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Diurnal variation of the fibrinolytic system
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46 FIBRINOLYSIS 113 Diurnal variation of the fibrinolytic system GRIUAUDO V HAUERTJ, BACHMANNF, KRUITHOF EKO Haematology Div., Dept. of Medicine, CHW Lausanne, Swirzerland Blood fibrinolytic activity in man, as measured by the eu- globulin lysis time (ELT) or by the activity of the euglobulin fraction on fibrin plates (FP) shows marked diurnal fluctua- tions. It is highest in the late afternoon and lowest in the early morning. Using specific activity and antigen assays for several components of the fibrinolytic system, determined at 8,10 and 12 a.m. and at 4 and 8 p.m. we found in 8 healthy volunteers, that ELT and FP activity increased 150% and 104% respectively from 8 a.m. to 8 p.m. The following components all decreased significantly: t-PA antigen (- 42%), PAI- activity (-37%) and PAI- antigen (-60%), u-PA antigen decreased slightly by 13%. Immunoquenching studies and SDS-PAGE of euglobulins followed by xymo- graphy demonstrated that in the early morning all t-PA is complexed to PA&l, whereas in the late afternoon some free t-PA circulates in the blood of most volunteers. This phenomenon is well explained by the greater decrease of PAI- than of t-PA antigen during the day. High PAI- activity has been reported as a risk factor for a recurrence of myocardial infarction. Higher PAI- activities in the morning, possibly in combination with an increased platelet aggregability also observed in the morning, may thus con- tribute to the high incidence of heart attacks and sudden deaths occurring at that time of the day. 114 Daytime, sex, age, and lifestyle variations of fibrinolysis STEGNAR M, PETERNEL P, KEBER D, PENTEK M, VENE N UniversityClinical Centre, Tmovo Hospital of Internal Medicine, Ljubljana, Yugoslavia Changes of global fibrinolytic activity due to normal causes of variation (diurnal rhythm, sex, age, etc.) have been ob- served with nonspecific methods to assess fibrinolytic activ- ity. With novel specific techniques for measuring activity and antigen of tissue plasminogen activator (t-PA) and its inhib- itor (PAI-l), twenty-four hour measurements of t-PA and PAI- antigens were performed in 18 healthy subjects. t-PA and PAI- antigens showed highest values in the morning and decreased by about 30% and 50%, respectively, during the day reaching the lowest value in the afternoon (PA&l) or midnight (t-PA). Decrease in PAI- antigen was accom- panied by 40% decrease in PAI- activity and about 15 fold increase in t-PA activity. Diurnal rhythm was preserved in old subjects, but modified in shift workers. In a sample of 174 healthy subjects aged 21 to 80 years both antigens showed three- (t-PA) and 1.5 (PA&l) fold increase with age comparing the sixth and the third decade of lifetime and then gradually decreased. t-PA and PAI- activities showed no consistent changes with age. Men had higher t-PA and PAI- antigens and activities than women, though sex differ- ence was statisticaly significant only for t-PA antigen and was also persisting in all age groups. Physiologic meaning of studied normal variations of fibrinolytic parameters remains largely unknown. 115 Physiological regulation of fibrinolysis; modulatory aspects JANSENJWCM DUPHAR BV Dept Pharmacology, DA Weesp, The Netherlands The haemostatic balance consists of mechanisms responsible for blood clot formation and clot dissolution. An imbalance of these systems can cause both thrombosis or bleeding tendency. Each of these systems is in itself a balance of pro- and contra-acting factors as well. The fibrinolytic capacity in blood is a balance between plasminogen activator(s) and their inhibitors in particular t-PA and PAI-1. Recent reports indicate that in patients with recurrent deep venous thrombosis or pulmonary embolism, a bad response in the venous stasis test is correlatedwith high PAI- levels or a low t-PA release (Nilsson et al 1985; Juhan-Vague 1987). Also increased PAI-1 activity in blood is associated with an increased risk of myocardial reinfarction (Hamsten 1987). It is also hypothesized that individuals with substantialvariation of PAI- caused by the diurnal rhythm may have an increased possibility of developing arterial thrombosis (Angleton et al 1989). It can therefore be inferred that the balance between t-PA and its inhibitor PAI- is of essential importance. Both components are synthesized and released into the blood by the endothelium which forms the inner lining of the blood vessel wall. In addition hepatocytes represent a second physiological source of plasma PAI- and this source is modulated by the plasma insulin level (Juhan-Vague et al 1989). A malfunctioning regulation of the fibrinolytic balance corresponds to an increased thrombogenic en- dothelial surface and low blood fibrinolytic potential. The fibrinolytic balance is modulated by several more or less physiological agents. In vitro experiments with cultured endothelial cells indicated that throm- bin mainly increased the PAI- level while histamine predominantly affected the t-PA level (Gelehrter et al 1986; Hams et al. 1987). IL-l, TNF and dexamethasone strongly increased the PAI- level with a concomitant lowered t-PA level (Schleefet al 1988).1n viva experiments with IL-l, endotoxin and dexamethasone have confirmed the in vitro observations: a decreased capacity of the blood clot lysis and increased PAI- activities (Emeis et al 1986, Jansen et al 1989). Based on these observations it may be concluded that physiological effecters can modu- late the fibrinolytic system. Possibilities of modulation towards non- thrombotic conditions will be discussed.
