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Low vascular fibrinolytic activity in obesity
THROMBOSIS RESEARCH Printed in the United
LOW
VASCULAR
FIBRINOLYTIC
Lars-Olof
Xedicine
ACTIVITY
IN
1975
Inc.
OBESITY
Almer and Lars Janzon
From the Coagulation Internal
vol. 6, pp. 171-175, Pergamon Press,
States
Laboratory
and the Departments
and Surgery,
Allmanna
of
Sjukhuset,
Malti, Sweden (Received
16.12.197&;
in revised form 13.1.1975. by Editor H.C. Godal)
Accepted ABSTPACT
The blood fibrinolytic activity is abnormally low in obesity. A significant correlation was found between the endothelial content of plasminoyen activator in the vessel walls and degree of overweight. It is suggested that this impairment of fibrinolysis might contribute to the high incidence of vascular complications in obesity.
INTRODUCTION Venous
thromboerrbolism
tic manifestations individuals.
(5,
7,
6,
15, 18, 20) and atherosclero-
are more common in obese than in non-obese
According
to Gordon and Rannel
cess risk of angina pectoris
(8) who found an ex-
and sudden death in obese individuals
with no known risk factors other than obesity, which
adiposity
contributes
fully established. cholesterol,
to cardiovascular
That it contributes
higher
blood pressure
incidence
by providing
and possibly
sugar seems clear, but it is not known whether unique extra morbidity
contribution".
and mortality
vessels,
because
normally
low in obesity
One possible
activity
(3, 9) for unknown 171
is not
increased
higher
blood
it makes some
in cardiovascular
lysis of fibrin deposits
the fibrinolytic
by
cause of the increased
of obese individuals
disease might be an impaired
"the mechanism
in the
of the blood reasons
(10).
is ab-
VASCULAR FIBRINOLYTIC ACTIVITY
172
vo1.6,pl'o.~
The aim of the present study was to investigate if a similar correlation does exist between overweight and the fibrinolytic activity of the vessel walls. We have previously reported a close correlation between the fibrinolytic activity of veins and arteries (4).
MATERIAL AND ivIETHODS The material consisted of a sub-sample of 110 randomly selected non-smokers and heavy smokers from the study group "Men born in 1914 and residing in Malmij" (12). In all subjects a biopsy specimen was obtained of a superficial vein on the back of the hand. The vessels were examined by the histochemical method of Todd (191, as modified by Pandolfi et al. (161, and the fibrinolytic activity determined. Four fibrin slides were prepared for each specimen and after incubation at 37OC for 0, 10, 20, and 30 minutes, the fibrinolytic activity was measured as the lysed areas in the fibrin film. Three fairly distinct degrees of fibrin digestion were recognized, namely grade I: microscopical punctate areas of lysis in most of the sections; grade II: gross lytic areas of irregular outline and sometimes confluent; grade III: dissolution of most or all the fibrin in contact with the sections. A grade I slide was allotted 1 point; a grade II slide, 2 points and a grade III, 3 points. Degrees of digestion between grades 0 and I, I and II, and II and III were allotted 0.5, 1.5 and 2.5 points, respectively. The total number of points scored by the set of four slides was taken as a measure of the fibrinolytic activity of the sample. The reproducibility of this system is high (17). with the use of height/weight tables (1) based on American data (11) as ideal weight, the patients were separated into four groups: A B C"" D
actual weight " " "
II
below o- 9.9 % above 10 - 19.9 % " )I 320 %
ideal weight " II II n II II
VASCULAR
v01.6,~0.2
FIBRINOLYTIC
-1 73
ACTIVITY
RESULTS The activator activity ranged between 1.5 and 10.0 arbitrary units. When the patients in the different weight groups were separated into those with 7 or more arbitrary units of activator activity and those with lower activity, it was found that there were significantly more patients (chi square test p
%
C 7 orbitrory units
T
III
70
L7
"
60
6
C
120 D
22
12
25
o-9.9 Number subjects
1049.9
% overweight
of 21
Fig. 1 Fibrinolytic activity (in arbitrary units) of vessel walls in relation to overweight
VASCULAR FIBRINOLYTIC ACTIVITY
174
Vo1.6,No.Z
DISCUSSION The fibrinolytic activity of the blood varies largely with the activator activity of the vessel wall (2). We have also shown that the spontaneous fibrinolytic activity and the fibrinolytic response to venous occlusion decrease with increasing overweight (3). In the present investigation a significant oorrelation was found between the plasminogen activator activity of the vessel walls and degree of overweight. This can evidently explain why the fibrinolytic activity of the blood falls with increasing overweight. An abnormally low fibrinolytic activity of the blood and vessel walls implies impairment of the defence against thrombotic deposits not only in the veins, as manifested by an excess risk of venous thrombosis and pulmonary embolism in obesity, but also in the arteries. Hypothetically, the known increased morbidity and mortality from cardiovascular disease among obese individuals might in part be related to the low fibrinolytic activity.
