Acta Med Scand 200: 289-291, 1976
H yperlipidaemia and Reduced Fibrinolytic Activity Associated with Thromboembolic Complications in a Family P. Andersen From the Haematological Research Laboratory. Medical Department I X . Ullevdl Hospital. University Clinic, Oslo, Norway
ABSTRACT. Although not significantly correlated, the Occurrence of reduced fibrinolytic activity and capacity in hyperlipidaemics has often been described. Hyperlipidaemia and reduced fibrinolysis might well enhance the possibility of thromboembolism. Such a coincidence of risk factors has probably caused thrombotic disease in a family, as described in this case report and family investigation.
Hypercoagulability is commonly accepted to precede thromboembolism, and depends chiefly on increased synthesis of coagulation factors (8, 15). A reduction in fibrinolytic activity might, however, also contribute to hypercoagulability in circulating blood. With improved methods for recording fibrinolytic activity and capacity (17, 18), an association has been shown between reduced fibrinolytic activity and thrombotic disease (9, 13). Recently, Almer and Nilsson (2) reported a significantly reduced fibrinolytic activity in patients with diabetes mellitus. Fibrinolytic activity was not, however, significantly correlated with hypercholesterolaemia and/or hypertriglyceridaemia. Nevertheless, in patients with hypercholesterolaemia the mean spontaneous fibrinolytic activity, and in patients with hypertriglyceridaemia the mean fibrinolytic capacity, were only two-thirds of the respective means in those with normal lipid values (2). The findings of hypertriglyceridaemia and reduced fibrinolytic capacity correspond well with the observations described below. CASEREPORT AND FAMILY INVESTIGATION A 24-year-old man, previously in good health, was on Feb. 9, 1975 admitted to the Department of Neurology, UllevN 19- 762984
Hospital. On admission he had a paresis in his right arm and leg which had developed during the last four days. Dysphasia was never observed (he is lefthanded), and the hemiparesis disappeared a few days after hospitalization. EEG, cerebral scintigraphy and cerebral angiography were normal on admission, and so was the cerebrospinal fluid except for a slightly increased protein value (48 mg/100 ml, normal values below 45). Routine coagulation tests revealed no signs of hypercoagulability. A considerable hypertriglyceridaemia (fasting value 4.28 mmol/l, normal range 0.40-1 :70) and a moderate hypercholesterolaemia (308 mg/100 ml=7.98 mmol/l) were discovered, however. A diagnosis of a minor cerebral infarction in the left hemisphere was made, and the patient was referred to the Haematological Laboratory for further investigations, since inherited thromboembolic risk factors had to be suspected. Thus, a younger brother had had a thrombus (at the age of 17 in 1972) in the right popliteal artery which had been removed by thrombendarterectomy. One year later he was treated with heparin for a venous thrombus in his left leg. On this occasion the routine coagulation tests were normal, as was the serum cholesterol, though triglycerides were not determined. The parents and a sister were in good health, but the father’s sister had had a myocardial infarction in 1953, at the age of 40. Xanthomata were present, but serum cholesterol was normal (192- 181 mgll00 m1=4.97-4.69 mmol/l). She developed a heart insufficiency and died 46 years old from a second myocardial infarction. As to acquired thromboembolic risk factors, it should be mentioned that all family members were cigarette smokers, but none of them were obese.
METHODS In all family members, the fibrinolytic response to venous occlusion (=fibrinolytic capacity) was examined (twice), and compared with the fasting serum levels of blood sugar, cholesterol and triglycerides. The lipoprotein patterns on paper electrophoresis were determined, and were compared with the individual fibrinolytic capacity. A platelet adhesiveness test and an antithrombin 111 assay in plasma were also performed. Acra Mcd Scand 200
LYU
P.Anaersen
Table I. Blood sugar and serum lipids (fasting values), lipoprotein pattern and fibrinolytic response to venous occlusion in the patient and his family See Methods for test references and normal ranges of values
Date of investigation (1975) Serum glucose" (mg1100 ml) Serum cholesterolb(mg1100 ml) Serum triglycerides (mmol/l) Type of lipoprotein pattern Euglobulin lysis time (min) Before stasis After stasis Fibrinolytic capacityc a
Patient
Brother
Sister
Father
Mother
(24.5 y.)
(20 Y.)
