Intravascular Hemolysis Research Articles

Study of vascular endothelial dysfunction in children with beta-thalassemia major before and after quercetin therapy

BackgroundBeta-thalassemia stands as an autosomal recessive disorder that occurs as a result of a defect in the beta-globin chain synthesis of hemoglobin. Oxidative stress has a crucial role in the β-thalassemia pathophysiology. It occurs due to erythroid expansion along with ineffective erythropoiesis. The free hemoglobin oxidation generates reactive oxygen species (ROS), free heme, and iron, thus inducing membrane oxidative damage as well as vascular endothelial dysfunction. Quercetin has a crucial impact on enhancing endothelial dysfunction in thalassemia major. This work aimed to investigate endothelial dysfunction among children diagnosed as beta-thalassemia major by assessing serum level of some endothelial markers (thrombomodulin as well as human ROS) and assessing the quercetin’s therapeutic value in improving endothelial dysfunction by measuring the previous markers 12 weeks following therapy. This randomized placebo-controlled study involved 72 children developing transfusion-dependent β-thalassemia major. Their age range fell between 8 and 18 years. They were categorized into two equal groups: group I: received 12 weeks of quercetin therapy and group II: served as control group and received 12 weeks of placebo.ResultsSerum ferritin, C-reactive protein, and lactate dehydrogenase levels showed significantly lower values among patients after 12 weeks of quercetin therapy compared with controls. Pre-transfusion hemoglobin was significantly higher in patients after 12 weeks of quercetin therapy in comparison to controls. Frequency of transfusion was significantly less in patients after 12 weeks of quercetin therapy in comparison to controls. Serum levels of ROS and thrombomodulin showed significantly lower values among cases after 12 weeks of quercetin therapy in comparison to controls (p < 0.001). ROS and thrombomodulin respectively carried the sensitivity of 83.33% and 77.78% and specificity of 80.56% and 83.33% in predicting the outcome with cutoff value ≤ 1073 and 232.ConclusionsTwelve weeks of 500-mg quercetin therapy had a potent role in decreasing iron overload and improving frequency of transfusion, oxidative stress ,and endothelial dysfunction in children with β-thalassemia major.

Quality comparison of autotransfusion devices in cardiac surgery: a prospective observational cohort study.

We sought to conduct a quality improvement initiative to compare the wash quality and speed of autologous red blood cell (RBC) processing of four autotransfusion devices during cardiac surgery. Using a prospective observational cohort study approach, we prospectively evaluated four commercially available autologous cell savage devices (autoLog IQ™, Medtronic plc, Minneapolis, MN, USA [135mL]; Xtra™, LivaNova, plc, Houston, TX, USA [125mL, 225mL]; Cell Saver® Elite®+, Haemonetics Corp., Boston, MA, USA [125mL, 225mL]; and CATSmart®, Fresenius Kabi AG, Bad Homburg vor der Höhe, Germany) in adult patients undergoing cardiac surgery. Device settings were determined by manufacturer recommendations for optimal wash quality. We collected pre- and postprocessing samples, volumes, and processing times from each device to calculate removal ratios of heparin, potassium, plasma free hemoglobin (PfHb), white blood cells (WBCs), platelets, reinfusion concentrations of heparin and potassium, and red blood cell (RBC) recovery rates. A total of 130 consecutive patients underwent autologous cell salvage, but 15 cases were excluded because of incomplete data. All devices removed > 99% heparin, > 95% potassium, > 94% platelets, and > 85% PfHb from collected shed blood. Comparison of processing sets showed significant differences in median [interquartile range] WBC removal ratios, ranging from 26 [19-33]% to 59 [42-68]%, and median heparin reinfusion concentrations, which ranged from 0.09 [0.08-0.11] to 0.63 [0.55-0.70] U·mL-1 processed red cells. Median RBC recovery rates also showed significant differences between processing sets, ranging from 8 [8-10] mL RBC·min-1 to 24 [22-25] mL RBC·min-1. Wash quality and processing speed differed between autotransfusion devices and processing sets. These findings may have clinical implications when large volumes of shed blood are processed and reinfused.

