The effect of thrombin inhibitors on coagulation activity and generation of activated protein C
Author: Linder, Rikard
Date: 2002-04-12
Location: Thoraxklinikens aula, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för medicin / Department of Medicine
Abstract
The direct thrombin inhibitor inogatran was, in the TRIM trial (n=1209),
compared with unfractionated heparin (UFH) concerning the effect on
cardiovascular end-points in unstable coronary artery disease. The
results in TRIM demonstrated a trend towards a benefit for UFH during the
treatment phase, which was reduced after drug withdrawal. The first phase
of this thesis investigates if the findings in the TRIM trial could be
explained by patterns of molecular markers for coagulation activity,
prothrombin fragment 1+2 (PF 1+2), thrombin-antithrombin (TAT) complexes,
soluble fibrin and fibrin D-dimers, in a subset of patients (n=320). The
relationship between treatment intensity measured by activated partial
thromboplastin time (APTT) and clinical end-points was also investigated.
Inhibition of thrombin anticoagulant activity, Le the generation of
activated protein C (APC) by thrombin bound to thrombomodulin, could be a
possible explanation for results in clinical trials with direct thrombin
inhibitors. This concept was evaluated in the second phase of this
thesis, which involved studies on the influence of different thrombin
inhibitors on the generation of APC and fibrin formation, measured by
release of fibrinopeptide A (FPA), in purified systems and on endothelial
cells (EC).
During treatment with inogatran, PF 1+2, TAT complexes and D-dimer
decreased to low levels, which lasted the entire infusion period. After
cessation of treatment the markers returned to baseline levels.
During treatment with heparin PF 1+2 and D-dimer rapidly decreased, but
later increased above baseline levels. The increase continued after
cessation of treatment. High APTT level during inogatran treatment was
related to increased risk of cardiovascular events whereas high APTT
level during heparin treatment was related to decreased risk of
cardiovascular events.
The in vitro experiments in this thesis demonstrated that clinically
relevant concentrations of inogatran, melagatran, hirudin and AT, in the
absence or presence of UFH or LMWH, inhibited thrombinthrombomodulin
(TM)-mediated APC generation, in solution or on EC. The irreversible
inhibitor PPACK, which lacks therapeutical potential, also inhibited
thrombin-TM mediated APC generation on EC, but exaggerated concentrations
of the hirudin derivative hirugen neither inhibited APC nor FPA
generation. Furthermore the experiments indicated that the tested
thrombin inhibitors inhibited FPA generation to the same extent as APC
generation.
Conclusions
Treatment with inogatran or UFH in unstable coronary artery disease
decreases markers of coagulation activity, but not in a consistent way.
After drug withdrawal a reactivation in biochemical markers of
coagulation activity is observed, which may be associated with the
increase in cardiovascular events during the same period.
Treatment intensity measured by activated partial thromboplastin time is
not well defined for low molecular weight direct thrombin inhibitors.
All tested thrombin inhibitors inhibited APC generation and fibrin
formation approximately to an equal extent. These findings may offer an
explanation of the lack of a dose-response effect in clinical trials but
do not support the hypothesis that inhibition of APC generation is a
likely cause for advantages or disadvantages of direct thrombin
inhibitors in comparison to unfractionated heparin in clinical trials on
patients with unstable coronary artery disease.
List of papers:
I. Linder R, Oldgren J, Egberg N, Grip L, Larson G, Siegbahn A, Wallentin L (1999). "The effect of a low molecular mass thrombin inhibitor, inogatran, and heparin on thrombin generation and fibrin turnover in patients with unstable coronary artery disease. " Eur Heart J 20(7): 506-18
Pubmed
II. Oldgren J, Linder R, Grip L, Siegbahn A, Wallentin L (1999). "Activated partial thromboplastin time and clinical outcome after thrombin inhibition in unstable coronary artery disease" Eur Heart J 20(22): 1657-66
Pubmed
III. Linder R, Blomback M, Egberg N, Grip L (1999). "Thrombin inhibitors suppress the thrombin-thrombomodulin-mediated generation of activated protein C. " Thromb Res 95(2): 117-25
Pubmed
IV. Linder R, Frebelius S, Jansson K, Swedenborg J (2002). "Inhibition of endothelial cell mediated generation of activated protein C by direct and antithrombin dependent thrombin inhibitors." (Submitted)
V. Linder R, Frebelius S, Grip L, Swedenborg J (2002). "The influence of direct and antithrombin dependent thrombin inhibitors on the procoagulant and anticoagulant effects of thrombin." (Submitted)
I. Linder R, Oldgren J, Egberg N, Grip L, Larson G, Siegbahn A, Wallentin L (1999). "The effect of a low molecular mass thrombin inhibitor, inogatran, and heparin on thrombin generation and fibrin turnover in patients with unstable coronary artery disease. " Eur Heart J 20(7): 506-18
Pubmed
II. Oldgren J, Linder R, Grip L, Siegbahn A, Wallentin L (1999). "Activated partial thromboplastin time and clinical outcome after thrombin inhibition in unstable coronary artery disease" Eur Heart J 20(22): 1657-66
Pubmed
III. Linder R, Blomback M, Egberg N, Grip L (1999). "Thrombin inhibitors suppress the thrombin-thrombomodulin-mediated generation of activated protein C. " Thromb Res 95(2): 117-25
Pubmed
IV. Linder R, Frebelius S, Jansson K, Swedenborg J (2002). "Inhibition of endothelial cell mediated generation of activated protein C by direct and antithrombin dependent thrombin inhibitors." (Submitted)
V. Linder R, Frebelius S, Grip L, Swedenborg J (2002). "The influence of direct and antithrombin dependent thrombin inhibitors on the procoagulant and anticoagulant effects of thrombin." (Submitted)
Issue date: 2002-03-22
Publication year: 2002
ISBN: 91-7349-172-1
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