Thrombin Generation Is a Sensitive Measure of Low Molecular Weight Heparin Anticoagulant Activity.

Abstract 1099

Current guidelines recommend monitoring of low molecular weight heparins (LMWHs) using the anti-Xa assay in high risk patients like those with renal impairment, pregnancy or overweight and in children. However, it is well accepted that this test does not accurately predict the anticoagulant effect of these drugs¹. This is understandable since the various LMWHs available affect the coagulation cascade in different ways relative to their different molecular structure. Notoriously, the larger LMWHs like Tinzaparin have a higher anti-IIa to anti-Xa ratio that is not detected by the anti-Xa assay.

We hypothesized that thrombin generation (TG) is a better, more sensitive way how to monitor LMWH anticoagulant activity since it is a measure of the interplay of all coagulation proteins.

Blood samples from patients with acute thrombosis, pregnancy and other conditions and having LMWH monitoring were analysed using a chromogenic anti-Xa assay and a TG assay as per Hemker et al² together with a chromogenic anti-IIa and FVIII clotting assay (FVIII:C). A tissue factor trigger of 10pM Innovin was used for the TG experiments. Patient samples were divided into 2 groups: those on Tinzaparin (n=45) or Enoxaparin (n=39).

There was no difference between the FVIII:C levels of the Tinzaparin and Enoxaparin groups (mean 250 vs 327IU/ml P>0.05). A higher lower mean anti-Xa and a higher mean anti-IIa level was achieved with Tinzaparin (0.48 vs 0.63 U/ml P= >0.05 for anti-Xa and 0.3 vs 0.15U/ml P=0.005 for anti-IIa respectively). The endogenous thrombin potential (ETP) was significantly lower with Tinzaparin than Enoxaparin despite a higher anti-Xa (705 vs 1216nM.min P=0.006). Linear regression analysing TG with anti-Xa of the two LMWHs shows that 1.0U/ml antiXa activity for Enoxaparin is as potent as 0.7U/ml Tinzaparin in suppressing TG to similar levels. Significant inter-individual variation in TG suppression was noted with both LMWHs.

This study demonstrates that anti-Xa results achieved for different LMWHs do not have the same anticoagulant significance. Using TG, we achieved similar therapeutic anti-Xa levels as achieved from the individual LMWH clinical trials³. It is clear that TG is a better test to predict LMWH anticoagulant activity. This needs to be proven in clinical studies.

1. Baglin T et al British Journal of Haematol. 2006; 133(1): 19–34.

2. Hemker HC et al Pathophysiol Haemost Thromb, 33, 4-15.

Boneu B and de Moorloose P. Semin Thromb Hemost 2001; 27(5): 519–522.