Observer reliability in counting erythrocyte ghost cells and impact of short-term storage of canine and feline blood samples.

The presence of erythrocyte ghost cells (EG) in blood smears indicates intravascular haemolysis or in-vitro haemolysis. However, observer reliability in detection of EG has not been documented. Immediate blood smear preparation is advised but may not always be practical. This study investigated the reliability of EG detection and the impact of delayed blood smear preparation. Forty blood smears from dogs and cats were evaluated twice by four observers. EG development was studied in 59 dogs and nine cats, with smears prepared at 0, 2, and 24 h post-collection. Intra- and inter-observer reliability, as assessed using Krippendorff's Alpha, ranged from 0.567 and 0.949, and 0.522 and 0.848, respectively, indicating moderate to substantial agreement. No significant increase in EG occurrence was noted between 0 and 2 h, but a significant increase was observed at 24 h. The findings suggest that EG can be reliably detected and that blood smears for the evaluation of EG can be prepared up to 2 h after blood collection without compromising detection of EG.

Pregnancy Favism and Severe Hemolytic Anemia in a Patient with Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency: A Case Report

Introduction: Favism is a genetic disease-causing hemolytic anemia in Mexico, primarily due to glucose-6-phosphate dehydrogenase (G6PD) deficiency. Factors triggering favism include infections, pregnancy, certain drugs, and eating beans. The disease is inherited recessively and is more common in men. Diagnosing and managing favism during pregnancy is crucial, as it can lead to severe hemolytic anemia and neonatal jaundice. Case presentation: A female patient, aged 18, presented with severe anemia and thrombocytopenia during her 20-week pregnancy. During pregnancy, the patient experienced jaundice and anemia at 21.5 weeks of gestation. Despite not presenting evidence of bleeding, transfusions were performed due to critical hemoglobin levels. G6PD deficiency was confirmed at 9 days of hospital admission, indicating severe hemolytic anemia. Clinical discussion: The hemolytic crisis in a pregnant woman with favism was triggered by pregnancy and repeated infections of candidiasis. Clinical symptoms of hemolysis were confirmed through G6PD and Coombs tests, and blood transfusion was recommended to prevent complications. The patient's hemoglobin was monitored for signs of active intravascular hemolysis, and a folic acid tablet was recommended during the crisis. Post-crisis management involved periodic controls of hemoglobin, hematocrit, lactate dehydrogenase, and bilirubin. Conclusion: Favism, a prevalent condition in Mexico, should be considered in patients with a family history of hemolytic anemia or compatible symptoms. Early diagnosis and proper management are crucial to prevent complications in the mother and fetus. A multidisciplinary approach, genetic counseling, and medical education are essential for effective management.

Effects of prosthetic heart valve-associated subclinical intravascular hemolysis on endothelium and cardiovascular system: a retrospective cohort study

