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Purpose: Anemia is a cardinal feature of myelofibrosis often managed with red blood cell (RBC) transfusions, which may contribute to negative prognostic, quality-of-life, and healthcare-related economic impacts. The Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib was approved for the treatment of patients with myelofibrosis and anemia based on clinical trial evidence of anemia, spleen, and symptom benefits illustrated using binomial response/nonresponse endpoints. In the present post hoc, descriptive analyses, the impact of momelotinib on RBC transfusion burden over time was further characterized across JAK inhibitor-naive and -experienced patients., Methods: All RBC units transfused were collected during the baseline and 24-week treatment periods, initially in a single-arm phase 2 study as proof-of-concept analysis, and then versus comparators (ruxolitinib, best available therapy [BAT], and danazol) in the phase 3 SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM studies, respectively., Results: In the phase 2 study, mean transfusion requirement changed by -1.5 units/28 days, with 85% of patients (35/41) achieving numeric transfusion reduction. Across SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM, mean transfusion requirements decreased with momelotinib (-0.1, -0.36, and -0.86 units/28 days), while mean requirements with ruxolitinib, BAT, and danazol changed by +0.39, 0, and ‒0.28 units/28 days, respectively. Overall, 87% (185/213), 77% (79/103), and 85% (110/130) of patients had improved or stable transfusion intensities with momelotinib versus 54% (117/216), 62% (32/52), and 63% (41/65) with ruxolitinib, BAT, and danazol., Conclusion: These novel time-dependent transfusion burden analyses demonstrate that momelotinib is associated with anemia-related benefits in most patients and greater transfusion burden reduction versus comparators., Trial Registration: ClinicalTrials.gov identifiers: NCT02515630, NCT01969838, NCT02101268, NCT04173494., Competing Interests: Disclosure CNH has received institutional research funding from BMS/Celgene, Constellation Pharmaceuticals Inc (a MorphoSys Company), and Novartis; consulting fees from AOP, Galecto, GSK, Keros, SOBI, and Roche; advisory role and speaker funding from AbbVie, AOP Pharma, BMS/Celgene, Constellation Pharmaceuticals Inc (a MorphoSys Company), CTI BioPharma, Galecto, Geron, GSK, Jannsen, Novartis, Roche, and Promedior; and support from Novartis for attending meetings. RM reports consulting fees from AbbVie, Blueprint, BMS, CTI Biopharma, Genentech, Geron, GSK, Incyte, MorphoSys, Novartis, and Sierra Oncology. MT reports research funding from BMS and advisory board participation for BMS, Kyowa Kirin, and SDP/Sumitomo. VG reports consulting fees from AbbVie, BMS Celgene, Daiichi Sankyo, GSK, and Pfizer and participation in a data safety monitoring/advisory board for AbbVie, BMS Celgene, and Daiichi Sankyo. ATG reports consulting fees from AbbVie, BMS, Constellation/MorphoSys, CTI Biopharma, Imago Biosciences/Merck, Incyte, PharmaEssentia, Sierra Oncology, and Telios. AP reports payment of honoraria from and participation in advisory board work with AbbVie, CTI BioPharma, GSK, Incyte, Kartos, and Novartis. YTG reports consulting fees from Amgen, Antengene, Astellas, AstraZeneca, GSK, Janssen, Pfizer, and Roche; and payment or honoraria from AbbVie, DKSH, and Recordati. MLF reports consulting fees from AbbVie, GSK, Novartis, Sanofi, and Sierra Oncology and participation in a Keros Therapeutics steering committee. DM reports grants from Imago Biosciences; payment or honoraria from AbbVie, Jazz Pharmaceuticals, and Novartis; participation in a data safety monitoring board for the UK ALL RIC trial; and a leadership role with the European Society for Blood and Marrow Transplantation. JP reports payment or honoraria from CTI Biopharma and participation in a data safety monitoring/advisory board for MorphoSys. LF reports honoraria from GSK and Novartis and advisory board participation with GSK, Medison, and Novartis. AV reports payment or honoraria from AbbVie, AOP, BMS, GSK, Incyte, Novartis, and Roche. SK reports research funding, consulting fees, honoraria, and/or travel grants from AbbVie, AOP Pharma, BMS/Celgene, CTI Biopharma, Geron, GSK, Incyte, Imago Biosciences, iOMEDICO, Janssen, Kartos, MPN Hub, MSD, Novartis, Pfizer, PharmaEssentia, and Sierra Oncology and intellectual property with RWTH Aachen University. FP reports grants from BMS; consulting fees from AbbVie, AOP Health, BMS/Celgene, Karo Pharma, Kyowa Kirin, MEI, Novartis, Roche, Sierra