Aims: To review and discuss the literature on recombinant tissue plasminogen activator (rtPA) for the treatment of a recent-onset submacular hemorrhage in patients with age-related macular degeneration. Methods: The administration technique of rtPA, the use of additional gas and vascular endothelial growth factor inhibitors (anti-VEGF), and the displacement rate of submacular hemorrhage and complications were noted from published reports, and a case series from the Rotterdam Eye Hospital (REH). Results: 38 studies with a total of 1,185 patients (1,176 eyes), and 28 patients from the REH were analyzed. Several methods for rtPA administration are available, which can be divided into two groups: submacular rtPA administration with vitrectomy; or intravitreal rtPA administration without vitrectomy. In both groups, the administration of gas and/or anti-VEGF agents could be additional. There appears to be no clear difference in complete displacement or complication rate between the more or the less invasive treatment groups. Conclusion: Although intravitreal injection of rtPA and gas only was reported to be as effective as subretinal rtPA with vitrectomy and gas, recent studies tend to use vitrectomy. These data underscore the need for a randomized controlled trial to choose the most effective and safe method of rtPA administration.

1.
Kiernan DF, Hariprasad SM, Rusu IM, Mehta SV, Mieler WF, Jager RD: Epidemiology of the association between anticoagulants and intraocular hemorrhage in patients with neovascular age-related macular degeneration. Retina 2010;30:1573–1578.
2.
Benner JD, Hay A, Landers MB, III, Hjelmeland LM, Morse LS: Fibrinolytic-assisted removal of experimental subretinal hemorrhage within seven days reduces outer retinal degeneration. Ophthalmology 1994;101:672–681.
3.
Toth CA, Morse LS, Hjelmeland LM, Landers MB III: Fibrin directs early retinal damage after experimental subretinal hemorrhage. Arch Ophthalmol 1991;109:723–729.
4.
Heriot WJ: Intravitreal gas and TPA: an outpatient procedure for submacular hemorrhage. American Academy of Ophthalmology Annual Vitreoretinal Update, 1996.
5.
Haupert CL, McCuen BW, Jaffe GJ, Steuer ER, Cox TA, Toth CA, Fekrat S, Postel EA: 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;131:208–215.
6.
Hillenkamp J, Surguch V, Framme C, Gabel VP, Sachs HG: Management of submacular hemorrhage with intravitreal versus subretinal injection of recombinant tissue plasminogen activator. Graefes Arch Clin Exp Ophthalmol 2010;248:5–11.
7.
Olivier S, Chow DR, Packo KH, MacCumber MW, Awh CC: Subretinal recombinant tissue plasminogen activator injection and pneumatic displacement of thick submacular hemorrhage in age-related macular degeneration. Ophthalmology 2004;111:1201–1208.
8.
Singh RP, Patel C, Sears JE: Management of subretinal macular haemorrhage by direct administration of tissue plasminogen activator. Br J Ophthalmol 2006;90:429–431.
9.
Thompson JT, Sjaarda RN: Vitrectomy for the treatment of submacular hemorrhages from macular degeneration: a comparison of submacular hemorrhage/membrane removal and submacular tissue plasminogen activator-assisted pneumatic displacement. Trans Am Ophthalmol Soc 2005;103:98–107.
10.
Arias L, Mones J: Transconjunctival sutureless vitrectomy with tissue plasminogen activator, gas and intravitreal bevacizumab in the management of predominantly hemorrhagic age-related macular degeneration. Clin Ophthalmol 2010;4:67–72.
11.
Meyer CH, Scholl HP, Eter N, Helb HM, Holz FG: Combined treatment of acute subretinal haemorrhages with intravitreal recombined tissue plasminogen activator, expansile gas and bevacizumab: a retrospective pilot study. Acta Ophthalmol 2008;86:490–494.
12.
Matt G, Sacu S, Stifter E, Prunte C, Schmidt-Erfurth U: Combination of Intravitreal rTPA, gas and ranibizumab for extensive subfoveal haemorrhages secondary to neovascular age-related macular degeneration. Klin Monbl Augenheilkd 2010;227:221–225.
13.
Sacu S, Stifter E, Vecsei-Marlovits PV, Michels S, Schutze C, Prunte C, Schmidt-Erfurth U: Management of extensive subfoveal haemorrhage secondary to neovascular age-related macular degeneration. Eye (Lond) 2009;23:1404–1410.
