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Is urinary infection a risk factor for ischemic cerebrovascular disease?
Medical Hypotheses (1987) 23, 219-224 0 Longman Group UK Ltd 1987
IS URINARY INFECTION A RISK FACTOR FOR ISCHEMIC CEREBROVASCULAR DISEASE? G. Uza Institute of Hygiene and Public Health, I Medical Clinic, Cluj-Napoca, R.S. Romania
ABSTRACT The hypothesis is put forward that urinary infection is a risk factor for ischemic cerebrovascular disease (ICVD). Bacteriuria exceding,105 units/ml actually occurred in 68% of the patients with ICVD while a similar number of bacteria was detected only in 12% of the age-matched control subjects. An increased concentration of circulating immune complexes was found in infected patients but the investigated hemostatic variables (plasma fibrinogen and factor VIII related antigen, platelet count and adhesivenes as well as dilute blood clot lysis time) did not significantly differ from patients with ICVD but no urinary infection. Although circulating immune complexes are able to cause endothelial lesions, further investigations on the hemostatic balance are required in order to substantiate the above mentioned hypothesis. INTRODUCTION Experimental evidence strongly suggests that infections may be involved in the development of thrombotic events. Mechanisms by which bacteria and their products could activate coagulation include a monocyte mediated increase of platelet procoagulant activities (1,2,3), a direct activation of cloting factor XII and of the intrinsic pathway (4) and a release of tissue thromboplastin from injured endothelial cells, which may subsequently activate factor VII and trigger the extrinsic pathway (5). On the other hand immune complexes occuring during infectious diseases (6) have been reported to cause platelet aggregation (7,3) and endotoxin lipopolysaccharides dramatically potentiate this effect (8). It was also shown that inflammatory reactions increase platelet responsiveness to aggregating agents such as norepinephrine (9) and angiotensine II (10). In spite of the above mentioned experimental data, clinical studies concerning the interrelationship between infection and thrombosis are almost exclusively limited to the syndromes of disseminated
219
intravascular coagulation occuring during acute septic processes (11, 12,1,3), while the possible role played by bacterial infections in the development of chronic vascular disease and in its thrombotic complications has received much less attention. It is however logical to presume that bacteria could trigger a chain of events which might eventually lead to recurrent thrombotic phenomena and even to thromboatherosclerosis. The incidence of urinary infection and its effect on several hemostatic variables were therefore investigated in the present paper in patients with acute ICVD. MATERIAL AND METHODS 100 randomly selected patients with ICVD caused by thrombotic events were investigated for urinary infection and were subsequently divided into two groups: Group A included 68 patients (40 men and 28 women) with ICVD associated with urinary infection. (Bacteriuria exceeding 10' germs/ml and a pyuria above 2000 leukocytes/min at the Addis-Hamburger sediment). Group B included 32 patients (15 men and 17 women) with ICDV who did not present urinary infection. Age (mean f SEM: 64.24 f 1.26 years in group A and 62.7 f 2 years in group B), and the incidence of arterial hypertension (60.3% in group A and 56.3% in group B) as well as the level of serum cholesterol (228 f 5.81 mg/dl in group A and 246 + 11.6 mg/dl in group B) were similar in both groups. A mild diabetes mellitus was found in six patients from group A and in four patients from group B. Incidence of bacteriuria was also assessed in 100 age-matched (63.2 + 0.95 years) control subjects. This group included 20 clinically healthy persons and 80 patients admitted in the clinic for miscellaneous complaints (gastroduodenal ulcers, cholecystopathies, ophtalmologic disease without ICVD or spondilerthrosis). In a number of patients (Table I) and in 20 healthy normal weight normolipidemic control subjects older than 40 years, plasma fibrinogen (13), dilute blood clot lysis time (14), platelet count (15), platelet adhesiveness (16) and factor VIII related antigen (17) as well circulating immune complexes (18) were investigated. Blood and urine for laboratory investigations