scholarly journals Paroxysmal Cold Hemoglobinuria Successfully Treated with Complement Inhibition

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4798-4798
Author(s):  
Sarah A Lau-Braunhut ◽  
Hannah Stone ◽  
Griffin Collins ◽  
Sigbjørn Berentsen ◽  
Matt Zinter ◽  
...  
Keyword(s):  
Single Dose ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Primary Care Visit ◽  
Intravascular Hemolysis ◽  
Increased Risk ◽  
History Of ◽  
Positive Direct ◽  
Environmental Warming ◽  
Paroxysmal Cold Hemoglobinuria

Introduction: Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia (AIHA) that causes intravascular hemolysis and profound, sometimes life-threatening anemia. It most commonly occurs in children following viral infection, and presents with acute onset anemia, pallor, jaundice, and hemoglobinuria. PCH is caused by a biphasic immunoglobulin G (IgG) autoantibody that targets the P-antigen on red blood cells (RBCs) with complement fixation at low temperatures. Subsequent warming in the central circulation leads to complement activation and intravascular hemolysis. Management of PCH has been primarily supportive, with environmental warming to prevent autoantibody binding and transfusion with warmed packed red blood cells (PRBCs) as clinically indicated. Efficacy of corticosteroids has not been demonstrated. We report on successful treatment of PCH by complement blockade using a single dose of eculizumab. Case Description: We treated a previously healthy 4-year-old boy who presented with 5-day history of transient maculopapular rash, 3-day history of fatigue, thigh and abdominal pain, 2-day history of cough, chills, vomiting, diarrhea and high-grade fevers, and on the day of presentation, developed jaundice and dark urine. Hemoglobin (Hgb) level was 6.4 g/dL at a primary care visit. On admission, he was febrile, tachycardic, with scleral icterus and pallor, worsening anemia (Hgb 5.6 g/dL) which 1 hour later dropped to 4.5 g/dL, with reticulocytopenia, spherocytosis, and positive direct antiglobulin test (DAT). Initially he received methylprednisolone as empiric treatment for AIHA. Monospecific DAT was positive for C3d and negative for IgG, leading to suspicion of cold-antibody mediated AIHA (cAIHA). Due to hemoglobinuria consistent with intravascular hemolysis, PCH was suspected and a Donath-Landsteiner (DL) test was ordered. Despite environmental warming and azithromycin for potential Mycoplasma pneumoniae induced cold agglutinin syndrome, he developed worsening anemia (nadir Hgb 3.0 g/dL) with signs of shock including altered mental status, tachycardia, lactic acidosis, and high oxygen extraction, and continued transfusion requirement. On hospital day 4, we decided to treat him with eculizumab 600 mg intravenously. That afternoon, definitive testing for PCH with the DL test returned positive, confirming PCH diagnosis. Markers of hemolysis, including lactate dehydrogenase and bilirubin, decreased immediately following eculizumab administration. No further transfusion was required. Hgb levels stabilized, and reticulocyte counts increased daily. Steroids were discontinued on hospital day 6. Complete complement blockade following a single dose of eculizumab was confirmed on hospital day 7, with total complement level (CH50) reported as <13.8 U/mL. The patient continued to improve and was discharged home on hospital day 15 with Hgb 6.6 g/dL, improving to 9.1 g/dL 6 days later. Diagnostic tests for infectious and toxin-mediated causes of PCH remained negative. He was given prophylaxis for encapsulated bacterial infections with penicillin VK, given increased risk of infection from ongoing complement blockade and his unvaccinated status. This was discontinued when CH50 levels normalized, 42 days after eculizumab administration. Discussion: To our knowledge, this is the first published observation of successful complement blockade for the treatment of PCH. Complement is a key effector of intravascular hemolysis in PCH. Eculizumab, an anti-C5 monoclonal antibody that blocks the terminal complement pathway, resulted in an efficient, complete, and sustained clinical improvement following a single dose. We observed no adverse effects. This case suggests a need for further investigation of complement-blockade, either at the terminal pathway or classical pathway level, in the treatment of this disease. Figure Disclosures Berentsen: Apellis: Consultancy, Honoraria; Alexion: Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Mundipharma: Research Funding; True North Therapeutics: Consultancy, Honoraria. OffLabel Disclosure: Eculizumab for paroxysmal cold hemoglobinuria

