Low-level HLA antibodies do not predict platelet transfusion failure in TRAP study participants.
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ABSTRACT:
SUBMITTER: Jackman RP
PROVIDER: S-EPMC3630837 | biostudies-other | 2013 Apr
REPOSITORIES: biostudies-other
Publications
Low-level HLA antibodies do not predict platelet transfusion failure in TRAP study participants.
Jackman Rachael P RP Deng Xutao X Bolgiano Douglas D Lebedeva Mila M Heitman John W JW Busch Michael P MP Slichter Sherrill J SJ Norris Philip J PJ
Blood 20130207 16
In the Trial to Reduce Alloimmunization to Platelets (TRAP) study, 101 of 530 participants became refractory to platelet transfusions without evidence of HLA or human platelet antigen (HPA) antibodies. We used a more sensitive bead-based assay to detect and quantify HLA antibodies and a qualitative solid-phase enzyme-linked immunosorbet assay for HPA to determine whether low-level antibodies could predict refractoriness in longitudinal panels from 170 lymphocytotoxicity assay (LCA)(-) and 20 LCA ...[more]
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Project description:In the Trial to Reduce Alloimmunization to Platelets (TRAP) study, 101 of 530 subjects became clinically refractory (CR) to platelets (PLTs) without lymphocytotoxicity assay (LCA)-detectable anti-HLA antibodies. The LCA only detects complement-binding antibodies and is less sensitive than newer assays. Utilizing a more sensitive bead-based assay that does not distinguish between complement-binding versus non-complement-binding antibodies, we have previously shown that while many LCA-negative (LCA-) patients do have anti-HLA antibodies, these low- to moderate-level antibodies do not predict refractoriness. As complement can contribute to PLT rejection, we assessed if previously undetected complement-binding antibodies account for refractoriness among LCA- patients.Samples from 169 LCA- (69 CR, 100 non-CR) and 20 LCA-positive (LCA+; 10 CR, 10 non-CR) subjects were selected from the TRAP study serum repository. Anti-Class I HLA immunoglobulin (Ig)G and C1q-binding antibodies were measured in serum or plasma with bead-based detection assays. Levels of C1q-binding antibodies were compared between CR and non-CR subjects and correlated with corrected count increments (CCIs).While some of the LCA- subjects had detectable C1q-binding anti-Class I HLA antibodies, and some LCA+ subjects did not, levels were significantly higher among LCA+ subjects. C1q-binding anti-Class I HLA antibody levels did not differ significantly between CR and non-CR among either the LCA- or the LCA+ subjects. Furthermore, there was no significant correlation observed between CCIs and either C1q-binding or any anti-HLA IgG antibodies.This work confirms that low- to moderate-level anti-Class I antibodies do not drive PLT rejection, suggesting a role for antibody-independent mechanisms.
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Project description:Alloimmune platelet refractoriness (alloPR) among actively bleeding surgical patients with thrombocytopenia represents a life-threatening problem. Here we present three cases in which surgical bleeding was complicated by life-threatening thrombocytopenia and alloPR. We demonstrate that the human leukocyte antigens (HLA) antibodies associated with alloPR are broadly reactive and in high concentration, are not removed by hemodilution, and are not absorbed by transfusion of multiple doses of platelet concentrates. HLA alloPR may be under-recognized among surgical patients. Research is needed to develop pre-operative screening methods that will identify patients in need of specialized platelet support using HLA compatible donor products.
