Recurrent acute splenic sequestration crisis due to interacting genetic defects: hemoglobin SC disease and hereditary spherocytosis

A 14-year-old boy with hemoglobin SC disease and alpha-thalassemia-2 experienced five episodes of acute splenic sequestration crisis (ASSC), while two of his siblings with identical globin genotypes (SC and - alpha/alpha alpha) had no such experience. To determine if an additional red blood cell (RBC) defect was responsible for the unusual occurrence of frequent ASSCs, we performed detailed rheologic characterization and membrane protein analysis on RBCs from the proband and other members of his family. Reduced surface area, increased mechanical instability, and decreased spectrin content of the membrane, distinguishing features of RBCs in hereditary spherocytosis, were observed in cells from the proband and his mother, but not in cells from other family members. These findings are consistent with the dominant inheritance of spherocytosis by the proband. We suggest that the combined effects of SC disease and spherocytosis in the proband resulted in decreased RBC deformability and led to increased splenic trapping, intrasplenic sickling, and consequently, recurrent sequestration crisis. Marked clinical and hematologic improvement occurred from splenectomy. Thus, inheritance of interacting genetic defects, sickling hemoglobinopathy, and hereditary spherocytosis appear to be responsible for the unusual clinical manifestation of recurrent ASSC in this patient.     

Philadelphia-positive metaphases in the marrow after bone marrow transplantation for chronic granulocytic leukemia

A 28-year-old man with Ph-positive chronic granulocytic leukemia (CGL) was treated by high-dose chemoradiotherapy and transplantation of marrow cells harvested from his HLA-identical brother. One year after bone marrow transplantation (BMT) examination of his marrow showed a minority population of Ph-positive cells; their proportion subsequently fell such that 2 years after transplant analysis of marrow cells showed only cytogenetically normal cells. The patient remains clinically normal with a persisting mild lymphocytosis but without hematological evidence of leukemia. We cannot in this patient distinguish between persisting leukemia that later could no longer be recognized and relapse of leukemia that is now suppressed, perhaps only temporarily. This case emphasizes the need for caution in interpreting chromosomal finding after BMT for CGL.     

Diminished extractable spectrin in the erythrocytes of a patient with 'sporadic' hereditary spherocytosis

A 51-year-old white man of Irish extraction was found to have apparent 'sporadic' hereditary spherocytosis with a reticulocyte count of 6%. Twelve of his 13 siblings were examined and found to be haematologically normal. The patient's erythrocytes were found to have a diminished amount of spectrin as compared to his siblings and to unrelated controls. It is suggested that the proband may represent either a new mutant or possibly double heterozygosity for two inherited biochemical variants of the red cell membrane skeleton which individually give no haematological abnormalities.     

An example of anti-Yta demonstrating a change in its clinical significance

The clinical significance of some red cell alloantibodies remains in doubt and can best be studied with long-term 51Cr survival studies. We report a patient whose IgG anti-Yta was initially shown not to shorten the lifespan of 51Cr-labeled Yt(a+) red cells. At the time of this study, the subclass of the antibody could not be determined. Twelve weeks after transfusion with 4 units of Yt(a+) red cells, the alloantibody for the first time was demonstrable as IgG1; a repeat radiolabeled red cell survival demonstrated significant shortening of the lifespan of Yt(a+) red cells when they were followed for 7 days. These cells had a marked 'two-component' survival curve. Because the patient also demonstrated autoantibody coating his red cells, the clinical effect of this autoantibody was followed with autologous red cells labeled with 111In; the survival of autologous red cells was normal throughout these studies. Evaluation of the clinical significance of an alloantibody in a patient may require long-term 51Cr red cell survival studies and repetition of these studies after exposure to large quantities of the antigen.     

