Central retinal vein occlusion associated with thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome: Complete resolution is possible
SA Issa, Q Qasem
Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, NE4 9JA, United Kingdom
S A Issa
Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, NE4 9JA
We aim to describe a case of central retinal vein occlusion associated with this is a case report of a 45-year-old patient who was admitted for management of thrombotic thrombocytopenic purpura (TTP). He developed left central retinal vein occlusion three months later. The retinal vein occlusion resolved gradually as his TTP started to respond to medical treatment but significant macular edema persisted. Focal argon laser treatment resulted in complete resolution of the macular edema.
|How to cite this article:|
Issa S A, Qasem Q. Central retinal vein occlusion associated with thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome: Complete resolution is possible.J Postgrad Med 2007;53:183-184
|How to cite this URL:|
Issa S A, Qasem Q. Central retinal vein occlusion associated with thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome: Complete resolution is possible. J Postgrad Med [serial online] 2007 [cited 2022 Jun 30 ];53:183-184
Available from: https://www.jpgmonline.com/text.asp?2007/53/3/183/33862
Thrombotic thrombocytopenic (TTP) purpura is an uncommon disease with an incidence of (1/1,000,000) and the age range is 5 to 86 with a female to male ratio of 3:2.  It is characterized by: fever, microangiopathic hemolytic anemia, thrombocytopenia, neurological abnormalities and renal impairment.  Without daily plasmapheresis, the mortality rate is 90%.  The triad of clinical features: microangiopathic hemolytic anemia, thrombocytopenia and uremia, constitutes hemolytic uremic syndrome (HUS). The distinction between TTP and HUS is not relevant for initial treatment. Hemolytic anemia and thrombocytopenia are the most frequent clinical indicators and sufficient to establish the diagnosis of TTP/HUS and to initiate plasmapheresis.  Patients with TTP can get central retinal vein occlusion,  Purtscher retinopathy, , bilateral combined occlusions of central retinal artery and vein  or exudative detachments. 
We report a 45-year-old male who presented in January 2003 with a history of being ill 10 days previously with severe bloody diarrhea, which required hospital admission. Significant colitis was seen at endoscopy but stools were negative for infection. Histology was suggestive of either pseudomembranous colitis or ischemic colitis. He responded to supportive measures (metronidazole and corticosteroids) and was discharged home after one week.
Thereafter, he was well for two days. Then he became unwell, feeling weak and thirsty when he presented to the hematology department. Investigations confirmed the presence of a micro-angiopathic hemolytic anemia with hemoglobin 12.1 g/dL, platelet count 15 ´ 10 9 /L and white cell count 10 ´ 10 9 /L. Lactate dehydrogenase (LDH) was raised to 900U/L and coagulation screen was normal. Urea was 19 mmol/L, creatinine 208 micromol/L and urinalysis revealed protein +++. Stools were negative for infection (including specific cultures for E. coli 0157).
He was commenced on intravenous hydrocortisone (250 mg every six hours) with subsequent rapid improvement in his symptoms. A diagnosis of TTP/HUS was suspected and plasma exchange was started (the replacement solution for plasmapheresis in this disease is plasma or cryo poor plasma and not albumin as is the case with all other conditions requiring plasmapheresis). After daily plasma exchange for 33 days his platelet count increased to 126 ´ 10 9 /L. Renal functions returned to normal, although trace protein has persisted on urinalysis. LDH decreased to 598U/L. Plasma exchange and steroids were gradually reduced over the next month. However, the LDH rose to 823U/L, so oral cyclosporin-A (2.5 mg/kg a day in two divided doses) was introduced (March) but his condition was refractory to treatment.
In April, he developed sudden onset of blurred vision in his left eye. Examination showed right visual acuity of 6/6 and left acuity of 6/60. There was no relative afferent papillary defect and fundoscopy revealed dot retinal hemorrhages, tortuous vessels and significant macular edema. Fundus flourescein angiography showed changes consistent with central retinal vein occlusion. Given the climbing LDH and the new ocular signs, and after exclusion of an occult infection, plasma exchange was increased and intravenous rituximab (375 mg/m 2 ) was also commenced. The platelet count and LDH started to improve after starting rituximab. A month after initiation of rituximab treatment, his left visual acuity improved to 6/24 and fundoscopy showed resolving hemorrhages but persistent macular edema. By June the retinal hemorrhages completely resolved and the macular edema was slightly reduced improving his left vision to 6/12. Focal argon laser treatment was given at that stage which resulted in complete resolution of the macular edema and his left vision was 6/6 in July.