were harvested within 72 hours since the acute event. RESULTS Urinary infection occured rather frequently in patients with ICVD (68% of the patients) but this infection was clinically asymptomatic in 85% of the cases and its presence could be detected only by bacteriological investigation. In 81% of the patients with bacteriuria, E. coli was identified. In contrast to ICVD patients, the presence of bacteriuria was found only in 12 of the 100 randomly selected control subjects and only in 6 cases could E. coli be identified. A statistically significant difference between the incidence of bacteriuria in ICVD patients and that noted in control subjects was thus obtained (x2 = 65,33; 220
F
VB
VB
vs
A
A
B
B
C
C
NS
NS
0.001
307 f 26 (14)
c CVID without UI
Statistical significance (p)
337 f 16 (22)
278 f 6.6 (20)
B CVID with UI
A Controls
Fibrinogen a&d1
NS
NS
NS
306 f 16.4 (23)
343 f 9.2 (32)
317 f 11.9 (20)
Platelet count x 10'
NS
NS
NS
38.52 f 4.52 (23)
38.18 f 2.65 (31)
34.03 f 2.61 (20)
Platelet adhesiveness (X adhesive platelets)
NS
NS
NS
280 f 43 (20)
247 2 37 (20)
243 f 42 (20)
DBCLT (minutes)
NS
0.001
0.001
291 f 24.06 (12)
325 f 40.71 (12)
116 f 5.56 (20)
VIIIR:Ag (% of normal)
x10'
0.005
NS
0.001
200 i 16.71 (21)
273 f 13.84 (28)
190 f 9.68 (ia)
0D450nm
CIC
Behaviour of plasma fibrinogen, platelet count, platelet adhesiveness, dilute blood lysis time (DBCLT), plasma factor VIII related antigen (VIIIR:Ag) and circulating irmnune complexes (CIC) in control subjects and in patients with acute cerebrovaacular ischemic disease (CVID) with or without urinary infection Mean f SRM. Number of investigated subjects in brackets. @I).
Group
Table I:
p < 0.001). As shown in Table 1 when compared to age-matched healthy control subjects - the only significant change noted in patients with ICVD was an obvious increase of factor VIII related antigen (VIIIR:Ag). Mean values of plasma fibrinogen level were higher in patients than in controls but this change reached statistical significance only in patients with urinary infection. On the other hand there were no significant differences concerning the investigated hemostatic variables between patients with and those without urinary infection. Significantly increased values of circulating immune complexes were however detected in patients with ICVD and urinary infection. DISCUSSION Since bacteriuria occurs more often in older people (19,ZO) and mainly in hypertensive ones (21), the high incidence of urinary infection in patients with ICVD could be easily explained. It is more difficult to state whether urinary infection is involved in the pathogenesis of acute cerebrovascular events, especially as the investigated hemostatic variables were similar in patients with or without urinary infection. It should be remembered that increased plasma levels of fibrinogen and VIIIR:Ag are components of the acute phase reaction and do not necessarily reflect thrombotic phenomena. Since obesity, hyperlipoproteinemia, diabetes and essential hypertension could be involved in changes affecting the hemostatic variables (22,23), it is even more difficult to identify the role played by urinary infection. Its high incidence in patients with ICVD and the increased level of circulating immune complexes in infected patients however deserves attention as it has been experimentally demonstrated that such immune complexes as well as endotoxin may injure vascular endothelia (3,23,25). A cross antigenicity between E. coli lipopolysaccharide (LPS) and aortic glycoproteins was also demonstrated and immune complexes were found to be bound to injured aortic areas of rabbits sensitized with LPS (26). If other conditions such as hyperlipidemia or diabetes mellitus, are considered to be risk factors for ICVD only because they accompany this disease, than urinary infection which was even more frequently detected, fully deserves to be included among such risk factors. The present study does not exceed the limits of a working hypothesis generated by clinical observations and a more thorough investigation of the hemostatic balance should be envisaged. Important prophylactic and therapeutic implications might nevertheless result if further studies will substantiate this hypothesis. REFERENCES 1.
LUscher EF. The role of blood cells and of the vessel wall in the induction of intravascular coagulation. Klin Wochenschr 60: 712, 1982.
222
2.
