Low-molecular Weight Heparin Reduces the Generation and Activity of Thrombin in Unstable Coronary Artery Disease

Abstract

SummaryUnstable 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.

Coagulation, inflammation and myocardial dysfunction in unstable coronary artery disease and the influence of glycoprotein IIb/IIIa inhibition and low molecular weight heparin

“…There is evidence that high dose dalteparin in placebo controlled ACS trials reduces thrombin generation and activity, as demonstrated by the reduction of the F1+2, TAT and SF levels (146). In the present study TAT and SF levels still increased during the initial 72 hours of dalteparin treatment, demonstrating an activation of the coagulation system.…”

Elevated TFPI in malignant disease: relation to cancer type and hypercoagulation

“…Further, we failed to demonstrate any correlation between the TFPI parameters and the markers of activated coagulation. Whereas D-dimer is a relatively unspecific marker of activated coagulation, the fibrin monomer assay we used is probably as sensitive as other markers, such as prothrombin F1þ2 fragment, for activated coagulation (Lill et al, 1993;Ernofsson et al, 1998).…”

Coagulation Activity and Clinical Outcome in Unstable Coronary Artery Disease

“…ELISAs from Enzygnost (Behringwerke AG) were used for the determination of F1ϩ2 11 and TAT, 12 with reference intervals for healthy individuals of 0.4 to 1.5 nmol/L and of 1.2 to 5.0 g/L, respectively; intra-assay and interassay coefficients of variation were between 5% and 9%. 6 An ELISA (TintElize D-dimer, Biopool) was also used for analysis of D-dimer, with a reference range of 10 to 130 g/L and a coefficient of variation of 10%. 13 SF was assessed by a chromogenic method (Chromogenix), in which the stimulatory effect of SF on the tissue-type plasminogen activator-catalyzed conversion of plasminogen to plasmin is exploited; the upper reference limit is 25 nmol/L, with a coefficient of variation of 7%.…”

“…Activation of the coagulation system in the acute phase of unstable angina or acute MI has been demonstrated by elevated levels of molecular markers of thrombin generation, ie, prothrombin fragment 1ϩ2 (F1ϩ2) and thrombin-antithrombin (TAT) complex, and of thrombin activity, such as fibrinopeptide A (FPA) and soluble fibrin (SF). [2][3][4][5][6] Elevated levels of D-dimer, a marker of fibrin turnover, have also been found in patients with unstable angina. 4,5 However, there are rather limited data concerning the prognostic importance of elevated coagulation markers in patients with unstable coronary artery disease.…”