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Monika Oliver,1 Christopher J Patriquin2 1Department of Medicine, University of Alberta; Division of Hematology, University of Alberta Hospital, Edmonton, Alberta, Canada; 2Department of Medicine (Hematology), University of Toronto, Division of Medical Oncology & Hematology, University Health Network, Toronto, Ontario, CanadaCorrespondence: Christopher J Patriquin, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, M5G2C4, Canada, Tel + 1-416-340-5233, Fax + 1-416-340-3799, Email christopher.patriquin@uhn.caAbstract: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired clonal abnormality, which renders hematopoietic cells exquisitely sensitive to complement-mediated destruction. Classical features of PNH include intravascular hemolytic anemia, increased thrombotic risk, and manifestations related to end-organ damage (eg fatigue, chest pain, dyspnea, renal failure, and pulmonary hypertension). With supportive care alone, mortality rate of patients with PNH is approximately 35%. The anti-C5 monoclonal antibody, eculizumab, was the first targeted therapy approved for PNH, and led to improved hemoglobin, quality of life, reduced transfusion need, reduced thrombosis, and greater overall survival. More recently, therapeutics such as longer acting anti-C5 (ravulizumab) and anti-C3 (pegcetacoplan) medications have been approved, along with other novel therapeutics in late-stage clinical trials. Biosimilars of eculizumab are also now available. Proximal inhibitors (against C3, factor B, and factor D) have shown significant improvements in hemoglobin and transfusion-avoidance in patients who remain anemic despite C5 inhibition. Despite these novel therapies, some unmet challenges remain, including management of breakthrough hemolysis, clinically significant iatrogenic extravascular hemolysis, optimal management in pregnancy, and infection risk mitigation as new targets in the complement system are blocked. In addition, the use of self-administered subcutaneous and oral therapies raises concerns around treatment adherence and the risks of uncontrolled terminal complement. Given the ultra-rare nature of PNH, development is underway of a centralized international registry to capture and analyze the data as they mature for various new therapies and characterize the clinical challenges related to PNH management.Keywords: complement, hemolysis, hemolytic anemia, PNH, thrombosis

