Hemolytic Episodes Research Articles

The Onerous task of managing paroxysmal nocturnal hemoglobinuria in a Low resource setting: a case report. A hematologist’s experience

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a form of red cell membrane defect characterized by increased sensitivity to complement-mediated cell lysis, resulting in intravascular hemolytic anemia, passage of hemoglobin-containing urine, a high risk of venous thrombosis and progression to pancytopenia.The diagnosis of PNH is based on the flow cytometric (FCM) detection of peripheral blood cell clones. Such clones lack expression of the surface molecules linked to the glycosylphosphatidylinositol (GPI) anchors. The underlying defect is a somatic mutation of the short arm of the phosphatidylinositol glycan class A gene (PIG-A). Case report: We report a case of a 34-year-old male, with recurrent hemolytic anemia and dural venous sinus thrombosis found to have PNH by flow cytometry. He is currently on anticoagulation, iron and folate supplements, intermittent steroids for hemolytic episodes as we await complement inhibitors. Conclusion: As part of the diagnostic workup for patients presenting with recurrent hemolytic anemia and thrombosis in unusual sites, clinicians should include PNH on the list of differential diagnoses. Effort should be taken to characterize the red urine reported on the urine dipstick as blood/hemoglobin by microscopy to differentiate hematuria and hemoglobinuria and order for flow cytometry as this has implications on patient management. Keywords: Thrombosis; hemolysis; complement; paroxysmal nocturia; hemoglobinuria.

Cost-Utility Analysis Comparing Pegcetacoplan to Anti-C5 Monoclonal Antibodies in the Treatment of Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria is a rare, acquired disease characterized by hemolytic episodes and associated with significant clinical burden. The introduction of C5 inhibitory monoclonal antibodies (C5i) represented a major breakthrough in PNH treatment, effectively reducing intravascular hemolysis (IVH) but showing limited impact on extravascular hemolysis (EVH). In 2021, the C3 inhibitor pegcetacoplan was approved by EMA and recently reimbursed in Italy, which also has the advantages in the reduction of both IVH and EVH, increasing hemoglobin values and simultaneously improving the quality of life and fatigue of patients. A cost-utility analysis was developed to compare pegcetacoplan to C5i (eculizumab and ravulizumab) in the PNH population who remain anemic after treatment with C5i for at least 3 months. The analysis employed a Markov model with a 5-year time horizon whereby patients can transition among 3 PNH health states, adopting the perspective of the Italian NHS. Efficacy data were sourced from the PEGASUS study, with drug prices reflecting ex-factory costs. Additionally, costs associated with resource utilization, adverse events, and complications were estimated based on outpatient and hospital care rates, excluding indirect expenses. Utility and disutility values related to transfusions were also considered, with pegcetacoplan allowing for dose escalation. The cumulative cost of treatment per individual patient at 5 years was estimated to be €1,483,454 for pegcetacoplan, €1,585,763 for eculizumab, and €1,574,826 for ravulizumab. Pegcetacoplan demonstrated a superior increase in quality-adjusted life years (QALYs) compared to both eculizumab (0.51 increase) and ravulizumab (0.27 increase). Furthermore, pegcetacoplan showed a reduction in complication management costs (€22,891 less compared to eculizumab and €22,611 less compared to ravulizumab) and lower transfusion-related expenses (€14,147 less than both C5i treatments). Pegcetacoplan emerged as the dominant strategy in this analysis, being more effective, less expensive and improves quality of life in the analyzed population affected by PNH.

Exploring Panchakarma therapy in the management of Wilson disease: An observation

Wilson disease is not just a disease of children and young adults but may present at any age. The key features of Wilson disease are liver disease and cirrhosis, neuropsychiatric disturbances, Kayser–Fleischer rings, and acute episodes of hemolysis, often in association with acute liver failure. The diagnosis of Wilson disease is not always straightforward as clinical presentation of the disease can vary widely. In Ayurveda, it can be correlated with Vatavyadhi (~disorders due to vitiated Vata). Furthermore, increased copper levels in the body are also to be considered while planning the management. A 30-year-old patient visited the outpatient department with slurred speech, repetition and slowness of physical activity, muscle stiffness all over the body, loss of physical coordination, difficulty and change in handwriting, mood swings, dropping of saliva, loss of appetite, belching, and nausea. The patient was examined, assessed, and treated with Udvartana karma (~therapeutic powder massage), Abhyanga (~therapeutic massage), Swedana (~sudation therapy), and Basti karma (~therapeutic enema) along with internal administration of suitable Ayurveda medicines. All the symptoms were subsided by the end of the management along with a reduction in the urine copper levels from 915 µg/24 h to 37.5 µg/24 h. This single observation inferred that a patient with Wilson disease can have an improved quality of life when rationally managed with internal Ayurveda medication along with suitable Panchakarma (~five internal bio-cleansing therapies) procedures.

