Rapid determination of anti-heparin/platelet factor 4 antibody titers in the diagnosis of heparin-induced thrombocytopenia

Alberio, Lorenzo; Kimmerle, Sabine; Baumann, Annalies; Taleghani, Behrouz Mansouri; Biasiutti, Franziska Demarmels; Lämmle, Bernhard

doi:10.1016/s0002-9343(03)00080-9

Cited by 72 publications

(66 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The three test-positive subjects each had an antibody titer (defined as the last positive detection followed by either borderline or negative results for undiluted and serially diluted plasma) of one [27]. The platelet-activating ability of these antibodies was not reported.…”

Section: Antibody Prevalence and Characterization Of Positive Resultsmentioning

confidence: 99%

“…In three of these seven articles, the described assay ultimately served as basis of a commercial assay [12,13,19]. The literature set comprised the remaining 11 articles [10,16,17,[20][21][22][23][24][25][26][27], each of which reported the prevalence of PF4/heparin antibodies in healthy subjects, as assessed by a commercial immunoassay according to manufacturer's directions (Table 1). …”

Section: Literature Data Setmentioning

confidence: 99%

“…In the literature set (Table 1), the PF4/heparin ELISA was used in nine studies [10,16,17,[20][21][22][23][24]26], the PF4/PVS ELISA in three studies [17,24,25], and the PF4/heparin PGIA in three studies [17,24,27]. No study used the PIFA.…”

Section: Literature Data Setmentioning

confidence: 99%

See 2 more Smart Citations

Platelet factor 4/heparin antibody (IgG/M/A) in healthy subjects: a literature analysis of commercial immunoassay results

Arepally

Hursting

2008

J Thromb Thrombolysis

View full text Add to dashboard Cite

Purpose-We determined the seroprevalence of platelet factor 4 (PF4)/heparin antibodies in healthy subjects.Methods-A literature search identified studies in which healthy subjects were evaluated using commercial immunoassays for PF4/heparin antibody (IgG/M/A). Proportions of test-positive subjects were calculated, by assay.Results-Across 11 eligible studies, 860 healthy subjects were tested using the Stago enzymelinked immunosorbent assay (ELISA) (nine studies), GTI ELISA (three studies), and/or DiaMed particle gel immunoassay (PGIA) (three studies). Seropositivity occurred in 17 of 790 (2.2%, 95% CI, 1.1-3.2%) subjects by Stago ELISA, one of 100 (1.0%, 95% CI, 0-3.0%) subjects by GTI ELISA, and three of 70 (4.3%, 95% CI, 0-9.0%) subjects by PGIA (P > 0.20). Of seven seropositive subjects tested further, none had platelet-activating antibodies.Conclusion-Commercial immunoassays detect PF4/heparin antibody in 1.0-4.3% of healthy subjects. Because this "background" prevalence overlaps seropositivity rates in heparin-treated patients in various clinical settings, normality cut-offs may require refinement.

show abstract

Section: Antibody Prevalence and Characterization Of Positive Resultsmentioning

confidence: 99%

Section: Literature Data Setmentioning

confidence: 99%

See 1 more Smart Citation

Platelet factor 4/heparin antibody (IgG/M/A) in healthy subjects: a literature analysis of commercial immunoassay results

Arepally

Hursting

2008

J Thromb Thrombolysis

View full text Add to dashboard Cite

show abstract

“…Our studies show that seroconversions in some patients are extremely high titer (Figure 2A), ranging from 1:1800 to 1: 175 000, far higher than those reported to occur in patients with HIT. 38 Whether titers of PRT/H Abs are predictive of greater biologic activity, as seen with Abs in HIT, 39,40 remains to be demonstrated. We also note that PRT/H Abs activated platelets in the presence of only PRT and additional heparin appeared to mitigate platelet activation.…”

