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Background Anti‐M is frequently observed as a naturally occurring antibody of little clinical significance. Naturally occurring anti‐M is often found in children although the specific triggers of production, persistence, and evanescence of anti‐M have yet to be elucidated. Methods In a retrospective, multicenter, nationwide cohort survey conducted from 2001 to 2015, alloantibody screening was performed before and after transfusion in 18,944 recipients younger than 20 years. Recipients were categorized into six cohorts based on their age at transfusion; within and among these cohorts, allo‐anti‐M was analyzed in regard to its production, persistence, and evanescence. Results In 44 patients, anti‐M detected before and/or after transfusion was an age‐related phenomenon, with a median age of 2 years and an interquartile range of 1–3 years; anti‐M was most frequently detected in a cohort of children 1 to

Red blood cell (RBC) transfusion to neonates is thought to rarely provoke an immune response. Neonatal testing guidelines suggest that antibody screening is not necessary when the mother has no antibodies. Alternatively, maternal blood samples can be used for antibody screening and cross-matching. However, the guidelines are based on small-scale studies of white-dominant populations. Furthermore, transfusion-related alloimmunization is less well established among children and adolescents as a whole among Japanese and East Asians. To elucidate the incidence of transfusion-related alloimmunization among neonates, children, and adolescents, and whether current guidelines are applicable to Japanese populations, a nationwide retrospective multicenter cohort survey was conducted in 50 tertiary-care hospitals in Japan. Between 2001 and 2015 inclusive, recipients of at least 1 allogeneic RBC transfusion were categorized into groups A-F according to their age at the time of transfusion: (A) neonates1 month; (B) infants 1 to12 months; (C) children 1 to5 years; (D) prepubescents 5 to10 years; (E) young pubescents 10 to15 years; and (F) adolescents/young adults 15 to20 years. Excluding maternally derived antibodies and naturally occurring, cold-reactive, and/or nonspecific antibodies, 69 (0.61%) of 11350 RBC recipients20 years old formed at least 1 clinically significant alloantibody. The alloimmunization rate differed significantly (P .0001) by age: none (0%) of 3407 in group A; 11 (0.46%) of 2410 in group B; 18 (0.76%) of 2361 in group C; 9 (0.80%) of 1119 in group D; 12 (1.15%) of 1043 in group E; and 19 (1.88%) of 1010 in group F. Clearly different incidences of alloimmunization emerged in group A compared to B, C, D, E, or F, as confirmed by logistic regression analysis adjusted by numbers of donor exposure. Alloimmunization did not occur from RBC transfusions within the first month of life and rarely occurred (0.46%-0.80%) after transfusion within the first decade of life. Alloimmunization occurred in 1.15%-1.88% of young pubescents and adolescents/young adults. These findings support the use of guidelines developed in Europe and the United States for East Asian pediatric recipients.

Purpose This study was conducted to time-course changes of clotting function of withdrawing blood for acute normovolemic hemodilution (ANH). Methods Twelve enrolled patients who underwent ANH from August, 2018 to January, 2019. Blood was withdrawn into blood collection pack and shaken at 60–80 rpm for 24 h in room temperature. Clot formation was evaluated using rotational thromboelastometry (ROTEM™) just after blood withdrawal (control) and 4, 8, 12 and 24 h after blood withdrawal. We compared with the control value and each value of extrinsically-activated test with tissue factor (EXTEM), intrinsically-activated test using ellagic acid (INTEM) and fibrin-based extrinsically activated test with tissue factor (FIBTEM). Results Maximum clot firmness (MCF) of FIBTEM did not change significantly. MCF of EXTEM was significantly decreased time-dependent manner but all MCF of EXTEM were within a normal range. Maximum percent change in MCF of EXTEM was 12.4% [95% confidence interval (CI): 9.0–15.8%]. The difference in the maximum clot elasticity (MCE) between EXTEM and FIBTEM (MCEEXTEM−MCEFIBTEM) was significantly decrease from 8 h after blood withdrawal. Maximum percent change in MCEEXTEM−MCEFIBTEM was 30.2% (95% CI:17.6–42.9%) at 24 h after blood withdrawal. Conclusion Even though the MCE significantly decreased in a time-dependent manner, MCF of FIBTEM and EXTEM was normal up to 24 h storage. The blood of ANH can use for the purpose of hemostasis at least 8 h stored at room temperature after blood withdrawal. Future studies are needed to elucidate the clinical impact on the patient after delayed transfusion of ANH blood with regard to patient’s hemostasis.

