Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non-drug risk factors and evidence for a stoichiometry-based model of immunization.
BACKGROUND
Heparin-induced thrombocytopenia is an antibody-mediated disorder exhibiting variable frequency in different clinical settings. Antibodies recognize PF4/heparin complexes formed at optimal stoichiometric molar ratios.


OBJECTIVE
To identify clinical factors influencing risk of anti-PF4/heparin immunization.


METHODS
We performed observational studies and exploratory analyses of the frequency of anti-PF4/heparin antibody formation in 6324 patients who received enoxaparin or fondaparinux in four randomized controlled trials of postorthopedic surgery thromboprophylaxis. Variables included surgery type (knee vs. hip), timing of first anticoagulant dose (pre- vs. postsurgery), circumstances of surgery (elective vs. hip fracture), anticoagulant (enoxaparin vs. fondaparinux) and body-mass index (BMI). We applied a stoichiometry-based model that predicts immunization risk based on expected differences in PF4/anticoagulant ratios in different settings, and specifically used this model to predict the effect of increasing BMI quartiles upon relative risk (RR) of immunization for fondaparinux vs. enoxaparin.


RESULTS
Anti-PF4/heparin immunization was more frequent after knee vs. hip surgery (particularly for enoxaparin), and when enoxaparin was given post- rather than pre-elective surgery; however, the opposite occurred with hip fracture surgery, that is, antibody formation was more frequent when enoxaparin or fondaparinux was given presurgery. The RR of immunization for fondaparinux vs. enoxaparin decreased significantly for increasing BMI quartiles, an effect predominantly because of increasing immunization with enoxaparin at increasing BMI quartiles.


CONCLUSIONS
Several non-drug factors--including type and circumstances of surgery, timing of first anticoagulant dose and BMI--influence risk of anti-PF4/heparin antibody formation, consistent with a stoichiometry-based immunization model of PF4 and anticoagulant ratios occurring during the early peri-operative period.
Warkentin
T E
TE
Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada. twarken@mcmaster.ca
Cook
R J
RJ
Marder
V J
VJ
Greinacher
A
A
D000906:Antibodies / Q000097:blood*; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D015992:Body Mass Index; D004334:Drug Administration Schedule; D017984:Enoxaparin / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D019317:Evidence-Based Medicine; D000077425:Fondaparinux; D006801:Humans; D015233:Models, Statistical; D019637:Orthopedic Procedures / Q000009:adverse effects*; D010978:Platelet Factor 4 / Q000276:immunology*; D011134:Polysaccharides / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology; D013927:Thrombosis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*
D000906:Antibodies; D000925:Anticoagulants; D017984:Enoxaparin; D011134:Polysaccharides; D010978:Platelet Factor 4; D000077425:Fondaparinux