(23 Y.)
(54 Y.)
(51 Y.)
3.3
3.3
11.4 86 212 2.47 N
18.3 11.4 102 90 315 340 2.50 2.28 IIB Im
18.3 11.4 87 93 347 358 5.82 4.72 IV IV
>I20 >120 15 24 N N
>120 >120 17 15 N N
>I20 >I20 65 48 R R
11.4 88 283 3.27 IV
>I20 >I20 >I20 130 R R
11.4 93 262 2.82 IV
>120 >I20 24 43 N R
3.3
100 mg/lOO ml=5.55 mmol/l. 100 mg/l00 ml=2.59 mmol/l. R=reduced; N=normal.
Fasting serum glucose. cholesterol and triglycerides
were determined at the Central Laboratory, UllevAl Hospital. The methods used are described in the Oslo Study (11). Normal ranges: glucose 70-115 mg/100 ml (3.51-6.4 mmol/l), cholesterol 150-350 mg/100 ml (3.9-9.1 mmol/l), triglycerides 0.40-1.70 mmol/l. The latter two values concern age groups 20-55 years. Lipoprotein paper electrophoresis was performed at the Lipid Laboratory of the Medical Outpatient Clinic, UIleva Hospital. The lipoprotein patterns were mainly typed in accordance with the classification of the WHO (19). Antithrombin I l l concentration in plasma was measured immunologically by the Mancini technique (12) at the Immunohaematological Laboratory, UllevAl Hospital. Normal range 100-150% of normal plasma concentration. Platelet adhesiveness tests (6) were performed by Dr J. Dale at the Institute for Thrombosis Research, Rikshospi-
talet, Oslo. Normal range 6040%. Fibrinolytic capacity, by which is meant the fibrinolytic response to venous occlusion (18), was tested at the Haematological Research Laboratory, UllevAl Hospital. It was evaluated by the euglobulin lysis time (16) before and after stasis (90 mmHg for 20 min). With this technique a normal lysis time prior to stasis should exceed 2 hours. A lysis time exceeding 30 min after stasis indicates reduced fibrinolytic response.
RESULTS No abnormalities in platelet adhesiveness were found, and the antithrombin 111 plasma concentrations were normal. The other results are listed in Table I. The fasting serum triglyceride levels were increased in all family members, but the lipoprotein patterns differed, as did the fibrinolytic capacity. Acta Med Scand 200
However, those family members who had experienced thrombotic disease (the patient and his brother) showed lipoprotein patterns (type IV) identical to that of their mother, and all three had reduced fibrinolytic capacity with the exception of one normal reading. Unfortunately, serum lipid determinations were not performed on that occasion.
DISCUSSION Reduced fibrinolytic activity and capacity have been correlated with diabetes mellitus (2, 3) and obesity ( I , 5). A negative correlation between fibrinolytic activity and serum triglycerides was found in a random sample of 788 men aged 54 (lo), but the correlation was not significant if the effect of obesity was taken into account. The present study suggests an association between hyper-pre-p-lipoproteinaemia and reduced fibrinolytic capacity, and possibly also between increased serum triglycerides and reduced fibrinolysis. Moderate lipid-reducing diet did not decrease the serum triglyceride level in this case. From April 24, 1975 the warfarin treatment was therefore supplemented with clofibrate medication. After five months' medication, and without a contemporary reduction in body weight, the serum triglyceride level had decreased from 3.27 to 2.30 mmol/l, but the patient still demonstrated a pre-8-lipoprotein pattern and the fibrinolytic capacity was unchanged (euglobulin lysis time after stasis still exceeded two hours). If the plasminogen activator content of the
Typerlipidaemia, reducedjibrinoly,ris and thrornboernbolisrn
vessel walls in this case were reduced due to an inborn defect, this might possibly explain the unchanged fibrinolytic response to venous occlusion. Studies on the effect of alimentary lipaemia upon the release of plasminogen activators have shown that the increased release which occurs in response to venous occlusion remains unmodified (4,7 , 14). It also seems unlikely that the presence of increased concentrations of circulating triglycerides per se influences the assay of fibrinolytic capacity. This assumption was supported by the fact that the patient’s plasma euglobulin fraction used in the fibrinolytic capacity test (16) did not contain lipoproteins. In accordance with this, euglobulin lysis time after and prior to stasis remained unmodified when the increased plasma triglyceride and chylomicron fractions, obtained after fat ingestion by a healthy volunteer, were mixed in equal proportions with the plasma samples collected for the test (unpublished data). In spite of numerous studies into the effects of plasma lipids upon fibrinolysis ( 5 , 7, 14), the importance of concomitant occurrence of hyperlipidaemia and reduced fibrinolysis for the development of thrombotic disease is still unclear. Therefore, in order to obtain further information about the possible relationship between reduced fibrinolytic capacity and various risk factors for atherosclerotic disease, co-operation has been established with the Oslo Study (1 1).