Anti-K13 and the K:-13 Phenotype

Abstract. A 'new' antibody that recognizes a high-frequency red-cell antigen in the Kell blood group system has been found in the serum of a K–k+, Kp(a–b+), Js(a–b+) person, who is heterozygous for the silent K ^o gene. The antibody, named anti-K13, reacted with all of 1,000 unselected blood samples, but does not react with the red cells of the propositus, one of his five siblings, nor with K_o cells. Red cells of a child with chronic granulomatous disease and the McLeod phenotype were weakly reactive.     

Bone marrow transplantation for constitutional pure red cell aplasia

Constitutional pure red cell aplasia (CPRCA) is a syndrome of failed erythropoiesis usually diagnosed within the first year of life. Four patients with CPRCA received transplants with marrow from their HLA- identical, mixed lymphocyte culture-nonreactive siblings. All patients were resistant to corticosteroid therapy and were dependent on regular red cell transfusions for at least 5 years. Three patients were conditioned with procarbazine, antithymocyte globulin, cyclophosphamide, and busulfan, and one was conditioned with antithymocyte serum, cyclophosphamide, and busulfan. Three patients promptly had successful engraftments with establishment of donor hematopoiesis. One patient initially rejected his graft but received a successful retransplant. All patients are currently alive with Karnofsky performance scores of 100 and normal erythropoiesis of donor origin. Despite a history of multiple transfusions, bone marrow transplantation is a potentially curative therapy for patients with CPRCA.     

Febrile transfusion reaction following initial transfusion in a man with immunoblastic lymphadenopathy and granulocyte autoantibodies

A 69-year-old man with immunoblastic lymphadenopathy and autoimmune hemolytic anemia who had no previous exposure to blood products developed a severe febrile nonhemolytic transfusion reaction following the initial infusion of packed red blood cells. The reaction recurred with transfusion of packed red blood cells, but not when freeze-thawed red blood cells were used. Immunofluorescence techniques demonstrated granulocyte antibodies in his serum and on the surface of his granulocytes. Circulating immune complex, HLA, and platelet antibodies were not present. The granulocyte antibodies fluctuated in titers with disease activities, and could be completely removed from the serum by autologous granulocyte absorption. We conclude that our patient had granulocyte autoantibodies which probably produced febrile transfusion reactions.     

Anti-C4 in the Serum of a Transfused C4-Deficient Patient with Systemic Lupus erythematosus

A C4-deficient patient with systemic lupus erythematosus had been transfused on several occasions. His red cells reacted with a proportion of anti-Rg (Rodgers) and anti-Ch (Chido) reagents, but this was due to a separable antibody that did not have anti-Rg or anti-Ch specificity. Eluates of anti-Rg and anti-Ch indicate his red cell phenotype to be Rg-Ch-. Anti-C4 has been identified in his serum that exhibits neither anti-Rg nor anti-Ch specificity, but has similar serological characteristics in reacting with C4- and C4d-coated red cells.     

Blood Chimeric Twins

A man and his twin sister were found to have two types of circulating red cells. The man had 89% A1 cells of his own and 11% A1B cells derived from his sister. The woman had 12% A1B cells of her own and 88% A1 cells derived from her brother. The two lines of red cells also had different Duffy and Kidd groups. The lymphocyte karyotype in the brother was 68% XY and 32% XX, and that in the sister was 60% XX and 40% XY. The possible mechanisms for producing different proportions of red cells and lymphocytes are discussed.     

Cefotetan-induced immune hemolytic anemia.

Immune hemolytic anemia due to a drug-adsorption mechanism has been described primarily in patients receiving penicillins and first-generation cephalosporins. We describe a patient who developed anemia while receiving intravenous cefotetan. Cefotetan-dependent antibodies were detected in the patient's serum and in an eluate prepared from his red blood cells. The eluate also reacted weakly with red blood cells in the absence of cefotetan, suggesting the concomitant formation of warm-reactive autoantibodies. These observations, in conjunction with clinical and laboratory evidence of extravascular hemolysis, are consistent with drug-induced hemolytic anemia, possibly involving both drug-adsorption and autoantibody formation mechanisms. This case emphasizes the need for increased awareness of hemolytic reactions to all cephalosporins.     

