A prospective study measuring the development of antibodies against platelet factor 4–heparin in healthy males after exposure to heparins

Kelton, John G.; Warkentin, Theodore E.; Moore, Jane C.; Arnold, Donald M.; Nazi, Ishac; Arepally, Gowthami M.; Roach, James; Fier, Ian

doi:10.1111/j.1538-7836.2012.04759.x

Cited by 8 publications

(9 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We included heparin in our list of drugs, even though heparin‐induced thrombocytopenia (HIT) is associated with some unique features that distinguish it from classic DITP: HIT is associated with thrombosis rather than bleeding and the thrombocytopenia is typically less severe [18]. Heparin also provides illustrative exceptions to our DITP rules: for one, it has been associated with drug‐induced but not drug‐dependent antibodies in the syndrome of delayed‐onset HIT [19]; it may cause antibodies that bind to platelets in a drug‐dependent fashion without causing thrombocytopenia [20]; and because the pathologic heparin‐dependent antibodies are transient, a heparin re‐challenge only produces recurrent thrombocytopenia when administered in close proximity to an episode of HIT [21]. Nevertheless, because it has been proven to cause thrombocytopenia in many reports, heparin (which includes unfractionated heparin, low‐molecular‐weight heparins, polysulfated chondroitin sulphate and other glycosaminoglycans) was included in our list of DITP drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Our laboratory criteria focused on the development of IgG antibodies binding to platelets, which is the most common mechanism of DITP; thus, our criteria would not capture antibodies that target megakaryocytes [24], complement-mediated thrombocytopenia and cell-mediated drug reactions. A fifth criterion may be considered for future prospective evaluations of DITP testing: the absence of antibody binding to platelets in individuals taking the drug who do not develop thrombocytopenia, as has been shown for heparin [20] and vancomycin [25]. Although the list we compiled represents those drugs with the strongest evidence for an association with DITP, such a list should be used with caution because other drugs should be considered in any patient with typical clinical features and a compatible temporal association.…”

Section: Flow Cytometrymentioning

confidence: 99%

See 1 more Smart Citation

A systematic evaluation of laboratory testing for drug‐induced immune thrombocytopenia

Arnold

Kukaswadia

Nazi

et al. 2013

Journal of Thrombosis and Haemostasis

Self Cite

126

114

View full text Add to dashboard Cite

To cite this article: Arnold DM, Kukaswadia S, Nazi I, Esmail A, Dewar L, Smith JW, Warkentin TE, Kelton JG. A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia. J Thromb Haemost 2013; 11: 169-76.Summary. Background: Drug-induced immune thrombocytopenia (DITP) can be confirmed by the demonstration of drugdependent platelet antibodies in vitro; however, laboratory testing is not readily accessible and test methods are not standardized. Objective: To identify drugs with the strongest evidence for causing DITP based on clinical and laboratory criteria. Patients/Methods: We developed a grading system to evaluate the quality of DITP laboratory testing. The ÔDITP criteriaÕ were: (i) Drug (or metabolite) was required for the reaction in vitro; (ii) Immunoglobulin binding was demonstrated; (iii) Two or more laboratories obtained positive results; and (iv) Platelets were the target of immunoglobulin binding. Laboratory diagnosis of DITP was considered definite when all criteria were met and probable when positive results were reported by only one laboratory. Two authors applied the DITP criteria to published reports of each drug identified by systematic review. Discrepancies were independently adjudicated. Results: Of 153 drugs that were clinically implicated in thrombocytopenic reactions, 72 (47%) were associated with positive laboratory testing. Of those, 16 drugs met criteria for a definite laboratory diagnosis of DITP and thus had the highest probability of causing DITP. Definite drugs were: quinine, quinidine, trimethoprim/sulfamethoxazole, vancomycin, penicillin, rifampin, carbamazepine, ceftriaxone, ibuprofen, mirtazapine, oxaliplatin and suramin; the glycoprotein IIbIIIa inhibitors abciximab, tirofiban and eptifibatide; and heparin. Conclusions: We identified drugs with the strongest evidence for an association with immune thrombocytopenia. This list may be helpful for ranking potential causes of thrombocytopenia in a given patient.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Flow Cytometrymentioning

confidence: 99%

A systematic evaluation of laboratory testing for drug‐induced immune thrombocytopenia