Aims: Alloimmune response to red cell transfusion has not been widely investigated in pediatric patients. We retrospectively compared the frequency and specificity of red cell antibody formation among pediatric recipients grouped by age, versus an adult control cohort. Methods: A total of 331 pediatric red cell transfusion recipients were studied in four age groups: 0 to 4.9 months (Group A), 5.0 to 11.9 months (Group B), 1.0 to 5.9 years (Group C), and 6.0 to 14.9 years (Group D). Similarly transfused adult males, 20.0 to 59.9 years old, as a control cohort group. Alloimmunization was defined as post-transfusion detection of red cell alloantibodies not detected prior to transfusion. Results: After red cell transfusion, no one in Group A (0 of 106) developed alloantibodies, whereas 8.0% (2 of 25) in Group B, 1.1% (1 of 95) in Group C, and 2.9% (3 of 105) in Group D, versus 2.1% (8 of 380) of adult male controls who developed alloantibodies. However, these differences did not achieve statistical significance. Conclusion: This investigation of alloimmunization in pediatric recipients found no cases in patients younger than five months old, however, the incidence rates of older age groups were statistically indistinguishable from a control cohort of male adults. Until larger studies suggest otherwise, current antibody screening and cross-matching policies should be continued.

There have been no studies on the distribution of causes of macrocytic anemia with respect to mean corpuscular volume (MCV) cutoff values. We retrospectively investigated the causes of macrocytic anemia (MCV ≥100 fL) among 628 patients who visited the outpatient hematology clinic in Tohoku University Hospital. To ensure data validity, we also analyzed data from 307 patients in eight other hospitals in the Tohoku district. The leading causes of macrocytic anemia (number of patients, %) were myelodysplastic syndromes (121, 19.3 %), suspected bone marrow failure syndromes (BMF; 74, 11.8 %), aplastic anemia (51, 8.1 %), plasma cell dyscrasia (45, 7.2 %), and vitamin B12 deficiency (40, 6.4 %) in Tohoku University Hospital. We made three primary findings as follows. First, the most common cause of macrocytic anemia is BMF. Second, lymphoid and solid malignancies are also common causes of macrocytosis. Third, macrocytic anemia may be classified into three groups: Group 1 (megaloblastic anemia and medications), which can exceed MCV 130 fL; Group 2 (alcoholism/liver disease, BMF, myeloid malignancy, and hemolytic anemia), which can exceed MCV 114 fL; and Group 3 (lymphoid malignancy, chronic renal failure, hypothyroidism, and solid tumors), which does not exceed MCV 114 fL. These conclusions were supported by the results from eight other hospitals.

We experienced an unexpected thrombocytopenia detected only in vitro during radical prostatectomy for a 66-year-old patient. Thrombocytopenia with platelet aggregation was observed in a blood sample obtained using a heparinized syringe (not by ethylene diamine tetra-acetic acid tube). Although we could not exclude platelet agglutination in vivo, no thrombosis or coagulation disorder was observed. We changed the anti-coagulant in the arterial catheter carrier fluid (saline) from heparin to argatroban, and continued with the operation. No embolic complications were observed during the perioperative period. Although pseudothrombocytopenia or heparin-induced thrombocytopenia was highly suspected in the present case, we were not able to confirm which of the two developed. Multi-directional attention and care may be required for perioperative unexpected thrombocytopenia.

