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Rikard Linder

Publications and source records attributed to Rikard Linder.

5 recordsLinked to original sources
PubMed2004

Myocardial damage, coagulation activity and the response to thrombin inhibition in unstable coronary artery disease.

Unstable coronary artery disease is in most cases associated with plaque rupture, activation of the coagulation system and subsequent intracoronary thrombus formation which may cause myocardial cell damage. The aim of the present analysis was to assess the relation between troponin T, markers of coagulation activity, i.e. prothrombin fragment 1+2, thrombin-antithrombin complex, soluble fibrin and D-dimer, and ischemic events, i.e. death, myocardial (re-)infarction or refractory angina. 320 patients with unstable coronary artery disease were randomized to 72 hours infusion with inogatran, a low molecular weight direct thrombin inhibitor, or unfractionated heparin. Patients with elevated troponin levels had higher levels of prothrombin fragment 1+2, soluble fibrin and D-dimer before, during, and at 24 hours after cessation of anticoagulant treatment. These troponin-positive patients tended to have worse short-term clinical outcome, without relation to markers of coagulation activity. Troponin-negative patients with unchanged or early increased thrombin generation during treatment had a cluster of ischemic events within 24 hours after cessation of the study drug. The 30-day ischemic event rate was 19 % in troponin-negative patients with unchanged or early increased prothrombin fragment 1+2, and 5.7 % in patients with decreased prothrombin fragment 1+2, p=0.006, and similarly 15 % in troponin-negative patients with unchanged or early increased thrombin-antithrombin complex and 4.5 % in patients with decreased thrombin-antithrombin complex, p=0.02. In conclusion, in unstable coronary artery disease a troponin elevation indicates higher risk and higher coagulation activity. However, among the troponin negative patients, with a lower risk and lower coagulation activity, a part of the patients seem to be non-responders to treatment with a thrombin inhibitor expressed as unchanged or raised coagulation activity and a raised risk of ischemic events early after cessation of treatment.

Adult↗
PubMed2003

The influence of direct and antithrombin-dependent thrombin inhibitors on the procoagulant and anticoagulant effects of thrombin.

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.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Inhibition of endothelial cell-mediated generation of activated protein C by direct and antithrombin-dependent thrombin inhibitors.

The present study investigated the effect of the thrombin inhibitors antithrombin (AT) (with and without unfractionated heparin or low molecular weight heparin), hirudin, inogatran and melagatran on thrombin-thrombomodulin-mediated generation of activated protein C (APC), in solution and on endothelial cells. Sequential incubation with thrombin, thrombin inhibitors and protein C was followed by measurement of APC by an amidolytic assay. The approximate concentrations resulting in 50% inhibition of endothelial cell-mediated APC generation for AT, AT-unfractionated heparin, AT-low molecular weight heparin, hirudin, melagatran and inogatran were 200, 4, 9, 1, 8 and 60 nmol/l, respectively. The normal plasma level of AT is 2800 nmol/l and relevant therapeutic concentrations from clinical trials are 200 nmol/l for hirudin, 500 nmol/l for melagatran and 1000 nmol/l for inogatran. The present study indicates that clinically relevant concentrations of the tested thrombin inhibitors interfere with endothelial-mediated APC generation, which may offer an explanation for the lack of a dose-response effect in clinical trials with thrombin inhibitors.

Antithrombins↗