Implementación de la PCR digital para el diagnóstico prenatal no invasivo de la enfermedad de células falciformes. Estudio piloto

Sickle Cell Disease (SCD) is one of the most prevalent autosomal recessive disease, affecting over 600,000 newborns globally each year. In Spain, the Spanish Registry of Hemoglobinopathies (REHem) has registered 1142 cases. Despite improvements in treatments, prophylaxis, and vaccines, it remains a chronic condition requiring lifelong care. Allogeneic transplantation is the only cure, contingent upon the availability of an HLA-compatible donor. SCD is considered a rare disease in some population, resulting from a mutation of a single nucleotide in codon 6 GAG>GTG (HBB: c.20A>T) of the β-globin gene, producing hemoglobin S (HbS), altering the shape of red blood cells and obstructing circulation, leading to severe complications in multiple organs. Heterozygous individuals (βS/βA) have the ‘sickle cell trait,’ typically asymptomatic. Homozygotes experience symptomatic disease, with chronic and acute infarctions in organs and tissues, episodes of intense pain, cerebral infarctions, splenomegaly, massive hemolytic episodes, and acute chest syndrome, causing a risk of premature death increasing the threat of premature mortality. Prenatal diagnosis provides expecting couples with information about the fetus’s genetic health, enabling informed decision-making. Although conventional techniques are invasive and carry risks, Non-Invasive Prenatal Diagnosis (NIPD) has been developed using cell free fetal DNA (cffDNA) in maternal blood to determine the fetus’s genotype. However, the co-presence of maternal DNA and cffDNA, along with the low concentration of the latter, has been a challenge in non-invasive studies. We present the results of a pilot study where the use of digital PCR (dPCR) has been established for NIPD of SCD, a highly sensitive technique allowing the detection of mutations in low-frequency samples, presenting itself as a safe alternative for SCD diagnosis.

High Rate of Passenger Lymphocyte Syndrome after ABO Minor Incompatible Lung Transplantation.

Rationale: Passenger lymphocyte syndrome (PLS) may complicate minor ABO mismatched lung transplantation (LuTX) via donor-derived red cell antibody-induced hemolysis.Objectives: To ascertain the incidence and specificity of PLS-relevant antibodies among the study population as well as the dynamics of hemolysis parameters and the transfusion requirement of patients with or without PLS.Methods: In this cohort study, 1,011 patients who received LuTX between January 2010 and June 2019 were studied retrospectively. Prospectively, 87 LuTX (July 2019 to June 2021) were analyzed. Postoperative ABO antibody and hemolytic marker determinations, transfusion requirement, and duration of postoperative hospital care were analyzed. Retrospectively, blood group A recipients of O grafts with PLS were compared with those without.Measurements and Main Results: PLS affected 18.18% (retrospective) and 30.77% (prospective) of A recipients receiving O grafts, 5.13% of B recipients of O grafts, and 20% of AB patients receiving O transplants. Anti-A and anti-A1 were the predominant PLS-inducing antibodies, followed by anti-B and anti-A,B. Significantly lower hemoglobin values (median, 7.4 vs. 8.3 g/dl; P = 0.0063) and an approximately twice as high percentage of patients requiring blood transfusions were seen in PLS. No significant differences in other laboratory markers, duration of hospital stay, or other complications after LuTX were registered.Conclusions: Minor ABO incompatible LuTX recipients are at considerable risk of developing clinically significant PLS. Post-transplant monitoring combining red cell serology and hemolysis marker determination appears advisable so as not to overlook hemolytic episodes that necessitate antigen-negative transfusion therapy.

