Mechanical prophylaxis is a heparin-independent risk for anti–platelet factor 4/heparin antibody formation after orthopedic surgery

Abstract

Key Points• Patients undergoing total knee arthroplasty can develop anti-PF4/heparin antibodies without heparin exposure.• Dynamic mechanical prophylaxis is a heparinindependent risk factor for anti-PF4/heparin antibody formation in this patient population.Platelet-activating antibodies, which recognize platelet factor 4 (PF4)/heparin complexes, induce spontaneous heparin-induced thrombocytopenia (HIT) syndrome or fondaparinuxassociated HIT without exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). This condition mostly occurs after major orthopedic surgery, implying that surgery itself could trigger this immune response, although the mechanism is unclear. To investigate how surgery may do so, we performed a multicenter, prospective study of 2069 patients who underwent total knee arthroplasty (TKA) or hip arthroplasty. Approximately half of the patients received postoperative thromboprophylaxis with UFH, LMWH, or fondaparinux. The other half received only mechanical thromboprophylaxis, including dynamic (intermittent plantar or pneumatic compression device), static (graduated compression stockings [GCSs]), or both. We measured anti-PF4/heparin immunoglobulins G, A, and M before and 10 days after surgery using an immunoassay. Multivariate analysis revealed that dynamic mechanical thromboprophylaxis (DMT) was an independent risk factor for seroconversion (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.34-3.02; P 5 .001), which was confirmed with propensity-score matching (OR, 1.99; 95% CI, 1.17-3.37; P 5 .018). For TKA, the seroconversion rates in patients treated with DMT but no anticoagulation and in patients treated with UFH or LMWH without DMT were similar, but significantly higher than in patients treated with only GCSs. The proportion of patients with ‡1.4 optical density units appeared to be higher among those treated with any anticoagulant plus DMT than among those not treated with DMT. Our study suggests that DMT increases risk of an anti-PF4/heparin immune response, even without heparin exposure. This trial was registered to

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

“…In a prospective study of over 2000 patients who underwent TKA or hip arthroplasty, dynamic mechanical prophylaxis was an independent risk factor for the development of anti-PF4/heparin antibody formation even in the absence of prior heparin exposure [7]. The authors speculate that the mechanical stimulation and subsequent tissue damage associated with dynamic mechanical thromboprophylaxis induces anti-PF4/heparin antibodies through the release of polyanions such as glycosaminoglycans or nucleic acids [7] [18].…”

“…The authors speculate that the mechanical stimulation and subsequent tissue damage associated with dynamic mechanical thromboprophylaxis induces anti-PF4/heparin antibodies through the release of polyanions such as glycosaminoglycans or nucleic acids [7] [18]. Alternatively, local tissue ischemia secondary to tourniquet use and the subsequent release of these active polyanions is another proposed mechanism accounting for the disproportionate prevalence of spontaneous HIT seen after TKA in comparison to total hip arthroplasty [7] [8].…”

Knee replacement and HIT without heparin

“…With improvements in the ex vivo expansion procedure, including the use of K562 antigen presenting expressing CD64 and CD86 in place of immunomagnetic beads expressing CD3 and CD28, and the refinements in the bead concentration described below, the investigators were able to generate CB Treg doses as high as 100 3 10 6 /kg. 1 In a double CB transplant setting with 4 to 6 antigen matches, the Minnesota group now reports important reductions in the acute GVHD rates (9% vs 45% in the controls (P 5 .05). This study underscores, however, that good manufacturing practice-compliant cell therapy procedures can be difficult and require meticulous diligence to generate the desired product.…”

Heparin-induced thrombocytopenia: research and clinical updates

“…An intriguing study by Bito et al 12 suggests that surgical inflammation may provide sufficient inflammatory signals for triggering PF4/heparin antibody formation in the absence of heparin. In this prospective study of~2000 patients who were either treated with pharmacologic thromboprophylaxis (n 5 1125; UFH, LMWH, or fondaparinux) or mechanical compression stockings (n 5 944; dynamic or static compression), seroconversion rates were surprisingly high in patients receiving only mechanical prophylaxis:~15% in patients receiving dynamic compression vs 6.5% for static compressions.…”

“…This effect of dynamic compression was additive in patients receiving fondaparinux as compared with fondaparinux-alone-treated patients without compression stockings (21% vs 5.7%; P 5 .025). 12 The authors did not examine whether PF4/heparin "autoantibodies" developing in the absence of heparin exposure have similar platelet-activating antibodies as HIT antibodies or carry a similar propensity for causing disease. As well, the study did not examine the mechanism of PF4/heparin autoantibody formation in patients receiving disease-modifying therapies.…”