Background Only a few cases of infantile anti-red blood cell alloantibody production have been reported. Methods A 7-month-old girl with acute lymphoid leukemia developed anti-E alloantibody 13 days after transfusion of E-positive red blood cells. Antibody screening was performed before and at 2, 6, 13, 18, 27, 34, and 49 days after red blood cell transfusion. Identification test, direct immunoglobulin test, acid elution, and dithiothreitol test were also performed. Results Anti-E alloantibody was detected in the blood 13 days after the first transfusion. The detected antibody was IgM and it decreased below detectable levels within 49 days after the first transfusion. Conclusions Follow-up testing for the presence of post-transfusion alloantibody at appropriate times is important, even in infants.

Patients with intracerebral hemorrhage during rivaroxaban treatment have small hematoma and favorable outcomes compared with those with warfarin. We investigated its possible mechanism, focusing on prothrombin fragment 1+2 (F1+2), a marker of thrombin generation.In 65 patients with acute cardioembolic stroke (median 77years), rivaroxaban was initiated at 5days after the onset. Plasma F1+2 level (normal range, 69-229pmol/L), prothrombin time (PT), and rivaroxaban concentration evaluated by anti-Xa activity were serially measured.Median plasma F1+2 was 276 (IQR, 195-454) pmol/L before starting rivaroxaban, and significantly decreased to 196 (141-267) and 192 (151-248) on 7 and 28days after rivaroxaban, respectively (both p0.05). Serial measurements of PT and rivaroxaban concentration at trough, 2, 4, and 6h after taking rivaroxaban showed a positive correlation (RRivaroxaban retains a normal thrombin generation even at its peak level with prolonged PT, whereas warfarin at therapeutic levels inhibits thrombin generation. This may partly explain different outcomes in patients complicated with bleeding events.

【背景】医療関係者は，輸血医療・業務に習熟している必要があるが，看護師の輸血業務に関しては論議されることが少なかった．安全な輸血医療提供のために，看護師責務は重大である． 【目的】看護師の輸血医療への関与の現状把握のため，輸血業務に対する意識・知識，疑問・要望を調査した． 【対象・方法】青森県地区拠点7病院のうちI&A認証施設の青森県立中央病院，黒石市国民健康保険黒石病院と，弘前大学医学部附属病院の看護師182名を対象に文書によるアンケート調査を施行した． 【結果・考察】輸血開始推奨速度（1ml/分）の正答率は61％であった．異型不適合輸血に関しては，16％の看護師がRh（-）患者にRh（+）赤血球を輸血しても良いと回答した．また，Major mismatchのABO不適合赤血球輸血の正答率は31％であった． 今回の調査で，輸血業務に習熟していると予想された3施設の看護師でも，輸血に関する理解度は満足いくものでなく，看護師は疑問がありながらも日常輸血業務を行っていた．より安全な輸血医療提供には，看護師の輸血に関する知識の啓発・意識の改革も重要であると思われた．

平成16，17年に輸血実績のあった青森県内186医療機関に対し，輸血前血清保管（検体保管），輸血前·後肝炎関連検査（輸血前·後検査）の実態をアンケート調査し，154施設より回答を得た（回答率82.8%）．検体保管実施施設は55.2%，保管専用冷凍庫使用施設は18.8%．輸血前·後検査実施施設はそれぞれ76.6%，21.4%で，そのうち厚生労働省ガイドラインに準拠した検査項目実施施設は，それぞれ14.4%，54.5%であった．青森県輸血療法委員会合同会議の参加施設で，検体保管実施，保管専用冷凍庫使用，輸血後検査実施，ガイドラインに準拠した検査項目実施が高い傾向にあった．その中でも，輸血療法委員会が設置されていた施設では，検体保管実施，保管専用冷凍庫使用，輸血後検査実施が高い傾向にあった．本解析の結果，合同会議へ参加していない施設や輸血療法委員会が設置されていない施設への情報伝達が重要と考えられた．

