Formation of anti–platelet factor 4/heparin antibodies after cardiac surgery: Influence of perioperative platelet activation, the inflammatory response, and histocompatibility leukocyte antigen status

Paparella, Domenico; Scrascia, Giuseppe; Galeone, Antonella; Coviello, M.; Cappabianca, Giangiuseppe; Venneri, Maria Teresa; Favoino, B; Quaranta, Michele; Schinosa, Luigi de Luca Tupputi; Warkentin, Theodore E.

doi:10.1016/j.jtcvs.2008.06.014

Cited by 22 publications

(19 citation statements)

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“…This suggests a possible mechanism of B-cell tolerance for PF4/heparin complexes in patients with chronic inflammatory disorders such as RA. A recent study of anti-PF4/ heparin immunization in patients after cardiac surgery suggested that perioperative inflammation affects the immune response [29]. Alternatively, chronic rheumatoid inflammation may downregulate these perioperative inflammations that contribute to occurrence of anti-PF4/ heparin Ab in RA patients.…”

Section: Discussionmentioning

confidence: 99%

Reduced induction of anti-PF4/heparin antibody in RA patients after total knee arthroplasty

et al. 2016

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BackgroundHeparin-induced thrombocytopenia is caused by antibodies (Abs) specific to platelet factor 4 (PF4)/heparin complexes. In this study, we evaluated the rates of seroconversion of anti-PF4/heparin Ab between patients with rheumatoid arthritis (RA) and with osteoarthritis (OA) who underwent total knee arthroplasty.MethodsThe subjects of this randomized controlled trial were 124 patients who underwent total knee arthroplasty (TKA) and received edoxaban with or without a foot pump as thromboprophylaxis. We measured anti-PF4/heparin Abs before and 10 days after surgery, as well as preoperative PF4, using commercially available ELISAs. We also used the database of J-PSVT, a hospital-based, prospective cohort study designed to document the effectiveness of thromboprophylactic agents during arthroplasty.ResultsThe rates of seroconversion to anti-PF4/heparin Ab were lower in RA patients (4.0 %) than in OA patients (25.5 %). The anti-PF4/heparin IgG optical density (OD) values did not differ before and after surgery in RA patients. In contrast, there was a significant increase in anti-PF4/heparin IgG OD values in OA patients after TKA. In the J-PSVT data, the postoperative seroconversion rates of anti-PF4/heparin Ab were lower in RA patients (10.4 %) than in OA patients (21.8 %) who received fondaparinux. The titers of anti-CCP Ab were significantly lower in RA patients with postoperative ant-PF4/heparin Ab compared with those without postoperative ant-PF4/heparin Ab There was no significant difference in preoperative PF4 levels between RA patients and OA patients. The heparin-binding affinity of the circulating PF4 was similar between RA patients and OA patients; however, the IgG fractions isolated from the sera of RA patients contained PF4 more frequently (69.2 %) than those from OA patients (10.2 %).ConclusionsOur results showed a reduced likelihood of postoperative anti-PF/heparin Ab production in RA patients compared with OA patients. This suggests that the mechanisms underlying the anti-PF4 immune response in RA patients differ from the mechanisms of the anti-PF4/heparin immune response seen in OA patients after joint replacement.Trial registrationISRCTN 18090286. Registered 8 July 2016

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Section: Discussionmentioning

confidence: 99%

Reduced induction of anti-PF4/heparin antibody in RA patients after total knee arthroplasty

et al. 2016

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“…A recent study of anti-PF4/heparin immunization in postcardiac surgery patients found evidence that proinflammatory factors support the costimulation of B cells. 38 This might also explain the decrease of antibody titers despite maintaining heparin, as any proinflammatory costimuli will typically decline soon after surgery.…”

