Macrocytosis secondary to hydroxyurea therapy.

A 10-year-old, male neutered Shetland Sheepdog was presented to the University of Florida for evaluation of a well-granulated mast cell tumor. Hydroxyurea therapy was instituted and serial CBCs showed persistent mild anemia and macrocytosis without a corresponding increase in polychromasia. The dog's MCV increased progressively, reaching its highest value of 100.0 fL after 6 months of treatment, and a diagnosis of macrocytosis associated with hydroxyurea therapy was made. The dog's increase in MCV was prominent, and rapidly decreased after the drug was discontinued, consistent with previous observations in human and canine subjects treated with hydroxyurea. Hydroxyurea is a cytotoxic chemotherapeutic agent used in a variety of conditions in human and veterinary medicine, and megaloblastic changes associated with its use have been described in multiple species. This report shows that hydroxyurea treatment is a differential diagnosis for prominent macrocytosis in dogs in the absence of other signs of erythrocyte regeneration.

Anemia and genotoxicity induced by sub-chronic intragastric treatment of rats with titanium dioxide nanoparticles.

Titanium dioxide nanoparticles (TiO2 NPs) are widely used for their whiteness and opacity. We investigated the hematological effects and genotoxicity of anatase TiO2 NPs following sub-chronic oral gavage treatment. TiO2-NPs were characterized by X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM). Wistar rats were treated with anatase TiO2 NPs by intragastric administration for 60 days. Hematological analysis showed a significant decrease in RBC and HCT and a significant increase in MCV, PLT, MPV and WBC at higher doses. Furthermore, abnormally shaped red cells, sometimes containing micronuclei, and hyper-segmented neutrophil nuclei were observed with TiO2 NPs treatment. The micronucleus test revealed damage to chromosomes in rat bone marrow at 100 and 200mg/kg bw; the comet assay showed significant DNA damage at the same doses.

Nonclinical Safety Profile of BMS-986001, a Nucleoside Transcriptase Inhibitor for Combination Retroviral Therapy.

Nucleoside reverse transcriptase inhibitors (NRTIs)/nucleotide reverse transcriptase inhibitors are key components of combination antiretroviral therapy for HIV infection. First-generation NRTIs are associated with mitochondrial toxicity in patients, mainly due to inhibition of human DNA polymerase γ (hDNA polγ) that manifests as adverse events such as lipodystrophy, lactic acidosis, myopathy, cardiomyopathy, or nephropathy in patients. In chronic nonclinical studies in rodents and nonrodents, eukaryotic (host) mitochondrial toxicity manifests as some drug-specific toxicities similar to human toxicity. BMS-986001, a novel thymidine analog with minimal hDNA polγ inhibition, has demonstrated antiretroviral activity in early clinical studies. The primary toxicity of BMS-986001 in rats and monkeys is bone marrow dyserythropoiesis with associated decreases in red blood cell mass. Additionally, at high doses, severe platelet reductions accompanied by cutaneous petechiae began during weeks 8 and 11 in 3 of 60 monkeys in chronic toxicity studies. In a 6-month study, platelet reductions required euthanasia of the 2 affected monkeys (300 mg/kg/d) at week 14, but with dose reduction (200 mg/kg/d) remaining monkeys had no platelet changes. One affected monkey (200 mg/kg/d) in a 9-month study completed dosing and its platelet counts recovered during a 1-month recovery. Formation of platelet-bound immunoglobulin in the presence of BMS-986001, together with rapid and complete platelet recovery in the absence of BMS-986001, suggested that platelet decreases in monkeys may be immune mediated. No findings indicative of mitochondrial toxicity were observed in rats or monkeys given BMS-986001, suggesting an improved safety profile compared to marketed NRTI or tenofovir disoproxil fumarate.

Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc.