Although high titers of neutralizing Abs in human serum are associated with protection from reinfection by SARS-CoV-2, there is considerable heterogeneity in human serum-neutralizing Abs against SARS-CoV-2 during convalescence between individuals. Standard human serum live virus neutralization assays require inactivation of serum/plasma prior to testing. In this study, we report that the SARS-CoV-2 neutralization titers of human convalescent sera were relatively consistent across all disease states except for severe COVID-19, which yielded significantly higher neutralization titers. Furthermore, we show that heat inactivation of human serum significantly lowered neutralization activity in a live virus SARS-CoV-2 neutralization assay. Heat inactivation of human convalescent serum was shown to inactivate complement proteins, and the contribution of complement in SARS-CoV-2 neutralization was often >50% of the neutralizing activity of human sera without heat inactivation and could account for neutralizing activity when standard titers were zero after heat inactivation. This effect was also observed in COVID-19 vaccinees and could be abolished in individuals who were undergoing treatment with therapeutic anti-complement Abs. Complement activity was mainly dependent on the classical pathway with little contributions from mannose-binding lectin and alternative pathways. Our study demonstrates the importance of the complement pathway in significantly increasing viral neutralization activity against SARS-CoV-2 in spike seropositive individuals., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first targeted complement component 3 (C3) PNH therapy, was safe and efficacious in treatment-naive and pre-treated patients with PNH in five clinical trials., Methods: The 307 open-label extension (OLE) study (NCT03531255) is a non-randomized, multicenter extension study of long-term safety and efficacy of pegcetacoplan in adult patients with PNH who completed a pegcetacoplan parent study. All patients received pegcetacoplan. Outcomes at the 48-week data cutoff (week 48 of 307-OLE or August 27, 2021, whichever was earlier) are reported. Hemoglobin concentrations, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and transfusion avoidance were measured. Hemoglobin > 12 g/dL and sex-specific hemoglobin normalization (i.e., male, ≥ 13.6 g/dL; female, ≥ 12 g/dL) were assessed as percentage of patients with data available and no transfusions 60 days before data cutoff. Treatment-emergent adverse events, including hemolysis, were reported., Results: Data from 137 patients with at least one pegcetacoplan dose at data cutoff were analyzed. Mean (standard deviation [SD]) hemoglobin increased from 8.9 (1.22) g/dL at parent study baseline to 11.6 (2.17) g/dL at 307-OLE entry and 11.6 (1.94) g/dL at data cutoff. At parent study baseline, mean (SD) FACIT-Fatigue score of 34.1 (11.08) was below the general population norm of 43.6; scores improved to 42.8 (8.79) at 307-OLE entry and 42.4 (9.84) at data cutoff. In evaluable patients, hemoglobin > 12 g/dL occurred in 40.2% (43 of 107) and sex-specific hemoglobin normalization occurred in 31.8% (34 of 107) at data cutoff. Transfusion was not required for 114 of 137 patients (83.2%). Hemolysis was reported in 23 patients (16.8%). No thrombotic events or meningococcal infections occurred., Conclusion: Pegcetacoplan sustained long-term improvements in hemoglobin concentrations, fatigue reduction, and transfusion burden. Long-term safety findings corroborate the favorable profile established for pegcetacoplan., Trial Registration: ClinicalTrials.gov identifier, NCT03531255., (© 2024. The Author(s).)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare condition caused by severe ADAMTS13 deficiency, leading to platelet aggregation and thrombosis. Despite treatment, patients are prone to cognitive impairment and depression. We investigated brain changes in iTTP patients during remission using advanced magnetic resonance imaging (MRI) techniques, correlating these changes with mood and neurocognitive tests. Twenty iTTP patients in remission (30 days post-haematological remission) were compared with six healthy controls. MRI scans, including standard and specialized sequences, were conducted to assess white matter health. Increased T1 relaxation times were found in the cingulate cortex (p < 0.05), and elevated T2 relaxation times were observed in the cingulate cortex, frontal, parietal and temporal lobes (p < 0.05). Pathological changes in these areas are correlated with impaired cognitive and depressive scores in concentration, short-term memory and verbal memory. This study highlights persistent white matter damage in iTTP patients, potentially contributing to depression and cognitive impairment. Key regions affected include the frontal lobe and cingulate cortex. These findings have significant implications for the acute and long-term management of iTTP, suggesting a need for re-evaluation of treatment approaches during both active phases and remission. Further research is warranted to enhance our understanding of these complexities., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Patients with alloimmune platelet refractoriness can present complex clinical conundrums. Herein we describe a case of platelet refractoriness in the setting of combined HLA and HPA alloimmunization in a patient with acute myeloid leukemia and life-threatening bleeding. We discuss causative antibodies and compare prevailing therapeutic modalities. We highlight plasma exchange as a potentially feasible, repeatable, and personalized treatment option for patients with extensive platelet alloimmunization who require transfusion., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Allogeneic hematopoietic stem cell transplant (HSCT) and gene therapy (GT) are two potentially curative approaches for sickle cell disease (SCD), but they have never been compared in clinical trials., Objective: To compare the safety and efficacy of HSCT and GT to assist clinicians and patients in making informed treatment decisions., Methods: Phase I-III clinical trials and case reports/series were included. Regimens included HSCT from all stem cell sources, lentiviral gene therapy, and gene editing, with any conditioning regimen. We searched Medline and EMBASE databases as of 1st June 2020 for studies reporting HSCT and GT outcomes in SCD. The Newcastle-Ottawa scale was used to assess the risk of bias. Descriptive statistics and post-hoc imputation for standard deviations of mean change in FEV1 and FVC were performed., Results: In total, 56 studies (HSCT, n  = 53; GT, n  = 3) representing 1,198 patients met inclusion criteria (HSCT, n  = 1,158; GT, n  = 40). Length of follow-up was 3,881.5 and 58.7 patient-years for HSCT and GT, respectively. Overall quality of evidence was low, with no randomized controlled trials identified. Two-year overall survival for HSCT was 91%; mortality was 2.5% for GT. Acute chest syndrome and vaso-occlusive episodes were reduced post-HSCT and GT. Meta-analysis was not possible due to lack of comparator and heterogeneity in outcome measures reporting. Very few studies reported post-transplant end-organ function. Six secondary malignancies (5 post-HSCT, 1 post-GT) were reported., Discussion: Reporting of SCD-related complications and patient-important outcomes is lacking for both strategies. We advocate for standardized reporting to better compare outcomes within and between treatment groups.

Objectives: Data from the International PNH Registry (NCT01374360) were used to estimate the overall survival and first occurrence of thromboembolic events/major adverse vascular events (TEs/MAVEs) for eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) compared with a contemporaneous untreated cohort., Methods: Patients enrolled in the Registry from March 16, 2007, to February 14, 2022, were included. Treated patients received eculizumab for >35 days; untreated patients did not receive eculizumab at any time. Univariable and multivariable analyses were performed using a Cox proportional hazards regression model comparing eculizumab treatment periods to untreated periods and were adjusted for baseline covariates (e.g., high disease activity [HDA], transfusion dependency, and eculizumab treatment status)., Results: The analysis included 4118 patients. The univariable hazard ratio (HR) (95% CI) for mortality in eculizumab-treated time versus untreated time was 0.51 (0.41-0.64; p < 0.0001). Significant baseline covariates included age, sex, history of bone marrow failure, ≥4 erythrocyte transfusions within 12 months before baseline, and an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m 2 (all p < 0.0001). In the adjusted analysis, patients with baseline HDA had the greatest reduction in mortality risk (HR [95% CI], 0.51 [0.36-0.72]). Treated patients had approximately 60% reduction in TE/MAVE risk during treated versus untreated time (HR [95% CI]: TE: 0.40 [0.26-0.62], MAVE: 0.37 [0.26-0.54]; p < 0.0001)., Conclusion: Using data from the largest Registry of patients with PNH, with ≥14 years of overall follow-up, we demonstrate that treatment with eculizumab conferred a 49% relative benefit in survival and an approximately 60% reduction in TE/MAVE risk., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