A Kidney Transplant Patient Who Died of COVID-19-associated Severe Acute Respiratory Distress Syndrome

We herein report a 67-year-old kidney transplant patient who died of COVID-19. He was treated with hydroxychloroquine and azithromycin and received mechanical ventilation that temporarily improved his respiratory status. Despite our efforts, however, he later developed respiratory failure and died 43 days after the disease onset. The autopsy revealed prominent organization of alveoli and alveolar ducts, with a massive accumulation of macrophages in the lungs. A few severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen-positive cells were detected in the lung, suggesting delayed virus clearance owing to his long-term immunosuppressed state, leading to constant lung damage and ultimately respiratory failure.     

Autoimmune Hemolytic Anemia Associated with an IgA Autoanti-Gerbich

A third patient with autoimmune hemolytic anemia due to autoantibodies against Gerbich antigens is described. The patient's serum contained strong hemagglutinating antibodies of the IgA plus IgG classes which reacted with all red blood cells (RBC) tested, but not with Gerbich-negative cells. Although the patient was typed as Gerbich positive, his serum failed to react with his own RBC, and the sensitization of his erythrocytes with autoantibodies was only demonstrable if eluates of his RBC were used. The failure of the autoantibodies to react with autologous RBC at the peak of hemolysis most likely reflects a weakening of Gerbich antigens during the course of autoimmune hemolytic anemia.     

Auto-anti-Jka in Evans''syndrome with negative direct antiglobulin test

A patient presented with haemolytic anaemia and a negative direct antiglobulin test (DAT), and was found to have an IgG antibody with anti-Jka specificity in his serum. His red cells were typed as Jk(a-b+). Later he developed idiopathic thrombocytopenic purpura (ITP), and had a positive DAT due to anti-Jka bound to his red cells, which now typed as Jk(a+b+). Family studies suggested that the patient's true type was Jk(a+b+). Splenectomy and immunosuppression were required to treat the thrombocytopenia. The autoanti-Jka was no longer detectable following therapy.     

Anti-Lu8, an Antibody Recognizing Another Lutheran-Related Antigen

Abstract. An antibody defining another high-frequency antigen within the Lutheran system, designated as anti-Lu8, has been found in the serum of a Caucasian woman. The serum is compatible with Lu(a-b-) cells of the dominant and recessive types but reacts with Lu(a-b+) cells that are Lu(-4), Lu(-5), Lu(-6) and Lu(-7). All of the family members are Lu(a-b+). The red cells of two of the four siblings are not agglutinated by the serum but the red cells of her parents and two children are agglutinated suggesting that Lu8 is controlled by an autosomal dominant gene.     

Establishment of erythropoiesis following bone marrow transplantation in a patient with congenital hypoplastic anemia (Diamond-Blackfan syndrome)

Marrow transplantation was attempted in a 13-yr-old boy with congenital hypoplastic anemia who had never responded to corticosteroid therapy. Prior to the transplant, he had received 238 transfusions, at least 12 of which were from his father. He was prepared for grafting with antilymphocyte globulin, procarbazine, and total body irradiation (1000 rads). The patient, whose red cells were Group B, then received marrow cells from his Group O, histocompatible, sister. Thereafter, reticulocytes, Group O erythrocytes, and female leukocytes appeared in the peripheral blood. Erythroid precursors were seen in the patient's marrow for the first time in his life, and all lacked fluorescent Y chromosomes. Dividing cells were all female. After initially progressing well, the patient developed interstitial pneumonia and died 55 days after the transplant. The successful erythroid graft suggested that this patient's failure to produce red blood cells was due to a defective stem cell rather than to a humoral defect, plasma inhibitor, or abnormal marrow microenvironment. It suggested further that sibling marrow may be engrafted in patients who have received multiple transfusions, even from a parent.     

