Maiko Kato

Autoimmune hemolytic anemia and autoimmune neutropenia in a child with erythroblastopenia of childhood (TEC) caused by human herpesvirus-6 (HHV-6).

Dear Editor, Transient erythroblastopenia of childhood (TEC) is a selflimiting disorder of young children that is characterized by moderate to severe anemia with reticulocytopenia and decreased numbers of erythroid precursors in the bone marrow. TEC was often complicated with neutropenia and thrombocytopenia [1–3]. Here, we document a unique clinical course in a child with TEC. A 1-year-old girl with anemia was admitted to our hospital. She had no recent episodes of viral infection such as fever and skin eruption. The values for hemoglobin (Hb) and reticulocytes were 57 g/L and 2.0% (Table 1). Although the direct Coombs test was highly positive, the haptoglobin level remained normal. In addition, the leukocyte fraction indicated agranulocytosis. Bone marrow findings were as follows: cellularity was normocellular, the erythroid series were reduced (M/E ratio, 4.2), and the myeloid series differentiated to a band form but not segmental neutrophils. Speculating that viral infection was involved in this bicytopenia, we performed multiplex PCR analyses for the following viruses: herpes simplex virus type 1, type 2, human herpesvirus type 6 (HHV-6), type 7, type 8, varicella-zoster virus, Epstein-Barr virus (EBV), cytomegalovirus, parvovirus B19, polyomavirus JC, and polyomavirus BK, as described previously [4]. As a result, HHV-6 DNA (10×10 copies/μg DNA) was detected in the peripheral whole blood. Because we assumed that HHV-6 infection suppressed erythropoiesis, we started ganciclovir (GCV) from day 15. The reticulocyte count responded rapidly to GCV and increased to 10.8% on day 22 (Table 1). The HHV-6 DNA level also decreased significantly (0.84 × 10 copies/μg DNA); however, the Hb level decreased to 40 g/L on day 25. As the haptoglobin level decreased, a diagnosis of hemolytic crisis was made. High-dose globulin (total dose, 1.5 g/kg) was given on days 25 to 27 with subsequent standard steroid therapy on days 37 to 74. The hemolysis resolved rapidly, and the Hb level increased up to 89 g/L on day 33. Coombs test became negative by day 67, and the patient was discharged on day 74. The level of HHV-6 antibody increased during this episode, which indicated a primary infection of HHV-6 (Table 1). At present (day 273), the patient has no relapse of anemia. In contrast, the neutrophil count did not change. Anti-neutrophil antibodies were identified by flow cytometric analysis, which was consistent with autoimmune neutropenia. The association between TEC and viral infection such as parvovirus B19, EBV, cytomegalovirus, and HHV-6 has been raised in few patients [5–7]. In our patient, HHV-6 infection was proven by a molecular technique and successfully treated using GCV. Another notable feature is that this patient presented with autoimmune hemolytic anemia and neutropenia, concurrently. We speculated that the immune response against HHV-6 has stimulated the production of multiple autoantibodies against red cells and H. Yagasaki (*) :M. Kato :H. Shichino :M. Chin : H. Mugishima Department of Pediatrics, Nihon University, Ohtaniguchi 30-1, Itabashi-ku, Tokyo, Japan 173-8610 e-mail: yagasaki@med.nihon-u.ac.jp

Successful treatment of disseminated intravascular coagulation in a child with acute myelogenous leukaemia using recombinant thrombomodulin.

Disseminated intravascular coagulation (DIC) is a serious complication that can occur during treatment of haematological malignancies, such as acute leukaemia. Conventional treatment of DIC consists of the administration of heparins as well as platelet transfusion or fresh frozen plasma (FFP) supplementation (Levi et al, 2009). Recombinant thrombomodulin (rTM, Recomodulin ; Asahi Kasei Pharma, Tokyo, Japan) has been developed as a novel treatment that inhibits activated Factors V and VIII (FVa and FVIIIa respectively) by activating protein C (Maruyama, 1999; Moll et al, 2004). This report presents a case study of a child with acute myeloid leukaemia (AML) in whom associated DIC was improved dramatically by administration of rTM. A 9-year-old girl, diagnosed with osteosarcoma at age 5 years and treated with multi-agent chemotherapy and surgery 3 years previously, presented to us for a regular follow up. She had purpura on her extremities and complained of gingival bleeding. A bone marrow finding showed acute myelomonocytic leukaemia (French-American-British classification M4) with a MLL-MLLT3 fusion transcript. The clinical course is shown in Fig 1. Induction therapy with fludarabine, high-dose cytarabine, idarubicin and granulocytecolony stimulating factor was started. However, on the second day of treatment, her general condition deteriorated and a coagulation test showed the following abnormalities: platelet count, 30 · 10/l; prothrombin time (PT) ratio, 2Æ0 (normal: 0Æ9–1Æ1); fibrin degradation products (FDP), 390 mg/l (normal: <4Æ0 mg/l); d-dimer, 170Æ1 mg/l FEU (normal: <0Æ5 mg/l FEU) and thrombin-antithrombin complex (TAT) level of 23Æ2 lg/l (normal: <3Æ0 lg/l) (Table I). A diagnosis of DIC was subsequently made according to the diagnostic criteria of the International Society of Thrombosis and Hemostasis (Taylor et al, 2001). Intravenous administration of rTM (380 U/kg/d) was started on the same day. The high-grade fever resolved and her general condition had improved very rapidly by the next morning. After 2 d of administration, the PT ratio, FDP, d-dimer and TAT levels were 1Æ16, 10Æ6 mg/l, 4Æ9 mg/l FEU and 2Æ7 lg/l respectively, indicating a significant improvement (Table I). We subsequently determined that the patient had recovered from the DIC state and discontinued the administration of rTM. No adverse events, such as bleeding, were observed and there was no recurrence of coagulation abnormalities after completing the administration of rTM. Consequently, we were able to carry out the induction therapy as originally scheduled. Following therapy, she received cord blood transplantation and is currently alive and well. Heparin has been shown to improve laboratory abnormalities associated with DIC, while recent reports have shown that antithrombin concentrate and human-activated protein C possess survival benefits for patients with DIC (Dhainaut et al, 2004; Kienast et al, 2006). However, serious bleeding is a concern in patients who are administered these drugs. Thrombomodulin (TM) is an endothelial cell surface glyco-