Adjuvant therapy with rituximab and vincristine (slow intravenous infusion of 1 mg once a week) was even needed before his condition started to improve. His last plasma exchange was in August and since then his blood counts stayed stable and within normal limits and he did not have further relapses until his last visit in March '05.
The mechanism of tissue damage in TTP is not fully understood. Endothelial cell injury and retinal vascular thrombosis are regarded to be important in the pathophysiology. Histopathology shows localized thrombi composed mainly of platelets in the involved and uninvolved vessels. , Similar histopathologic findings have been reported for ocular manifestations of TTP.  A milestone was reached with the discovery of defective degradation of von Willebrand Factor (vWF) by a newly described metalloprotease. Patients with TTP have severe deficiency of vWF-cleaving protease, whereas patients with HUS have normal levels. In most cases of nonfamilial TTP, an immunoglobulin-G antibody to the protease was identified. The protease was identified as a member of the ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin motif-13) metalloprotease family and the responsible gene was mapped to Chromosome 9q34. 
Most patients with TTP respond to treatment with PE. However, a substantial fraction of idiopathic TTP cases (10%-20%) might not respond to PE alone and, therefore, interest has been gathering around the use of rituximab and vincristine. Rituximab is a monoclonal antibody that induces a sustained depletion of B-cells. There have been reports of refractory TTP in which the combined use of plasma exchange and rituximab was associated with full resolution.  Others reported the benefit of vincristine to be attributed to inducing immediate increase in ADAMTS-13 activity. 
The main weaknesses in our report include the fact that the clinical picture was a mixture, TTP/HUS, due to lack of fever and neurological abnormalities. However, development of CRVO implies a more widespread process than HUS, supporting diagnosis of TTP. Although the disease course was very long for TTP, the initial presentation, blood investigations and initial good response to intravenous steroids and daily plasma exchange made diagnosis of TTP very likely. Another weakness is the lack of a frozen sample to measure ADAMTS-13. The patient had some investigations for secondary causes of TTP, though not extensive, including an autoimmune screen and cultures for E. coli 0157 which were negative.
To our knowledge, this case is unique in that the central retinal vein occlusion resolved completely with the resolution of the underlying TTP/HUS. This shows that medical treatment of TTP, even if refractory at the beginning with appropriate ophthalmologic management can reverse the associated ocular pathology and improve the patient's vision to normal.
|1||Terrell DR, Williams LA, Vesely SK, Lammle B, Hovinga JA, George JN. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: All patients, idiopathic patients and patients with severe ADAMTS-13 deficiency. J Thromb Haemost 2005;3:1432-6.|
|2||Elkins SL, Wilson PP Jr, Files JC, Morrison FS. Thrombotic thrombocytopenic purpura: Evolution across 15 years. J Clin Apher 1996;11:173-5.|
|3||Murphy PT, Rao P. Central retinal venous occlusion with co-existent thrombotic thrombocytopenic purpura and antiphospholipid syndrome. Br J Ophthalmol 2003;87:658-9.|
|4||Patel MR, Bains AK, O'Hara JP, Kallab AM, Marcus DM. Purtscher retinopathy as the initial sign of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Arch Ophthalmol 2001;119:1388-9.|
|5||Percival SP. Ocular findings in thrombotic thrombocytopenic purpura (Moschowitz's disease). Br J Ophthalmol 1970;54:73-8.|
|6||Power MH, Regillo MC, Custis PH. Thrombotic thrombocytopenic purpura associated with Purtscher retinopathy. Arch Ophthalmol 1997;115:128-9.|
|7||Schwartz SG, McPherson AR, Mieler WF, Sessoms SL, Moake JL, Holz ER. Bilateral combined occlusion of the central retinal artery and vein secondary to thrombotic thrombocytopenic purpura. Arch Ophthalmol 2000;118:1304-5.|
|8||Melton RC, Spaide RF. Visual problems as a presenting sign of thrombotic thrombocytopenic purpura. Retina 1996;16:78-80.|
|9||Costa JR, Krause M, Friedman E, D'Amico DJ. Central retinal vein occlusion in a patient with thrombotic thrombocytopenic purpura. Am J Ophthalmol 2001;131:669-71.|
|10||Mayer SA, Aledort LM. Thrombotic microangiopathy: Differential diagnosis, pathophysiology and therapeutic strategies. Mt Sinai J Med 2005;72:166-75.|
|11||Darabi K, Berg AH. Rituximab can be combined with daily plasma exchange to achieve effective B-cell depletion and clinical improvement in acute autoimmune TTP. Am J Clin Pathol 2006;125:592-7.|
|12||Bohm M, Betz C, Miesbach W, Krause M, von Auer C, Geiger H, et al . The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine. Br J Haematol 2005;129:644-52.|