Ikuko Suzuki

Management of erythropoiesis: cross‐sectional study of the relationships between erythropoiesis and nutrition, physical features, and adiponectin in 3519 Japanese people

Although erythroid abnormalities (anemia and polycythemia) are commonly observed pathological conditions, not much information about borderline abnormalities is available. In this study, a cross‐sectional study to analyze the relationships between erythropoiesis and nutrition, physical features, and laboratory test findings was conducted in middle‐aged and older men and women. The study included 3519 Japanese people (1579 men and 1940 women), age 40 years and over. Analysis of variance showed that the group with a tendency to anemia was older, had a lower body mass index and diastolic blood pressure, and had higher serum adiponectin and creatinine. Multiple regression analysis showed that adiponectin, triglycerides, and total protein were common factors that affected erythropoiesis in both men and women. Hepatic, renal, and cardiac functions were also factors involved in erythropoiesis in men and in postmenopausal women. In addition, nutrient factors such as alcohol, vitamins, and carbohydrates were also significantly involved in erythropoiesis in men, but there were no significant nutrient factors involved in erythropoiesis in either premenopausal or postmenopausal women. This study showed that factors that influence erythropoiesis differ between men, premenopausal women, and postmenopausal women, and it suggested that appropriately modifying erythropoiesis management for each group of people is essential.

High Serum Adiponectin Level Is a Risk Factor for Anemia in Japanese Men: A Prospective Observational Study of 1,029 Japanese Subjects.

Erythroid abnormalities including anemia and polycythemia are often observed in the general clinical setting. Because recent studies reported that adiponectin negatively affects hematopoiesis, we performed a prospective observational study to assess the relationship between anemia and adiponectin, as well as other parameters, in 1029 Japanese subjects (477 men and 552 women) 40 years of age and older. Body measurements, blood tests, and nutrition intake studies were performed at baseline, and 5 to 7 years later (follow-up). Hemoglobin (Hb) and hematocrit (Hct) levels in men with high serum adiponectin levels were lower at follow-up than at baseline. Multiple regression analysis showed that age, body mass index, adiponectin, and glutamic-pyruvic transaminase were significantly associated with erythroid-related variables (red blood cells, Hb, and Hct) in both men and women (P <0.05). In a logistic regression analysis, adiponectin, fasting blood glucose, and β-natriuretic peptide were significant risk factors for anemia in men, and blood urea nitrogen and amylase were significant risk factors in women. Physical features and nutrient intake were not risk factors for anemia. Our study demonstrates, both clinically and epidemiologically, that a high serum adiponectin level decreases the amounts of erythroid-related variables and is a risk factor for anemia in Japanese men.

Applying spatial epidemiology to hematological disease using R: a guide for hematologists and oncologists

“Spatial statistics” is an academic field that deals with the statistical analysis of spatial data, and has been applied to econometrics and various other policy fields. These methods are easily applied by hematologists and oncologists using better and much less expensive software. To encourage physicians to use these methods, this review introduces the methods and demonstrates the analyses using R and FleXScan, which can be freely downloaded from the website, with sample data. It is demonstrated that spatial analysis can be used by physicians to analyze hematological diseases. In addition, applying the technique presented to the investigation of patient prognoses may enable generation of data that are also useful for solving health policy-related problems, such as the optimal distribution of medical resources.

Autoimmune hemolytic anemia with warm-reactive immunoglobulin M antibody in multicentric Castleman disease