14.
Treumer F, Roider J, Hillenkamp J: Long-term outcome of subretinal coapplication of rtPA and bevacizumab followed by repeated intravitreal anti-VEGF injections for neovascular AMD with submacular haemorrhage. Br J Ophthalmol 2012;96:708–713.
15.
Bennett SR, Folk JC, Blodi CF, Klugman M: Factors prognostic of visual outcome in patients with subretinal hemorrhage. Am J Ophthalmol 1990;109:33–37.
16.
Scupola A, Coscas G, Soubrane G, Balestrazzi E: Natural history of macular subretinal hemorrhage in age-related macular degeneration. Ophthalmologica 1999;213:97–102.
17.
Avery RL, Fekrat S, Hawkins BS, Bressler NM: Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration. Retina 1996;16:183–189.
18.
Lincoff H, Kreissig I, Stopa M, Uram D: A 40 degrees gaze down position for pneumatic displacement of submacular hemorrhage: clinical application and results. Retina 2008;28:56–59.
19.
Stopa M, Lincoff A, Lincoff H: Analysis of forces acting upon submacular hemorrhage in pneumatic displacement. Retina 2007;27:370–374.
20.
Holladay JT: Visual acuity measurements. J Cataract Refract Surg 2004;30:287–290.
21.
Ohji M, Saito Y, Hayashi A, Lewis JM, Tano Y: Pneumatic displacement of subretinal hemorrhage without tissue plasminogen activator. Arch Ophthalmol 1998;116:1326–1332.
22.
Gopalakrishan M, Giridhar A, Bhat S, Saikumar SJ, Elias A, et al: Pneumatic displacement of submacular hemorrhage: safety, efficacy, and patient selection. Retina 2007;27:329–334.
23.
Ron Y, Ehrlich R, xer-Siegel R, Rosenblatt I, Weinberger D: Pneumatic displacement of submacular hemorrhage due to age-related macular degeneration. Ophthalmologica 2007;221:57–61.
24.
Cakir M, Cekic O, Yilmaz OF: Pneumatic displacement of acute submacular hemorrhage with and without the use of tissue plasminogen activator. Eur J Ophthalmol 2010;20:565–571.
25.
Fang IM, Lin YC, Yang CH, Yang CM, Chen MS: Effects of intravitreal gas with or without tissue plasminogen activator on submacular haemorrhage in age-related macular degeneration. Eye (Lond) 2009;23:397–406.
26.
Mizutani T, Yasukawa T, Ito Y, Takase A, Hirano Y, Yoshida M, Ogura Y: Pneumatic displacement of submacular hemorrhage with or without tissue plasminogen activator. Graefes Arch Clin Exp Ophthalmol 2011;249:1153–1157.
27.
Yang PM, Kuo HK, Kao ML, Chen YJ, Tsai HH: Pneumatic displacement of a dense submacular hemorrhage with or without tissue plasminogen activator. Chang Gung Med J 2005;28:852–859.
28.
Tsymanava A, Uhlig CE: Intravitreal recombinant tissue plasminogen activator without and with additional gas injection in patients with submacular haemorrhage associated with age-related macular degeneration. Acta Ophthalmol 2011 Feb 18. doi 10.1111/ j.1755-3768.2011.02115.x, Epub ahead of print.
29.
Chen CY, Hooper C, Chiu D, Chamberlain M, Karia N, Heriot WJ: Management of submacular hemorrhage with intravitreal injection of tissue plasminogen activator and expansile gas. Retina 2007;27:321–328.
30.
Handwerger BA, Blodi BA, Chandra SR, Olsen TW, Stevens TS: Treatment of submacular hemorrhage with low-dose intravitreal tissue plasminogen activator injection and pneumatic displacement. Arch Ophthalmol 2001;119:28–32.
31.
Hassan AS, Johnson MW, Schneiderman TE, Regillo CD, Tornambe PE, Poliner LS, Blodi BA, Elner SG: Management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement. Ophthalmology 1999;106:1900–1906.
32.
Hattenbach LO, Klais C, Koch FH, Gumbel HO: Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions. Ophthalmology 2001;108:1485–1492.
33.
Hesse L, Schmidt J, Kroll P: Management of acute submacular hemorrhage using recombinant tissue plasminogen activator and gas. Graefes Arch Clin Exp Ophthalmol 1999;237:273–277.
34.
