A Significant Contribution of the Classical Pathway of Complement in SARS-CoV-2 Neutralization of Convalescent and Vaccinee Sera.

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.

Safety and Efficacy of Pegcetacoplan in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria over 48 Weeks: 307 Open-Label Extension Study.

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.

Impact of intraoperative therapeutic plasma exchange on bleeding in lung transplantation.

BACKGROUND: Our program uses a desensitization protocol that includes intraoperative therapeutic plasma exchange (iTPE) for crossmatch-positive lung transplants, which improves access to lung transplant for sensitized candidates while mitigating immunologic risk. Although we have reported excellent outcomes for sensitized patients with the use of this protocol, concern for perioperative bleeding appears to have hindered broader adoption of it at other programs. We conducted a retrospective cohort study to quantify the impact of iTPE on perioperative bleeding in lung transplantation. METHODS: All first-time lung transplant recipients from 2014 to 2019 who received iTPE were compared to those who did not. Multivariable logistic regression was used to determine the association between iTPE and large-volume perioperative transfusion requirements (≥5 packed red blood cell units within 24 hours of transplant start), adjusted for disease type, transplant type, and extracorporeal membrane oxygenation or cardiopulmonary bypass use. The incidence of hemothorax (requiring reoperation within 7 days of lung transplant) and 30-day posttransplant mortality were compared between the 2 groups using chi-square test. RESULTS: One hundred forty-two patients (16%) received iTPE, and 755 patients (84%) did not. The mean number of perioperative pRBC transfusions was 4.2 among patients who received iTPE and 2.9 among patients who did not. iTPE was associated with increased odds of requiring large-volume perioperative transfusion (odds ratio 1.9; 95% confidence interval: 1.2-2.9, p-value = 0.007) but was not associated with an increased incidence of hemothorax (5% in both groups, p = 0.99) or 30-day posttransplant mortality (3.5% among patients who received iTPE vs 2.1% among patients who did not, p = 0.31). CONCLUSIONS: This study demonstrates that the use of iTPE in lung transplantation may increase perioperative bleeding but not to a degree that impacts important posttransplant outcomes.

Paroxysmal Nocturnal Hemoglobinuria: Current Management, Unmet Needs, and Recommendations.

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.

Propensity Score Matching Analysis Comparing the Efficacy and Steroid Tapering Benefit of Extracorporeal Photopheresis to Best Available Therapy in Third-Line or Beyond Treatment for Chronic GvHD.

Graft-versus host disease (GVHD) is one of the major limitations to allogeneic hematopoietic stem cell transplantation (HCT). Although corticosteroids with calcineurin inhibitors are established first line-therapy for chronic graft-versus-host disease (cGVHD), approximately one-half of cGVHD patients are refractory to corticosteroid therapy. The goal of the present study was to compare treatment outcomes of patients treated with extracorporeal photopheresis (ECP) and best available therapy (BAT) as third-line or beyond treatment for cGVHD. Using propensity score matching (PSM), treatment outcomes were compared between ECP-treated patients (n = 74) and a historical cohort of cGVHD patients treated with BAT (n = 132). By adjusting for unbalanced risk factors between the groups, including GVHD severity at the start of therapy, acute GVHD history, and baseline corticosteroid dose, 62 patients were balanced and selected for PSM. In the PSM cohort, the ECP group showed a 12-month failure-free survival (FFS) rate of 70.1% versus 32.5% in the BAT group (P < .0001; hazard rate [HR], .214), and 93.1% 12 months' overall survival (OS) rate of 93.1% versus 68.1% in the BAT group (P = .0249; HR, .3811); multivariate analysis confirmed ECP's superior FFS and OS compared with BAT. Generalized linear model analysis showed faster tapering of corticosteroids and higher rates of prednisone discontinuation in the ECP versus BAT PSM groups in the first 6 months. The ECP group also had a higher percentage of prednisone discontinuation, by 6% at month 0, by 14.9% at month 3, and by 22.5% at month 6. The current study demonstrates superior FFS, OS, and steroid tapering efficacy for ECP compared with BAT as third-line therapy or beyond in cGVHD patients.

Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case-control study in the International PNH Registry.

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.

Long-term effectiveness of eculizumab: Data from the International PNH Registry.