The objective of this analysis was to identify risk factors for thromboembolic events (TE) in patients with paroxysmal nocturnal hemoglobinuria (PNH) who were not treated with C5 inhibitors. Patients with PNH and a history of ≥ 1 TE at enrollment in the International PNH Registry (NCT01374360; registration date, January 2011) were each matched with up to 5 patients without TE. Multivariable analysis was performed with the following variables: percentage glycosylphosphatidylinositol (GPI)-negative cells, high disease activity (HDA), non-TE major adverse vascular event history, and recent anticoagulation. Of 2541 eligible patients, 57 with TE and 189 matched controls were analyzed. Multivariable analysis (odds ratio [95% CI]) identified the following factors as being associated with increased thrombotic risk: patients with no history of TE (with recent anticoagulation, 9.30 [1.20-72.27]), patients with history of TE (with recent anticoagulation, 8.91 [0.86-92.62]; without recent anticoagulation, 5.33 [0.26-109.57]), patients with ≥ 30% GPI-negative granulocytes (≥ 30% to < 50%, 4.94 [0.54-45.32]; ≥ 50%, 1.97 [0.45-8.55]), or patients with lactate dehydrogenase (LDH) ratio ≥ 1.5 × upper limit of normal (ULN) plus ≥ 2 HDA criteria (2-3 criteria, 3.18 [0.44-23.20]; ≥ 4 criteria, 3.60 [0.38-33.95]). History of TE, ≥ 30% GPI-negative granulocytes, and LDH ratio ≥ 1.5 × ULN with ≥ 2 HDA criteria are TE risk factors for patients with PNH. These findings will aid physicians by providing important clinical and laboratory risk factors that can be used to identify and manage patients with PNH who are at risk of developing TE., (© 2023. The Author(s).)

Competing Interests: Declaration of Competing Interest MO has participated in industry trials for Alexion and consulted for Alexion, Roche, Sobi and Takeda. CJP has participated in industry trials (Alexion, Apellis, Regeneron, Sanofi) and has consulted for Alexion, Apellis, BioCryst, Regeneron, Roche, Sanofi, Sobi, and Takeda. KP has participated in industry trials (Ablynx/Sanofi, Shire/Takeda) and has consulted for Sanofi and Takeda.

Objectives: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, non-malignant haematological disorder associated with disabling fatigue and reduced health-related quality of life. Post hoc analysis of PEGASUS phase 3 trial (NCT03500549) characterised improvements in patient-reported fatigue measured by functional assessment of chronic illness therapy-fatigue (FACIT-fatigue) instrument item-level ratings for pegcetacoplan and eculizumab for the treatment of PNH., Methods: Item-level responder analysis was conducted on a ≥2-level change from baseline (CFB) clinically important response (CIR) for the FACIT-fatigue 13 individual items rated on a 5-level Likert scale. We evaluated ≥2-level change against the minimal clinically important difference (MCID) of the FACIT-fatigue total score (≥5 points) and clinical parameters, haemoglobin (Hb; ≥1 g/dL) and normalised absolute reticulocyte count (ARC; 30-100 pg/cells). Logistic regressions estimated baseline-to-Week-16 FACIT-fatigue item-level transitional probabilities; Kaplan-Meier analysis estimated time to FACIT-fatigue item CIR., Results: Pegcetacoplan versus eculizumab was associated with significantly greater odds of Week 16 CIR across 8/13 items and on total score MCID (OR [CI] = 11.19 [3.73, 33.57]) and faster times to responses. The item-level CIR threshold also showed clinical relevance on Hb level and ARC normalization., Conclusions: Compared with eculizumab, pegcetacoplan was associated with clinically meaningful greater improvements on a majority of FACIT-fatigue items., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Therapeutic plasma exchange (TPE) and red blood cell exchange (RBCX) are life-saving apheresis procedures offered in 7 Ontario hospitals. Most referrals are directed by CritiCall Ontario (CritiCall), a 24/7 service funded by the Ontario Ministry of Health and Long-Term Care. We used CritiCall data to examine referral requests, acceptances, and transfers for urgent apheresis to our centre., Methods: Retrospective CritiCall referral and transfer data for urgent apheresis between October 2013 and December 2018 were included. Continuous variables were analyzed by linear regression. Categorical variables were analyzed using nonparametric tests., Results: Eighty-five cases (52 TPE, 33 RBCX) were identified. Median patient age was 52 years (interquartile range [IQR] 32) for TPE, 29 years (IQR 18) for RBCX. Most patients (58%) were female. Total time from referral to arrival at our centre was 243 (IQR 166) minutes. The greatest proportion of this total was from patient acceptance to arrival (169 [IQR 112] minutes). Median distance between referring and accepting centres was 39 (IQR 30) kilometres, with ground transportation used most often. Multiple linear regression examining factors that contribute to total time demonstrated that the number of physicians contacted prior to patient acceptance and inter-hospital distance were independently associated (p = 0.007 and p = 0.048, respectively)., Interpretation: Addressing modifiable factors to reduce time is important given that time to initiate treatment is associated with better outcomes. Quality improvement strategies should be aimed at coordinated provincial resource sharing, pairing referrals with nearest available apheresis centres, and creating efficiency in the interval between patient acceptance and arrival., Competing Interests: Declaration of Competing Interest K.M: Educational and/or research grants: Canadian Hematology Society, University Health Network Blood Disorders Program, Royal College of Physicians and Surgeons Canada. K.H.M.K: Educational and/or research grants: NHLBI/NIH, Thalassemia Foundation Canada, Peter Munk Cardiac Centre, University of Toronto, Canadian Hematology Society, Pfizer. Consulting fees: Agios, Alexion, Apellis, Aruvant, Bluebirdbio, Celgene/BMS, Forma, Novarits, Pfizer. Lecture Honoraria: Agios, Alexion, Apellis, Bluebirdbio, Celgene/BMS, Forma. Data Safety Monitoring Board: Bioreativ/Sanofi. C.J.P: Advisory board/consultancy honouraria: Alexion, Apellis, BioCryst, Octapharma, Sanofi, Sobi, Takeda. Speaking honouraria: Alexion, Octapharma, Sobi. Educational and/or research grants: Alexion, Octapharma, Sanofi. A.B. and D.B. No competing interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy. Prompt investigation and empirical treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach and both empirical and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies., (Copyright © 2023. Published by Elsevier Inc.)