Although antiplatelet agents are widely used for the treatment and prevention of thrombotic diseases, only a few studies have reported the validity of the cessation period prior to endoscopic procedures. In 2002, the American Society for Gastrointestinal Endoscopy (ASGE) published a reference on the management of anticoagulation and antiplatelet therapy for endoscopic procedures, but it should be confirmed as appropriate for use in Asian patients. To evaluate the optimal cessation period of antiplatelet agents prior to endoscopic procedures for Japanese, we have studied: (i) the current clinically adopted cessation period of antiplatelet agents prior to invasive endoscopic procedures in Japan; (ii) the relationship between the cessation period of antiplatelet agents and complications around the invasive endoscopic procedures; (iii) colonic mucosal bleeding time after aspirin ingestion; and (iv) the time course of primary hemostasis after cessation of antiplatelet agents. We conclude that 3 days cessation period for aspirin, 5 days cessation for ticlopidine and 7 days cessation for aspirin + ticlopidine administration should be sufficient for Japanese.

Background We tested whether administration of FK633, a short-acting glycoprotein IIb/IIIa inhibitor, before median sternotomy and cardiopulmonary bypass was able to interrupt the platelet activation loop and thereby preserve platelet number and function. Methods This study investigated 16 pigs that underwent median sternotomy and 120 minutes of normothermic cardiopulmonary bypass (100 mL/kg) adding pericardial blood to the perfusate. FK633 was administered with heparin to one group (group F, n=8), whereas only heparin was administered to the control group (group C, n=8). Blood samples were obtained at several times, and complete blood count, platelet aggregation to adenosine diphosphate, thrombin-antithrombin complex, and bradykinin were evaluated. P-selectin expression and fibrinogen binding on platelet surfaces were measured by flow cytometry. Template bleeding times were measured before and after cardiopulmonary bypass. Chest tube drainage and hematocrit were determined at 2 and 6 hours after cardiopulmonary bypass. Results In group F, platelet counts were preserved from 90 minutes of cardiopulmonary bypass. Platelet aggregation was inhibited at the beginning of cardiopulmonary bypass and showed no change at wound closure, and bleeding times were shortened at 2 hours after cardiopulmonary bypass. There were significant reductions in hematocrit of drainage. Flow cytometry showed no changes in P-selectin expression and fibrinogen binding in group F, whereas P-selectin expression and fibrinogen binding were elevated in group C. Conclusions Platelet inhibition with FK633 before invasive surgical procedure preserved platelet counts during and after cardiopulmonary bypass, and produced normal or near-normal bleeding times in the immediate postoperative period.

For addressing, and eventually being able to predict and prevent, both disease-related complications and changes in social status in long-term acute leukemia survivors, the follow-up is the most important factor after treatment. To this end, we assessed the complications following the attainment of complete remission in adult acute leukemia patients and the changes in social status of patients surviving more than 5 years after disease onset. In our study population of 42 survivors, 24 (57.1%) suffered from various combinations of 18 types of identified complications including posttransfusion hepatitis, diabetes mellitus, and idiopathic osteonecrosis. Regarding fertility, 9 live births were recorded in this cohort, from 2 female patients and the partner of a male patient. Of these 42 long-term survivors, at the time of this report 48.5% were working full- or part-time, 9.0% were unemployed, 30.3% were homemakers, and 12.2% were retired.

72 congenital or acquired bleeding disorder patients who all showed prolonged BT (more than 15 minutes).

This study examined the impact of platelet transfusion (PLT) on the survival of intracerebral hemorrhage (ICH) patients who had been administered anti-platelet agents (APA). This retrospective cohort analysis investigated 432 patients (259 men, 60%) who were newly diagnosed with ICH between January 2006 and June 2011 at the tertiary emergency center of Kitasato University Hospital. Median age on arrival was 67.0 years (range, 40–95 years). ICH was subcortical in 72 patients (16.7%), supratentorial in 233 (53.9%), and infratentorial in 133 (30.8%). PLT was performed in 16 patients (3.7%). Within 90 days after admission to the center, 178 patients (41.2%) had died due to ICH. Before the onset of ICH, 66 patients had been prescribed APA because of atherosclerotic diseases. Multivariate regression analysis indicated APA administration was an independent risk factor for death within 7 days (odds ratio, 5.12; P = 0.006) and within 90 days (hazard ratio, 1.87; P = 0.006) after arrival. Regarding the effect of a PLT in ICH patients with APA, no patient with PLT died. PLT had a survival benefit on patients with ICH, according to our analysis. Further prospective analysis is necessary to confirm the effects of PLT on survival in ICH with APA.

