Ophthalmologica, Basel 170: 353-361 (1975)
The Fibrinolytic System in Patients with Diabetes mellitus with Special Reference to Diabetic Retinopathy' L. O. A lm er , M. P andolfi and S. Ö sterlin Coagulation Laboratory, Department of Ophthalmology, and Department of Internal Medicine, University of Lund, Malmö
The organism has at its disposal fibrinolytic agents whose functions are to induce fibrin dissolution and thrombolysis and - possibly - to prevent thrombosis and atherosclerosis [A stru p , 1968], The agents are contained in the endothelium of blood vessels [T o d d , 1959] and are believed to be continuously released into the blood stream [N ilsson and P andolfi , 1970], In recent years evidence has been produced that a low fibrinolytic activity is often associated with thromboembolic diseases [N ilsson and I sacson , 1973]. Since patients with diabetes mellitus (DM) are especially prone to develop vascular complications we have studied the fibrinolytic system in this disease. We were also interested to see whether differences in the fibrinolytic system existed between patients with and without diabetic retinopathy.
Materiell and Methods
1 Supported by grants from the Swedish Diabetes Association and Tore Nilson’s Fond for Medical Research.
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The clinical material consisted of 168 randomly selected patients with DM attending the antidiabetic dispensary of the Medical Clinic of Malmö. The patients were classified according to sex, age group (in decades; fig. 1), weigh!, duration of the disease (up to 3 months, up to 5 and 20 years, and more than 20 years after the diagnosis), treatment (diet alone, insulin, sulphonylurea, biguanide or combi nations of them). All the patients were submitted to routine ophthalmic examination including refraction, biomicroscopy, tonometry, fundus examination after dilatation of the pupil and, although not as a rule, fundus biomicroscopy and fundus photo graphy.
354
A i mer P andolfi/O stf.rlin
Blood samples were taken in the morning after breakfast and antidiabetic treat ment. The patients were examined for the following fibrinolytic factors. Spontaneous fibrinolytic activity. It was measured testing on fibrin plates re dissolved euglobulin precipitate [N ilsson and O low , 1962], In an age- and sexmatched control material of 153 healthy persons, the mean spontaneous fibrinolytic activity was 34.4 ± SE 3.3 mm2 of lysis. ‘Fibrinolytic capacity’ (fibrinolytic response to venous stasis). The local fibrinolytic activity developing during artificial venous occlusion of the arms was studied according to R obertson et al. [ 1972J. In the age- and sex-matched control material, the mean fibrinolytic activity on stimulation was 313.8 ± SE 10.2 mm2 of lysis. Fibrinolytic activity of the vein walls. The content of fibrinolytic activators in a biopsy specimen of a superficial dorsal vein of the hand was assessed histochemically by a modification [P andolfi et al., 1972] of the histochemical method of T odd [1959]. Normal range was 6.0-10.0 arbitrary units of possible 12; median value, 7.5.
Ophthalmic examination. Of 168 diabetic patients only 46 had a com pletely normal ocular status. In the remaining 122, diabetic retinal changes, i.e. microaneurysms and/or haemorrhages and exudates, were found in 46 cases. In 10 of these patients there were microaneurysms but no ophthalmologically visible exudates or haemorrhages. The mean diabetes duration of these patients was the same as in the whole retinopathy group. Metabolic cataract was found in 6 cases, while 43 presented lenticular changes indistinguishable from those of true senile cataract. In 14 cases (in four of which the presence of retinopathy could be established) the
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Results
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Fibrinolytic activity, AU
intraocular tension (IOP) was found to exceed 24 mm Hg. Three of these cases were glaucoma simplex showing optic disk excavation and/or visual field defects. The others were classified as ocular hypertension. Forty had miscellaneous changes without necessary relation with diabetes, such as vitreous floaters, senile macular degeneration, hypertonic changes of the fundus and other abnormalities. The patients were divided into three groups: group I: without ophthalmoscopically visible diabetic retinopathy (89 patients); group II: with ophthalmoscopically visible diabetic retinopathy (46 patients); group III: with complications, which made a firm diagnosis of microangiopathy im possible, such as several cases with glaucoma and advanced cataract (33 patients). Since the presence or absence of diabetic microangiopathy and its relation to the fibrinolytic system was the aim of this investigation, only groups I and II (135 patients) are used in calculations below. Plasminogen activator content in the vessel wall was assayed in 129 pa tients in groups I and II (fig. 2). It was found to be abnormally low (i.c. < 6 . 0 arbitrary units) in 21°/o of the cases, but there was no significant difference between patients with and without retinopathy. However, the 10 patients with only minor fundus changes (i.e. composed only by micro aneurysms) showed a significanctly ( p < 0 .0 1 ) higher activator content
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Fig. 2. Fibrinolytic activity of the vessel wall of diabetic patients without retino pathy (empty bars) and with retinopathy (hatched bars). The filled portions of the hatched bars denote patients with slight retinopathy (microaneurysms only). Fibrino lytic activity expressed in arbitrary units.