Comorbidities of Sickle Cell Disease with Obstructive Sleep Apnea

BACKGROUND Sickle cell disease (SCD) is a devastating inherited disease process that greatly impairs quality of life and lifespan. It is a common genetic hemoglobinopathy that is vulnerable to hypoxemia due to the sickling property of red blood cells. Desaturation of the hemoglobin S (HbS) molecule leads to the polymerization of HbS, causing the blockage of microvasculature, oxidative stress, and endothelial damage. The clinical sequelae of SCD include vaso-occlusive crisis, hemolytic episodes, and end-organ damage. Obstructive sleep apnea (OSA) is a common but underdiagnosed condition associated with nocturnal hypoxemia due to intermittent upper airway closure. Repetitive episodes of hypoxemia can cause nocturnal sympathetic activation, selectively activate vascular inflammatory pathways leading to endothelial dysfunction, and can impact cardiac output to predispose patients to ischemia. The impact of this pathophysiology on SCD remains unclear and the literature reviews evaluating the relationship of SCD and OSA are scarce. METHODS We performed a retrospective analysis of the Nationwide Inpatient Sample data in adult patients (age greater than 18 years) hospitalized with SCD as the primary diagnosis in 2020 using ICD-10-CM codes. The NIS is the largest all-payer publicly accessible inpatient healthcare database in the United States. We compared the SCD cohort of 164,990 patients to another consisting of SCD with associated secondary diagnosis of OSA, which consisted of 32,998 patients. The Pearson chi-square test and Student's t test were used to assess categorical and continuous variables, respectively. RESULTS Data revealed that patients diagnosed with SCD and OSA had a statistically significant (p < 0.001) greater incidence of comorbidities compared to SCD alone. These included uncomplicated hypertension (29.8 vs 15.5%), complicated hypertension (24.5 vs 10.6%), uncomplicated diabetes mellitus (9.8 vs 3.4%), complicated diabetes mellitus (17.1 vs 5.1%), obesity (38.9 vs 9.2%), peripheral vascular disease (6.0 vs 3.2%), chronic pulmonary disease (39.7 vs 21.1%), chronic kidney disease (10.0 vs 4.1%), coronary artery disease (15.3 vs 5.1%), and heart failure (13.4 vs 5.4%). Illicit drug use was higher (8.4%) in SCD only compared to SCD with OSA (5.1%). CONCLUSION In this study, co-diagnoses of SCD and OSA revealed a greater likelihood of having other comorbidities, typically 2-3 fold. A striking finding is the increased prevalence of complicated hypertension and diabetes mellitus which are known to give way to vasculopathies, a sequela that is unfavorable in patients with SCD. Considering the clinical implications of these comorbidities and concern for overall underdiagnosis of OSA, it may prove beneficial to lower the threshold for OSA screening in patients with SCD who exhibit hypertension, diabetes, obesity, and other disease processes associated with OSA. Furthermore, should OSA screening in patients with SCD prove favorable, a prospective study evaluating outcomes, such as number of hospitalizations due to sickle cell crisis or acute chest syndrome, of patients diagnosed with OSA and subsequently treated with therapeutic measures such as nocturnal continuous positive airway pressure. Likewise, patients with established co-diagnosis of SCD and OSA should have diligent surveillance and treatment of these aforementioned comorbidities.

Sickle Cell Disease Management Practices across Nigeria: A Cross-Sectional Analysis

Introduction Of 300,000 children born with sickle cell disease (SCD) in the world, approximately 75% of these are born in Sub-Saharan Africa. Owing to the frequent painful vaso-occlusive and hemolytic episodes associated with this disease, irreversible multi-organ damage and premature mortality are common. For instance, in Nigeria, 490 deaths per 1000 births among children under 5 have been attributed to SCD; this is four times higher compared to mortality in children born without SCD. On the other hand, those with SCD who survive beyond childhood are faced with an estimated life expectancy of 21 years. To address these challenges, guidelines for SCD management were developed by the Nigerian Federal Health Ministry, National Heart, Lung, and Blood Institute (NHLBI), and the American Society of Hematology but their dissemination and implementation has been difficult. To better understand current management practices, we present a preliminary, descriptive analysis of hydroxyurea and blood transfusion practices for sickle cell disease management across Nigeria. Methods Using a cross-sectional design, we collected demographic and practice-related information from eligible clinicians that provide SCD care in Nigeria. The “SCD Knowledge, Attitudes, and Practices - Nigeria” survey was disseminated to pediatric and adult consultant physicians, resident doctors, and nurses through their respective professional communication platforms. SCD-related practices questions were based on the NHLBI recommendations for SCD management which informed the Nigerian Federal Ministry's National SCD Guideline. A 5-point Likert scale was used to answer each question on hydroxyurea use and blood transfusion. Descriptive analyses of current practices were used to characterize these results and bivariate analyses were conducted using Chi-square or Fisher's test as appropriate. Data analysis was performed using SAS 9.4 (SAS Institute; Cary, NC). Ethical approval was obtained from Duke University Institutional Review Board and the University of Nigeria, College of Medicine Health Research Ethics Committee. Results Analysis of SCD-related practices from the first 73 participants who have completed the survey, revealed most respondents to be female (62%), between 35-65 years old (77%), and adult hematologists or nurses (37% and 40% respectively). This group of clinicians provide care mainly to adults (47%), but 45% admitted providing care to both adults and children. Nearly half (45%) of this group provides care for 0-5 individuals with SCD weekly and 57 participants (78%) work in tertiary-level hospitals. Only 22 of those working in tertiary hospitals had a comprehensive SCD center in their hospital compared to those without an SCD center (39% vs. 61%, p=0.0148). SCD experts were also found in tertiary-level hospitals (75% vs. 25%, p<0.0001). General hematologist expertise was also common in tertiary care (88% vs. 12%, p=0.2424). Figures 1 and 2 report HU and blood transfusion practices. Although 73% confirmed hydroxyurea (HU) prescribing and 90% endorsed the use of simple blood transfusions, HU and blood transfusion practices varied greatly. Respondents indicated most educated patients about HU (frequently/always = 74%) and started HU for patients with >3 VOCs in past year (frequently/always = 62%), however, only 31% frequently/always begin at age 9 months (Figure 1). Most respondents reported prophylactic blood transfusions to reduce HbS below 30% (frequently/always = 71%) and 73% frequently/always performed transfusions for acute SCD complications, yet, 60% indicated they never/rarely match for RBC antigens. Conclusion The data highlights SCD-related expertise and specialty care are found more in tertiary-level hospitals. HU practices described may be attributed to the more conservative approach suggested by the Nigerian SCD Management Guideline compared to the NHLBI recommendations, however there is an important opportunity to expand HU prescribing. Blood transfusion, which has historically been considered difficult in this differently resourced setting, was common. However, chelation, leukoreduction/white blood cell filtration, and red blood cell antigen testing were not common. These preliminary findings represent an opportunity for a larger study and future studies to investigate strategies to increase uptake of existing SCD management recommendations.