Therapy-related myeloid neoplasms (t-MN) are a late complication of the successful use of cytotoxic therapy for patients with cancer. A heterozygous deletions of the long arm of chromosome 5 [del(5q)], observed in 40% of patients, is associated with prior exposure to alkylating agents, and a high frequency of TP53 loss or mutation. In previous studies, we demonstrated that haploinsufficiency of 2 del(5q) genes, Egr1, and Apc, individually play a role in the pathogenesis of hematologic disease in mice. We now show that loss of one copy of Egr1 or Tp53 in an Apc haploinsufficient background (Apc (del/+)) accelerated the development of a macrocytic anemia with monocytosis, early features of t-MN. The development of anemia was significantly accelerated by treatment of mice with the alkylating agent, N-ethyl-N-nitrosourea (ENU), regardless of the levels of expression of Egr1 and Tp53. Transplantation of either wild type; Egr1(+/-); Tp53(+/-); Apc(del/+); or Egr1(+/-), Apc(del/+) bone marrow cells into lethally irradiated Apc(del/+) recipients resulted in rapid development of anemia that was further accelerated by administration of ENU to recipients, demonstrating that the Apc(del/+)-induced anemia was cell extrinsic and potentiated by ENU mutagenesis. These data emphasize the synergistic role of cell intrinsic and cell extrinsic (microenvironment) factors in the pathogenesis of t-MN, and raise awareness of the deleterious effects of cytotoxic therapy on the stromal microenvironment.

An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents.

Black cohosh rhizome (Actaea racemosa) is used as a remedy for pain and gynecological ailments; modern preparations are commonly sold as ethanolic extracts available as dietary supplements. Black cohosh was nominated to the National Toxicology Program (NTP) for toxicity testing due to its widespread use and lack of safety data. Several commercially available black cohosh extracts (BCE) were characterized by the NTP, and one with chemical composition closest to formulations available to consumers was used for all studies. Female B6C3F1/N mice and Wistar Han rats were given 0, 15 (rats only), 62.5 (mice only), 125, 250, 500, or 1000 mg/kg/day BCE by gavage for 90 days starting at weaning. BCE induced dose-dependent hematological changes consistent with a non-regenerative macrocytic anemia and increased frequencies of peripheral micronucleated red blood cells (RBC) in both species. Effects were more severe in mice, which had decreased RBC counts in all treatment groups and increased micronucleated RBC at doses above 125 mg/kg. Dose-dependent thymus and liver toxicity was observed in rats but not mice. No biologically significant effects were observed in other organs. Puberty was delayed 2.9 days at the highest treatment dose in rats; a similar magnitude delay in mice occurred in the 125 and 250 mg/kg groups but not at the higher doses. An additional uterotrophic assay conducted in mice exposed for 3 days to 0.001, 0.01, 0.1, 1, 10, 100 and 500 mg/kg found no estrogenic or anti-estrogenic activity. These are the first studies to observe adverse effects of BCE in rodents.

Macrocytosis is a predictor of resting lactate concentrations in persons on dideoxynucleoside therapy for HIV infection.

OBJECTIVES: Mitochondrial toxicity is an important toxicity of antiretroviral therapy and may manifest as elevated blood lactate. Macrocytosis has been hypothesized to act as a marker of mitochondrial toxicity in persons with HIV infection. As part of a larger study on markers of mitochondrial toxicity we evaluated the relationship between resting lactate and erythrocyte mean corpuscular volume (MCV). METHODS: We studied the effect of micronutrient supplementation on lactate metabolism in three groups: those with HIV on and not on dideoxynucleoside-containing antiretroviral therapy and those without HIV. As part of the study we measured resting lactate and erythrocyte MCV after a 14-h fast. RESULTS: Erythrocyte MCV was significantly higher among the 11 participants on antiviral therapy (109.3 femtoliters (fl)) compared to five controls without HIV (89.3 fl) and four controls with HIV not on antiviral therapy (88.3 fl). In addition a strong predictive relationship was seen between MCV and resting lactate (R(2)=0.548, p<0.01). CONCLUSIONS: Macrocytosis may be a marker of treatment-related mitochondrial dysfunction in persons on treatment for HIV. Evaluating patients for early evidence of mitochondrial dysfunction in resource-constrained settings could be facilitated by this marker.