Abstract Background Mechanical prosthetic heart valve implantation is a surgical treatment method used in the treatment of severe and symptomatic valvular disease. Regular follow-up of prosthetic valve functions, clinical and laboratory parameters is of great importance in patients who have undergone valve implantation. Chronic subclinical intravascular hemolysis is frequently seen in this patient group, but its management and long-term adverse effects are uncertain. In this study, it was aimed to determine the effects of subclinical hemolysis on the endothelium by comparing the frequency of clinical events such as pulmonary hypertension and atherosclerotic vascular events in patients with mechanical valves. Methods In this single-center, retrospective cohort, patients with functional mechanical prosthetic valves were evaluated. A total of 346 patients who underwent aortic and/or mitral valve replacement were included in the study according to the inclusion and exclusion criteria. The severity of mechanical intravascular hemolysis (MIH) in patients was evaluated based on serum lactate dehydrogenase (LDH) levels measured during follow-up after valve implantation. The study population was divided into two groups according to the median follow-up LDH value (fLDH) of 264.5 U/L: non-hemolysis/mild hemolysis (Group 1) and moderate hemolysis (Group 2). Study patients were evaluated for pulmonary hypertension (PHT) and major adverse cardiovascular events (MACE) during the retrospective follow-up period. Results The mean age of the study patients was 57.5±12.5 years, and the study population consisted of 65% male patients. The mean follow-up period of the patients was 9.4 years (±3.3). MACE (composite of non-fatal cerebrovascular event, myocardial infarction, new-onset arrhythmia, cardiovascular death, and elective coronary revascularization) were observed in 5.2% (n=18) of the study population. New-onset PHT was detected in 122 patients (35.3%) during follow-up period. When compared in terms of MACE, 1 event (0,6%) occurred in group 1, while 17 events (9,8%) occurred in group 2 (p&amp;lt;0.001). In the multivariate analysis performed with logistic regression method to determine statistical significance of the parameters that stand out in terms of MACE prediction, fLDH value ≥ 265 and having DM were found to be statistically significant variables (fLDH; OR = 37.18, 95% CI: 3.24-426.35, p=0.004, DM; OR = 27.14, 95% CI: 1.22-601.72, p=0.037). Conclusion The results of the study show that subclinical intravascular hemolysis in prosthetic heart valve patients may be associated with the development of MACE and PHT. Evaluation of the severity of hemolysis, which can be evaluated by LDH level in routine clinical practice, can be a prognostic factor in this patient group and may contribute to the appropriate management and treatment of patients. Baseline characteristics Critical outcomes of study

Scrub Typhus Infection Precipitating Hemolysis in a Patient With G6PD Deficiency: A Case Report.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a well-known red blood cell enzymopathy and a cause of intravascular hemolysis. This case report presents a child with underlying G6PD deficiency who experienced an acute episode of extensive intravascular hemolysis induced by a scrub typhus infection. The key takeaway from this report is that scrub typhus infection can trigger extensive hemolysis in patients with even "mild" G6PD deficiency, and normal G6PD levels found during the acute phase of hemolysis do not rule out the possibility of underlying G6PD deficiency.

Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring.

The C3 protein is the central molecule within the complement system and undergoes proteolytic activation to C3b in the presence of pathogens. Pattern-independent activation of C3 also occurs via hydrolysis, resulting in C3(H2O), but the structural details of C3 hydrolysis remain elusive. Here we show that the conformation of the C3(H2O) analog, C3MA, is indistinguishable from C3b. In contrast, the reaction intermediate C3* adopts a conformation dramatically different from both C3 and C3MA. In C3*, unlocking of the macroglobulin (MG) 3 domain creates a large opening in the MG ring through which the anaphylatoxin (ANA) domain translocates through a transient opening. C3MA formation is inhibited by an MG3-specific nanobody and prevented by linking the ANA domain to the C3 β-chain. Our study reveals an unexpected dynamic behavior of C3 and forms the basis for elucidation of the in vivo contribution of C3 hydrolysis and for controlling complement upon intravascular hemolysis and surface-contact-induced activation.

Perioperative Free Plasma Hemoglobin Level and the Development of Acute Kidney Injury Following Cardiac Surgery at Dr Sardjito Hospital

