scholarly journals Intravenous Immunoglobulin in the Management of Severe Early Onset Red Blood Cell Alloimmunization

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2140-2140
Author(s):  
Evangelia Vlachodimtropoulou Koumoutsea ◽  
Tsz Kin Lo ◽  
Clarissa Bambao ◽  
Greg Denomme ◽  
Gareth Seaward ◽  
...  
Keyword(s):  
Blood Cell ◽  
Intravenous Immunoglobulin ◽  
Red Blood Cell ◽  
Early Onset ◽  
Conflicts Of Interest ◽  
Fetal Loss ◽  
Ivig Treatment ◽  
Haemolytic Disease ◽  
Intrauterine Transfusion ◽  
Perinatal Survival

Abstract OBJECTIVE: We report the outcome of pregnancies treated with intravenous immunoglobulin (IVIG) for severe red blood cell alloimmunization, evaluating whether IVIG defers the development of severe fetal anaemia and its consequences. BACKGROUND: Although fetal anemia can be treated very successfully with intrauterine transfusion (IUT), procedures before 20 weeks' gestation can be very challenging technically and may be hemodynamically stressful to an extremely premature and already compromised fetus. The procedure-related fetal loss rate is approximately 5.6% for IUTs performed < 20 weeks' gestation, compared to 1.6% overall. IVIG may prevent hemolysis and could therefore be a noninvasive alternative for early transfusions. STUDY DESIGN: We included consecutive pregnancies over a nineteen year period in the Fetal Medicine Unit, Mount Sinai Hospital, University of Toronto, Canada, of alloimmunized women with a history of severe early onset haemolytic disease who received IVIG until intrauterine transfusion could safely be performed. Previous untreated pregnancies were used as controls. IVIG therapy was commenced between 11 and 14 weeks' gestation. Our usual protocol was IVIG 2 g/kg per week every 3 weeks, until the first IUT could be performed. Each 2g/kg dose was administered over 2 days, 1g/kg per day, to reduce the chance of severe headaches. In three pregnancies, IVIG 1g/kg was given weekly. We compared the clinical outcomes (gestation at first IUT, fetal Hb at first FBS, gestation at delivery, perinatal survival) between previous pregnancies without IVIG and the subsequent pregnancy treated with IVIG. In comparing fetal Hb's between two pregnancies, a linear relationship between fetal Hb and gestation was used to correct for variable gestations. The fetal Hb was converted to a standardized fetal Hb value (multiples of the standard deviation [SD]). Statistical analysis was performed on 'Statistical Package for Social Science Version 16.0' (SPSS Inc, Chicago, Illinois). RESULTS: Seventeen women referred to our unit for a previous pregnancy loss secondary to severe RBC alloimmunization received IVIG treatment in 20 subsequent pregnancies; all eventually requiring intrauterine transfusion. For previous early losses despite transfusion, immunoglobulin was associated with a relative increase in fetal hemoglobin between treated and untreated pregnancies of 32.6 g/L (95%CI 15.2-50.0, P=0.003) and improved perinatal survival (8/8 vs 0/6, P=0.001). For previous losses <20 weeks, it enabled first transfusion deferral in subsequent pregnancies to at least 19.9 (mean 23.2) weeks. Of the 17 live-born babies from IVIG-treated pregnancies, three (18%) required an exchange transfusion, eight (47%) a simple "top-up" transfusion, and six (35%) phototherapy. CONCLUSION: Our results show that, among severely sensitized cases with previous early fetal loss despite IUT, use of IVIG in subsequent pregnancies is associated with a significantly higher fetal Hb before first IUT, deferral of first IUT, delivery at a later gestation and increased perinatal survival. The timing of the first FBS/IUT was delayed by 3 weeks in pregnancies treated with IVIG compared to a previous untreated pregnancy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Antigen specificity determines anti-red blood cell IgG-Fc alloantibody glycosylation and thereby severity of haemolytic disease of the fetus and newborn