Rivers RPA, Hathway WE, Weston WL. The endotoxin-induced coagulant activity of human monocytes. Br J Haematol 30: 311, 1985.
3.
Someraro N, Lattanzio A. Interaction of platelet with bacterial endotoxin. Agents and Actions 5/6:461, 1983.
4.
Morrison DC, Cochrane CG. Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxin). J Exp Med 140: 797, 1974.
5.
Lyberg T, Galdal KS, Evenson SA. Cellular cooperation in endothelial cell thromboplastin synthesis. Br J Haematol 53: 1983.
85,
6.
Delire M. Role des complexes immuns en pathologie humaine. Revue de Medicine 33: 2039, 1981.
La
7.
Movat HZ, Mustard JP, Taichman NS, Uriuhara T. Platelet aggregation and release of ADP, serotonin and histamine associated with phagocytosis of antigen-antibody complexes. Proc Sot Exp Biol Med 120: 232, 1965.
8.
Ginsberg MH, Henson PM. Enhancement of platelet response to immune complexes and IgG aggregated by a rich bacterial lipopolysaccharides. J Exp Med 147: 207, 1978.
9.
Hampton JR, Mitchell JRA. Abnormalities in platelet behaviour in acute illnesses. Br Med J 1: 1078, 1966.
10.
Uza G, Crisnic I. Effect of Angiotensine II upon platelet adhesiveness and thrombelastogram in patients with essential arterial hypertension. Path Europ 10: 327, 1975.
11.
Cook JA, Wise WC, Halushka PV. Elevated thromboxane levels in the rat during endotoxin shock. Protective effect of imidazole, 13azaprostanoic acid on essential fatty acid deficiency. J Clin Invest 65: 227, 1980.
12.
Crisnic I, Cucuianu M, Manasia M, Uza G. Disseminated intravascular coagulation and acute renal failure. Thrombos Diathes Haemorrh XXVI, 2: 332, 1971.
13.
Ratnoff OD, Menzie CAA. A new method for the determination of fibrinogen in small samples of plasma. J Lab Clin Med 37: 316, 1951.
14.
Gallimore MJ, Tyler HM, Shan ITB. The measurement of fibrinolysis in the rat. Thrombos Diathes Haemorrh 26: 293, 1971.
15.
Brecher G, Cronkite EP. Morphology and enumeration of blood platelets. J Appl Physiol 3: 356, 1950.
16.
Perlick E. Gerinungslaboratorium in Klinik and Praxis. G. Thieme Ver 1960.
17.
Laurel1 CB. Electroimmunoassay. Stand J Clin Invest 29 (suppl 124): 21, 1972.
18.
Riba I, Haskova V, Kaslik J, Maierova M, Stransky J. The use of polyethyleneglycol for immune complex detection in human sera. Molecular Immunology 16: 489, 1979.
223
Leipzig,
19.
Akhtar AJ, Andrews GR, Caird FI, Fallon RJ. Urinary tract infection in the elder1y. A population study. Age Aging I: 1972.
48,
Infections of urinary tract. Med Clin North AM 67:
20.
Farrar WE. 187, 1983.
21.
Grieble HG, Jackson GG. Churchill 1960.
22.
Lowe GDO. Laboratory evaluation of hypercoagulability, in C.R.M. Prentice (ed) Clinics in haematology. Thrombosis. W.H. Saunders Comp. Ltd. London-Philadelphia-Toronto. 10: 407, 1981.
23,
Mettinger KIA. A study of hemostasis in ischemic cerebrovascular disease. V. A multivariante evaluation of risk indicators and predictors. Early results of a longitudinal study. Thrombos Res 28: 521, 1982.
24.
Calabrese LH, Clough JP. Hypersensitivity vasculitis group (HVG) Cleve Clin Q 49: 17, 1982.
25.
Williams RC. Immune complexes: A critical perspective. J Med 71: 743, 1981.
26.
Scebat L, Renais J, Goldstein I, Groult N, Hdjiisky P. Cross antigenicity between Escherichia coli lipopolysaccharide and aortic glycoproteins in Constantinides P (ed) Immunity and atherosclerosis. Academic Press, London, 10: 121, 1980.