Introduction: Cardiac surgery-associated acute kidney injury (CS-AKI) is a common and lethal complication of cardiac surgery. The cardiopulmonary bypass (CPB) machine breaks erythrocytes and releases free hemoglobin (FHb) into plasma, leading to acute kidney injury (AKI). The ratio of free hemoglobin before and after cardiac surgery (post/pre-CPB FHb ratio) is a promising parameter for detecting hemolysis and predicting CS-AKI. Objectives: The study aims to determine the relationship between the post/pre-CPB FHb ratio and CS-AKI and evaluate risk factors for CS-AKI. Methods: A prospective cohort study was conducted on patients undergoing open heart surgery at Dr. Sardjito Hospital, Yogyakarta, Indonesia. Serial perioperative free hemoglobin levels were obtained, and all subjects were followed through to identify whether they developed CS-AKI. The appropriate statistical analyses were executed. A p-value of &lt;0.05 was considered significant. Results: A total of 21% of subjects experienced CS-AKI. The post/pre-CPB FHb ratio of ≥1.86 predicted CS-AKI with moderate discrimination (AUC 0.751; p=0.016). Notably, the CPB duration and mean arterial pressure were identified as independent risk factors for CS-AKI, underscoring the importance of these factors in predicting and managing CS-AKI.Conclusion: When considered alongside other risk factors, the post/pre-CPB FHb ratio ≥1.86 emerges as a potent predictor for CS-AKI. This finding underscores the potential of measuring perioperative free hemoglobin levels, monitoring blood pressure, and optimizing the duration of CPB as valuable strategies to mitigate CS-AKI and improve patient outcomes.

Ravulizumab demonstrates long-term efficacy, safety and favorable patient survival in patients with paroxysmal nocturnal hemoglobinuria.

Ravulizumab is a second-generation complement component 5 (C5) inhibitor (C5i) approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) following positive results from two pivotal trials in patients with PNH originally naive to C5i treatment and eculizumab-experienced patients with PNH. In both trials, after the 26week primary evaluation period, all patients received ravulizumab for up to 6 years. To report ravulizumab treatment outcomes in patients with PNH originally naive to C5i treatment and eculizumab-experienced patients with PNH treated for up to 6 years. Originally C5i-naive (N = 244) and eculizumab-experienced (N = 191) patients with PNH continued ravulizumab treatment for up to 6 years. Major adverse vascular events (MAVEs; including thrombotic events [TEs]) and survival are reported, including a comparison of survival with untreated patients from the International PNH Registry. Laboratory parameters for intravascular hemolysis (IVH) are also described. For up to 6 years (1468.0 patient-years of exposure), ravulizumab provided durable control of terminal complement activity and IVH, resulting in a low incidence of MAVEs (including TEs) reported (MAVE rate: 0.7-1.4 per 100 patient-years) and, compared with untreated patients from the International PNH Registry, reduced the risk of mortality by five-fold. The few breakthrough IVH events reported (N = 122) were commonly associated with complement-amplifying conditions, and only two events (1.8%) were associated with suboptimal inhibition of C5 (i.e. serum free C5 ≥ 0.5µg/mL). These results support the long-term use of ravulizumab as the first-line treatment of choice for patients with PNH. Trial registration details: NCT01374360; registered: October 29, 2004; NCT02946463; registered: October 27, 2016; NCT03056040; registered: June 05, 2017.

Transcriptomic atlas reveals organ-specific disease tolerance in sickle cell mice.

Sickle cell disease (SCD) is the most common genetic disease in the world and a societal challenge. SCD is characterized by multi-organ injury related to intravascular hemolysis. To understand tissue-specific responses to intravascular hemolysis and exposure to heme, we present a transcriptomic atlas in the primary target organs of HbSS vs HbAA transgenic SCD mice. We explored the transcriptomes of liver, kidney, heart, lung and bone marrow from HbAA and HbSS Townes littermates at resting state and their changes after injection of heme, assessed by RNA sequencing. Inflammation and myeloid cell signatures were omnipresent in resting HbSS organs, liver being the most affected. The injection of heme triggered a robust inflammatory response in HbAA mice. Signatures of exposure to heme in HbAA mice were downstream of TLR4 (sensor of LPS but also of heme), IL1b, IL6 and IFNg, similarly to HbSS mice at rest. Nevertheless, HbSS mice were strikingly unresponsive to heme administration, irrespective of the organ. This tolerance was driven by upregulation of the heme-detoxifying enzyme HO-1 and was abrogated by its specific inhibition. Therefore, HbSS mice develop robust protective mechanisms, which may explain how they and SCD patients survive bouts of severe hemolysis.