Diagnosis, management and prevention of Pediatric Acute Hemolytic Anemia: Egyptian adapted evidence-based clinical practice guidelines

BackgroundAcute hemolytic anemia (AHA) is a common emergency in pediatric emergency departments, hence the need to adapt pre-existing high-quality practice guidelines for the diagnosis, management, and prevention of AHA to be available for national use.MethodsThe guideline panel used the adapted ADAPTE methodology. The panel prioritized the health questions and recommendations according to their importance for clinicians and patients. The procedure included searching for existing guidelines, quality appraisal, and adaptation of the recommendations to be used in low-resource countries.ResultsThe guideline provided approach to a child with AHA: laboratory diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency, autoimmune hemolytic anemia (AIHA), and hemolytic uremic syndrome (HUS); treatment of AHA including indications for red cell transfusion, medical treatment, plasma exchange, and indications of antibiotic in HUS; how to avoid further episodes of hemolysis; and when to refer to a hematologist. Implementation tools included a checklist for history and examination, lists of differential diagnoses, flow charts for the diagnosis of AHA, and a list of medications and food to be avoided in patients with G6PD deficiency.ConclusionThis adapted guideline will aid decision-making related to the diagnosis, management, and prevention of AHA.

A Study of Glucose-6-Phosphate Dehydrogenase Deficiency among Children attending the Emergency Hospital in Zakho City Kurdistan Region, Iraq

Background: G6PD deficiency, which affects 400 million individuals globally, is an X-linked hereditary enzymopathy that causes acute hemolysis after exposure to specific oxidative agents such as fava beans, more than 37 drugs, and infections viral or bacterial. Neonatal jaundice worsened by kernicterus is one of the condition's significant consequences. It can be prevented by avoiding the oxidative factors that cause a hemolytic episode alongside neonatal screening programs for early detection of afflicted individuals. Objectives: This research aimed at investigating the variability in clinical and biochemical manifestations among children with G6PDD. This is the first study to be carried out in the Zakho area. Methods: A cross-sectional study was used, recruiting 112 children attending Zakho Emergency Hospital from January 2022 to April 2023. Laboratory aids involved in obtaining CBC, liver enzyme activities, and blood grouping were all investigated. The IBM SPSS 26 program was used to analyze the obtained data. Results: There was no statistically significant difference between male and female patients in terms of age, time of admission, hemoglobin level, WBC count, and liver enzymes. The majority of cases who visited Zakho Emergency Hospital within 72 hours of exposure to the triggering agent were males (67.9%), with the most common clinical features being jaundice, dark urine, and abdominal pain. Conclusion: In this study, the three main symptoms in G6PD deficient patients with acute hemolysis were pallor, jaundice, and black urine. These signs appeared several hours or even days after consuming fava beans. The primary clinical symptoms and the patient's gender, family history, or prior newborn jaundice were not related, according to our research.

Propensity score matched analysis and risk stratification of donors with G6PD deficiency in living donor liver transplantation.

Glucose 6 phosphate dehydrogenase (G6PD) deficiency (G6PDd) can trigger hemolysis following surgical stress. Differentiating G6PDd-related post-operative hemolytic episodes (PHE) and post-hepatectomy liver failure may be challenging especially in living donors where donor safety is paramount. We analysed outcomes of our cohort of G6PDd liver donors. G6PDd individuals with no evidence of hemolysis were considered as living donors if there was no alternative family donor. Outcomes of G6PDd donors undergoing left lateral/left lobe donation (Group LL) and right lobe donation (Group RL) were compared with non-G6PDd donors matched in a 1:3 ratio using propensity score matching. 59 G6PDd donors (5.8% of 1011) underwent living donor hepatectomy (LiDH) during the study period. LL-G6PDd donors (22.37%) had higher post-operative peak bilirubin level compared to matched controls, but no difference in morbidity or need for post-operative blood transfusion.RL-G6PDd donors (37.63%) had higher peak bilirubin level, morbidity (16.2% vs. 3.6%, p = 0.017) and more post-operative blood transfusion (21.6% vs. 6.4%, p = 0.023) as compared to matched non-G6PDd cohort. Four RL-G6PDd donors (10.8%) developed PHE. Low G6PD activity (15% vs. 40%, p = 0.034) and lower future liver remnant (FLR) (34.3% vs. 37.8%, p = 0.05) were identified as risk factors for PHE. We report the largest to-date series of G6PDd individuals undergoing LiDH and confirm the safety of LL donation in G6PDd. Our analysis identifies specific risk factors for PHE and suggests that right lobe LiDH be avoided in individuals with less than 25% G6PD activity when the FLR is less than 36%.