Biology of Pyelonephritis. London,
224
IS URINARY INFECTION A RISK FACTOR FOR ISCHEMIC CEREBROVASCULAR DISEASE? G. Uza Institute of Hygiene and Public Health, I Medical Clinic, Cluj-Napoca, R.S. Romania
ABSTRACT The hypothesis is put forward that urinary infection is a risk factor for ischemic cerebrovascular disease (ICVD). Bacteriuria exceding,105 units/ml actually occurred in 68% of the patients with ICVD while a similar number of bacteria was detected only in 12% of the age-matched control subjects. An increased concentration of circulating immune complexes was found in infected patients but the investigated hemostatic variables (plasma fibrinogen and factor VIII related antigen, platelet count and adhesivenes as well as dilute blood clot lysis time) did not significantly differ from patients with ICVD but no urinary infection. Although circulating immune complexes are able to cause endothelial lesions, further investigations on the hemostatic balance are required in order to substantiate the above mentioned hypothesis. INTRODUCTION Experimental evidence strongly suggests that infections may be involved in the development of thrombotic events. Mechanisms by which bacteria and their products could activate coagulation include a monocyte mediated increase of platelet procoagulant activities (1,2,3), a direct activation of cloting factor XII and of the intrinsic pathway (4) and a release of tissue thromboplastin from injured endothelial cells, which may subsequently activate factor VII and trigger the extrinsic pathway (5). On the other hand immune complexes occuring during infectious diseases (6) have been reported to cause platelet aggregation (7,3) and endotoxin lipopolysaccharides dramatically potentiate this effect (8). It was also shown that inflammatory reactions increase platelet responsiveness to aggregating agents such as norepinephrine (9) and angiotensine II (10). In spite of the above mentioned experimental data, clinical studies concerning the interrelationship between infection and thrombosis are almost exclusively limited to the syndromes of disseminated
219
intravascular coagulation occuring during acute septic processes (11, 12,1,3), while the possible role played by bacterial infections in the development of chronic vascular disease and in its thrombotic complications has received much less attention. It is however logical to presume that bacteria could trigger a chain of events which might eventually lead to recurrent thrombotic phenomena and even to thromboatherosclerosis. The incidence of urinary infection and its effect on several hemostatic variables were therefore investigated in the present paper in patients with acute ICVD. MATERIAL AND METHODS 100 randomly selected patients with ICVD caused by thrombotic events were investigated for urinary infection and were subsequently divided into two groups: Group A included 68 patients (40 men and 28 women) with ICVD associated with urinary infection. (Bacteriuria exceeding 10' germs/ml and a pyuria above 2000 leukocytes/min at the Addis-Hamburger sediment). Group B included 32 patients (15 men and 17 women) with ICDV who did not present urinary infection. Age (mean f SEM: 64.24 f 1.26 years in group A and 62.7 f 2 years in group B), and the incidence of arterial hypertension (60.3% in group A and 56.3% in group B) as well as the level of serum cholesterol (228 f 5.81 mg/dl in group A and 246 + 11.6 mg/dl in group B) were similar in both groups. A mild diabetes mellitus was found in six patients from group A and in four patients from group B. Incidence of bacteriuria was also assessed in 100 age-matched (63.2 + 0.95 years) control subjects. This group included 20 clinically healthy persons and 80 patients admitted in the clinic for miscellaneous complaints (gastroduodenal ulcers, cholecystopathies, ophtalmologic disease without ICVD or spondilerthrosis). In a number of patients (Table I) and in 20 healthy normal weight normolipidemic control subjects older than 40 years, plasma fibrinogen (13), dilute blood clot lysis time (14), platelet count (15), platelet adhesiveness (16) and factor VIII related antigen (17) as well circulating immune complexes (18) were investigated. Blood and urine for laboratory investigations were harvested within 72 hours since the acute event. RESULTS Urinary infection occured rather frequently in patients with ICVD (68% of the patients) but this infection was clinically asymptomatic in 85% of the cases and its presence could be detected only by bacteriological investigation. In 81% of the patients with bacteriuria, E. coli was identified. In contrast to ICVD patients, the presence of bacteriuria was found only in 12 of the 100 randomly selected control subjects and only in 6 cases could E. coli be identified. A statistically significant difference between the incidence of bacteriuria in ICVD patients and that noted in control subjects was thus obtained (x2 = 65,33; 220