Oncology, and Sumitomo; and payment or honoraria from AbbVie, AOP Health, BMS/Celgene, Novartis, and Roche. STO reports consulting fees from AbbVie, Constellation, BMS, Cogent, CTI Biopharma, Geron, Incyte, Protagonist, and Sierra Oncology. CE, BS, and FJGC report employment with and stock/stock options at GSK. SEL declares no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2., Methods: The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement., Results: In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs., Conclusions: This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies., Competing Interests: Author Disclosures Author disclosure forms can be accessed in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Background: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis., Methods: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting., Findings: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%])., Interpretation: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia., Funding: Sierra Oncology., Competing Interests: Declaration of interests SV reports consulting fees from Bristol Myers Squibb/Celgene, Incyte, Novartis, and Sierra Oncology. ATG reports consulting fees from AbbVie, Bristol Myers Squibb, Constellation/MorphoSys, CTI Biopharma, Novartis, Pharma Essentia, and Sierra Oncology. ATK reports grants from AbbVie, Bristol Myers Squibb, Prelude, and Sierra; consulting fees from AbbVie and Prelude; honoraria from Bristol Myers Squibb, Incyte, and Novartis; and participation on a data safety monitoring board or advisory board for AbbVie, Bristol Myers Squibb, CTI Biopharma, Geron, Imago, and Incyte. MLF reports payment for expert testimony from OncLive; meeting attendance or travel support from Novartis; and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Novartis, and Sierra Oncology. DM reports research grants from Bristol Myers Squibb/Celgene, and Constellation Biopharma; honoraria from AbbVie, Celgene, Jazz, and Novartis; meeting attendance or travel support from Jazz; participation on a data safety monitoring board or advisory board for the ALL-RIC study; and leadership role with the European Society of Hematology and the EBMT Chronic Malignancies Working Party. AP reports honoraria, meeting attendance and travel support, and participation on an advisory board from Novartis Oncology. S-SY reports research grants from Kyowa Kirin and Roche/Genentech; consulting fees from Astellas, Amgen, Antengene, and Celgene; and honoraria from Novartis. VG reports consulting fees from AbbVie, Bristol Myers Squibb/Celgene, Constellation Biopharma, Novartis, Pfizer, and Sierra Oncology; honoraria from Bristol Myers Squibb, Constellation Biopharma, and Novartis; and participation on data safety monitoring board or advisory board for AbbVie, Bristol Myers Squibb/Celgene, Pfizer, and Roche. J-JK reports honoraria from Novartis; participation on a data safety monitoring board or advisory board for AbbVie, Bristol Myers Squibb, Incyte, and Novartis. NG reports consulting fees from Alexion, Bristol Myers Squibb/Celgene, Incyte, and Novartis; honoraria from Bristol Myers Squibb/Celgene, Janssen, and Novartis; leadership or fiduciary role for Alexion, Incyte, and Novartis; and meeting attendance or travel support from AbbVie, Genzyme, and Sanofi. FP reports research grant from Bristol Myers Squibb/Celgene; consulting fees from AbbVie, APO, Bristol Myers Squibb/Celgene, Karyopharm, Kyowa Kirin, MEI, Novartis, and Roche; and honoraria from Bristol Myers Squibb/Celgene, Janssen, and Novartis. CNH reports grant support from Bristol Myers Squibb/Celgene, Constellation Biopharma, and Novartis; consulting fees from AOP, Galecto, Keros, and Roche; honoraria from AbbVie, Celgene, Constellation Biopharma, CTI Biopharma, Janssen, and Novartis; participation in data safety monitoring board or advisory board for AbbVie, AOP, CTI Biopharma, Geron, Promedior, Roche, and Sierra Oncology; and leadership or fiduciary role in the European Hematology Association and MPN Voice. BJK, SR, and RD report employment and stock or stock options at Sierra Oncology. JK reports employment and stock or stock options at Sierra Oncology and former employment and stock and stock options from Gilead. RM reports research grants from AbbVie, Celgene, CTI Biopharma, Constellation Biopharma, Genotech, Incyte, Promedior, Samus, and the Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute (CA054174); and consulting fees from Constellation Biopharma, LaJolla, Novartis, and Sierra Oncology. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT., (© 2022 by The American Society of Hematology.)

Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378., (© 2020 by The American Society of Hematology.)

Background: Aspirin 'resistance' is a widely used term for hyporesponsiveness to aspirin in a platelet function test. Serum thromboxane (TX) B(2) is the most specific test of aspirin's effect on platelets., Objectives: (i) To examine the role of pre-existent platelet hyperreactivity in aspirin 'resistance'. (ii) To determine the correlation between aspirin resistance defined by serum TXB(2) and other assays of platelet function., Methods: To enable pre-aspirin samples to be drawn, platelet function was measured in normal subjects (n = 165) before and after aspirin 81 mg daily for seven days., Results: The proportion of the post-aspirin platelet function predicted by the pre-aspirin platelet function was 28.3 +/- 7.5% (mean +/- asymptotic standard error) for serum TXB(2), 39.3 +/- 6.8% for urinary 11-dehydro TXB(2), 4.4 +/- 7.7% for arachidonic acid-induced platelet aggregation, 40.4 +/- 7.1% for adenosine diphosphate-induced platelet aggregation, 26.3 +/- 9.2% for the VerifyNow Aspirin Assay, and 45.0 +/- 10.9% for the TEG PlateletMapping System with arachidonic acid. There was poor agreement between aspirin-resistant subjects identified by serum TXB(2) vs. aspirin-resistant subjects identified by the other five assays, irrespective of whether the analysis was based on categorical or continuous variables. Platelet count correlated with pre-aspirin serum TXB(2) and VerifyNow Aspirin Assay, but not with any post-aspirin platelet function test., Conclusions: (i) Aspirin 'resistance' (i.e. hyporesponsiveness to aspirin in a laboratory test) is in part unrelated to aspirin but is the result of underlying platelet hyperreactivity prior to the institution of aspirin therapy. (ii) Aspirin resistance defined by serum TXB(2) shows a poor correlation with aspirin resistance defined by other commonly used assays.

Background: Prasugrel is a novel antiplatelet prodrug of the same thienopyridine class as clopidogrel and ticlopidine. Metabolism of prasugrel generates the active metabolite R-138727, an antagonist of the platelet P2Y(12) adenosine diphosphate (ADP) receptor, leading to inhibition of ADP-mediated platelet activation and aggregation. ADP also enhances the platelet response to collagen, and these two agonists contribute to the generation of platelet procoagulant activity. We therefore examined whether R-138727 inhibits ADP- and collagen-triggered platelet procoagulant activities., Methods and Results: As shown by whole blood flow cytometry, R-138727 inhibited surface phosphatidylserine expression on ADP plus collagen-stimulated platelets and tissue factor (TF) expression on ADP-, collagen-, and ADP plus collagen-stimulated monocyte-platelet aggregates. R-138727 reduced monocyte-platelet aggregate formation, thereby further inhibiting TF expression. ADP, collagen, and ADP plus collagen accelerated the kinetics of thrombin generation in recalcified whole blood and R-138727 significantly inhibited this acceleration. Clot strength in a modified thromboelastograph system was also inhibited by R-138727 (IC50 0.7 +/- 0.1 microM)., Conclusions: In addition to its previously known inhibitory effects on platelet activation and aggregation, the active metabolite of prasugrel, R-138727, inhibits platelet procoagulant activity in whole blood (as determined by phosphatidylserine expression on platelets and TF expression on monocyte-platelet aggregates), resulting in the functional consequences of delayed thrombin generation and impaired clot development.