BACKGROUND: Many patients who require endoscopic treatments such as biopsy and polypectomy are given antiplatelet agents reluctantly. We have studied the effects of aspirin on colonic mucosal hemostasis. METHODS AND PATIENTS: We developed a new endoscopic device to make a standard incision (7-mm length) on the colonic mucosa to study colon bleeding time. We measured the colon bleeding time of normal colonic mucosa in 47 cases. The colon bleeding time and skin bleeding time (Simplate method) were measured before and one hour after aspirin ingestion (990 mg) in ten healthy subjects. RESULTS: The bleeding time of normal colonic mucosa was 156±71 (mean±standard deviation) seconds. Significant prolongation was noted in both skin bleeding time (357±192vs.477±183 seconds;P

The diagnostic hallmark of the dystrophic forms of epidermolysis bullosa (DEB), a group of heritable blistering skin diseases, is abnormalities in the anchoring fibrils at the dermal-epidermal basement membrane zone. Since type VII collagen is the major, if not the exclusive, component of the anchoring fibrils, the corresponding gene (COL7A1) is the candidate gene in DEB. Recent cloning of the type VII collagen cDNA and elucidation of the exon-intron organization of the gene have provided the basis for us to develop a novel strategy for identification of sequence variants in COL7A1. Optimization of 72 balanced primer pairs corresponding to flanking intronic sequences allowed PCR amplification of all 118 exons directly from genomic DNA. The PCR products were examined by heteroduplex analysis followed by comparative nucleotide sequencing. More than 100 sequence variants have been identified thus far in COL7A1 using this method, some of which are single base pair polymorphisms and many of which are pathogenetic mutations contributing to the blistering phenotype in DEB. The comprehensive method described is useful for rapid, reliable, and sensitive detection of sequence variants in COL7A1. We demonstrate the utility of this novel strategy in mutation detection and prenatal exclusion of RDEB in a consanguineous family at risk for recurrence. Hum Mutat 10:408–414, 1997. © 1997 Wiley-Liss, Inc.