A lmer P andolfi Osterlin
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Duration of diabetes, years Fig. 3. Spontaneous blood fibrinolytic activity in diabetic patients with and with out retinopathy in relation to the duration of the disease. Empty bars: no diabetic retinopathy: black bars: diabetic retinopathy. Fig. 4. Same as figure 3, patients exceeding 120°/« of the ideal weight excluded.
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Duration of diabetes, years
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Fig. 5. Fibrinolytic response to venous stasis (stimulated fibrinolytic activity, 'fibrinolytic capacity’) of diabetic patients with and without retinopathy in relation to the duration of the disease. Empty bars: no diabetic retinopathy; black bars: diabetic retinopathy. Fig. 6. Same as figure 5, patients exceeding 120°/o of the ideal weight excluded.
than both the patients with more marked retinopathy and the patients who did not show any sign of retinopathy. Spontaneous fibrinolytic activity. The mean activity in the 135 patients with or without retinopathy was 28.2 ± SE 2.8, compared to the somewhat higher activity 34.4 ± S E 3.3 in the control material. The 89 patients without retinopathy had a mean spontaneous fibrinolytic activity of 27.7 + SE 3.8, while the 46 patients with retinopathy had 31.3 + SE 4.5. These differences were not significant. In both groups ( I + 11) the activity was lowest during the first 10 years of diabetes, and there was a steady increase of the activ
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ity later, more pronounced in the group without retinopathy (fig. 3). Obe sity, known to decrease the fibrinolytic activity [G race and G oldrick , 1968; A lm er , 1974], did not influence the results since the same finding was obtained excluding overweight ( > 1 2 0 % of ideal weight) patients (fig- 4). Stimulated fibrinolytic activity (‘fibrinolytic capacity'). In the 135 pa tients in groups I and II, the activity averaged 247.0 ± S E 11.4, which is significantly ( < 0.001) lower than in the 153 control subjects (313.8 ± SE 10.2). In the retinopathy group there was a mean activity of 238.4 ± S E 17.0 and in the non-retinopathy group 251 .6 ± S E 15.0, both being significantly (p < 0.001) lower than in the control material. In the patients with retinopathy there was a steady decrease of the fibrinolytic activity with duration of diabetes, while the activity in the patients without retinopathy did not show this tendency (fig. 5). Excluding overweight patients did not change the results (fig. 6).