Interleukin 6 exacerbates the progression of warm autoimmune hemolytic anemia by influencing the activity and function of B cells

To explore the effect of IL-6 on the activity and secretory function of B cells and analyze its effect on clinical indicators and efficacy in wAIHA patients. This study included 25 hemolytic wAIHA patients, 13 remission patients, and 10 HCs. Plasma levels of various cytokines were detected using CBA. PBMCs were extracted from 12 hemolytic wAIHA patients and divided into three wells, stimulation with IL-6 and IL-6 + tocilizumab, the blank control wells were also set. After 48 h of in vitro cell culture, percentage of CD5+CD80+, CD5–CD80+,CD5+CD86+,CD5–CD86+,CD5+IL-10+,CD5–IL-10+B cells were determined by flow-cytometry. Plasma levels of IL-6 and IL-10 in hemolytic episode group were significantly higher than that in HCs group (p = 0.0243; p = 0.0214). RBC and Hb levels were negatively correlated with IL-6 levels in wAIHA patients, while LDH levels were positively correlated.Therapeutic effects of glucocorticoid and duration of efficacy were also significantly correlated with IL-6 levels in wAIHA patients. After 48 h in vitro cell culture, percentages of CD80+/CD5+CD19+and CD80+/CD5–CD19+ cells in the IL-6 stimulation group were higher than those in blank control group (p = 0.0019; p = 0.0004), while CD86+/CD5+ CD19+ and CD86+/CD5–CD19+ cells were not statistically different before and after IL-6 stimulation. Percentage of IL-10+/CD5+ CD19+ cells in IL-6 stimulation group was lower than that in blank control (p = 0.0017) and IL-6 + toc (p = 0.0117) group. Percentage of IL-10+/CD5– CD19+cells in the IL-6 stimulation group was lower than that in the blank control group (p = 0.0223). Plasma levels of IL-6 were significantly elevated in hemolytic wAIHA patients and correlated with clinical indicators and efficacy. IL-6 promotes the activation of B cells. Although the results were not statistically significant, IL-6R antagonist tocilizumab may hopefully become a targeted therapy for wAIHA patients.

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade.

Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Plain Language Summary of PEGASUS, a Study Comparing Pegcetacoplan with Eculizumab for 16 Weeks in People with Paroxysmal Nocturnal Hemoglobinuria

What is this summary about? This plain language summary is about a phase 3 clinical trial called PEGASUS. The PEGASUS trial studied adults with paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder usually acquired in adulthood without a known cause. Patients with PNH have defects in the complement system, which is part of the immune defense system. This complement defect results in the destruction of red blood cells; this is called hemolysis. Hemolysis then causes anemia. People with anemia do not have enough red blood cells to carry oxygen around the body, which can cause fatigue (extreme tiredness), shortness of breath, or headache. Anemia can be measured by the level or amount of hemoglobin in the blood. Hemolysis can be measured by the amount of hemoglobin, lactate dehydrogenase (LDH), and reticulocytes in the blood. Hemoglobin and LDH are proteins inside red blood cells. In patients with PNH, hemolysis causes hemoglobin levels to go down and LDH levels go up. Reticulocytes are immature red blood cells; their level goes up during hemolysis to replace destroyed red blood cells. Eculizumab is the current standard of care for patients with PNH. Eculizumab is a medicine that blocks or inhibits the complement component 5 (C5). Pegcetacoplan is a new medicine, the first that inhibits the complement component C3. The PEGASUS study compared the new medicine pegcetacoplan with eculizumab in adults with PNH who remained anemic even after being treated with eculizumab for at least 3 months. In PEGASUS, 41 participants received pegcetacoplan and 39 people received eculizumab for 16 weeks. What were the results? The trial results showed that pegcetacoplan decreased signs of hemolysis compared to eculizumab. Participants treated with pegcetacoplan for 16 weeks had increased blood levels of hemoglobin, and decreased levels of LDH and reticulocytes; also, 85% of them no longer needed a blood transfusion compared with 15% of those treated with eculizumab. A patient survey showed that 73% of patients who received pegcetacoplan had decreased fatigue. None of the participants treated with eculizumab had decreased fatigue. Most participants in both treatment groups had side effects. However, no serious infections or thrombosis (blood clots) occurred with either treatment group. Episodes of hemolysis during treatment, called breakthrough hemolysis, happened in 10% of pegcetacoplan- and 23% of eculizumab-treated participants. What do the results mean? Pegcetacoplan reduced the level of hemolysis in adults with PNH better than eculizumab did. Pegcetacoplan was well tolerated by most patients in this study.

