Hemostatic balance between pro- and anticoagulant is maintained during glucocorticoid treatment.

BACKGROUND: Glucocorticoids are associated with an increased risk of venous thrombosis. Glucocorticoid treatment increases coagulation factor and anticoagulant levels; however, its effect on hemostatic function remains unclear. This study aimed to investigate the changes in comprehensive coagulation profiles after glucocorticoid treatment in noninflammatory diseases to elucidate the direct contribution of glucocorticoids to hemostatic function. PROCEDURE: Patients diagnosed with primary immune thrombocytopenia requiring glucocorticoid treatment were prospectively enrolled in this study. Changes in coagulation factors and anticoagulants during glucocorticoid treatment and changes in thrombin generation potential were determined in the absence and presence of soluble thrombomodulin (sTM). RESULTS: Seven treatment cases (four for steroid pulse therapy and three for oral glucocorticoid therapy) in six patients with immune thrombocytopenia were examined. After glucocorticoid treatment, activated partial thromboplastin time significantly shortened, and activities of factor VIII, IX, XI, and XII significantly increased, except for von Willebrand factor antigen. Moreover, antithrombin and protein C (PC) activities significantly increased after glucocorticoid treatment. Two major parameters of thrombin generation potential, endogenous thrombin potential (ETP) and peak thrombin (Peak), significantly increased in the absence of sTM after glucocorticoid treatment. However, no significant increases in either parameter were observed in the presence of sTM. ETP-TM and Peak-TM ratios, which represent resistance to the anticoagulant effect of the PC pathway, significantly decreased after glucocorticoid treatment, suggesting that anticoagulant function via the PC pathway is elevated after glucocorticoid treatment. CONCLUSIONS: As glucocorticoids increase intrinsic coagulation factor and anticoagulant levels, hemostatic balance between pro- and anticoagulant functions is maintained.

Clinical and pathophysiological delineation of musculocontractural Ehlers-Danlos syndrome caused by dermatan sulfate epimerase deficiency (mcEDS-DSE): A detailed and comprehensive glycobiological and pathological investigation in a novel patient.

Musculocontractural Ehlers-Danlos syndrome caused by dermatan sulfate epimerase deficiency (mcEDS-DSE) is a rare connective tissue disorder. This is the first report describing the detailed and comprehensive clinical and pathophysiological features of mcEDS-DSE. The patient, with a novel homozygous nonsense variant (NM_013352.4:c.2601C>A:p.(Tyr867*)), exhibited mild skin hyperextensibility without fragility and small joint hypermobility, but developed recurrent large subcutaneous hematomas. Dermatan sulfate (DS) moieties on chondroitin sulfate/DS proteoglycans were significantly decreased, but remained present, in skin fibroblasts. Electron microscopy examination of skin specimens, including cupromeronic blue-staining to visualize glycosaminoglycan (GAG) chains, revealed coexistence of normally assembled collagen fibrils with attached curved GAG chains and dispersed collagen fibrils with linear GAG chains from attached collagen fibrils across interfibrillar spaces to adjacent fibrils. Residual activity of DS-epi1, encoded by DSE, and/or compensation by DS-epi2, a minor homolog of DS-epi1, may contribute to the mild skin involvement through this "mosaic" pattern of collagen fibril assembly.

Association of physical activity with bleeding events and safety in patients with haemophilia A starting emicizumab prophylaxis: an interim analysis of the TSUBASA study.

INTRODUCTION: Little information exists on the relationship between bleeding outcomes and physical activity in patients with haemophilia A (PwHA). AIM: This interim analysis of the TSUBASA study (UMIN-CTR ID: UMIN000037448) evaluated the association of physical activity with bleeding and safety in PwHA starting emicizumab. METHODS: PwHA without factor VIII inhibitors were recruited. Physical activity and bleed data were obtained using an electronic patient-reported outcome application and wearable activity tracker. Adverse events (AEs) were documented. RESULTS: At data cut-off (31-May-2021), 107 PwHA were enrolled, with a median (range) age of 35 (0-73) years. Physical activity data were obtained for 74 participants. Of these, 47 (63.5%) recorded a total of 396 exercise events. The most common exercise events were walking (32.4%), cycling (14.9%), and football (5.4%). Two (0.5%) exercise events in the same individual were associated with bleeding (running, weight training). The safety analysis population consisted of 106 participants treated with emicizumab (median observation period: 241.5 days). Twenty-one (19.8%) participants experienced a total of 39 AEs. Five (4.7%) experienced a serious AE, none of which was emicizumab-related, and three (2.8%) experienced an adverse drug reaction. CONCLUSIONS: PwHA receiving emicizumab in the TSUBASA study experienced minimal bleeding associated with physical activity. TRIAL REGISTRATION: Trial registration: UMIN-CTR ID: UMIN000037448.

T-cell large granular lymphocyte leukemia in a child with anemia and Crohn's disease.

T-LGL leukemia has been rarely reported in children. We report a child with T-LGL leukemia who presented with anemia and went on to develop Crohn's disease. Although prednisolone treatment proved effective in the treatment of anemia, large granular lymphocyte counts increased as the doses were tapered. T-cell rearrangement studies revealed a clonal rearrangement of the TCR Vß/jß2 gene. Concurrently, the patient developed severe diarrhea. Inflammatory changes across the upper and lower intestines led to the diagnosis of Crohn's disease. This case highlights that T-LGL leukemia could be occurred in children. Flow cytometry and/or T-cell gene rearrangement studies are recommend in patients of anemia and various kind of autoimmune diseases including Crohn's disease, even in children.