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. In the Ninth Edition, the JCA Special Issue Writing Committee has incorporated systematic review and evidence-based approaches in the grading of evidence and categorization of apheresis indications to make recommendations on the use of apheresis in a wide variety of diseases and conditions. This edition has largely maintained the general layout and concept of a fact sheet introduced in the Fourth Edition (2007). Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease or medical condition. The Ninth Edition of the JCA Special Issue comprises 91 fact sheets and 166 graded and categorized indications. This includes seven new fact sheets, nine new indications on existing fact sheets, and eight changes in the category for existing indications. The Ninth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease., (© 2023 Wiley Periodicals LLC.)

Background: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of intracranial hemorrhage (ICH) in thrombocytopenic term infants. We investigated clinical and laboratory predictors of severe FNAIT in a tertiary care referral center., Study Design and Methods: Retrospective cohort study over a 30-year period. We defined FNAIT as recurrence of neonatal thrombocytopenia in a subsequent pregnancy; and severe outcomes as any of: (1) a birth platelet count below 20 × 10 9 /L; (2) ICH or (3) fetal death. We used a generalized estimating equations analysis and classification tree analysis to identify risk factors for severe FNAIT in a subsequent pregnancy., Results: During index pregnancies (n = 135 in 131 mothers), 71 infants (52.6%) had severe outcomes including a platelet count <20 × 10 9 /L (n = 45), fetal or neonatal ICH (n = 32), or fetal death (n = 4). During subsequent pregnancies (n = 72), 15 infants (20.8%) had severe outcomes including birth platelets <20 × 10 9 /L (n = 10), ICH (n = 2), or death (n = 3). Forty-two women (58.3%) received antenatal intravenous immune globulin (IVIG) during subsequent pregnancies. Eight mothers (n = 9 infants) had severe FNAIT outcomes despite receiving antenatal IVIG. Maternal antibodies to human platelet antigens (HPA) was the only independent predictor of severe FNAIT in a subsequent pregnancy (OR = 25.3, p = .004). Nevertheless, one of 43 infants from antibody-negative mothers had a severe outcome., Conclusions: The presence of anti-HPA is highly indicative of the diagnosis of severe FNAIT; however, we observed one infant who had severe FNAIT recurrence, defined using strict clinical criteria, without a maternal antibody. Improved diagnostic and therapeutic strategies are needed to prevent severe FNAIT in high-risk mothers., (© 2022 AABB.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic hematologic disorder associated with inappropriate terminal complement activity on blood cells that can result in intravascular hemolysis (IVH), thromboembolic events (TEs), and organ damage. Untreated individuals with PNH have an increased risk of morbidity and mortality. Patients with PNH experiencing IVH often present with an elevated lactate dehydrogenase (LDH; ⩾ 1.5 × the upper limit of normal) level which is associated with a significantly higher risk of TEs, one of the leading causes of death in PNH. LDH is therefore used as a biomarker for IVH in PNH. The main objective of PNH treatment should therefore be prevention of morbidity and mortality due to terminal complement activation, with the aim of improving patient outcomes. Approval of the first terminal complement inhibitor, eculizumab, greatly changed the treatment landscape of PNH by giving patients an effective therapy and demonstrated the critical role of terminal complement and the possibility of modulating it therapeutically. The current mainstays of treatment for PNH are the terminal complement component 5 (C5) inhibitors, eculizumab and ravulizumab, which have shown efficacy in controlling terminal complement-mediated IVH, reducing TEs and organ damage, and improving health-related quality of life in patients with PNH since their approval by the United States Food and Drug Administration in 2007 and 2018, respectively. Moreover, the use of eculizumab has been shown to reduce mortality due to PNH. More recently, interest has arisen in developing additional complement inhibitors with different modes of administration and therapeutics targeting other components of the complement cascade. This review focuses on the pathophysiology of clinical complications in PNH and explores why sustained inhibition of terminal complement activity through the use of complement inhibitors is essential for the management of patients with this chronic and debilitating disease., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AK received consulting fees from Alexion, Celgene/BMS, Novartis, Ra Pharma, BioCryst, Amgen, Apellis, and Roche, and honoraria from Alexion, Celgene/BMS, Novartis, Ra Pharma, BioCryst, Amgen, Apellis, Roche, Takeda, and Jansen. AK received support for attending meetings and/or travel from Alexion, Ra Pharma, and Takeda, and has participated on a data safety monitoring board or advisory board for Alexion, Celgene/BMS, Novartis, Ra Pharma, BioCryst, Amgen, Apellis, and Roche. CJP has received honoraria and consulting fees from Alexion, Apellis/Sobi, Regeneron, and BioCryst Pharmaceuticals. CJP has participated on an outcomes adjudication committee for Amgen. HS received travel support, honoraria, and research support (all to University of Ulm) from Alexion, AstraZeneca Rare Disease, and honoraria (to University of Ulm) from Novartis, Roche, Apellis, and Sanofi. JN received honoraria from Alexion and Chugai, and served as an advisor to Apellis Pharmaceuticals, Alexion, Novartis, Chugai, F. Hoffmann-La Roche, and BioCryst Pharmaceuticals. RB received research funding and consultancy fees from Alexion and received honoraria from UpToDate, Indy Hematology Review, Alexion, ISTH Congress and American Society of Hematology., (© The Author(s), 2022.)