The Effect of Respiratory Viral Infections on Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolysis and thrombosis and is associated with significant morbidity and mortality. Although complement inhibitors have significantly changed the outcomes in PNH patients, breakthrough hemolysis (BTH) may still occur as a response to stress factors such as pregnancy, surgery, and infections. Despite the well-described association between bacterial infections and hemolysis in PNH patients, little is known about the effect of respiratory viruses on triggering hemolytic episodes. This is the first study, to our knowledge, addressing this question. We retrospectively analyzed 34 patients with PNH disease between 2016 and 2018, who were on eculizumab treatment and who presented with respiratory symptoms and were subsequently tested for 10 respiratory viruses (influenza A, influenza B, parainfluenza, respiratory syncytial virus, adenovirus, rhinovirus, and human metapneumovirus). NTS+ patients had higher inflammatory markers, with the majority requiring antibiotics. Acute hemolysis, along with a significant drop in hemoglobin, was noted in the NTS+ group, with three of them requiring a top-up transfusion and two requiring an extra dose of eculizumab. Furthermore, the time from the last eculizumab dose was longer in the NTS+ patients who had BTH, than those who did not. Our data indicate that respiratory virus infections pose a significant risk for BTH in PNH patients on complement inhibitor treatment, underlining the need for regular screening and close monitoring of patients with respiratory symptoms. Furthermore, it implies a higher risk for patients who are not established on complement inhibitors, suggesting the necessity for greater vigilance in these patients.

The potential role of vitamin E in patients with glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis.

As an antioxidant, vitamin E (VitE) may benefit the erythrocytes by protecting glutathione from oxidation by free radicals and peroxide-generating processes. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines when reporting this systematic review. We searched 6 electronic databases (PubMed, Scopus, Web of Science, and Cochrane Library) until May 8, 2022. We included all relevant studies. According to the study design, the Cochrane assessment tool (Risk of Bias 2), Risk Of Bias In Non-randomized Studies - of Interventions checklists, and National Institutes of Health tools were used to assess the risk of bias.Continuous data were pooled as a mean difference (MD) with a relative 95% confidence interval. The protocol was registered on PROSPERO (CRD42022333848). Six studies were included in the meta-analysis with a total of 181 patients. Compared with the control group, VitE significantly improved the hemoglobin level for chronic hemolysis (MD = 2.72 g/dL, P < .0001) and for acute hemolysis (MD = 1.18 g/dL, P < .0001). It also decreased the reticulocyte level for chronic hemolysis (MD = -1.39 P < .0001) and for acute hemolysis (MD = -1.42%, P < .0001). For before and after studies, the use of VitE significantly improved the level of packed cell volume (MD = 0.56%, P < .00001), red blood cell half-life (MD = 2.19 days, P < .0001), and decreased the reticulocytes level (MD = -1.41%, P < .00001). Among patients with glucose-6-phosphate dehydrogenase deficiency, VitE might provide benefits such as increasing the hemoglobin, packed cell volume levels, red blood cell half-life, and decreasing the reticulocyte level, so reducing hemolysis. Further high-quality, well-designed randomized controlled trials are recommended.

Sickle Cell Disease and Thromboembolism: New Insights on the Pathophysiology, Diagnosis, and Treatment.

Sickle cell disease (SCD) is a genetic hemoglobinopathy caused by the abnormal hemoglobin S (HbS) in red blood cells. As a result of its deoxygenation and polymerization, the properties and formation of red blood cells become altered, which ultimately leads to the development of SCD. Chronic inflammatory processes produced by hemolytic and vaso-occlusive episodes, define SCD clearly. These processes result in various effects, including organ damage and increased mortality in people suffering from the disease. Thromboembolism, a potentially fatal disease, is common in patients with sickle cell disease. Despite the known association between hypercoagulability and SCD, thromboembolism is often overlooked as a major complication of SCD. However, thromboembolism affects nearly one-quarter of adult patients and appears to be a risk factor for death in SCD. It has been well documented that in SCD, hemostatic alterations and thrombotic events are associated with endothelium and leukocyte activation. In SCD, inflammatory pathways play an important role in the activation of coagulation and the generation of platelet activation. Although among other mechanisms, it also involves the activation of tissue factors, the expression of adhesion molecules, and the stimulation of innate immune responses. So, mouse model studies may provide novel mechanistic pathways. These studies on mice models are yet to be applied to humans which will lead to the development of clinical lab treatments and therapeutic drugs. Additionally, SCD is a condition that responds favorably to biological treatments like gene therapy. SCD patients now have more potentially curative alternatives with recent developments in hematopoietic stem cell (HSC) transplantation and gene therapy platforms, including Lentiglobin vectors. In the present review, a discussion of the pathophysiology and thromboinflammation of sickle cell disease, along with its global burden in terms of both diagnosis and treatment, is presented.

