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Year : 1981  |  Volume : 29  |  Issue : 3  |  Page : 277-282

Platelet aggregation in diabetic retinopathy

Dr. Rajendra Prasad Centre for Ophthalmic Sciences and Department of Pathology, A.I.I.M.S. New Delhi, India

Correspondence Address:
P K Khosla
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, New Delhi 29
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Source of Support: None, Conflict of Interest: None

PMID: 7346443

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How to cite this article:
Khosla P K, Mahabaleshwara M, Tewari H K, Saraya A K. Platelet aggregation in diabetic retinopathy. Indian J Ophthalmol 1981;29:277-82

How to cite this URL:
Khosla P K, Mahabaleshwara M, Tewari H K, Saraya A K. Platelet aggregation in diabetic retinopathy. Indian J Ophthalmol [serial online] 1981 [cited 2023 Jun 1];29:277-82. Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?1981/29/3/277/30901

Diabetic Retinopathy is significant due to its morbidity and help it affords in recognition of vascular component of the disease. The know­ledge of its natural history may help us to arrest its further progress. Its pathogenesis is still an enigma. The value of various parameters studied (hypergIycaemia, elevated fatty acids and even growth hormone) have been equivo­cal but now one thing is getting clear on the basis of fluorescein angiography that dia­betic retinopathy is a manifestation of retinal ischaemia due to obstructive pathology where vascular damage and hypercoagulable states play significant role. Role of platelets in these will be outstanding as these may adhere to diseased vessel wall or platelet aggregates may induce vessel wall lesion creating a hypoxic environment. Several authors[1],[2],[3] have repor­ted increased platelet aggregation in diabetic retinopathy patients while it is also reported [4] in early diabetes mellitus without retinopathy but exact mechanism is not clarified.

This study was undertaken to study platelet hyper aggregation in cases of diabetes without or with retinopathy and to know the exact mechanism of aggregation.

  Materials and methods Top

10 patients each of diabetes without (Group I) and with retinopathy (Group II) were taken up for study -clinical examination, biochemical investigations were done in addition to fluorescein angiography to exactly delineate the changes of retinopathy even at the capillary level.

Platelet aggregation was studied in the above two groups alongwith age and sex matched controls. Platelet aggregation is the term used to denote the adherence of one platelet to another and can be studied by adding aggregating agents to -, platelet rich plasma. A.D.P. (Adenosine-5-diphosphate) as an aggregating agent. The plasma in which platelets are suspended becomes progressively clearer as platelets aggregate and this is recorded [Figure - 1]. Primary aggregation (rever­sible) is due to addition of external aggregating agent and the secondary (irreversible) aggrega­tion is due to release of intrinisic ADP inside platelet after the initial primary aggregation disaggregation can take place. Born's[5] method employing Chronolog Aggregometer was used wherein change in optical density as explained and increment rate of aggregation as computed by the differentiometer hooked to the aggregometer was studied with different concentrations of ADP (0.25μ g and 0.50 μ g). Graphic recordings were analysed statistically with respect to latent period, maximum aggregation as well as its rate and duration.

  Observations Top

Average age of pateints of diabetes without retinopathy was 54 years (SD±16.46) and mean duration of diabetes was 5.72 years (SD + 3.97) while in those with retinopathy­ it was 51.9 years (SD + 9.90) and mean dura­tion of diabetes was 7.42 years (SD±4.90).

No significant difference was observed between diabetics with or without retinopathy regarding fasting or postprandial blood sugar levels and this may support the contention that severity of diabetes does not determine the onset of diabetic retinopathy.

The diabetics with retinopathy showed higher serum cholesterol levels (264 + 68.07) as compared to cases without retinopathy (221±65.90) which were not significant and supports our previous contention.[13]

The fluorescein angiography revealed two types of changes i.e. capillary abnormalities in background retinopathy and new vessel formation (in plane of retina or off its plane into the vitreous) in proliferative retinopathy. Basic defect seen in all the cases was the areas of nonperfusion. The capillary abnormalities including dilation of capillary system and formation of microaneurysms were seen in the areas of nonperfusion (hypoxic areas due to vasoobstructive phenomenon) usually seen clinically as soft exudates. Formation of hard exudates and consequent circinate retinopathy and macular oedema are late developments.

The results of platelet aggregation studied were compiled taking into consideration the latent period, degree of aggregation, rate of aggregation.

Latent period is the period between expo­sure of platelets to aggregating agent and initiation of aggregation and represents initial sensitivity of platelets. Latent period was lower with higher dose in both groups with A.D.P. With A.D.P., latent period was increased in group I and decreased in group II, and the readings were significant from normal and also between the groups.

Degree of aggregation represents percentage of platelets taking part in the aggregation and was more intense with higher concentration of A.D.P. Mean aggregation was significantly greater statistically in Group II (with retino­pathy) as compared to normal and group I where no difference was seen from the controls.

