Iron toxicity - Its effect on the bone marrow.

Excess iron can be extremely toxic for the body and may cause organ damage in the absence of iron chelation therapy. Preclinical studies on the role of free iron on bone marrow function have shown that iron toxicity leads to the accumulation of reactive oxygen species, affects the expression of genes coding for proteins that regulate hematopoiesis, and disrupts hematopoiesis. These effects could be partially attenuated by iron-chelation treatment with deferasirox, suggesting iron toxicity may have a negative impact on the hematopoietic microenvironment. Iron toxicity is of concern in transfusion-dependent patients. Importantly, iron chelation with deferasirox can cause the loss of transfusion dependency and may induce hematological responses, although the mechanisms through which deferasirox exerts this action are currently unknown. This review will focus on the possible mechanisms of toxicity of free iron at the bone marrow level and in the bone marrow microenvironment.

Hepatitis associated aplastic anemia: case report and discussion.

Aplastic anemia (AA) is thought to represent an autoimmune disorder leading to generation of activated CD8+ T-cells that target the bone marrow precursors. Hepatitis associated aplastic anemia (HAAA) is a subtype of aplastic anemia that develops within several months ofan episode of acute hepatitis. Etiologic agents include hepatitis viruses (A-E and G), Epstein-Bar virus, cytomegalovirus, HIV, parvovirus B19, and echoviruses amongst others. However, most HAAA cases are labeled "idiopathic" as the inciting agent cannot be identified. Drugs and/or toxins are rarely causal factors. We describe herein a unique case of HAAA linked with the anabolic steroid methasterone that caused a transient cholestatic hepatitis and, subsequently, a severe aplastic anemia in a young man.

[Hematologic improvement with deferasirox following tandem antithymocyte globulin treatment in a transfusion-dependent patient with severe aplastic anemia].

A 62-year-old man with transfusion-dependent severe aplastic anemia received immunosuppressive therapy (IST) with rabbit antithymocyte globulin and cyclosporine A in April 2010. However, his transfusion dependency did not improve. As more than 100 red blood cell (RBC) transfusions had been performed, he was administered iron chelation therapy (ICT) with deferasirox (DFX) to improve iron overload starting in July 2011. Consequently, both RBC and platelet transfusion dependency gradually improved concomitant with a decrease in serum ferritin. The bone marrow (BM) biopsy findings before administration of DFX showed severe iron accumulation and strong positive immunostaining for 8-OHdG, a marker of oxidative stress due to free iron. One year after ICT, the number of BM hematopoietic cells was increased and both iron deposition and oxidative stress were decreased. These findings suggest that DFX may contribute to hematological improvement in patients with IST-refractory aplastic anemia.

[Therapeutic effect of fuzheng yangying oral solution on immune-induced aplastic anemia mice].

OBJECTIVE: To observe the effect of fuzheng yangying oral solution on bone marrow proliferation and serum interleukin 2 in immune-induced aplastic anemia mice. METHODS: The immune-induced aplastic anemia mouse models were built up, and then were divided into 4 groups by randomized allocation. The models were fed with physical salts (Group A, n = 10 ), fuzheng yangying oral solution (Group B, n = 10), cyclosporin A (Group C, n = 10), and fuzheng yangying oral solution plus cyclosporin A (Group D, n =10), respectively. Another 10 healthy mice served as controls (Group E). The changes in blood cells, bone marrow karyocyte count, marrow hematopoietic tissue capacity, and serum interleukin 2 level were observed. RESULTS: The blood cells, bone marrow karyocyte count, and marrow hematopoietic tissue capacity in Group A were significantly lower than those of Group E (P < 0. 05) ; those in the 3 treated groups (Group B, C, and D) were significantly higher than those of Group A ( P < 0. 05 ); and Group D was the highest ( P < 0. 05 ). There were no significant difference between Group B and C ( P > 0. 05 ). The level of interleukin 2 in Group A was obviously higher than that of Group E (P < 0. 05 ); The levels of interleukin 2 in the 3 treated group ( Group B, C, and D) were significantly lower than those of Group A ( P < 0. 05 ); and Group D was the lowest ( P < 0. 05). There was no significant difference in the level of interleukin 2 between Group B and C ( P < 0. 05). CONCLUSION: Fuzeng yangying oral solution can impove the bone marrow proliferation and reduce the level of serum interleukin 2 in immune-induced aplastic anemia mice.