Rationale: Thrombotic microangiopathies (TMAs) are systemic disorders that often affect the kidneys and encompass a heterogeneous group of conditions, including atypical hemolytic uremic syndrome (aHUS). The complement pathway is thought to play a crucial role in the pathogenesis of aHUS, and a favorable response can be obtained through complement C5 inhibition. There is emerging evidence to suggest that the same is also true for several other forms of TMA., Objective: The purpose of this series is to report cases of aHUS in which both an innate defect of the alternative complement pathway and a complement-amplifying condition were suspected., Methods: This case series describes 8 patients who were managed in Canadian tertiary centers for aHUS and who presented initially with complement-amplifying conditions., Results: In all cases, aHUS was associated with organ dysfunction and in some, with an innate defect of the alternative complement pathway. The complement-amplifying conditions identified were diverse including immune disorders, pregnancy, and a Shiga toxin infection. Patients improved rapidly when treated with eculizumab or plasma exchange., Conclusions: These observations illustrate the seriousness of secondary aHUS. They also add to existing lines of evidence that the complement pathway is potentially involved in this condition and that it should be considered as a therapeutic target of interest under such circumstances., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr C.J.P. has received advisory board honoraria from Alexion, Apellis, Octapharma, Sanofi, and Biocryst, and is site investigator for clinical trials sponsored by Alexion, Apellis, and Sanofi. Dr K.P. has received honoraria for speaking and consulting from Ablynx/Sanofi, Bioverativ/Sanofi, Shire/Takeda, and Alexion Pharmaceuticals. She participated in industry-sponsored clinical trials for Ablynx/Sanofi and Bioverativ/Sanofi. Dr J.G. has received honoraria from Alexion Canada for provision of continuing medical education activities and advisory board participation. Dr L.-P.G. has received honoraria from Alexion Pharma Canada and is participating in an Alexion-funded clinical trial. Dr P.I. has received support from the Canadian Institutes of Health Research and the Kidney Foundation of Canada. He has also received honoraria from Alexion Canada for advisory board participation. The results presented within this article have not been published previously in whole or in part., (© The Author(s) 2022.)