CH50 Activity Correlates with Residual Intravascular Hemolysis in Pts with Paroxysmal Nocturnal Hemoglobinuria Treated by Eculizumab

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3193-3193
Author(s):  
Regis Peffault de Latour ◽  
Veronique Fremeaux-Bacchi ◽  
Raphael Porcher ◽  
Paula Rodriguez-Otero ◽  
Stephane Roncellin ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cells ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Factor H ◽  
Intravascular Hemolysis ◽  
Upper Limit ◽  
History Of ◽  
Circulating Levels

Abstract Abstract 3193 Background: Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by intravascular hemolysis, which is effectively controlled with eculizumab. However, in some cases, unexplained upper limit lactate dehydrogenase levels (LDH), as well as low haptoglobin levels are not unusual under treatment, suggesting residual low-level hemolysis. C3-mediated clearance of PNH red blood cells has been recently suggested in patients (pts) under eculizumab (Risitano Blood 2010). We hypothesized residual hemolysis may also be due to incomplete C5 blockage under treatment. CH50 activitiy (residual functional C5 activity) as well as C3 deposition on PNH red blood cells were assessed among eculizumab-treated pts. We also examined the hypothesis that mutations in complement genes are implicated in residual hemolytic process. Patients and Methods: From October 2010 to February 2012, 22 pts (7 male, median age 42 years range 21 to 72) with hemolytic PNH treated with eculizumab (900 mg intravenously every 14±2 days) were prospectively followed systematically every 2 weeks. Before each Eculizumab infusion, clinical data (abdominal pain, thrombosis events and transfusion requirements) as well as complete blood count, LDH, bilirubin levels and reticulocytes were systematically collected. Concomitantly, CH50 using sensibilized sheep red blood cells, C3d deposition on red blood cells using flow cytometry as well as C3 and C4 circulating levels were also studied. Complete C5 blockage was defined by a CH50 activity ≤10% (as for pts with hereditary complete C5 deficiency). All pts included in the study have at least 6 months follow-up under treatment. Only measurements performed after at least 6 months of treatment were considered. Residual intravascular hemolysis was defined by upper limit LDH level before eculizumab injection. CH50 was analyzed with a longitudinal tobit regression model accounting for repeated sampling and the limit of detection. The model was fit in a Bayesian framework, so no p-values are presented. Results: Before starting eculizumab, 21 pts were transfusion-dependent with a mean of 7 red blood cell (RBC) transfusions per year and 9 pts had a significant PNH-related complication (9 thrombosis and 7 with a previous history of aplastic anemia). During the study period, 6 pts received at least one transfusion (mean of 3 RBC transfusions per year) and 1 patient presented a deep vein thrombosis. All pts were analyzed for CH50 activity (412 samples; median 19 per patient; range, 4 to 31). Overall, CH50 measurements showed substantial variability for most pts (Figure 1). Residual CH50 activity (>10%) was significantly associated with higher LDH levels whereas pts who were still transfused (as well as pts with lower hemoglobin level and higher reticulocytes counts) tended to have higher CH50. Type III PNH red blood cell C3d deposition (assessed in all but 1 patient; 277 samples; median 14 per patient; range, 2 to 21) was found in all pts evaluated during the study period (Fig. 1). However, we did not find any correlation between C3 opsonization and clinical or biological signs of hemolysis. The association between CH50 and higher C3 deposition was weak (on average −0.8% CH50 per 10%) more C3 deposition (95%CI −1.7 to 0.2) (Fig. 1). Those results were confirmed in the subset of 15 patients with pure hemolytic PNH (no history of aplastic anemia). C3 and C4 circulating levels were in the normal range during the study period in all but one patient (pts#15, Fig. 1), who carry a complement factor H (CFH) mutation, leading to a quantitative Factor H deficiency. Systematic screening was positive for 2 other pts (CFH, pts#1; C3 mutation, pts#14) but with no phenotypical consequence. Conclusion: Our results confirm the excellent overall clinical and biological response of hemolytic PNH pts to eculizumab. We found that unblocked CH50 activity, reflecting the residual C5 activity, was significantly associated with residual intravascular hemolysis while the selective C3d deposition of PNH red cells (found in all pts under treatment) was not. We also identified mutations in C3 and factor H genes. Whether incomplete C5 blockade is due to low residual level of eculizumab, complement mutations or polymorphisms, or other mechanisms are under investigation. Disclosures: No relevant conflicts of interest to declare.