Dear Editor, Multicentric Castleman disease (MCD) is accompanied by systemic manifestations [1]. Autoimmune hemolytic anemia (AIHA) resulting from warm-reactive immunoglobulin M (wIgM) autoantibodies is rare and associated with a poor prognosis [2–4]. We report here the first case of MCD in which the clinical course was complicated by AIHA with wIgM and IgG antibodies. A 50-year-old male was admitted to our hospital because of weakness, swelling of multiple lymph nodes, and splenomegaly. Lymph node biopsy demonstrated MCD. He was treated with prednisolone (PSL) (0.5 mg/kg/day) and continued to receive maintenance therapy with PSL (10 mg/day). Three years later, he developed fever and fatigue. Upon hospital admission, he had icterus and severe anemia, but MCD activity was absent. Laboratory findings were: Hb, 3.3 g/dL; WBCs, 9,420/μL; platelets, 298,000/μL; reticulocytes, 11.3 %; total bilirubin, 2.4 mg/dL; D-dimer, 3.46 ng/mL; and CRP, 0.95 mg/dL. Anti-autoantibodies (including antiphospholipid antibody) were all negative, as were blood cultures. RBC histograms indicating the mean corpuscular volume (MCV), by a Blood Cell Counter, revealed several large peaks, suggesting hemagglutination in vivo (Fig. 1a). RBCs showed spontaneous agglutination at 37 °C in vitro and, after washing with physiological saline at 43 °C, hemagglutination was finally resolved. We could not carry out a direct antiglobulin test (DAT) due to undissolved material. After treatment of RBCs with 2mercaptoethanol (2-ME), the DAT for IgG and C3d remained positive. Eluted autoantibodies revealed direct hemagglutination. Finally, we confirmed a large amount of IgM and a small amount of IgG on the surface of RBCs by flow cytometry (FCM) (Fig. 1b). Thus, the patient was diagnosed with AIHA due to a high titer of wIgM and a low titer of IgG. Although he received combination treatment of PSL (1 mg/kg/day) and intravenous Ig, he had ongoing hemolysis, hemagglutination, and severe anemia (Hb, 2.2–4.7 g/dL) and required multiple blood transfusions. Ten days after hospital admission, he developed fluctuant disturbances in consciousness, and multiple cerebral thromboembolism (TE) as diagnosed by magnetic resonance imaging (MRI) of the brain (Fig. 1c). We immediately administered chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab (CHOP-R)) with continuous intravenous infusion of low-molecular-weight heparin. Hb levels gradually increased to 9.9 g/dL, and the large peaks of MCV in the RBC histogram disappeared (Fig. 1a). On follow-up, symptoms including neurological deficits had resolved, and MRI showed recovery from TE. DAT remained weakly positive for IgG and C3d. Sometimes, wIgM antibodies cannot be detected by the DAT. This may be because DAT cannot be carried out due to strong resistant hemagglutination; also, the routine DAT does not contain anti-IgM antibody [5]. The indirect AT is frequently negative or weak because most of the wIgM antibodies are absorbed by RBCs [5]. In our patient, the DAT could not be carried out but the indirect AT revealed K. Tajima (*) Department of Radiation Emergency Medicine, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan e-mail: tajima@nirs.go.jp

The pharmacokinetic analysis of cyclosporine is essential for the management of refractory pure red cell aplasia

Dear Editor, Pure red cell aplasia (PRCA) is a rare disease characterized by selective erythropoietic failure. Cyclosporine (CSA) is one of the initial agents used in the treatment of PRCA [1]. However, some PRCA patients are refractory to CSA, and the mechanism involved in this refractoriness is unknown. To determine the relationship between CSA blood concentration and clinical response in patients with anemia and PRCA, we evaluated the pharmacokinetic profile of CSA in two patients refractory to CSA. The first patient was a 63-year-old man diagnosed with idiopathic PRCA. He underwent treatment with antithymocyte globulin and the original formulation of cyclosporine (CSA-OF) at a dose of 5 mg/kg. His hemoglobin level reached more than 13 g/dl, and he continued to receive maintenance therapy with CSAOF. Although this patient was adherent to CSA, 5 years later, he showed severe anemia (hemoglobin, 6.6 g/dl) and was diagnosed with relapsed PRCA. We suspected poor absorption of CSA-OF, and performed a pharmacokinetic analysis of CSA-OF at C0, trough, and at 1h intervals for 4 h after administration of CSA-OF (C1, C2, C3, and C4), which showed no apparent peak level (C0, 82 ng/mL; C2, peak, 462 ng/mL) (Fig. 1a). Therefore, we changed CSA-OF to cyclosporine microemulsion (CSA-ME) at the same dose and reexamined the pharmacokinetics of CSA-ME 7 days later. An increase at C2 and in the area under the curve 0–4 (AUC0–4) were observed following CSA-ME administration compared with CSA-OF (C2, 1,211 ng/mL vs. 462 ng/mL; AUC0–4, 2,541 ng/mL vs. 1,189 ng/mL) (Fig. 1a). Sixty days later, the patient achieved normal hemoglobin levels (Fig. 1b). The second patient was a 40-year-old man diagnosed with PRCA at 33 years of age. He initially received prednisolone, which increased his hemoglobin (12.1 g/dl). However, his hemoglobin levels gradually decreased to 6.2 g/dl during a 7-year period. He was subsequently treated with CSA-OF and prednisolone. This combination did not improve his anemia. A pharmacokinetic evaluation revealed no apparent peak levels of CSA-OF as shown Y. Kato : I. Suzuki :K. Kohno :Y. Hiroshima : T. Kato Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology (DNHMED), Yamagata University School of Medicine, Yamagata, Japan