Treatment responses for disseminated intravascular coagulation in 25 children treated with recombinant thrombomodulin: A single institution experience

INTRODUCTION Recombinant thrombomodulin (rTM), which degrades factors Va and VIIIa by activating protein C, has been developed as a new drug for treating disseminated intravascular coagulation (DIC). MATERIALS AND METHODS Since July 2009, we have treated 25 children with DIC using rTM (380 U/kg/day, or 130 U/kg/day for newborns) as a first-line therapy. Median duration of rTM administration was 5 consecutive days (range, 2-13 days). We employed DIC criteria of the Japan Welfare and Health Ministry. The first day on which rTM treatment was given was defined as day 1. RESULTS Median patients age was 3 years. Underlying diseases were hematological disorders (n=13) and severe infection (n=12). Overall, 20 of the 25 patients had recovered from DIC by day 7 and 22 of the 25 patients remained alive at day 28. Median Pediatric Logistic Organ Dysfunction score improved from 11 on day 1 to 2 on day 7 (p=0.009). Laboratory data (median) on day 7 (prothrombin time (PT) ratio, 1.15; fibrin and fibrinogen degradation products (FDP), 9.6 mg/l; D-dimer, 1.6 mg/l FEU; antithrombin, 112%; protein C, 105%) were significantly improved compared to results on day 1 (PT ratio, 1.39; FDP, 21.6 mg/l; D-dimer, 6.4 mg/l FEU; antithrombin, 86%; protein C, 54%). Whereas, 5 patients failed to respond and serious bleeding events were observed in 2 newborns. CONCLUSION The efficacy of rTM cannot be assessed from the present dataset, due to several limitations such as the small heterogenous patient cohort, and the lack of age- and disease-matched controls. Nevertheless, this case-series remains important in terms of enabling further prospective control studies to evaluate the efficacy of rTM in children.

A novel mechanism of transplacental cancer transmission: natural killer/T-cell lymphoma in the paratesticular region is of maternal origin

To the editor: The placental syncytiotrophoblast layer is a barrier that protects the fetus from infection and cancer metastasis. Even if mother-derived cells enter the fetus, they are usually rejected and cannot be engrafted. Materno-fetal transmission of leukemia/lymphoma is therefore extremely

Quantification of progenitors capable of generating T cells in human cord blood

Objective:  For transplantation of cord blood (CB) cells, it is important to select a CB sample that can reconstitute not only myelo‐erythropoiesis but also lymphopoiesis in recipients. However, until now the reconstitution ability of CB samples has been assessed by colony forming unit‐culture (CFU‐C) assay or by simply counting CD34+ cells. The present study aims at establishing a method capable of assessing the potential of T lymphopoieses of CB samples.

Acute lymphoblastic leukemia in a patient with Prader-Willi syndrome under growth hormone therapy.

Prader–Willi syndrome (PWS) was first described in 1956 by Prader, Labhart, and Willi. 1 It has an incidence of 1 in every 10 000–12 000 births and is characterized by infantile hypotonia, hyperphagia, obesity, mild to moderate mental retardation, hypogonadism and short stature, involving deletion of paternal alleles at chromosome 15q11–13. 2 Growth failure is a common feature in this disorder, and this has recently been treated with growth hormone (GH). 3 Recently, it was reported that there appeared to be an increased risk of leukemia among patients with PWS. 4 In the present report we describe a patient with PWS who developed acute lymphoblastic leukemia (ALL) expressing myeloid antigens while receiving GH therapy.