Importance Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function. Objective To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass. Design, Setting, and Participants A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration–ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025. Intervention Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage. Main Outcomes and Measures The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output. Results Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, −0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, −1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group. Conclusions and Relevance For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs. Trial Registration ClinicalTrials.gov Identifier: NCT04834414

BACKGROUND:Plasma exchange (PLEX) therapy is indicated for several disorders. The 5% albumin is often used as a sole replacement fluid during most PLEX. However, each 1.0 plasma volume exchange depletes coagulation factors by ~65%. Although most coagulation factors recover to hemostatic levels within 24 h post-PLEX, fibrinogen requires 48-72 h to recover. Fibrinogen is the key coagulation protein for hemostasis. Therefore, fibrinogen is often monitored during the acute course of PLEX, and plasma is supplemented to prevent bleeding if fibrinogen is <100 mg/dL. STUDY DESIGN AND METHODS:We conducted a prospective, single-center, observational study to evaluate bleeding risk in adults who received an acute course of PLEX with a fibrinogen level of 80-100 mg/dL without plasma supplementation during the procedure or before central venous catheter removal. The study group was compared to patients with plasma fibrinogen >100 mg/dL. RESULTS:Among the 275 patients who received 1406 PLEXes, 62 patients (23%) who underwent 323 PLEXes met the inclusion criteria, and only 2 (3%) patients had bleeding while on oral anticoagulants. In contrast, out of 275 patients, 143 (52%) with fibrinogen levels >100 mg/dL received 751 PLEX treatments, and bleeding occurred in 2 (1%) while on low-molecular-weight heparin. CONCLUSIONS:Our findings suggest that a pre-procedure fibrinogen threshold of 80-100 mg/dL without plasma supplementation does not increase bleeding risk unless patients were on anticoagulation.

Autoimmune disorders (AID) are chronic conditions that involve the loss of immunological tolerance to self-antigens, and result in systemic or tissue-specific damage. Current treatment regimens for AID are often nonspecific and involve long-term administration of immunosuppressive agents such as corticosteroids, calcineurin inhibitors, and cytotoxic chemotherapeutics [ [1] Lallana E.C. Fadul C.E. Toxicities of immunosuppressive treatment of autoimmune neurologic diseases. Curr Neuropharmacol. 2011; 9: 468-477 Crossref PubMed Scopus (23) Google Scholar ]. While effective, these medications render the patient vulnerable to opportunistic infections, as well as increasing long-term risk of secondary malignancy [ [2] Franks A.L. Slansky J.E. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res. 2012; 32: 1119-1136 PubMed Google Scholar ]. The optimal treatment for AID would achieve several goals, including targeting the pathogenic immune cells while leaving the remaining immune system functional, reestablishing immune tolerance that leads to reduction or discontinuation of other therapies, and would have low toxicity with few side effects [ [3] Rosenblum M.D. et al. Treating human autoimmunity: current practice and future prospects. Sci Transl Med. 2012; 4 (Mar 14): 125sr1 Crossref PubMed Scopus (147) Google Scholar ]. Extracorporeal photopheresis (ECP) is a leukapheresis-based immunomodulatory therapy developed in the 1980 s and is predominantly used in the treatment of erythrodermic cutaneous T-cell lymphoma, as well as immune-mediated complications of transplantation such as acute and chronic graft-versus-host disease, cardiac allograft rejection, and bronchiolitis obliterans syndrome [ [4] Padmanabhan A. Connelly-Smith L. Aqui N. et al. Guidelines on the use of therapeutic apheresis in clinical practice - evidence-based approach from the writing committee of the american society for apheresis: the eighth special issue. J Clin Apher. 2019; 34: 171-354 Crossref PubMed Scopus (728) Google Scholar ]. Though the exact mechanism remains unclear, the immunomodulatory effects achieved by ECP suggest a rationale for its use in AID. During ECP, peripheral blood mononuclear cells (PBMCs) are collected by apheresis, incubated with the photosensitizing agent 8-methoxypsoralen (8-MOP), and exposed to UVA (320–400 nm), resulting in irreversible crosslinking of DNA and subsequent apoptosis. While only 5–10% of circulating PBMCs are treated at each session and undergo cell death, it is the downstream immunomodulatory effects of ECP that are thought to confer the majority of benefits in ECP. Apoptotic cells then undergo phagocytosis by immature dendritic cells (DCs), stimulating development of a tolerogenic phenotype that improves peripheral tolerance [ [5] Lamioni A. et al. The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo. Transplantation. 2005; 79 (April 15) (April 15): 846-850 Crossref PubMed Scopus (170) Google Scholar ]. Cytokine profiles are also affected, with tolerogenic DCs producing increased levels of the anti-inflammatory cytokine IL-10 [ [6] Di Renzo M. et al. Extracorporeal photopheresis affects co-stimulatory molecule expression and interleukin-10 production by dendritic cells in graft-versus-host disease patients. Clin Exp Immunol. 2008; 151: 407-413 Crossref PubMed Scopus (52) Google Scholar ], and increased secretion of TGF-β through the interaction with antigen presenting cells with apoptotic leukocytes [ [7] Fadok V.A. et al. Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J Clin Invest. 2001; 108: 957-962 Crossref PubMed Scopus (409) Google Scholar ]. Other immunological changes achieved through ECP therapy include a restoration of Th1/Th2 balance[ [8] Di Renzo M. Rubegni P. De Aloe G. Paulesu L. Pasqui A.L. Andreassi L. et al. Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T-cell lymphoma. Immunology. 1997; 92: 99-103 Crossref PubMed Scopus (109) Google Scholar ] and normalization of the CD4/CD8 ratio [ [9] Alcindor T. Gorgun G. Miller K.B. Roberts T.F. Sprague K. Schenkein D.P. et al. Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease. Blood. 2001; 98: 1622-1625 Crossref PubMed Scopus (102) Google Scholar ]. Additionally, ECP is associated with a significant increase in the activity of T-regulatory cells (Tregs), and a corresponding reduction in the production of T-helper 17 cells, a pro-inflammatory T-cell subset named for the proinflammatory cytokine IL-17, which induces chemokine production that recruits monocytes and neutrophils [ [10] Di Biaso I. et al. Regulatory T cells and extracorporeal photochemotherapy: correlation with clinical response and decreased frequency of proinflammatory T cells. Transplantation. 2009; 87 (May 15): 1422-1425 Crossref PubMed Scopus (71) Google Scholar ]. Activation of IL-17 signaling is observed in some AID, such as psoriasis [ [11] Blauvelt A. Chiricozzi A. The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis. Clin Rev Allergy Immunol. 2018; 55 (Dec): 379-390 Crossref PubMed Scopus (379) Google Scholar ], while others such as systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and rheumatoid arthritis (RA) are associated with decreased levels of Tregs [ 12 Gerli R. et al. Identification of regulatory T cells in systemic lupus erythematosus. Autoimmun Rev. 2009; 8: 426-430 Crossref PubMed Scopus (66) Google Scholar , 13 Kamikozuru K. et al. The expression profile of functional regulatory T cells, CD41CD25high1/forkhead box protein P31, in patients with ulcerative colitis during active and quiescent disease. Clin Exp Immunol. 2009; 156: 320-327 Crossref PubMed Scopus (38) Google Scholar , 14 Cooles F.A. et al. Treg cells in rheumatoid arthritis: an update. Curr Rheuma Rep. 2013; 15: 352 Crossref PubMed Scopus (84) Google Scholar ]. Therefore, decreased IL-17 signaling, increased Tregs, restoration of Th1/Th2 balance, an enhanced anti-inflammatory cytokine profile, and induction of peripheral tolerance may all explain the potential benefits of ECP in the treatment of AID. The current American Society for Apheresis (ASFA) Guidelines include twelve indications for ECP, six of which are autoimmune conditions. All are Category III conditions, with variable levels of supporting evidence [ [4] Padmanabhan A. Connelly-Smith L. Aqui N. et al. Guidelines on the use of therapeutic apheresis in clinical practice - evidence-based approach from the writing committee of the american society for apheresis: the eighth special issue. J Clin Apher. 2019; 34: 171-354 Crossref PubMed Scopus (728) Google Scholar ].

"Laboratory-guided repeat dosing of idarucizumab for dabigatran reversal." Clinical Toxicology, ahead-of-print(ahead-of-print), pp. 1–2 Disclosure statementNo potential conflict of interest was reported by the author(s).Additional informationFundingThe authors reported there is no funding associated with the work featured in this article.

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