REFERENCES 1 . Almtr, L.-0. & Janzon, L.: Low vascular fibrinolytic activity in obesity. Thromb Res 6: 171, 1975. 2. AlmCr, L.-0. & Nilsson, I. M.: On fibrinolysis in diabetes mellitus. Acta Med Scand 198: 101, 1975. 3. Almbr, L.-O., Pandolfi, M. & Aberg, M.: The plasminogen activator activity of arteries and veins in diabetes mellitus. Thromb Res 6: 177, 1975. 4. Cronberg, S. & Nilsson, I. M.: Coagulation studies after administration of a fat emulsion, Intralipid”. Thromb Diath Haemorrh 18: 664,1%7. 5. Grace, L. S. & Goldrick, R. B.: Fibrinolysis and body
6.
7. 8.
9.
10.
11.
12.
build. Interrelationships between blood fibrinolysis, body composition and parameters of lipid and carbohydrate metabolism. J Atheroscler Res 8: 705, 1%8. Hellem, A. J.: Platelet adhesiveness in v. Willebrand‘s disease. A study with a new modification of the glass-bead filter method. Scand J Haematol 7: 374, 1970. Howell, M.: Effects of plasma lipids on fibrinolysis. Br Med Bull 20: 200, 1964. Isacson, S. & Nilsson, I. M.: Coagulation and platelet adhesiveness in recurrent “idiopathic” venous thrombosis and thrombophlebitis. Acta Chir Scand 138: 263, 1972. - Defective fibrinolysis in blood and vein walls in recurrent “idiopathic” venous thrombosis. Acta Chir Scand 138: 313, 1972. Korsan-Bengtsen, K., Wilhelmsen, L. & Tibblin, G.: Blood coagulation and fibrinolysis in a random sample of 788 men 54 years old. 11. Relations of the variables to “risk factors” for myocardial infarction. Thromb Diath Haemorrh 28: 99, 1972. Leren, P., Askevold, E. M., Foss, 0. P., Frnili, A., Grymyr, D., Helgeland, A., Hjermann, I., Holme, I., Lund-Larsen, P. G. & Norum, K. R.: The Oslo Study. Cardiovascular disease in middle-aged and young Oslo men. Acta Med Scand (Suppl) 588, 1976. Mancini, G., Carbonara, A. 0. & Heremans, J. F.: Immunochemical quantitation of antigens by single radial immunodiffusion. Int J Immunochem 2: 235,
1%5. 13. Menon, I . S . , McCollum, J. P. K. & Gibson, A. L.: Blood fibrinolytic activity in deep-vein thrombosis. Lancet 1:242, 1Y71. 14. Merskey, C. & Marcus, A. J.: Lipids, blood coagulation and fibrinolysis. Annu Rev Med 14: 323, 1%3. 15. Nilsson, I. M.: The development of thrombosis. Thule International Symposia. Stroke, p. 191. Nordiska Bokhandeln, Stockholm 1%7. 16. Nilsson, I. M. & Olow, B.: Fibrinolysis induced by streptokinase in man. Acta Chir Scand 123: 247, 1%2. 17. Pandolfi, M., Robertson, B. R., Isacson, S. & Nilsson, I. M.: Fibrinolytic activity of human veins in arms and legs. Thromb Diath Haemorrh 20: 247, 1%8. 18. Robertson, B. R., Pandolfi, M. & Nilsson, I. M.: Response of local fibrinolytic activity to venous occlusion of arms and legs in healthy volunteers. Acta Chir Scand 138:437, 1972. 19. WHO Memoranda: Classification of hyperlipidaemias and hyperlipoproteinaemias. Bull WHO 43: No. 6, 1970.
