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   Table of Contents      
ARTICLES
Year : 1982  |  Volume : 30  |  Issue : 6  |  Page : 605-612

Mechanisms of platelet hyperaggregation in diabetic retinopathy


Dr. Rajendra Prasad Centre for Ophthalmic Sciences, A.II.M.S. New Delhi, India

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


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How to cite this article:
Khosla P K, Seth V, Tewari H K, Saraya A K. Mechanisms of platelet hyperaggregation in diabetic retinopathy. Indian J Ophthalmol 1982;30:605-12

How to cite this URL:
Khosla P K, Seth V, Tewari H K, Saraya A K. Mechanisms of platelet hyperaggregation in diabetic retinopathy. Indian J Ophthalmol [serial online] 1982 [cited 2019 Jun 16];30:605-12. Available from: http://www.ijo.in/text.asp?1982/30/6/605/29296

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Alteration in platelets, in their tendency to hyperaggregate, in diabetic patients with retinopathy has been shown by several workers (1-6). Hyperaggregation has also been shown In prediabetic, latent diabetics, and diabetics without vasculopathy (7). The mechanism of this platelet abnormality is, however, not clearly known.

In the present study total changes in platelets with respect to induction phase, qualitative and quantitative aggregation and the inhibitory affects of acetylsalicylic on the aggregability of platelets, as defined by the parameters recommended by Barbui and Battista (8) have been studied.


  Material and methods Top


Diabetics with or without retinopathy attending the outpatient department were taken up for study. The work up included a detailed clinical examination and laboratory investiga­tion including fluorescein angiography.

Two groups of patients were studied. Group I consisted of thirteen patients of diabetes without retinopathy; the average age of the patients was 53.6 years. the mean duration of diabetes being 4.7 years. Group II consisted of sixteen patients of diabetes with retinopathy; the average age was 53.2 years and the mean duration of diabetes 7.31 years.

Controls were amongst the healthy laboratory workers, doctors and patients of cataract (otherwise healthy) without diabetes and hypertension, and not on any drugs known to affect platelet aggregation atleast ten days prior to study. Platelet aggregation was studied by the method of Born (9) using a chronolo­gaggregometer. The change in optical density and the increment rate of aggregation as com­puted by the differentiometer connected to the aggregometer were studied with collagen and arachidonic acid.

Platelet aggregation was studied with 1.0,0 50 and 0.25 sg. of collagen and with 300 and 15014g. of arachidonic acid in 0.02 ml imidazole buffer, ph. 7.2/0. 4 ml. of platelet rich plasma (plate let count 300,000/ml).

The effect of acetyl salicylic acid on collagen and arachidonic acid induced aggregation was studied, both invivo and invitro. Inviro 900 mg. of acetylsalicyclic acid was given in two divided doses, one 48 hours, and the other 24 hours, before the experiment. For invitro studies acetylsalicyclic acid in strength of 2 mg/20u1 of distilled water was employed. All the graphic recordings were analysed statistically with respect to latent period (L.P) and maximum aggregation as well as its rate and duration by the student `t' test.


  Results Top
[Table - 1][Table - 2][Table - 3][Table - 4]

The response was dose related both with collagen and arachidonic acid, but for the L.P. [Table - 1][Table - 2].

The L.P. was significantly shorter in patients than normal subjects. Group IL patients showed the shortest latent period. Both groups of patients showed a faster rate, greater degree and longer duration of aggre­gation with all doses of collagen but with only 300 pg. of arachidonic acid, the results being statistically significant [Table - 1][Table - 2]. Com­parison between the two groups of patients showed aggregation to be more in Group 11 though significant differences was seen only in duration (I µg collagen) and degree (300 pg arachidonic acid) of aggregation. Disaggrega­tion was seen more frequently in controls.

Acetylsalicylic acid, both invivo and invitro, effectively blocked, the rate, degree and duration of aggregation with both collagen and arachidonic acid, the L.P. not being affected. The residual aggregation in patients was significantly greater than that in normals [Table - 3][Table - 4]. In the doses employed, acetylsalicyclic acid reversed the hyperaggre­gated state in diabetic patients

Studying the affect of invivo and invitro acetylsalicyclic acid it was seen that invitro acetylsalicyclic acid had a greater blocking effect on rate and degree of collagen induced aggregation in both normals and patients. On archidonic acin induced aggregation, no diffe­rence was seen in patients though the normals showed a greater blocking effect with invivo acetylsalicyclic acid. Disaggregation was brought only with invitro acetylsalicyclic acid and was seen to occur in a greater percent­age of normals as compared to patients [Table - 4].


  Discussion Top


Parameters of platelet function studied show distinct differences between normal subjects and patients. The latter show a shorter L.P., and a greater rate, degree and duration of aggregation, the differences being more marked when compared with diabetics with retinopathy (Group II).

Collagen brings about aggregation mainly by the cyclo-oxygenase mediated pathway [Figure - 1]. Arachidonic acid is a substrate for cyclo-oxygenase. This enzyme catalyses the conversion of arachidonic acid to the prosta­glandin endoperoxides PGG 2 and PGH, (10,11) which display aggregating activity (12), particularly afted conversion into labile thormboxane A 2 (13.) Thus both collagen and arachidonic acid principally have a rate limi­ting step in cyclo-oxygenase, for their platelet aggregation activity. Increased levels and activity of this enzyme seem to be present in diabetes, as shown by the hyperaggregation with these agents. This is especially seen in diabetics with retinopathy, though the trend is also seen in diabetics alone.