β-Spectrin Sta Bárbara: a novel frameshift mutation in hereditary spherocytosis associated with detectable levels of mRNA and a germ cell line mosaicism

Hereditary spherocytosis (HS) is a common inherited anaemia characterized by the presence of spherocytic red cells and by a heterogeneous nature in terms of its clinical presentation, molecular basis and inheritance. Defects in several membrane protein genes have been involved in the pathogenesis of HS, including defects in the beta-spectrin gene. We detected a novel frameshift mutation in the beta-spectrin gene, a C deletion at codon 638, in a patient presenting with HS and spectrin deficiency. The mutant protein was not detected in the membrane or in other cellular compartments, but detectable levels of mutant mRNA were found in the patient. Interestingly, this mutation was not present in the patient's parents, suggesting a genetic mosaicism, especially as the patient has an affected brother with the same molecular defect. We analysed DNA from different tissues of the parents and the mutation was absent from all tissues analysed. This mutation seems to be confined to the germ cell lineage of the patient's mother and must present a mosaic pattern in these cells as the patient also has unaffected siblings.     

A Japanese family with hereditary HbH disease--a case report and its gene analysis

Hereditary HbH disease was found in a Japanese family. The propositus showed hypochromic microcytic anemia and chronic hemolysis. HbH inclusion bodies were detected in red cells, and an abnormal band corresponding HbH was found in an isoelectric focusing of the hemolysate. Gene analysis of the propositus revealed double heterozygosity for alpha + and alpha zero thalassemias. Four of six his siblings shared the alpha zero thalassemia and one the alpha + thalassemia. Another one was normal. The alpha + thalassemia was of 3.7 kb-deletion type and alpha zero was close to Southeast Asian type. This is the fourth Japanese family with hereditary HbH disease.     

Holocarboxylase synthetase deficiency: 9-year follow-up of a patient on chronic biotin therapy and a review of the literature

Summary We report on the long-term medical and neurodevelopmental follow-up of a patient with the rare and potentially lethal disease, holocarboxylase synthetase deficiency. He was originally treated prenatally with biotin megatherapy and for 9 years with 6 mg/day since his only episode of fulminant acidosis at 3 months of age. While growth and general health have been normal, the patient has exhibited signs of minimal brain dysfunction. However, evaluation of unaffected siblings suggests that this may be unrelated to his metabolic disease. A review of the literature and recommendations for optimal treatment are provided.     

A Negative Direct Antiglobulin Test with Strong IgG Red Cell Autoantibodies Present in the Serum of a Patient with Autoimmune Haemolytic Anaemia

The case is presented of a boy with an autoimmune haemolytic anaemia of 10 years duration. He had a positive direct antiglobulin test with IgG and complement detected on the red cells and with IgG autoantibodies in the serum. During a recent episode of severe haemolysis, the Hb level fell to 3.8 g/dl and the direct antiglobulin test became negative although his autoantibodies still reacted with all the red cells in a panel. The serum reacted more strongly with C- and e-positive cells. The Rh phenotype of the patient was CcDee as it had always been. Possible explanations of the unexpected findings are discussed.     

The effect of alpha-thalassemia on the expression of the beta- thalassemia/HPFH heterozygote in a black family

A 2-yr-old black girl presented with a thalassemic clinical picture and was found to have nearly 100% fetal hemoglobin in her red cells. Pedigree analysis indicated that she was a heterozygote for the hereditary persistence of fetal hemoglobin gene and for a beta O- thalassemia gene. A brother, who also had nearly 100% fetal hemoglobin in his red cells, manifested, in contrast to his sister, no anemia and only minimal splenomegaly. Examination of the family's alpha-globin loci using the restriction endonuclease Eco Rl demonstrated that the brother had a single alpha-locus deletion that he had inherited from his mother. The mild clinical manifestations of this boy are consistent with the often expressed view that excess alpha chains may contribute significantly to the hematologic manifestation of beta-thalassemia.