The present investigation dealing with the fibrinolytic system of patients with DM was designed to comprehend the main fibrinolytic parameters, i.e. the source of fibrinolytic activators (assay of plasminogen activator in the vessel wall), the normal release of these agents into the blood stream (spontaneous blood fibrinolytic activity), and finally the faculty of the organism to release fibrinolytic activators in large amounts following appropriate stimuli (fibrinolytic response to venous stasis, ‘fibrinolytic capacity’). The results show that, compared to the healthy, patients with DM have, as a group, these three fibrinolytic parameters depressed in various de grees. Thus, in view of the antithrombotic and, possibly, antiarteriosclerotic role of fibrinolysis, the fundamentally depressed fibrinolytic activity in DM may be thought to be a contributory factor to the develop ment of the vascular complication often occurring in this disease. The pathogenesis of microangiopathy in DM is essentially unknown. Patients with DM often develop a hypercoagulable state including in creased platelet stickiness and decreased fibrinolytic activity [E geberg , 1963; F earnley et ah, 1963; Shaw et al., 1967; V aldore -H ansen , 1967; A bastado et al., 1968; C ash and M c G ill , 1969; B adawi et al., 1970; H eath et al., 1971; F ukuda , 1972; K waan et al., 1972; R egnault , 1972],
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Discussion
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These changes are believed to play a role in the development of renal [F arquahr el al., 1972] and ocular [F ukuda , 1972; R egnaui.t , 1972] microangiopathies. With this in mind, the study was also directed to ascer tain whether absence or presence of ophthalmoscopically visible retino pathy in diabetic patients was accompanied or not by characteristic changes of the fibrinolytic system. However, as far as retinopathy is con cerned, the results do not consent general conclusions although they are suggestive of interesting differences between subgroups. No significant dif ference was found between patients with and without retinopathy as far as the fibrinolytic activity of the vessel wall and the spontaneous and stimulated fibrinolytic activity are concerned. However, the 10 patients with minor fundus changes (venous stasis and microaneurysms) had a significantly higher activator content in the vessel wall both compared to patients without retinopathy and with more advanced retinopathy. Hypothetically, this result might be interpreted as a transitory fibrinolytic activation aimed to prevent the progress of the microangiopathy. The behaviour of the spontaneous and stimulated fibrinolytic activity in relation to the duration of the disease is also of interest. Spontaneous fibrinolytic activity increased with the duration of the diabetes in all patients but at a much lower rate in patients with retinopathy. Stimulated fibrinolytic activity, on the other hand, remained stationary in patients without retinopathy and progressively decreased in those showing fundus changes. These results are suggestive of fibrinolytic activity as a selective factor in the occurrence of retinopathy, i.e. patients with a depressed fibrinolytic system being more prone to develop retinopathy. Prospective studies may verify this hypothesis.
The fibrinolytic system has been studied in 168 patients with diabetes mellitus (DM) and compared to that of a group of 153 sex- and age-matched control subjects. The following determination were made: spontaneous fibrinolytic activity of the blood: fibrinolytic response to standardised venous stasis (stimulated fibrinolytic activity, •fibrinolytic capacity’); histochemical determination of fibrinolytic activators in the walls of superficial veins collected by biopsy. Diabetic patients were found as a group to have an impaired fibrinolytic system with the above fibrinolytic parameters decreased to various degrees in comparison with those of the controls. Less clear differences were observed between patients with and without ophthalmoscopically visible diabetic changes of the retina. However, patients with beginning angiopathy were found to have a significantly higher amount
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Summary
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of fibrinolytic activators in their vessel walls than patients with more advanced retinopathy and without ophthalmoscopically detectable retinopathy. Furthermore, unlike patients without retinopathy, patients with retinopathy increased less or did not increase at all their spontaneous and stimulated fibrinolytic activity along the duration of the disease. The defective fibrinolytic system of diabetic patients may contribute to the occur rence of the vascular complications frequently seen in this disease. In the diabetic group, those patients who develop retinopathy show an impaired fibrinolytic defense with the duration of the disease.
Zusammenfassung Das fibrmolytische System bei 168 Patienten mit Diabetes mellitus (DM) wurde untersucht und verglichen mit einer Gruppe von 153 geschlechts- und alterentspre chenden Kontrollpersonen. Folgende Bestimmungen wurden durchgeführt: Die spon tane fibrmolytische Aktivität des Blutes, die fibrinolytische Reaktion auf eine stan dardisierte venöse Stasis (stimulierte fibrinolytische Aktivität, fibrinolytische Kapazität); histochemische Bestimmung des fibrinolytischen Aktivators innerhalb der Wand ober flächlich gelegener Venen gewonnen durch Biopsie. Bei den Patienten, die an einem Diabetes litten, wurde ein vermindertes fibrinolytisches System gefunden, das bei der Bestimmung der obengenannten fibrinolyti schen Parameter um verschiedene Grade niedriger war als bei den Vergleichspersonen. Weniger klare Unterschiede Hessen sich bei Patienten mit und ohne ophthalmoskopisch sichtbare Veränderungen im Sinne einer Retinopathia diabetica beobachten. Patienten jedoch mit beginnender Angiopathie zeigten einen signifikant höheren Betrag des fibrinolytischen Aktivators in den Wänden der Gefässe als Patienten mit einer weiter fortgeschrittenen Retinopathie und ohne ophthalmoskopisch sichtbare Retinopathia diabetica. Darüber hinaus, anders als Patienten ohne Retinopathia diabetica, zeigten Patienten mit einer Retinopathia diabetica nur eine geringe oder gar keine Zunahme aller ihrer spontanen oder stimulierten fibrinolytischen Aktivität im Verlauf der Er krankung. Das mangelhafte fibrinolytische System bei Patienten mit einem Diabetes dürfte beitragen zu dem Auftreten der vascularen Komplikationen, die häufig bei dieser Er krankung gefunden werden. In der Gruppe der Diabetiker zeigten diejenigen Patien ten. die eine Retinopathia diabetica entwickelten, einen verminderten fibrinolytischen Schutz, je länger die Erkrankung dauerte.