Computer Modeling of Fluid-Stress-Induced Blood Damage in a Mechanical Ventricular Assist Device

2009 ◽  
Author(s):  
Alexandrina Untaroiu ◽  
Houston G. Wood ◽  
Paul E. Allaire
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Damage Index ◽  
Computational Domain ◽  
Ventricular Assist ◽  
Blood Damage ◽  
History Of ◽  
Number Of Particles

Congestive heart failure results the heart is unable to pump the required amount of blood to maintain the systemic circulation. World-wide, millions of patients are diagnosed with congestive heart failure every year, many of which ultimately become candidates for heart transplants. The limited number of available donor hearts, however, has resulted in a tremendous demand for alternative, supplemental circulatory support in the form of artificial heart pumps to serve as a “Bridge-to-Transplant”. The prospect of artificial heart pumps used for long-term support of congestive heart failure patients is directly dependent upon excellent blood compatibility. High fluid stress levels may arise due to high rotational speeds and narrow clearances between the stationary and rotating parts of the pump. Thus, fluid stress may result in damage to red blood cells and activation of platelets, contributing to thrombus formation. Therefore, it is essential to evaluate levels of blood trauma for successful design of a mechanical Ventricular Assist Device. Estimating the fluid stress levels that occur in a blood pump during the design phase also provides valuable information for optimization considerations. This study describes the CFD evaluation of blood damage in a magnetically suspended axial pump that occurs due to fluid stress. Using CFD, a blood damage index, reflecting the percentage of damaged red blood cells, was numerically estimated based on the scalar fluid stress values and exposure time to such stresses. A number of particles, with no mass and reactive properties, was injected at the inflow of the computational domain and traveled along their corresponding streamlines. A Lagrangian particle tracking technique was employed to obtain the stress history of each particle along its streamline, making it possible to consider the damage history of each particle. Maximum scalar stresses of approximately 430 Pa were estimated to occur along the tip surface of the impeller blades, more precisely at the leading edge of the impeller blades. The maximum time required for the vast majority of particles to pass through the pump was approximately 0.085sec. A small number of particles (approximately 5%), which traveled through the narrow gap between the stationary and rotating part of the pump, exited the computational domain in approximately 0.2 sec. The mean value of blood damage index was found to be 0.15% with a maximum value of approximately 0.47%. These values are one order of magnitude lower than the approximated damage indices published in the literature for other Ventricular Assist Devices. The low blood damage index indicates that red blood cells traveling along the streamlines considered are not likely to be ruptured, mainly due to the very small time of exposure to high stress.

The Effects of Infusing Thrombin and Its Acetylated Derivative

1968 ◽  
Vol 20 (03/04) ◽  
pp. 469-476 ◽  
Author(s):  
J. M Bennett ◽  
Dinah Yu ◽  
J Suyemoto ◽  
L Pechet
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Intravascular Hemolysis ◽  
Short Term ◽  
Unique Role ◽  
Indirect Action

Summary and ConclusionsIn conjunction with experiments designed to test the effects of infusing acetylated thrombin (Thrombin E) and Clotting thrombin (Thrombin C) into dogs, the occurrence of hemolysis was noted. Serial observations on its magnitude, its relationship to thrombin-induced defibrination, and the formation of thrombi were made. The findings suggest a unique role for thrombin in inducing “in vivo” intravascular hemolysis in short term experiments, possibly via an indirect action on red blood cells.

