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Thrombophilias are usually caused by loss-of-function mutations in natural anticoagulants or gain-of-function mutations in procoagulants. A mutation in a Japanese family documents a novel mechanism, procoagulant (prothrombin) resistance to anticoagulant (antithrombin). Patients with hereditary thrombophilia often present with unusual clinical episodes of venous thrombosis at a young age and recurrence in atypical vessels, often with a family history of the condition. 1 Genetic studies of hereditary thrombophilia have revealed two types of genetic defects: loss-of-function mutations in the natural anticoagulants antithrombin, protein C, and protein S, along with gain-of-function mutations in procoagulant factors V (factor V Leiden) and II (prothrombin G20210A). 2 To date, numerous genetic defects have been found in families with hereditary thrombophilia, but there may be many undiscovered causative mutations. 3 Here, we describe a case of hereditary thrombosis induced by . . .

Treatment of congenital hemophilia A (HA) in Japan has greatly improved with the widespread adoption of prophylactic factor (F)VIII concentrates. However, it is unknown ifhas translated into a real‐world reduction in disease and treatment burden. To describe HA disease burden in Japan based on information from two medical information databases, JMDC and Real World Data Co., Ltd. (RWD). Eligible individuals were diagnosed with congenital HA and prescribed FVIII concentrates, bypassing agents, or emicizumab. Treatment patterns and disease burden data were derived from health insurance claims and electronic medical records. Data on 459 people with HA were retrospectively collected from 2005 to 2020 in the JMDC database (median [min, max] of 37 [2, 186] months of available records), and 229 people with HA from 1985 to 2020 in the RWD database (median [min, max] of 154 [0, 409] months of available records). Mean (standard deviation) ages at the time of the first record were 25.0 (16.8) years (JMDC) and 19.2 (20.3) years (RWD). In the JMDC database, mean monthly FVIII dose increased from 2201 IU in 2005 to 8239 IU in 2013 to 11,377 IU in 2019; HA‐related drug costs increased accordingly. Mean (95% confidence interval) annual outpatient and out‐of‐hours visits decreased slightly between 2013 and 2019 (outpatient visits: from 22.9 [16.8–29.0] to 14.3 [12.6–16.1] per person; out‐of‐hours visits: from 1.3 [0.2–2.5] to 0.6 [0–1.4]). There was no change in mean number of hospitalizations. Challenges remain in HA, including treatment burden, outpatient visits, and hospitalizations. [Display omitted]

The Baxject II Hi-Flow device has previously been used to reconstitute the factor VIII products antihemophilic factor (recombinant) (ADVATE ) and rurioctocog alfa pegol (ADYNOVATE ). In this crossover study in healthy men, the convenience of an advanced device, Baxject III with and without a nonslip sleeve, was compared with that of Baxject II Hi-Flow. The primary endpoint was the operational time for reconstitution; secondary endpoints included participants' assessment of the usability of the devices for reconstitution and their preference for using each of the devices. Twelve healthy adult men (mean ± standard deviation [SD] age: 36.7 ± 7.0 years) and 12 healthy elderly men (mean ± SD age: 70.3 ± 4.8 years) participated in the study. In the adult group, the mean operational time for reconstitution was shorter using Baxject III (mean ± SD: 19.7 ± 2.7 and 19.9 ± 5.2 seconds with and without a nonslip sleeve, respectively) than when using Baxject II Hi-Flow (49.6 ± 7.2 seconds, < 0.0001 for both comparisons). Adult participants rated preference ( < 0.0001) and ease of reconstitution ( < 0.0001) as higher for Baxject III with a nonslip sleeve than for Baxject II Hi-Flow. Results were consistent regardless of age group or the use of the nonslip sleeve. Owing to the convenience of Baxject III, this device will improve the reconstitution process for patients with hemophilia treated with rurioctocog alfa pegol or antihemophilic factor (recombinant) at home.

Rurioctocog alfa pegol (BAX 855) is a novel third-generation recombinant factor VIII whose active ingredient is chemically modified with polyethylene glycol. A global multicenter phase 2/3 study of the product in 137 patients (including 11 patients from Japan) with severe hemophilia A aged 12–65 years, reported an extended half-life and a good tolerability profile, as well as a significantly lower annualized bleeding rate in the prophylactic treatment arm than in the on-demand treatment arm. Using descriptive statistics, a post hoc analysis was performed to compare the pharmacokinetics, safety, and efficacy profiles of the product in the Japanese subpopulation and the overall population. Extended half-life was demonstrated in the Japanese subpopulation. The mean [standard deviation (SD)] annualized bleeding rates in the prophylactic treatment arm were 3.7 (4.7) for the overall population ( n  = 120) and 4.0 (3.4) for the Japanese subpopulation ( n  = 11). The proportion of bleeds reported as excellent or good was 94.9% (149/157) in the overall population, whereas that in the Japanese subpopulation was 92.3% (12/13). No FVIII inhibition or anaphylactic reaction was reported in the Japanese subpopulation. The post hoc comparisons demonstrated similar pharmacokinetic, safety, and efficacy profiles between the overall population and the Japanese subpopulation.