I.c système fibrinolytique a été étudié chez 168 patients atteints de diabète (mellitus) et camparé à celui d’un groupe de contrôle à sexe et âge correspondants. On a déterminé: l’activité fibrinolytique spontanée du sang, la réponse fibrinolytique à une stase veineuse standardisée (activité fibrinolytique stimulée, «capacité fibrinoly
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Résumé
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tique»), détermination histochimique des activateurs fibrinolytiques dans les parois des veines superficielles rassemblées par biopsie. Considérés comme une groupe, les diabétiques ont un système fibrinolytique dimi nué, dont les paramètres (mentionnés plus haut) sont diminués à des degrés variés en comparaison de ceux des contrôles. Des différences moins accusées ont été observées entre patients avec ou sans modification ophtalmologiquement visibles de la rétine. Cependant, les patients à angiopathie débutante ont un plus grand taux significatif d’activateurs fibrinolytiques dans les parois de leurs vaisseaux que les patients à rétinopathie et à rétinopathie pas détectable à l’ophtalmoscope. De plus, contrairement aux malades sans rétinopathie, ceux à rétinopathie augmentent moins ou pas du tout toute leur activité fibrinolytique spontanée ou stimulée durant le cours de la maladie. Le système fibrinolytique défectueux des patients diabétiques peut contribuer à l’apparition des complications vasculaires fréquemment rencontrées dans cette ma ladie. Dans le groupe diabétique, les patients qui acquièrent une rétinopathie ont une défense fibrinolytique défectueuse au cours de la maladie.
References
le premier temps de l’hémostase chez les diabétiques. Presse méd. 76: 1317-1320 (1968). A i .mér , L. O.: Unpublished results (1974). A strup , T.: Blood coagulation and fibrinolysis in tissue culture and tissue repair. Biochem. Pharmacol., suppl. pp. 241-257 (1968). Badawi, H.; E i.-Sawy, M.; M ikhail, M.; N omeir , A. M., and T ew fik , S.: Platelet, coagulation and fibrinolysis in diabetics and non-diabetic patients with quiescent coronary heart disease. Angiology, Baltimore 21: 511-515 (1970). Cash, J. D. and McG ill, R. C.: Fibrinolytic response to moderate exercise in young male diabetics and non-diabetics. J. clin. Path. 22: 32-35 (1969). E geberg , O.: The blood coagulability in diabetic patients. Scand. J. clin. Lab. Invest. 15: 533-538 (1963). F arquahr, A.; M c D onald, M. K., and I reland, J. T.: The role of fibrin deposition in diabetic glomerulosclerosis: a light, electron immunofluorescence microscopic study. J. clin. Path. 25: 657-667 (1972). F earnley, G. R.; C hakrabarti, R., and Avis, P. R. D.: Blood fibrinolytic activity in diabetes mellitus and its bearing on ischaemic heart disease and obesity. Brit, med. J. i: 921-923 (1963). F ukuda, M.: Blood fibrinolytic activity and fibrinogen concentration in diabetic retinopathy. Eye, Ear, Nose Thr. mon. 51: 266-272 (1972). G race, C. S. and G oldrick , R. B.: Fibrinolysis and body build. J. Atheroscler. Res. 8: 705-719 (1968). H eath, H.; Brigden , W. D.; C anever, J. V.; P ollock, J.; H unter , P. R.; K elsey , J., and Bloom, A.: Platelet adhesiveness and aggregation in relation to diabetic retinopathy. Diabetologia 7: 308-315 (1971).