A Hemolytic Transfusion Reaction Caused by an Unexpected Leb Antibody

2021 ◽  
Author(s):  
Alexander A Delk ◽  
Richard R Gammon ◽  
Harold Alvarez ◽  
Nancy Benitez ◽  
Frieda Bright
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Black Male ◽  
Blood Cells ◽  
Reference Laboratory ◽  
Transfusion Reaction ◽  
Cell Disease ◽  
Hemolytic Transfusion Reaction ◽  
History Of ◽  
Possible Cause

Abstract A Black male patient aged 21 years with a history of sickle cell disease and HIV was admitted to the hospital with vaso-occlusive crisis. A transfusion reaction was called after the patient developed a fever (39.5°C), tachycardia, chills, and hematuria after receiving 300 mL of red blood cells. A posttransfusion specimen was submitted to the Immunohematology Reference Laboratory for investigation. Antibody identification revealed an anti-Leb as the probable cause of the immediate acute hemolytic transfusion reaction. Lewis antibodies are considered clinically insignificant. This case shows the importance of considering cold antibodies, including Lewis antibodies, as a possible cause of an acute hemolytic transfusion reaction.

scholarly journals Transfusion of packed red blood cells at the end of shelf life is associated with increased risk of mortality – a pooled patient data analysis of 16 observational trials

Haematologica ◽  
2018 ◽  
Vol 103 (9) ◽  
pp. 1542-1548 ◽  
Author(s):  
Monica S.Y. Ng ◽  
Michael David ◽  
Rutger A. Middelburg ◽  
Angela S.Y. Ng ◽  
Jacky Y. Suen ◽  
...  
Keyword(s):  
Data Analysis ◽  
Red Blood Cells ◽  
Shelf Life ◽  
Blood Cells ◽  
Patient Data ◽  
Packed Red Blood Cells ◽  
Risk Of Mortality ◽  
Increased Risk

scholarly journals Hereditary Spherocytosis Due to a Novel Variant, P.Q1034X, in the Beta Subunit of the Spectrin Gene

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Faraz A Afridi ◽  
Jennifer Van Helmond ◽  
Rafat Ahmed ◽  
Jaya Ganesh
Keyword(s):  
Cell Membrane ◽  
Red Blood Cells ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Blood Cells ◽  
Hereditary Spherocytosis ◽  
Red Cell ◽  
Red Cell Membrane ◽  
Whole Exome ◽  
History Of

Introduction: Hereditary Spherocytosis (HS) is the most common red cell membrane disorder. 25-30% of cases involve the SPTB gene which encodes for β-Spectrin, a protein that maintains red blood cell shape. Heterozygous variants in SPTB are associated with autosomal dominant HS and elliptocytosis. While genetic testing is not routinely done to confirm HS, it is useful in atypical presentations. Case Description: A 1 week old male presented to the pediatric hematology/oncology clinic for anemia. He was born late preterm and had a history of hyperbilirubinemia requiring phototherapy, failure to thrive, and developmental delay. On examination, he was noted to have hypotonia. There was no known family history of hematologic problems. Based on this constellation of signs and symptoms, he had a comprehensive hematologic and genetic workup. On lab evaluation, his peripheral blood smear showed normocytic normochromic red blood cells with some spherocytes, significant polychromasia, normal WBC and normal platelet morphology. His newborn screen was normal, direct coombs' negative, osmotic fragility test was positive, and protein band 3 reduction was abnormal. His abdominal ultrasound was normal. Whole exome sequencing with variant segregation analysis was significant for heterozygosity of the p.Q1034X variant of the SPTB gene. This variant in the SPTB gene has not been previously reported. Discussion: We found a novel, de novo variant in an infant with HS through whole exome sequencing. This variant is predicted to cause loss of normal protein function either through protein truncation or non-mediated mRNA decay resulting in fragile red blood cells. While neither parent was found to carry this mutation, germline mosaicism should not be excluded. Physicians should be aware that prenatal diagnosis is available to address the risk of recurrence in future pregnancies. References: 1. Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis Stefan Eber-Jennifer Gonzalez-Marcia Lux-Alphonse Scarpa-William Tse-Marion Dornwell-Jutta Herbers-Wilfried Kugler-Refik Ozcan-Arnulf Pekrun-Patrick Gallagher-Werner Schroter-Bernard Forget-Samuel Lux - Nature Genetics - 1996 2. Characterization of the underlying molecular defect in hereditary spherocytosis associated with spectrin deficiency. H Hassoun-JN Vassiliadis-J Murray-PR Njolstad-JJ Rogus-SK Ballas-F Schaffer-P Jarolim-V Brabec-J Palek - Blood - 1997 3. The Complexity of Genotype-Phenotype Correlations in Hereditary Spherocytosis: A Cohort of 95 Patients Vuren-Annelies & Zwaag-Bert & Huisjes-Rick & Lak-Nathalie & Bierings-M.B. & Gerritsen-Egbert & van Beers-Eduard & Bartels-Marije & Van Wijk-Richard - HemaSphere - 2019 4. Hereditary spherocytosis with spectrin deficiency due to an unstable truncated beta spectrin. H Hassoun-JN Vassiliadis-J Murray-SJ Yi-M Hanspal-CA Johnson CA-J Palek - Blood - 1996 5. LL Peters- Semin Hematol-2018 6. Red cell membrane: past, present, and future Narla Mohandas-Patrick Gallagher - Blood - 2008 7. Spectrum of Ankyrin Mutations in Hereditary Spherocytosis: A Case Report and Review of the Literature Yeping Luo-Zhuoying Li-Lihua Huang-Jing Tian-Menglong Xiong-Zuocheng Yang - Acta Haematologica - 2018 Figure: A map of all the pathogenic mutations found on the protein structures of ankyrin-1, a-spectrin, b-spectrin and band 3. Figure Disclosures No relevant conflicts of interest to declare.

