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t-Plasminogen activator and von Willebrand factor in patients with unstable angina
International
Journal
of
cardiology ELSEVIER
International Journal of Cardiology 54 (1996) 89-92
t-Plasminogen activator and von Willebrand factor in patients with unstable angina Dimitris Tousoulisa**, Eirini Bosinakoub, Costas Tentolourisa, Theodoros Apostolopoulos”, Clio Copsharib, Michael Kyriakides”, Pavlos Toutouzasa “Cardiology Unit, Hippokration Hospital, Athens University Medical School, Vasilisis So&s 114, Athens, Greece bHaematology Unit, Hippokration Hospital, Athens University Medical School, Vasilisis Sojias 114, Athens, Greece R.eceived 14 November 1995; revised 23 January 1996; accepted 23 January 1996
Abstract We investigated whether the clinical evolution of symptomsin patients admitted with unstable angina is associatedwith changesin t-plasminogen activator antigen (t-PA) and von Willebrand (VW) factor levels. Concentrations of VW factor antigen and t-PA antigen were measuredby an enzyme-linked immunoassaymethodin 10 patients who becameclinically stable within 24 h of admission and remained so for 5 days. A significant rise in morning t-PA plasmalevel occurred 24 h after the admission (15.15 +- 2.1 rig/ml, P < 0.05), whereasthe VW factor remained unchanged.No significant changes were found in the night concentration in t-PA and VW factor during the 5 day period. Thus t-PA level is significantly raised 24 h after admission in patients with unstable angina who stabilize in responseto medical treatment. Keywords: Fibrinolysis; t-Plasminogen activator; von Willebrand factor; Unstable angina
1. Introduction Previous studies have shown that intracoronary thrombosis plays a pathogenetic role in patients with unstable angina and non-Q-wave myocardial infarction [ 11. Concentrations of the endotheliumderived proteins, tissue plasminogen activator and plasminogen activator inhibitor- 1 have been related to the presence of coronary artery disease [2], and therefore these factors may provide indirect in*Corresponding author, Cardiology Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, UK. Tel.: +44 181 7432030, Fax: +44 181 7433987.
formation on the state of the vessel wall. It is well known that plasma von Willebrand factor is the principal mediator of platelet adhesion to sites of vascular injury under conditions of high shear stress [3]. Rapid changes in the concentration of tissue plasminogen activator and von Willebrand factor are a major feature of the acute phase reaction induced by tissue damage, and have been reported during the acute phase of myocardial infarction, in unstable angina, in thromboembolism and in variant angina [4-l 11. Thus, the responses of the endogenous fibrinolytic system and the platelet aggregation may be important factors in the clinical evolution of unstable angina. In this study
0167-5273/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII SO167-5273(96)02600-9
90
D. Tousoulis et al. I International
we assessed whether the clinical evolution of symptoms in patients admitted with unstable angina is associated with changes in tissue plasminogen activator and von Willebrand factor.
2. Patients and methods 2.1. Study patients Ten of 13 consecutive patients (9 men and 1 woman aged 58 2 9 years) admitted with unstable angina which stabilized within 24 h were studied. All presented with persistent chest pain typical of unstable angina (at rest or new onset of the pain) less than 30 min duration and associated with electrocardiographic ST-segment changes. Eight normal subjects (3 men and 5 women aged 46 + 7 years) without clinical history and risk factors for coronary artery disease were also studied. An intravenous infusion of heparin was administered after admission to maintain an APTT of 2-3 times normal. All received an intravenous infusion of glyceryl trinitrate at a rate of 1- 10 mg / h titrated against systolic blood pressure. Oral aspirin (75 mg daily) and conventional anti-anginal treatment were prescribed. Following this, patients were managed in routine fashion. The study protocol was approved by the Research Ethics Committee of our Hospital and all patients gave informed and written consent to participate in the study. 2.2. Laboratory investigations Blood samples for plasminogen activator inhibitor activity, von Willebrand factor and fibrinogen were taken every morning (08.00) and every evening (20.00) for 5 after admission days. Plasma concentrations of von Willebrand factor antigen and tissue plasminogen activator were determined by a commercially available enzyme-linked immunosorbent assay (ELISA, Stago Diagnostica Inc., Franconville, France) [12,13]. von Willebrand values are expressed as a percent of a pooled normal plasma with 100% corresponding to 1 IU/ml, (range 50-150% normal plasma). Values of tissue plasminogen activator are expressed in rig/ml (normal values 1-12 rig/ml). Fibrinogen level was
Journal of Cardiology 54 (1996) 89-92
determined with reagents (g/l).