Anaemias of oral significance

Anaemia is not a disease in itself. It is a sign of a single or multiple diseases. Anaemia is said to exist when the haemoglobin concentration is below normal for the age and sex of an individual. The synthesis and normal circulatory level of haemoglobin in any given individual depend on factors such as an adequate supply of haemopoietic nutrients, normal functioning of bone marrow, and proper utilization of haemoglobin. Based on these factors anemia can be broadly grouped into three categories: 1. Anaemia due to lack of haemopoietic nutrients (nutritional anemia) 2. Anaemia due to bone marrow dysfunction (aplastic anaemia) 3. Anaemia due to excessive breakdown of red blood cells (haemolytic anaemia) (AU)

[Effect of Panax notoginsenosides on the proliferation of hematopoietic progenitor cells in mice with immune-mediated aplastic anemia].

OBJECTIVE: To study the effect of panax notoginsenosides (PNS) on the proliferation of hematopoietic progenitor cells (HPC) in mice with immune-mediated aplastic anemia. METHODS: Balb/c mice model of immune-mediated aplastic anemia was established by radiation with sublethal dose of 60Co following the intravenously infusing lymphocytes of DBA/2 mice. Model mice in the treated groups were treated separately with high, middle and low dose of PNS, 3.2 mg, 1.6 mg and 0.8 mg per day respectively by intraperitoneal injection. Model mice in the control group and normal mice in the normal control group were treated with normal saline. The peripheral white blood cell (WBC) count and pathological examination of bone marrow were carried out 12 days later, the bone marrow was taken to be incubated in semi-solid culture system for observing proliferation of HPC. RESULTS: PNS could (1) increase peripheral WBC count: as compared with that in the model control, WBC in the high, middle and low dose PNS groups was raised by (34.3 +/- 2.9)%, (29.2 +/- 1.7)% and (14.5 +/- 1.6)% respectively, P < 0.01 and P < 0.05; (2) improve the bone marrow inhibition: pathological examination showed in the model group, the hematopoietic structure was destroyed and replaced by fatty tissue, while in the PNS treated groups, the structure of marrow was rather complete and filled with abundant hematopoietic cells; (3) promote the proliferation of HPC: as compared with the model group, the colony formation of CFU-GM were increased by (64.4 +/- 2.8)%, (67.3 +/- 2.4)% and (21.9 +/- 1.8)% respectively and that of CFU-E increased by (31.9 +/- 3.6)%, (20.7 +/- 2.4)% and (12.8 +/- 2.6)% respectively in the three PNS treated group (P < 0.01 and P < 0.05). CONCLUSION: PNS could enhance hematopoiesis by promoting proliferation of CFU-GM and CFU-E progenitors so as to improve the hematopoietic function in mice of immune-mediated aplastic anemia.

[Effect of ligustrazine on CD34 antigen expression of bone marrow cells in immune-mediated aplastic anemia mice].

OBJECTIVE: To explore the effect of ligustrazine on CD34 antigen expression of bone marrow cells in immune-mediated aplastic anemia (AA) mice. METHODS: The model of immune aplastic anemia mice was induced by means of 6.0 Gy60Co gamma-ray irradiation and lymphocyte infusion through tail vein. The mice were divided into 3 groups: the normal group, the AA control group and the ligustrazine group. Mice of the ligustrazine group were fed by 4 mg of ligustrazine injection twice a day by gastrogavage. On the 10th day, CD34 antigen expression intensity of bone marrow cell membrane was measured by flow cytometer analysis system. RESULTS: CD34 antigen expression intensity of ligustrazine group was 77.6 +/- 6.5, with no statistic difference from that in the normal group (80.0 +/- 2.6), while that of the control group was much higher (68.6 +/- 4.5, P < 0.05). CONCLUSIONS: Ligustrazine could promote proliferation of stem and progenitor cell of AA mice through influencing on bone marrow micro-environment so as to increase the CD34 antigen expression of bone marrow cells.

Combination therapy for radiation-induced bone marrow aplasia in nonhuman primates using synthokine SC-55494 and recombinant human granulocyte colony-stimulating factor.