2016 ◽  
Vol 176 (4) ◽  
pp. 651-660 ◽  
Author(s):  
Myrthe E. Sonneveld ◽  
Joke Koelewijn ◽  
Masja de Haas ◽  
Jon Admiraal ◽  
Rosina Plomp ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Antigen Specificity ◽  
Haemolytic Disease

scholarly journals Factors associated with persistence of red blood cell antibodies in woman after pregnancies complicated by fetal alloimmune haemolytic disease treated with intrauterine transfusions

2014 ◽  
Vol 168 (3) ◽  
pp. 443-451 ◽  
Author(s):  
Esther P. Verduin ◽  
Anneke Brand ◽  
Leo M. G. van de Watering ◽  
Frans H. J. Claas ◽  
Dick Oepkes ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Haemolytic Disease ◽  
Factors Associated

Hemoglobinuria and Mechanical Hemolysis Associated with Red Blood Cell Transfusion in Pediatric Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3429-3429 ◽  
Author(s):  
Janet McNaughton ◽  
Jonathan Hughes ◽  
Jennifer C. Andrews ◽  
Tracy I. George ◽  
Cassandra Bergero ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Conflicts Of Interest ◽  
Infusion Pump ◽  
Red Blood Cell Transfusion ◽  
Treatment Center ◽  
Outpatient Unit ◽  
Time Period ◽  
Additive Solution

Abstract Abstract 3429 Introduction: Mechanical hemolysis is a non-immune mediated destruction of red blood cells that can be associated with blood transfusion. Various etiologies include the use of blood warmers, small bore needles or high infusion rates. We report the investigation of hemoglobinuria cases observed post-packed red blood cell (PRBC) transfusion with subsequent changes in management. Case report: Over a time period of 2 months, 6 events of hemoglobinuria and hemolysis were reported in 5 patients in the pediatric hematology/oncology treatment center. Each child presented with abnormally tea-colored urine following PRBC transfusion. Transfusion reaction workup included a direct antiglobulin test (DAT), urinalysis (UA), serum haptoglobin (H), lactate dehydrogenase (LDH), and total bilirubin (T-B). All patients had a negative or unchanged DAT, negative RBC antibody screen, decreased H, increased T-B, and increased LDH (4 out of 6), suggestive of intravascular hemolysis (Table). In spite of hemolysis, hemoglobin (Hgb)/hematocrit(Hct) increased normally. Multiple factors were investigated to determine a cause: collection and processing of blood units; handling of blood at the transfusion service; and blood administration by nursing staff. The only significant change identified was the implementation of a new infusion pump (pump A) replacing a model that was phased out. A hospital-wide retrospective review of urinalysis (UA) was performed over a one month time period, along with prospective UA surveillance in the outpatient unit. Results: In the 6 cases, a total of 10 irradiated PRBC units (7 with citrate phosphate dextrose buffer (CPDA1, HCT 65–80%) and 3 with additive solution (AS-5, HCT 55–65%)) were transfused. Although Pump A had been validated by the manufacturer with non-irradiated additive solution units, an in vitro study with irradiated CPDA1 RBC units was performed to compare pump A with an alternative pump B. Samples were taken after infusion using the pumps only (no needle or catheter) and dripped directly into the test tube for measurement of free hemoglobin (FHb). Irradiated CPDA1 units infused at a low rate (50ml/hr) showed an increase in FHb level at 1998mg/dL with pump A versus 496 mg/dL with pump B. Non-irradiated AS-5 units tested as controls resulted in a FHb level at 246mg/dL with pump A versus 117mg/dL with pump B. CPDA1 units were subsequently replaced with AS-5 units for transfusion. Finally, pump A was replaced by pump B in the outpatient hematology oncology unit. In vitro studies are still ongoing to determine if irradiation of the PRBC may also play a role in the mechanical hemolysis observed with pump A. One month retrospective UA review found no association between patients with hemoglobinuria and RBC transfusion. The UA prospective surveillance performed in the outpatient unit revealed that 7 of 26 patients had trace hemoglobinuria. Each one had a confounding factor (chronic hemolysis) for hemoglobinuria. Conclusion: Preliminary investigation determined that the infusion of highly concentrated irradiated RBC (CDPA1) using a specific commercial pump was associated with mechanical hemolysis. The change to less concentrated RBC units through an alternative pump has been to date, an effective corrective action. Disclosures: No relevant conflicts of interest to declare.