the MLA
system using Dade
2.3. Statistical analysis All data are expressed as mean t S.E.M. For comparisons of data a one-way analysis of variance, with an allowance for repeated measures, was performed. When an F value was found to be significant, a two-tailed Student’s t-test for paired observations with the Bonferroni correction was used to test differences among means. A P value < 0.05 was considered significant.
3. Results In 8 normal subjects the mean plasma level of tissue plasminogen activator antigen, von Willebrand factor antigen and fibrinogen were 7.14 2 1.26 rig/ml, 81.87 + 5.34 IU/ml and 3.29 + 0.3 g/l respectively in the morning, and 7.03 2 1.27 rig/ml, 78.92 2 5.52 IU/ml and 3.23 ? 0.28 g/l respectively in the evening. In the unstable angina patients a significant rise in tissue plasminogen activator antigen occurred 24 h after the admission in the morning plasma (15.15 rt 2.1.~~. 9.9 + 1.7 rig/ml respectively, P < O.OS),whereas von Willebrand factor antigen and fibrinogen levels remained unchanged (Table 1). No significant changes were found in the evening plasma concentration of tissue plasminogen activator antigen, von Willebrand factor antigen and fibrinogen during the 5 days period (Table 1). A significant rise in the mean tissue plasminogen activator antigen and fibrinogen level compared with the normal subjects was found 24 h after admission which persisted for 4 days (Fig. 1).
4. Discussion This study documents the variations of tissue plasminogen activator antigen and von Willebrand factor antigen in patients with unstable angina over a period of 5 days after admission to hospital. It shows that plasma tissue plasminogen activator
D. Tousoulis et al. I International
91
Journal of Cardiology 54 (1996) 89-92
Table 1 Plasma concentrations of von Willebrand factor antigen &Wag), tisstie-plasminogen activator antigen (t-PAag) and fibrinogen in patients with unstable angina daring the morning and during the night 1 It day
2°d day
31d day
41h day
51h day
Morning 08.00 t-PAag (nglml) vWFag @J/ml) Fibrinogen (g/l)
9.93 2 1.7 90.5 -c 6.1 4.03 k 0.24
15.15 2 2.1* 91.4 5 5.8 4.23 t 0.27*
14.7 t 2.0* 88.0 2 8.2 4.24 k 0.26”
13.3 2 1.3* 99.1 2 6.2 4.38 2 0.35*
13.3 -c 1.4* 96.5 2 6.5 4.15 2 0.32*
Night 20.00 t-PAag (ng /ml) vWFag (IUlml) Fibrinogen (g/l)
11.2 2 2.6 79.6 t 5.4 3.58 I 0.30
12.8 2 2.1 84.4 k 6.4 3.70 i 0.19
14.4 + 2.5* 88.8 k 7.2 3.91 t 0.26
9.2 2 1.5 88.2 2 5.6 3.77 t 0.32
8.7 2 1.5 95.5 + 7.1 3.53 2 0.57
*P < 0.05 vs. normal subjects.
antigen levels increase after 24 h in those who stabilize in response to medical treatment. Although the mechanisms of unstable angina and myocardial infarction are similar, their clinical characteristics are different [14]. Studies have showed that plaque disruption and thrombus formation is the main pathogenetic substrate for both myocardial infarction and unstable angina [ 11. This suggest than the prothrombotic reactivity of blood to the vessel wall injury may be greater in patients with myocardial infarction than in those with unstable angina [ 1,141. The response of endogenous fibrinolytic system and platelet adhesion and aggregation may play an important role in distinguishing the mechanisms of these two syndromes. von
20
1
0
1
2
Days
3
4
5
Fig. 1. Plasma tissue-plasminogen activator antigen (t-PAag) levels determined for 5 consecutive days after the admission in the morning and in the evening, in patients with unstable angina. A significantly (*P < 0.05 vs. admission level) increased level was found after 24 h.
