SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
Fibrinolytic Activity in Patients with Diabetes Mellitus: Characterization of the Effects of Thrombolytic Agents on Plasma Clot Lysis In Vitro
Patients with diabetes mellitus have an increased incidence of occlusive vascular disease. Although some of the studies indicating diabetes mellitus to be a risk factor for acute myocardial infarction (AMI) predate modern diagnostic and coronary care techniques, recent work1 confirms an increased incidence of AMI, partic ularly in younger diabetic patients without other risk factors. Although not specifically mentioning diabetes, Virchow was the first to describe morphologic changes in the erythrocyte in the presence of a high concentration of glucose, and there have been many subsequent efforts to identify abnormalities in blood cell function and in fluid phase coagulation in diabetes. It has often not been clear whether such abnormalities contribute to the vascular changes or whether it is the arterial injury that induced the prothrombotic tendency, for example, an increase in plasma fibrinogen, as part of the acute-phase reaction. The effect of diabetes mellitus on the operation of the fibrinolytic pathway is also controversial. The poten tial for fibrinolysis when measured ex vivo may be decreased in some diabetic patients,2'3 although mea surement of the circulating level of plasmin-α2-antiplasmin complex suggests that activation of fibrinolysis can also occur.4 Part of the discrepancy between findings may be related to uncertainties regarding the validity of experimental techniques: the simple measurement of spontaneous lysis ex vivo may not correlate with changes
in specific, insulin-dependent regulatory factors such as plasminogen activator inhibitor type I (PAI-1).5 It is possible that both an increase in endogenous inhibitor level and a reduction in the ability to activate plasminogen as a result of nonenzymatic glycosylation6 may contribute to a prothrombotic tendency and in creased risk of AMI in patients with diabetes. Further more, such changes in fibrinolytic potential could influ ence the therapeutic response to plasminogen activators used in the treatment of AMI. There is little specific information on the response of patients with diabetes mellitus, but there is renewed enthusiasm generally for the use of thrombolytic agents in patients with AMI as a result of the clearer understanding of the pathogenesis of coronary thrombosis. Thrombolytic agents can improve survival in AMI populations: early reductions in mortal ity range from 20 to 30% for streptokinase (SK)7 and tissue-type plasminogen activator (t-PA)8 to 40 to 50% for anisoylated lys-plasminogen streptokinase activator complex9,10 (APSAC, anistreplase, Eminase). In view of the importance of this pharmacologic approach in AMI, it was the purpose of the present study, in vitro, to define the fibrinolytic response to the standard thrombolytic agents using plasma obtained from patients with diabetes mellitus. The implications of our results are considered from the perspective of the published clinical data.
CHARACTERIZATION OF PATIENTS From SmithKline Beecham Pharmaceuticals, Epsom, and Depart ment of Endocinology, Central Middlesex Hospital, London, United Kingdom. Reprint requests: Dr. Fears, SmithKline Beecham Pharmaceuti cals, Great Burgh, Epsom, Surrey, KT18 5XQ, UK.
Eleven randomly selected patients with diabetes mellitus (six male, five female) were studied. The mean age was 56 years (range, 33 to 80 years), four had type I diabetes, although all except one were routinely receiv ing insulin. The mean concentration of HbA lc was
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
407
Downloaded by: National University of Singapore. Copyrighted material.
ROBIN FEARS, Ph.D., RUTH STANDRING, Ph.D., and RALPH ABRAHAM, Ph.D., B.M., B.Ch., M.R.C.P.
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
10 ± 0.6% (range, 7.4 to 12.5%, normal range,
Fibrinolytic Activity in Patients with Diabetes Mellitus: Characterization of the Effects of Thrombolytic Agents on Plasma Clot Lysis In Vitro
Patients with diabetes mellitus have an increased incidence of occlusive vascular disease. Although some of the studies indicating diabetes mellitus to be a risk factor for acute myocardial infarction (AMI) predate modern diagnostic and coronary care techniques, recent work1 confirms an increased incidence of AMI, partic ularly in younger diabetic patients without other risk factors. Although not specifically mentioning diabetes, Virchow was the first to describe morphologic changes in the erythrocyte in the presence of a high concentration of glucose, and there have been many subsequent efforts to identify abnormalities in blood cell function and in fluid phase coagulation in diabetes. It has often not been clear whether such abnormalities contribute to the vascular changes or whether it is the arterial injury that induced the prothrombotic tendency, for example, an increase in plasma fibrinogen, as part of the acute-phase reaction. The effect of diabetes mellitus on the operation of the fibrinolytic pathway is also controversial. The poten tial for fibrinolysis when measured ex vivo may be decreased in some diabetic patients,2'3 although mea surement of the circulating level of plasmin-α2-antiplasmin complex suggests that activation of fibrinolysis can also occur.4 Part of the discrepancy between findings may be related to uncertainties regarding the validity of experimental techniques: the simple measurement of spontaneous lysis ex vivo may not correlate with changes
in specific, insulin-dependent regulatory factors such as plasminogen activator inhibitor type I (PAI-1).5 It is possible that both an increase in endogenous inhibitor level and a reduction in the ability to activate plasminogen as a result of nonenzymatic glycosylation6 may contribute to a prothrombotic tendency and in creased risk of AMI in patients with diabetes. Further more, such changes in fibrinolytic potential could influ ence the therapeutic response to plasminogen activators used in the treatment of AMI. There is little specific information on the response of patients with diabetes mellitus, but there is renewed enthusiasm generally for the use of thrombolytic agents in patients with AMI as a result of the clearer understanding of the pathogenesis of coronary thrombosis. Thrombolytic agents can improve survival in AMI populations: early reductions in mortal ity range from 20 to 30% for streptokinase (SK)7 and tissue-type plasminogen activator (t-PA)8 to 40 to 50% for anisoylated lys-plasminogen streptokinase activator complex9,10 (APSAC, anistreplase, Eminase). In view of the importance of this pharmacologic approach in AMI, it was the purpose of the present study, in vitro, to define the fibrinolytic response to the standard thrombolytic agents using plasma obtained from patients with diabetes mellitus. The implications of our results are considered from the perspective of the published clinical data.
CHARACTERIZATION OF PATIENTS From SmithKline Beecham Pharmaceuticals, Epsom, and Depart ment of Endocinology, Central Middlesex Hospital, London, United Kingdom. Reprint requests: Dr. Fears, SmithKline Beecham Pharmaceuti cals, Great Burgh, Epsom, Surrey, KT18 5XQ, UK.
Eleven randomly selected patients with diabetes mellitus (six male, five female) were studied. The mean age was 56 years (range, 33 to 80 years), four had type I diabetes, although all except one were routinely receiv ing insulin. The mean concentration of HbA lc was
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
407
Downloaded by: National University of Singapore. Copyrighted material.
ROBIN FEARS, Ph.D., RUTH STANDRING, Ph.D., and RALPH ABRAHAM, Ph.D., B.M., B.Ch., M.R.C.P.
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
10 ± 0.6% (range, 7.4 to 12.5%, normal range,