Transfusion Of Thawed Rare Red Blood Cell Units In Finland

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4823-4823
Author(s):  
Eeva Juvonen ◽  
Inna Sareneva ◽  
Katri Haimila ◽  
Anu Elina Korhonen ◽  
Susanna Sainio
Keyword(s):  
Blood Cell ◽  
Blood Group ◽  
Red Blood Cell ◽  
Conflicts Of Interest ◽  
Blood Groups ◽  
Red Cross ◽  
Reference Laboratory ◽  
Red Cell ◽  
Chronic Anemia ◽  
Blood Hemoglobin

The Finnish Red Cross Blood Service performs blood grouping of all blood donations in Finland and serves as a national reference laboratory in pre-transfusion testing of patients. In addition to ABO and RhD blood groups, other Rh antigens and K antigen are also determined from all red cell units. The antigens of JK, FY, and MNS blood group systems are analyzed from selected donors. The extensive donor typing procedure includes antigens from KEL, LW, LU, CO, DO, DI, YT, GE and CROM blood group systems, performed either serologically or by genotyping. Patients negative for a high frequency blood group antigen present a challenge for transfusion laboratories. A blood group is considered rare if the prevalence is 1:1000 or less, with the most common rare phenotypes in Finland being LWa neg, Jk:-3 and Pk. To ensure the availability of matching blood for patients with a rare blood group, we started a freezing program of rare blood in Finland with Haemonetics ACP 215 process in April 2010. The system is closed, therefore after thawing the units are safe for use for 7 days. 18 blood groups which were included in the program were determined based on the known rare blood groups in the Finnish population. Blood groups which are globally rare but more common in Finland, such as Jk:-3 and LWa neg, are represented in our storage and also available internationally. The aim of the present study was to analyze the status of the freezing program of rare red blood cells in Finland. For the analysis we asked the transfusion data of rare red blood cell units delivered to 10 national and 2 international hospitals. Results: In 2010-2012, altogether 204 units of rare blood were stored, including units of all the predefined rare phenotypes except Vel neg. With the exception of Vel neg, Hrs neg and Oh blood groups, we have been able to meet the need for rare blood in Finland using Finnish donors. Altogether 55 units have been thawed and distributed to 27 adult patients. The indication was delivery in 3 cases, surgery in 6 cases, and chronic anemia in 4 cases. For the present analyses the transfusion data of 49 units was available. The data of 6 Coa neg units is missing. Altogether 22 / 49 (45%) of the units were transfused. In 14 cases the blood was transfused to the patient it was intended for, and in 8 cases to another patient, 27 units were discarded. There were no transfusion associated complications. The hemoglobin response was evaluable in 7 patients. In 4 patients with a chronic anemia the median blood hemoglobin response per a unit was +8 g/l, range +2 - +16 g/l. In 3 patients with blood loss during an operation the median increase in blood hemoglobin value was +7 g/l per unit, range +4 – +12 g/l. Conclusions: Compared to the common 24 hour eligibility of thawed red cell units, our units valid for 7 days are preferable in countries like Finland with long distances and in international rare blood deliveries. We have been able to offer rare blood to Finnish patients. The hemoglobin response was reasonable and there were no transfusion associated complications. Our next challenge will be to recruit Finnish blood donors with different ethnic backgrounds (eg. immigrants) and identify their rare blood groups. We have already expanded our program to include rare combinations of common blood groups. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Toward a Proteome-Complete Computational Model of the Human Red Blood Cell