Willebrand factor plays a pivotal role in the process of platelet adhesion [3,15]. When there is loss of endothelial integrity, platelet adhesion is a critical step in the response of platelets, allowing interaction with exposed subendothelial components of the damaged vessel with the platelets. In our study plasma von Willebrand factor antigen levels in patients with unstable angina were within normal limits indicating that there is a tendency for reduction of platelet adhesion and aggregation. Previous studies [4] in patients with acute myocardial infarction have shown elevated plasma levels of von Willebrand factor. There may, therefore, be a different pattern of aggregation and adhesion of platelets in patients with unstable angina compared with myocardial infarction. The maintained presence of thrombus depends not only on its formation, but also on its lysis [lo]. The fibrinolytic system is activated by tissue plasminogen activator which is rapidly inactivated by plasma plasminogen activator inhibitor- 1 [ 161. Plasma plasminogen activator inhibitor is also known to be an acute phase reactant in response to tissue injury and synthesized mainly by endothelial and hepatic cells [16]. Previous investigators [9,17] have measured the plasma levels of plasminogen activator inhibitor- 1 activity and von Willebrand factor every 6 h for 48 h in patients with unstable angina and showed no significant elevation of von Willebrand factor, although plasminogen activator inhibitor- 1 activity was significantly elevated and was not influenced by the extent of underlying coronary artery disease. Increased plasma levels of plasminogen activator inhibitor-l were demonstra-
92
D. Tousoulis et al. / International Journal of Cardiology 54 (1996) 89-92
ted in patients with acute myocardial infarction those who survival myocardial infarction [18,19]. Furthermore, in our study the fibrinogen level was found to be elevated in the morning plasma, indicating an increased thrombotic process in the morning period [20]. The changes of fibrinolytic activity it is more likely to reflect either a systemic acute phase response or the effect of sympathetic activation on the arterial tree as a whole. In this study we have not examined these possibilities. In conclusion, the changesin tissue plasminogen activator antigen level represent an index of the functional capacity of the fibrinolytic/proteolytic system. A raised tissue plasminogen activator antigen level and stable von Willebrand factor level antigen maybe used to predict clinical stability in patients who present with unstable angina. References [l] Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988; 77: 1213-1220. [2] Paramo JA, Colucci M, Collen D, Werf F. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 1985; 291: 573-574. [3] Stel HV, Sakariassen KS, de Groot PG, van Mourik JA, Sixma JJ. von Willebrand factor in the vessel wall mediates platelet adherence. Blood 1985; 65: 85-90. [4] Andreotti F, Roncaglioni MC, Hackett DR et al. Early coronary reperfusion blunts the procoagulant response of plaaminogen activator inhibitor-l and von Willebrand factor in acute myocardial infarction. J Am Co11 Cardiol 1990; 16: 15.53-1560. [5] Sakamoto T, Yasue H, Ogawa H, Misumi 1, Masuda T. Association of patency of the infarct-related coronary artery with plasma levels of plasminogen activator inhibitor activity in acute myocardial infarction. Am J Cardiol 1992; 70: 271-276. [6] Sane DC, Stump DC, Top01 EJ et al. Correlation between baseline plasminogen activator inhibitor levels and clinical outcome during therapy with tissue plasminogen activator for acute myocardial infarction. Tbromb Haemost 1991; 65: 275-279. [7] Gram J, Kluft C, Jespersen J. Depression of tissue plasminogen activator (t-PA) activity and rise of t-PA inhibition and acute phase reactants in blood of patients with acute myocardial infarction. Thromb Haemost 1987; 58: 817821.