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A bastado, M.; D oumenc , J.; P rost, R.; Bara, L.; Samama, M.; D érot , M. et Bousser , J.: Étude de l’activité fibrinolytique et des fonctions plaquettaires dans
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K waan, H. C.; C alwell , J. A., and S uwanwela , N.: Disseminated intravascular
coagulation in diabetes mellitus, with reference to the role of increased platelet aggregation. Diabetes, N.Y. 21: 108-113 (1972). N ilsson, I. M. and Isacson, S.: New aspects of the pathogenesis of thrombo embolism. Progr. Surg., vol. 11, pp. 44-68 (Karger, Basel 1973). N ilsson , 1. M. and Oi.ow, B.: Fibrinolysis induced by streptokinase in man. Acta chir. scand. 123: 247-266 (1962). N ilsson , 1. M. and P andolfi, M.: Fibrinolytic response of the vessel wall. Thromb. Diath. haemorrh., suppl. 40, pp. 231-242 (1970). P andolfi, M.; Bjernstad , A., and N ilsson , 1. M.: Technical remarks on the micro scopical demonstration of tissue plasminogen activator. Thromb. Diath. haemorrh. 25: 469-480 (1972). R égnault, F.: Rôle des plaquettes dans le pathogénie de la rétinopathie diabétique. Sem. Hôp., Paris 13: 893-902 (1972). Robertson , B.; P andoi.fi , M., and N ilsson , 1. M.: ‘Fibrinolytic capacity’ in healthy volunteers as estimated from effect of venous occlusion of arms. Acta chir. scand. 138: 429-436 (1972). Shaw , S.; P egrum , G. D.; W olff , S., and A shton , W. L.: Platelet adhesiveness in diabetes mellitus. J. clin. Path. 20: 845-847 (1967). T odd , A. S.: Histochemical localisation of fibrinolysin activator. J. Path. Bact. 78: 281-283 (1959). Valdorf -H ansen, F.: Coagulability in diabetes. Acta med. scand., suppl. 476, pp. 147158 (1967).
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Request reprints from: M aurizio P andolfi, Coagulation Laboratory, Allmanna Sjukhuset, 8-214 01 Mahno (Sweden)
The Fibrinolytic System in Patients with Diabetes mellitus with Special Reference to Diabetic Retinopathy' L. O. A lm er , M. P andolfi and S. Ö sterlin Coagulation Laboratory, Department of Ophthalmology, and Department of Internal Medicine, University of Lund, Malmö
The organism has at its disposal fibrinolytic agents whose functions are to induce fibrin dissolution and thrombolysis and - possibly - to prevent thrombosis and atherosclerosis [A stru p , 1968], The agents are contained in the endothelium of blood vessels [T o d d , 1959] and are believed to be continuously released into the blood stream [N ilsson and P andolfi , 1970], In recent years evidence has been produced that a low fibrinolytic activity is often associated with thromboembolic diseases [N ilsson and I sacson , 1973]. Since patients with diabetes mellitus (DM) are especially prone to develop vascular complications we have studied the fibrinolytic system in this disease. We were also interested to see whether differences in the fibrinolytic system existed between patients with and without diabetic retinopathy.
Materiell and Methods
1 Supported by grants from the Swedish Diabetes Association and Tore Nilson’s Fond for Medical Research.
Downloaded by: University of Chicago Library 205.208.116.24 - 4/14/2018 6:17:03 AM
The clinical material consisted of 168 randomly selected patients with DM attending the antidiabetic dispensary of the Medical Clinic of Malmö. The patients were classified according to sex, age group (in decades; fig. 1), weigh!, duration of the disease (up to 3 months, up to 5 and 20 years, and more than 20 years after the diagnosis), treatment (diet alone, insulin, sulphonylurea, biguanide or combi nations of them). All the patients were submitted to routine ophthalmic examination including refraction, biomicroscopy, tonometry, fundus examination after dilatation of the pupil and, although not as a rule, fundus biomicroscopy and fundus photo graphy.
354
A i mer P andolfi/O stf.rlin
Blood samples were taken in the morning after breakfast and antidiabetic treat ment. The patients were examined for the following fibrinolytic factors. Spontaneous fibrinolytic activity. It was measured testing on fibrin plates re dissolved euglobulin precipitate [N ilsson and O low , 1962], In an age- and sexmatched control material of 153 healthy persons, the mean spontaneous fibrinolytic activity was 34.4 ± SE 3.3 mm2 of lysis. ‘Fibrinolytic capacity’ (fibrinolytic response to venous stasis). The local fibrinolytic activity developing during artificial venous occlusion of the arms was studied according to R obertson et al. [ 1972J. In the age- and sex-matched control material, the mean fibrinolytic activity on stimulation was 313.8 ± SE 10.2 mm2 of lysis. Fibrinolytic activity of the vein walls. The content of fibrinolytic activators in a biopsy specimen of a superficial dorsal vein of the hand was assessed histochemically by a modification [P andolfi et al., 1972] of the histochemical method of T odd [1959]. Normal range was 6.0-10.0 arbitrary units of possible 12; median value, 7.5.
