Junji Tomiyama

Pregnancy-induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw-Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients

Upshaw–Schulman syndrome (USS) is a congenital thrombotic thrombocytopenic purpura (TTP) due to mutations in the gene that encodes for ADAMTS13 (ADAMTS13), but its clinical signs may be mild or absent during childhood. We have identified 37 patients with USS (24 females, 13 males) belonging to 32 families. The nine women from six families who were diagnosed during their first pregnancy are the focus of this report. Six of the nine women had episodes of thrombocytopenia during childhood misdiagnosed as idiopathic thrombocytopenic purpura. Thrombocytopenia occurred during the second–third trimesters in each of their 15 pregnancies, with 16 babies (one twin pregnancy), often followed by TTP. Of 15 pregnancies, eight babies were stillborn or died soon after birth, and the remaining seven were all premature except one, who was born naturally following plasma infusions to the mother that had started at 8 weeks’ gestation. All nine USS women had severely deficient ADAMTS13 activity. ADAMTS13 analyses demonstrated that eight women were compound heterozygotes of Y304C/G525D (2 siblings), R125VfsX6/Q1302X (2 siblings), R193W/R349C (2 siblings), I178T/Q929X, and R193W/A606P; one woman was homozygous for R193W. Only the R193W mutation has been previously reported. These observations emphasize the importance of measuring ADAMTS13 activity in the evaluation of thrombocytopenia during childhood and pregnancy.

Comparison of Allogeneic Hematopoietic Cell Transplantation and Chemotherapy in Elderly Patients with Non-M3 Acute Myelogenous Leukemia in First Complete Remission

The benefits of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with acute myelogenous leukemia (AML) in first complete remission (CR1) have mostly been evaluated in younger patients. Although favorable outcomes of allo-HCT over chemotherapy have been reported with the use of reduced-intensity conditioning (RIC) regimens in elderly patients with AML in CR1, information is still limited, especially on the effects of cytogenetic risks and donor sources. We collected data from AML patients aged 50 to 70 years who achieved CR1, and compared the outcome in 152 patients who underwent allo-HCT in CR1 (HCT group) to that in 884 patients who were treated with chemotherapy (CTx group). The cumulative incidence of relapse in the HCT group was significantly lower than that in the CTx group (22% versus 62%). Both overall survival (OS) and relapse-free survival (RFS) were significantly improved in the HCT group (OS: 62% versus 51%, P = .012), not only in the whole population, but also in the intermediate-risk group. Among patients who had a suitable related donor, the outcomes in the HCT group were significantly better than those in the CTx group. The introduction of appropriate treatment strategies that include allo-HCT may improve the outcome in elderly patients with AML in CR1.

A Markov decision analysis of allogeneic hematopoietic cell transplantation versus chemotherapy in patients with acute myeloid leukemia in first remission

Various prospective trials have been performed to assess the roles of allogeneic hematopoietic cell transplantation (allo-HCT) and chemotherapy in patients with acute myeloid leukemia (AML) in first complete remission (CR1). However, the results have not always been consistent, and there has been a limited evaluation of quality of life (QOL) in these postremission strategies. We performed a Markov decision analysis that enabled us to compare survival outcomes with a QOL evaluation using a database of 2029 adult AML patients who achieved CR1. The Markov decision model compared 2 strategies: allo-HCT or chemotherapy in CR1. Patients who had intermediate- or unfavorable-risk AML had a longer life expectancy when they received allo-HCT in CR1 than patients treated with chemotherapy alone. Likewise, patients who had a suitable related donor who received allo-HCT in CR1 had a longer life expectancy. The life expectancy was shortened to a greater degree by adjustment for QOL in the allo-HCT group. Nevertheless, QOL-adjusted life expectancies in most of the subgroups remained longer in the allo-HCT group than in the chemotherapy group. Our results showed that older patients with a related donor and younger patients with unfavorable cytogenetics benefited the most from allo-HCT in CR1.

Deficiency of glycosyl-phosphatidylinositol anchored proteins on paroxysmal nocturnal haemoglobinuria (PNH) neutrophils and monocytes : heterogeneous deficiency of decay-accelerating factor (DAF) and CD16 on PNH neutrophils

