PROLIFERATIVE DIABETIC RETINOPATHY IN PATIENTS WITH DEFECTS OF PLATELET FUNCTION P A T R I C K C. H O , M.D., S T E P H E N S. F E M A N , M.D., R I C H A R D S. S T E I N , M.D., AND L. C L I F F O R D M C K E E , M.D. Nashville,

Increased rates of intravascular coagu­ lation have been implicated in the genesis of proliferative diabetic retinopathy. 1 - 9 Enhanced platelet functions have been reported to initiate this hypercoagulation. 2 - 8 For this reason, drugs that reduce platelet activity may play a role in the prevention of proliferative diabetic reti­ nopathy. Many investigators are explor­ ing this hypothesis; for example, a large collaborative study involving multiple medical centers, the "Early TreatmentDiabetic Retinopathy Study," is designed to examine different drug regimens. We describe herein two patients who had proliferative diabetic retinopathy and diminished platelet activity, and compare the unexpected hematologic findings with prevalent theories. CASE REPORTS Case 1—A 71-year-old woman developed a bleed­ ing problem in 1945. She was noted to have diabetes mellitus in 1964. In 1969, because her Factor VIII level was 7% and platelet adhesiveness was de­ creased, the diagnosis of von Willebrand's disease was established. In May 1978, she developed a subhyaloid hemorrhage in the right eye. In the left eye, intraretinal microvascular abnormalities, hem­ orrhages, exudates, and macular edema were noted along with one-half disk area of neovascularization on the optic nerve. Hematologic tests determined Factor VIII activity, 22% of normal (100 to 150%); From the Departments of Ophthalmology (Drs. Ho and Feman), and Medicine (Drs. Stein and McKee), Vanderbilt University School of Medicine, Nashville, Tennessee. This study was supported in part by National Institutes of Health Training Grant No. 5T32EY07007 and an unrestricted grant from Research to Prevent Blindness, Inc. This study was presented in part at the Macula Society meeting, Key Biscayne, Florida, Jan. 12, 1979. Reprint requests to Stephen S. Feman, M.D., Department of Ophthalmology, School of Medicine, Vanderbilt University, Nashville, TN 37232.

Tennessee

Factor VIII antigen, less than 1%; ristocetin platelet aggregation, pathologically reduced; and bleeding time, 12 minutes (Table). 10 To reduce the risk of vitreous hemorrhage in the left eye, photocoagulation was recommended. 1 1 A transfusion of two units of fresh frozen plasma was followed by focal treat­ ment and panretinal photocoagulation. Case 2—A 59-year-old man was noted to have had increased bleeding after dental surgery in 1949, and multiple episodes of spontaneous epistaxis. He had diabetes mellitus in 1960. Increased numbers of platelets and leukocytosis were reported in his pe­ ripheral blood samples in 1972. In 1977, he had a leukocytosis of 16,800/mm 3 and a platelet count of 2.5 million/mm 3 that had been produced by a myeloproliferative disorder with thrombocythemia. This was controlled with busulfan. In May 1978, he developed an intravitreous hemorrhage in the right eye. One third of the left optic nerve head was covered with neovascularization. His lengthened bleeding time led to the diagnosis of a defect of platelet function associated with the myeloproliferative process. The tests performed (Table) confirmed the abnormality of platelet activity; the decreased platelet aggregation was the result of the underlying disorder. Busulfan therapy, to the best of our knowl­ edge, has never been reported to cause such chang­ es. 10 To reduce the risk of intravitreal hemorrhage in the left eye, photocoagulation was recommended. 1 1 A transfusion of platelets was followed by argon laser panretinal photocoagulation. DISCUSSION

Some investigators believe that focal ischemia plays a role in the cause of proliferative diabetic retinopathy. They suggest that focal arteriole occlusions produce this ischemia. 2 ' 12,13 Several phe­ nomena in diabetes mellitus patients may lead to the formation of the microvascular thrombi that can produce arteriole occlu­ sions. 1 " 9 ' 1 2 - 1 4 Increased platelet adhesiveness and ag­ gregation, a modality of microcirculatory sludging and focal ischemia, is found in many diabetic patients. 3 - 8 ' 1 3 ' 1 4 The adhe­ siveness is attributed to a heat soluble, nondialyzable factor in diabetic plasma. 7

AMERICAN JOURNAL O F OPHTHALMOLOGY 88:37-39, 1979

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JULY, 1 9 7 9

TABLE H E M A T O L O G I C F I N D I N G S A T DISCOVERY o r D I A B E T I C P R O L I F E R A T I V E R E T I N O P A T H Y

Patient No. 1 3

Platelets/mm Bleeding time (Normal, 6 minutes) Platelet adhesiveness (Normal, 25-65%) Platelet aggregation With adeninediphosphate With collagen With ristocetin With epinephrine Factor VIII level (functional) Factor VIII level (antigenic) Prothrombin time (Patient/control) Partial thromboplastin time (Patient/control)