Ophthalmic examination. Of 168 diabetic patients only 46 had a com pletely normal ocular status. In the remaining 122, diabetic retinal changes, i.e. microaneurysms and/or haemorrhages and exudates, were found in 46 cases. In 10 of these patients there were microaneurysms but no ophthalmologically visible exudates or haemorrhages. The mean diabetes duration of these patients was the same as in the whole retinopathy group. Metabolic cataract was found in 6 cases, while 43 presented lenticular changes indistinguishable from those of true senile cataract. In 14 cases (in four of which the presence of retinopathy could be established) the
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Results
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Fibrinolytic activity, AU
intraocular tension (IOP) was found to exceed 24 mm Hg. Three of these cases were glaucoma simplex showing optic disk excavation and/or visual field defects. The others were classified as ocular hypertension. Forty had miscellaneous changes without necessary relation with diabetes, such as vitreous floaters, senile macular degeneration, hypertonic changes of the fundus and other abnormalities. The patients were divided into three groups: group I: without ophthalmoscopically visible diabetic retinopathy (89 patients); group II: with ophthalmoscopically visible diabetic retinopathy (46 patients); group III: with complications, which made a firm diagnosis of microangiopathy im possible, such as several cases with glaucoma and advanced cataract (33 patients). Since the presence or absence of diabetic microangiopathy and its relation to the fibrinolytic system was the aim of this investigation, only groups I and II (135 patients) are used in calculations below. Plasminogen activator content in the vessel wall was assayed in 129 pa tients in groups I and II (fig. 2). It was found to be abnormally low (i.c. < 6 . 0 arbitrary units) in 21°/o of the cases, but there was no significant difference between patients with and without retinopathy. However, the 10 patients with only minor fundus changes (i.e. composed only by micro aneurysms) showed a significanctly ( p < 0 .0 1 ) higher activator content
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Fig. 2. Fibrinolytic activity of the vessel wall of diabetic patients without retino pathy (empty bars) and with retinopathy (hatched bars). The filled portions of the hatched bars denote patients with slight retinopathy (microaneurysms only). Fibrino lytic activity expressed in arbitrary units.
A lmer P andolfi Osterlin
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Duration of diabetes, years Fig. 3. Spontaneous blood fibrinolytic activity in diabetic patients with and with out retinopathy in relation to the duration of the disease. Empty bars: no diabetic retinopathy: black bars: diabetic retinopathy. Fig. 4. Same as figure 3, patients exceeding 120°/« of the ideal weight excluded.
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Fig. 5. Fibrinolytic response to venous stasis (stimulated fibrinolytic activity, 'fibrinolytic capacity’) of diabetic patients with and without retinopathy in relation to the duration of the disease. Empty bars: no diabetic retinopathy; black bars: diabetic retinopathy. Fig. 6. Same as figure 5, patients exceeding 120°/o of the ideal weight excluded.
than both the patients with more marked retinopathy and the patients who did not show any sign of retinopathy. Spontaneous fibrinolytic activity. The mean activity in the 135 patients with or without retinopathy was 28.2 ± SE 2.8, compared to the somewhat higher activity 34.4 ± S E 3.3 in the control material. The 89 patients without retinopathy had a mean spontaneous fibrinolytic activity of 27.7 + SE 3.8, while the 46 patients with retinopathy had 31.3 + SE 4.5. These differences were not significant. In both groups ( I + 11) the activity was lowest during the first 10 years of diabetes, and there was a steady increase of the activ
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5
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ity later, more pronounced in the group without retinopathy (fig. 3). Obe sity, known to decrease the fibrinolytic activity [G race and G oldrick , 1968; A lm er , 1974], did not influence the results since the same finding was obtained excluding overweight ( > 1 2 0 % of ideal weight) patients (fig- 4). Stimulated fibrinolytic activity (‘fibrinolytic capacity'). In the 135 pa tients in groups I and II, the activity averaged 247.0 ± S E 11.4, which is significantly ( < 0.001) lower than in the 153 control subjects (313.8 ± SE 10.2). In the retinopathy group there was a mean activity of 238.4 ± S E 17.0 and in the non-retinopathy group 251 .6 ± S E 15.0, both being significantly (p < 0.001) lower than in the control material. In the patients with retinopathy there was a steady decrease of the fibrinolytic activity with duration of diabetes, while the activity in the patients without retinopathy did not show this tendency (fig. 5). Excluding overweight patients did not change the results (fig. 6).
