Atsuhisa Shirakami

Bleeding tendency in chronic neutrophilic leukemia.

To define the clinical and pathologic features and natural history of chronic neutrophilic leukemia (CNL), as defined by the World Health Organization (WHO), Elliott critically reviewed the literature and identified a total of 34 patients meeting strictly defined WHO criteria for CNL [1]. Of the 34 patients, 9 died of intracranial hemorrhage and 3 demonstrated easy bruising. Elliot indicated that a disproportionate number of reports of intracranial hemorrhage must be considered in the context of an association with chemotherapy-induced thrombocytopenia during treatment of progressive disease. Furthermore, he described that excess hemorrhagic events were not a significant finding in chronic stable-phase disease in the absence of chemotherapy-induced thrombocytopenia. Here, we describe platelet dysfunction in a patient with CNL complicated by bleeding tendency. At the time this patient showed bleeding symptoms, she had not received chemotherapy and her platelet count was normal. On 20 August 2003, an 83-year-old Japanese woman was referred to our department for examination of bleeding tendency. She had a 3-year history of recurrent purpura and occasional nasal bleeding. Neither the patient nor any members of her family had a history of bleeding tendencies. On physical examination, purpura was detected on the face, back and extremities. A CT scan of the abdomen demonstrated splenomegaly. Peripheral blood showed: hemoglobin, 9.7 g/dl; platelets, 284 9 10/l; leukocytes, 29.0 9 10/l with 0.2% myelocytes, 0.6% metamyelocytes, 2.0% stabs, 90.8% segments, 1.0% eosinophils, 2.2% basophils, 1.2% monocytes and 2.0% lymphocytes. Neutrophil alkaline phosphatase (NAP) score was 352 (normal, 190–370). The serum concentration of granulocyte colonystimulating factor (G-CSF) was under 10.0 pg/ml. Immunoelectrophoresis did not show any M protein in serum or urine. The bone marrow was grossly hypercellular with marked myeloid hyperplasia and 1.0% blasts. There were no dysplastic features, minimal fibrosis, normal megakaryocytes and erythropoiesis. Chromosomal analysis demonstrated a normal karyotype. Reverse transcriptasepolymerase chain reaction (RT-PCR) studies failed to demonstrate the presence of BCR-ABL fusion. The patient was diagnosed as having CNL. Routine hemostatic tests demonstrated: bleeding time, more than 8 min (normal, 1–5 min); prothrombin time, 14.9 s (normal, 10.0–13.5 s); activated partial thromboplastin time, 39.8 s (normal, 25.0–40.0 s); plasma fibrinogen level, 295 mg/dl; plasma FDP concentration, 4.1 lg/ml (normal, below 10 lg/ml). Factor VIII activity was 180% (normal, 62–145%), von Willebrand factor antigen was 136% (normal, 50–150%), and ristocetin cofactor activity was 133% (normal, 50–150%). Activities of factor XIII and a2-plasmin inhibitor were 76% (normal, over 70%) and 86% (normal, 85–118%), respectively. Platelet aggregation induced by ADP, collagen, epinephrine or ristocetin was decreased when compared to that in the control. In contrast, arachidonic acid induced platelet aggregation was normal (Fig. 1). Similar patterns of abnormal platelet aggregation were repeatedly demonstrated on three different occasions. Flow cytometric analyses of her platelets for CD41 and CD42b expression showed normal patterns. These findings suggested that this patient had storage pool disease. In this disease, platelet aggregation induced by ADP, collagen, or epinephrine is impaired, but that induced by arachidonic T. Shigekiyo (&) J. Miyagi M. Chohraku K. Kawauchi E. Sekimoto A. Shirakami H. Shibata Department of Internal Medicine, Tokushima Prefectural Central Hospital, 1-10-3 Kuramoto-cho, Tokushima 770-0042, Japan e-mail: shigekiyo@tph.gr.jp

Pulmonary-Renal Syndrome with Negative ANCAs and Anti-GBM Antibody

We report the case of a 76-year-old woman who was referred to our hospital for a gradually worsening cough and renal dysfunction. Although pneumonia was initially suspected, imaging findings of the lungs revealed diffuse alveolar hemorrhage at a later date. Renal failure developed and hemodiafiltration was performed on the 9th day. Rapidly progressive glomerulonephritis with crescent formation was diagnosed by renal biopsy. This case presentation has important clinical implications because uncategorizable pulmonary-renal syndrome (PRS) without the presence of ANCAs and anti-GBM antibody is extremely rare and has high rates of morbidity and mortality. No treatment has been established.