F
VB
VB
vs
A
A
B
B
C
C
NS
NS
0.001
307 f 26 (14)
c CVID without UI
Statistical significance (p)
337 f 16 (22)
278 f 6.6 (20)
B CVID with UI
A Controls
Fibrinogen a&d1
NS
NS
NS
306 f 16.4 (23)
343 f 9.2 (32)
317 f 11.9 (20)
Platelet count x 10'
NS
NS
NS
38.52 f 4.52 (23)
38.18 f 2.65 (31)
34.03 f 2.61 (20)
Platelet adhesiveness (X adhesive platelets)
NS
NS
NS
280 f 43 (20)
247 2 37 (20)
243 f 42 (20)
DBCLT (minutes)
NS
0.001
0.001
291 f 24.06 (12)
325 f 40.71 (12)
116 f 5.56 (20)
VIIIR:Ag (% of normal)
x10'
0.005
NS
0.001
200 i 16.71 (21)
273 f 13.84 (28)
190 f 9.68 (ia)
0D450nm
CIC
Behaviour of plasma fibrinogen, platelet count, platelet adhesiveness, dilute blood lysis time (DBCLT), plasma factor VIII related antigen (VIIIR:Ag) and circulating irmnune complexes (CIC) in control subjects and in patients with acute cerebrovaacular ischemic disease (CVID) with or without urinary infection Mean f SRM. Number of investigated subjects in brackets. @I).
Group
Table I:
p < 0.001). As shown in Table 1 when compared to age-matched healthy control subjects - the only significant change noted in patients with ICVD was an obvious increase of factor VIII related antigen (VIIIR:Ag). Mean values of plasma fibrinogen level were higher in patients than in controls but this change reached statistical significance only in patients with urinary infection. On the other hand there were no significant differences concerning the investigated hemostatic variables between patients with and those without urinary infection. Significantly increased values of circulating immune complexes were however detected in patients with ICVD and urinary infection. DISCUSSION Since bacteriuria occurs more often in older people (19,ZO) and mainly in hypertensive ones (21), the high incidence of urinary infection in patients with ICVD could be easily explained. It is more difficult to state whether urinary infection is involved in the pathogenesis of acute cerebrovascular events, especially as the investigated hemostatic variables were similar in patients with or without urinary infection. It should be remembered that increased plasma levels of fibrinogen and VIIIR:Ag are components of the acute phase reaction and do not necessarily reflect thrombotic phenomena. Since obesity, hyperlipoproteinemia, diabetes and essential hypertension could be involved in changes affecting the hemostatic variables (22,23), it is even more difficult to identify the role played by urinary infection. Its high incidence in patients with ICVD and the increased level of circulating immune complexes in infected patients however deserves attention as it has been experimentally demonstrated that such immune complexes as well as endotoxin may injure vascular endothelia (3,23,25). A cross antigenicity between E. coli lipopolysaccharide (LPS) and aortic glycoproteins was also demonstrated and immune complexes were found to be bound to injured aortic areas of rabbits sensitized with LPS (26). If other conditions such as hyperlipidemia or diabetes mellitus, are considered to be risk factors for ICVD only because they accompany this disease, than urinary infection which was even more frequently detected, fully deserves to be included among such risk factors. The present study does not exceed the limits of a working hypothesis generated by clinical observations and a more thorough investigation of the hemostatic balance should be envisaged. Important prophylactic and therapeutic implications might nevertheless result if further studies will substantiate this hypothesis. REFERENCES 1.
LUscher EF. The role of blood cells and of the vessel wall in the induction of intravascular coagulation. Klin Wochenschr 60: 712, 1982.
222
2.
Rivers RPA, Hathway WE, Weston WL. The endotoxin-induced coagulant activity of human monocytes. Br J Haematol 30: 311, 1985.