The present investigation dealing with the fibrinolytic system of patients with DM was designed to comprehend the main fibrinolytic parameters, i.e. the source of fibrinolytic activators (assay of plasminogen activator in the vessel wall), the normal release of these agents into the blood stream (spontaneous blood fibrinolytic activity), and finally the faculty of the organism to release fibrinolytic activators in large amounts following appropriate stimuli (fibrinolytic response to venous stasis, ‘fibrinolytic capacity’). The results show that, compared to the healthy, patients with DM have, as a group, these three fibrinolytic parameters depressed in various de grees. Thus, in view of the antithrombotic and, possibly, antiarteriosclerotic role of fibrinolysis, the fundamentally depressed fibrinolytic activity in DM may be thought to be a contributory factor to the develop ment of the vascular complication often occurring in this disease. The pathogenesis of microangiopathy in DM is essentially unknown. Patients with DM often develop a hypercoagulable state including in creased platelet stickiness and decreased fibrinolytic activity [E geberg , 1963; F earnley et ah, 1963; Shaw et al., 1967; V aldore -H ansen , 1967; A bastado et al., 1968; C ash and M c G ill , 1969; B adawi et al., 1970; H eath et al., 1971; F ukuda , 1972; K waan et al., 1972; R egnault , 1972],
Downloaded by: University of Chicago Library 205.208.116.24 - 4/14/2018 6:17:03 AM
Discussion
358
A lmkr Pandolfi O stkri.in
These changes are believed to play a role in the development of renal [F arquahr el al., 1972] and ocular [F ukuda , 1972; R egnaui.t , 1972] microangiopathies. With this in mind, the study was also directed to ascer tain whether absence or presence of ophthalmoscopically visible retino pathy in diabetic patients was accompanied or not by characteristic changes of the fibrinolytic system. However, as far as retinopathy is con cerned, the results do not consent general conclusions although they are suggestive of interesting differences between subgroups. No significant dif ference was found between patients with and without retinopathy as far as the fibrinolytic activity of the vessel wall and the spontaneous and stimulated fibrinolytic activity are concerned. However, the 10 patients with minor fundus changes (venous stasis and microaneurysms) had a significantly higher activator content in the vessel wall both compared to patients without retinopathy and with more advanced retinopathy. Hypothetically, this result might be interpreted as a transitory fibrinolytic activation aimed to prevent the progress of the microangiopathy. The behaviour of the spontaneous and stimulated fibrinolytic activity in relation to the duration of the disease is also of interest. Spontaneous fibrinolytic activity increased with the duration of the diabetes in all patients but at a much lower rate in patients with retinopathy. Stimulated fibrinolytic activity, on the other hand, remained stationary in patients without retinopathy and progressively decreased in those showing fundus changes. These results are suggestive of fibrinolytic activity as a selective factor in the occurrence of retinopathy, i.e. patients with a depressed fibrinolytic system being more prone to develop retinopathy. Prospective studies may verify this hypothesis.
The fibrinolytic system has been studied in 168 patients with diabetes mellitus (DM) and compared to that of a group of 153 sex- and age-matched control subjects. The following determination were made: spontaneous fibrinolytic activity of the blood: fibrinolytic response to standardised venous stasis (stimulated fibrinolytic activity, •fibrinolytic capacity’); histochemical determination of fibrinolytic activators in the walls of superficial veins collected by biopsy. Diabetic patients were found as a group to have an impaired fibrinolytic system with the above fibrinolytic parameters decreased to various degrees in comparison with those of the controls. Less clear differences were observed between patients with and without ophthalmoscopically visible diabetic changes of the retina. However, patients with beginning angiopathy were found to have a significantly higher amount
Downloaded by: University of Chicago Library 205.208.116.24 - 4/14/2018 6:17:03 AM
Summary
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of fibrinolytic activators in their vessel walls than patients with more advanced retinopathy and without ophthalmoscopically detectable retinopathy. Furthermore, unlike patients without retinopathy, patients with retinopathy increased less or did not increase at all their spontaneous and stimulated fibrinolytic activity along the duration of the disease. The defective fibrinolytic system of diabetic patients may contribute to the occur rence of the vascular complications frequently seen in this disease. In the diabetic group, those patients who develop retinopathy show an impaired fibrinolytic defense with the duration of the disease.