Acute pancreatitis due to massive hemolysis in a child with glucose-6-phosphate dehydrogenase deficiency: A case Report

The incidence of massive intravascular hemolysis causing pancreatitis is 25%; however, it is an often missed entity. Proinflammatory and immunoregulatory cytokines during hemolysis along with heme-induced neutrophil activation, chemoattraction, and disturbance in microcirculation are suggested as causative factors. We describe a case of glucose-6-phosphate dehydrogenase deficiency in a child which was latent through his childhood, triggering a hemolytic episode induced by Leptospira infection. In a patient with acute hemolysis, presenting with severe epigastric pain, one should therefore be aware of the possibility of the occurrence of pancreatitis.

Iron metabolism abnormalities in autoimmune hemolytic anemia and Jianpishengxue keli can ameliorate hemolysis and improve iron metabolism in AIHA mouse models

Objective Autoimmune hemolytic anemia (AIHA) is rare heterogeneous disorder characterized by red blood cell (RBC) destruction via auto-antibodies, and after RBC is destroyed, proinflammatory danger-associated molecular patterns including extracellular hemoglobin, heme, and iron which causing cell injury. And oxidative stress represents one of the most significant effects of chronic hemolysis. Jianpishengxue keli can improve the symptoms of anemia patients with kidney disease and tumors and are beneficial in promoting recovery from chronic inflammation. Therefore, it is presumed that Jianpishengxue keli can improve the symptoms of AIHA. We aimed to investigate iron metabolism in AIHA and effects of Jianpishengxue keli on AIHA murine model. Methods Nineteen hemolytic episode AIHA patients, 10 remission patients and 10 healthy controls (HCs) were enrolled in this study. Serum hepcidin, ferritin and other related indicators of iron metabolism were measured. Mouse models of AIHA were established and received high, medium, or low doses of Jianpishengxue keli by gavage daily for 14 and 28 days respectively. The level of RBCs, Hb, bilirubin, LDH, hepcidin, and the expression level of hepcidin mRNA, and hepatic ferroportin 1(FPN1) protein were evaluated. Results Serum hepcidin in hemolytic episode AIHA patients and remission patients were significantly higher than that in HCs (p = 0.0083 and p = 0.0473, respectively). Serum ferritin in hemolytic AIHA patients was significantly higher than that in HCs (p = 0.008). Serum transferrin saturation levels are increased in patients with AIHA[ (57.21 ± 8.96) %]. EPO in hemolytic group was higher than that in healthy control (p＜0.05). In AIHA mouse models, IBIL decreased after 14 days of high dose drug intervention. After 28 days, TBIL and IBIL both significantly decreased in all dose groups and LDH significantly decreased in the medium-and high-dose groups. Body weight improved, and the level of RBCs, Hb and hepcidin in the high-dose group returned to normal. After 14 and 28 days of intervention, hepatic hepcidin mRNA in all dose group significantly decreased. Hepatic FPN1 protein which were significantly lower in the AIHA mouse models, increased in all dose groups after drug intervention for 28 days. Conclusion Iron metabolism abnormalities exists in AIHA patients and Jianpishengxue keli can ameliorate hemolysis and improve iron metabolism in AIHA mouse models. KEY MESSAGES Iron metabolism abnormalities exists in hemolytic episode AIHA patients. Hepcidin and ferritin levels significantly elevated and also correlated with the severity of AIHA patients. Jianpishengxue keli can ameliorate hemolysis and prompt the recovery of AIHA.

Impact of Hydroxyurea Therapy in Reducing Pain Crises, Hospital Admissions, and Length of Stay Among Sickle Cell Patients in the Eastern Region of Saudi Arabia.

Background In Saudi Arabia, sickle cell disease (SCD) is a major public health issue, especially in the eastern region. Sickle cell patients have major health-related issues, resulting in a poor quality of life and increased morbidity. Abnormal hemoglobin production in SCD causes various complications, such as vaso-occlusive crises, hemolytic episodes, and acute chest syndrome. These disease manifestations increase the need for hospital admission and long-term care. Most therapies for SCD are supportive and include episodic red blood cell transfusions, narcotics, antibiotics, and intravenous fluids. Hydroxyurea is a disease-modifying therapy. This study aimed to assess the effectiveness of hydroxyurea therapy on reducing pain crises, hospital admissions, and length of stay for SCD patients and discern reasons that would prevent SCD patients from using hydroxyurea as a treatment option. Methodology We conducted a descriptive cross-sectional study on SCD patients from the eastern Saudi Arabian province. The study included 202 SCD patients from hematology clinics and medical wards. We used a validated questionnaire tested for reliability after a pilot study of 15 randomly selected patients. We surveyed participants on demographic data, use of hydroxyurea, compliance with the regimen, hospitalization rates, durations, and complications. The study used IBM SPSS Statistics for Windows, Version 22.0. (IBM Corp., Armonk, NY) to analyze the data. All statistical analysis was done using two-tailed tests. P-values < 0.05 were considered statistically significant. Results The study included 202 participants who agreed to participate and completed the study questionnaire. The respondents comprised 150 SCD patients (74.3%) and 52 caregivers of SCD patients (25.7%). Patient ages ranged from one year to older than 36 years (mean age: 26.8 ± 12.3 years). The most common reason for not using hydroxyurea was that it was never offered to patients as a treatment option (40.9% of respondents), followed by respondents who had never heard of it (34.4%), think that they do not need it (24.7%), and fears of long-term consequences (23.7%). More hydroxyurea users (35.1%) suffered no acute painful crises during the last year than nonusers (32%), and more nonusers suffered more than four crises (20%) than hydroxyurea users (9.1%; p=.046). As for hospitalization due to SCD-related complications, 66.2% of hydroxyurea users were never hospitalized, while 51.2% of nonusers were never hospitalized. While 19.5% of hydroxyurea users were hospitalized one to two times, 28.8% of nonusers were hospitalized one to two times (p=.049). Conclusions The study revealed that hydroxyurea is effective in reducing painful vaso-occlusive crises and the number of hospital admissions. The prevalence of hydroxyurea use among SCD patients in the eastern province of Saudi Arabia remains low. Therefore, education campaigns and programs to increase awareness among health care providers regarding the benefits of hydroxyurea use are warranted in our region to help improve patient outcomes.