Congenital sideroblastic anemia (CSA) is an inherited microcytic anemia characterized by the presence of bone marrow ring sideroblasts, reflecting excess mitochondrial iron deposition. The most common form of CSA is X-linked sideroblastic anemia (XLSA), which is attributed to mutations in the X-linked gene erythroid-specific 5-aminolevulinate synthase (ALAS2). ALAS2 encodes the enzyme that catalyzes the first and rate-limiting steps in the heme biosynthesis pathway in erythroid cells. This pathway converts glycine and acetyl-coenzyme A to 5-aminolevulinic acid and also requires pyridoxal 5'-phosphate (PLP) as a cofactor. Although PLP has been used for treating XLSA, a marked proportion of patients with XLSA remain refractory to treatment (Ohba et al. Ann Hematol 2013). Therefore, to elucidate the details of the underlying molecular mechanisms that contribute to ringed sideroblast formation as well as to explore novel therapeutic strategies for XLSA, we generated induced pluripotent stem (iPS) cells from a patient with XLSA. Bone-marrow derived mesenchymal stem cells (BM-MSCs) were generated from a healthy volunteer and from the patient with XLSA, who harbored mutations in ALAS2 (c.T1737C, p.V562A). To establish iPS cells, episomal vectors encoding OCT3/4, SOX2, KLF4, L-MYC, LIN28, SHP53, and GLIS1 (gift from K. Okita, Kyoto University, Japan) were electroporated into BM-MSCs.The iPS cells were expanded in hESC medium containing DMEM/F-12 and 20% KSR (KnockoutTM Serum Replacement) (Life Technologies). We established one iPS clone from a healthy subject (NiPS) and two clones from the patient with XLSA (XiPS1 and XiPS2). G-band karyotype analysis demonstrated that all three clones had a normal karyotype. Immunocytochemical staining of the clones revealed the expression of transcription factors such as OCT3/4 and NANOG as well as surface markers such as SSEA-4 and TRA-1-60. Pluripotency of each clone was confirmed by the spontaneous differentiation of embryoid bodiesin vitro and teratoma formation in vivo. No clear characteristic differences were observed between XiPS and NiPS. Next, we evaluated the phenotype of iPS-derived erythroid precursors. The iPS cells were induced to undergo erythroid differentiation with Stemline II serum-free medium (Sigma). Both NiPS- and XiPS-derived erythroblasts were nucleated, and predominately expressed embryonic globin genes. Expression profiling of CD235a-positive erythroblasts from NiPS, XiPS1, and XiPS2, revealed 315 and 359 genes that were upregulated and downregulated (>1.5-fold), respectively, in XiPS relative to NiPS. The downregulated genes included globins (HBQ, HBG, HBE, HBD, and HBM) and genes involved in erythroid differentiation (GATA-1, ALAS2, KLF1, TAL1, and NFE2). Gene ontology analysis revealed significant (p < 0.01) enrichment of genes associated with erythroid differentiation, cellular iron homeostasis, and heme biosynthetic processes, implying that heme biosynthesis and erythroid differentiation are compromised in XiPS-derived erythroblasts. Finally, to examine whether XiPS-derived erythroblasts exhibited a phenotype reflective of defective ALAS2 enzymatic activity, we merged the microarray results with a previously reported microarray analysis in which ALAS2 was transiently knocked down using iPS-derived erythroid progenitor (HiDEP) cells (Fujiwara et al. BBRC 2014). The analysis revealed a relatively high degree of overlap regarding downregulated genes in XiPS relative to NiPS, demonstrating a >1.5-fold upregulation and downregulation of eight and 41 genes, respectively. Commonly downregulated genes included those encoding various globins (HBM, HBQ, HBE, HBG, and HBD) and ferritin (FTH1), GLRX5, ERAF, and ALAS2, which are involved in iron/heme metabolism in erythroid cells, suggesting that the phenotype of XiPS-derived erythroid cells resembles that of ALAS2-knockdown HiDEP cells. Interestingly, when the XiPS was induced to undergo erythroid differentiation by co-culture with OP9 stromal cells (ATCC), aberrant mitochondrial iron deposition was detected by prussian blue staining and electron microscope analysis. We are currently conducting biological analyses to characterize established ring sideroblasts. In summary, XiPS can be used as an important tool for clarifying the molecular etiology of XLSA and to explore novel therapeutic strategies. Disclosures Fujiwara: Chugai Pharmaceuticals. Co., Ltd.: Research Funding.

The 230-kD bullous pemphigoid antigen (BPAG1), a hemidesmosomal protein, is encoded by a gene at the human chromosomal locus 6p11-12. We have elucidated the exon-intron organization of the entire human BPAG1 gene, including approximately 2.6 kb of 5'-flanking DNA. Seven overlapping genomic clones, spanning approximately 20 kb, contained the entire approximately 9 kb coding sequence of BPAG1 and consisted of 22 separate exons, which varied from 78 to 2,810 bp in size. The 5' flanking region of DNA, upstream from the ATG initiation codon for translation, was found to contain several putative transcriptional response elements. Most interestingly, two motifs potentially conferring keratinocyte specific expression to the gene were detected. The presence of such elements was suggested by approximately 20-fold higher expression of a promoter/chloramphenicol acetyl transferase (CAT) construct in normal human epidermal keratinocytes that express the endogenous gene, as compared to several non-expressing cell types. Transient transfections with 5'-deletion clones of the promoter/reporter gene (CAT) constructs identified a region containing a putative tissue specific element, KRE2, which also conferred tissue specificity to the expression of the truncated promoter downstream from this element, however, a mutated derivative of KRE2 was not functional. Detailed knowledge of the structure and regulation of the BPAG1 gene will aid in further elucidation of diseases affecting the cutaneous basement membrane zone.

