Heparin-Associated Thrombocytopenia :
No Association of Immune Response with HLA

Greinacher, A.; Mueller-Eckhardt, G.

doi:10.1159/000462405

Cited by 7 publications

(8 citation statements)

References 21 publications

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“…[12][13][14] To date, only a minor role for patientspecific risk factors for HIT has been reported. In particular, no association with human leukocyte antigen (HLA) genes is observed, 15 and the potential role of Fc receptor polymorphisms in HIT is debated. [16][17][18] We previously observed in large retrospective studies that females constituted 56.4% 2 and 58.9% 19 of HIT patients, suggesting a possible gender imbalance.…”

Section: Introductionmentioning

confidence: 99%

Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia

Warkentin

Sheppard

Sigouin

et al. 2006

Blood

268

150

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Heparin-induced thrombocytopenia (HIT)is caused by antibodies against a "self" protein-platelet factor 4-bound to heparin. We observed an overrepresentation of the female gender in 290 patients who developed HIT after cardiac or orthopedic surgery compared with the representation found in national databases (study 1). Therefore, we investigated gender imbalance in HIT by logistic regression analysis of a randomized controlled trial of unfractionated heparin (UFH) and lowmolecular-weight heparin (LMWH) (study 2), and we analyzed individual patient data from 7 prospective studies comparing HIT frequency between UFH and LMWH, evaluating effects of gender, heparin (UFH vs LMWH), and patient type (surgical vs medical) (study 3). All 3 studies showed female overrepresentation, which for study 3 was a common odds ratio (OR) of 2.37 (95% confidence interval [95% CI], 1.37-4.09; P ‫؍‬ .0015). Study 3 also showed an interaction between gender, heparin, and patient type. Although UFH was more likely than LMWH to cause HIT (P < .0001), this effect was predominantly seen in women compared with men (common OR, 9.22 vs 1.83; P ‫؍‬ .020) and in surgical patients compared with medical patients (common OR, 13.93 vs 1.75; P ‫؍‬ .005). We conclude that females are at greater risk for HIT and that using LMWH to prevent HIT may have greatest absolute benefit in females undergoing surgical thromboprophylaxis. IntroductionHeparin-induced thrombocytopenia (HIT) is a relatively common drug-induced immune reaction affecting platelets. 1 The immunologic basis of this disorder is the transient production 2 of plateletactivating antibodies of IgG class 3-5 that recognize multimolecular complexes of platelet factor 4 (PF4) and heparin. [6][7][8] An evolving concept is that HIT resembles an autoimmune disorder 9 because the pathogenic antibodies recognize one or more neoepitopes found on the "self" protein, PF4, rather than on heparin. 10,11 Indeed, in some patients, HIT strongly resembles an autoimmune process because heparin treatment initiates the anti-PF4/heparin antibody formation but then is no longer required for the development of thrombocytopenia. [12][13][14] To date, only a minor role for patientspecific risk factors for HIT has been reported. In particular, no association with human leukocyte antigen (HLA) genes is observed, 15 and the potential role of Fc receptor polymorphisms in HIT is debated. [16][17][18] We previously observed in large retrospective studies that females constituted 56.4% 2 and 58.9% 19 of HIT patients, suggesting a possible gender imbalance. Together with the emerging concept of HIT as a drug-induced transient autoimmune disorder, we hypothesized that there might be a gender imbalance in risk for this adverse drug reaction, with a greater frequency among females, as observed in certain chronic autoimmune disorders. [20][21][22] We also examined whether the striking difference in risk for HIT between unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) 23 is consistent for both genders and in ...

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Section: Introductionmentioning

confidence: 99%

Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia

Warkentin

Sheppard

Sigouin

et al. 2006

Blood

268

150

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“…However, no association between HITff and any particular Class II HLA haplotype has been identified [62]. Moreover, as already noted, antibodies specific for PF4 : heparin complexes are absent in normal subjects not exposed to heparin, i.e., they do not occur spontaneously [4].…”

Section: The Cellular Immune Response In Hit/tmentioning

confidence: 87%

Heparin-induced thrombocytopenia: Molecular pathogenesis

2002

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Heparin-induced thrombocytopenia (HIT) is a common and often serious complication of heparin therapy [1,2]. Although the reduction in platelet levels associated with HIT is usually not severe, about 10% of patients experience arterial and/or venous thromboses (HITT), which can be incapacitating or fatal [3]. Recent work done in our laboratory [4] and by others [5-7] has shown that patients with HIT/T* almost invariably have antibodies specific for complexes consisting of heparin and platelet factor 4 (PF4), a heparin-binding protein found normally in platelet alpha granules. We [4] and others [8] have developed hypotheses to explain how these antibodies cause HIT/T in patients given heparin, but knowledge of the disease process is far from complete. An unusual feature of HIT/T is that antibodies important in pathogenesis are specific for complexes made up of two normal body constituents: PF4 and heparin. These antibodies are produced by a high percentage of certain patient populations treated with heparin, but only a minority of antibody formers are adversely affected. We postulate that a fuller understanding of the molecular basis for this immune response could lead to improved diagnosis, treatment and prevention of HIT/T and to the identification of risk factors that predispose to this complication.

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“…It is particularly in recent years that the pathophysiology, diagnostic methods, incidence, complication rates, prophylaxis, and potential therapy of this drug-induced and immune-mediated disease have been widely discussed. Despite the widespread medication, the generally increasing allergization effect has been clearly disputed to date, but it was substantiated by Greinacher and co-workers for a much exposed group of dialysis patients [3,15,16]. However, the immunological problems existing with HIT type II (subgroups?)…”

Section: Discussionmentioning

confidence: 99%

Can a coated Dacron vascular graft maintain a heparin-induced thrombocytopenia type II?

Bürger

Tautenhahn

Böck

et al. 2001

Langenbeck’s Arch Surg

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In the course of reconstruction of peripheral arterial occlusion processes, two gelatin-coated Dacron grafts and one collagen-coated Dacron patch were implanted in a 52-year-old male patient. Eight days following low-dose heparinization (5 days prior to surgery, 3 days postoperatively) with unfractionated heparin, with no clinical symptoms present, a dramatic isolated thrombocyte depression occurred, from 212 Gpt/l prior to surgery to 14 Gpt/l on postoperative day 3. Laboratory tests verified an HIT type II [heparin-induced platelet aggregation assay (HIPAA) and ELISA]. Despite immediate discontinuation of heparin and commencement of an anticoagulant therapy with Revasc and Refludan, an 8-week thrombocyte depression occurred which was eliminated only temporarily by administration of gammaglobulin. The specific antibody tests turned out positive for more than 5 months. Having ruled out other causes of thrombocytopenia, we assume that the case presented was either due to an interaction not elucidated to date or triggered by the grafts (gelatin/collagen/Dacron). The manufacturers of the grafts have disputed a heparinoid action.

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Heparin-Associated Thrombocytopenia : No Association of Immune Response with HLA

Cited by 7 publications

References 21 publications

Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia

Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia: Molecular pathogenesis

Can a coated Dacron vascular graft maintain a heparin-induced thrombocytopenia type II?

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