rate of massive submacular hemorrhage and its risk factors in polypoidal choroidal vasculopathy[J]. Am J Ophthalmol, 2016, 169: 79-88. DOI: 10.1016/j.ajo.2016.06.014.
3. Scupola A, Coscas G, Soubrane G, et al. Natural history of macular subretinal hemorrhage in age-related macular degeneration[J]. Ophthalmologica, 1999, 213(2): 97-102. DOI: 10.1159/000027400.
4. Glatt H, Machemer R. Experimental subretinal hemorrhage in rabbits[J]. Am J Ophthalmol, 1982, 94(6): 762-773. DOI: 10.1016/0002-9394(82)90301-4.
5. Vander JF, Federman JL, Greven C, et al. Surgical removal of massive subretinal hemorrhage associated with age-related macular degeneration[J]. Ophthalmology, 1991, 98(1): 23-27. DOI: 10.1016/s0161-6420(91)32348-0.
6. Machemer R, Steinhorst UH. Retinal separation, retinotomy, and macular relocation: Ⅱ. A surgical approach for age-related macular degeneration?[J]. Graefe's Arch Clin Exp Ophthalmol, 1993, 231(11): 635-641. DOI: 10.1007/BF00921957.
7. Joussen AM, Heussen FM, Joeres S, et al. Autologous translocation of the choroid and retinal pigment epithelium in age-related macular degeneration[J]. Am J Ophthalmol, 2006, 142(1): 17-30. DOI: 10.1016/j.ajo.2006.01.090.
8. Ma Z, Han L, Wang C, et al. Autologous transplantation of retinal pigment epithelium-Bruch's membrane complex for hemorrhagic age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2009, 50(6): 2975-2781. DOI: 10.1167/iovs.08-2573.
9. van Zeeburg EJ, van Meurs JC. Literature review of recombinant tissue plasminogen activator used for recent-onset submacular hemorrhage displacement in age-related macular degeneration[J]. Ophthalmologica, 2013, 229(1): 1-14. DOI: 10.1159/000343066.
10. Gopalakrishan M, Giridhar A, Bhat S, et al. Pneumatic displacement of submacular hemorrhage: safety, efficacy, and patient selection[J]. Retina, 2007, 27(3): 329-334. DOI: 10.1097/01.iae.0000231544.43093.40.
11. Shienbaum G, Garcia Filho CA, Flynn HW Jr, et al. Management of submacular hemorrhage secondary to neovascular age-related macular degeneration with anti-vascular endothelial growth factor monotherapy[J]. Am J Ophthalmol, 2013, 155(6): 1009-1013. DOI: 10.1016/j.ajo.2013.01.012.
12. Kim JH, Chang YS, Kim JW, et al. Intravitreal anti-vascular endothelial growth factor for submacular hemorrhage from choroidal neovascularization[J]. Ophthalmology, 2014, 121(4): 926-935. DOI: 10.1016/j.ophtha.2013.11.004.
13. Hattenbach LO, Klais C, Koch FH, et al. Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions[J]. Ophthalmology, 2001, 108(8): 1485-1492. DOI: 10.1016/s0161-6420(01)00648-0.
14. Olivier S, Chow DR, Packo KH, et al. Subretinal recombinant tissue plasminogen activator injection and pneumatic displacement of thick submacular hemorrhage in age-related macular degeneration[J]. Ophthalmology, 2004, 111(6): 1201-1208. DOI: 10.1016/j.ophtha.2003.10.020.
15. Treumer F, Klatt C, Roider J, et al. Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related macular degeneration with submacular haemorrhage[J]. Br J Ophthalmol, 2010, 94(1): 48-53. DOI: 10.1136/bjo.2009.164707.
16. Meyer CH, Scholl HP, Eter N, et al. Combined treatment of acute subretinal haemorrhages with intravitreal recombined tissue plasminogen activator, expansile gas and bevacizumab: a retrospective pilot study[J]. Acta Ophthalmol, 2008, 86(5): 490-494. DOI: 10.1111/j.1600-0420.2007.01125.x.
17. Kitagawa Y, Shimada H, Mori R, et al. Intravitreal tissue plasminogen activator, ranibizumab, and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy[J]. Ophthalmology, 2016, 123(6): 1278-1286. DOI: 10.1016/j.ophtha.2016.01.035.
18. Sharma S, Kumar JB, Kim JE, et al. Pneumatic displacement of submacular hemorrhage with subretinal air and tissue plasminogen activator: initial United States experience[J]. Ophthalmol Retina, 2018, 2(3): 180-186. DOI: 10.1016/j.oret.2017.07.012.
19. 徐惠娟, 杨正林. 抗血管内皮生长因子药物治疗渗出型老年性黄斑变性的局限性研究现状[J]. 中华眼底病杂志, 2020, 36(2): 156-161. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.017.Xu HJ, Yang ZL. The limitation of anti-vascular endothelial growth factor treatment for wet age-related macular degeneration[J]. Chin J Ocul Fundus Dis, 2020, 36(2): 156-161. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.017.
20. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration[J]. N Engl J Med, 2006, 355(14): 1419-1431. DOI: 10.1056/NEJMoa054481.
21. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular a ge-related macular degeneration[J]. N Engl J Med, 2006, 355(14): 1432-1444. DOI: 10.1056/NEJMoa062655.
22. de Jong JH, van Zeeburg EJ, Cereda MG, et al. Intravitreal versus subretinal administration of recombinant tissue plasminogen activator combined with gas for acute submacular hemorrhages due to age-related macular degeneration: an exploratory prospective study[J]. Retina, 2016, 36(5): 914-925. DOI: 10.1097/IAE.0000000000000954.
23. Hillenkamp J, Surguch V, Framme C, et al. Management of submacular hemorrhage with intravitreal versus subretinal injection of recombinant tissue plasminogen activator[J]. Graefe's Arch Clin Exp Ophthalmol, 2010, 248(1): 5-11. DOI: 10.1007/s00417-009-1158-7.
24. Fassbender JM, Sherman MP, Barr CC, et al. Tissue plasminogen activator for subfoveal hemorrhage due to age-related macular degeneration: comparison of 3 treatment modalities[J]. Retina, 2016, 36(10): 1860-1865. DOI: 10.1097/IAE.0000000000001030.
25. Shin JY, Lee JM, Byeon SH. Anti-vascular endothelial growth factor with or without pneumatic displacement for submacular hemorrhage[J]. Am J Ophthalmol, 2015, 159(5): 904-914. DOI: 10.1016/j.ajo.2015.01.024.
26. Kamei M, Misono K, Lewis H. A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits[J]. Am J Ophthalmol, 1999, 128(6): 739-746. DOI: 10.1016/s0002-9394(99)00239-1.
27. Maggio E, Polito A, Guerriero M, et al. Vitreomacular adhesion and the risk of neovascular age-related macular degeneration[J]. Ophthalmology, 2017, 124(5): 657-666. DOI: 10.1016/j.ophtha.2017.01.018.
28. 陶继伟, 陈亦棋, 毛剑波, 等. 玻璃体黄斑粘连与渗出型老年性黄斑变性相关性的meta分析[J]. 中华眼底病杂志, 2017, 33(6): 626-630. DOI: 10.3760/cma.j.issn.1005-1015.2017.06.017.Tao JW, Chen YQ, Mao JB, et al. The correlation between the vitreomacular adhesion and exudative age-related macular degenerationa meta-analysis[J]. Chin J Ocul Fundus Dis, 2017, 33(6): 626-630. DOI: 10.3760/cma.j.issn.1005-1015.2017.06.017.
29. Benner JD, Morse LS, Toth CA, et al. Evaluation of a commercial recombinant tissue-type plasminogen activator preparation in the subretinal space of the cat[J]. Arch Ophthalmol, 1991, 109(12): 1731-1736. DOI: 10.1001/archopht.1991.01080120115039.
30. Kadonosono K, Arakawa A, Yamane S, et al. Displacement of submacular hemorrhages in age-related macular degeneration with subretinal tissue plasminogen activator and air[J]. Ophthalmology, 2015, 122(1): 123-128. DOI: 10.1016/j.ophtha.2014.07.027.
31. 姚一民, 马景学, 柴艳霞, 等. 玻璃体腔注射t-PA和SF₆治疗外伤性黄斑部视网膜下出血的临床研究[J]. 眼外伤职业眼病杂志, 2010, 31(1): 51-53. DOI: 10.3760/cma.j.issn.2095-1477.2010.03.004.Yao YM, Ma JX, Cai YX, et al. Intravitreous injection of t-PA and GAS of SF₆ to treat traumatic hemorrhage of submacular[J]. Chin J Ocul Traum Occupat Eye Dis, 2010, 31(1): 51-53. DOI: 10.3760/cma.j.issn.2095-1477.2010.03.004.
32. 张霜, 张杰, 徐鑫彦, 等. 组织型纤溶酶原激活剂、雷珠单抗联合C₃F₈治疗息肉样脉络膜血管病变并发早期黄斑下出血的疗效观察[J]. 中华眼底病杂志, 2018, 34(5): 448-452. DOI: 10.3760/cma.j.issn.1005-1015.2018.05.007.Zhang S, Zhang J, Xu XY, et al. The efficacy of intravitreal injection of tissue plasminogen activator, ranibizumab and C₃F₈ in the treatment of early submacular hemorrhage induce to polypoid choroid vasculopathy[J]. Chin J Ocul Fundus Dis, 2018, 34(5): 448-452. DOI: 10.3760/cma.j.issn.1005-1015.2018.05.007.

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Combination therapy for thick submacular hemorrhage

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