Krepler K, Kruger A, Tittl M, Stur M, Wedrich A: Intravitreal injection of tissue plasminogen activator and gas in subretinal hemorrhage caused by age-related macular degeneration. Retina 2000;20:251–256.
35.
Meier P, Zeumer C, Jochmann C, Wiedemann P: Management of submacular hemorrhage by tissue plasminogen activator and SF(6) gas injection. Ophthalmologe 1999;96:643–647.
36.
Schulze SD, Hesse L: Tissue plasminogen activator plus gas injection in patients with subretinal hemorrhage caused by age-related macular degeneration: predictive variables for visual outcome. Graefes Arch Clin Exp Ophthalmol 2002;240:717–720.
37.
Buhl M, Scheider A, Schonfeld CL, Kampik A: Intra-vitreal rt-PA and gas introduction in submacular hemorrhage. Ophthalmologe 1999;96:792–796.
38.
Framme C, Toukhy HE, Sachs HG, Spiegel D, Roider J, Gabel VP, Lohmann CP: Clinical results of intravitreal administration of tissue-type plasminogen activator (tPA) and gas for removal of subretinal hemorrhage in senile macular degeneration. Klin Monbl Augenheilkd 2000;216:33–39.
39.
Hattenbach LO, Brieden M, Koch F, Gumbel H: Intravitreal injection of rt-PA and gas in the management of minor submacular haemorrhages secondary to age-related macular degeneration. Klin Monbl Augenheilkd 2002;219:512–518.
40.
Kung YH, Wu TT, Hong MC, Sheu SJ: Intravitreal tissue plasminogen activator and pneumatic displacement of submacular hemorrhage. J Ocul Pharmacol Ther 2010;26:469–474.
41.
Ratanasukon M, Kittantong A: Results of intravitreal tissue plasminogen activator and expansile gas injection for submacular haemorrhage in Thais. Eye (Lond) 2005;19:1328–1332.
42.
Tsai SC, Lin JM, Chen HY: Intravitreous recombinant tissue plasminogen activator and gas to treat submacular hemorrhage in age-related macular degeneration. Kaohsiung J Med Sci 2003;19:608–616.
43.
Wu TT, Kung YH, Hong MC: Vitreous hemorrhage complicating intravitreal tissue plasminogen activator and pneumatic displacement of submacular hemorrhage. Retina 2011;31:2071–2077.
44.
Guthoff R, Guthoff T, Meigen T, Goebel W: Intravitreous injection of bevacizumab, tissue plasminogen activator, and gas in the treatment of submacular hemorrhage in age-related macular degeneration. Retina 2011;31:36–40.
45.
Mayer WJ, Hakim I, Haritoglou C, Gandorfer A, Ulbig M, Kampik A, Wolf A: Efficacy and safety of recombinant tissue plasminogen activator and gas versus bevacizumab and gas for subretinal haemorrhage. Acta Ophthalmol 2011 Sep 22. doi 10.1111/ j.1755-3768.2011.02264.x, Epub ahead of print.
46.
Sandhu SS, Manvikar S, 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.
47.
Fine HF, Iranmanesh R, Del Priore LV, Barile GR, Chang LK, Chang S, Schiff WM: Surgical outcomes after massive subretinal hemorrhage secondary to age-related macular degeneration. Retina 2010;30:1588–1594.
48.
Treumer F, Klatt C, Roider J, Hillenkamp J: Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related macular degeneration with submacular haemorrhage. Br J Ophthalmol 2010;94:48–53.
49.
Kamei M, Estafanous M, Lewis H: Tissue plasminogen activator in the treatment of vitreoretinal diseases. Semin Ophthalmol 2000;15:44–50.
50.
Ranby M, Bergsdorf N, Nilsson T: Enzymatic properties of the one- and two-chain form of tissue plasminogen activator. Thromb Res 1982;27:175–183.
51.
Bunt-Milam AH, Saari JC, Klock IB, Garwin GG: Zonulae adherentes pore size in the external limiting membrane of the rabbit retina. Invest Ophthalmol Vis Sci 1985;26:1377–1380.
52.
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. Am J Ophthalmol 1999;128:739–746.
53.
Hrach CJ, Johnson MW, Hassan AS, Lei B, Sieving PA, Elner VM: Retinal toxicity of commercial intravitreal tissue plasminogen activator solution in cat eyes. Arch Ophthalmol 2000;118:659–663.
54.