A case of false hypoglycemia by SMBG due to improper storage of glucometer test strips

Many types of glucometer test strips deteriorate in the presence of humidity. Storing test strips outside their container or removing them from their individual wrappers could worsen their measurement accuracy. While the measurement accuracy can gradually deteriorate under such conditions, some patients are unaware of this aspect of test strip care and handling. Although such a deterioration in glucometer accuracy is often seen in clinical practice, there are few reports that warn about this issue. This is the first case report of pseudohypoglycemia caused by the inappropriate storage of test strips, which resulted in inadequate use of medications and deterioration of glycemic control. In clinical practice, patients sometimes handle glucometers in unexpected ways. This can arise due to inadequate instruction. Patients should be advised to read the manual associated with the device carefully and to store the test strips in their original container, closing the cap tightly, and to take each test strip out of its individual wrapper just before it is used. Careful patient instruction is needed to ensure safe and stable diabetic control.

Type 2B-like acquired von Willebrand syndrome

More than 300 cases of acquired von Willebrand syndrome (AVWS) have been reported, but it is thought that this number reflects only the tip of the iceberg [1]. Data from an international registry has shown that AVWS may be associated with lymphoproliferative (48%) or myeloproliferative (15%) disorders, neoplasia (5%), immunological (2%), cardiovascular (21%) and miscellaneous conditions (9%) [2]. AVWS usually mimics von Willebrand disease (VWD) type 1 or 2A [3, 4]. To our knowledge, only two cases of type 2B-like AVWS have been reported previously [4, 5]. They were both associated with plasma cell dyscrasia. Here we show a new case of type 2B-like AVWS. On 2 November 2000, a 74-year-old man was referred to our hospital for the follow-up of monoclonal gammopathy of undetermined significance (MGUS). Serum immunoelectrophoresis showed two kinds of M protein, IgG (j) and IgG (k). The serum immunoglobulin levels were IgG 2289 mg/dl, IgA 175 mg/dl, and IgM 63 mg/dl. He remained relatively well until 24 July 2008, when he developed a high fever. A diagnosis of hydronephrosis and urinary tract infection due to prostatic hypertrophy was made and after transurethral resection of the prostate, which was performed on 22 August 2008, macrohematuria persisted for 4 weeks despite administration of tranexamic acid. There was no other mucocutaneous bleeding. His serum IgG level had hardly changed up to that point. Routine coagulation tests demonstrated: prothrombin time, 11.4 s (normal 10.0–13.5 s); activated partial thromboplastin time, 48.5 s (normal 25.0–40.0 s); plasma fibrinogen level, 298 mg/dl. Factor VIII activity (FVIII:C) was 17% (normal 50–150%), von Willebrand factor antigen (VWF:Ag) was 11% (normal 50–150%) and von Willebrand factor ristocetin cofactor activity (VWF:RCo) was below 10% (normal 50–150%). Activities of factor IX, factor XI and factor XII were all normal. Bleeding time was 2.0 min (normal 1.0–5.0 min). The platelet count was consistently normal. Platelet aggregation induced by ADP, collagen or epinephrine was increased when compared to that in the control. Ristocetin-induced platelet aggregation (RIPA) was also enhanced, showing 70% aggregation with 0.3 mg/ml ristocetin compared with absent aggregation in a normal control (Fig. 1). His platelet-rich plasma (PRP) aggregated spontaneously without the addition of any agonists. All aggregation studies were performed with an aggregometer (MC Medical, Tokyo, Japan) in siliconized glass cuvettes at 37.0 ± 0.5 C with constant stirring at 1000 ± 100 rpm. Plasma VWF multimeric analysis showed that large multimers were absent and medium multimers were markedly decreased. Since these results T. Shigekiyo (&) E. Sekimoto A. Shirakami H. Yamaguchi H. Shibata S. Ozaki Department of Internal Medicine, Tokushima Prefectural Central Hospital, 1-10-3 Kuramoto-cho, Tokushima 770-0042, Japan e-mail: shigekiyo@tph.gr.jp

Reactive Hypoglycemia Associated with Mild Adrenal Dysfunction, So-called Adrenal Fatigue

