Fixed dosage of low-molecular-weight heparins causes large individual variation in coagulability, only partly correlated to body weight.
BACKGROUND
Low-molecular-weight heparins (LMWHs) are routinely given without the control of their effect on coagulation. The endogenous thrombin potential (ETP) is a sensitive detector of the heparin effect.


OBJECTIVE
What is the interindividual variation in TG after a fixed dose of LMWH in normal volunteers, is it explained by variation in weight?


METHODS
Subcutaneous (s.c.) injection, in 12 healthy volunteers, of 9000 aXa-units of unfractionated heparin (UFH) and of three heparins with narrow MW distribution around 10.5, 6.0 and 4.5 kD. Measurement of anti-thrombin (aIIa) and antifactor Xa (aXa)-activities and ETP at 11 time points over 24 h.


RESULTS
The coefficient of variation (CV) of the AUCs of aXa- and aIIa-activities is 50% for UFH and 22-37% for LMWHs. Because of the hyperbolic form of the dose-response curve, the CV of the inhibition of the ETP is lower: 32% for UFH and 13-21% for the LMWHs. Fixed dosage of LMWH caused under-dosage in 10-13% of the samples and over-dosage in 5-11%. High or low response is an individual property independent of the type of heparin injected and only partially explained by variation in body weight.


CONCLUSIONS
Optimized individual dosage of LMWH is possible through recognition of high and low responders, which requires one measurement of the heparin concentration or, preferably, the heparin effect on the ETP, 2-5 h after a first injection.
Al Dieri
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Synapse BV, Cardiovascular Research Institute, Maastricht, The Netherlands. r.aldieri@thrombin.com
Alban
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Béguin
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Hemker
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HC
D000293:Adolescent; D000328:Adult; D000990:Antithrombin III / Q000032:analysis; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D001835:Body Weight / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D015951:Factor Xa / Q000032:analysis; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008970:Molecular Weight; D015203:Reproducibility of Results; D019851:Thrombophilia / Q000139:chemically induced
D006495:Heparin, Low-Molecular-Weight; D000990:Antithrombin III; D015951:Factor Xa