Acta Med Scand 200
H yperlipidaemia and Reduced Fibrinolytic Activity Associated with Thromboembolic Complications in a Family P. Andersen From the Haematological Research Laboratory. Medical Department I X . Ullevdl Hospital. University Clinic, Oslo, Norway
ABSTRACT. Although not significantly correlated, the Occurrence of reduced fibrinolytic activity and capacity in hyperlipidaemics has often been described. Hyperlipidaemia and reduced fibrinolysis might well enhance the possibility of thromboembolism. Such a coincidence of risk factors has probably caused thrombotic disease in a family, as described in this case report and family investigation.
Hypercoagulability is commonly accepted to precede thromboembolism, and depends chiefly on increased synthesis of coagulation factors (8, 15). A reduction in fibrinolytic activity might, however, also contribute to hypercoagulability in circulating blood. With improved methods for recording fibrinolytic activity and capacity (17, 18), an association has been shown between reduced fibrinolytic activity and thrombotic disease (9, 13). Recently, Almer and Nilsson (2) reported a significantly reduced fibrinolytic activity in patients with diabetes mellitus. Fibrinolytic activity was not, however, significantly correlated with hypercholesterolaemia and/or hypertriglyceridaemia. Nevertheless, in patients with hypercholesterolaemia the mean spontaneous fibrinolytic activity, and in patients with hypertriglyceridaemia the mean fibrinolytic capacity, were only two-thirds of the respective means in those with normal lipid values (2). The findings of hypertriglyceridaemia and reduced fibrinolytic capacity correspond well with the observations described below. CASEREPORT AND FAMILY INVESTIGATION A 24-year-old man, previously in good health, was on Feb. 9, 1975 admitted to the Department of Neurology, UllevN 19- 762984
Hospital. On admission he had a paresis in his right arm and leg which had developed during the last four days. Dysphasia was never observed (he is lefthanded), and the hemiparesis disappeared a few days after hospitalization. EEG, cerebral scintigraphy and cerebral angiography were normal on admission, and so was the cerebrospinal fluid except for a slightly increased protein value (48 mg/100 ml, normal values below 45). Routine coagulation tests revealed no signs of hypercoagulability. A considerable hypertriglyceridaemia (fasting value 4.28 mmol/l, normal range 0.40-1 :70) and a moderate hypercholesterolaemia (308 mg/100 ml=7.98 mmol/l) were discovered, however. A diagnosis of a minor cerebral infarction in the left hemisphere was made, and the patient was referred to the Haematological Laboratory for further investigations, since inherited thromboembolic risk factors had to be suspected. Thus, a younger brother had had a thrombus (at the age of 17 in 1972) in the right popliteal artery which had been removed by thrombendarterectomy. One year later he was treated with heparin for a venous thrombus in his left leg. On this occasion the routine coagulation tests were normal, as was the serum cholesterol, though triglycerides were not determined. The parents and a sister were in good health, but the father’s sister had had a myocardial infarction in 1953, at the age of 40. Xanthomata were present, but serum cholesterol was normal (192- 181 mgll00 m1=4.97-4.69 mmol/l). She developed a heart insufficiency and died 46 years old from a second myocardial infarction. As to acquired thromboembolic risk factors, it should be mentioned that all family members were cigarette smokers, but none of them were obese.
METHODS In all family members, the fibrinolytic response to venous occlusion (=fibrinolytic capacity) was examined (twice), and compared with the fasting serum levels of blood sugar, cholesterol and triglycerides. The lipoprotein patterns on paper electrophoresis were determined, and were compared with the individual fibrinolytic capacity. A platelet adhesiveness test and an antithrombin 111 assay in plasma were also performed. Acra Mcd Scand 200
LYU
P.Anaersen
Table I. Blood sugar and serum lipids (fasting values), lipoprotein pattern and fibrinolytic response to venous occlusion in the patient and his family See Methods for test references and normal ranges of values
Date of investigation (1975) Serum glucose" (mg1100 ml) Serum cholesterolb(mg1100 ml) Serum triglycerides (mmol/l) Type of lipoprotein pattern Euglobulin lysis time (min) Before stasis After stasis Fibrinolytic capacityc a
Patient
Brother
Sister
Father
Mother
(24.5 y.)
(20 Y.)
(23 Y.)
