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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2162.)
© 2000 American Heart Association, Inc.

Thrombosis

In Vivo Thrombin Generation and Activity During and After Intravenous Infusion of Heparin or Recombinant Hirudin in Patients With Unstable Angina Pectoris

Piera Angelica Merlini; Diego Ardissino; Robert D. Rosenberg; Elisabetta Colombi; Pietro Agricola; Luigi Oltrona; Filippo Ottani; Marcello Galvani; Kenneth A. Bauer; Bianca Bottasso; Federico Bertocchi; Pier Mannuccio Mannucci

From the Division of Cardiology (P.A.M., L.O.), Ospedale Niguarda Ca’ Granda, Milan; the Division of Cardiology (D.A.), Ospedale Civile di Parma, Parma IRCCS; and Policlinico San Matteo and University of Pavia (E.C., P.A., F.B.), Pavia, Italy; the Charles A. Dana Research Institute and Harvard-Thorndike Laboratory, Department of Medicine (R.D.R.), Beth Israel Hospital and Harvard Medical School, Boston, and the Department of Biology (K.A.B.), Massachusetts Institute of Technology, Cambridge, Mass; the Division of Cardiology (F.O.), Ospedale di Ravenna, Ravenna; Division of Cardiology (M.G.), Ospedale Gian Battista Morgagni, Forli’; and the Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre and the Department of Internal Medicine (B.B., P.M.M.), IRCCS Ospedale Maggiore, University of Milan, Milan, Italy.

Correspondence to Piera Merlini, MD, Division of Cardiology, Ospedale Niguarda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy. E-mail ARDIS001{at}planet.it

Abstract—In patients with unstable angina, intravenous heparin reduces thrombin activity but does not influence thrombin generation. Recombinant hirudin, a direct thrombin inhibitor, may be more effective in inhibiting both thrombin generation and activity. We measured the plasma levels of prothrombin fragment 1+2 (a marker of thrombin generation) and fibrinopeptide A (a marker of thrombin activity) in 67 patients with unstable angina enrolled in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial who were receiving either recombinant hirudin (31 patients) or heparin (36 patients). Blood samples were obtained at baseline (before any treatment), after 3 to 5 days of study drug infusion (immediately before discontinuation), and 1 month later. In the patients receiving recombinant hirudin, the prothrombin fragment 1+2 levels measured immediately before drug discontinuation were significantly lower than at baseline (P=0.0014), whereas they had not changed in the patients receiving heparin; at this time point, the difference between patients receiving hirudin and those receiving heparin was statistically significant (P=0.032). One month later, the prothrombin fragment 1+2 levels in both groups were similarly persistently high and did not differ from baseline. Fibrinopeptide A plasma levels at the end of infusion were significantly lower than at baseline in both treatment groups (P=0.0005 for hirudin and P=0.042 for heparin) and remained lower after 1 month (P=0.0001 for both hirudin and heparin). The fibrinopeptide A plasma levels were not different between patients treated with hirudin versus heparin at baseline, at the end of infusion, and after 1 month. Thus, in patients with unstable angina, in vivo thrombin generation and activity are reduced during intravenous infusion of recombinant hirudin. However, the inhibition of thrombin generation is not sustained, and after 1 month, the majority of patients have biochemical signs of increased thrombin generation.

Key Words: hirudin • thrombin generation • unstable angina

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