[8] Sakamoto T, Yasue H, Ogawa H, Misumi 1, Masuda T. Association of patency of the infarct-related coronary artery with plasma levels of plasminogen activator inhibitor activity in acute myocardial infarction. Am J Cardiol 1992; 70: 271-276. [9] Margulis T, David M, Maor N et al. The von Willebrand factor in myocardial infarction and unstable angina: a kinetic study. Thromb Haemost 1986; 55: 366-368. [lo] Vermylen JG, Chamone DAF. The role of the fibrinolytic system in thromboembolism. Prog Cardiovasc Dis 1979; 21: 255-266. [ 111 Misumi I, Ogawa H, Masuda T, Sakamoto T, Okumura K, Yasue H. Increased plasma plasminogen activator inhibitor activity after coronary spasm. Int J Cardiol 1993; 41: 21-29. [12] Ingerslev J. A sensitive ELISA for von Willenbrand factor (vWt: Ag). Stand J Clin Lab Invest 1987; 47: 143-149. [13] Amiral J, Plassart V, Grosley M, Mimilla F, Contant G, Guyader AM. Measurement of tPA-PAI- complexes by ELISA, using monoclonal antibodies: clinical relevance. Thromb Res 1988; 8: 99-113. [14] Fuster V, Chesebro JH. Mechanisms of unstable angina. N Engl J Med 1986; 315: 1023-1025. [15] McGhie IA, McNatt J, Ezov N et al. Abolition of cyclic flow variations in &nosed, endothelium-injured coronary arteries in nonhuman primates with a peptide fragment (VCL) derived from human plasma von Willebrand factorglycoprotein Ib binding domain. Circulation 1994; 90: 2976-298 1. [16] Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387. [17] Huber K, Rose D, Resch I et al. Circadian fluctuations of plasminogen activator inhibitor and tissue plasminogen activator levels in plasma of patients with unstable coronary artery disease and acute myocardial infarction. Thromb Haemost 1988; 60: 372-376. [18] Lucore Cl, Sobel BE. Interaction of tissue-type plasminogen activator with plasma inhibitors and their pharmacological implications. Circulation 1988; 77: 660-669. [19] Hamsten A, Wiman B, De Faire U, Blomback M. Increased plasma levels of rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563. [20] Braunwald E. Morning resistance to thrombolytic therapy. Circulation 1995; 91: 1604-1606.
Journal
of
cardiology ELSEVIER
International Journal of Cardiology 54 (1996) 89-92
t-Plasminogen activator and von Willebrand factor in patients with unstable angina Dimitris Tousoulisa**, Eirini Bosinakoub, Costas Tentolourisa, Theodoros Apostolopoulos”, Clio Copsharib, Michael Kyriakides”, Pavlos Toutouzasa “Cardiology Unit, Hippokration Hospital, Athens University Medical School, Vasilisis So&s 114, Athens, Greece bHaematology Unit, Hippokration Hospital, Athens University Medical School, Vasilisis Sojias 114, Athens, Greece R.eceived 14 November 1995; revised 23 January 1996; accepted 23 January 1996
Abstract We investigated whether the clinical evolution of symptomsin patients admitted with unstable angina is associatedwith changesin t-plasminogen activator antigen (t-PA) and von Willebrand (VW) factor levels. Concentrations of VW factor antigen and t-PA antigen were measuredby an enzyme-linked immunoassaymethodin 10 patients who becameclinically stable within 24 h of admission and remained so for 5 days. A significant rise in morning t-PA plasmalevel occurred 24 h after the admission (15.15 +- 2.1 rig/ml, P < 0.05), whereasthe VW factor remained unchanged.No significant changes were found in the night concentration in t-PA and VW factor during the 5 day period. Thus t-PA level is significantly raised 24 h after admission in patients with unstable angina who stabilize in responseto medical treatment. Keywords: Fibrinolysis; t-Plasminogen activator; von Willebrand factor; Unstable angina
1. Introduction Previous studies have shown that intracoronary thrombosis plays a pathogenetic role in patients with unstable angina and non-Q-wave myocardial infarction [ 11. Concentrations of the endotheliumderived proteins, tissue plasminogen activator and plasminogen activator inhibitor- 1 have been related to the presence of coronary artery disease [2], and therefore these factors may provide indirect in*Corresponding author, Cardiology Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, UK. Tel.: +44 181 7432030, Fax: +44 181 7433987.