(54 Y.)
(51 Y.)
3.3
3.3
11.4 86 212 2.47 N
18.3 11.4 102 90 315 340 2.50 2.28 IIB Im
18.3 11.4 87 93 347 358 5.82 4.72 IV IV
>I20 >120 15 24 N N
>120 >120 17 15 N N
>I20 >I20 65 48 R R
11.4 88 283 3.27 IV
>I20 >I20 >I20 130 R R
11.4 93 262 2.82 IV
>120 >I20 24 43 N R
3.3
100 mg/lOO ml=5.55 mmol/l. 100 mg/l00 ml=2.59 mmol/l. R=reduced; N=normal.
Fasting serum glucose. cholesterol and triglycerides
were determined at the Central Laboratory, UllevAl Hospital. The methods used are described in the Oslo Study (11). Normal ranges: glucose 70-115 mg/100 ml (3.51-6.4 mmol/l), cholesterol 150-350 mg/100 ml (3.9-9.1 mmol/l), triglycerides 0.40-1.70 mmol/l. The latter two values concern age groups 20-55 years. Lipoprotein paper electrophoresis was performed at the Lipid Laboratory of the Medical Outpatient Clinic, UIleva Hospital. The lipoprotein patterns were mainly typed in accordance with the classification of the WHO (19). Antithrombin I l l concentration in plasma was measured immunologically by the Mancini technique (12) at the Immunohaematological Laboratory, UllevAl Hospital. Normal range 100-150% of normal plasma concentration. Platelet adhesiveness tests (6) were performed by Dr J. Dale at the Institute for Thrombosis Research, Rikshospi-
talet, Oslo. Normal range 6040%. Fibrinolytic capacity, by which is meant the fibrinolytic response to venous occlusion (18), was tested at the Haematological Research Laboratory, UllevAl Hospital. It was evaluated by the euglobulin lysis time (16) before and after stasis (90 mmHg for 20 min). With this technique a normal lysis time prior to stasis should exceed 2 hours. A lysis time exceeding 30 min after stasis indicates reduced fibrinolytic response.
RESULTS No abnormalities in platelet adhesiveness were found, and the antithrombin 111 plasma concentrations were normal. The other results are listed in Table I. The fasting serum triglyceride levels were increased in all family members, but the lipoprotein patterns differed, as did the fibrinolytic capacity. Acta Med Scand 200
However, those family members who had experienced thrombotic disease (the patient and his brother) showed lipoprotein patterns (type IV) identical to that of their mother, and all three had reduced fibrinolytic capacity with the exception of one normal reading. Unfortunately, serum lipid determinations were not performed on that occasion.
DISCUSSION Reduced fibrinolytic activity and capacity have been correlated with diabetes mellitus (2, 3) and obesity ( I , 5). A negative correlation between fibrinolytic activity and serum triglycerides was found in a random sample of 788 men aged 54 (lo), but the correlation was not significant if the effect of obesity was taken into account. The present study suggests an association between hyper-pre-p-lipoproteinaemia and reduced fibrinolytic capacity, and possibly also between increased serum triglycerides and reduced fibrinolysis. Moderate lipid-reducing diet did not decrease the serum triglyceride level in this case. From April 24, 1975 the warfarin treatment was therefore supplemented with clofibrate medication. After five months' medication, and without a contemporary reduction in body weight, the serum triglyceride level had decreased from 3.27 to 2.30 mmol/l, but the patient still demonstrated a pre-8-lipoprotein pattern and the fibrinolytic capacity was unchanged (euglobulin lysis time after stasis still exceeded two hours). If the plasminogen activator content of the
Typerlipidaemia, reducedjibrinoly,ris and thrornboernbolisrn
vessel walls in this case were reduced due to an inborn defect, this might possibly explain the unchanged fibrinolytic response to venous occlusion. Studies on the effect of alimentary lipaemia upon the release of plasminogen activators have shown that the increased release which occurs in response to venous occlusion remains unmodified (4,7 , 14). It also seems unlikely that the presence of increased concentrations of circulating triglycerides per se influences the assay of fibrinolytic capacity. This assumption was supported by the fact that the patient’s plasma euglobulin fraction used in the fibrinolytic capacity test (16) did not contain lipoproteins. In accordance with this, euglobulin lysis time after and prior to stasis remained unmodified when the increased plasma triglyceride and chylomicron fractions, obtained after fat ingestion by a healthy volunteer, were mixed in equal proportions with the plasma samples collected for the test (unpublished data). In spite of numerous studies into the effects of plasma lipids upon fibrinolysis ( 5 , 7, 14), the importance of concomitant occurrence of hyperlipidaemia and reduced fibrinolysis for the development of thrombotic disease is still unclear. Therefore, in order to obtain further information about the possible relationship between reduced fibrinolytic capacity and various risk factors for atherosclerotic disease, co-operation has been established with the Oslo Study (1 1).