Section: Discussionmentioning

confidence: 99%

High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass

Lee¹,

Welsby

Phillips-Bute

et al. 2013

Blood

View full text Add to dashboard Cite

Key Points• A single exposure to protamine and heparin during CPB is highly sensitizing; 29% of patients develop Abs to PRT/H complexes by day 30 after CPB.• PRT/H Abs share several features with platelet factor 4/ heparin Abs, including high titer formation after CPB, heparin dependence, antigen specificity, and platelet activation.Protamine is routinely used to reverse heparin anticoagulation during cardiopulmonary bypass (CPB). Heparin interacts with protamine to form ultralarge complexes that are immunogenic in mice. We hypothesized that patients exposed to protamine and heparin during CPB will develop antibodies (Abs) to protamine/heparin (PRT/H) complexes that are capable of platelet activation. Specimens from a recently completed prospective clinical trial (HIT [for heparin-induced thrombocytopenia] 5801 study; n 5 500) of CPB patients were examined for PRT/H Abs at baseline, at time of hospital discharge (between days 3 through 7), and 30 days after CPB. PRT/H antibody features were characterized and correlated with adverse cardiovascular outcomes. We found a high incidence of PRT/H antibody formation (29%) in patients undergoing cardiac surgery. PRT/H Abs were of high titer (mean titer 1:14 744), showed heparin-dependent binding, and activated platelets in the presence of protamine. PRT/H Abs showed no cross-reactivity to platelet factor 4/heparin complexes, but were cross-reactive with protamine-containing insulin preparations.In the absence of circulating antigen at day 30, there were no complications of thrombocytopenia, thrombotic events, or long-term cardiovascular events. These studies show that Abs to PRT/H occur commonly after cardiac bypass surgery, share a number of serologic features with HIT Abs, including platelet activation, and may pose health risks to patients requiring drug reexposure. (Blood. 2013;121(15):2828-2835 IntroductionProtamine sulfate is currently the only therapeutic agent approved by the US Food and Drug Administration for reversal of heparin anticoagulation. It is the mainstay of therapy in cardiopulmonary bypass (CPB), where rapid reversal of heparin anticoagulation is essential for achieving surgical hemostasis. However, protamine use in CPB is associated with the development of a number of adverse effects, ranging from minor hemodynamic instability to life-threatening anaphylactic complications and fatal cardiovascular collapse. [1][2][3][4] Major adverse reactions related to protamine exposure have been reported to occur in 2.6% of cardiac surgical procedures, 3 and these complications of protamine therapy are highly associated with adverse postoperative outcome. 5,6 Protamine, a highly basic protein, binds heparin through charge interactions and sequesters heparin from its catalytic effects on antithrombin. Recently, we have shown that heparinbinding proteins such as protamine and lysozyme interact with heparin in a charge-dependent manner to form protamine/heparin (PRT/H) or lysozyme/H ultralarge complexes that are immunogenic in mice. 7 In this preliminary clinical...

show abstract

“…To aid in the interpretation of a positive EIA, the clinician should consider the clinical scenario (i.e., the pretest probability based on the ''4Ts'') and the absolute value of the OD. Several studies have documented that high OD values (corresponding to high titers of HIT antibodies) are associated with a higher likelihood of a positive HIPA, a higher ''4Ts'' score (clinical HIT), and a higher probability of thrombotic complications [31][32][33][34][35].…”

Section: Laboratory Detection Of Hit Antibodiesmentioning

confidence: 99%

Heparin‐induced thrombocytopenia: Current status and diagnostic challenges

Otis

Zehnder

2010

American J Hematol

View full text Add to dashboard Cite

Heparin‐induced thrombocytopenia (HIT) is a fairly common and potentially catastrophic complication of heparin therapy. Diagnosing HIT remains a challenge, as the patients at risk often have other reasons for thrombocytopenia and/or thrombosis. HIT is considered a clinicopathologic disorder whose diagnosis is generally made on the basis of both clinical criteria and the presence of “HIT antibodies” in the patient's serum or plasma. There are two basic laboratory approaches to detect HIT antibodies. The immunoassays detect antibodies based on their binding properties, whereas the functional assays detect antibodies based on their platelet‐activating properties. Prompt and accurate diagnosis of HIT is imperative, as overdiagnosis exposes patients to alternative anticoagulants and their associated bleeding risks, whereas under‐ or delayed diagnosis leaves patients vulnerable to the thromboembolic sequelae of HIT, which can be life threatening. A critical interpretation of laboratory results by the clinician is an essential component of diagnosing HIT. This requires a keen understanding of the current concepts in the pathophysiologic mechanisms of the disease, and the application of these concepts when interpreting the results of both the functional and immunoassays. Equally important is an awareness of the strengths and weaknesses, as well as the current lack of standardization and proficiency testing, of these assays. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.

show abstract

Rapid determination of anti-heparin/platelet factor 4 antibody titers in the diagnosis of heparin-induced thrombocytopenia

Cited by 72 publications

References 32 publications

Platelet factor 4/heparin antibody (IgG/M/A) in healthy subjects: a literature analysis of commercial immunoassay results

Platelet factor 4/heparin antibody (IgG/M/A) in healthy subjects: a literature analysis of commercial immunoassay results

High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass

Heparin‐induced thrombocytopenia: Current status and diagnostic challenges

Contact Info

Product

Resources

About