ACKNOWLEDGEMENTS This investigation was supported by grants from the Medical Faculty, University of Lund, and Svenska Tobaks Aktiebolaget.
REFERENCES 1. ABRAMSON,E. Nya n%zingsnormer. NBringsforskning, p 97, 1964. 2. ALMER,L.-0. On the relation between fibrinolytic activity of the blood and vessel walls. To be published. 3. AL&R,L.-0. Effect of obesity on fibrinolysis in diabetes mellitus. To be published. 4. ALMl?R,L.-O., PANDOLFI,M., and ABERG,M. The plasminogen activator activity of arteries and veins in diabetes mellitus. To be published. 5. BARKER,N.W., NYGAARD,K.K., WALTERS,W., and PRIESTLEY,J.T. A statistical study of post-operative venous thrombosis and pulmonary embolism: Predisposing factors. Mayo Clin. Proc.: 16., 1. 1941.
~~1.6,~0.2
VASCULAR FIBRINOLYTIC ACTIVITY
175
6. BRENE!MAN,J.C. Postoperative thromboembolic disease. Computer analysis leading to statistical prediction. J. Amer. med. ASS.: 193., 576. 1965. 7. COON ,W. W. , and COLLER,F.A. Some epidemiological considerations of thromboembolism. Surg. Gynec. Obstet.: log., 487. 1959. 8. GORDON,T., and KANNEL,W.B. The effects of overweight on cardiovascular diseases. Geriatrics: 28., 80. 1973. 9. GRACE,C.S., and GOLDRICK,R.B. Fibrinolysis and body build. J. Atheroscler. Res.: 8., 705. 1968. 10. GFACE,C.S., and GOLDRICK,R.R. Tissue fibrinolytic activity in obesity. AuSt. J. exp. Biol. med. Sci.: 47., 397. 1969. 11. HATHAWAY,M.L., and FOARD,E.D. Heights and weights of adults in the United States. Home Economics Research Report No. 10, table 80. 1960. 12. ISACSSOIJ,S.O.Venous occlusion plethysmography in 55-year-oli men. A population study in Malmij, Sweden. Acta med. stand.: Suppl. 537. 1972. 13. JANZON,L. Smoking and peripheral circulation in 59-year-old men studied with plethysmography and segmental measurements of systolic blood pressure. VASA. In press. 14. JANZON,L., and NILSSON,I.M. Smoking and fibrinolysis. To be published. 15. KAKKAR,V.V., HO!JE,C.T.,NICOLAIDES,A.N., RENNEY,J.T.G., and CLARKE,M.B. Deep vein thrombosis of the leg. Amer. J. Surq.: 120., 525. 1970. 16. PANDOLFI,M., NILSSON,I.M., ROBERTSON,B., and ISACSON,s. Fibrinolytic activity of human veins. Lancet: 2., 127. 1967. 17. PANDOLFI,M., BJERNSTAD,A., and NILSSON,I.M. Technical remarks on the microscopical demonstration of tissue plasminogen activator. Thromb. Diath. haemorrh.: 27., 88. 1972. 18. SNELL,A.M. The relation of obesity to fatal postoperative pulmonary embolism. Arch. Surq.: 15., 237. 1927. 19. TODD,A.S. Fibrinolysis autographs. Nature (Land.): 181., 495. 1958. 20. VESSEY,M.P., and DOLL,R. Investigation of relation between use of oral contraceotives and thromboembolic disease. A further report. Brit: med. J.: 2., 651. 1969.