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 m2 (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.

Single centre retrospective analysis of extracorporeal photopheresis (ECP) therapy in patients heavily pre-treated for chronic graft-versus-host disease (cGvHD) with steroid failure.

BACKGROUND: Extracorporeal photopheresis (ECP) is recommended as a second- or later-line therapy for chronic GvHD (cGvHD). Benefits include reasonable response with avoidance of intense systemic immunosuppression, which can translate into lowering the risk of systemic toxicity and opportunistic infection. METHODS: We evaluated 75 patients treated with ECP for cGvHD from 2007 to 2021 at Princess Margaret Cancer Centre, and analyzed overall response rate (ORR) and clinical benefit (CB) at 3, 6 and 12 months plus other long-term treatment outcomes. RESULTS: With a median follow-up of 72 months, a gradual increase in ORR was noted over time: 21% (16 out of 75 patients), 57% (36/63) and 70% (32/46) at month 3, 6 and 12, respectively. Gradual increase in CB was also observed over time with CB rate of 23% (17/75), 62% (39/63), and 76% (35/46) at months 3, 6 and 12, respectively. A total of 27 failures (36%) were noted, due to: 1) ECP resistance requiring switch to other therapy (n = 14, 19%), 2) non-relapse mortality (n = 10, 13%), 3) relapse of primary disease (n = 1, 1%) or 4) ECP procedure-related complication (n = 1, 1%, line infection), with 20 deaths (27%) observed. Failure-free survival (FFS) and overall survival (OS) rates were 68.3% and 85.9% at 12 months, respectively. After starting ECP, the proportions of patients who completely discontinued steroids were 17%, 32%, and 64% at months 3, 6 and 12, respectively. CONCLUSION: ECP is an effective treatment option for heavily pre-treated cGvHD patients.

Therapeutic plasma exchange in alloimmune platelet refractoriness.

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.

Characterizing the process of urgent referrals and transfers to a large tertiary care apheresis centre in Ontario: A retrospective database review.

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.

Outcomes after flow cytometry crossmatch-positive lung transplants managed with perioperative desensitization.

Our program previously reported successful outcomes following virtual crossmatch (VXM)-positive lung transplants managed with perioperative desensitization, but our ability to stratify their immunologic risk was limited without flow cytometry crossmatch (FCXM) data before 2014. The aim of this study was to determine allograft and chronic lung allograft dysfunction (CLAD)-free survival following VXM-positive/FCXM-positive lung transplants, which are performed at a minority of programs due to the high immunologic risk and lack of data on outcomes. All first-time lung transplant recipients between January 2014 and December 2019 were divided into 3 cohorts: VXM-negative (n = 764), VXM-positive/FCXM-negative (n = 64), and VXM-positive/FCXM-positive (n = 74). Allograft and CLAD-free survival were compared using Kaplan-Meier and multivariable Cox proportional hazards models. Five-year allograft survival was 53% in the VXM-negative cohort, 64% in the VXM-positive/FCXM-negative cohort, and 57% in the VXM-positive/FCXM-positive cohort (P = .7171). Five-year CLAD-free survival was 53% in the VXM-negative cohort, 60% in the VXM-positive/FCXM-negative cohort, and 63% in the VXM-positive/FCXM-positive cohort (P = .8509). This study confirms that allograft and CLAD-free survival of patients who undergo VXM-positive/FCXM-positive lung transplants with the use of our protocol does not differ from those of other lung transplant recipients. Our protocol for VXM-positive lung transplants improves access to transplant for sensitized candidates and mitigates even high immunologic risk.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Ninth Special Issue.

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.

Fatigue and health-related quality of life in paroxysmal nocturnal haemoglobinuria: A post hoc analysis of the pegcetacoplan PEGASUS trial data.

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.

A systematic review comparing allogeneic hematopoietic stem cell transplant to gene therapy in sickle cell disease.

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.

Renal Thrombotic Microangiopathy: A Review.

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.

Clinical and laboratory predictors of fetal and neonatal alloimmune thrombocytopenia.

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 × 109 /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 × 109 /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 × 109 /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.

The importance of terminal complement inhibition in paroxysmal nocturnal hemoglobinuria.

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.