Section: Discussionmentioning

confidence: 99%

The temporal profile of the anti-PF4/heparin immune response

Greinacher

Kohlmann

Strobel

et al. 2009

Blood

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“…Such an association could represent the effects of a common factor, such as the degree of intra-or postoperative inflammation, which could influence both seroconversion frequency as well as venous graft occlusion. In this regard, it is worth noting that one group has reported an association between a marker of inflammation and antibody formation in cardiac surgery patients [19] (however, we did not examine markers of inflammation in our current study). Moreover, Selleng et al [20] found an association between the pre-operative presence of IgM class antibodies and subsequent nonthrombotic morbid events in post-cardiac surgery patients, which they concluded was unlikely to reflect any HIT-related pathomechanism, but which they speculated could represent an independent factor such as inflammation.…”

Section: Discussionmentioning

confidence: 77%

Anti‐PF4/heparin antibodies and venous graft occlusion in postcoronary artery bypass surgery patients randomized to postoperative unfractionated heparin or fondaparinux thromboprophylaxis

Warkentin

Sheppard

Sun

et al. 2013

Journal of Thrombosis and Haemostasis

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To cite this article: Warkentin TE, Sheppard JI, Sun JCJ, Jung H, Eikelboom JW. Anti-PF4/heparin antibodies and venous graft occlusion in postcoronary artery bypass surgery patients randomized to postoperative unfractionated heparin or fondaparinux thromboprophylaxis. J Thromb Haemost 2013; 11: 253-60.Summary. Background: Anti-PF4/heparin antibodies are frequently generated after coronary artery bypass grafting (CABG) surgery, with platelet-activating IgG implicated in heparin-induced thrombocytopenia (HIT). It is controversial whether non-platelet-activating antibodies are associated with thrombosis. Objectives: To determine in post-CABG patients whether thromboprophylaxis using fondaparinux vs. unfractionated heparin (UFH) reduces the frequency of anti-PF4/heparin antibodies, and whether anti-PF4/heparin antibodies are associated with early graft occlusion. Methods/patients: In a pre-planned secondary analysis of a randomized control trial (RCT) comparing fondaparinux vs. UFH thromboprophylaxis post-CABG, we determined the frequency of anti-PF4/ heparin antibody formation by solid-phase enzymeimmunoassay (EIA) and of platelet-activating antibodies by serotonin-release assay (SRA); the SRA and fluidphase EIA were used to assess fondaparinux crossreactivity. We also examined whether anti-PF4/heparin antibodies were associated with early arterial or venous graft occlusion (6-week CT angiography). Results: We found no significant difference in the frequency of antibody formation between patients who received fondaparinux vs. UFH (65.3% vs. 46.0%; P = 0.069), and no significant fondaparinux cross-reactivity. Venous graft occlusion(s) occurred in 6/26 patients who formed 'strong' IgG antibodies ( ! 1.0 optical density [OD] units and ! 29 baseline) vs. 3/66 who did not (P = 0.0139). In both unadjusted and adjusted analyses, strong postoperative (but not pre-operative) anti-PF4/heparin IgG responses were associated with a markedly increased risk of early venous (but not arterial) graft occlusion (adjusted OR, 9.25 [95% CI, 1.73, 49.43]; P = 0.0093); notably, none of the three SRA-positive patients developed a venous graft occlusion. Conclusions: Fondaparinux vs. UFH thromboprophylaxis postCABG does not reduce anti-PF4/heparin antibody formation. Non-platelet-activating anti-PF4/heparin IgG antibodies generated post operatively are associated with early venous graft occlusion.

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Formation of anti–platelet factor 4/heparin antibodies after cardiac surgery: Influence of perioperative platelet activation, the inflammatory response, and histocompatibility leukocyte antigen status

Cited by 22 publications

References 22 publications

Reduced induction of anti-PF4/heparin antibody in RA patients after total knee arthroplasty

Reduced induction of anti-PF4/heparin antibody in RA patients after total knee arthroplasty

The temporal profile of the anti-PF4/heparin immune response

Anti‐PF4/heparin antibodies and venous graft occlusion in postcoronary artery bypass surgery patients randomized to postoperative unfractionated heparin or fondaparinux thromboprophylaxis

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