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MYH9-related disorder (MYH9-RD) is characterized by congenital macrothrombocytopenia and granulocyte inclusion bodies. MYH9-RD is often misdiagnosed as chronic immune thrombocytopenia. In this study, we investigated age at definitive diagnosis and indicative thrombocytopenia in 41 patients with MYH9-RD from the congenital thrombocytopenia registry in Japan. Our cohort comprises 54.8% adults over 18 years at confirmed diagnosis. We found a significant difference (p < 0.0001) between the median age at definitive diagnosis of 25.0 years and for indicative thrombocytopenia it was 9.0 years. Our findings strongly suggest diagnostic delay of MYH9-RD in Japan. Our registry system will continue to contribute to this issue., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Severe fever with thrombocytopenia syndrome (SFTS) is an infection mediated by ticks and has been reported to have a high mortality rate in Japan. At our hospital, we reported three cases of SFTS with relatively positive outcomes. We reviewed reports of SFTS cases in Japan to clarify the current state of the disease in Japan, the treatment provided, and its outcome. The Ichushi Web was searched for literature using the following terms as keywords: "SFTS" or "severe fever with thrombocytopenia syndrome". Overall, 174 cases were collected and reviewed. The mean age of patients was 70.69 years old, and the mortality rate was 35%. The dead group was significantly older ( p < 0.001) than the alive group, had a significantly shorter period from symptom onset to hospital admission, and experienced significantly more hemorrhage-related and neurological symptoms. Further, the most frequently provided treatment methods were adrenocorticosteroids, antibiotics, and conservative treatment. The low recognition rate of SFTS in Japan might lead to a misdiagnosis or delay in diagnosis and treatment, especially in mild to moderate cases. Medical professionals and citizens who live in areas inhabited by ticks need to be informed about SFTS to appropriately diagnose and manage SFTS cases in Japan in the future.

Background: Severe fever with thrombocytopenia syndrome virus (SFTSV) causes severe hemorrhagic fever in humans and cats. Clinical symptoms of SFTS-infected cats resemble those of SFTS patients, whereas SFTS-contracted cats have high levels of viral RNA loads in the serum and body fluids. Due to the risk of direct infection from SFTS-infected cats to human, it is important to diagnose SFTS-suspected animals. In this study, a reverse transcription polymerase chain reaction (RT-PCR) was newly developed to diagnose SFTS-suspected animals without non-specific reactions., Methodology/principle Findings: Four primer sets were newly designed from consensus sequences constructed from 108 strains of SFTSV. A RT-PCR with these four primer sets successfully and specifically detected four clades of SFTSV. Their limits of detection are 1-10 copies/reaction. Using this RT-PCR, 5 cat cases among 56 SFTS-suspected animal cases were diagnosed as SFTS. From these cats, IgM or IgG against SFTSV were detected by enzyme-linked immunosorbent assay (ELISA), but not neutralizing antibodies by plaque reduction neutralization titer (PRNT) test. This phenomenon is similar to those of fatal SFTS patients., Conclusion/significance: This newly developed RT-PCR could detect SFTSV RNA of several clades and from SFTS-suspected animals. In addition to ELISA and PRNT test, the useful laboratory diagnosis systems of SFTS-suspected animals has been made in this study., Competing Interests: The authors have declared that no competing interests exist.

Background: Cases of severe fever with thrombocytopenia syndrome (SFTS) have increasingly been observed in Miyazaki, southwest Japan. It is critical to identify and elucidate the risk factors of infection at community level. In the present study, we aimed to identify areas with a high risk of SFTS virus infection using a geospatial dataset of SFTS cases in Miyazaki., Methods: Using 10 × 10-km mesh data and a geographically weighted logistic regression (GWLR) model, we examined the statistical associations between environmental variables and spatial variation in the risk of SFTS. We collected geospatial and population census data as well as forest and agriculture mesh information. Altitude and farmland were selected as two specific variables for predicting the presence of SFTS cases in a given mesh area., Results: Using GWLR, the area under the receiver operating characteristic curve (AUC) was estimated at 73.9%, outperforming the classical logistic regression model (72.4%). The sensitivity and specificity of the GWLR model were estimated at 90.9 and 58.7%, respectively. We identified altitude (odds ratio (OR) = 0.996, 95% confidence interval (CI): 0.994-0.999 per one-meter elevation) and farmland (OR = 0.999, 95% CI: 0.998-1.000 per % increase) as useful negative predictors of SFTS cases in Miyazaki., Conclusions: Our study findings revealed that the risk of SFTS is high in geographic areas where farmland area begins to diminish and at mid-level altitudes. Our findings can help to improve the efficiency of ecological and animal surveillance in high-risk areas. Using finer geographic resolution, such surveillance can help raise awareness among local residents in areas with a high risk of SFTS.