Glycosyl‐phosphatidylinositol (GPI) anchored membrane proteins have been reported to be deficient on affected paroxysmal nocturnal haemoglobinuria (PNH) blood cells. In the present study we investigated the deficiency of several GPI anchored membrane proteins on PNH neutrophils (PMN) and monocytes from 10 patients with PNH. Decay‐accelerating factor (DAF) and FcyR‐III (CD 16) on PMN, DAF and CD14 on monocytes, were investigated by two‐colour immunofluorocytometry. Neutrophil alkaline phosphatase activity was also assayed on PNH neutrophils. Normal human PMN were always shown phenotypically to be DAF+/CD16+. A DAF−/CD16− subpopulation of PMN was demonstrated in all the patients studied. In six out of the 10 patients, deficiencies of DAF and CD16 were found simultaneously on affected PNH PMN. The percentage of DAF− PMN showed a positive correlation with the neutrophil alkaline phosphatase (NAP) score. However, it should be noted that, in four out of the 10 patients with PNH, a DAF+/CD16− subpopulation of PMN was also clearly found. This may indicate that the deficiencies of DAF and CD16 on PNH PMN are heterogeneous. Normal human monocytes were demonstrated to be DAF+/CD14+, whereas PNH monocytes consisted of subpopulations of DAF+/CD14+ and DAF−/CD14−. In the same patients with PNH, the deficiencies of DAF on PMN and monocytes correlated well with each other. These results suggest that, at least in some patients with PNH, the mechanisms which induce the membrane defects of PNH blood cells are heterogeneous.

HUMAN PARVOVIRUS B19-INDUCED APLASTIC CRISIS IN AUTOIMMUNE HAEMOLYTIC ANAEMIA

0.04 x 109/1) and a platelet count of 90 x 1OY/1. He was placed in protective isolation and treated with intravenous gentamicin and piperacillin. Bone marrow examination showed an absence of red cell precursors with ‘maturation arrest’ of granulopoiesis at the early metamyelocyte stage and normal numbers of megakaryocytes. No reticulocyte counts were performed as he was transfusion dependent. He became apyrexial within 24 h and his white cell count rose to 5.1 x 10y/l (neutrophils 3.7 x 10y/l, lymphocytes 0.74 x 10y/l, eosinophils 0.15 x 10y/l, basophils 0.01 x loy/ I, monocytes 0.41 x 10y/l) with a platelet count of 3 15 x lo9/ 1 over the next 3 d. His haemoglobin increased to 12.0 g/dl after a 5 unit transfusion and he was discharged. Sputum, urine and blood cultures and throat swabs were all bacteriologically negative but a serum sample showed 100 units of anti-HPV IgM. (Reported by Dr P. Mortimer, PHLS, Colindale.) Between 30% and 60% of adults in this country have antiHPV IgG, indicating a previous infection, but the incidence of the virus in donated blood is very low, less than 1 in 50000 donations. One study by Mortimer et al (1983) showed no significant increase in anti HPV antibodies in those receiving multiple red cell transfusions ( 3 6%) over matched controls (23%) although haemophiliacs had a much higher incidence of seroconversion after receiving pooled factor concentrates (97%). The incubation period of HPV infection has been demonstrated with human volunteers to be 13-18 d (Anderson et al, 19 8 5) and in the same study IgM levels of 100 units were not achieved in less than 20 d from the onset of symptoms for HPV infection. It is therefore unlikely that the transfusion 6 d before the onset of symptoms was the origin of the HPV infection. It is likely that the presenting symptoms were not of the primary HPV infection, which may have been sub-clinical. but of an opportunistic infection secondary to the neutropenia. A fall in white count was noted in healthy volunteers infected with HPV and low white cell counts and platelet counts were seen accompanying red cell aplasia in cases of HPV infection with congenital spherocytosis reported by Saunders et a1 (1 986). Here a patient whose red cells were supplied by transfusion presents with neutropenia, a rare complication of this common infectious disease.

Development of a liquid culture system for megakaryocyte terminal differentiation: fibrinogen promotes megakaryocytopoiesis but not thrombopoiesis

Summary. Megakaryocyte differentiation is composed of three distinct stages: formation of erythromegakaryocytic progenitor cells, maturation of megakaryocytes and production of platelets. We have developed a liquid culture system for megakaryocyte terminal differentiation from haematopoietic stem cells into proplatelets. In this system, CD34+ cells isolated from human cord blood, differentiated to CD41+ cells, were classified either as propidium iodide (PI)+ cells (large) or PI– cells (small) by fluorescence‐activated cell sorting analysis on the late‐stage CD41+ cells. Transmission electron microscopy showed that the cultured small cells were morphologically identical to platelets isolated from normal peripheral blood. Moreover, the number of differentiated cells that were CD42b‐positive attained an approximately 60‐fold expansion over that of the primary CD34+ cells in this culture system. Furthermore, gene expression of megakaryocytopoietic transcriptional factors, GATA‐1 and NF‐E2, and several megakaryocytic markers such as glycoprotein (GP)IIb and thromboxane synthase was observed in the individual differentiation stage. Treatment with fibrinogen, a ligand of GPIIb/IIIa, increased the number of CD41+/PI+ cells, but treatment in the late stage suppressed CD41+/PI– cell formation, suggesting that fibrinogen promotes megakaryocytopoiesis, but not thrombopoiesis. We conclude that this liquid culture system using human CD34+ cells may be used to mimic the physiological development from haematopoietic stem cells into megakaryocytes, as well as promote subsequent thrombopoiesis.