[Impact of antiretroviral therapy on occurrences of macrocytosis in patients with HIV/AIDS in Maringá, State of Paraná]. / Impacto do tratamento antirretroviral na ocorrência de macrocitose em pacientes com HIV/AIDS do município de Maringá, Estado do Paraná

INTRODUCTION: AIDS is a disease caused by HIV that compromises the organism's immune system. The advent of highly active antiretroviral therapy (HAART) has promoted substantial improvement in the prognosis for this disease and in HIV/AIDS patients' quality of life. During prolonged treatment, certain hematological disorders are observed, such as anemia and macrocytosis, as well as deficiencies of micronutrient such as vitamin B12 and folic acid. The objective of this study was to correlate the presence of macrocytosis and anemia with HAART use or vitamin B12 and folic acid deficiencies. METHODS: 110 HIV-positive patients were included, in three groups: HAART use with zidovudine (AZT) (group 1), HAART use without AZT (group 2) and no HAART (group 3). RESULTS: None of the patients in any of the three groups presented statistically significant differences relating to hemoglobin level (p = 0.584) or folic acid level (p = 0.956). Group 1 (G1) had a higher mean corpuscular volume (MCV) than G3 (p < 0.05), and group 2 (G2) had a higher volume than group 3 (G3) (p < 0.001). Vitamin B12 levels in G1 and G3 were smaller than those in G2 (p = 0.008). CONCLUSIONS: It was concluded that patients undergoing HAART treatment presented macrocytosis, even though this could not be correlated with the type of HAART or with vitamin B12 deficiency. However, folic acid deficiency was unrelated to either HAART or macrocytosis.

Impacto do tratamento antirretroviral na ocorrência de macrocitose em pacientes com HIV/AIDS do município de Maringá, Estado do Paraná / Impact of antiretroviral therapy on occurrences of macrocytosis in patients with HIV/AIDS in Maringá, State of Paraná

INTRODUÇÃO: AIDS é uma doença causada pelo HIV que compromete o sistema imune do organismo. O advento da terapia antirretroviral (TARV) altamente eficaz promoveu melhora substancial do prognóstico da doença e da qualidade de vida dos pacientes com HIV/AIDS. Durante seu tratamento prolongado, notam-se algumas alterações hematológicas, dentre elas, anemia e macrocitose, bem como carências de micronutrientes, tais como, de vitamina B12 e ácido fólico. O objetivo do presente trabalho é relacionar a macrocitose e anemia ao uso de TARV, ou à deficiência de vitamina B12 ou de ácido fólico. MÉTODOS: Foram avaliados 110 pacientes HIV positivos, comparando-se aqueles em uso de TARV com zidovudina (AZT) (grupo 1), TARV sem AZT (grupo 2) ou sem uso de TARV (grupo 3). RESULTADOS: Os pacientes dos três grupos não apresentaram diferenças estatísticas significativas quanto aos níveis de hemoglobina (p = 0,584) e de ácido fólico (p = 0,956). Os pacientes do grupo 1 (G1) apresentaram volume corpuscular médio (VCM) aumentado quando comparado ao grupo 3 (G3) (p < 0,05), bem como do grupo 2 (G2) em relação ao G3 (p < 0,001). As dosagens de vitamina B12 do G1 e G3 foram menores do que as encontradas pelo G2 (p = 0,008). CONCLUSÕES: Conclui-se que os indivíduos em uso de TARV apresentaram macrocitose, embora não pudesse ser relacionada ao tipo de TARV ou a deficiência de vitamina B12. Entretanto, a deficiência de ácido fólico não esteve relacionada ao uso de TARV e nem à macrocitose.

INTRODUCTION: AIDS is a disease caused by HIV that compromises the organism's immune system. The advent of highly active antiretroviral therapy (HAART) has promoted substantial improvement in the prognosis for this disease and in HIV/AIDS patients' quality of life. During prolonged treatment, certain hematological disorders are observed, such as anemia and macrocytosis, as well as deficiencies of micronutrient such as vitamin B12 and folic acid. The objective of this study was to correlate the presence of macrocytosis and anemia with HAART use or vitamin B12 and folic acid deficiencies. METHODS: 110 HIV-positive patients were included, in three groups: HAART use with zidovudine (AZT) (group 1), HAART use without AZT (group 2) and no HAART (group 3). RESULTS: None of the patients in any of the three groups presented statistically significant differences relating to hemoglobin level (p = 0.584) or folic acid level (p = 0.956). Group 1 (G1) had a higher mean corpuscular volume (MCV) than G3 (p < 0.05), and group 2 (G2) had a higher volume than group 3 (G3) (p < 0.001). Vitamin B12 levels in G1 and G3 were smaller than those in G2 (p = 0.008). CONCLUSIONS: It was concluded that patients undergoing HAART treatment presented macrocytosis, even though this could not be correlated with the type of HAART or with vitamin B12 deficiency. However, folic acid deficiency was unrelated to either HAART or macrocytosis.