Patient No. 2

222,000

129,000*

12 min 10%

72%

Normal Normal Decreased Normal 22% 1% 10/10

Normal Decreased Decreased Decreased 120% Not Tested 9/10

34/32

23/31

*Before onset of busulfan therapy this patient's platelet count was 2.5 million/mm 3

Adeninediphosphate induced hyperag­ gregation is related to a plasma membrane factor identified on the platelets of diabet­ ics. 3 Immunofluorescence studies re­ vealed that the retinal vessel intima of diabetics contains a protein, antigenically related to the von Willebrand factor, capable of inducing the ad­ hesion-aggregation of platelets. 14 Addi­ tionally, increased circulating levels of von Willebrand factor, a plasma cofactor of platelet function is identified in many patients with proliferative diabetic retino­ pathy. 1 ' 2 ' 5,8 Our patients had proliferative diabetic retinopathy and defects causing a reduc­ tion of platelet function. This suggests that increased platelet activity may not be a requirement for the development of retinal vascular disease. Whereas the changes in platelet function produced by drugs differ from the defects seen in these patients, our findings indicate that such drugs may not be effective in the manage­ ment of diabetic retinopathy. Therefore, alternate mechanisms for the production of diabetic neovascularization warrant in­ vestigation.

SUMMARY

A 71-year-old woman had von Willebrand's disease, an inheritable abnormal­ ity of platelet activity, and developed diabetic retinal neovascularization. A 59year-old man had a myeoloproliferative disorder with thrombocythemia but may have had retinal changes before the de­ velopment of his platelet dysfunction. The occurrence of diabetic proliferative retinopathy in patients with reduced platelet activity suggests that platelet in­ d u c e d microcirculatory abnormalities may not be required for neovasculariza­ tion. REFERENCES 1. Little, H. L., and Sacks, A. H.: T h e role of abnormal blood rheology in the pathogenesis of diabetic retinopathy. Trans. Am. Acad. Ophthalmol. Otolaryngol. 83:522, 1977. 2. Little, H. L., Sacks, A., Vassiliadis, A., and Greer, R.: Current concepts on pathogenesis of diabetic retinopathy. A dysproteinemia. Trans. Am. Ophthalmol. Soc. 75:397, 1977. 3. Bensoussan, D., Levy-Toledano, S., Passa, P., Caen, J., and Canever, J.: Platelet hyperaggregation and increased plasma level of von Willebrand factor in diabetics with retinopathy. Diabetologia 11:307, 1975.

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4. Dobbie, J. G., Kwaan, H. D., Colwell, J. A., and Suwanwela, N.: The role of platelets in pathogenesis of diabetic retinopathy. Trans. Am. Acad. Ophthalmol. Otolaryngol. 77:43, 1973. 5. Coller, B. S., Frank, R. N., Milton, R. C., and Gralnick, R.: Plasma cofactor of platelet function. Correlation with diabetic retinopathy and hemoglo­ bins Ala.c. Ann. Intern. Med. 88:311, 1978. 6. Heath, H., Brigden, W. D., Canever, J. V., Pol­ lock, J., Hunter, P. R., Kelsey, J., and Bloom, A.: Platelet adhesiveness and aggregation in relation to diabetic retinopathy. Diabetologia 7:308, 1971. 7. Kwaan, H. C., Colwell, J. A., Cruz, S., Suwan­ wela, N., and Dobbie, J. G.: Increased platelet ag­ gregation in diabetes mellitus. J. Lab. Clin. Med. 80:236, 1972. 8. Pandolfi, M., Aimer, L. O., and Holmbert, L.: Increased von Willebrand-antihemophilic factor A in diabetic retinopathy. Acta. Ophthalmol. 52:823, 1974. 9. Aimer, L. O., Pandolfi, M., and Osterlin, S.: The fibrinolytic system in patients with diabetes

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mellitus with special reference to diabetic retinopa­ thy. Ophthalmologica (Basal) 170:353, 1975. 10. Weiss, H. J.: Platelet physiology and abnor­ malities of platelet function. N. Engl. J. Med. 293: 531, 1975. 11. The Diabetic Retinopathy Study Research Group: Photocoagulation treatment of proliferative diabetic retinopathy. The second report of diabetic retinopathy study findings. Trans. Am. Acad. Oph­ thalmol. Otolaryngol. 85:82, 1978. 12. Ashton, N.: Studies of the retinal capillaries in relation to diabetic and other retinopathies. Br. J. Ophthalmol. 47:521, 1963. 13. O'Malley.B. C , Timperly, W. R.,Ward,J. D., Porter, N. R., and Preston, F. E.: Platelet abnormali­ ties in diabetic peripheral neuropathy. Lancet 1: 1274, 1975. 14. Pandolfi, M., Holmbert, L., and Turesson, I.: Coagulation and platelet adhesion-inducing factor in the endothelium of the retinal vessels. Am. J. Ophthalmol. 80:47, 1975.

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Proliferative diabetic retinopathy in patients with defects of platelet function.

PROLIFERATIVE DIABETIC RETINOPATHY IN PATIENTS WITH DEFECTS OF PLATELET FUNCTION P A T R I C K C. H O , M.D., S T E P H E N S. F E M A N , M.D., R I C...
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