Erythroid-specific 5-aminolevulinate synthase (ALAS2) is essential for hemoglobin production, and a loss-of-function mutation of ALAS2 gene causes X-linked sideroblastic anemia. Human ALAS2 protein consists of 587 amino acids and its carboxyl(C)-terminal region of 33 amino acids is conserved in higher eukaryotes, but is not present in prokaryotic ALAS. We explored the role of this C-terminal region in the pathogenesis of X-linked sideroblastic anemia. In vitro enzymatic activity was measured using bacterially expressed recombinant proteins. In vivo catalytic activity was evaluated by comparing the accumulation of porphyrins in eukaryotic cells stably expressing each mutant ALAS2 tagged with FLAG, and the half-life of each FLAG-tagged ALAS2 protein was determined by Western blot analysis. Two novel mutations (Val562Ala and Met567Ile) were identified in patients with X-linked sideroblastic anemia. Val562Ala showed the higher catalytic activity in vitro, but a shorter half-life in vivo compared to those of wild-type ALAS2 (WT). In contrast, the in vitro activity of Met567Ile mutant was about 25% of WT, while its half-life was longer than that of WT. However, in vivo catalytic activity of each mutant was lower than that of WT. In addition, the deletion of 33 amino acids at C-terminal end resulted in higher catalytic activity both in vitro and in vivo with the longer half-life compared to WT. In conclusion, the C-terminal region of ALAS2 protein may function as an intrinsic modifier that suppresses catalytic activity and increases the degradation of its protein, each function of which is enhanced by the Met567Ile mutation and the Val562Ala mutation, respectively.

To clarify whether measurement of serum haptoglobin (Hp) has impact on understanding pathophysiology in bone marrow failure (BMF) syndromes, we investigated concentrations of serum Hp by nephelometric procedure in 156 Japanese patients with BMF, including 54 aplastic anemia (AA), 50 paroxysmal nocturnal hemoglobinuria (PNH), and 52 myelodysplastic syndromes (MDS) patients. The frequencies with low concentrations of serum Hp (

Autoantibodies to factor VIII in nonhemophilic patients can develop in association with autoimmune diseases, malignancies, and pregnancy [1,2]. It is a rare condition but its accurate diagnosis is important because an ensuing hemorrhage could be fatal. A 29-year-old woman presented with a sudden onset of abdominal pain. Her first child had been normally delivered 4 months previously, and he had no history of bleeding. Laboratory tests indicated normal platelet count, bleeding time, and prothrombin time (PT), but a hemoglobin level of 7.2 g/dL and a mild prolongation of the activated partial thromboplastin time (APTT) (48.1 s). A computed tomographic scan showed a great quan

Anti-platelet agents are widely used for the treatment and prevention of thrombotic diseases. On the other hand, continuation of anti-platelet agents increases the risk of hemorrhagic complications in gastrointestinal endoscopy, and cessation of anti-platelet agents exposes the patient to the risk of thromboembolism. Only a few studies have actually studied the whether a cessation period is required prior to endoscopic procedures and if so, the optional duration of the period. The present study assessed the time course of primary hemostasis after the cessation of anti-platelet agents.Eleven healthy men (age range, 19-29 years) were assigned to each of the following regimens: aspirin (ASA; 100 mg/day), ticlopidine (TP; 300 mg/day), and a combination of ASA (100 mg/day) and TP (300 mg/day) for 7 days. There was a washout period of more than 3 weeks between each regimen. A quantitative bleeding time test (QBT test) and platelet aggregation test were performed before the beginning of administration, on the last day of administration, and at 1, 3, and 5 days after cessation, and also at 7 days after cessation for the combination regimen.The average bleeding time (BT) and total bleeding loss volume (Tv) of the 11 subjects after administration of the three regimens were significantly increased compared with those before administration. With the administration of ASA, increases of BT and Tv at 3 days after cessation were not significant. The Tv at 5 days after cessation of TP was not significantly increased. With the combination regimen, the BT and Tv at 7 days after cessation were not significantly increased.A 3-day cessation period for ASA, a 5-day cessation period for TP, and a 7-day cessation period for ASA+TP administration seem to be sufficient.