Zusammenfassung Das fibrmolytische System bei 168 Patienten mit Diabetes mellitus (DM) wurde untersucht und verglichen mit einer Gruppe von 153 geschlechts- und alterentspre chenden Kontrollpersonen. Folgende Bestimmungen wurden durchgeführt: Die spon tane fibrmolytische Aktivität des Blutes, die fibrinolytische Reaktion auf eine stan dardisierte venöse Stasis (stimulierte fibrinolytische Aktivität, fibrinolytische Kapazität); histochemische Bestimmung des fibrinolytischen Aktivators innerhalb der Wand ober flächlich gelegener Venen gewonnen durch Biopsie. Bei den Patienten, die an einem Diabetes litten, wurde ein vermindertes fibrinolytisches System gefunden, das bei der Bestimmung der obengenannten fibrinolyti schen Parameter um verschiedene Grade niedriger war als bei den Vergleichspersonen. Weniger klare Unterschiede Hessen sich bei Patienten mit und ohne ophthalmoskopisch sichtbare Veränderungen im Sinne einer Retinopathia diabetica beobachten. Patienten jedoch mit beginnender Angiopathie zeigten einen signifikant höheren Betrag des fibrinolytischen Aktivators in den Wänden der Gefässe als Patienten mit einer weiter fortgeschrittenen Retinopathie und ohne ophthalmoskopisch sichtbare Retinopathia diabetica. Darüber hinaus, anders als Patienten ohne Retinopathia diabetica, zeigten Patienten mit einer Retinopathia diabetica nur eine geringe oder gar keine Zunahme aller ihrer spontanen oder stimulierten fibrinolytischen Aktivität im Verlauf der Er krankung. Das mangelhafte fibrinolytische System bei Patienten mit einem Diabetes dürfte beitragen zu dem Auftreten der vascularen Komplikationen, die häufig bei dieser Er krankung gefunden werden. In der Gruppe der Diabetiker zeigten diejenigen Patien ten. die eine Retinopathia diabetica entwickelten, einen verminderten fibrinolytischen Schutz, je länger die Erkrankung dauerte.
I.c système fibrinolytique a été étudié chez 168 patients atteints de diabète (mellitus) et camparé à celui d’un groupe de contrôle à sexe et âge correspondants. On a déterminé: l’activité fibrinolytique spontanée du sang, la réponse fibrinolytique à une stase veineuse standardisée (activité fibrinolytique stimulée, «capacité fibrinoly
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Résumé
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A lmér 'P andoi.fi /O sierlin
tique»), détermination histochimique des activateurs fibrinolytiques dans les parois des veines superficielles rassemblées par biopsie. Considérés comme une groupe, les diabétiques ont un système fibrinolytique dimi nué, dont les paramètres (mentionnés plus haut) sont diminués à des degrés variés en comparaison de ceux des contrôles. Des différences moins accusées ont été observées entre patients avec ou sans modification ophtalmologiquement visibles de la rétine. Cependant, les patients à angiopathie débutante ont un plus grand taux significatif d’activateurs fibrinolytiques dans les parois de leurs vaisseaux que les patients à rétinopathie et à rétinopathie pas détectable à l’ophtalmoscope. De plus, contrairement aux malades sans rétinopathie, ceux à rétinopathie augmentent moins ou pas du tout toute leur activité fibrinolytique spontanée ou stimulée durant le cours de la maladie. Le système fibrinolytique défectueux des patients diabétiques peut contribuer à l’apparition des complications vasculaires fréquemment rencontrées dans cette ma ladie. Dans le groupe diabétique, les patients qui acquièrent une rétinopathie ont une défense fibrinolytique défectueuse au cours de la maladie.
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