formation on the state of the vessel wall. It is well known that plasma von Willebrand factor is the principal mediator of platelet adhesion to sites of vascular injury under conditions of high shear stress [3]. Rapid changes in the concentration of tissue plasminogen activator and von Willebrand factor are a major feature of the acute phase reaction induced by tissue damage, and have been reported during the acute phase of myocardial infarction, in unstable angina, in thromboembolism and in variant angina [4-l 11. Thus, the responses of the endogenous fibrinolytic system and the platelet aggregation may be important factors in the clinical evolution of unstable angina. In this study
0167-5273/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII SO167-5273(96)02600-9
90
D. Tousoulis et al. I International
we assessed whether the clinical evolution of symptoms in patients admitted with unstable angina is associated with changes in tissue plasminogen activator and von Willebrand factor.
2. Patients and methods 2.1. Study patients Ten of 13 consecutive patients (9 men and 1 woman aged 58 2 9 years) admitted with unstable angina which stabilized within 24 h were studied. All presented with persistent chest pain typical of unstable angina (at rest or new onset of the pain) less than 30 min duration and associated with electrocardiographic ST-segment changes. Eight normal subjects (3 men and 5 women aged 46 + 7 years) without clinical history and risk factors for coronary artery disease were also studied. An intravenous infusion of heparin was administered after admission to maintain an APTT of 2-3 times normal. All received an intravenous infusion of glyceryl trinitrate at a rate of 1- 10 mg / h titrated against systolic blood pressure. Oral aspirin (75 mg daily) and conventional anti-anginal treatment were prescribed. Following this, patients were managed in routine fashion. The study protocol was approved by the Research Ethics Committee of our Hospital and all patients gave informed and written consent to participate in the study. 2.2. Laboratory investigations Blood samples for plasminogen activator inhibitor activity, von Willebrand factor and fibrinogen were taken every morning (08.00) and every evening (20.00) for 5 after admission days. Plasma concentrations of von Willebrand factor antigen and tissue plasminogen activator were determined by a commercially available enzyme-linked immunosorbent assay (ELISA, Stago Diagnostica Inc., Franconville, France) [12,13]. von Willebrand values are expressed as a percent of a pooled normal plasma with 100% corresponding to 1 IU/ml, (range 50-150% normal plasma). Values of tissue plasminogen activator are expressed in rig/ml (normal values 1-12 rig/ml). Fibrinogen level was
Journal of Cardiology 54 (1996) 89-92
determined with reagents (g/l).
the MLA
system using Dade
2.3. Statistical analysis All data are expressed as mean t S.E.M. For comparisons of data a one-way analysis of variance, with an allowance for repeated measures, was performed. When an F value was found to be significant, a two-tailed Student’s t-test for paired observations with the Bonferroni correction was used to test differences among means. A P value < 0.05 was considered significant.
3. Results In 8 normal subjects the mean plasma level of tissue plasminogen activator antigen, von Willebrand factor antigen and fibrinogen were 7.14 2 1.26 rig/ml, 81.87 + 5.34 IU/ml and 3.29 + 0.3 g/l respectively in the morning, and 7.03 2 1.27 rig/ml, 78.92 2 5.52 IU/ml and 3.23 ? 0.28 g/l respectively in the evening. In the unstable angina patients a significant rise in tissue plasminogen activator antigen occurred 24 h after the admission in the morning plasma (15.15 rt 2.1.~~. 9.9 + 1.7 rig/ml respectively, P < O.OS),whereas von Willebrand factor antigen and fibrinogen levels remained unchanged (Table 1). No significant changes were found in the evening plasma concentration of tissue plasminogen activator antigen, von Willebrand factor antigen and fibrinogen during the 5 days period (Table 1). A significant rise in the mean tissue plasminogen activator antigen and fibrinogen level compared with the normal subjects was found 24 h after admission which persisted for 4 days (Fig. 1).