Arnold

Kukaswadia

Nazi

et al. 2013

Journal of Thrombosis and Haemostasis

Self Cite

126

114

View full text Add to dashboard Cite

show abstract

“…This model of immune sensitization has been demonstrated by studies reporting PF4 binding to bacterial surfaces are capable of binding anti‐PF4–heparin antibodies . In addition, some healthy individuals exposed to heparin in the absence of surgery also produce anti‐PF4–heparin antibodies . Zheng et al .…”

Section: Introductionmentioning

confidence: 86%

Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin‐induced thrombocytopenia

Nazy

Clare

Staibano

et al. 2018

Journal of Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

Background Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin characterized by thrombocytopenia and thrombotic complications. HIT is caused by pathogenic antibodies that bind to complexes of platelet factor 4 (PF4) and heparin, leading to platelet activation and inducing a hypercoagulable state. Previous studies have shown immunity to PF4-heparin complexes occurs early in life, even before heparin exposure; however, the immunogenesis of HIT is not well characterized. Objectives To investigate cellular proliferation in response to PF4-heparin complexes in patients with HIT. Patients/Methods Peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 30), postoperative cardiac surgery patients who had undergone cardiopulmonary bypass (CPB) (n = 17) and patients with confirmed HIT (n = 41) were cultured with PF4 and PF4-heparin complexes. Cellular proliferation was assessed by [ H]thymidine uptake and 5-ethynyl-2'-deoxyuridine detection. Results and Conclusions PBMCs proliferated in the presence of PF4, and this was enhanced by the addition of heparin in all study groups. CPB and HIT patients showed significantly greater proliferative responses than healthy controls. PBMC proliferation was antigen-specific, depended on the presence of platelets, and only CD14 cells were identified as proliferating cells. Culture supernatants were tested for the levels of regulatory cytokines, and both CPB and HIT patients produced significantly lower levels of interleukin-10 and transforming growth factor-β1 than healthy controls. These findings further demonstrate cellular immune sensitization to PF4-heparin complexes occurs before heparin exposure, and suggests immune dysregulation can contribute to HIT.

show abstract

“…Thus, in contrast to other drug‐induced thrombocytopenias, HIT is additionally characterized by an increased risk of venous and arterial thrombosis, which can lead to devastating clinical outcomes in affected patients . Of note, PF4/heparin‐specific antibodies are also found in the general population, and it was recently demonstrated that heparin administration in healthy subjects without a history of HIT induces PF4/heparin antibody formation without a concomitant drop in platelet count or HIT …”

Section: Introductionmentioning

confidence: 99%

Immobilization and high platelet count are associated with thromboembolic complications in heparin-induced thrombocytopenia

Bolbrinker

Garbe

Douros

et al. 2017

Pharmacoepidemiol Drug Saf

View full text Add to dashboard Cite

show abstract

A prospective study measuring the development of antibodies against platelet factor 4–heparin in healthy males after exposure to heparins

Abstract: To cite this article: Kelton JG, Warkentin TE, Moore JC, Arnold DM, Nazi I, Arepally GM, Roach JM, Fier I. A prospective study measuring the development of antibodies against platelet factor 4–heparin in healthy males after exposure to heparins. J Thromb Haemost 2012; 10: 1446–9.

Cited by 8 publications

References 12 publications

A systematic evaluation of laboratory testing for drug‐induced immune thrombocytopenia

A systematic evaluation of laboratory testing for drug‐induced immune thrombocytopenia

Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin‐induced thrombocytopenia

Immobilization and high platelet count are associated with thromboembolic complications in heparin-induced thrombocytopenia

Contact Info

Product

Resources

About