Inter-individual variability of effect of 7 low molecular weight antithrombin-dependent anticoagulants studied in vitro with calibrated automated thrombography.
BACKGROUND
Low-molecular-weight heparins (LMWHs) and fondaparinux are antithrombin dependent anticoagulant drugs considered to need no laboratory monitoring because of their reputedly predictable anticoagulant effect. However it has been suggested in the literature the existence of an inter-individual variability in response to LMWHs that would be not fully attributable to pharmacokinetics causes.


METHODS
In order to separate pharmacokinetic from pharmacodynamics effects we studied in 12 platelet-depleted plasmas from normal donors the inhibitory effect on TG determined with the CAT of added UFH, 5 LMWHs and 2 oligosaccharides with anti-Xa activity only.


RESULTS
A concentration-dependent inhibition of thrombin generation was found with all molecules tested. The concentration-response relation was very different when the concentrations were expressed in anti-Xa unit but became very similar when expressed in anti-thrombin units regarding LMWHs. Most importantly, we noticed a large inter-individual variability of the inhibitory effects with all molecules tested, UFH and LMWHs alike. The IC40 value varied at least twofold between the highest and the lowest responder. For any given anti-Xa level of any heparin and of pentasaccharide the inhibition of the ETP showed scattering of around 25%.


CONCLUSIONS
In contrast to what is generally assumed the inter-individual variation of the in vitro pharmacodynamics response is equally high for UFH and any LMWH (~25%) and even for the synthetic pentasaccharide. This questions the rationale for standard dosage, the more so as in clinical practice pharmacokinetic variation (e.g. due to body weight) will add to this pharmacodynamic variability.
Hacquard
Marie
M
U734 INSERM, Vandoeuvre les Nancy, France. m.toussaint-hacquard@chu-nancy.fr
Perrin
Julien
J
Lelievre
Nicolas
N
Vigneron
Claude
C
Lecompte
Thomas
T
D000925:Anticoagulants / Q000494:pharmacology*; D000991:Antithrombins / Q000097:blood*; D057205:Automation, Laboratory / Q000592:standards*; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests / Q000592:standards*; D002138:Calibration; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D000077425:Fondaparinux; D006493:Heparin / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D011134:Polysaccharides / Q000494:pharmacology; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013050:Spectrometry, Fluorescence / Q000592:standards*; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors
D000925:Anticoagulants; D000991:Antithrombins; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D011134:Polysaccharides; D006493:Heparin; D013917:Thrombin; D000077425:Fondaparinux