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Low-molecular weight heparin reduces the generation and activity of thrombin in unstable coronary artery disease
M Ernofsson1, F Strekerud, H Toss
1Department of Clinical Laboratory Sciences, Clinical Chemistry, University Hospital Uppsala, Sweden.
Insights
High-dose dalteparin significantly reduced thrombin generation in unstable coronary artery disease patients. However, a lower dose was insufficient to maintain this effect, potentially explaining increased event rates.
Area of Science:
- Cardiology
- Hematology
- Pharmacology
Background:
- Unstable coronary artery disease (UCAD) carries a high risk of recurrent events.
- Previous studies indicated dalteparin (a low-molecular-weight heparin) reduced risk at high doses but not lower doses.
- The pathophysiological basis for these observed event rate changes requires investigation.
Purpose of the Study:
- To investigate the impact of different dalteparin dosing regimens on thrombin generation and activity in UCAD patients.
- To correlate changes in coagulation markers with clinical outcomes during dalteparin treatment.
Main Methods:
- A 6-week placebo-controlled study involving UCAD patients randomized to dalteparin or placebo.
- Subcutaneous administration of dalteparin: high dose (120 IU/kg twice daily for 5-8 days) followed by a lower dose (7,500 IU once daily for 35-40 days).
- Analysis of plasma markers of thrombin generation: prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), and soluble fibrin (SF).
Main Results:
- High-dose dalteparin significantly reduced F1+2, TAT, and SF levels, indicating suppressed thrombin generation and activity.
- During the reduced-dose period, TAT and SF remained low, but F1+2 increased, though remaining below placebo levels.
- The placebo group exhibited persistently elevated thrombin generation and activity throughout the study.
- The transition to a lower, once-daily dalteparin dose was associated with a partial return towards a procoagulable state.
Conclusions:
- High-dose, twice-daily dalteparin effectively inhibits thrombin generation in UCAD.
- A lower, once-daily dose of dalteparin may not be sufficient to prevent a procoagulable state.
- Observed alterations in coagulation activity during different dosing regimens likely explain variations in clinical event rates.
Abstract:
Unstable coronary artery disease (UCAD) is associated with an increased risk of further coronary events. In the FRISC study, the risk was decreased during treatment with a high, twice-daily, dose of dalteparin, a low-molecular-weight heparin. However, lowering the dose resulted in raised risk of recurrences. To investigate the underlying pathophysiology, the thrombin generation and activity in patients with UCAD randomized to a 6-week placebo-controlled treatment with dalteparin were evaluated. Plasma prothrombin fragment 1+2 (F1+2) (n = 342), thrombin-antithrombin complex (TAT) (n = 186) and soluble fibrin (SF) (n = 298) were analyzed before and during treatment with dalteparin/placebo administered subcutaneously, 120 IU/kg bw twice daily for 5-8 days and 7.500 IU once daily the following 35-40 days. High-dose treatment with dalteparin resulted in significantly reduced levels of all coagulation markers, demonstrating diminished thrombin generation and activity. When reducing the dalteparin dose, plasma TAT and SF remained low, indicating minimal fibrin formation. However, F1+2 increased during this period. though the level at day 45 was still lower than in the placebo group. In the placebo group elevated thrombin generation and activity persisted during the entire period. In conclusion, high-dose treatment with dalteparin twice daily resulted in significantly reduced thrombin generation and activity. However, after changing to a lower, once-daily dose, the treatment was not sufficient in preventing a return to a procoagulable state. These changes of the coagulation activity might explain the changes in event rate observed during dalteparin treatment.