3.
Someraro N, Lattanzio A. Interaction of platelet with bacterial endotoxin. Agents and Actions 5/6:461, 1983.
4.
Morrison DC, Cochrane CG. Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxin). J Exp Med 140: 797, 1974.
5.
Lyberg T, Galdal KS, Evenson SA. Cellular cooperation in endothelial cell thromboplastin synthesis. Br J Haematol 53: 1983.
85,
6.
Delire M. Role des complexes immuns en pathologie humaine. Revue de Medicine 33: 2039, 1981.
La
7.
Movat HZ, Mustard JP, Taichman NS, Uriuhara T. Platelet aggregation and release of ADP, serotonin and histamine associated with phagocytosis of antigen-antibody complexes. Proc Sot Exp Biol Med 120: 232, 1965.
8.
Ginsberg MH, Henson PM. Enhancement of platelet response to immune complexes and IgG aggregated by a rich bacterial lipopolysaccharides. J Exp Med 147: 207, 1978.
9.
Hampton JR, Mitchell JRA. Abnormalities in platelet behaviour in acute illnesses. Br Med J 1: 1078, 1966.
10.
Uza G, Crisnic I. Effect of Angiotensine II upon platelet adhesiveness and thrombelastogram in patients with essential arterial hypertension. Path Europ 10: 327, 1975.
11.
Cook JA, Wise WC, Halushka PV. Elevated thromboxane levels in the rat during endotoxin shock. Protective effect of imidazole, 13azaprostanoic acid on essential fatty acid deficiency. J Clin Invest 65: 227, 1980.
12.
Crisnic I, Cucuianu M, Manasia M, Uza G. Disseminated intravascular coagulation and acute renal failure. Thrombos Diathes Haemorrh XXVI, 2: 332, 1971.
13.
Ratnoff OD, Menzie CAA. A new method for the determination of fibrinogen in small samples of plasma. J Lab Clin Med 37: 316, 1951.
14.
Gallimore MJ, Tyler HM, Shan ITB. The measurement of fibrinolysis in the rat. Thrombos Diathes Haemorrh 26: 293, 1971.
15.
Brecher G, Cronkite EP. Morphology and enumeration of blood platelets. J Appl Physiol 3: 356, 1950.
16.
Perlick E. Gerinungslaboratorium in Klinik and Praxis. G. Thieme Ver 1960.
17.
Laurel1 CB. Electroimmunoassay. Stand J Clin Invest 29 (suppl 124): 21, 1972.
18.
Riba I, Haskova V, Kaslik J, Maierova M, Stransky J. The use of polyethyleneglycol for immune complex detection in human sera. Molecular Immunology 16: 489, 1979.
223
Leipzig,
19.
Akhtar AJ, Andrews GR, Caird FI, Fallon RJ. Urinary tract infection in the elder1y. A population study. Age Aging I: 1972.
48,
Infections of urinary tract. Med Clin North AM 67:
20.
Farrar WE. 187, 1983.
21.
Grieble HG, Jackson GG. Churchill 1960.
22.
Lowe GDO. Laboratory evaluation of hypercoagulability, in C.R.M. Prentice (ed) Clinics in haematology. Thrombosis. W.H. Saunders Comp. Ltd. London-Philadelphia-Toronto. 10: 407, 1981.
23,
Mettinger KIA. A study of hemostasis in ischemic cerebrovascular disease. V. A multivariante evaluation of risk indicators and predictors. Early results of a longitudinal study. Thrombos Res 28: 521, 1982.
24.
Calabrese LH, Clough JP. Hypersensitivity vasculitis group (HVG) Cleve Clin Q 49: 17, 1982.
25.
Williams RC. Immune complexes: A critical perspective. J Med 71: 743, 1981.
26.
Scebat L, Renais J, Goldstein I, Groult N, Hdjiisky P. Cross antigenicity between Escherichia coli lipopolysaccharide and aortic glycoproteins in Constantinides P (ed) Immunity and atherosclerosis. Academic Press, London, 10: 121, 1980.
Biology of Pyelonephritis. London,
224