4. Discussion This study documents the variations of tissue plasminogen activator antigen and von Willebrand factor antigen in patients with unstable angina over a period of 5 days after admission to hospital. It shows that plasma tissue plasminogen activator
D. Tousoulis et al. I International
91
Journal of Cardiology 54 (1996) 89-92
Table 1 Plasma concentrations of von Willebrand factor antigen &Wag), tisstie-plasminogen activator antigen (t-PAag) and fibrinogen in patients with unstable angina daring the morning and during the night 1 It day
2°d day
31d day
41h day
51h day
Morning 08.00 t-PAag (nglml) vWFag @J/ml) Fibrinogen (g/l)
9.93 2 1.7 90.5 -c 6.1 4.03 k 0.24
15.15 2 2.1* 91.4 5 5.8 4.23 t 0.27*
14.7 t 2.0* 88.0 2 8.2 4.24 k 0.26”
13.3 2 1.3* 99.1 2 6.2 4.38 2 0.35*
13.3 -c 1.4* 96.5 2 6.5 4.15 2 0.32*
Night 20.00 t-PAag (ng /ml) vWFag (IUlml) Fibrinogen (g/l)
11.2 2 2.6 79.6 t 5.4 3.58 I 0.30
12.8 2 2.1 84.4 k 6.4 3.70 i 0.19
14.4 + 2.5* 88.8 k 7.2 3.91 t 0.26
9.2 2 1.5 88.2 2 5.6 3.77 t 0.32
8.7 2 1.5 95.5 + 7.1 3.53 2 0.57
*P < 0.05 vs. normal subjects.
antigen levels increase after 24 h in those who stabilize in response to medical treatment. Although the mechanisms of unstable angina and myocardial infarction are similar, their clinical characteristics are different [14]. Studies have showed that plaque disruption and thrombus formation is the main pathogenetic substrate for both myocardial infarction and unstable angina [ 11. This suggest than the prothrombotic reactivity of blood to the vessel wall injury may be greater in patients with myocardial infarction than in those with unstable angina [ 1,141. The response of endogenous fibrinolytic system and platelet adhesion and aggregation may play an important role in distinguishing the mechanisms of these two syndromes. von
20
1
0
1
2
Days
3
4
5
Fig. 1. Plasma tissue-plasminogen activator antigen (t-PAag) levels determined for 5 consecutive days after the admission in the morning and in the evening, in patients with unstable angina. A significantly (*P < 0.05 vs. admission level) increased level was found after 24 h.
Willebrand factor plays a pivotal role in the process of platelet adhesion [3,15]. When there is loss of endothelial integrity, platelet adhesion is a critical step in the response of platelets, allowing interaction with exposed subendothelial components of the damaged vessel with the platelets. In our study plasma von Willebrand factor antigen levels in patients with unstable angina were within normal limits indicating that there is a tendency for reduction of platelet adhesion and aggregation. Previous studies [4] in patients with acute myocardial infarction have shown elevated plasma levels of von Willebrand factor. There may, therefore, be a different pattern of aggregation and adhesion of platelets in patients with unstable angina compared with myocardial infarction. The maintained presence of thrombus depends not only on its formation, but also on its lysis [lo]. The fibrinolytic system is activated by tissue plasminogen activator which is rapidly inactivated by plasma plasminogen activator inhibitor- 1 [ 161. Plasma plasminogen activator inhibitor is also known to be an acute phase reactant in response to tissue injury and synthesized mainly by endothelial and hepatic cells [16]. Previous investigators [9,17] have measured the plasma levels of plasminogen activator inhibitor- 1 activity and von Willebrand factor every 6 h for 48 h in patients with unstable angina and showed no significant elevation of von Willebrand factor, although plasminogen activator inhibitor- 1 activity was significantly elevated and was not influenced by the extent of underlying coronary artery disease. Increased plasma levels of plasminogen activator inhibitor-l were demonstra-
92
D. Tousoulis et al. / International Journal of Cardiology 54 (1996) 89-92