Transcript of Diurnal variation of the fibrinolytic system
46 FIBRINOLYSIS
113 Diurnal variation of the fibrinolytic system GRIUAUDO V HAUERTJ, BACHMANNF, KRUITHOF EKO Haematology Div., Dept. of Medicine, CHW Lausanne, Swirzerland
Blood fibrinolytic activity in man, as measured by the eu- globulin lysis time (ELT) or by the activity of the euglobulin fraction on fibrin plates (FP) shows marked diurnal fluctua- tions. It is highest in the late afternoon and lowest in the early morning. Using specific activity and antigen assays for several components of the fibrinolytic system, determined at 8,10 and 12 a.m. and at 4 and 8 p.m. we found in 8 healthy volunteers, that ELT and FP activity increased 150% and 104% respectively from 8 a.m. to 8 p.m. The following components all decreased significantly: t-PA antigen (- 42%), PAI- activity (-37%) and PAI- antigen (-60%), u-PA antigen decreased slightly by 13%. Immunoquenching
studies and SDS-PAGE of euglobulins followed by xymo- graphy demonstrated that in the early morning all t-PA is complexed to PA&l, whereas in the late afternoon some free t-PA circulates in the blood of most volunteers. This phenomenon is well explained by the greater decrease of PAI- than of t-PA antigen during the day. High PAI- activity has been reported as a risk factor for a recurrence of myocardial infarction. Higher PAI- activities in the morning, possibly in combination with an increased platelet aggregability also observed in the morning, may thus con- tribute to the high incidence of heart attacks and sudden deaths occurring at that time of the day.
114 Daytime, sex, age, and lifestyle variations of fibrinolysis STEGNAR M, PETERNEL P, KEBER D, PENTEK M, VENE N University Clinical Centre, Tmovo Hospital of Internal Medicine, Ljubljana, Yugoslavia
Changes of global fibrinolytic activity due to normal causes of variation (diurnal rhythm, sex, age, etc.) have been ob- served with nonspecific methods to assess fibrinolytic activ- ity. With novel specific techniques for measuring activity and antigen of tissue plasminogen activator (t-PA) and its inhib- itor (PAI-l), twenty-four hour measurements of t-PA and PAI- antigens were performed in 18 healthy subjects. t-PA and PAI- antigens showed highest values in the morning and decreased by about 30% and 50%, respectively, during the day reaching the lowest value in the afternoon (PA&l) or midnight (t-PA). Decrease in PAI- antigen was accom-
panied by 40% decrease in PAI- activity and about 15 fold increase in t-PA activity. Diurnal rhythm was preserved in old subjects, but modified in shift workers. In a sample of 174 healthy subjects aged 21 to 80 years both antigens showed three- (t-PA) and 1.5 (PA&l) fold increase with age comparing the sixth and the third decade of lifetime and then gradually decreased. t-PA and PAI- activities showed no consistent changes with age. Men had higher t-PA and PAI- antigens and activities than women, though sex differ- ence was statisticaly significant only for t-PA antigen and was also persisting in all age groups. Physiologic meaning of studied normal variations of fibrinolytic parameters remains largely unknown.
115 Physiological regulation of fibrinolysis; modulatory aspects JANSENJWCM DUPHAR BV Dept Pharmacology, DA Weesp, The Netherlands
The haemostatic balance consists of mechanisms responsible for blood clot formation and clot dissolution. An imbalance of these systems can cause both thrombosis or bleeding tendency. Each of these systems is in itself a balance of pro- and contra-acting factors as well. The fibrinolytic capacity in blood is a balance between plasminogen activator(s) and their inhibitors in particular t-PA and PAI-1. Recent reports indicate that in patients with recurrent deep venous thrombosis or pulmonary embolism, a bad response in the venous stasis test is correlatedwith high PAI- levels or a low t-PA release (Nilsson et al 1985; Juhan-Vague 1987). Also increased PAI-1 activity in blood is associated with an increased risk of myocardial reinfarction (Hamsten 1987). It is also hypothesized that individuals with substantialvariation of PAI- caused by the diurnal rhythm may have an increased possibility of developing arterial thrombosis (Angleton et al 1989). It can therefore be inferred
that the balance between t-PA and its inhibitor PAI- is of essential importance. Both components are synthesized and released into the blood by the endothelium which forms the inner lining of the blood vessel wall. In addition hepatocytes represent a second physiological source of plasma PAI- and this source is modulated by the plasma insulin level (Juhan-Vague et al 1989). A malfunctioning regulation of the fibrinolytic balance corresponds to an increased thrombogenic en- dothelial surface and low blood fibrinolytic potential. The fibrinolytic balance is modulated by several more or less physiological agents. In vitro experiments with cultured endothelial cells indicated that throm- bin mainly increased the PAI- level while histamine predominantly affected the t-PA level (Gelehrter et al 1986; Hams et al. 1987). IL-l, TNF and dexamethasone strongly increased the PAI- level with a concomitant lowered t-PA level (Schleefet al 1988).1n viva experiments with IL-l, endotoxin and dexamethasone have confirmed the in vitro observations: a decreased capacity of the blood clot lysis and increased PAI- activities (Emeis et al 1986, Jansen et al 1989). Based on these observations it may be concluded that physiological effecters can modu- late the fibrinolytic system. Possibilities of modulation towards non- thrombotic conditions will be discussed.
