PMID- 14512086
OWN - NLM
STAT- MEDLINE
DCOM- 20040525
LR  - 20190727
IS  - 0049-3848 (Print)
IS  - 0049-3848 (Linking)
VI  - 110
IP  - 4
DP  - 2003 Jun 1
TI  - The influence of direct and antithrombin-dependent thrombin inhibitors on the 
      procoagulant and anticoagulant effects of thrombin.
PG  - 221-6
AB  - INTRODUCTION: Clinical trials evaluating direct thrombin inhibitors in unstable 
      coronary artery disease (CAD) have been disappointing. The hypothesis tested in 
      the present study was that these agents may inhibit the anticoagulant effect of 
      thrombin to a further extent than the procoagulant effect of thrombin. MATERIALS 
      AND METHODS: We studied both reversible and irreversible thrombin inhibitors and 
      compared the effects of each inhibitor on activated protein C (APC) generation 
      vs. the effect on fibrinopeptide A (FPA) generation. A mixture of protein C, 
      thrombin inhibitor, fibrinogen, fibrin polymerisation blocker and thrombin was 
      incubated with thrombomodulin (TM)-expressing human saphenous vein endothelial 
      cells (HSVECs). The inhibitors investigated were melagatran, inogatran, hirudin, 
      hirugen, D-Phe-D-Pro-D-arginyl chloromethyl ketone (PPACK), and antithrombin (AT) 
      alone or in combination with unfractionated heparin (UFH) or low-molecular-weight 
      heparin (LMWH). RESULTS: All agents, except hirugen, inhibited APC and FPA 
      generation in a dose-dependent manner. FPA inhibition/APC inhibition ratios, 
      based on IC50 for inogatran, melagatran, hirudin, PPACK, AT, AT-UFH and AT-LMWH 
      were 1.73, 0.85, 0.55, 2.1, 0.5, 0.65 and 3.1 respectively. CONCLUSIONS: All 
      agents, except hirugen, inhibited APC and FPA generation approximately to a 
      similar extent. Thus, it can be inferred that the poor efficacy of thrombin 
      inhibitors in recent clinical trials in patients with unstable CAD is unlikely to 
      be a consequence of their effects on the protein C system.
FAU - Linder, Rikard
AU  - Linder R
AD  - Department of Cardiology, Karolinska Hospital, S-171 76, Stockholm, Sweden. 
      rikard.linder@medks.ki.se
FAU - Frebelius, Siw
AU  - Frebelius S
FAU - Grip, Lars
AU  - Grip L
FAU - Swedenborg, Jesper
AU  - Swedenborg J
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Thromb Res
JT  - Thrombosis research
JID - 0326377
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Anticoagulants)
RN  - 0 (Azetidines)
RN  - 0 (Benzylamines)
RN  - 0 (Coagulants)
RN  - 0 (Hirudins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Piperidines)
RN  - 0 (Protein C)
RN  - 121822-23-9 (hirugen)
RN  - 25422-31-5 (Fibrinopeptide A)
RN  - 2A9QP32MD4 (melagatran)
RN  - 428409I84L (inogatran)
RN  - EC 3.4.21.5 (Thrombin)
RN  - N62UL02WW4 (phenylalanyl-prolyl-arginine-chloromethyl ketone)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - *Anticoagulants/antagonists & inhibitors/metabolism
MH  - Azetidines
MH  - Benzylamines
MH  - Clinical Trials as Topic
MH  - *Coagulants/antagonists & inhibitors/metabolism
MH  - Coronary Artery Disease/drug therapy
MH  - Fibrinopeptide A/*drug effects
MH  - Glycine/*analogs & derivatives/pharmacology
MH  - Hirudins/*analogs & derivatives/pharmacology
MH  - Humans
MH  - Peptide Fragments/pharmacology
MH  - Piperidines/pharmacology
MH  - Protein C/*drug effects
MH  - *Thrombin/antagonists & inhibitors/drug effects/metabolism
EDAT- 2003/09/27 05:00
MHDA- 2004/05/27 05:00
CRDT- 2003/09/27 05:00
PHST- 2003/09/27 05:00 [pubmed]
PHST- 2004/05/27 05:00 [medline]
PHST- 2003/09/27 05:00 [entrez]
AID - S004938480300344X [pii]
AID - 10.1016/s0049-3848(03)00344-x [doi]
PST - ppublish
SO  - Thromb Res. 2003 Jun 1;110(4):221-6. doi: 10.1016/s0049-3848(03)00344-x.