LOW
VASCULAR
FIBRINOLYTIC
Lars-Olof
Xedicine
ACTIVITY
IN
1975
Inc.
OBESITY
Almer and Lars Janzon
From the Coagulation Internal
vol. 6, pp. 171-175, Pergamon Press,
States
Laboratory
and the Departments
and Surgery,
Allmanna
of
Sjukhuset,
Malti, Sweden (Received
16.12.197&;
in revised form 13.1.1975. by Editor H.C. Godal)
Accepted ABSTPACT
The blood fibrinolytic activity is abnormally low in obesity. A significant correlation was found between the endothelial content of plasminoyen activator in the vessel walls and degree of overweight. It is suggested that this impairment of fibrinolysis might contribute to the high incidence of vascular complications in obesity.
INTRODUCTION Venous
thromboerrbolism
tic manifestations individuals.
(5,
7,
6,
15, 18, 20) and atherosclero-
are more common in obese than in non-obese
According
to Gordon and Rannel
cess risk of angina pectoris
(8) who found an ex-
and sudden death in obese individuals
with no known risk factors other than obesity, which
adiposity
contributes
fully established. cholesterol,
to cardiovascular
That it contributes
higher
blood pressure
incidence
by providing
and possibly
sugar seems clear, but it is not known whether unique extra morbidity
contribution".
and mortality
vessels,
because
normally
low in obesity
One possible
activity
(3, 9) for unknown 171
is not
increased
higher
blood
it makes some
in cardiovascular
lysis of fibrin deposits
the fibrinolytic
by
cause of the increased
of obese individuals
disease might be an impaired
"the mechanism
in the
of the blood reasons
(10).
is ab-
VASCULAR FIBRINOLYTIC ACTIVITY
172
vo1.6,pl'o.~
The aim of the present study was to investigate if a similar correlation does exist between overweight and the fibrinolytic activity of the vessel walls. We have previously reported a close correlation between the fibrinolytic activity of veins and arteries (4).
MATERIAL AND ivIETHODS The material consisted of a sub-sample of 110 randomly selected non-smokers and heavy smokers from the study group "Men born in 1914 and residing in Malmij" (12). In all subjects a biopsy specimen was obtained of a superficial vein on the back of the hand. The vessels were examined by the histochemical method of Todd (191, as modified by Pandolfi et al. (161, and the fibrinolytic activity determined. Four fibrin slides were prepared for each specimen and after incubation at 37OC for 0, 10, 20, and 30 minutes, the fibrinolytic activity was measured as the lysed areas in the fibrin film. Three fairly distinct degrees of fibrin digestion were recognized, namely grade I: microscopical punctate areas of lysis in most of the sections; grade II: gross lytic areas of irregular outline and sometimes confluent; grade III: dissolution of most or all the fibrin in contact with the sections. A grade I slide was allotted 1 point; a grade II slide, 2 points and a grade III, 3 points. Degrees of digestion between grades 0 and I, I and II, and II and III were allotted 0.5, 1.5 and 2.5 points, respectively. The total number of points scored by the set of four slides was taken as a measure of the fibrinolytic activity of the sample. The reproducibility of this system is high (17). with the use of height/weight tables (1) based on American data (11) as ideal weight, the patients were separated into four groups: A B C"" D
actual weight " " "
II
below o- 9.9 % above 10 - 19.9 % " )I 320 %
ideal weight " II II n II II
VASCULAR
v01.6,~0.2
FIBRINOLYTIC
-1 73
ACTIVITY
RESULTS The activator activity ranged between 1.5 and 10.0 arbitrary units. When the patients in the different weight groups were separated into those with 7 or more arbitrary units of activator activity and those with lower activity, it was found that there were significantly more patients (chi square test p
%
C 7 orbitrory units
T
III
70
L7
"
60
6
C
120 D
22
12
25
o-9.9 Number subjects
1049.9
% overweight
of 21
Fig. 1 Fibrinolytic activity (in arbitrary units) of vessel walls in relation to overweight
VASCULAR FIBRINOLYTIC ACTIVITY
174
Vo1.6,No.Z
DISCUSSION The fibrinolytic activity of the blood varies largely with the activator activity of the vessel wall (2). We have also shown that the spontaneous fibrinolytic activity and the fibrinolytic response to venous occlusion decrease with increasing overweight (3). In the present investigation a significant oorrelation was found between the plasminogen activator activity of the vessel walls and degree of overweight. This can evidently explain why the fibrinolytic activity of the blood falls with increasing overweight. An abnormally low fibrinolytic activity of the blood and vessel walls implies impairment of the defence against thrombotic deposits not only in the veins, as manifested by an excess risk of venous thrombosis and pulmonary embolism in obesity, but also in the arteries. Hypothetically, the known increased morbidity and mortality from cardiovascular disease among obese individuals might in part be related to the low fibrinolytic activity.