Introduction: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune blood disorder, which presents with microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis and is caused by severe deficiency of ADAMTS13. iTTP may result in both acute and chronic complications and is rapidly fatal without expedient treatment. Life-time risk of relapse is approximately 40%., Areas Covered: A number of predictors of relapse has been described in the literature. The most well-studied predictor of relapse is persistent ADAMTS13 deficiency; however, it is not a perfect marker. Relapse can be prevented by treatment with immunosuppressive medications, with rituximab being the most studied., Expert Opinion: Patients who recover from iTTP should be regularly assessed, including with ADAMTS13 activity testing. The optimal frequency of assessments has not been established, but every 3 months is recommended. Considering the potential for significant organ damage and mortality associated with iTTP relapse, patients in remission and with persistent ADAMTS13 activity of 10-20% should be prophylactically treated with immunosuppression. Additional markers to precisely identify patients at higher risk of relapse are needed.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder of systemic microthrombosis and organ ischemia. The etiology of chronic cerebrovascular outcomes in iTTP survivors is largely unknown. In this pilot study, we measured blood-brain barrier (BBB) permeability in patients with iTTP at the start of remission and 6 months later. This prospective pilot study included 7 adult patients with incident iTTP. Eligibility criteria included ADAMTS13 activity < 10% and detectable inhibitor at diagnosis. Patients were recruited from London Health Sciences Centre in Canada (2017-2019) within 3 days of hospital admission and followed for 6 months after remission (defined as normalization of platelet count and lactate dehydrogenase with no clinical signs or symptoms of microvascular injury for more than 30 days after the last plasma exchange). All patients had cerebral computed tomography perfusion scans with BBB permeability surface product measurements. Patients (5 women, 2 men) had a mean age of 48 years (range, 21-77 years). At diagnosis, patients had a mean platelet count of 22 (standard deviation [SD], 25) × 109/L. At the start of remission, mean BBB permeability surface product was 0.91 (0.30) mL/min/100 g. Six months later, the mean permeability surface product was 0.56 (0.22) mL/min/100 g, with a mean difference of -0.312 mL/min/100 g (95% confidence interval: -0.4729 to -0.1510; P = .0032). In this pilot study of patients with iTTP, pathologically increased BBB permeability was evident, and although there was some improvement, this persisted 6 months after remission. Future work will explore the chronicity of these findings and their clinical implications., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs), but haematological irAEs are rare. We report a case of presumed complement-mediated thrombotic microangiopathy (CM-TMA) in a 78-year-old man with metastatic melanoma following treatment with ICIs. Following two doses of combination nivolumab and ipilimumab therapy, he developed microangiopathic haemolytic anaemia, thrombocytopenia and increased creatinine. ADAMTS13 activity was preserved, CH50 was high, haptoglobin was depleted and a blood film demonstrated fragments. Given this constellation of findings, a diagnosis of CM-TMA was made. Immunotherapy was held and the patient received steroids and supportive care. Six months after his last dose of immunotherapy, he has no evidence of melanoma or CM-TMA. CM-TMA should be suspected in patients on ICI with unexplained anaemia and thrombocytopenia with preserved ADAMTS13 activity. Suspicion of complement dysregulation may have therapeutic implications, such as the necessity of complement pathway inhibition., Competing Interests: Competing interests: CP has received speaking honoraria and educational grant from Alexion and Octapharma and has also worked on the advisory board of Alexion. SDS has worked on advisory boards for Novartis and Janssen., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli -induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment., Sources of Information: Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors., Methods: This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies., Key Findings: Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli -induced hemolytic uremic syndrome, also known as "typical" HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA., Limitations: The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The membership of the group of authors was identified following a series of meetings and conferences related to thrombotic microangiopathy (TMA). The final membership was struck following an industry-sponsored TMA meeting; however, the sponsor was not involved in the genesis or content of the project or the selection of physician members. There was no support either financial or otherwise provided to this group from any industry or other sponsors. P.A.M and J.G. received honoraria from Alexion and Sanofi Genzyme. M.B., A.-L.L., K.G., and D.B. from Alexion. C.B. from Alexion, Sanofi, Argenx, and Appelis. L.-P.G. from Alexion and Genzyme and clinical trials from Chemocentryx and Alexion. C.J.P. from Alexion, Octapharma, Apellis, Biocryst, and Sanofi; received research support from Alexion, Octapharma, and Sanofi; and clinical trial participation—Site PI—Alexion, Ra Pharma, Apellis, and Sanofi. K.P. from Alexion, Sanofi, and Takeda and clinical trials from Sanofi and Takeda. C.L. received honoraria and unrestricted grants from Alexion, Apellis, Aurin, and Novartis., (© The Author(s) 2021.)

High-dose chemotherapy and autologous stem cell transplant (ASCT) remains a cornerstone of treatment in relapsed/refractory (R/R) aggressive-histology lymphomas. This retrospective study examined efficacy and safety of peripheral blood stem cell (PBSC) mobilization using cyclophosphamide/etoposide and GCSF (CE + GCSF, n  = 129) versus gemcitabine, dexamethasone and cisplatin and GCSF (GDP + GCSF, n  = 210). All patients received first salvage with GDP. Patients mobilized with CE + GCSF required fewer days of leukapheresis (median 1 vs 2 day; p  = .001) and achieved higher total CD34+ yield than GDP + GCSF patients (8.5 vs 7.1 × 10 6 CD34+ cells/kg, p  = .001). Rates of febrile neutropenia and CD34+ collection ≥5 × 10 6 CD34+ cells/kg were similar (OR 1.19, 95% CI: 0.54-2.6, p  = .66). In multivariable analysis, days to engraftment and admission duration were not statistically different between the two mobilization strategies. While CE + GCSF appeared more efficacious for mobilization after GDP salvage, this did not translate to significant differences in clinical outcomes.

Background: Apheresis treatments require adequate venous access using peripheral intravenous (PIV) catheterization or central venous catheters (CVC). Ultrasound-guided PIV (USGPIV) can be used to decrease the need of CVC insertions for apheresis procedures., Method: A hybrid model of USGPIV and standard of care (SOC) for PIV access was developed. Nurses performed USGPIV on all patients considered for PIV access if felt SOC PIV access was not possible. Information was collected regarding nurses' confidence with access, number of attempts required, site of access, complications, and need for CVC., Results: In all, 226 PIV access attempts were made during a 2-month period. All apheresis procedure types were represented. A total 65% were accessed by SOC and 35% by USGPIV. USGPIV was successful on first try on 90% draw/inlet access and 87% successful on first try on return access. Access above the antecubital fossa was required in 31% of USGPIV for draw/inlet veins, and 22% of return veins. Nurses' confidence with accessing PIV was increased by USGPIV, based on 7-point Likert scale assessments. During the recording period, 2/226 (0.9%) apheresis procedures required a CVC. In a separate cohort of only hematopoietic progenitor cell collections, CVC insertion was required in 44/238 (18.5%) patients, in 7 months prior to adoption of USGPIV and 5/152 (3.3%) patients in 7 months following adoption of USGPIV., Conclusion: A hybrid model of using SOC and USGPIV for PIV access for apheresis procedures resulted in decreased need for CVC access, high levels of successful initial access attempts, and increased nursing confidence in PIV access., (© 2020 Wiley Periodicals LLC.)

Indications for therapeutic and donor apheresis continue to increase and expand into new domains of therapy. The level and amount of apheresis education in residency programs remains heterogeneous, which may translate into varying degrees of clinical confidence in providing care. The purpose of this study was to assess Canadian clinicians' perceptions of their apheresis training in order to help demonstrate a need for a concrete apheresis education in residency curricula. A 22-question survey was distributed to Canadian graduates who recently completed training (2013-2017) in the following specialties: hematology, nephrology, transfusion medicine, and hematologic pathology. Questions regarding clinician perception of their training were asked using a Likert scale. Fifty-seven survey responses (32% response rate) were obtained from recent graduates from hematology (29/57, 51%), nephrology (21/57, 37%), hematologic pathology (4/57, 7%) and transfusion medicine (3/57, 5%). Although most respondents (68%) received some form of apheresis exposure during residency, only 23% reported a formal apheresis rotation. Only 40% felt that the amount of time devoted to apheresis education was sufficient, and only four respondents (7%) felt confident providing independent apheresis care at the end of training. Overall, these findings suggest that a common, dedicated apheresis curriculum in these training programs could possibly increase knowledge and competence of trainees, and provide a more solid foundation in apheresis for future practice., Competing Interests: Declaration of Competing Interest None., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Dysregulation of the complement system underlies the pathophysiology of many diseases. Renewed interest in complement occurred with the recognition that its therapeutic inhibition was possible. Terminal complement blockade with the anti-C5 monoclonal antibody eculizumab significantly changed management and clinical outcomes of patients with paroxysmal nocturnal hemoglobinuria, and served as a proof of concept for other complement-mediated diseases. Eculizumab is also approved for atypical hemolytic uremic syndrome and myasthenia gravis. Multiple new disease indications have been identified, and novel complement inhibitors are in various stages of development, with several currently in human trials. Beyond C5, these new drugs block proximal complement, pathway-specific targets, convertase activity, and anaphylatoxin function. Though monoclonal antibodies are still common, peptides, RNAi, and small molecule inhibitors provide the opportunity for different administration routes and schedules. Several challenges still exist or will soon present themselves, including mitigation of infection risk, effective monitoring strategies, and how to choose between therapeutics when more than one is available. In this review, we will describe the lessons learned from the "eculizumab era," present many of the novel therapeutics currently or soon to be in trials, and highlight some of the challenges that will require attention as the field progresses., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by intravascular hemolysis, thrombophilia, and marrow failure. Its phenotype is due to absent or reduced expression of GPI-linked complement regulators and subsequent sensitivity of hematopoietic cells to complement-mediated damage and lysis. Introduction of the terminal complement inhibitor eculizumab drastically improved outcomes in PNH patients; however, despite this improvement, there remain several challenges faced by PNH patients and physicians who care for them. One of the most important is increasing awareness of the heterogeneity with which patients can present, which can lead to significant delays in recognition. Data from the Canadian PNH Registry are presented to demonstrate the variety of presenting symptoms. In Canada, geography precludes consolidation of care to just a few centers, so management is distributed across academic hospitals, linked together as the Canadian PNH Network. The Network over the last several years has developed educational programs and clinical checklists and has worked to standardize access to diagnostics across the country. Herein, we address some of the common diagnostic and therapeutic challenges faced by PNH physicians and give our recommendations. Gaps in knowledge are also addressed, and where appropriate, consensus opinion is provided., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disease with 90% mortality if untreated. Since the Canadian Apheresis Group (CAG) trial showed greater survival with therapeutic plasma exchange (TPE) versus plasma infusion, there has been widespread adoption of TPE. Beyond TPE, there is significant practice variation. To characterize this, we developed a survey sent to physicians who might be directly involved in TTP management., Methods: The survey was sent to CAG members as well as hematologists and nephrologists nationwide and addressed areas of controversy or recognized practice heterogeneity. Descriptive statistics were used to summarize responses, and the χ 2 test was used to compare respondents who were and were not CAG physicians. We also compared responses by estimated frequency of TTP cases per year., Results: The CAG response rate was 31% (13 of 42). The survey was sent to 665 non-CAG physicians, of whom 41 responded (6.1%). Though not statistically different, CAG and non-CAG respondents varied regarding use of corticosteroids, aspirin, and venous thromboembolism (VTE) prophylaxis. Significant differences were found between CAG and non-CAG groups regarding cryosupernatant as fluid choice (69.2% vs. 22.5%, P = .004) and the use of TPE tapering (84.6% vs. 51.3%, P = .034), respectively., Conclusion: TTP treatment is variable across centres in Canada. Areas of significant variation include the choice of replacement fluid for TPE and whether or not and how to taper TPE. Our survey highlights the practice heterogeneity that exists and identifies areas where more evidence is needed and perhaps where trials should be performed., (© 2016 Wiley Periodicals, Inc.)

