Anti‐PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non‐drug risk factors and evidence for a stoichiometry‐based model of immunization

Abstract

To cite this article: Warkentin TE, Cook RJ, Marder VJ, Greinacher A. Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non-drug risk factors and evidence for a stoichiometry-based model of immunization. J Thromb Haemost 2010; 8: 504-12.Summary. 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. Patients/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 perioperative period.

Treatment and Prevention of Heparin-Induced Thrombocytopenia

“…18 Differences in the stoichiometry of heparin/PF4 complexes are believed to explain the 10-fold higher likelihood of HIT in patients who receive unfractionated heparin (UFH) compared with patients who receive low-molecular weight heparin (LMWH) or fondaparinux. 19,20 Patients who undergo cardiac or orthopedic surgery and receive UFH have a higher risk of HIT (1%-5%) than medical or obstetric patients (0.1%-1%). 13,14,[21][22][23][24] Women have approximately twice the risk of developing HIT as men.…”

Heparin‐induced thrombocytopenia: Current status and diagnostic challenges

“…The EIA is a highly sensitive assay, but its specificity is considerably lower and varies depending on the patient population and type of heparin used [51][52][53]. Of all patients exposed to heparin, only a subset will have a positive EIA, and only a fraction of that subset will make antibodies capable of activating platelets in the SRA or HIPA.…”

Spontaneous Heparin-Induced Thrombocytopenia Following Orthopaedic Surgery: Case Report and Review of the Literature

“…Since this inaugural report, there have been at least 10 other described diagnoses of spontaneous HIT in patients after orthopaedic surgery with the vast majority of presentations occurring after TKA. Simultaneous bilateral surgery, intraoperative tourniquet use, and postoperative utilization of dynamic mechanical thromboprophylaxis have been theorized as risk factors [6] [7] [8].…”