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Project description:IMPORTANCE:Thrombocytopenia and intraventricular hemorrhage (IVH) are common among very-low-birth-weight (VLBW) infants. Survey results suggest that US neonatologists frequently administer platelet transfusions to VLBW infants with mild to moderate thrombocytopenia. OBJECTIVES:To characterize platelet transfusion practices in US neonatal intensive care units (NICUs), to determine whether severity of illness influences platelet transfusion decisions, and to examine the association between platelet count (PCT) and the risk for IVH in the first 7 days of life. DESIGN, SETTING, AND PARTICIPANTS:This multicenter, retrospective cohort study included 972 VLBW infants treated in 6 US NICUs, with admission dates from January 1, 2006, to December 31, 2007. Data were collected from all infants until NICU discharge or death (last day of data collected, December 4, 2008). Data were entered into the central database, cleaned, and analyzed from May 1, 2009, to February 11, 2016. INTERVENTION:Platelet transfusion. MAIN OUTCOMES AND MEASURES:Number of platelet transfusions and incidence of IVH. RESULTS:Among the 972 VLBW infants (520 [53.5%] male; mean [SD] gestational age, 28.2 [2.9] weeks), 231 received 1002 platelet transfusions (mean [SD], 4.3 [6.0] per infant; range, 1-63 per infant). The pretransfusion PCT was at least 50?000/?L for 653 of 998 transfusions (65.4%) with this information. Two hundred eighty-one transfusions (28.0%) were given during the first 7 days of life. During that period, platelet transfusions were given on 35 of 53 days (66.0%) when the patient had a PCT less than 50?000/?L and on 203 of 436 days (46.6%) when the patient had a PCT of 50?000/?L to 99?000/?L. At least 1 marker of severe illness was present on 198 of 212 patient-days (93.4%) with thrombocytopenia (PCT, <100?000/?L) when a platelet transfusion was given compared with 113 of 190 patient-days (59.5%) with thrombocytopenia when no platelet transfusion was given. Thrombocytopenia was a risk factor for intraventricular hemorrhage during the first 7 days of life (hazard ratio, 2.17; 95% CI, 1.53-3.08; P?<?.001). However, no correlation was found between severity of thrombocytopenia and risk for IVH. After controlling for significant clinical factors and thrombocytopenia, platelet transfusions did not have a significant effect on the incidence of IVH (hazard ratio, 0.92; 95% CI, 0.49-1.73; P?=?.80). CONCLUSIONS AND RELEVANCE:A large proportion of platelet transfusions were given to VLBW infants with PCT greater than 50?000/?L. Severity of illness influenced transfusion decisions. However, the severity of thrombocytopenia did not correlate with the risk for IVH, and platelet transfusions did not reduce this risk.
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Project description:HLA antibodies are associated with refractoriness to platelet transfusion, leading to rapid platelet clearance, sometimes coinciding with clinical side effects such as fever and chills. The presence of HLA antibodies is not always manifested by clinical symptoms. It is currently unclear why refractoriness to platelet transfusion is only observed in a subset of patients. Here, we utilized the availability of a unique panel of human monoclonal antibodies to study whether these were capable of activating platelets. Three out of eight human HLA-specific monoclonal antibodies induced activation of HLA-matched platelets from healthy donors as evidenced by enhanced α-granule release, aggregation, and αIIbb3 activation. The propensity of HLA monoclonal antibodies to activate platelets was independent of the HLA subtype to which they were directed, but was dependent on the recognized epitope. Activation was fully inhibited either by blocking FcγRIIa, or by blocking FcγRIIa-dependent signaling with Syk inhibitor IV. Furthermore, activation required the presence of the IgG-Fc part, as F(ab')2 fragments of HLA monoclonal antibodies were unable to induce platelet activation. Mixing experiments revealed that activation of platelets occurred in an intra-platelet dependent manner. Accordingly, a proportion of sera from refractory patients with HLA antibodies induced FcγRIIa-dependent platelet activation. Our data show that a subset of HLA antibodies is capable of crosslinking HLA and FcγRIIa thereby promoting platelet activation and enhancing these cells' phagocytosis by macrophages. Based on these findings we suggest that FcγRIIa-dependent platelet activation may contribute to the decreased platelet survival in platelet-transfusion-dependent patients with HLA antibodies.
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Project description:PURPOSE:Pegaspargase (PEG-ASP) has largely replaced native Escherichia coli asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome. PATIENTS AND METHODS:PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics. RESULTS:Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; P = 1.4 × 10-23). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions (P = 2.4 × 10-5), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance (P = 5.0 × 10-6). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP (P = .0078) and was predicted by the occurrence of angioedema with first reaction (P = .01). CONCLUSION:Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.
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Project description:The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 × 109/L compared with 50 × 109/L for major bleeding and/or mortality in preterm neonates (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 × 109/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 × 109/L- and 25 × 109/L-threshold groups. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval, 0.58-0.68). The 25 × 109/L threshold was associated with absolute-risk reduction in all risk groups, varying from 4.9% in the lowest risk group to 12.3% in the highest risk group. These results suggest that a 25 × 109/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. This trial was registered at www.isrctn.com as #ISRCTN87736839.
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