The effects of three antiplatelet drugs, aspirin, clopidogrel and cilostazol, were examined and compared using a quantitative bleeding time (QBT) test apparatus. In 12 healthy adult male subjects, a QBT test and platelet aggregation test were performed before and after medication. Cilostazol was found to be as effective as aspirin and clopidogrel in inhibiting platelet aggregation. Following the oral administration of aspirin and clopidogrel for 7 days, the bleeding time was significantly prolonged. In contrast, none of these QBT parameters were altered by the cilostazol treatment. This suggests that cilostazol has potent efficacy in inhibiting platelet aggregation without prolonging the bleeding time and changing the bleeding pattern.

In this article, we refer to thrombocytopenia caused by increased destruction/consumption of platelets(immune thrombocytopenia and non-immune thrombocytopenia), abnormal pooling, and dilutional loss. The cause of idiopathic thrombocytopenic purpura (ITP) is a accelerated platelet destruction due to autoimmune mechanism. Differential diagnosis is important between ITP and other thrombocytopenic disorders, because the treatment and prognosis are distinct. Drug-induced thrombocytopenia is the most common among secondary autoimmune thrombocytopenia and clinically important. The immediate cessation of all suspect drugs is necessary when drug-induced thrombocytopenia is suspected. Thrombocytopenia of disseminated intravascular coagulation(DIC) and thrombotic microangiopathy(TMA) occur in diffuse intravascular coagulation and induce thrombocytopenia by the consumption of the platelet.

It is known that some products of endothelial cells or their analogs can attenuate the platelet aggregation response and initiate the platelet disaggregation response. Since platelets are involved in the initiation of many clinically important occlusive vascular diseases, we hypothesized that the endothelial cell products act synergistically to disperse platelet aggregates. In this study we examined the synergistic platelet disaggregating effects among the products of endothelial cells. We used urokinase, prostaglandin I2 (PGI2), and sodium nitroprusside (SNP) (which is the chemical substitute as nitric oxide(NO)-donor) for endothelium-derived relaxing factor (EDRF). Platelet disaggregation rate was increased in a dose-dependent manner and decreased in a time-dependent manner, and the combined use of two or three agents had synergistic effects on platelet disaggregation. Furthermore, flow cytometric analysis showed decreases in the binding of fibrinogen to activated platelets by the addition of PGI2 or SNP. These data revealed that these products or their analogs could inactivate the activated platelets or aggregated platelets by detaching fibrinogen from platelets. In addition our data revealed that PGI2 and SNP can act synergistically with fibrinolytic agents. These findings suggest a potential strategy for improving the efficacy of thrombolytic therapy by a combination of these products or their substitutes.

We examined and compared the effects of aspirin (ASA), ticlopidine (TP) and cilostazol (CS) on bleeding time (BT) in 10 healthy adult male subjects using a newly developed quantitative bleeding time (QBT) test apparatus capable of simultaneously measuring total blood loss (Tv), maximum bleeding rate (Rmax), and bleeding pattern in addition to BT. All 3 drugs inhibited platelet aggregation response to ADP, collagen, epinephrine and arachidonic acid (p < 0.05), but not to ristocetin. Following oral administration of ASA (330 mg/day) or TP (300 mg/day) for 3 days, BT was significantly prolonged (mean BT increased from 359.3 to 646.0 s, p < 0.001, and from 323.3 to 528.7 s, p < 0.01, respectively) and Tv was significantly increased (from 14.5 to 30.2 μl, p < 0.05, and from 12.5 to 19.2 μl, p < 0.01, respectively). Aspirin also increased Rmax (from 0.118 to 0.159 μl/s, p < 0.05). The prolonged bleeding patterns after administration of ASA and TP were both type III, which has been reported to be less likely to lead to bleeding accidents. In contrast, none of these QBT parameters were altered by CS administration.