We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301&#95;303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain. In silico structural analysis suggested that this mutation results in protein folding instability. CYCS is one of the key factors regulating the intrinsic apoptotic pathway and the mitochondrial respiratory chain. Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies thrombocytopenia. The clinical features of known CYCS variants have been reported to be confined to mild or asymptomatic thrombocytopenia, as was observed for the patient in our study. This study clearly demonstrates that thrombocytopenia can result from CYCS loss-of-function variants., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Skeletal muscle is known to be damaged by falciparum malaria via sequestration of infected erythrocytes. We present a case of rhabdomyolysis caused by Plasmodium knowlesi infection. The patient had fever, myalgia, and muscle weakness 5 days after returning to Japan from Palawan, the Philippines. Blood test revealed thrombocytopenia and an elevated creatine kinase level. Although rhabdomyolysis resolved with fluid therapy, fever of 24-hour cycle continued and thrombocytopenia intensified. On day 7 of illness, Giemsa-stained thin blood smear revealed malaria parasites, with a parasite count of 2,380/μL, which were morphologically indistinguishable between P. knowlesi and Plasmodium malariae . Rapid diagnostic test showed a negative result. The pathogen was later confirmed to be P. knowlesi by nested polymerase chain reaction (PCR). The patient was successfully treated with artemether/lumefantrine. This case suggests that knowlesi malaria might be able to cause skeletal muscle damage.

Purpose: Peripheral sensory neuropathy (PSN) and thrombocytopenia are the main dose-limiting toxicities of oxaliplatin for the treatment of advanced gastric cancer (AGC). Because the risk factors for those toxicities in practice have not been clarified, we conducted this prospective study., Methods: AGC patients who received oxaliplatin-based therapy at any of seven institutions participating in the Kyushu Medical Oncology Group were assessed after we obtained written informed consent., Results: A total of 60 patients including 39 males and 21 females were examined. The median age was 66 years. The numbers of patients receiving oxaliplatin as the first, second, or third and later lines of therapy were 39, 16, and 5, respectively. An initial dose of 130, 100, or < 100 mg/m 2 oxaliplatin was administered to 12, 39, and 9 patients, respectively. S-1 or capecitabine as a concomitant drug was administered in 54 and 6 patients, respectively. In multivariate analysis, the comorbidity of diabetes mellitus was associated with ≥ grade 2 thrombocytopenia (p = 0.035). No significant risk factor was associated with ≥ grade 2 PSN. However, the accumulated dose of oxaliplatin exhibited a strong correlation with ≥ grade 2 PSN (p = 0.0043), and the predicted accumulated dose of oxaliplatin in which 10% of patients developed ≥ grade 2 PSN was 800 mg/m 2 . The frequency of PSN in subsequent paclitaxel therapy in patients with ≥ grade 2 or worse PSN in oxaliplatin-based chemotherapy did not increase compared to those with none or grade 1 PSN in oxaliplatin., Conclusion: Thrombocytopenia in AGC patients with diabetes mellitus should be carefully monitored during oxaliplatin-based therapy.