Onconephrology. The main approaches to determining the nephrotoxicity of antitumor drugs

This is a review of the literature on the problem of nephrotoxicity of antitumor drugs. Clinical manifestations of nephrotoxicity are considered, including acute/chronic tubulointerstitial nephritis (due to infection, hyperuricemia, calciuria, drug effects, etc.); thrombotic microangiopathy with kidney damage; acute tubular necrosis; acute cortical necrosis; thrombosis of the renal artery and its branches; thrombosis of the renal vein, its branches, inferior vena cava; glomerulonephritis (nephritic syndrome, nephrotic syndrome, isolated urinary syndrome; morphological patterns of IgA nephropathy, membranous nephropathy, disease of minimal changes, focal segmental glomerulosclerosis, C3 dominant nephropathy, etc.); hempigmental nephropathy (a consequence of acute intravascular hemolysis, less often – rhabdomyolysis); nephrocalcinosis, urolithiasis; pyelonephritis, etc. The classification of antitumor drugs is given. Since different classes of drugs have different mechanisms for the development of nephrotoxicity, the article discusses the main ones with examples. The article also presents well-known and promising approaches to the prevention and treatment of nephrotoxicity of antitumor drugs.

Cell-free hemoglobin released from hemolysis induces programmed cell death through iron overload and oxidative stress in grass carp (Ctenopharyngodon idella).

Intravascular hemolysis releases hemoglobin (Hb) from red blood cells under specific conditions, yet the effect of hemolysis in aquaculture systems remain poorly understood. In this study, a continuous hemolysis model for grass carp was established by injection of phenylhydrazine (PHZ) to investigate the mechanistic impacts of sustained hemolysis. PHZ-induced hemolysis altered liver color, and subsequent hematoxylin and eosin staining revealed substantial Hb accumulation in the head kidney, accompanied by inflammatory cell infiltration and vacuolization in liver tissue. Quantitative real-time PCR and western blotting confirmed that PHZ treatment significantly upregulated Real-time fluorescence quantitative PCR and Western blot confirmed that PHZ treatment significantly up-regulated the expression of iron metabolism-related genes and proteins, including transferrin (Tf), ferritin, ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), nuclear receptor coactivator 4 (NCOA4), divalent metal transporter 1 (DMT1), and six-transmembrane epithelial antigen of prostate 3 (STEAP3). Further investigation of PHZ-induced hemolysis effects on tissues showed that inflammation- and antioxidant enzyme-related genes in the liver and head kidney were significantly upregulated, indicating that hemolysis activated the antioxidant system and intensified inflammatory responses. Perls' staining revealed iron deposition in the head kidney and liver at ten and fourteen days post-PHZ injection. Moreover, β-galactosidase staining and transmission electron microscopy showed increased cellular senescence and mitochondrial damage, respectively, as a result of PHZ-induced hemolysis. In vitro assays with hemin treatment demonstrated increased Fe2+ content in CIK and L8824cells, which induced oxidative stress, upregulated iron metabolism and inflammatory genes, and ultimately led to cell death. These findings suggest that excessive Hb release during sustained hemolysis leads to iron overload, elevates reactive oxygen species production, disrupts antioxidant balance, and ultimately causes cellular damage.

A study of polymorphism and the serum level of Haptoglobin of people suffering from sickle cell disease and/or hepatitis C