AKATSUKI study: a prospective, multicentre, phase IV study evaluating the safety of emicizumab under and immediately after immune tolerance induction therapy in persons with congenital haemophilia A with factor VIII inhibitors.

INTRODUCTION: For persons with haemophilia A with factor (F) VIII inhibitors (PwHAwI), immune tolerance induction (ITI) therapy is indicated for inhibitor eradication; however, since PwHAwI on ITI were excluded from the emicizumab clinical development programme, there are limited safety data for emicizumab treatment under/immediately after ITI in PwHAwI. Accordingly, there is a need to collect safety and efficacy data on this concomitant treatment strategy. The AKATSUKI study aims to evaluate the safety of emicizumab under/immediately after ITI in PwHAwI; here we report details of the study protocol. METHODS AND ANALYSIS: AKATSUKI is an open-label, non-randomised, interventional, multicentre study. Twenty participants with congenital HA with FVIII inhibitors will be enrolled from 17 sites across Japan. Emicizumab will be administered subcutaneously, with an initial loading dose of 3 mg/kg once per week (QW) for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg QW, 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks. For ITI therapy, 50 IU/kg FVIII will be administered three times per week. For extended half-life FVIII, a dosing frequency of twice per week will be permitted. The primary endpoint is a comprehensive safety evaluation of adverse events (mainly thromboembolic events) and abnormal laboratory values over time. Secondary endpoints are the number of bleeds requiring coagulation factor treatment, the number of participants achieving a partially successful ITI response, FVIII inhibitor titres under/immediately after ITI, quality of life and time to achieve a negative FVIII inhibitor result (<0.6 BU/mL) and partial success in PwHAwI starting ITI after study enrolment. CONCLUSIONS: AKATSUKI will evaluate the safety of emicizumab administered under/immediately after ITI, providing reference data to inform treatment strategies in PwHAwI. ETHICS AND DISSEMINATION: The results of this study will be published in a peer-reviewed international journal and presented at national and/or international medical scientific conferences; the major findings of this study will be published on the jRCT registry website (https://jrct.niph.go.jp). TRIAL REGISTRATION NUMBER: jRCTs041200037.

First case report of hemophilia B Leyden in Japan.

Hemophilia B Leyden is a unique subtype of hemophilia B, characterized by increasing factor IX activity (FIX:C) after puberty and a lower normal range of FIX:C throughout adulthood. However, to date, no Japanese case has been reported. Here, we report a case of hemophilia B Leyden in a 22-year-old male. He suffered from subgaleal hematoma, and was subsequently diagnosed with hemophilia B (FIX:C 0.2%) in the neonatal period. Both his parents are Japanese. There was no history of hemophilia in his family. FIX:C gradually increased with age (8% at age = 1; 14% at age = 7; 19% at age = 12; 32% at age = 18). FIX:C is within the range 30-40% in recent several years. He once required administration of FIX concentrate against traumatic tongue bleeding at 7 years of age. Genotyping analysis of FIX was performed after informed consent at 21 years of age, and a point mutation (c.-35G>A) was detected. This mutation has been reported previously as the Leyden mutation. Although it has been reported that hemophilia B Leyden is seen in 1.9% of patients with hemophilia B, the present case is the first report of hemophilia B Leyden from Japan.

A cohort study of the usefulness of primary prophylaxis in patients with severe haemophilia A.

Primary prophylaxis is a method of haemostatic management to prevent bleeding and arthropathy in patients with severe haemophilia. The aim of this study was to evaluate the usefulness of primary prophylaxis in patients with severe haemophilia A. This study included 15 patients with haemophilia A who received primary prophylaxis at our institution for a minimum of 5 years. We evaluated the annualized bleeding ratio of joints or other sites, current joint function, and X-ray images and MRI scans taken when patients were 6 years old. The range of patients' ages at the end of the study was 6.2-16.8 years, and at the start of primary prophylaxis it was 0.8-2.4 years. Factor VIII concentrates (25-40 units kg(-1) dose(-1)) were administered 3 times/week or every other day, according to the Swedish protocol. Mean joint and non-joint annualized bleeding ratios were 0.49 ± 0.5 and 1.54 ± 1.69, respectively. At the final evaluation, all patients displayed a normal range of motion for both elbows, knees, and ankles. The radiography and MRI findings at the age of 6 were unremarkable in all patients. Overall, primary prophylaxis for patients with severe haemophilia A was performed safely, reduced the number of bleeding events, and prevented progression to arthropathy.

Is a vesicoamniotic shunt intrinsically bad? Shunting a normal fetal bladder.

INTRODUCTION: We previously demonstrated that in utero vesicoamniotic shunting of obstructive uropathy in fetal lambs produces a shrunken noncompliant bladder. We hypothesized that the normal fetal bladder filling and emptying cycle in fetal life is critical to the development of normal bladder function. MATERIALS AND METHODS: We placed vesicoamniotic shunts in 4 normal fetal lambs at 74 days' gestation. The fetuses were delivered at term (145 days), and bladder volume and compliance were measured and compared with those measurements in 3 normal term fetuses. The lambs were then killed and the renal tracts and bladders removed submitted to histologic examination. RESULTS: All shunted lambs survived to term. Three normal control lambs were delivered at term. The mean bladder volume in shunted lambs was 4 +/- 2.8 mL (n = 4) compared with 60 +/- 17 mL (n = 3) in control lambs (P < .05). Bladders in the shunted lambs had very poor compliance compared with normal lambs' bladders. Histologic examination of the shunted bladders showed increased fibrosis and distortion of the muscle layers compared with control bladders. CONCLUSION: Even in the absence of obstruction, preventing normal bladder filling and emptying in fetal life produces fibrotic bladders with poor compliance.