Hematological effects of valproate in psychiatric patients: what are the risk factors?

BACKGROUND: Sodium valproate is an anticonvulsant that is also one of the common treatments used for bipolar disorder. The present study was conducted in psychiatric patients with the aim of examining the effects of valproate on hematological parameters and to explore any association with sex and age. METHODS: A list of all psychiatric patients who underwent valproate level estimation in the years 2004-2008 in Newcastle upon Tyne was drawn from the biochemistry database of the local hospital. The names and date of births of these patients were used to draw corresponding hematological data, including hemoglobin, white blood cell count, mean corpuscular volume (MCV), and platelet count, conducted on the same day or within a week of the valproate level measurement. RESULTS: : The data from 126 patients were analyzed. The prevalence of thrombocytopenia (platelet count, <150,000/microL) was found to be approximately 5%. In female subjects, a significant negative correlation was found between serum valproate level and platelet count; also, a positive correlation between valproate level and MCV was found. Neither correlation was found in male subjects. The risk of a low platelet count was found to be significantly increased at serum valproate level above 80 microg/mL in female subjects. The regression analysis in female patients showed a trend toward fall in platelet count and an increase in MCV with increasing age. CONCLUSIONS: In psychiatric patients on valproate therapy, close monitoring of full blood count is required in women particularly at valproate serum level above 80 microg/mL. This may be particularly important in older patients.

Clinico-hematological and micronuclear changes induced by cypermethrin in broiler chicks: Their attenuation with vitamin E and selenium.

This study was carried out on 90 one-day-old broiler chicks to know clinico-hematological alterations, DNA damage caused by cypermethrin (CY), and attenuation of toxic effects by vitamin E (Vit E) and selenium (Se). Birds were randomly divided into five equal groups. Groups 1-4 received CY (600mlkg(-1)b.wt) daily for 30 days by crop tubing. In addition to CY, groups 2, 3 and 4 received Vit E (150mgkg(-1)b.wt), Se (0.25mgkg(-1)b.wt), and Vit E (150mgkg(-1)b.wt)+Se (0.25mgkg(-1)b.wt), respectively. Group 5 served as control. Birds were monitored twice daily for clinical signs. They were weighed and blood samples were collected at experimental days 10, 20 and 30 for hematological studies. CY-treated birds showed more prominent signs of toxicity compared to CY+Vit E, CY+Se and CY+Vit E+Se birds. Body weight in groups 1-3 was significantly (P<0.05) smaller at days 20 and 30 when compared with the control group. Significantly (P<0.001) higher numbers of micronuclei appeared in chicks treated with CY compared to CY+Vit E- and CY+Se-treated birds. Significantly decreased total erythrocyte counts (TEC), hemoglobin (Hb) concentration and packed cell volume (PCV) in all treated groups were recorded. Treated birds suffered from macrocytic hypochromic anemia. Leukocytosis in early stage and later leucopenia was seen in treated birds. It can be concluded that CY induces toxic effects in broilers chicks; however, these toxic effects can be ameliorated by Vit E or Se. Combination of Vit E and Se was more effective to ameliorate toxic effects of cypermethrin.

Tyrosine kinase inhibitor-induced macrocytosis.