Background. Haptoglobin is a type of alpha2 globulin found in human plasma. Its primary function is to bind to the globin portion of free hemoglobin in the bloodstream. Objectives. To examine the genetic polymorphism of the Haptoglobin (Hp) gene in patients diagnosed with sickle cell anemia, hepatitis C, and the co-occurrence of sickle cell anemia and hepatitis C . Patients and methods. A total of 130 participants were categorized into several groups: 40 patients with sickle cell anemia, 40 patients with hepatitis C, 10 patients with both sickle cell anemia and hepatitis C, and 40 individuals in the control group. The DNA was extracted and the polymerase chain reaction (PCR) was conducted using genotype-specific primers for the three areas of the haptoglobin gene. The genotypes were identified by running electrophoresis on agarose gels and calculating the proportion of each allele that was amplified. After obtaining the sequencing results of the haptoglobin gene and for the studied samples and for the three plots Hp2, Hp 1S and Hp 1F, Sequences for all three segments were registered in the NCBI Genome Bank for the first time locally and some were given independent accession numbers, and it will be considered a database for any future researcher working on the Hp genotypes in Iraq. Results. In Sickle cell Patient Hp1-1(0.13), Hp2-2(0.55), Hp2-1(0.32), Hepatitis-C Patient Hp1-1(0.13), Hp2-2(0.63), Hp2-1(0.24), Sickle cell with Hepatitis C Patient Hp1-1(0.20), Hp2-2(0.60), Hp2-1(0.20), and Control group Hp1-1 (0.30), Hp2-2 (0.50), Hp2-1 (0.20). Hp2-2 was the most common phenotype across all categories, The T allele and TT genotype seem more visible in sickle cell anemia and hepatitis diseases than the AA genotypes of Hp-2 643 T&gt;, and no correlation between patients and health control group with Hp1S gene. Also, the present study reports that there is no correlation between patients of sickle cell anemia and health control group with Hp-1F 867 G &gt; A gene, but the G allele and GG genotype more visible in hepatitis diseases than the AA genotypes of Hp-1F 867 G &gt; A gene. Conclusions. The Hp2-2 haptoglobin phenotype was the most common among patients. Different groups may have an influence on the development of sickle cell anemia and hepatitis C.

Etiological study of polyclonal hypergammaglobulinemia in a French cohort of hospitalized patients and proposal of a diagnostic aid algorithm

Serum protein electrophoresis can sometimes reveal polyclonal hypergammaglobulinemia. This electrophoretic abnormality can be caused by a variety of conditions and can be difficult to investigate. We sought to investigate screening practices in patients with hypergammaglobulinemia in order to establish diagnostic guidance strategies. We selected all patients with polyclonal hypergammaglobulinemia greater than or equal to 20 g/L over one year to identify the etiologies causing a significant increase in gammaglobulins in the absence of a monoclonal abnormality. We then selected patients who presented with this abnormality for the first time, with no known etiology. Clinical, medication, biological and imaging data were collected. In our study population with polyclonal hypergammaglobulinemia (n = 155), the main etiologies identified were infections (56%), autoimmune and autoinflammatory diseases (20%), liver diseases (18%) and hematological and non-hematological malignancies (6%). Once hypergammaglobulinemia was identified, the clinical examination provided diagnostic orientation but was not sufficient to make the diagnosis. The initial assessment must investigate the most common pathologies including analysis of liver function, viral status, the search for signs of intravascular haemolysis, inflammatory markers, and blood cell count. At the second time point (unless there were suggestive clinical signs at presentation), more specific biological and imaging analyses were required. Finally, we propose a diagnostic guideline for a current, rational and optimal medical practice to assist clinicians in the management of patients with hypergammaglobulinemia.

The course of plasma alpha-1-microglobulin and haemolysis during cardiac surgery and the relationship to acute kidney injury, a pilot study