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4888-4888
Author(s):  
James T Yurkovich ◽  
Laurence Yang ◽  
Bernhard O Palsson
Keyword(s):  
Systems Biology ◽  
Blood Cell ◽  
Computational Model ◽  
Red Blood Cell ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Protein Complexes ◽  
Proteomics Data ◽  
Hemoglobin Binding ◽  
Starting Point

Abstract The human red blood cell has served as a starting point for the application and development of systems biology approaches due to its simplicity, intrinsic experimental accessibility, and importance in human health applications. Here, we present a multi-scale computational model of the human red blood cell that accounts for metabolism and macromolecules. Proteomics data are used to place quantitative constraints on individual protein complexes that catalyze metabolic reactions, as well as a total proteome capacity constraint. We explicitly describe molecular mechanisms-such as hemoglobin binding and the formation and detoxification of reactive oxygen species-and account for sequence variations between individuals, allowing for personalized physiological predictions. This model allows for direct computation of the oxyhemoglobin curve as a function of model species and a more accurate computation of the flux state of the metabolic network. More broadly, this work represents another step toward building increasingly more complete systems biology whole-cell models. Disclosures No relevant conflicts of interest to declare.

Perinatal outcomes of intrauterine transfusion for foetal anaemia due to red blood cell alloimmunisation

2019 ◽  
Vol 40 (5) ◽  
pp. 649-653
Author(s):  
Ayşe Özge Şavkli ◽  
Berna Aslan Çetin ◽  
Zuat Acar ◽  
Zeynep Özköse ◽  
Mustafa Behram ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Perinatal Outcomes ◽  
Intrauterine Transfusion

ULK1-Hsp90-Cdc37 and AMPK: Novel Insight Into the Regulation of Mitophagy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 987-987
Author(s):  
Joung Hyuck Joo ◽  
Mondira Kundu
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Kinase Activity ◽  
Conflicts Of Interest ◽  
Cell Maturation ◽  
Physical Interaction ◽  
Intrinsically Disordered ◽  
Ampk Phosphorylation ◽  
Mitochondrial Turnover ◽  
Insight Into

Abstract Abstract 987 Autophagy plays an important role in maintaining mitochondrial integrity, directing lysosome-mediated destruction of cellular cargo, including damaged or dysfunctional mitochondria. Flux through the autophagy pathway is rapidly induced to promote survival in response to metabolic or proteotoxic stress resulting from exposure to noxious environmental cues, such as starvation, hypoxia or heat stress and likely contributes to the increase in mitochondrial turnover observed under each of these conditions. Dysregulation of this process has been linked to the pathogenesis of diseases, including anemia, diabetes, neurodegeneration and cancer. Atg1 is a serine-threonine kinase that directs the autophagy machinery to appropriate cargo in responses to changes in the availability of carbon and nitrogen in yeast. Ulk1, one of the mammalian homologues of Atg1, is required for starvation-induced autophagy and clearance of mitochondria in terminally differentiating erythroid cells. The function of Ulk1 is also regulated by AMP dependent Kinase (AMPK)-mediated phosphorylation, however, the precise molecular consequence of this post-translational modification has not been explored. Our preliminary findings indicate that AMPK phosphorylates Ulk1 during red blood cell maturation and in response to mitochondrial uncoupling, and that this phosphorylation is critical for mitochondrial clearance. Therefore, we sought to use these systems to explore the mechanism by which AMPK phosphorylation regulates Ulk1 function. We previously demonstrated that the stability and kinase activity of Ulk1 depends on its physical interaction with Hsp90 and the kinase-specific co-chaperone, Cdc37. Hsp90 is an abundant chaperone that directs the maturation and activation of a restricted group of metastable proteins, typically kinases and signaling molecules, and orchestrates a broad response to cellular stress. Here, we demonstrate that AMPK phosphorylation of Ulk1 does not affect Ulk1 kinase activity, but instead promotes its release from Hsp90 and its localization to damaged mitochondria. Preliminary studies indicate that the serine-proline rich domain of Ulk1, which contains at least 4 residues that are phosphorylated by AMPK, is an intrinsically disordered domain. We hypothesize that phosphorylation of Ulk1 by AMPK stabilizes a predicted alpha-helical structure within this domain and contributes to release of Hsp90. These findings are important because they provide significant insight into the regulation and function of Ulk1, a protein involved in mitochondrial turnover during red blood cell maturation and in proliferating cells. Disclosures: No relevant conflicts of interest to declare.