Rate of aggregation on addition of A.D.P. varied with the quantity of aggregating agent i.e. higher rate with greater concentration. Rate was significantly faster statistically in group II (with retinopathy) as compared to normal and group I where no difference was seen from normals.

Mean total duration of aggregation was longer with higher concentration of ADP. The changes in group II from normal and group I were highly suggestive but not statistically significant.

Disaggregation followed primary aggrega­tion with ADP in group I but could not be seen in group 11 where a sharp and prolonged aggregation occurred.

  Discussion Top

Platelet alteration has been reported in Diabetes mellitus although platelet count is found to be normal. Mayne et al[6] found an increase in the level of coagulating factors (fibrinogen and factor VIII) in association with platelet adhesiveness in diabetes which might be responsible for increased incidence of occlusive vascular disease. Jagenson et al[7] has shown vascular lesiondue to platelet aggre­gates and hence these might be responsible for vessel wall change in cases of diabetes mellitus. Heath et al[1] postulated that microthrombi cause­occlusion of micro circulation in diabetes. Bloodsworth et al[8] supported by reporting stru­ctures resembling degenerating platelets in the wall of microaneurysms in patients of diabetic retinopathy. Regnault's[9] electron microscopic study of conjunctival veins in cases of diabetic retinopathy revealed platelet aggregates. It is thus apparent that platelet aggregates may be responsible for development of hypoxic environment in cases of retinal capillary three in diabetes mellitus.

In view of the presence of hypoxic areas in all cases of diabetic retinopathy as seen on fluorescein angiography and the reported in­volvement of platelet aggregates in process of producing obstructive capillary pathology, we wanted to see in detail the process of the aggregability of platelets. A statistical analy­sis of the aggregation reaction as seen from the graphs was done to understand the events leading to altered platelet aggregation as suggested by Barbui and Battisa[10] and to the best of our knowledge it has not been reported in cases of diabetic retinopathy.

The altered platelet - aggregation has been reported but various authors have reported only few parameters each i.e. only rate of aggregation[9] rate and degree[3] duration of aggregation and disaggregation[11].

Latent period was increased in diabetes but was decreased in diabetic retinopathy and was significantly shorter with higher concen­tration of A.D.P. This significant inverse relationship of latent period with A.D.P. dose may be supposed to be due to increased sen­sitivity of platelets and mediated through A.D.P. receptors[12], as has been postulated that A.D.P. is bound on specific receptor on platelets, it is stated that the binding protein may be related to actomyosin and reassocia­tion of dissociated actin myosin on adjacent platelets may cause aggregation. It is not clear whether hyperaggregation occurs due to increase of these substances or in active recep­tor sites. This dose relationship suggests that saturable receptors are sensitive to differing concentrations of the aggregating substance, thus a required stimulus for inducing aggre­gation is achieved with higher concentration in lesser time. The intergroup (between group I & II) differences with A.D.P. suggest that a qualitative change has occurred which could either be due to changed affinity of receptors to bind A.D.P. or due to binding of greater number of active receptors to initiate aggrega­tion in retinopathy cases.

Shorter latent period could be a contribu­tory factor in increased and faster aggregation. The subnormal aggregation in cases with retinopathy and an increased aggregation in diabetes without retinopathy has been reported. Both degree and rate of aggregation is increased in cases with retinopathy as com­pared to those without retinopathy. Study of duration of aggregation in diabetics without retinopathy indicates that aggregation takes place to the same degree in a less than normal duration but in retinopathy group it is longer, indicating that initial aggregation is faster in diabetics and is continued for alonger time in cases with retinopathy which may be either due to increase in number of active receptors or with increased sensitively to A.D.P. or both or due to sustained release of intrinsic A.D.P. causing secondary aggregation merging with primary leading to an increase in degree of aggregation.

Disaggregation occurred in diabetics with­out retinopathy which was comparable to normals while none of the patients with retino­pathy showed significant disaggregation. This suggests that cohesive bond between platelets was stronger in retinopathy patients indicating qualitative change in platelet receptors of A.D.P. or their increased sensititity. While studying secondary aggregation, absence of aggregation following disaggregation in normals and diabetics without retinopathy and conti­nued aggregation in patients with retinopathy suggests a greater release of intrinsic A.D.P. in retinopathy cases sufficient to induce second­ary aggregation. These findings also indicate that diabetes alone is not associated with changes in platelet aggaegation.

We can presume on the basis of the above study that in cases of diabetics without retino­pathy there is increase in number of A.D.P. bound receptors with subnormal sensitivity manifesting as a sharp and short normal aggregation once initiated after an initial lag. Perhaps effect gained by increased receptors is nullified by poor sensitivity. However, in cases with diabetic retinopathy, there is incre­ased number of active receptors on platelets associated with increased senstivity to A.D.P. leading to a shorter time for induction of aggregation, higher velocity and greater release of intrinsic ADP leading to continued aggregation.