Haemolysis occurring during cardiac surgery with cardiopulmonary bypass (CPB) is assumed to be a risk factor for postoperative acute kidney injury (AKI). Plasma alpha-1 microglobulin (A1M) may have a protective role as haem scavenger. The aim of this study was to evaluate the association between AKI and the degree of haemolysis and the course of A1M concentrations during cardiac surgery, respectively. We analysed plasma concentrations of free haemoglobin (pfHb) and A1M in 25 patients undergoing cardiac surgery: before CPB; during CPB in 15 min intervals; after CPB; and at four additional time points until 24 h after surgery. Markers of kidney function were followed until 4 days after surgery. Detection of AKI was based on the KDIGO (Kidney Disease, Improving Global Outcome) criteria. The plasma concentration of free haemoglobin during CPB was found to be significantly higher in patients with postoperative AKI at 60 min after start of CPB [mean 1379 µg/mL (95% CI: 1037–1721)]; compared to [820 µg/mL (622–1018)]; p = 0.034, in patients without AKI, and at one hour post-CPB [2600 µg/mL (969–4230)] vs [1037 µg/mL (722–1353)]; p = 0.044]. There was no significant difference found for pA1M levels between the groups with and without postoperative AKI development. Haemolysis during cardiac surgery with CPB increases the risk of postoperative AKI. Levels of pA1M did not differ for patients who developed postoperative AKI compared with those who did not. The data did not allow conclusions regarding the hypothesis that pA1M has a reno-protective effect.

Long-Term Efficacy and Safety of Danicopan as Add-On Therapy to Ravulizumab or Eculizumab in PNH With Significant EVH.

Complement C5 inhibitor treatment with ravulizumab or eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) improves outcomes and survival. Some patients remain anemic due to clinically significant extravascular hemolysis (cs-EVH: hemoglobin [Hgb] ≤9.5 g/dL and absolute reticulocyte count [ARC] ≥120×109/L). In the phase 3 ALPHA trial, participants received oral factor D inhibitor danicopan (150 mg 3 times daily) or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period (TP) 1; those receiving placebo switched to danicopan during the subsequent 12-week, open-label TP2 and continued during the 2-year long-term extension (LTE). There were 86 participants randomized in the study, of whom 82 entered TP2 and 80 entered LTE. The primary endpoint was met, with Hgb improvements from baseline at week 12 (Wk12) (LS mean change: 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at Wk12, improvements in mean Hgb were observed at Wk24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hgb increase, ARC, proportion of participants achieving transfusion avoidance, and Functional Assessment of Chronic Illness Therapy-Fatigue scale scores. Improvements were maintained up to week 72. No new safety signals were observed. The breakthrough hemolysis rate was 6 events per 100 patient-years. These long-term data demonstrate sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, intravascular hemolysis, and cs-EVH in PNH. Registration: Clinicaltrials.gov, NCT04469465.

Atypical Complement-Mediated Hemolytic Uremic Syndrome Triggered by Molar Pregnancy

Complement-mediated hemolytic uremic syndrome (CM HUS) is a rare but potentially devastating disease that results in intravascular hemolysis and thrombocytopenia, precipitating severe end-organ damage. CM HUS is a specific disorder under the collective group of thrombotic microangiopathies along with thrombotic thrombocytopenic purpura (TTP). Pregnancy itself can be a precipitant of CM HUS, although rare, due to dysregulated complement activation. Typical pregnancy induces elevated complement activation in effect with equal elevation of inhibitory factors to protect the fetus. In a susceptible individual, pregnancy itself may contribute to complement dysregulation resulting in CM HUS. A high index of suspicion is required to differentiate the true cause of the presentation, as there is no specific testing for CM HUS. A devastating result of CM HUS is complete renal failure. Management strategies may include plasma exchange and anti-complement immunotherapies. In this report, we will present a case of postpartum precipitated CM HUS complicated by acute kidney injury requiring hemodialysis and anti-monoclonal therapy.

Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria is a rare blood disorder characterized by life-threatening hemolysis and thrombosis. Complement C5 inhibitor therapy improves symptoms and life prognosis; however, it can result in insufficient hemolysis control, with residual intravascular hemolysis and extravascular hemolysis in some patients. Pegcetacoplan, the first complement C3 inhibitor approved for patients with paroxysmal nocturnal hemoglobinuria, targets both intravascular and extravascular hemolysis. This analysis evaluated population pharmacokinetic/pharmacodynamic profiles of pegcetacoplan. Pooled clinical study data were used to predict pegcetacoplan concentrations and biomarker responses indicative of hemolysis (hemoglobin and lactate dehydrogenase) over time, including the impact of patient characteristics and prior or concurrent complement C5 inhibitor treatment, to support the approved dose of subcutaneous pegcetacoplan 1080 mg twice weekly. The population pharmacokinetoc analysis included 284 subjects, and the pharmacokinetic/pharmacodynamic analysis included 165 subjects. Subcutaneous pegcetacoplan 1080 mg twice weekly resulted in rapid serum exposures and robust biomarker response within 4 weeks after treatment initiation. Steady-state serum concentrations demonstrated consistent exposure (median ≥ 600 µg/mL) with minimal peak-to-trough variation. The median effective half-life was 8.6 days in patients with paroxysmal nocturnal hemoglobinuria. Body weight significantly impacted pegcetacoplan exposure, and other covariates impacted hemoglobin (sex and creatinine clearance) or lactate dehydrogenase (prior or concurrent complement C5 inhibitor treatment); however, effects were not clinically meaningful. The approved dose of pegcetacoplan is predicted to produce rapid and sustained exposure and robust hemoglobin and lactate dehydrogenase responses in adult patients with paroxysmal nocturnal hemoglobinuria, with no initial dose adjustments required for any specific patient population.

Inflammatory pathways and anti-inflammatory therapies in sickle cell disease.

Sickle cell disease (SCD) is a monogenic disease, resulting from a single-point mutation, that presents a complex pathophysiology and high clinical heterogeneity. Inflammation stands as a prominent characteristic of SCD. Over the past few decades, the role of different cells and molecules in the regulation of the inflammatory process has been elucidated. In conjunction with the polymerization of hemoglobin S (HbS), intravascular hemolysis, which releases free heme, HbS, and hemoglobin-related damage-associated molecular patterns, initiates multiple inflammatory pathways that are not yet fully comprehended. These complex phenomena lead to a vicious cycle that perpetuates vaso-occlusion, hemolysis, and inflammation. To date, few inflammatory biomarkers can predict disease complications; conversely, there is a plethora of therapies that reduce inflammation in SCD, although clinical outcomes vary widely. Importantly, whether the clinical heterogeneity and complications are related to the degree of inflammation is not known. This review aims to further our understanding of the roles of main immune cells, and other inflammatory factors, as potential prognostic biomarkers for predicting clinical outcomes or identifying novel treatments for SCD.

Factors related to acute kidney injury after AngioJet rheolytic thrombectomy.

AngioJet rheolytic thrombectomy is associated with a higher risk of acute kidney injury due to its potential for inducing mechanical harm and intravascular hemolysis. However, previous studies have focused on a single disease entity. To identify predictors associated with acute kidney injury after AngioJet rheolytic thrombectomy across a range of disease entities. A total of 95 patients who underwent AngioJet rheolytic thrombectomy between October 2018 and April 2023 were retrospectively reviewed. In total, 11 patients were excluded due to the absence of a postprocedural serum creatinine test within 72 h; finally, 84 patients were included. Acute kidney injury was defined as a ≥1.5-fold increase or ≥0.3 mg/dL rise in serum creatinine within 72 h after the procedure. Univariate and multivariate analysis were performed to identify risk factors for acute kidney injury. Technical and clinical success were achieved in all patients (84/84, 100%). Of the 84 patients (40 men [47.6%], 44 women [52.4%]; mean age = 67.2 ± 15.9 years), 15 (17.8%) had developed acute kidney injury. Multivariate analysis showed concurrent malignancy (odds ratio [OR] = 42.231, 95% confidence interval [CI] = 2.332-764.693; P = 0.011) and AngioJet rheolytic thrombectomy in arterial system (OR = 24.109, 95% CI = 1.319-440.551; P = 0.032) as statistically significant predictors of acute kidney injury. AngioJet rheolytic thrombectomy is a potential risk for acute kidney injury. Concurrent malignancy and AngioJet rheolytic thrombectomy in the arterial system are independent predictors of acute kidney injury.