Red Blood Cell Alloimmunization and Hemolytic Disease of the Fetus and Newborn: New Approaches Using Animal Models

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-49-SCI-49
Author(s):  
Jeanne E. Hendrickson
Keyword(s):  
Bone Marrow ◽  
Blood Cell ◽  
Immune Globulin ◽  
Red Blood Cell ◽  
Placental Transfer ◽  
Conflicts Of Interest ◽  
Fetal Liver ◽  
Igg Subclasses ◽  
Hemolytic Disease ◽  
Blood Exchange

Abstract Women may become alloimmunized to foreign red blood cell (RBC) antigens after exposure during transfusion or pregnancy/delivery. These alloantibodies can be detrimental to developing fetuses/neonates, with six in every 1000 pregnancies being affected by maternal alloantibodies. Despite being described more than 80 years ago, hemolytic disease of the fetus and newborn (HDFN) has few preventive or therapeutic options. Outside of antigen avoidance, the most effective maternal preventive therapy to date is Rh immune globulin. However, it targets just one of the more than 50 antigens implicated in HDFN, and its mechanism of action remains unknown. Furthermore, treatment options for affected fetuses are limited largely to intrauterine transfusions of antigen negative RBCs. With a decrease in HDFN cases due to Rh(D), KEL has emerged as one of the most widely implicated antigens. We now describe a transgenic murine model in which the human KEL antigen is expressed on murine RBCs, with clinical significance in both pregnancy and transfusion settings. Transgenic animals were generated with expression of the human KEL2 antigen (referred to herein as KEL) on their RBCs using a β-globin promoter. KEL expression was evaluated on fetal liver and bone marrow erythroid precursors, mature RBCs, and organs. C57BL/6 or MuMT females were bred with transgenic heterozygous KEL males. Maternal serum was collected during pregnancy and after delivery, with anti-KEL glycoprotein responses measured by flow cytometric crossmatch. Newborn pups were evaluated for KEL positivity, degree of anemia, and presence of maternal anti-KEL. Additionally, the effect of anti-KEL alloantibodies on fetal RBC precursors was evaluated at multiple stages of gestation. Lastly, females alloimmunized through pregnancy were transfused with incompatible KEL RBCs labeled with a lipophilic dye, and females alloimmunized through transfusion were bred with KEL males. Transgenic mice have RBC specific expression of the KEL glycoprotein, with antigen detected on early and late RBC precursors in the fetal liver and bone marrow but not on any tested organ. Fetal/maternal blood exchange was maximally detected after delivery, with the majority of mothers developing anti-KEL glycoprotein antibodies (IgM and all IgG subclasses) within weeks of delivery. All IgG subclasses of anti-KEL crossed the placenta and bound to RBC precursors and mature RBCs in developing KEL positive pups; KEL negative pups had positive indirect antiglobulin tests. Maternal anti-KEL glycoprotein titers increased with antigen exposure, with fewer KEL positive pups born during successive pregnancies to alloimmunized C57BL/6 but not MuMT females. Affected KEL positive pups were anemic, and some were stillborn and hydropic-appearing. As has been described in humans, maternal anti-KEL alloantibodies suppressed the development of fetal KEL RBC precursors at all levels of maturation. Additionally, newborn pups had a relative reticulocytopenia, with reticulocyte recovery within a week after birth. Multiparous alloimmunized females exhibited rapid clearance of transfused incompatible KEL RBCs, and females alloimmunized through KEL RBC transfusion also had pups affected by HDFN. To the best of our knowledge, this is the first animal model of HDFN in which pregnancy stimulates alloantibodies to a paternally derived RBC antigen, with these alloantibodies being clinically significant in both pregnancy and transfusion settings. The anti-KEL glycoprotein alloantibodies generated in this model have similar effects on murine RBCs as anti-KEL1 alloantibodies have on human RBCs. Such effects include suppression of erythropoiesis, fetal anemia, and even hydrops fetalis. This model thus provides a platform to study not only the induction, placental transfer, and consequences of maternal RBC alloantibodies, but also to investigate potential preventive therapies (including “KEL” immune globulin). Long-term translational goals of this work include minimizing the dangers of RBC alloantibodies to developing fetuses and neonates, through the development of targeted maternal immunomodulatory therapies. Disclosures: No relevant conflicts of interest to declare.