REFERENCES 1 . Almtr, L.-0. & Janzon, L.: Low vascular fibrinolytic activity in obesity. Thromb Res 6: 171, 1975. 2. AlmCr, L.-0. & Nilsson, I. M.: On fibrinolysis in diabetes mellitus. Acta Med Scand 198: 101, 1975. 3. Almbr, L.-O., Pandolfi, M. & Aberg, M.: The plasminogen activator activity of arteries and veins in diabetes mellitus. Thromb Res 6: 177, 1975. 4. Cronberg, S. & Nilsson, I. M.: Coagulation studies after administration of a fat emulsion, Intralipid”. Thromb Diath Haemorrh 18: 664,1%7. 5. Grace, L. S. & Goldrick, R. B.: Fibrinolysis and body
6.
7. 8.
9.
10.
11.
12.
build. Interrelationships between blood fibrinolysis, body composition and parameters of lipid and carbohydrate metabolism. J Atheroscler Res 8: 705, 1%8. Hellem, A. J.: Platelet adhesiveness in v. Willebrand‘s disease. A study with a new modification of the glass-bead filter method. Scand J Haematol 7: 374, 1970. Howell, M.: Effects of plasma lipids on fibrinolysis. Br Med Bull 20: 200, 1964. Isacson, S. & Nilsson, I. M.: Coagulation and platelet adhesiveness in recurrent “idiopathic” venous thrombosis and thrombophlebitis. Acta Chir Scand 138: 263, 1972. - Defective fibrinolysis in blood and vein walls in recurrent “idiopathic” venous thrombosis. Acta Chir Scand 138: 313, 1972. Korsan-Bengtsen, K., Wilhelmsen, L. & Tibblin, G.: Blood coagulation and fibrinolysis in a random sample of 788 men 54 years old. 11. Relations of the variables to “risk factors” for myocardial infarction. Thromb Diath Haemorrh 28: 99, 1972. Leren, P., Askevold, E. M., Foss, 0. P., Frnili, A., Grymyr, D., Helgeland, A., Hjermann, I., Holme, I., Lund-Larsen, P. G. & Norum, K. R.: The Oslo Study. Cardiovascular disease in middle-aged and young Oslo men. Acta Med Scand (Suppl) 588, 1976. Mancini, G., Carbonara, A. 0. & Heremans, J. F.: Immunochemical quantitation of antigens by single radial immunodiffusion. Int J Immunochem 2: 235,
1%5. 13. Menon, I . S . , McCollum, J. P. K. & Gibson, A. L.: Blood fibrinolytic activity in deep-vein thrombosis. Lancet 1:242, 1Y71. 14. Merskey, C. & Marcus, A. J.: Lipids, blood coagulation and fibrinolysis. Annu Rev Med 14: 323, 1%3. 15. Nilsson, I. M.: The development of thrombosis. Thule International Symposia. Stroke, p. 191. Nordiska Bokhandeln, Stockholm 1%7. 16. Nilsson, I. M. & Olow, B.: Fibrinolysis induced by streptokinase in man. Acta Chir Scand 123: 247, 1%2. 17. Pandolfi, M., Robertson, B. R., Isacson, S. & Nilsson, I. M.: Fibrinolytic activity of human veins in arms and legs. Thromb Diath Haemorrh 20: 247, 1%8. 18. Robertson, B. R., Pandolfi, M. & Nilsson, I. M.: Response of local fibrinolytic activity to venous occlusion of arms and legs in healthy volunteers. Acta Chir Scand 138:437, 1972. 19. WHO Memoranda: Classification of hyperlipidaemias and hyperlipoproteinaemias. Bull WHO 43: No. 6, 1970.
Acta Med Scand 200