ACKNOWLEDGEMENTS This investigation was supported by grants from the Medical Faculty, University of Lund, and Svenska Tobaks Aktiebolaget.
REFERENCES 1. ABRAMSON,E. Nya n%zingsnormer. NBringsforskning, p 97, 1964. 2. ALMER,L.-0. On the relation between fibrinolytic activity of the blood and vessel walls. To be published. 3. AL&R,L.-0. Effect of obesity on fibrinolysis in diabetes mellitus. To be published. 4. ALMl?R,L.-O., PANDOLFI,M., and ABERG,M. The plasminogen activator activity of arteries and veins in diabetes mellitus. To be published. 5. BARKER,N.W., NYGAARD,K.K., WALTERS,W., and PRIESTLEY,J.T. A statistical study of post-operative venous thrombosis and pulmonary embolism: Predisposing factors. Mayo Clin. Proc.: 16., 1. 1941.
~~1.6,~0.2
VASCULAR FIBRINOLYTIC ACTIVITY
175
6. BRENE!MAN,J.C. Postoperative thromboembolic disease. Computer analysis leading to statistical prediction. J. Amer. med. ASS.: 193., 576. 1965. 7. COON ,W. W. , and COLLER,F.A. Some epidemiological considerations of thromboembolism. Surg. Gynec. Obstet.: log., 487. 1959. 8. GORDON,T., and KANNEL,W.B. The effects of overweight on cardiovascular diseases. Geriatrics: 28., 80. 1973. 9. GRACE,C.S., and GOLDRICK,R.B. Fibrinolysis and body build. J. Atheroscler. Res.: 8., 705. 1968. 10. GFACE,C.S., and GOLDRICK,R.R. Tissue fibrinolytic activity in obesity. AuSt. J. exp. Biol. med. Sci.: 47., 397. 1969. 11. HATHAWAY,M.L., and FOARD,E.D. Heights and weights of adults in the United States. Home Economics Research Report No. 10, table 80. 1960. 12. ISACSSOIJ,S.O.Venous occlusion plethysmography in 55-year-oli men. A population study in Malmij, Sweden. Acta med. stand.: Suppl. 537. 1972. 13. JANZON,L. Smoking and peripheral circulation in 59-year-old men studied with plethysmography and segmental measurements of systolic blood pressure. VASA. In press. 14. JANZON,L., and NILSSON,I.M. Smoking and fibrinolysis. To be published. 15. KAKKAR,V.V., HO!JE,C.T.,NICOLAIDES,A.N., RENNEY,J.T.G., and CLARKE,M.B. Deep vein thrombosis of the leg. Amer. J. Surq.: 120., 525. 1970. 16. PANDOLFI,M., NILSSON,I.M., ROBERTSON,B., and ISACSON,s. Fibrinolytic activity of human veins. Lancet: 2., 127. 1967. 17. PANDOLFI,M., BJERNSTAD,A., and NILSSON,I.M. Technical remarks on the microscopical demonstration of tissue plasminogen activator. Thromb. Diath. haemorrh.: 27., 88. 1972. 18. SNELL,A.M. The relation of obesity to fatal postoperative pulmonary embolism. Arch. Surq.: 15., 237. 1927. 19. TODD,A.S. Fibrinolysis autographs. Nature (Land.): 181., 495. 1958. 20. VESSEY,M.P., and DOLL,R. Investigation of relation between use of oral contraceotives and thromboembolic disease. A further report. Brit: med. J.: 2., 651. 1969.