We here described a case of a 38-year-old woman who was referred to our hospital for general malaise, slight fever, and palpitations after a meal for the past several years. She became hungry at approximately 3:00 or 4:00 p.m. every day, and simultaneously felt the urge to eat something sweet. During a five-hour 75g OGTT test, her blood glucose level dropped sharply twice (79 mg/dL at 60 min and 76 mg/dL at 300 min) due to the excessive secretion of insulin (29.9 µU/mL at 30 min and 43.1 µU/mL at 120 min). She was diagnosed with a mild adrenal insufficiency due to a decrease in her serum cortisol value in the early morning and an insufficient response to the rapid ACTH stress test. We speculated that the reactive hypoglycemic symptoms observed in this patient may have developed due to the inadequate secretion of serum cortisol as a counterregulation against insulin, which resulted in a relative excess of serum insulin after a meal. Her clinical manifestations and laboratory data were similar to a state called adrenal fatigue. Since the presentation of mild adrenal insufficiency is often insidious and difficult to recognize, careful

Fibrinogen Tokushima II: a new case of congenital dysfibrinogenemia with a γ methionine-310 to threonine substitution

The first case of congenital dysfibrinogenemia with a c methionine (Met)-310 to threonine (Thr) substitution and consequent N-glycosylation at c asparagine (Asn)-308, fibrinogen Asahi, was reported by Yamazumi et al. [1] in 1989. To our knowledge, only two cases of congenital dysfibrinogenemia with this mutation have subsequently been reported [2, 3]. Here, we report a new case of congenital dysfibrinogenemia with this mutation. This case is characteristic in two points. The first is that the proband received fibrinogen replacement therapy. The second is that her affected son showed no bleeding tendency. A 86-year-old woman (Fig. 1a; II-2) was referred to us in late May 2011, as her plasma fibrinogen level was very low on a preoperative examination. She had a past history of persistent bleeding after tooth extraction, but had shown neither hypermenorrhea nor excessive bleeding post-partum. She also had suffered no miscarriages. Her family history was negative for bleeding or thrombotic tendencies. There was no consanguinity. Routine hemostatic tests revealed a platelet count of 180 9 10/ll, bleeding time 1.5 min (reference range 1–5 min), prothrombin time 19.5 s (reference range 10.0–13.5 s), activated partial thromboplastin time 31.7 s (reference range 25.0–40.0 s), functional fibrinogen concentration below 50 mg/dl (reference range 160–360 mg/dl), and plasma FDP concentration 1.6 lg/ml (reference range below 10 lg/ml). Her thrombin time and reptilase time were over 600.0 s (reference range 12.0–14.6 s) and over 600.0 s (reference range 22.9–33.9 s), respectively. Her immunological fibrinogen concentration was 422 mg/dl (reference range 228–388 mg/dl). Functional and immunological fibrinogen concentrations were determined by the thrombin time method and single radial immunodiffusion, respectively. Reptilase time was measured using Pefakit Reptilase Time (Pentapharm, Basel, Switzerland). Her 66-year-old son (Fig. 1a; III-1) had a functional fibrinogen concentration of below 50 mg/dl and immunological fibrinogen concentration of 434 mg/dl. Her 58-year-old daughter (Fig. 1a; III-2) had a functional fibrinogen concentration of 293 mg/dl and immunological fibrinogen concentration of 315 mg/dl. These results suggested that congenital dysfibrinogenemia had been transmitted in this family. To elucidate the genetic basis of congenital dysfibrinogenemia in this family, we first examined the proband’s fibrinogen gene. This study was approved by the ethics committee of Tokushima Prefectural Central Hospital. Informed consent was provided according to the Declaration of Helsinki. Genomic DNA was isolated from whole blood, and 23 exons were amplified under standard PCR conditions. The primer sequences used for PCR were the same as those used by Terasawa et al. [4]. The PCR products were directly sequenced on an ABI 3730 9 1 DNA Analyzer. The sequence determined for exon 8 of the c-chain gene is shown in Fig. 1b. The nucleotide at position 7581, numbered according to the GenBank database, of the c-chain gene was heterozygous for T and C. A single T to C substitution results in replacing wild-type Met at residue 310 by Thr. No other mutation was found in either T. Shigekiyo (&) E. Sekimoto A. Shirakami H. Yamaguchi H. Shibata S. Ozaki Department of Internal Medicine, Tokushima Prefectural Central Hospital, 1-10-3 Kuramoto-cho, Tokushima 770-0042, Japan e-mail: shigekiyo@tph.gr.jp