Aim: To determine whether indices of platelet activation are associated with the stability of coronary artery disease (CAD)., Methods: Platelet function was examined in 677 consecutive aspirin-treated patients presenting for cardiac catheterization. Patients were grouped into recent myocardial infarction (MI), no MI but angiographically documented CAD (non-MI CAD) and no angiographically detectible CAD (no CAD), as well as additional subgroups., Results: Compared with non-MI CAD or no CAD patients, more patients with recent MI had a shortened platelet function analyzer (PFA)-100 collagen-epinephrine closure time (CT) and increased circulating monocyte-platelet aggregates, neutrophil-platelet aggregates, activated platelet surface GPIIb-IIIa and plasma soluble CD40 ligand (sCD40L). More patients with non-MI CAD had shortened PFA-100 CTs and increased monocyte-platelet aggregates compared with patients with no CAD. Platelet surface P-selectin did not differ among the groups. Subgroup analysis revealed that decreasing PFA-100 CT correlated with the stability of CAD., Conclusions: Indices of platelet activation, especially the PFA-100 CT, are associated with the stability of CAD, and may reflect plaque instability, an ongoing thrombotic state and/or reduced responsiveness to aspirin.

Background: Clopidogrel is a widely used antithrombotic agent that inhibits the platelet P2Y(12) adenosine diphosphate (ADP) receptor. There is increasing interest in 'clopidogrel resistance'., Objectives: To determine whether 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP., Methods: Platelet response to 20 microm ADP was analyzed by four independent whole blood flow cytometric assays: platelet surface activated GPIIb-IIIa, platelet surface P-selectin, monocyte-platelet aggregates and neutrophil-platelet aggregates. In 25 consecutive, non-aspirin-treated healthy subjects, we studied platelet response before and after clopidogrel administration. In addition, we studied the platelet response in 613 consecutive aspirinated patients with or without coronary artery disease (CAD, as determined by angiography) who had or had not been treated with clopidogrel. In these patients, we tested for homogeneity of variance across all durations of clopidogrel exposure and severity of CAD by estimating the 'goodness of fit' of two independent models., Results: In the healthy subjects, pre-clopidogrel response to ADP predicted post-clopidogrel response to ADP. In the patients, clopidogrel, as expected, inhibited the platelet response to ADP. However, irrespective of the duration of clopidogrel administration, the severity of CAD, and the dose of aspirin, clopidogrel did not increase the variance in the platelet response to ADP in any of the four assays of platelet response., Conclusions: These studies provide evidence that 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP and this variability is not increased by clopidogrel administration.