BACKGROUND: The tyrosine kinase inhibitors (TKI) sunitinib and imatinib were shown to induce macrocytosis in patients with renal cell cancer (RCC) and gastrointestinal stromal tumors (GIST), presumably through inhibition of the c-KIT dependent signaling pathway of erythroid progenitor cells of the bone marrow. PATIENTS AND METHODS: Hematology charts of patients with RCC, breast cancer (BC), GIST, non-small cell lung cancer (NSCLC) and hepatocellular cancer (HCC), receiving single-agent sunitinib, imatinib, sorafenib, erlotinib and BI 2992 (Tovok) at the recommended dose for at least 3 months were reviewed retrospectively for the occurrence of macrocytosis. RESULTS: Macrocytosis occurred in all patients with RCC and BC treated with sunitinib and in all patients with GIST treated with imatinib. The percentage increase of the mean corpuscular volume (MCV) of peripheral red blood cells (RBC) compared with baseline at 3, 6, 9 and 12 months was 12.4%, 16.8%, 16.6%, 12.7% and 0.7%, 5.6%, 5.9%, 5% with sunitinib and imatinib respectively. The values at 3, 6 and 9 months between both groups were significantly different. Sorafenib, erlotinib and BI 2992 did not induce macrocytosis. CONCLUSION: Sunitinib-induced macrocytosis was not confined to patients with RCC alone but also occurred in patients with BC. Imatinib also induced macrocytosis in patients with GIST but to a significantly lower degree. Because both drugs were used at an effective pharmacodynamic dose inhibiting c-KIT, these data strongly suggest that pathways in addition to c-KIT and not common to both agents are involved in the TKI-induced macrocytosis.

Sunitinib-induced macrocytosis in patients with metastatic renal cell carcinoma.

BACKGROUND: Sunitinib and sorafenib are small molecules that inhibit the vascular endothelial growth factor and related receptors with substantial clinical activity reported in metastatic renal cell carcinoma (RCC). Cytopenia and macrocytosis have been described in patients treated with these agents. METHODS: A retrospective review of all patients with metastatic RCC who were treated with sunitinib or sorafenib for at least 3 months at the Cleveland Clinic Taussig Cancer Institute was undertaken. Complete blood count (CBC) data including red blood cell indices were recorded at baseline, after 3 months of therapy, and at the end of treatment. RESULTS: A total of 61 patients were treated with sunitinib and 37 patients were treated with sorafenib with available CBC data. In patients treated with sunitinib, the median corpuscular volume (MCV) increased significantly at 3 months compared with baseline (median increase of 5.1 femtoliters [fL]; P < .001) and continued to increase throughout treatment. Patients who developed hypothyroidism had a larger MCV increase at 3 months than patients who remained euthyroid (P = .06), although macrocytosis was observed in patients without hypothyroidism. Ten patients discontinued sunitinib therapy, and the MCV decreased in all patients within 2 to 4 months, without further intervention. Bone marrow analysis of 4 patients revealed a hypocellular bone marrow with trilineage hematopoiesis and no evidence of metastasis. There was no evidence of folate or vitamin B12 deficiency. In contrast to sunitinib, there was no change in the MCV for patients treated with sorafenib. CONCLUSIONS: Macrocytosis was a common occurrence after treatment with sunitinib but not sorafenib in patients with metastatic RCC. Sunitinib-induced macrocytosis is reversible with drug discontinuation.

Pancytopenia, including macrocytic anemia, associated with leflunomide in a rheumatoid arthritis patient.

A female rheumatoid arthritis patient was admitted for productive cough and general fatigue that had gradually developed after leflunomide therapy. Side effects including severe hypoxia, thrombocytopenia, lymphocytopenia, and macrocytic anemia with schistocytes (probably drug-induced megaloblastic anemia) were noted. Leflunomide-eliminating cholestyramine therapy successfully treated all conditions excluding severe hypoxia, which occurred owing to deteriorating interstitial pneumonia and complicated bacterial pneumonia following antibiotic treatment. This is a rare case of leflunomide-associated multiple hematopoietic impairments.

Lamivudine-associated macrocytosis in HIV-infected patients.

Macrocytosis has been increasingly observed in HIV-infected population and is an early indicator of bone marrow toxicity. A retrospective study was conducted among these patients in a HIV clinic to assess risk factors of macrocytosis. We found that lamivudine was strongly associated with macrocytosis (OR = 24.6 [2.9-3223.0], P = 0.001). This association may be due to lamivudine's effect on erythrocyte synthesis.