An equivocal correlation was found bet­ween serum cholestrol level and degree of aggregation. Platelet function and lipid meta­bolism may be linked as platelet aggregation is increased when human platelets are enriched in cholestrol by incubation and also A.D.P. induced platelet aggregation is increased in patients with raised level of low density lipo­proteins so it is proposed that a detailed study of parameters of fat metabolism in cases of diabetic retinopathy should be carried out and compared statistically to the parameters of platelet dysfunction.

It is also possible that in diabetic retino­pathy some plasma factor may be responsible for increased aggregation which may be A.H. factor or Von Willbrand factor or LASS related to prostaglandins PGE[2] and such a release of endogenous prostaglandin may well be one of the fundamental mechanisms.

Intrinsic A.D.P. release is responsible for secondary aggregation and our studies have shown continued aggregation in which primary agreggation could not be delineated from secondary indicating a quicker and greater release of A.D.P. in cases with retinopathy. This greater reactivity of platelets could also be due to increase in its energy metabolism. It is known that ATP is required for platelet reactions and for release of endogenous A.D.P. Role of prostaglandings in mediating release of A.D.P. has also been emphasized through its precursor (Labile Aggregation Stimulating Substance-LASS).

It is proposed, that retinopathy and altered platelet reactivity may be aetiopathogenetically related. Increased sensitivity of platelets to A.D.P. together with increased reactivity to aggregate and release intrinsic ADP may cause hyperaggregation and maybe due to increased affinity of A.D.P. receptors and changes in platelet metabolism wherein release of intrinsic A.D.P. is accelerated.

Once we believe that platelet hyPeraggre­gation is an important mechanism in the chain of events of microangiopathy, it can open new vistas of treatment by altering of either (i) increased sensitivity of platelets leading to primary aggregation or (ii) release reaction i.e. secondary aggregation or (iii) number of receptors. Pyrimodopynmedine group of drugs inhibit both primary and secondary aggregation. Aspirin affects the platelet release reaction and the action persists during the entire life span of a pletelet. A negative correlation between regular aspirin intake and nonfatal myocardial infraction has been found and even random survey to esta­blish the efficacy of aspirin in preventing myocardial infraction is under way. A similar survey may be contemplated in diabetes and if antiplatelet drugs are beneficial in preventing microan; iopathy, one may infer that tests of platelet aggregation would be of direct releva­nce in measuring ocular morbidity[14].

  References Top

Heath, H., Brigden, W.D. ; Canevar, J.V. ; Pollock, J.; Hunter, P.R.; Kelsey, J. and Bloom A. 1971, Diabetologica 7. , 308.  Back to cited text no. 1
Kwaan, H.C., Colwell, J.A. ; Cruz, S. ; Suwan­wala, N. and Dobbie, J.G., 1972, J. Lab. Clin. Med. 80 : 236.  Back to cited text no. 2
Bensoussan, D. ; Levy-Tolendano, Passa, P.; Caeh, J. Canivet, J. 1975, Diabetologica 11, 307.  Back to cited text no. 3
Sagel, J. Colwell, J.A., Crook, L. and Laimins, M., 1975, Ann. Int. Med. 82: 733.  Back to cited text no. 4
Born, G.V.R.; 1962 Nature (London) 194, 927.  Back to cited text no. 5
Mayne, E.E.; Bridges, J.J. ; Weaver, J.A., 1970, Diabetclogica 6 : 436.  Back to cited text no. 6
Jogenson, L. ; Hovig, L., Rowsell H.C.; Mustard J.K. 1970 Amer. J. Pathol. 61 : 161.  Back to cited text no. 7
Bloodworth. J.M.B. and Engermann, R.L., 1971, Acta Diabetologica 8 : 263.  Back to cited text no. 8
Regnault, F. ; Ket n P. 1971 C.R. Soc. Biol. Par s 165, 769.  Back to cited text no. 9
Barbui, T. and Battista, R. 1779 Clin. Lab. 2: 299.  Back to cited text no. 10
Fleishmann, A.I., Biernbaum, M.L., Stier, A. ; Somol, S.H. and Watson, P.B. 1976 Thrombosi Research 9 : 467.  Back to cited text no. 11
Nachman, R.L. ; Ferris, B. 1974 J. Biol. Chem. 249, 704.  Back to cited text no. 12
Khosla, P K., Tewari, H.K., Bajaj, J. S. 1976 Acta Diabetologica-Proc. of IX Cong. Int. Diab. Federation.  Back to cited text no. 13
Khosla, P.K. ; Mahableshwara, M. ; Tewari, H.K. and Saraya, A.K. 1978 Acta Haematologica (In press).  Back to cited text no. 14


  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]


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