Background: Monocytes and neutrophils form heterotypic aggregates with platelets initially via engagement of platelet surface P-selectin with leukocyte surface P-selectin glycoprotein ligand-1 (PSGL-1). The resultant intracellular signaling causes the leukocyte surface expression of tissue factor and activation of leukocyte surface Mac-1 (integrin alphaMbeta2, CD11b/CD18). The activation-dependent conformational change in monocyte surface Mac-1 results in the binding of coagulation factor Xa (FXa) and/or fibrinogen to Mac-1. The aim of this study was to develop whole blood flow cytometry assays of these procoagulant activities and to investigate the effects of platelet binding to monocytes and neutrophils., Methods: Citrate or D-Phe-Pro-Arg-chloromethylketone (PPACK) anticoagulated whole blood was incubated with monoclonal antibodies against CD14 (PECy5), CD42a (PE), FITC-conjugated test antibody and an agonist, and then fixed with FACS lyse. Appropriate isotype negative controls were prepared in parallel. A BD FACSCalibur was used to analyze monocytes and neutrophils, which were identified based on CD14 fluorescence, forward and 90 degrees light scatter. These populations were further gated into CD42a-positive (platelet-bound) and CD42a-negative (platelet-free). Geometric mean fluorescence and per cent positive data were collected for each subpopulation to measure the binding of test antibodies directed at CD42a, tissue factor, coagulation FXa, bound fibrinogen, activated Mac-1, and CD11b. Compensation controls were prepared on six normal donors prior to the study and these settings were used throughout the 10 donor study. Negative controls verified the lack of cross talk, particularly in the quantified FITC and PE parameters., Results: The physiologic agonists collagen and ADP increased monocyte-platelet and neutrophil-platelet aggregates and increased leukocyte surface Mac-1/CD11b and surface-bound tissue factor, FXa and fibrinogen. Whereas the increases in Mac-1/CD11b were mainly independent of leukocyte-platelet binding, the increases in surface-bound tissue factor, FXa and fibrinogen were mainly dependent on leukocyte-platelet binding., Conclusions: (i) We have developed novel whole blood flow cytometry assays to measure bound tissue factor, coagulation FXa, fibrinogen, activated Mac-1 and CD11b on the surface of monocytes and neutrophils, allowing independent analysis of monocytes and neutrophils with and without surface-adherent platelets. (ii) The monocyte and neutrophil surface binding of tissue factor, FXa and fibrinogen is mainly dependent on platelet adherence to monocytes and neutrophils, whereas the monocyte and neutrophil surface expression of CD11b and activated Mac-1 is mainly independent of platelet adherence to monocytes and neutrophils.

Objective: To investigate the effects of abciximab, eptifibatide and no GPIIb-IIIa antagonist (control) on soluble CD40 ligand (sCD40L) and the formation of leukocyte-platelet aggregates (LPA) in 98 ACS patients undergoing percutaneous coronary intervention (PCI)., Background: sCD40L and LPA are increased in patients with ACS., Methods: sCD40L was measured by enzyme-linked immunosorbent assay (ELISA) and LPA by whole blood flow cytometry., Results: There were no baseline differences between the three groups in sCD40L and LPA. At the end of PCI, sCD40L was unchanged in the controls, decreased by 30% (P < 0.001) in the abciximab group and by 11% (P < 0.02) in the eptifibatide group. Eighteen to 24 h after PCI, sCD40L was unchanged in the controls, reduced 30% (P < 0.001) in the abciximab-treated group and 9% (P < 0.01) in the eptifibatide-treated group. At the end of PCI, circulating monocyte-platelet aggregates (MPA) were reduced by 12% (P = NS) in the abciximab-treated group, 13% in the eptifibatide-treated group (P = NS), but slightly increased in the controls (P = NS). Eighteen to 24 h after PCI, MPA were reduced by 41% (P < 0.001) compared to baseline in the abciximab-treated group, by 23% (P = NS) in the eptifibatide-treated group, and 15% (P = NS) in the controls. In contrast to control patients presenting while on clopidogrel, control patients presenting not on clopidogrel demonstrated a reduction in sCD40L and LPA 18-24 h post-PCI (P = NS). At low receptor occupancy, GPIIb-IIIa antagonists did not augment the release of sCD40L or the number of circulating LPA., Conclusions: GPIIb-IIIa antagonists reduce circulating sCD40L and LPA formation in patients with ACS undergoing PCI. At low receptor occupancy, GPIIb-IIIa antagonists do not activate platelets.