Search

Introduction Congenital dyserythropoietic anemias are rare blood disorders characterized by congenital anemia and a wide range of morphological and functional abnormalities of erythroid precursors. Objectives To analyze the relative frequency of both light microscopic (LM) and electron microscopic (EM) morphological features of erythroblasts in a large group of patients with molecular proven congenital dyserythropoietic anemia type I (CDAI). Methods We retrospectively evaluated the LM and EM of bone marrow (BM) erythroblasts in 35 patients with CDAI. Thirty-four patients carried the CDAN1 Arg1042Trp founder mutation and one the p.Pro1130Leu mutation. BM slides of 24 patients were available for LM examination. EM studies were performed in all 35 patients. Results On LM, marked erythroid hyperplasia, binuclear erythroblasts and various non-specific dyserythropoietic features were documented in every case; internuclear chromatin bridges were detected in 19 patients (79%). In all EM of erythroblasts revealed a spongy appearance of heterochromatin, a widening of nuclear pores and invagination of cytoplasm into the nuclear region. Conclusions EM studies revealed high morphological frequency of specific ultrastructural changes in erythroblasts which facilitate prompt diagnosis of CDAI. Due to low specificity of BM LM findings, when BM EM is unavailable diagnostic approach should also include other inherited anemias. This article is protected by copyright. All rights reserved.

Background Precursor-targeted immune-mediated anemia (PIMA) has been suspected in dogs with nonregenerative anemia and bone marrow findings varying from erythroid hyperplasia to pure red cell aplasia. Phagocytosis of erythroid precursors/rubriphagocytosis (RP) reported in some affected dogs suggests a destructive component to the pathogenesis of PIMA. Objectives The purpose of the study was to characterize laboratory and clinical findings in dogs with suspected PIMA and RP, with emphasis on cytologic and histologic bone marrow findings. Methods Dogs with PIMA and RP were identified by review of paired bone marrow aspirate and core biopsy slides collected over a 4-year period. Samples were systematically assessed and characterized along with other pertinent laboratory data and clinical findings. Results Twenty-five dogs met criteria for PIMA and had RP that was relatively stage-selective. Erythropoiesis was expanded to the stage of erythroid precursors undergoing most prominent phagocytosis, yielding patterns characterized by a hypo-, normo-, or hypercellular erythroid lineage. A 4th pattern involved severe collagen myelofibrosis, and there was a spectrum of mild to severe collagen myelofibrosis overall. Evidence of immune-mediated hemolysis was rare. Immunosuppressive therapy was associated with remission in 77% of dogs treated for at least the median response time of 2 months. Conclusions Bone marrow patterns in dogs fulfilling criteria for PIMA were aligned with stage-selective phagocytosis of erythroid precursors and the development of collagen myelofibrosis, common in dogs with PIMA. Recognition of these patterns and detection of RP facilitates diagnosis of PIMA, and slow response to immunosuppressive therapy warrants further investigation into its pathogenesis.

BACKGROUND Passenger lymphocyte syndrome occurs when donor lymphocytes are transplanted with a solid organ and produce alloantibodies that react with antigens on the recipient's red blood cells (RBCs). Typically, passenger lymphocyte syndrome presents as immunoglobulin G antibody-mediated, extravascular hemolytic anemia with reticulocytosis. Often, the donor was alloimmunized before transplantation. CASE REPORT A 34-year-old Group O, D+ man with a negative antibody screen received a liver transplant from a Group O, D− donor. Twenty Group O, D+ RBC units were transfused on Postoperative Days (PODs) 0 through 2. On POD 7, the patient developed anemia, a weakly positive antibody screen, and a positive direct antiglobulin test with anti-D in the eluate. After POD 8, a D− transfusion protocol was initiated. Despite laboratory evidence of hemolysis, two initial peripheral blood smears showed no increase in schistocytes or spherocytes, the reticulocyte count was depressed, and a marrow biopsy revealed erythroid hyperplasia. Eventually, anemia resolved after a period of medication non-compliance; however, a positive direct antiglobulin test persisted to the last follow-up date (POD 233). RESULTS Other potential causes of aplastic anemia were investigated, but no alternative cause was found. History excluded passive anti-D. D+, LW− cells were reactive, excluding anti-LW. Genotyping showed no evidence of a partial D genotype. Chart review revealed that the liver donor had a history of anti-D. A diagnosis of passenger lymphocyte syndrome was reached. CONCLUSION Although antibody-mediated hemolytic anemia has been reported to cause reticulocytopenia in the presence of marrow erythroid hyperplasia, this report of passenger lymphocyte syndrome causing a similar post-transplant anemia in association with reticulocytopenia is noteworthy.

BACKGROUND Low-risk myelodysplastic syndromes (MDS) show several immunologic abnormalities, including increased frequency of autoimmune manifestations and/or overt autoimmune diseases, whose prognostic significance still remains controversial. STUDY DESIGN AND METHODS We studied the presence of erythroblast antibodies in mitogen-stimulated bone marrow (BM) cultures of 70 patients with early-stage MDS (refractory anemia and refractory anemia with ringed sideroblasts). RESULTS Sixty-six percent of patients showed positive erythroblast antibodies, along with BM erythroid hyperplasia and a hemolytic picture in the peripheral blood. Supernatants from positive cultures induced an increase of overall cellularity, the appearance of erythroblastic clustering, and dyserythropoietic signs in normal BM. We identified CD45dimGly-AdimCD71bright cells (red blood cell precursors at different maturation stage) as the target of the antibodies. Erythropoietin (EPO) levels were reduced and EPO receptors (EPO-R) increased in BM culture supernatants from positive patients. However, flow cytometric analysis showed that neither EPO nor EPO-R was involved in an abnormal stimulation driven by these autoantibodies. Values of the proapoptotic protein Bax were increased in positive patients and Bcl-2 levels were decreased, although not significantly. CONCLUSION MDS patients with anti-erythroblast autoimmunity showed increased BM apoptosis, suggesting that the autoimmune reaction may contribute to an unfavorable BM microenvironment for optimal erythropoiesis.

UNLABELLED Hereditary sequence variants in globin genes are usually silent and are rarer in α-globin chains than β-globin chains. Some may lead to an unstable protein with a hemolytic or thalassemic phenotype. Hb Taybe is an unstable α-chain hemoglobin variant caused by the deletion of a threonine residue at codon 38 or 39 of the α1 globin gene. This deletion results in a structural abnormality that affects the α1 β2 contact and the α1 β1 interface, producing a highly unstable Hb. OBJECTIVE We describe the clinical, laboratory, and morphological characteristics of 43 patients with Hb Taybe, sixteen of whom are heterozygous, eight are homozygous, and nineteen are double heterozygous for Hb Taybe and other α-gene mutations or deletions. RESULTS The clinical presentation is very variable from a mild hemolytic anemia to the need for red cell transfusion. Morphological characteristics include erythroid hyperplasia, defective hemoglobin production, and dyserythropoietic features. On electron microscopy dyserythropoiesis and cytoplasmic precipitation of globin compatible optical dense material is seen. CONCLUSIONS This is the largest report of Hb Taybe patients. Previous reported cohorts are not related to these cases. We conclude that patients carrying Hb Taybe have a unique hematological and clinical phenotype distinct from other hemoglobinopathies and from congenital dyserythropoietic anemia.

Infection of erythroid cells by Friend spleen focus-forming virus (SFFV) leads to acute erythroid hyperplasia in mice, due to expression of its unique envelope glycoprotein, gp55. Erythroid cells expressing SFFV gp55 proliferate in the absence of their normal regulator, erythropoietin, because of the interaction among the viral envelope protein, the erythropoietin receptor, and a short form of the receptor tyrosine kinase Stk (sf-Stk). This leads to constitutive activation of several signal transduction pathways. Our previous studies showed that sf-Stk interacts with SFFV gp55, forming disulfide-linked complexes. This covalent interaction, along with other noncovalent interactions with SFFV-gp55, results in constitutive tyrosine phosphorylation of sf-Stk and rodent fibroblast transformation. Here, we determined the precise amino acid region within sf-Stk that contributes to fibroblast transformation by the polycythemia-inducing (SFFV-P) and the anemia-inducing (SFFV-A) strains of SFFV. Sf-Stk deletion mutants showed different transforming abilities in fibroblasts infected with SFFV-P and SFFV-A, although the N-terminal extracellular domain of sf-Stk was essential for fibroblast transformation by both viruses. Point mutations of sf-Stk indicated that cysteine 19 was critical for fibroblast transformation by SFFV-P, although all four cysteines (8, 19, 37 and 42) appeared to be important for fibroblast transformation by both SFFV-P and SFFV-A. Mutation of sf-Stk cysteine 19 abolished its ability to form dimers with SFFV-P and SFFV-A gp55. These results suggest that the interaction between sf-Stk and the envelope proteins of the polycythemia- and anemia-inducing variants of SFFV is architecturally different.

A family with congenital dyserythropoietic anaemia type III was studied. Twenty patients and 10 of their healthy siblings were clinically examined and questioned about their medical history. Blood sampling and bone marrow aspirations were also performed. Forty-five percent of the patients reported symptoms of anaemia and 35% regularly felt weakness, fatigue, or headache. However, the majority of the patients regarded themselves as healthy. The bone marrow showed a uniform picture of erythroid hyperplasia with multinuclear erythroblasts and gigantoblasts with up to 12 nuclei. There was laboratory evidence of intravascular haemolysis and mild anaemia. We also observed a high prevalence of monoclonal gammopathy of undetermined significance (3 cases) and myeloma (1 case) among the patients.

Groups of mice have been autopsied at regular intervals during the period of lymphomyeloid tissue regeneration which follows the phase of hypocellularity induced by the i.v. injection of 100 mug (4 mg/kg bodyweight) nitrogen mustard. The marrow cellularity recovered to levels in the normal range by the 8th day and remained in this range up to the 40th day. Subsequently, the marrow showed a slight degree of hypocellularity up to day 120. Granulocytes were predominant during the initial phase of marrow regeneration during the second week post-injection. The thymus exhibited periodic size variations such that it was substantially larger than the thymus of age-matched controls from 20-30 d, 46-73 d, and 75-100 d after injection. The lymph nodes and lymphoid tissue of the spleen regenerated only slowly to reach control values by 40-50 d. Superimposed on the recovering lymphoid tissue of the spleen was a phase of erythroid hyperplasia lasting from 10-18 d post-injection. This coincided with a shift from granulocytosis to erythroid hyperplasia in the marrow. This erythroid hyperplasia lasted until day 30 when the cellular composition of the marrow and spleen returned to normal. A possible explanation of these results is that nitrogen mustard introduces a degree of synchrony into stem cell proliferation and differentiation. Additionally, these results emphasize the role of the haematopoietic microenvironment in the control of stem cell differentiation.

To investigate the possibility that a proliferative non-neoplastic process influences extracellular cyclic nucleotide concentrations, we measured plasma cyclic AMP and cyclic GMP levels in 38 patients with homozygous beta-thalassaemia. This group consisted of 20 patients with thalassaemia major transfused regularly (mean pre transfusion Hb levels, 11 g/dl), and 18 patients with thalassaemia intermedia who did not require regular blood transfusion (mean Hb levels, 8.7 g/dl). In the patient group, plasma cyclic AMP levels were similar to those of 37 normal subjects matched for age and sex, whereas plasma cyclic GMP levels were markedly higher. Moreover, in the thalassaemic patients there was a significant negative correlation between plasma cyclic GMP levels and haemoglobin concentrations, suggesting that their marked erythroid hyperplasia may play a role in determining alterations in extracellular cyclic GMP levels.

Transcription factor GATA-1 is essential for erythroid cell differentiation. GATA-binding motifs have been found in the regulatory regions of various erythroid-specific genes, suggesting that GATA-1 contributes to gene regulation during the entire process of erythropoiesis. A GATA-1 germ-line mutation results in embryonic lethality due to defective primitive erythropoiesis and GATA-1-null embryonic stem cells fails to differentiate beyond the proerythroblast stage. Therefore, the precise roles of GATA-1 in the later stages of erythropoiesis could not be clarified. Under the control of a GATA-1 gene hematopoietic regulatory domain, a GATA-1 mutant lacking the N-finger domain (DeltaNF mutant) was over-expressed in mice. These mice exhibited abnormal morphology in peripheral red blood cells (RBCs), reticulocytosis, splenomegaly, and erythroid hyperplasia, indicating compensated hemolysis. These mice were extremely sensitive to phenylhydrazine (PHZ), an agent that induces hemolysis, and their RBCs were osmotically fragile. Importantly, the hemolytic response to PHZ was partially restored by the simultaneous expression of wild-type GATA-1 with the DeltaNF mutant, supporting our contention that DeltaNF protein competitively inhibits the function of endogenous GATA-1. These data provide the first in vivo evidence that the NF domain contributes to the gene regulation that is critical for differentiation and survival of mature RBCs in postnatal erythropoiesis.

Summary. Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of the haemopoietic stem cell (HSC). The pathogenetic link with bone marrow failure is well recognized; however, the process of clonal expansion of the glycosylphosphatidylinositol (GPI)-deficient cells over normal haemopoiesis remains unclear. We have carried out detailed analysis of the stem cell population in 10 patients with de novo haemolytic PNH using the long-term culture-initiating cells (LTC-IC) assay in parallel with measurements of CD34+ cells and mature haemopoietic progenitors, granulocyte–macrophage colony-forming unit (CFU-GM) and CFU-erythroid [burst-forming units erythroid (BFU-E) + CFU granulocyte/erythroid/macrophage/megakaryocyte (GEMM)]. All patients had hypercellular bone marrows with erythroid hyperplasia, normal blood counts or mild peripheral blood cytopenias, increased reticulocyte counts and evidence of deficient GPI-anchored proteins. We found a significant reduction in the LTC-IC frequency in the CD34+ compartment of PNH patients (mean 2, range 1·3–3·0; n = 6) compared with normal donors (mean 13, range 5·2–45·5; n = 21) (P

We describe a new case of congenital dyserythropoietic anemia (CDA) type III. This least common type of CDA was diagnosed at the age of 59 in a 70-year-old woman who suffered from a young age from mild macrocytic anemia, while the long follow up since diagnosis documented a benign clinical course. No family history of blood diseases was obtained and no anemia was documented in the medical records of any of her four children. The bone marrow (BM) examination on light microscopy revealed a severe erythroid hyperplasia with the presence of giant multinucleated erythroblasts. Ultrastructural examination of the BM disclosed the presence of many large multinucleated erythroblasts bearing a variety of ultrastructural findings: nuclear clefts, autophagic vacuoles, iron-loaded mitochondria, and intracytoplasmic myelin figures. In addition, extensive hyperlobulation of the nucleus and partial loss of nuclear membrane with “spilling” of nuclear material to the adjacent cytoplasm was also noted in some of the erythroblasts. These last two findings have not been previously described in CDA III. Am. J. Hematol. 70:72–76, 2002. © 2002 Wiley-Liss, Inc.

Changes in bone marrow macrophages may be associated with abnormal hematopoiesis in various hematologic disorders. We immunohistochemically evaluated the density of macrophages in bone marrow trephine biopsies. In reactive erythroid hyperplasia (hemolytic anemia and megaloblastic anemia), the macrophages slightly increased in density, extending their cytoplasmic processes between hematopoietic cells. In erythroid hypoplasia (pure red cell aplasia), they became rounded and frequently had hemosiderin granules. There was no significant difference in the macrophage density in the hematopoietic area between erythroid hyperplasia and hypoplasia. The macrophages increased in density in myeloproliferative disorders (polycythemia vera, chronic myelogenous leukemia and primary thrombocythemia). In myelofibrosis, some macrophages became extremely elongated along the line of the fibroblastic cells. In contrast, in conditions in which myelopoietic activity is considerably impaired (aplastic anemia, acute leukemia and multiple myeloma), they significantly decreased in density. These results suggest that the morphologic change in bone marrow macrophages is associated with erythropoietic activity and that there is a correlation between macrophage density and myelopoietic activity.

We report here a new frameshift mutation in exon 3 of the β-globin gene, a single nucleotide deletion (-C) in between codons 140/141 (GCC/CTG→GCC/TG), found in an 8-year-old Argentinean girl with clinical picture of thalassemia intermedia. It leads to a β-chain that is elongated to 156 amino acids [(141)Trp-Pro-Thr-Ser-Ile-Thr-Lys-Leu-Ala-Phe-Leu-Leu-Ser-Asn-Phe-(156)Tyr-COOH]. The resulting hemoglobin, which we named Hb Florida, was not detected in peripheral blood; however, erythroid hyperplasia and dyserythropoiesis with large inclusion bodies on methyl violet staining were observed in bone marrow, suggesting that this is a hyperunstable variant producing a dominant β-thalassemia phenotype, since the other β-allele was completely normal. Am. J. Hematol. 81:358–360, 2006. © 2006 Wiley-Liss, Inc.

Predicting the treatment response of aplastic anaemia (AA) is essential when considering cyclosporine (CyA) therapy among several treatment options, because it requires at least 2 months determine whether the therapy is beneficial to a patient with AA. To identify the characteristics of patients with AA who are likely to respond to CyA therapy we retrospectively reviewed the clinical records and bone marrow smears of patients treated with CyA. Among 30 patients who received the therapy for at least 3 months within 1 year after diagnosis of AA, and who had not been exposed to antilymphocyte or antithymocyte globulin, 16 (53%) responded with disease remission. CyA-responsive patients had a significantly higher ratio of erythroblasts to granulocytes (E/G ratio) in the bone marrow at the time of diagnosis as compared with patients refractory to therapy (P = 0.004). Multivariate analysis revealed that a high E/G ratio ( > 0.6) was significantly associated with a good response to CyA (P = 0.03): 15 (83%) of the 18 patients with an E/G ratio > 0.6 responded, but only one (8%) of the 12 with an E/G ratio > or = 0.6 did. Although the presence of subclinical paroxysmal nocturnal haemoglobinuria was suspected from the relative erythroblastosis observed in the bone marrow of these patients, flow cytometric analysis of neutrophils in the peripheral blood failed to reveal neutrophils deficient for glycosyl-phosphatidylinositol (GPI) anchored membrane proteins in all but one case. Identification of the presence of relative erythroid hyperplasia in he bone marrow when AA is diagnosed may help to predict a favourable response to CyA therapy, and therefore facilitate the selection of optimal therapy for AA.

Extramedullary hematopoiesis (EMH) is a rare cause of an intrathoracic mass. Fine-needle aspiration biopsy (FNAB) has been only occasionally documented as a useful tool in diagnosing EMH tumor. We report a case of posterior mediastinal extramedullary hematopoietic mass in an 80-yr-old man with sickle-cell anemia. The mass was revealed incidentally on chest X-ray. The definitive diagnosis of this mass lesion was achieved by FNAB. The cytologic smears showed hematopoietic elements with erythroid hyperplasia. A correct cytologic diagnosis can thus help to avoid unnecessary surgical intervention, particularly in an asymptomatic patient. Diagn. Cytopathol. 2004;30:119–121. © 2004 Wiley-Liss, Inc.

An eight-month-old male West Highland white terrier (WHWT) presented with mild exercise intolerance and splenomegaly caused by a severe and highly regenerative haemolytic anaemia that persisted until the dog died at two years of age. There was marked erythroid hyperplasia in the bone marrow and progressive osteosclerosis. Erythrocyte pyruvate kinase (PK) deficiency was confirmed by demonstrating a block in glycolysis at the PK step, abnormal erythrocyte PK kinetics, absence of R-type PK isoenzyme, and the presence of M2-type PK not normally expressed in erythrocytes. From the study of family members it is concluded that erythrocyte PK deficiency in the WHWT is inherited as an autosomal recessive trait. Heterozygotes have about half-normal erythrocyte PK activity, do not express the M2-type PK isoenzyme and are asymptomatic. This disease closely resembles erythrocyte PK deficiency in the basenji breed and should be considered as a differential diagnosis in young dogs with severe haemolytic anaemia.

On cytological bone marrow examination we distinguished between pure sideroblastic anaemia (PSA), which is confined to dyserythropoiesis, and refractory anaemia with ring sideroblasts (RARS), which is characterized by additional dysplastic features of granulopoiesis and/or megakaryopoiesis. In a follow-up study of 94 patients with AISA diagnosed according to FAB criteria for myelodysplastic syndromes we found a striking difference in the risk of leukaemic transformation between PSA and RARS (5 year cumulative rate 1.9% v. 48%). Overall survival was much better in PSA than in RARS (5 year cumulative chance 69% v. 19%). Infections and haemorrhages were frequent causes of death in RARS but not in PSA. Bone marrow culture studies (CFU-GM) were performed on 10 consecutive patients with PSA and RARS, respectively. RARS patients showed grossly impaired colony growth, typical of the myelodysplastic syndromes. Patients with PSA had persisting colony formation, even if moderately decreased in frequency, with numbers of CFU-GM being inversely correlated with the degree of erythroid hyperplasia in the bone marrow. We conclude that on cytomorphological grounds AISA can be divided into pure (dyserythropoietic) sideroblastic anaemia (PSA) and a true myelodysplastic form (RARS), with both types differing considerably in terms of survival, risk of leukaemic transformation and findings on bone marrow culture (CFU-GM).

Severe iron overload is a reported complication of certain erythroid disorders which are characterized by increased erythropoietic activity. Proposed mechanisms include enhancement of iron absorption secondary to increased erythroid activity and coexistent heterozygosity or homozygosity for haemochromatosis. We performed PCR-based analysis for the haemochromatosis-related HFE C282Y mutation in an extended family with inherited haemolytic anaemia in which several members exhibited iron overload. The results demonstrated iron overload was associated with homozygosity but not heterozygosity for this mutation. Such an association may also exist in other erythroid disorders in which iron overload has been reported.

Summary. Clinical and laboratory data are presented for two patients with a dyshaematopoietic disorder, and monosomy 7 in their bone marrow cells. The first patient, a 55–year-old woman, had been treated with chlorambucil for an ovarian carcinoma. After 4 years an oligoblastic myeloid leukaemia was diagnosed and she later died with an acute transformation of the disease. The second patient, a 21–year-old male, has had a dyserythropoietic anaemia with transient pancytopenia for over 5 years without any signs of malignancy. The possible relationship between therapy, the monosomy 7 and the other bone marrow abnormalities is briefly discussed. From an analysis of the data of these and comparable cases in the literature it appears that loss of chromosome No. 7 material is often associated with erythropoietic disorders such as erythroid hyperplasia and erythraemia. The reduction or absence of the Colton blood group antigens found in our patients and in a few other monosomy 7 cases also points to an abnormality of the red cell line.

Out of a total of 185 cases of acute leukemia at our institution from 1967 to 1978, fifteen cases (8.1%) were identified as erythroleukemia or erythremic myelosis. The symptoms at presentation were often related to anemia (10/15 cases); the presenting hemoglobin value was lower than 10.0 gm/100 ml. Nucleated red cells were present in the peripheral blood and reticulocyte response was inappropriate to the degree of anemia. Marrow biopsy showed erythroid hyperplasia with megaloblastic and dyserythropoietic features, increase in myeloblasts greater than 5% (10/15 cases), positive PAS staining of erythroid precursors (12/12 cases), and erythrophagocytosis by abnormal erythroid precursors (6/15 cases). Abnormalities were noted in monocytic and megakaryocytic cell lines, and it was concluded that erythroleukemia is probably a stem cell disorder. Response to chemotherapy was poor with median survival of four months from initial diagnosis. Intracranial hemorrhage and bacterial or fungal infection were the most frequent cause of death.

Idiopathic transient normocytic, normochromic anaemia of childhood. The paediatric literature recognises an uncommon, self-limiting condition characterised by a severe normocytic, normochromic anaemia occurring in otherwise healthy children. Previous descriptions report erythroblastopenia as the characteristic bone marrow finding. Fifteen children are described with the essential features of this condition. Of these, erythroblastopenia was present in only seven; four showed an erythroid hyperplasia and in four the bone marrow was only marginally abnormal. The latter two groups of patients demonstrated a “shift to the left” in their erythroid precursors. Contrary to earlier reports, it is suggested that the bone marrow changes in this condition are variable.

Summary. A chronic myeloproliferative disorder associated with monosomy 7 is described in a 3 1/2-year-old boy. His presenting features closely resembled those of juvenile chronic myeloid leukaemia (JCML). Cytogenetic study of bone marrow cells showed that all of the metaphases examined had chromosome 7 deletions. He developed an erythroblastic phase, characterized by anaemia, marked erythroid hyperplasia of bone marrow and the appearance of nucleated red blood cells in the peripheral blood. During the erythroblastic phase, blood transfusion resulted in a suppression of erythropoiesis as evidenced in both the peripheral blood and bone marrow. The in vitro culture studies showed that the erythroid precursor was dependent upon erythropoietin (Ep) for differentiation and proliferation during the erythroblastic phase. However, the Ep dose-response curve showed that a peak of erythroid colony formation occurred at a lower concentration than in the healthy controls. These findings suggest that although the erythroid precursor remains under the control of Ep, it has an increased sensitivity to Ep during the erythroblastic phase of monosomy 7.

Three patients with drug-induced hypoplastic anemia terminating 2 to 6 years after presentation with erythroleukemia are described. All were treated for prolonged periods with androgen and corticosteroid and two of the patients showed apparent dependence on this therapy for optimal hematologic status. The leukemic phase was heralded by loss of this dependence and development of sideroblastic dyserythropoiesis with progression to bizarre erythroid hyperplasia and fatal cytopenia. The exact relationship between androgen and corticosteroid therapy and the erythroleukemia remains speculative.

A 50-year-old woman with typical acquired primary pure red cell aplasia (PRCA) was successfully treated with prednisone. A later relapse was preceded by a period of ineffective erythropoiesis characterized by a reticulocyte response inappropriately low for the degree of anemia, serum iron of 189 micrograms/dl, total iron-binding capacity (TIBC) of 213 micrograms/dl, and erythroid hyperplasia. In addition there was marked dyserythropoiesis and erythroblast-phagocytosis. One month later, bone marrow examination showed classic PRCA. This rarely reported evolutionary stage of PRCA has several implications: 1) it suggests antibody induced erythroblast cytotoxicity as one mechanism of PRCA; 2) at a particular time in the development of PRCA there is potential for misdiagnosis as primary refractory anemia (PRA); and 3) some cases of PRA with similar morphologic and laboratory findings may be pathogenetically related to PRCA and may benefit from evaluation for immune-mediated suppression of erythropoiesis.

An autopsy case of autoimmune hemolytic anemia which revealed typical clinical symptoms, and complicated with toxic epidermal necroly-sis in its terminal stage, has been reported. Morphological changes which imply the pathogenesis of this disease have been reported. The liver was the main site of extravascular hemolysis. Various stage of red cell destruction in the Kupffer cells, erythrophagocytosis by the mononuclear cells in the peripheral blood and multiple thrombi might be relatively specific findings which suggest the hemolytic process of this disease. Hemosiderosis, erythroid hyperplasia in the bone marrow and myeloid metaplasia were also noted.

Erythropoiesis has been studied in three patients with sideroblastic anaemia and one case of erythraemic myelosis. The marrows showed erythroid hyperplasia, plasma iron turnover was high, red cell iron utilization low, and retention of 59Fe prolonged in the marrow. A combined quantitative cytochemical and autoradiographic analysis showed an accumulation of early polychromatic cells in G2 and the presence of several cells which were apparently arrested after a period in DNA synthesis. DNA synthesis was rarely seen in cells with pronounced siderotic deposits. These results indicate the presence of ineffective erythropoiesis with a disturbance in the progress of early polychromatic cells through interphase, probably leading to intra-marrow cell death. In erythraemic myelosis there was also a reduced red cell production due to faults of cell division; the nature and consequence of the bizarre forms of cell replication are discussed.

Summary. What appears to be a hitherto unreported type of congenital anaemia has been found in six members of an Irish family. It is inherited in an autosomal dominant manner and is characterized by moderate anaemia, lifelong jaundice, cholelithiasis and splenomegaly, marked morphological abnormalities of the red cells (which are, however, well haemoglobinized), erythroid hyperplasia of the bone marrow with increased numbers of multinucleate red cell precursors, and the presence of large inclusion bodies in the normoblasts, both in the marrow, and in the peripheral blood after splenectomy. Potassium flux across the red cell membranes is increased and there is imbalanced globin chain synthesis with α-chain production exceeding that of β-chains by a factor of 2/1. Excess α-chains in the bone marrow form a pool of similar magnitude to that observed in β-thalassaemia heterozygotcs but the latter do not have red cell precursor inclusion bodies or the degree of ineffective erythropoiesis seen in the present cases. The most likely molecular mechanisms for this disorder are either an ‘overproduction abnormality’ of α-chain synthesis, or a defect in cell division leading to increased amounts of genetic material per cell, a mechanism postulated recently as a basis for the unusual distribution of red cell enzyme levels in congenital dyserythropoietic anaemia.