Pharmacological characterization of cepharanthin in chronic idiopathic thrombocytopenic purpura

Cepharanthin, a bisbenzylisoquinoline (biscolaurine) alkaloid drug, has been reported to improve the symptoms of intractable or steroid-resistant chronic idiopathic thrombocytopenic purpura (ITP). To clarify the mechanism by which the cepharanthin is beneficial to ITP, we examined the effects of cepharanthin on thrombocytopenia in (NZW 2 BXSB) F1 (W/B F1) mice and on the formation of colony forming unit of megakaryocyte (CFU-MK) derived from human CD34-positive progenitor cells. The decrease in platelet numbers in W/B F1 was diminished by the administration of 5 mg/kg cepharanthin for 6 weeks as well as by 2 mg/kg prednisolone. Furthermore, the administration of over 0.2 mg/kg cepharanthin enhanced the therapeutic effect of prednisolone. From the data in this animal model, it is suggested that cepharanthin may prolong the platelet lifespan. The treatment of CD34-positive progenitor cells isolated from cord blood with cepharanthin (over 5 2 10 -10 g/ml) caused an increase in the formation of CFU-MK induced by the cocktail of thrombopoietin, interleukin (IL)-6 and IL-3. The addition of 0.1% normal human serum dramatically increased the number of CFU-MK. In contrast, the serum isolated from patients with ITP at the same concentration decreased the number of CFU-MK. However, the simultaneous addition of 5 2 10 -8 g/ml cepharanthin recovered the number of CFU-MK to the level induced by normal serum. These findings indicate that cepharanthin has the potent therapeutic activity not only on the platelet destruction process, but also on the platelet production process of thrombocytopenia in chronic ITP.

Increased phosphatidylserine exposure on the erythrocyte membrane in patients with polycythaemia vera

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Losartan potassium/hydrochlorothiazide (Preminent®) and hyponatremia: case series of 40 patients.

The clinical course of losartan potassium/hydrochlorothiazide (Preminent®)-induced hyponatremia has not been described. We summarized 40 patients with Preminent-induced hyponatremia. The study involved 15 (37.5%) men and 25 (62.5%) women (mean age [SD], 76.4 [8.3] years; range, 55–95). Their sodium levels before Preminent administration were 139.5 (4.9) mEq/L (range, 131–145; reference range, 135–147). The duration from the day of Preminent administration to the day with the lowest sodium level was 59.3 (64.9) days (range, 2–207; median, 24). Most patients for whom this duration was <50 days exhibited progressive symptoms, whereas most of those for whom this duration was >50 days did not exhibit progressive symptoms but exhibited symptoms after fever or appetite loss. The lowest sodium value was 114.4 (8.2) mEq/L (range, 99–133). The duration from the time of Preminent discontinuation to (1) the time of early recovery and (2) the time of final recovery was 6.8 (5.5) days (range, 1–20; median, 5) and 11.6 (7.6) days (range, 2–29; median, 7.5), respectively. Of the 40 patients, 36 (90.0%) achieved full recovery, 1 (2.5%) suffered from after-effects due to central pontine myelinolysis, 1 (2.5%) died, and 2 (5.0%) were unknown. In the analysis of other adverse effects of Preminent and the same adverse effects of other three angiotensin II receptor blocker (ARB)/thiazide combinations, hyponatremia was observed as a primary adverse effect of all ARB/thiazide combinations. However, hyperesthesia dermatitis was reported as an adverse effect of Preminent only.

Idiopathic Plasmacytic Lymphadenopathy with Polyclonal Hypergammaglobulinemia Accompanied with Cutaneous Involvement and Renal Dysfunction

Idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hypergammaglobulinemia has been proposed as a new disease entity resembling the plasma cell type of multicentric Castlemans disease. Here, we report a case of IPL accompanied by renal failure and skin involvement. A 35-year-old man was admitted for advanced renal failure, anemia, systemic lymphadenopathy and skin rashes. Laboratory examinations indicated polyclonal hypergammaglobulinemia and elevated serum interleukin-6 (IL-6). Biopsy of a cervical lymph node revealed follicular hyperplasia with normal germinal centers, sheets of polyclonal proliferating plasma cells and the absence of marked proliferation of blood vessels in the interfollicular area. Lesions of the kidney and skin also had pathological characteristics of IPL. Following a diagnosis of IPL, corticosteroid therapy successfully improved the anemia and hypergammaglobulinemia, and serum IL-6 levels decreased to a normal range. This case may give suggestions about diagnosing and preventing the progression of complications from this disease entity.