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Inflammation and Coagulation Activity in Unstable Coronary Artery Disease and the Influences of Thrombin Inhibition
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In patients with unstable coronary artery disease, this study evaluated the degree of inflammation and coagulation activity, relations to myocardial cell damage, prognosis, and influences of randomisation to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor (n=904), or unfractionated heparin (n=305).

Anticoagulant treatment effects were evaluated with aPT time. In inogatran treated patients with aPT times ≥ 44 s (median), the 7-days event rate - death, myocardial infarction or refractory angina – was 11.6 %, compared to 6.6 % with aPT times < 44 s (p=0.01). Higher aPT times was related to improved outcome during heparin treatment.

Markers of inflammation, i.e. fibrinogen and C-reactive protein (CRP), and coagulation, i.e. prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), soluble fibrin (SF) and D-dimer were analysed in serial samples (n=320). High fibrinogen, F1+2 and D-dimer levels persisted at 30 days. Patients with myocardial damage, detected by elevated troponin, had higher levels of all markers except TAT.

Ischemic events occurred at 30 days in 17 % of patients with high (pre-treatment top tertile) and 8.5 % of patients with lower fibrinogen levels (p=0.03), while high CRP levels only were related to increased mortality. At 30 days, patients with high compared to low pre-treatment levels of TAT or SF had 40 % lower event rate. Patients with early decreased compared to raised F1+2 or TAT levels during treatment had 50 % lower 30-days event rate (p<0.05).

Conclusions: The aPT time is an inappropriate indicator of antithrombotic efficacy. The raise in fibrinogen in the acute phase is sustained, and indicates risk of thrombosis and new ischemic events. The pronounced CRP elevation is transient, but associated with increased mortality. Higher coagulation activity may identify patients with a thrombotic condition as the major cause of instability, who are best responders to anticoagulant therapy. However, reactivation of coagulation activity with raised risk of ischemic events is a concern at cessation of treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2001. , p. 68
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1103
Keywords [en]
Medical sciences, Unstable coronary artery disease, inflammation, coagulation, thrombin inhibition
Keywords [sv]
MEDICIN OCH VÅRD
National Category
Medical and Health Sciences
Research subject
Cardiology
Identifiers
URN: urn:nbn:se:uu:diva-1539ISBN: 91-554-5182-9 (print)OAI: oai:DiVA.org:uu-1539DiVA, id: diva2:161127
Public defence
2001-12-07, Robergsalen, ingång 40, 4 tr, Akademiska sjukhuset, Uppsala, 13:15
Opponent
Available from: 2001-11-15 Created: 2001-11-15Bibliographically approved
List of papers
1. Activated Partial Thromboplastin Time and Clinical Outcome after Thrombin Inhibition in Unstable Coronary Artery Disease
Open this publication in new window or tab >>Activated Partial Thromboplastin Time and Clinical Outcome after Thrombin Inhibition in Unstable Coronary Artery Disease
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1999 In: Eur Heart J, Vol. 20, no 22, p. 1657-66Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89548 (URN)
Available from: 2001-11-15 Created: 2001-11-15Bibliographically approved
2. Myocardial Damage, Inflammation and Thrombin Inhibition in Unstable Coronary Artery Disease
Open this publication in new window or tab >>Myocardial Damage, Inflammation and Thrombin Inhibition in Unstable Coronary Artery Disease
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2003 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 24, no 1, p. 86-93Article in journal (Refereed) Published
Abstract [en]

AIM:

Unstable coronary artery disease (CAD) is a multifactorial disease involving both thrombotic and inflammatory processes. We have assessed the time-course and the influence of thrombin inhibitors on changes in fibrinogen and C-reactive protein levels, and their relation to myocardial ischaemia in unstable CAD.

METHODS AND RESULTS:

Three hundred and twenty patients were randomized to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor, or unfractionated heparin. There were no significant differences between the treatment groups in fibrinogen or C-reactive protein levels. Overall, the fibrinogen levels were significantly increased in the first 24-96 h and still elevated at 30 days. The C-reactive protein levels showed a more pronounced increase during the first 24-96 h, but then markedly decreased over 30 days. Troponin-positive compared to troponin-negative patients had higher fibrinogen and C-reactive protein levels up to 96 h, although there was an increase compared to pre-treatment levels in both groups. A high fibrinogen level (pre-treatment top tertile) was associated with an increased rate of death or myocardial (re-)infarction at 30 days, 13% vs 5.6%, P=0.03, and increased long-term mortality. A high C-reactive protein level was related to increased 30-day mortality, 4% vs 0%, P=0.01.

CONCLUSION:

Myocardial cell injury was related to a high degree of inflammation, only some of which is an acutephase response due to tissue damage. The rise in fibrinogen was sustained, which might reflect low grade inflammation with long-term risk of thrombosis. The transient elevation of C-reactive protein levels might indicate a propensity to a pronounced inflammatory response and is associated with increased mortality.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89549 (URN)10.1016/S0195-668X(02)00312-3 (DOI)12559940 (PubMedID)
Available from: 2001-11-15 Created: 2001-11-15 Last updated: 2017-12-14Bibliographically approved
3. 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
Open this publication in new window or tab >>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
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1999 In: Eur Heart J, Vol. 20, no 7, p. 506-18Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89550 (URN)
Available from: 2001-11-15 Created: 2001-11-15Bibliographically approved
4. Coagulation Activity and Clinical Outcome in Unstable Coronary Artery Disease
Open this publication in new window or tab >>Coagulation Activity and Clinical Outcome in Unstable Coronary Artery Disease
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2001 In: Arterioscler Thromb Vasc Biol, Vol. 21, no 6, p. 1059-64Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89551 (URN)
Available from: 2001-11-15 Created: 2001-11-15Bibliographically approved
5. Myocardial Damage, Coagulation Activity and the Response to Thrombin Inhibition in Unstable Coronary Artery Disease
Open this publication in new window or tab >>Myocardial Damage, Coagulation Activity and the Response to Thrombin Inhibition in Unstable Coronary Artery Disease
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-89552 (URN)
Available from: 2001-11-15 Created: 2001-11-15Bibliographically approved

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