Johnson MW, Olsen KR, Hernandez E, Irvine WD, Johnson RN: Retinal toxicity of recombinant tissue plasminogen activator in the rabbit. Arch Ophthalmol 1990;108:259–263.
55.
Luke M, Januschowski K, Warga M, Beutel J, Leitritz M, Gelisken F, Grisanti S, Schneider T, Luke C, Bartz-Schmidt KU, Szurman P: The retinal tolerance to bevacizumab in co-application with a recombinant tissue plasminogen activator. Br J Ophthalmol 2007;91:1077–1082.
56.
Chen SN, Yang TC, Ho CL, Kuo YH, Yip Y, Chao AN: Retinal toxicity of intravitreal tissue plasminogen activator: case report and literature review. Ophthalmology 2003;110:704–708.
57.
Feiner L, Barr EE, Shui YB, Holekamp NM, Brantley MA Jr: Safety of intravitreal injection of bevacizumab in rabbit eyes. Retina 2006;26:882–888.
58.
Manzano RP, Peyman GA, Khan P, Kivilcim M: Testing intravitreal toxicity of bevacizumab (avastin). Retina 2006;26:257–261.
59.
Sari A, Adiguzel U, Canacankatan N, Yilmaz N, Dinc E, Oz O: Effects of intravitreal bevacizumab in repeated doses: an experimental study. Retina 2009;29:1346–1355.
60.
Heiduschka P, Julien S, Hofmeister S, Bartz-Schmidt KU, Schraermeyer U: Bevacizumab (avastin) does not harm retinal function after intravitreal injection as shown by electroretinography in adult mice. Retina 2008;28:46–55.
61.
Ameri H, Chader GJ, Kim JG, Sadda SR, Rao NA, Humayun MS: The effects of intravitreous bevacizumab on retinal neovascular membrane and normal capillaries in rabbits. Invest Ophthalmol Vis Sci 2007;48:5708–5715.
62.
Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T: Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009;116:57–65.
63.
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY: Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431.
64.
Lux A, Llacer H, Heussen FM, Joussen AM: Non-responders to bevacizumab (avastin) therapy of choroidal neovascular lesions. Br J Ophthalmol 2007;91:1318–1322.
65.
van Bilsen K, van Hagen PM, Bastiaans J, van Meurs JC, Missotten T, Kuijpers RW, Hooijkaas H, Dingjan GM, Baarsma GS, Dik WA: The neonatal Fc receptor is expressed by human retinal pigment epithelial cells and is downregulated by tumour necrosis factor-alpha. Br J Ophthalmol 2011;95:864–868.
66.
Klettner A, Puls S, Treumer F, Roider J, Hillenkamp J: Compatibility of recombinant tissue plasminogen activator and bevacizumab co-applied for neovascular age-related macular degeneration with submacular hemorrhage. Arch Ophthalmol 2012;130:875–881.
67.
Glatt H, Machemer R: Experimental subretinal hemorrhage in rabbits. Am J Ophthalmol 1982;94:762–773.
68.
Bhisitkul RB, Winn BJ, Lee OT, Wong J, Pereira DS, Porco TC, He X, Hahn P, Dunaief JL: Neuroprotective effect of intravitreal triamcinolone acetonide against photoreceptor apoptosis in a rabbit model of subretinal hemorrhage. Invest Ophthalmol Vis Sci 2008;49:4071–4077.
69.
Gillies A, Lahav M: Absorption of retinal and subretinal hemorrhages. Ann Ophthalmol 1983;15:1068–1074.
70.
el Baba F, Jarrett WH, Harbin TS Jr, Fine SL, Michels RG, Schachat AP, Green WR: Massive hemorrhage complicating age-related macular degeneration. Clinicopathologic correlation and role of anticoagulants. Ophthalmology 1986;93:1581–1592.
71.
Scupola A, Coscas G, Soubrane G, Balestrazzi E: Natural history of macular subretinal hemorrhage in age-related macular degeneration. Ophthalmologica 1999;213:97–102.
72.
Lewis H: Intraoperative fibrinolysis of submacular hemorrhage with tissue plasminogen activator and surgical drainage. Am J Ophthalmol 1994;118:559–568.
73.
Morse LS, Benner JD, Hjelmeland LM, Landers MB, III: Fibrinolysis of experimental subretinal haemorrhage without removal using tissue plasminogen activator. Br J Ophthalmol 1996;80:658–662.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.