Background: Thrombocytopenia during intoxication, rebound thrombocytosis during 1 to 3 weeks of abstinence, and subsequent normalization of the platelet count are common in alcoholics., Methods: We evaluated 989 Japanese alcoholic men to identify the effects of genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984) and aldehyde dehydrogenase-2 (ALDH2; rs671) on platelet counts during an 8-week in-hospital abstinence period., Results: Thrombocytopenia (<15 × 10 4 /μl) was observed in 25.9% of the subjects upon admission. The platelet counts increased from 21.4 ± 0.3 × 10 4 /μl (mean ± SE) to 27.6 ± 0.3 × 10 4 /μl, and a rebound platelet increase of  ≥10 × 10 4 /μl was observed in 28.6% of the patients during the first 2 weeks after admission. By 4 weeks, the mean platelet counts had returned to intermediate levels and remained stable thereafter. The reversible suppression and rebound increase in the platelet counts were more prominent in the slow-metabolizing ADH1B*1/*1 group than in the fast-metabolizing ADH1B*2 group. Throughout the 8 weeks, the mean platelet counts of the active ALDH2*1/*1 group were consistently lower than those in the inactive ALDH2*1/*2 group. Cirrhosis was a strong determinant of a lower platelet count. After adjustments for nongenetic factors including cirrhosis, multiple linear regression analyses showed that the ADH1B*1/*1 genotype was associated with a lower platelet count (partial regression coefficient = -1.3 × 10 4 /μl) on the admission day, but subsequently had a positive effect on the platelet count at 1 and 2 weeks after admission (+1.5 and +3.8 × 10 4 /μl, respectively). The ALDH2*1/*1 genotype was associated with a lower platelet count (-2.1 to -3.9 × 10 4 /μl) consistently throughout the 8 weeks. Multiple logistic regression analyses showed that the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission (odds ratio [95% confidence interval] = 1.61 [1.14 to 2.27]) and of a rebound platelet increase during the first 2 weeks (3.86 [2.79 to 5.34]). The ALDH2*1/*1 genotype increased the risk of thrombocytopenia upon admission (1.73 [1.06 to 2.82])., Conclusions: In alcoholics, the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission and of a rebound platelet increase 2 weeks thereafter, while the ALDH2*1/*1 genotype was associated with lower platelet counts throughout the 8-week hospital stay., (Copyright © 2016 by the Research Society on Alcoholism.)

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by tick-borne SFTS virus infection that was first described in rural areas of China in 2011. Since then, SFTS has also been found in the western part of Japan in 2013. The clinical pictures of SFTS are characterized by abrupt onset of fever and gastrointestinal symptoms, followed by a progressive decline in platelet and white blood cell counts. Disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis are also frequently observed in the patients with advanced phase of SFTS. No specific treatment of SFTS is available, and avoiding tick bites is an important way to prevent the infection of SFTS virus. Standard precautions should be applied to SFTS patients to prevent human-to-human transmission of SFTS virus. Since ticks bearing SFTS virus are found in all area of Japan including Hokkaido, this disease has become a substantial risk to public health in all parts of Japan.

Heparin-induced thrombocytopenia (HIT) is a 'clinicopathologic syndrome'; therefore, its diagnosis depends on clinical criteria including the presence of thrombocytopenia and/or thrombosis and a pathological criterion implying the detectability of HIT antibodies. Recently, medical reimbursement (390 points) for assays of HIT antibodies using three new assay kits [HemosIL HIT-Ab(PF4-H), HemosIL AcuStar HIT IgG(PF4-H), HemosIL AcuStar HIT-Ab(PF4-H)] was approved in Japan. The HemosIL HIT-Ab(PF4-H) kit is a latex particle-enhanced immunoturbidimetric assay to detect total heparin-associated antibodies found in HIT patients. A monoclonal antibody that mimics human HIT antibodies is coated onto latex particles. HemosIL AcuStar HIT-IgG(PF4-H) (specific for IgG anti-PF4/heparin antibodies) and HemosIL AcuStar HIT Ab(PF4-H) (detecting IgG, IgM and IgA anti-PF4/heparin antibodies) are applicable to a fully automated quantitative chemiluminescent immnunoassay instrument 'ACL AcuStar'. HIT can be excluded in all patients by a negative antigen assay using HemosIL HIT-Ab(PF4-H) or HemosIL AcuStar HIT-Ab(PF4-H). Furthermore, in patients with previous HIT who require heparin treatment, pretesting by HemosIL HIT-Ab(PF4-H) or HemosIL AcuStar HIT-Ab(PF4-H) might be useful for preventing the onset of rapid-type HIT.