ted in patients with acute myocardial infarction those who survival myocardial infarction [18,19]. Furthermore, in our study the fibrinogen level was found to be elevated in the morning plasma, indicating an increased thrombotic process in the morning period [20]. The changes of fibrinolytic activity it is more likely to reflect either a systemic acute phase response or the effect of sympathetic activation on the arterial tree as a whole. In this study we have not examined these possibilities. In conclusion, the changesin tissue plasminogen activator antigen level represent an index of the functional capacity of the fibrinolytic/proteolytic system. A raised tissue plasminogen activator antigen level and stable von Willebrand factor level antigen maybe used to predict clinical stability in patients who present with unstable angina. References [l] Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988; 77: 1213-1220. [2] Paramo JA, Colucci M, Collen D, Werf F. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 1985; 291: 573-574. [3] Stel HV, Sakariassen KS, de Groot PG, van Mourik JA, Sixma JJ. von Willebrand factor in the vessel wall mediates platelet adherence. Blood 1985; 65: 85-90. [4] Andreotti F, Roncaglioni MC, Hackett DR et al. Early coronary reperfusion blunts the procoagulant response of plaaminogen activator inhibitor-l and von Willebrand factor in acute myocardial infarction. J Am Co11 Cardiol 1990; 16: 15.53-1560. [5] Sakamoto T, Yasue H, Ogawa H, Misumi 1, Masuda T. Association of patency of the infarct-related coronary artery with plasma levels of plasminogen activator inhibitor activity in acute myocardial infarction. Am J Cardiol 1992; 70: 271-276. [6] Sane DC, Stump DC, Top01 EJ et al. Correlation between baseline plasminogen activator inhibitor levels and clinical outcome during therapy with tissue plasminogen activator for acute myocardial infarction. Tbromb Haemost 1991; 65: 275-279. [7] Gram J, Kluft C, Jespersen J. Depression of tissue plasminogen activator (t-PA) activity and rise of t-PA inhibition and acute phase reactants in blood of patients with acute myocardial infarction. Thromb Haemost 1987; 58: 817821.
[8] Sakamoto T, Yasue H, Ogawa H, Misumi 1, Masuda T. Association of patency of the infarct-related coronary artery with plasma levels of plasminogen activator inhibitor activity in acute myocardial infarction. Am J Cardiol 1992; 70: 271-276. [9] Margulis T, David M, Maor N et al. The von Willebrand factor in myocardial infarction and unstable angina: a kinetic study. Thromb Haemost 1986; 55: 366-368. [lo] Vermylen JG, Chamone DAF. The role of the fibrinolytic system in thromboembolism. Prog Cardiovasc Dis 1979; 21: 255-266. [ 111 Misumi I, Ogawa H, Masuda T, Sakamoto T, Okumura K, Yasue H. Increased plasma plasminogen activator inhibitor activity after coronary spasm. Int J Cardiol 1993; 41: 21-29. [12] Ingerslev J. A sensitive ELISA for von Willenbrand factor (vWt: Ag). Stand J Clin Lab Invest 1987; 47: 143-149. [13] Amiral J, Plassart V, Grosley M, Mimilla F, Contant G, Guyader AM. Measurement of tPA-PAI- complexes by ELISA, using monoclonal antibodies: clinical relevance. Thromb Res 1988; 8: 99-113. [14] Fuster V, Chesebro JH. Mechanisms of unstable angina. N Engl J Med 1986; 315: 1023-1025. [15] McGhie IA, McNatt J, Ezov N et al. Abolition of cyclic flow variations in &nosed, endothelium-injured coronary arteries in nonhuman primates with a peptide fragment (VCL) derived from human plasma von Willebrand factorglycoprotein Ib binding domain. Circulation 1994; 90: 2976-298 1. [16] Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387. [17] Huber K, Rose D, Resch I et al. Circadian fluctuations of plasminogen activator inhibitor and tissue plasminogen activator levels in plasma of patients with unstable coronary artery disease and acute myocardial infarction. Thromb Haemost 1988; 60: 372-376. [18] Lucore Cl, Sobel BE. Interaction of tissue-type plasminogen activator with plasma inhibitors and their pharmacological implications. Circulation 1988; 77: 660-669. [19] Hamsten A, Wiman B, De Faire U, Blomback M. Increased plasma levels of rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563. [20] Braunwald E. Morning resistance to thrombolytic therapy. Circulation 1995; 91: 1604-1606.