Data on long-term outcomes of children with refractory immune thrombocytopenia (ITP) treated with rituximab are limited. We retrospectively analyzed the long-term effect of rituximab on 22 pediatric ITP patients (11 boys and 11 girls). Compete response (CR) (platelet count ≥100 × 10 9 /L) and partial response (PR) (platelet count 30–99 × 10 9 /L) were achieved in nine (41 %) and two (9 %) patients, respectively. Of the 11 responders, eight subsequently relapsed 2–26 months after initial rituximab treatment. The 5-year relapse-free rate was 14 % (3/22, 95 % confidence interval: 0–27 %) with a median follow-up period of 6.4 years. Five initial responders with subsequent relapse and one non-responder received multiple rituximab treatments of nine courses; all patients responded to the second rituximab therapy without any significant toxicity. All eight patients who relapsed after an initial response and six of 11 non-responders achieved CR or PR with subsequent treatment, including repeated courses of rituximab, splenectomy, steroids, and other immunomodulating agents. Our findings indicated that the sustained effect of rituximab on children with refractory ITP is low, but that the long-term outcome of ITP itself is not poor. Furthermore, repeated rituximab administration may be a promising therapy for those who relapse after an initial response.

The International Immune Tolerance Induction (I-ITI) Study in hemophilia A patients with inhibitors included 16 Japanese patients among a total of 115 test subjects. The results within this group of Japanese patients were 11 cases of I-ITI off-study, three cases of I-ITI on-study, and two cases of tolerance on prophylaxis. There was no significant difference in success rate between the low-dose and high-dose groups (Study I). Successively, independent follow-up survey in Japan was conducted in 14 cases, with consent (Study II). Ten cases were off-study at the end of the I-ITI Study. Of these 10 cases, seven of seven successful cases remained clinical successes at the end of the follow-up study, one partial success became a full success while a second relapsed, and one failure was subsequently evaluated as a partial success. Four cases that were on-study at the end of I-ITI Study were classified as three successes and one failure at the end of the follow-up study. As a result, the status at the end of follow-up study was: 11 ITI successes (78.6 %); one partial success; one failure; and one relapse. Thus, the ITI follow-up study was helpful in providing a long-term prognostic determination of inhibitors.

Approximately 30% of patients with hemophilia in Japan were infected with human immunodeficiency virus (HIV) in early 1980s through contaminated blood products. In 1995, a cohort of HIVinfected, asymptomatic patients with hemophilia was set up for follow-up study. Although the patients met the criteria for long-term non-progressor (LTNP) at the entry to the cohort, some of them later developed lymphopenia during five more years of observation. We collected blood samples from 80 long-term survivors; 42 of them did not require antiviral therapy, but the rest were under treatment. Analysis of HLA-B genotype revealed that carriers of known HIV-resistant alleles such as HLA-B*5701, B*5801, and alleles of B27 antigenic group were not increased in frequency, but that HLA-B*1507 was increased in the cohort (6.25% vs. 1.03%, OR = 6.40, p = 0.039). We also observed the decrease in carriers of HLA-B*5401 (3.75% vs. 14.95%, OR = 0.22, p = 0.016). HLAB* 5401 is a relatively common allele in East Asian populations and belongs to the same B22 antigenic group as B55 and B56 which were reported to associate with rapid progression. Our data indicated that HLA class I is one of the host factors involved in the retardation of HIV disease progression as also reported in the previous studies; however, the alleles associated with this resistance were not the same because of divergent host genetic background.

The authors would like to correct the error in Table 2 in the original publication of the article. The “Blood type” is not described in any part of “Results” and “Discussion” and had no impact on the conclusion hence the bottom of the table is removed.

To determine whether the fibrinolytic system is related to the occurrence of cardiac complication in Kawasaki disease, we measured tissue plasminogen activator, plasminogen activator inhibitor-1, and related factors in the plasma of children with Kawasaki disease. Patients (mean age, 1.8 years) were classified into patients with cardiac complication (n = 9) and no complication (n = 14) groups echocardiographically. They underwent single, high-dose, intravenous γ-globulin infusion therapy. Blood was drawn just before and the day after the single high-dose intravenous γ-globulin infusion therapy (acute phase), and at early and late convalescent phases. Leukocytosis was normalized immediately after the single, high-dose, intravenous γ-globulin infusion therapy. C-reactive protein and fibrinogen were increased in the acute phase and normalized by convalescent phases. D-dimer fraction of fibrin degradation products changed in a similar manner. Tissue plasminogen activator and plasminogen activator inhibitor-1 were increased in acute phase. The tissue plasminogen activator/plasminogen activator inhibitor-1 ratio was lower in the complication group than in the no complication group throughout the observation period (0.095 versus 0.208 after single, high-dose, intravenous γ-globulin infusion therapy, p = 0.006; 0.094 versus 0.183 at late convalescent phase, p = 0.024). A low tissue plasminogen activator/plasminogen activator inhibitor-1 ratio can predict the propensity for cardiac complication, and can help the physician to decide whether additional therapies are necessary in acute phase Kawasaki disease.