Thymic-Derived Tolerizing Dendritic Cells Are up-Regulated upon Treatment with Intravenous Immunoglobulin or Splenectomy in a Murine Model of Immune Thrombocytopenia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2251-2251 ◽  
Author(s):  
Rick Kapur ◽  
Rukhsana Aslam ◽  
Edwin R. Speck ◽  
Michael Kim ◽  
Anne Zufferey ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Intravenous Immunoglobulin ◽  
Murine Model ◽  
Immune Thrombocytopenia ◽  
Conflicts Of Interest ◽  
Scid Mice ◽  
Ivig Treatment ◽  
High Dose ◽  
Platelet Counts ◽  
Inflammatory State

Abstract Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by low platelet counts. ITP has a complex pathogenesis, in which both anti-platelet antibodies as well as T cells have been shown to be important. Initial management of newly diagnosed ITP may be either watchful waiting or pharmacologic intervention, such as glucocorticoids or Intravenous Immunoglobulin (IVIg), a blood product consisting of polyclonal immunoglobulin G (IgG) derived from thousands of donors. Second-line therapy may include dexamethasone, high-dose methylprednisolone, rituximab, thrombopoietin (TPO)-receptor agonists, or splenectomy. The working mechanism of IVIg is actively under investigation and is still a matter of debate, as various different working mechanisms have been suggested. One of them is that IVIg may shift the balance from a pro- to anti-inflammatory state through immunomodulating the activity of dendritic cells (DCs). To gain more insights into the role of DCs in ITP, upon IVIg treatment or splenectomy, we analyzed DC subsets in a murine model of ITP, which features both the antibody and T cell mediated thrombocytopenia. Severe combined immunodeficient (SCID) mice were administrated 4x104 splenocytes from CD61 (GPIIIa) knockout mice immunized against CD61 (or naïve control splenocytes) and the mice were treated with or without 1 g/kg IVIg twice a week. Also the same type of splenocytes were transferred into splenectomized SCID mice. Weekly platelet counts were assessed and after 4 weeks the mice were sacrificed and spleen and thymuses were harvested. Splenocytes and thymocytes were isolated and examined by flow cytometry for cross-presenting (XCR1+) and non-presenting tolerizing (SIRP alpha+) DCs. Without IVIg or splenectomy, both splenic DC subset numbers correlated positively with platelet counts and both the thymic DC subset numbers correlated negatively with platelet counts, indicating thymic retention of DC in a setting of thrombocytopenia. Interestingly, splenectomized SCID mice, apart from increased platelet counts, demonstrated a complete reversal of the DC pattern in the thymus, as thymic DC subsets correlated positively with platelet counts in splenectomized mice. Upon IVIg treatment, apart from a general increase in platelet counts, the splenic tolerizing DCs significantly increased in numbers. Moreover, the thymic retention of tolerizing DCs and thus the negative correlation with platelet counts (R2: 0.46, p<0.05) was fully abrogated upon IVIg treatment (R2: 0.02, NS). Overall, our results indicate that both splenectomy as well as IVIg treatment can immunomodulate thymic tolerizing DCs significantly, in a murine model of ITP. Disclosures No relevant conflicts of interest to declare.

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