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening condition caused by autoantibody-mediated inhibition of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type-1 motif, 13). Therapeutic plasma exchange (TPE) improves survival, but disease may be refractory despite therapy. Management and treatment response of refractory TTP is variable, with rituximab and other immunosuppression often being used. Case reports have suggested a benefit of the proteasome inhibitor, bortezomib, possibly due to elimination of the autoreactive plasma cells producing anti-ADAMTS13 antibodies. We evaluated the effect of bortezomib in a series of primary refractory TTP patients unresponsive to intensive therapy. Bortezomib-treated patients were identified from consecutive cases managed at two UK referral centres. Demographic and clinical data were extracted from hospital records. ADAMTS13 activity was measured using a fluorescence resonance energy transfer VWF73 assay, and anti-ADAMTS13 IgG using enzyme-linked immunosorbent asssay. We identified six bortezomib-treated patients out of 51 consecutive cases of acute, acquired TTP. All patients received TPE, methylprednisolone and rituximab. Five of the six achieved complete remission with bortezomib, and one died of cardiac arrest due to underlying disease. No treatment-related adverse events were observed. Mean follow-up time after hospital discharge was 17 months (range: 3-33). Bortezomib appears effective in the treatment of a subgroup of cases with severe, refractory TTP. Prospective trials are required to further investigate this effect., (© 2016 John Wiley & Sons Ltd.)

Background: Eculizumab, a humanized monoclonal antibody against complement protein C5 that inhibits terminal complement activation, has been shown to prevent complications of paroxysmal nocturnal hemoglobinuria (PNH) and improve quality of life and overall survival, but data on the use of eculizumab in women during pregnancy are scarce., Methods: We designed a questionnaire to solicit data on pregnancies in women with PNH and sent it to the members of the International PNH Interest Group and to the physicians participating in the International PNH Registry. We assessed the safety and efficacy of eculizumab in pregnant patients with PNH by examining the birth and developmental records of the children born and adverse events in the mothers., Results: Of the 94 questionnaires that were sent out, 75 were returned, representing a response rate of 80%. Data on 75 pregnancies in 61 women with PNH were evaluated. There were no maternal deaths and three fetal deaths (4%). Six miscarriages (8%) occurred during the first trimester. Requirements for transfusion of red cells increased during pregnancy, from a mean of 0.14 units per month in the 6 months before pregnancy to 0.92 units per month during pregnancy. Platelet transfusions were given in 16 pregnancies. In 54% of pregnancies that progressed past the first trimester, the dose or the frequency of use of eculizumab had to be increased. Low-molecular-weight heparin was used in 88% of the pregnancies. Ten hemorrhagic events and 2 thrombotic events were documented; both thrombotic events occurred during the postpartum period. A total of 22 births (29%) were premature. Twenty cord-blood samples were examined for the presence of eculizumab; the drug was detected in 7 of the samples. A total of 25 babies were breast-fed, and in 10 of these cases, breast milk was examined for the presence of eculizumab; the drug was not detected in any of the 10 breast-milk samples., Conclusions: Eculizumab provided benefit for women with PNH during pregnancy, as evidenced by a high rate of fetal survival and a low rate of maternal complications. (ClinicalTrials.gov number, NCT01374360.).

Prothrombin complex concentrates (PCC) are recommended for urgent warfarin reversal. However, disagreement exists regarding the proper dosing strategy (i.e. fixed vs. weight-based). We measured the in vitro effect of PCC dosing on international normalised ratio (INR) and factor activity. Plasma from warfarin-anticoagulated patients with stable INRs was collected. PCC doses of 1,000, 2,000 and 3,000 IU were added to the samples, and INR and factor activity were analysed before and after PCC. Twenty-three of thirty subjects enrolled had complete data for analysis. INRs were below 1.5 in all samples post-1,000 IU, and decreased further with subsequent doses (p<0.001). Factors II, VII, and X increased with consecutive doses (p<0.01). Linear correlation was seen between INR and factors II, VII and X. Factor IX did not increase consistently nor show correlation with INR reversal. Weight-based dosing was then estimated; INRs were all <1.2 (0.9-1.2) and activity >0.50 IU for factors II, VII and X (0.96-1.52, 0.51-1.45 and 0.81-1.38, respectively). Factor IX did not uniformly correct above 0.50 IU (0.31-1.31). We confirm in vitro that 1,000 IU of Octaplex(®) is able to correct INR to <1.5 but factors were not uniformly >0.50 IU until 2,000 IU, and not >1.00 IU until 3,000 IU. This suggests that INR correction alone may not accurately reflect factor activity, and lends support for weight-based dosing.