Pregnancy in Paroxysmal Nocturnal Hemoglobinuria - a Systematic Review

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal disorder of hematopoietic stem cells, characterized by complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure. Pregnancy exacerbates the clinical features of PNH, increasing maternal and fetal morbidity and mortality. Pregnancy in patients with PNH has traditionally been discouraged. Terminal complement inhibition with eculizumab gained regulatory approval in 2007 and has revolutionized the management of PNH. Limited data suggest that eculizumab is also safe and efficacious during pregnancy. Owing to the rarity of PNH and the inability to conduct randomized controlled trials on this population, most reports are small case series, with even the largest retrospective studies including well below 100 patients. We therefore present the first comprehensive systematic review and meta-analysis of outcomes in 190 pregnancies from 135 women with PNH. We compare pregnancy complications between those receiving eculizumab and those not, since complement blockade is not universally available. For the first time we demonstrate that eculizumab is associated with a lower risk of fetal loss. Methods The PubMed (Medline) database was searched for studies reporting primary data on pregnancy outcomes in the context of classical hemolytic PNH, diagnosed through flow cytometry, acid Ham's or sucrose lysis (Figure 1). Women with evidence of recurrent hemolytic episodes including serum lactate dehydrogenase >1.5 times the upper limit of normal, and typical PNH symptoms were included. We excluded papers where there was insufficient information for meaningful downstream analysis, or where cases were duplicated elsewhere in the literature. The search was restricted to English language papers. Two reviewers independently screened articles for inclusion with a third opinion sought where there was disagreement. References of included papers and review articles were screened to identify further papers. Thirty-six papers published between 1968 to 2021 were selected for inclusion. The majority were small case series or single case studies. There were two larger retrospective studies reporting on 45 and 75 pregnancies respectively. There was one prospective study (n=15 pregnancies). Results Eculizumab was used in 130 pregnancies. No maternal deaths were reported in patients on eculizumab. One woman who had never received eculizumab died at 12 weeks postpartum from intra-abdominal sepsis following a severe episode of acalculous cholecystitis. A higher rate of fetal survival was observed in pregnancies where eculizumab was used (82%) than in pregnancies when it was not (69%) (Table 1). Thrombosis occurred at a higher rate than in the healthy pregnant population but did not significantly differ in incidence between treatment groups (Table 1). The incidence of pre-eclampsia was high in this population. There was a trend towards a reduced risk of pre-eclampsia and infection in eculizumab pregnancies, but this did not reach statistical significance (Table 1). No Neisserial infections were observed in patients treated with eculizumab. The rate of spontaneous miscarriage (<24 weeks') was nearly twice as high in women who had not received eculizumab (18.6%) compared to those who received it (9.7%). The rate of intrauterine death did not significantly differ between treatment groups (Table 1). Fetal structural anomalies occurred in three cases, none of which had been exposed to eculizumab, supporting the notion that the drug does not have a teratogenic effect. Intrauterine growth restriction (IUGR) occurred in just over 8% of pregnancies that progressed beyond 20 weeks and did not differ between treatment groups (Table 1). IUGR was associated with pre-eclampsia in eight cases (61%). 148 pregnancies progressed to delivery, the majority by vaginal delivery. Premature birth (<37 weeks' gestation) was observed in 32% of eculizumab pregnancies and 44% of non-eculizumab pregnancies. Premature delivery was usually iatrogenic due to maternal or fetal complications, with spontaneous premature labor in only eight cases (15%). Conclusion Eculizumab appears to be safe and provide a benefit in pregnancy in PNH. There were less premature births and spontaneous miscarriages and greater fetal survival when eculizumab was given. A tendency to fewer cases of pre-eclampsia and maternal infections was also seen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal