Arsenic-induced bone marrow toxicity: ultrastructural and electron-probe analysis.

A patient with severe arsenic poisoning that resulted in marked peripheral blood and bone marrow abnormalities, including megaloblastic erythropoiesis experienced many of the previously reported hematologic complications of arsenic poisoning: leukopenia, granulocytopenia, absolute eosinophilia, and profound anemia. In this study we report an ultrastructural and electron-probe analysis of the bone marrow. Although megaloblastic anemia associated with arsenic poisoning has been described rarely, the presence of arsenic in the local bone marrow milieu has not been demonstrated previously. The ultrastructural features of arsenic-induced bone marrow toxicity are similar to those described in other dyserythropoietic states and include marked nuclear aberrations involving shape, chromatin distribution, and nuclear envelope. Using the technique of energy-dispersive x-ray analysis (electron probe) we demonstrated arsenic in bone marrow spicules; this supports the contention that arsenic can cause megaloblastic anemia. We suggest that this technique may be a useful tool in further studies that attempt to explore the mechanism of arsenic-induced hematologic toxicity. Finally, we suggest that arsenic has a direct toxic effect on DNA synthesis that results in marked disturbances of nuclear division. We recommend that the most appropriate screening procedure to evaluate possible arsenic poisoning is tissue arsenic measurements (hair and nails) rather than 24-hr urinary measurements.     

Megaloblastic pancytopenia vis-à-vis non-megaloblastic pancytopenia: is mean platelet volume useful discriminating indicator

Introduction: Megaloblastic anaemia may present with pancytopenia and clinically mimic other causes of pancytopenia including myelodysplastic syndrome or aplastic anaemia. Bone marrow examination may be required for precise differentiation. The study was conducted to evaluate the role of mean platelet volume (MPV) to discriminate between pancytopenia due to megaloblastic anaemia or non‐megaloblastic causes. Methods: A total of 268 cases of pancytopenia were divided into megaloblastic and non‐ megaloblastic group depending on clinical, laboratory and bone marrow examination. Mean MPV was statistically analyzed in both the groups along with comparison with healthy controls. Results: The mean MPV in 88 cases of megaloblastic group (7.97 fl) was although statistically significantly higher than mean MPV in 180 cases of non‐megaloblastic group (7.04 fl) with P value <0.05 but had limited sensitivity and specificity to discriminate megaloblastic and non‐megaloblastic pancytopenia (cut off of 7.45 fl was 63.6% sensitive and 67.3% specific as observed by receptor operating characteristic curve analysis).The mean MPV in aplastic/hypocellular marrow and acute leukaemia category of non‐megaloblastic group was significantly lower than megaloblastic group of pancytopenia (P value <0.05). MPV was also significantly lower in non‐megaloblastic pancytopenia as compared to controls (P < 0.001) while there was no statistical difference in MPV between megaloblastic pancytopenia and controls (P < 0.057). Conclusion: MPV has limited sensitivity and specificity to discriminate between megaloblastic and non‐megaloblastic pancytopenia. Pancytopenia due to aplastic/hypocellular marrow and acute leukaemia has significantly lower MPV than megaloblastic group while other pancytopenic cases do not show any statistical difference in MPV from megaloblastic pancytopenia.     

Pancytopenia in a child associated with hepatitis A infection.

Pancytopenia is a very rare condition associated with hepatitis A infection. We managed a 12 year old boy who had hepatitis A infection with anemia. His hemogram and bone marrow examination were suggestive of pancytopenia. Pancytopenia recovered without any specific therapy. There are case reports of severe aplastic anemia with hepatitis A infection that required immunosuppressive therapy. The present case did not require any aggressive therapy and recovered. In a young child with hepatitis A infection and anemia, bone marrow depression should be suspected. The pancytopenia may be transient as exemplified by the present case.     

Acute Psychosis: A Presentation of Cyanocobalamin Deficiency Megaloblastic Anemia

Cyanocobalamin deficiency is not rare in India. Patients present with megaloblastic anemia, pancytopenia and sometimes neuropsychiatric manifestations. Subacute combined degeneration of the cord, peripheral neuropathy, dementia, psychotic depression and paranoid schizophrenia are well reported. We are reporting a case of cyanocobalamine deficiency anemia who presented with acute psychosis which readily reversed on cyanocobalamin replacement.     

Life-threatening megaloblastic pancytopenia with normal mean cell volume: Case series

The mean red blood cell volume (MCV) is usually increased in severe megaloblastic anemia due to pernicious anemia. However, during one year in a university hospital, three patients with life-threatening pancytopenia and normal MCV were proven to have severe vitamin B12 deficiency. The red blood cell distribution width was markedly increased (three times normal) and led to review of the blood smear and recognition of megaloblastosis as well as prominent red cell fragmentation. These three cases illustrate that vitamin B12 status should be evaluated in cases of pancytopenia, independent of the MCV value.     

Severe vitamin B12 deficiency resulting in pancytopenia, splenomegaly and leukoerythroblastosis

Deficiency of vitamin B12 is a well known cause of megaloblastic anemia and pancytopenia. Splenomegaly and leukoerythroblastosis are much less well known manifestations of B12 deficiency. We report a B12 deficient female with severe pancytopenia including normocytic anemia who also had enlarged spleen and circulating nucleated red blood cells as well as circulating immature myeloid cells. Although these findings are reported in the earlier literature, more modern reviews of the subject often fail to mention this association. We review the literature on these unusual manifestations of B12 deficiency and remind clinicians that splenomegaly and erythroblastosis can serve as diagnostic clues in cases of severe megaloblastic anemia secondary to B12 deficiency.     

Pancytopenia with hypercellular bone marrow—a possible paraneoplastic syndrome in carcinoma of the lung: A report of three cases

Three patients with idiopathic pancytopenia and hypercellular bone marrow who developed carcinoma of the lung within two years of diagnosis are reported. All three patients had macrocytic anemia associated with a megaloblastic marrow in the presence of normal serum vitamin B12 and folic acid levels. Neutropenia with monocytosis, elevated serum muramidase and LAP scores, and increased fetal hemoglobin levels were also found. In all cases Ham's tests were negative with a normal bone marrow karyotype. In all three patients, pancytopenia due to myelodysplasia, a probable preleukemic state, was diagnosed initially prior to the appearance of carcinoma of the lung. One of the patients showed improved leukocyte and platelet counts during chemotherapy, while the other two died before chemotherapy could be administered. In the light of the above findings we suggest that carcinoma of the lung may be the cause of a paraneoplastic syndrome with pancytopenia, particularly in patients with a hypercellular marrow with a normal karyotype.     

ORIGINAL ARTICLE: Role of mean platelet volume as discriminating guide for bone marrow disease in patients with thrombocytopenia

Recently, platelet indices have been evaluated to determine their utility in knowing the mechanism of thrombocytopenia. This study was conducted to analyze the role of mean platelet volume (MPV) as a guide or an indicator for bone marrow disease in thrombocytopenic patients. All the patients with thrombocytopenia for various causes followed by bone marrow examination were divided into two groups, one group with and another without bone marrow disease, depending on pathophysiology. The MPV was statistically analyzed in both the groups to assess its role as guide for bone marrow disease in these patients. Mean MPV (average score of all individual mean values in patients) in the group with bone marrow disease was 7.3 fl, while in the group without bone marrow disease, it was 8.62 fl. Although the difference in MPV in the two groups of with (including megaloblastic anemia) and without bone marrow involvement was statistically significant (P value <0.001), its sensitivity and specificity scores as observed by receptor operating characteristic (ROC) curve at cut-off of <8.15 fl were not highly sufficient (67.7% sensitive and 65% specific). The study concluded that although MPV can be used as an initial hint for bone marrow disease in thrombocytopenic patients, it has limited sensitivity and specificity. The differentiation of megaloblastic anemia from other causes of pancytopenia involving the marrow requires bone marrow examination rather than using MPV as an indicator. Bone marrow examination remains the gold standard for discriminating hypoproductive type of thrombocytopenia from the hyperdestructive one. In addition, the role of other platelet indices should also be assessed further to know a better indicator for bone marrow involvement in thrombocytopenic patients.     

Mechanism of arsenic-induced inhibition of erythropoiesis in mice

Anemia accompanies arsenic intoxication in man. The present studies were undertaken to clarify further the effects of arsenic on erythropoiesis. A dose-related inhibition of red cell ⁵⁹Fe incorporation and reticulocyte response was observed in normal mice treated with a single injection of arsenic. Arsenite was approximately two times as inhibitory as arsenate. The effects of arsenic on erythropoietin-induced erythroid differentiation revealed a significant inhibitory effect on young, proliferating marrow nucleated erythroid precursor cells. More mature, nonproliferating nucleated erythroid cells were resistant to the toxic action of arsenic. A dose-related inhibitory effect of arsenic on DNA synthesis was observed in fetal liver nucleated erythroid cells incubated with ³H thymidine. Ineffective erythropoiesis as well as the megaloblastic morphology accompanying aberrant DNA synthesis – manifestations of arsenic toxicity in man – were not evident in the present studies.     

Sulphasalazine associated pancytopenia may be caused by acute folate deficiency.

Agranulocytosis and aplastic anaemia associated with sulphasalazine are well recognised, but pancytopenia caused by acute megaloblastic arrest of haemopoiesis while taking sulphasalazine has not previously been described. We report three patients who, after taking sulphasalazine for over two years, suddenly developed severe pancytopenia with gross megaloblastic changes in the marrow. In two patients there was a good response to high dose oral folic acid but the third required folinic acid. The mechanism appears to be acute folate deficiency, and the requirement for folinic acid in one case suggests that the known inhibition of folate metabolism by sulphasalazine also contributes. The syndrome appears to be associated with high dosage and slow acetylator status. The drug has been successfully restarted at reduced dosage with folate supplements in two patients both of whom were slow acetylators. In the third case, whose acetylator status is not known, progression of her disease led to colectomy.     

Diabetes insipidus associated with dysplastic pancytopenia

This case report describes a 60-year-old man who presented with a three-year history of generalized malaise, decreased libido, polyuria, and polydipsia. He had been previously investigated for pancytopenia, and found to have a hypoplastic bone marrow. A diagnosis of central diabetes insipidus was established; the patient was also found to have a number of other defects in his hypothalamic-pituitary function. Hematologic studies again revealed peripheral pancytopenia associated with a hypoplastic megaloblastic bone marrow. Computed axial and nuclear magnetic resonance tomography failed to establish the nature of the morphologic lesion in the hypothalamus. A possible relationship between the hematologic and endocrine disturbance is discussed.     

Schwere mikrozyt?re An?mie bei megaloblast?ren Ver?nderungen im Knochenmark

We discuss the case of a 32 year-old male with severe microcytic anemia (hemoglobin 2,9 g/dl) and megaloblastic changes in the bone marrow. The patient reported of substantial dietary weight loss. The family history was positive for β-thalassemia. Previous blood work showed iron deficiency with mild anemia. Further work-up verified β-thalassemia minor and revealed severely decreased vitamin B12 levels with positive anti intrinsic-factor antibodies, pathognomonic for autoimmune pernicious anemia. The paradoxon therefore dissolved as a pernicious anemia with megaloblastic changes with microcytic erythrocytes due to β-thalassemia.     

Arsenic intoxication presenting as a myelodysplastic syndrome: a case report

A case of arsenic intoxication presenting as a myelodysplastic syndrome is reported. A 41-year-old woman with a 6-month history of gastrointestinal and neurological symptoms was noted to be pancytopenic at presentation. A bone marrow aspirate revealed dysmyelopoietic changes involving all three marrow cell lines. Subsequent analysis of urine for heavy metals demonstrated very high levels of arsenic. Treatment with British anti-Lewisite (BAL) resulted in the resolution of gastrointestinal symptoms and hematological abnormalities although the neurological complications progressed. This case emphasizes that heavy metal intoxication should be considered in the differential diagnosis of any individual presenting with the hematological features of myelodysplasia especially when accompanied by clinical features considered atypical for primary or secondary myelodysplasia.     

Reversible bone marrow aplasia induced by naproxen

Summary We report a case of reversible bone marrow aplasia related to the use of naproxen. A 71-year-old women developed severe pancytopenia after she had been treated with naproxen for more than 8 weeks. Bone marrow examination showed marked hypocellularity compatible with aplastic anemia. Full recovery of the pancytopenia and bone marrow was observed when naproxen was discontinued. Absence of exposure to other drugs and lack of underlying disorders known to cause bone marrow aplasia makes this case unique.     

Aplastic Anemia in a Professional Musician Exposed to Instrument Polish

Chemicals are known to cause toxin-induced aplastic anemia. However, some chemicals documented in only a few cases to possess only a possibility of toxic potential may also be responsible for the development of aplastic anemia. This report presents a case of a string musician with bone marrow failure. The patient used a certain type of polish (komalak) to shine his musical instrument and did this frequently. He presented with nasal bleeding, and a workup on admission revealed pancytopenia. Aplastic anemia was diagnosed on the basis of bone marrow histology results. An analysis for gene polymorphism related to the metabolic detoxification enzymes glutathione S-transferase and N-acetyltransferase 2 indicated that the patient was genetically susceptible to developing toxicity. This case suggests that frequent use of this polish may cause a toxic effect that leads to bone marrow failure. Musicians should be made aware of the risks associated with these types of chemicals.     

Amiodarone-associated bone marrow granulomas: a report of 2 cases and review of the literature

Amiodarone therapy is associated with several adverse effects, including hematologic ones such as pancytopenia, hemolytic anemia, and aplastic anemia. Very few cases of amiodarone-associated bone marrow granulomas have been reported. We report 2 cases of amiodarone-associated bone marrow granulomas. Patient 1 was an 81-year-old man who presented with leukopenia, thrombocytopenia, and hepatosplenomegaly after 2 years of amiodarone therapy. Patient 2 was an 80-year-old man who presented with pancytopenia 2 1/2 years after starting amiodarone treatment. Both patients had normal blood counts before amiodarone therapy. Bone marrow biopsies showed noncaseating granulomas in both patients. We reviewed the literature available on Medline for amiodarone-associated bone marrow granulomas and found 8 reported cases of amiodarone-associated bone marrow granulomas. One case also featured amiodarone-associated hepatic granulomas. Amiodarone therapy was stopped in 5 cases, with improvement of the granulomas occurring in 3 cases. We conclude that bone marrow granulomas, although rare, should be considered as a differential diagnosis for patients undergoing amiodarone therapy and presenting with cytopenias.     

Aplastic anemia in a male with loss of the Y chromosome.

We carried out chromosomal analysis of a 33-year-old male who was diagnosed as having aplastic anemia. The patient showed severe pancytopenia, a normal NAP score, hypoplastic marrow and no myelodysplastic changes. 45,XO was found in all bone marrow cells examined, and in 10% of peripheral blood cells examined. To our knowledge, this is the first reported case of male aplastic anemia to show loss of the Y chromosome in all bone marrow cells examined, and this case may suggest a possible mechanism of juvenile onset of aplastic anemia.     

Aplastic anemia associated with antithyroid drugs

Prognosis in aplastic anemia is usually linked to the degree of hypoplasia in the bone marrow and pancytopenia in the blood. The authors were, therefore, intrigued when a patient with methimazole-associated aplastic anemia who satisfied criteria for severe disease recovered rapidly and completely once her drug was withdrawn. Review of the English language literature revealed ten fully documented cases of aplastic anemia associated with use of the antithyroid drugs methimazole, carbimazole, and propylthiouracil. Analysis of the ten and of an eleventh case presented here indicated that the disorder is typically characterized by severe pancytopenia and profound marrow hypoplasia, yet surprisingly good prognosis, ie, minimum survival of more than 70% with partial or complete recovery from symptoms and cytopenias in survivors within 2-5 weeks. The only deaths, both in the 1950s, were from brain hemorrhage in patients who were not transfused with platelets. The discrepancy between the clinical and laboratory severity of antithyroid drug-associated aplasia, on the one hand, and its relatively good prognosis and short term course, on the other, should be kept in mind when considering these patients for bone marrow transplantation or for therapy with antithymocyte globulin.     

Megaloblastic anemia associated with psoriasis: case report and review of the literature.

A 68-yr-old male with severe psoriasis developed megaloblastic anemia due to folate deficiency 3 months after the cessation of low-dose methotrexate therapy. The mechanism of megaloblastic anemia in this case was suggested to be multifactorial. The case report and a review of megaloblastic anemia associated with psoriasis are presented.     

Parvovirus B19-related anaemia after renal transplantation

We describe here the case of a renal transplant recipient treated by sirolimus based immunosuppresive therapy, who developed severe and unusual pancytopenia 2 months after renal transplantation. Parvovirus B19 primo-infection was diagnosed. The first course of intravenous immunoglobulin failed. Bone marrow aspiration confirmed megaloblastic anaemia associated with parvovirus B19. Finally, this infection was succesfully treated by the reduction of immunosuppression combined with a second course of intravenous immunoglobulin.