Acute ischaemic stroke patients sometimes receive heparin for treatment and/or prophylaxis of thromboembolic complications. This study was designed to elucidate the incidence and clinical features of heparin-induced thrombocytopenia (HIT) in acute stroke patients treated with heparin. We conducted a prospective multicentre cohort study of 267 patients who were admitted to three stroke centres within 7 d after stroke onset. We examined clinical data until discharge and collected blood samples on days 1 and 14 of hospitalization to test anti-platelet factor 4/heparin antibodies (anti-PF4/H Abs) using an enzyme-linked immunosorbent assay (ELISA); platelet-activating antibodies were identified by serotonin-release assay (SRA). Patients with a 4Ts score ≥4 points, positive-ELISA, and positive-SRA were diagnosed as definite HIT. Heparin was administered to 172 patients (64·4%: heparin group). Anti-PF4/H Abs were detected by ELISA in 22 cases (12·8%) in the heparin group. Seven patients had 4Ts ≥ 4 points. Among them, three patients (1·7% overall) were also positive by both ELISA and SRA. National Institutes of Health Stroke Scale score on admission was high (range, 16-23) and in-hospital mortality was very high (66·7%) in definite HIT patients. In this study, the incidence of definite HIT in acute ischaemic stroke patients treated with heparin was 1·7% (95% confidence interval: 0·4-5·0). The clinical severity and outcome of definite HIT were unfavourable., (© 2011 Blackwell Publishing Ltd.)

Streptococcus dysgalactiae ssp. equisimilis (SDSE) is increasingly being identified as a pathogen responsible for invasive and non-invasive infections. We compared the clinical features of invasive SDSE infections with those of invasive infections caused by Streptococcus pyogenes (group A streptococcus (GAS)) and Streptococcus agalactiae (group B streptococcus (GBS)). Active surveillance for invasive SDSE, GAS and GBS was maintained over 1 year at 142 medical institutions throughout Japan. Clinical information was collected together with isolates, which were characterized microbiologically. Two hundred and thirty-one invasive SDSE infections were identified, 97 other patients had infections with GAS, and 151 had infections with GBS. The median age of the SDSE patients was 75 years; 51% were male and 79% had underlying diseases. Forty-two SDSE patients (19%) presented to the emergency department. Among the 150 patients (65%) for whom follow-up was completed, 19 (13%) died and eight (5%) had post-infective sequelae (poor outcome). Insufficient white blood cell responses (<5000 cells/microL) and thrombocytopenia on admission each suggested significantly higher risk of poor outcome (ORs 3.6 and 4.5, respectively). Of 229 isolates, 55 (24%) showed an stG6792 emm type, which was significantly associated with poor outcome (OR 2.4). Clinical manifestations of invasive SDSE infections were distinct from those of invasive GBS infections. Primary-care doctors should consider invasive SDSE infections when treating elderly patients.

Chronic active Epstein-Barr virus infection (CAEBV) is a high-mortality and high-morbidity disease. To clarify the prognostic factors, a national survey was performed in Japan, and data for 82 patients who met the criteria for CAEBV were analyzed. Of these 82 patients, 47 were alive and 35 had already died. Multivariate analysis revealed that thromobocytopenia and age at disease onset were correlated with mortality. The probability of 5-year survival was 0.45 for older patients (onset age, > or = 8 years), 0.94 for younger patients (P<.001), 0.38 for patients with thrombocytopenia (platelet count < 12 x 10(4) platelets/microL at diagnosis), and 0.76 for patients without thrombocytopenia (P=.01). Furthermore, patients with T cell infection by EBV had shorter survival times than patients with natural killer cell infection (probability of 5-year survival, 0.59 vs. 0.87; P<.009). Patients with CAEBV with late onset of disease, thrombocytopenia, and T cell infection had significantly poorer outcomes.

Ultrastructural studies of granulocytes were performed on two unrelated patients with hereditary thrombocytopenia, giant platelets, and inclusion bodies in granulocytes. Each patient had been diagnosed with May-Hegglin anomaly. In both cases, inclusion bodies in granulocytes consisted of clusters of ribosomes and small segments of rough endoplasmic reticulum. Additional clinical features suggesting Alport syndrome were lacking in these propositi and their family members. These observations imply that the patients were affected not with May-Hegglin anomaly but with Sebastian platelet syndrome. They would thus represent the seventh and eighth families known to carry this hereditary disease.

A case of May-Hegglin anomaly, a rare autosomal dominant thrombocytopenia, is reported. This disorder is characterized by giant platelets, basophilic inclusion bodies within the cytoplasm of granulocytes and an occasional bleeding tendency. This bleeding tendency depends on the platelet count. The fetuses of such patients run the risk of intracranial hemorrhage in utero and during the early neonatal period following vaginal delivery. Prenatal diagnosis of this disorder has not yet been reported. We describe a case of this disorder, diagnosed in pregnancy, which, following prenatal diagnosis of mild thrombocytopenia in the fetus and confirmation by cordocentesis, could successfully undergo a vaginal delivery.