B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia

Zheng, Yongwei; Wang, Alexander W.; Yu, Mei; Padmanabhan, Anand; Tourdot, Benjamin E.; Newman, Debra K.; White, Gilbert; Aster, Richard H.; Wen, Renren; Wang, Demin

doi:10.1182/blood-2013-11-540781

Cited by 53 publications

(54 citation statements)

References 23 publications

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“…26 To explain this atypical response, previous studies have proposed that the pattern of antibody formation might be more compatible with a non-T cell-dependent immune reaction, which is induced efficiently when an antigen is presented in a repetitive rigid form. 5,[27][28][29] The antigenic PF4/heparin complex can expose such repetitive epitopes, which are similar to repetitive viral epitopes known to cause T cell-independent B-cell activation. 5,30 A recent study of anti-PF4/heparin immunization in patients after cardiac surgery suggested that perioperative inflammation affects the immune response.…”

Section: Discussionmentioning

confidence: 99%

“…31 An inflammatory stimulus can break down PF4/heparin-specific B-cell tolerance, resulting in spontaneous production of PF4/heparin-specific antibodies, especially IgG antibodies. 5,28 DMT-associated inflammation may modify the immune system as an additional danger signal to trigger B cells, probably primitive marginal zone B cells, 29,32 with specificity for PF4/polyanion complexes. In the present study, the proportion of patients with high OD values ($1.4 units) appears to be higher in patients treated with any anticoagulant plus DMT than in patients treated with any anticoagulant but no DMT, although a significant difference was observed between TKA patients treated with and without DMT only when no anticoagulant was administered (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

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

Bito

Miyata

Migita

et al. 2016

Blood

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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

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Bito

Miyata

Migita

et al. 2016

Blood

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“…These complexes are more common with UFH than LMWH and can trigger pre-existing PF4/heparin-intolerant B cells [59]. The chances of a B cell reaction leading to proliferation and antibody production may increase in some patients with repeated exposure to exogenous UFH, leading to a condition called heparin-induced thrombocytopenia (HIT).…”

Section: Heparin-induced Thrombocytopeniamentioning

confidence: 99%

ECMO Biocompatibility: Surface Coatings, Anticoagulation, and Coagulation Monitoring

Maul¹,

Massicotte²,

Wearden³

2016

Extracorporeal Membrane Oxygenation: Advances in Therapy

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The interaction between the patient and the ECMO (extracorporeal membrane oxygenation) circuit initiates a significant coagulation and inflammatory response due to the large surface area of foreign material contained within the circuit. This response can be blunted with the appropriate mix of biocompatible materials and anticoagulation therapy. The use of anticoagulants, in turn, requires appropriate laboratory testing to determine whether the patient is appropriately anticoagulated. Physicians must balance the risks of bleeding with the risks of thrombosis; the proper interpretation of these tests is often shrouded in mystery. It is the purpose of this chapter to help demystify the coagulation system, anticoagulants, biocompatible surfaces, and coagulation testing so that ECMO practitioners can make informed decisions about their patients and to spur coordinated efforts for future research to improve our understanding of these complex processes.

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“…Auto-reactive B-cells with anti-PF4 specificity were found in healthy mice and humans [16], suggesting that inflammation, surgery, and/or infection may breach selftolerance and lead to proliferation of auto-reactive B-cells and PF4-heparin antibody production. Recently, it has been shown that monocytes take up PF4-heparin complexes by an active endocytic pathway and then transport them to late endosomes, where the complexes still express the antigen recognized by HIT antibodies [17].…”

Section: Pathogenesismentioning

confidence: 99%

Current management of heparin-induced thrombocytopenia

Cosmi

2015

Expert Review of Hematology

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Heparin-induced thrombocytopenia (HIT) is an immune adverse reaction to heparin (both unfractionated and low-molecular-weight), which is mediated by the formation of IgG antibodies against platelet factor 4-heparin complexes. The IgG/platelet factor 4 immunocomplexes activate platelets with resulting thrombocytopenia, which is not associated with bleeding, but with paradoxical life-threatening thrombotic complications, for coagulation activation. HIT diagnosis requires the assessment of pre-test clinical probability in combination with the measurement of platelet activating antibodies against platelet factor 4-heparin complexes with immunological and functional assays. When HIT is diagnosed, any form of heparin should be stopped and a non-heparin alternative anticoagulant should be started. Argatroban and danaparoid are currently the only drugs licensed for HIT, with different country availability. Bivalirudin is an option in cardiac surgery and procedures in HIT patients.

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B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia

Abstract: Key Points B-cell tolerance plays a critical role in controlling production of PF4/heparin-specific antibodies.

Cited by 53 publications

References 23 publications

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

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

ECMO Biocompatibility: Surface Coatings, Anticoagulation, and Coagulation Monitoring

Current management of heparin-induced thrombocytopenia

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