Combination cytokine therapy continues to be evaluated in an effort to stimulate multilineage hematopoietic reconstitution after bone marrow myelosuppression. This study evaluated the efficacy of combination therapy with the synthetic interleukin-3 receptor agonist, Synthokine-SC55494, and recombinant methionyl human granulocyte colony-stimulating factor (rhG-CSF) on platelet and neutrophil recovery in nonhuman primates exposed to total body 700 cGy 60Co gamma radiation. After irradiation on day (d) 0, cohorts of animals subcutaneously received single-agent protocols of either human serum albumin (HSA; every day [QD], 15 micrograms/kg/d, n = 10), Synthokine (twice daily [BID], 100, micrograms/kg/d, n = 15), rhG-CSF (QD, 10 micrograms/kg/d, n = 5), or a combination of Synthokine and rhG-CSF (BID, 100 and 10 micrograms/kg/d, respectively, n = 5) for 23 days beginning on d1. Complete blood counts were monitored for 60 days postirradiation and the durations of neutropenia (absolute neutrophil count < 500/microL) and thrombocytopenia (platelet count < 20,000/microL) were assessed. Animals were provided clinical support in the form of antibiotics, fresh irradiated whole blood, and fluids. All cytokine protocols significantly (P < .05) reduced the duration thrombocytopenia versus the HSA-treated animals. Only the combination protocol of Synthokine + rhG-CSF and rhG-CSF alone significantly shortened the period neutropenia (P < .05). The combined Synthokine/rhG-CSF protocol significantly improved platelet nadir versus Synthokine alone and HSA controls and neutrophil nadir versus rhG-CSF alone and HSA controls. All cytokine protocols decreased the time to recovery to preirradiation neutrophil and platelet values. The Synthokine/rhG-CSF protocol also reduced the transfusion requirements per treatment group to 0 among 5 animals as compared with 2 among 5 animals for Synthokine alone, 8 among 5 animals for rhG-CSF, and 17 among 10 animals for HSA. These data showed that the combination of Synthokine, SC-55494, and rhG-CSF further decreased the cytopenic periods and nadirs for both platelets and neutrophils relative to Synthokine and rhG-CSF monotherapy and suggest that this combination therapy would be effective against both neutropenia and thrombocytopenia consequent to drug- or radiation- induced myelosuppression.

Hematologic problems in pediatric patients.

OBJECTIVE: To provide a review of the common hematologic disorders of childhood: iron deficiency anemia, aplastic anemia, sickle cell disease, and hemophilia. DATA SOURCES: Review articles and book chapters pertaining to the care and treatment of children with hematologic disorders. CONCLUSIONS: These common hematologic disorders of childhood have the potential to cause not only acute illness but chronic medical problems, particularly in the growing child. Anticipating and preventing the long-term effects of the illness and treatment are the primary goals of care. IMPLICATIONS FOR NURSING PRACTICE: Nursing assessment, patient education, and long-term follow-up are major factors in the care of children with hematologic disorders. Nurse-managed comprehensive care clinics have provided successful programs directed at acute care and maintenance care for these children and their families.

Therapeutic efficacy of recombinant human leukemia inhibitory factor in a primate model of radiation-induced marrow aplasia.

The therapeutic efficacy of recombinant human leukemia inhibitory factor (LIF) was examined in a nonhuman primate model of radiation-induced marrow aplasia. Rhesus monkeys received 450 cGy of total-body, 1:1 mixed neutron:gamma radiation. For 23 days thereafter, each monkey received a daily subcutaneous injection of LIF or human serum albumin (HSA) at a dose of 15 micrograms/kg body weight. Complete blood counts and white blood cell differentials were monitored for 60 days postirradiation. Administration of LIF significantly decreased (P < or = .05) the duration of thrombocytopenia (platelet count < 30,000 or 20,000/microL), ie, 9.3 days or 6.3 days, respectively, versus the HSA-treated control monkeys, 12.2 days or 10.2 days, respectively. Treatment with LIF did not alter the duration of neutropenia (absolute neutrophil count < 1,000/microL) as compared with the HSA-treated control monkeys. Cytokine administration did not exacerbate the radiation-induced anemia observed in the HSA-treated control monkeys.

Diamond-blackfan anemia: etiology, pathophysiology, and treatment.

Diamond-Blackfan anemia (DBA) is manifested by a wide variety of clinical and in vitro abnormalities. Despite this biological diversity, the hematological phenotype is remarkably similar for all patients and consists of a normochromic-macrocytic anemia in early childhood, reticulocytopenia, and a normocellular marrow with a selective deficiency of red cell precursors. Fetal hemoglobin is usually increased, distributed heterogeneously, has a fetal G gamma/A gamma pattern, and is associated with increased expression of red cell i antigen. Although most cases are sporadic, there are examples of autosomal recessive and autosomal dominant inheritance patterns. Approximately 70% of patients with DBA respond to prednisone, and many can be maintained on tapered doses. Those who are steroid-dependent at high dosage as well as those who do not respond are managed on a transfusion and iron chelation program. Claims of efficacy for other therapies, such as cyclosporine or high-dose intravenous methylprednisolone, require substantiation. Bone marrow transplantation has been successfully performed in patients who have tissue-matched donors, and the procedure cures the anemia. Recombinant growth factors may be a therapy of the future. Regarding pathophysiology, initial reports of humoral or cellular inhibitors of erythropoiesis were not confirmed in all laboratories. However, some patients have lymphocyte dysfunction with decreased T cells, decreased T4/T8 ratios, and defective lymphocyte-mediated suppression of lymphoproliferation. A large body of data indicates that the erythroid stem cells are intrinsically defective in DBA, and they are partly or completely refractory to erythropoietin. The role of elevated red cell adenosine deaminase activity in the pathogenesis of this abnormal erythropoiesis is not clear, but this finding is characteristic of the syndrome in most patients. Present studies using recombinant growth factors have demonstrated a diversity of defects in erythropoiesis in patients with DBA. Blocks in red cell production and red cell maturation were seen at various levels along the differentiation pathway. Of clinical interest, interleukin-3 has a corrective effect in vitro on the aberrant marrow erythropoiesis of steroid-refractory patients, and, hence, it may have therapeutic application.