Volume of red blood cells and plasma is associated with increased risk of venous thromboembolism in trauma patients

2014 ◽  
Vol 219 (4) ◽  
pp. e190 ◽  
Author(s):  
Greg Magee ◽  
Kenji Inaba ◽  
Konstantinos Chouliaras ◽  
Aaron Strumwasser ◽  
Kazuhide Matsushima ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Trauma Patients ◽  
Increased Risk

Transforming growth factor–β1 in supernatants from stored red blood cells inhibits neutrophil locomotion

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 1100-1107 ◽  
Author(s):  
Massimo Ghio ◽  
Luciano Ottonello ◽  
Paola Contini ◽  
Massimo Amelotti ◽  
Clemente Mazzei ◽  
...  
Keyword(s):  
Growth Factor ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Fas Ligand ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Increased Risk ◽  
High Dilutions ◽  
Formyl Peptides ◽  
Tgf Β1

Abstract Studies comparing transfusion and nontransfusion patients suggest an increased risk of postoperative infections in transfusion groups. Supernatants of blood components have been shown to affect the function of T lymphocytes and natural killer cells. Here, we found that supernatants from stored red blood cells (RBCs) inhibit human neutrophil migration in response to formyl peptides and stimulate neutrophil locomotion. These effects can be observed with high dilutions of RBC supernatants, such as 1:5 × 106 (vol/vol), able to trigger locomotion as well as desensitization of the cells to alternative chemoattractants. The phenomenon might be mediated by chemoattractants present in the supernatants. As RBC supernatants failed to mobilize intracellular free calcium, the chemoattractants should belong to the group of pure chemoattractants, that is, soluble Fas ligand (sFasL) and transforming growth factor–β1 (TGF-β1), known to act without increasing calcium levels. Recombinant TGF-β1, but not sFasL, was found to reproduce the ability of RBC supernatants to both inhibit neutrophil response to formyl peptides and stimulate neutrophil locomotion. Moreover, TGF-β1–immunodepleted supernatants did not display neutrophil-directed activities. Finally, RBC supernatants from RBCs stored after depletion of leukocytes were incapable of affecting neutrophil function. With neutrophils acting as a first-line antimicrobial defense, the ability, shown here, of high dilutions of RBC supernatants to inhibit neutrophil chemotaxis through TGF-β1 may be a relevant determinant of infections in the postoperative period for transfusion patients. Consistently, the neutrophil chemotactic response to formyl peptide was inhibited by the plasma obtained from 5 transfusion patients.

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