The fact that increased cyclo-oxygenase activity is playing the principal role is supported by our studies with acetylsalicylic acid. The latter is a specific inhibitor of cyclo­oxygenase (14-17), and thereby is effective in blocking the collagen and arachidonic acid induced aggregation. Acetylsalicyclic acid in a given amount blocks a given amount of enzyme, and the initial cyclo-oxygenase levels, will determine the residual aggregation The latter is seen to be greater in patients, parti­cularly retinopathy subjects as compared to normals, once again supporting the increased enzyme levels in diabetes. Disaggregation will result if the amount of aggregating agent is inadequate to bring about a sustained reaction. The aggregating effect as we have seen is basically dependent upon cyclo-oxygenase levels. Disaggregation is seen more frequently in normals as compared to diabetics with retinopathy (Group II) and points towards a lower cyclo-oxygenase activity in normal subjects as compared to retinopathy subjects.

For induction of aggregation as seen by the L.P., changes in intrinsic platelet metabolism are not called for, as shown by, no relation between L.P. and the other parameters of aggregation. Instead, physio-chemical changes on the platelet membranes receptors possibly determins the onset of aggregation.

Invitro acetylsaclicyclic acid more effecti­vely blocks aggregation than acetylsalicyclic acid given invivo. This may be attributed to an effectively larger dose of a cetylsalicyclic acid invitro. Another possibility could be meta­bolic changes initiated by the body systems to nullify the effect of acetylsalicyclic acid on hemostasis; the latter being a very important function to sustain life. This metabolic change could be in form of decreased production of prostagladin PGI 2 (18) a known inhibitor of platelet aggregation. It is possible that another pathway, independent of prostaglandin meta­bolism, induces platelet aggregation. This could possibly occur due to enhanced direct intrinsic ADP release.

Platelet prostaglandin metabolism appears to be disturbed in diabetes. The basic defect is the increased cyclo-oxygenase levels with resultant increased production of endoperoxi­des and thromboxanes. All these changes manifest in the form of increased platelet aggregation and possibly clinically as a micro­angiopathy. Though changes are more marked and more consistently seen in retinopathy subjects they are also seen to a lesser degree in diabetics alone, suggesting that the prosta­glandin metabolism disturbance leading to increased platelet aggregation is the cause of diabetic retinopathy, rather than its effect. However, this can only be confirmed by longitudinal studies.

Endeavours which would reduce cyclo­oxygenase activity may prove to be of benefit, both in prevention and progression of diabetic retinopathy ; such potent inhibitor is acetylsa­licyclic acid. A long term trial with acetylsali­cyclic acid to study its effects on platelet aggregation and the occurrence/progression of retinopatny in diabetic subjects is suggested.[18]

 
  References Top

1.
Heath, H.; Brigdon, W.D. ; Canevar, J.V. ; Rollock, J.; Hunter, P.R.; Kelsey, J. and Bloom, A. Diabetologica 7 :308-315 (1971).  Back to cited text no. 1
    
2.
Kwann, H.C. ; Colwell, J.A. ; Cuas, S.; Suwanmela, N.L. and Bobbie' J.G. J. Lab. Clin. Med.80 : 236-245 (1972).  Back to cited text no. 2
    
3.
Passa, P.; Bensoussan, D, ; Levy-Toloianee, S.; Caen, J. et Caniver J. Atheroscleros is 19 : 277-285 (1974).  Back to cited text no. 3
    
4.
Bensousson, D.; Levy-Toledene, S. ; Passa, P.; Coen, J. and Canivet., J. Diabetologica 11 :307-312 (1975).  Back to cited text no. 4
    
5.
Colwell, J.A. ; Halushika, P.V. ; Sanji, K.; Levene, J : Sagel, J. and Nair R M.C. Diabetes 25 (Suppl. 2) 826-831 (1976).  Back to cited text no. 5
    
6.
Khosla, P.K.; Mahableshwara, M. ; Tewari, H.K. and Saraya A.K. Acta Haem 61,161 (1979).  Back to cited text no. 6
    
7.
Sagel, J. ; Colwell, J.A.; Crooke, L. and Laimins, M. Ann. Int. Med. 82 : 733-738, (1975).  Back to cited text no. 7
    
8.
Barbui, I.C. ; Battisira, R. ERic. Clin. Lab. 2 299-312, (1972)  Back to cited text no. 8
    
9.
Born C.V. Nature (London) ,194 : 927-929 (1962).  Back to cited text no. 9
    
10.
Hamberg, M. and Samucisson, B. Proc. Nath. Acad. Sci. U.S.A. 70: 899 (1973).  Back to cited text no. 10
    
11.
Hamberg, LM. and Samuelsson Proc. Aath. Acad, Sci, U.S.A. 71 : 3400-3404 (1974).  Back to cited text no. 11
    
12.
Hamberg, M.; Svenson, J. and Samuolsson, B. Lancet Vol. 2: 223-224 (1974).  Back to cited text no. 12
    
13.
Hamberg, M.; Svenson, J. and Samuelsson,B. Pro, Natn. Acad. Sci. U.S.A. 72 :2994 (1975).  Back to cited text no. 13
    
14.
Al, Mondhiry H. ; Harous, A,J. and Spaeth T,H. Proc. Soc. Exp. Biol. Med. 133 : 632-636 (1970)  Back to cited text no. 14
    
15.
Willis, A.L.: Kuhn D.C. and Weiss, H.J. Science 183 : 325-329, (1974).  Back to cited text no. 15
    
16.
Rome L.H- and Lands, W.E.M. Ped. Proc. 34: 790, (1975).  Back to cited text no. 16
    
17.
Roth. C.J.; Stanford, N and Majerus P.M, Proc. Natn. Acad. Sci, U.S.A. 72 :3073 (1975).  Back to cited text no. 17
    
18.
Moncado, S, & lane, J.R.: Br. Med. Bull 34 :122,(1978)  Back to cited text no. 18
    


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