Effect of subcutaneous deferoxamine and oral vitamin C on iron excretion in congenital hypoplastic anemia and refractory anemia associated with the 5q-syndrome.

Chronic refractory anemia associated with congenital hypoplastic anemia (CHA, Blackfan-Diamond syndrome) and with the 5q-syndrome may require chronic transfusion therapy to sustain life. Hemosiderosis and death from chronic iron overload may result from such a program. The effect of subcutaneous (SC) deferoxamine (DF) and supplemental oral vitamin C (vit. C) on urinary iron excretion was studied in two patients with congenital hypoplastic anemia and one patient with 5q-syndrome. In the two patients with CHA, urinary iron excretion in response to DF given SC over 24 hours was comparable to the results following intravenous (I.V.) administration. Both of these cases had low levels of plasma ascorbate on initial evaluation and excreted more iron in response to two different doses of DF after they had received supplemental vit C and their stores were repleted. Significant iron excretion occurred in all three patients for 12 hours during the SC infusion of DF and for 12 hours after the end of the infusion. In all three patients, increasing the dose of DF up to 3-4 g given SC over 12 hours resulted in a linear increase in iron excretion. Once normal body stores of ascorbate were achieved by oral supplementation, increasing doses of vit C did not appear to cause a further increment in iron excretion. DF administered by a slow SC infusion appears to be an effective approach to iron overload in patients with refractory anemia and hemosiderosis secondary to chronic transfusions. Only small amounts of supplemental vit. C necessary to sustain adequate body stores are required for optimal iron excretion.

Aplastic anaemia and optic fundus haemorrhages due to traditional herbal remedies.

Aplastic anaemia as a consequence of use of traditional African herbal remedies in Zambia is reported in 5 cases. Three patients died. A feature of the haemorrhagic tendency from severe thrombocytopenia was optic fundus and vitreous haemorrhage.

Refractory anaemia of pregnancy as an expression of zinc deficiency.

Thirty-three gravidae with anemia in spite of iron and vitamin supplementation were examined, and 31 were found to have low or very low serum zinc concentrations with regard to the week of gestation. Twenty-three of the 33 showed no bone marrow haemosiderin or only traces. Thirty showed moderate or great increase in intracellular cell debris in the bone marrow macrophages, indicating an increase in intramedullary cell destruction. Two women showed low serum vitamin B-12 or folate concentrations and they also showed lowest zinc concentrations recorded in the series. Twelve of the 33 women gave birth to mature infants by normal delivery; 21 developed complications during labour or gave birth to immature, dysmature, or, in one case, malformed infants and/or were not delivered at normal term. Low serum zinc in pregnant women increases maternal morbidity and involves a higher risk to the fetus. It is suggested that an aetiological relationship exists between low serum zinc concentrations and refractory anaemia of pregnancy resulting in increased intramedullary cell destruction. This effect might be aggravated by iron deficiency.

Acute folate deficiency in surgical patients on aminoacid/ethanol intravenous nutrition.

Acute folate deficiency with pancytopenia and megaloblastic haemopoiesis developed in four patients after abdominal operations; all four responded to folic acid over 3-9 days. Three of them had been given intravenous nutrition with amino-acid/ethanol before the blood changes developed. A prospective study of twenty-five surgical patients with gastrointestinal diseases revealed a high frequency of acutely developing negative folate balance. Megaloblastic haemopoiesis and consequent blood changes were found in five patients. Treatment with intravenous nutrition correlated strongly with a fall in serum-folate and megaloblastic haemopoiesis. Some surgical patients develop acute folate deficiency which may proceed to megaloblastic arrest of haemopoiesis. Patients receiving intravenous nutrition containing ethanol are especially prone to this complication, which may be life-threatening if untreated. It is not yet known whether other forms of intravenous nutrition carry a similar risk.