Objectives: We undertook an international, multicenter study to describe the clinical picture and to estimate the bleeding risk in a group of obligatory carriers of type 3 von Willebrand disease (VWD). Patients and methods: Obligatory carriers (OC) of type 3 VWD were identified by the presence of offspring with type 3 VWD or by being an offspring of a type 3 patient. Normal controls were age- and sex-matched with the obligatory carriers. A physician-administered standardized questionnaire was used to evaluate hemorrhagic symptoms at presentation. A score system ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion) was used to quantitate bleeding manifestations. Odds ratios were computed for each symptom. Results: Ten centers participated to the study, enrolling a total of 35 type 3 VWD families, with 70 OC. A total of 215 normal controls and 42 OC for type 1 VWD were also included. About 40% of type 3 OC had at least one bleeding symptom compared to 23% of normal controls and 81.8% of type 1 OC (P < 0.0001 by chi-squared test), showing that type 3 OC clearly represent a distinct population from type 1 OC. The clinical situations associated with an increase of bleeding risk in type 3 OC were epistaxis [odds ratio 3.6; 90% confidence intervals (CI) 1.84-21.5], cutaneous bleeding (odds ratio 5.5; 90% CI 2.5-14.1) and postsurgical bleeding (odds ratio 16.3; 90% CI 4.5-59). The severity of bleeding score correlated with the degree of factor (F) VIII reduction in plasma. Conclusions: OC for type 3 VWD represent a distinctive population from type 1 OC. These patients, however, present with more frequent bleeding symptoms in comparison to normal controls, especially in case of significantly low FVIII. Desmopressin and/or tranexamic acid might be useful to prevent or treat bleeding in these cases.

Treatment of previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe hemophilia A using FVIII concentrates is complicated by FVIII inhibitor formation in ∼30% of patients. The incidence of FVIII inhibitors was determined in a prospective clinical trial of sucrose‐formulated full‐length recombinant FVIII (rFVIII‐FS, KOGENATE® Bayer; Kogenate® FS) in pediatric patients.Methods: PUPs and MTPs (=4 exposure days‐EDs) with hemophilia A (<2% FVIII) were enrolled from 19 EU and 13 US centers. Sixty patients were evaluable for inhibitor formation (EU, 31; US, 29). Patients were tested regularly with the Nijmegen‐modified Bethesda assay (negative, ≤0.6 BU; Low Titer, >0.6‐5 BU; High Titer, >5 BU).Results: In the EU cohort (31 Caucasian), 4 patients developed inhibitors (3 Low; 1 High). Five high titer inhibitors developed in the US cohort (17 Caucasian; 5 Black; 7 Other). Median EDs at inhibitor detection was 8 [range, 3‐16], and at study end 1 EU and 4 US patients had <20 EDs. The incidence of inhibitors in patients achieving 20 ED was 16.4% (9/55).Conclusions: The rate of inhibitor formation in pediatric patients with severe hemophilia A treated with rFVIII‐FS is consistent with that observed with plasma‐derived and other recombinant FVIII products. Major gene disruptions were observed in all inhibitor patients.

Growth and pubertal development in hemophilic males, age 6-19 years at baseline, were evaluated over a 3.5-year period in 207 HIV-positive and 126 HIV-negative subjects as part of the Hemophilia Growth and Development Study.Methods: Thyroid function, insulin-like growth factor I(IGF-1) levels, bone age, cranial magnetic resonance image normality, CD4(+) counts, and serum testosterone levels of study participants were measured at baseline. An extensive endocrine evaluation was performed in subjects who demonstrated declines in height for age (measurement <5th percentile with two pervious heights >10th percentile), who had not achieved Tanner stage 4 level of pubertal development by age 15 years or who had abnormal growth velocity, which included assessment of peak stimulated growth hormone response after clonidine stimulation, 12-hour growth hormone profiles, and serum beta carotene levels (triggered protocol).Results: For almost the entire group (similar to 99%), thyroid function tests were normal for age. IGF-1 levels were normal for 93% of the cohort. A total of 120 subjects, 89 HIV-positive and 31 HIV-negative, had an abnormality of growth, pubertal development, or both; 34 (11.1%) HIV-positive and 4 (3.6%) HIV-negative subjects had declines in height (p =.001), 20 (23.3%) HIV-positive and 5 (15.8%) HIV-negative subjects had not achieved Tanner stage 4 by 15 years of age (p =.372) and 59 (43.4%) HIV-positive and 23 (25.6) HIV-negative subjects had abnormal growth velocity (p < 0.001). Among subjects with abnormal height or growth velocity, the HIV-positive group had significantly lower mean age-adjusted testosterone levels than did the HIV-negative group (p =.030). Within the HIV-positive group, older subjects with abnormal height or growth velocity had significantly lower mean bone age than subjects of similar age without growth abnormalities (p =.0092). Extensive testing was done in 39 patients (32 HIV-positive, 7 HIV-negative). Half of the HIV-positive subjects had mean 12-hour growth hormone levels <3 ng/ml, 47% had peak stimulated levels <10 ng/ml, 28% had peak spontaneous values <10 ng/ml, and 38% had low levels of IGF-1. In the HIV-positive cohort, there was no difference in the rate of abnormalities of growth hormone secretion between those with CD4(+) counts greater than or equal to or <200 cells/mm(3) and between those subjects that met the 1987 Centers for Disease Control (CDC) surveillance definition of AIDS. In the subset of HIV-positive patients with abnormal peak growth hormone levels after clonidine stimulation, growth hormone response correlated positively with CD4(+) count (r =.657, p =.0056) and beta carotene concentration (R =.596, p =.0192).Conclusions: The results of this longitudinal study suggest that abnormalities of growth and pubertal development, particularly an abnormal growth velocity, are common in HIV-infected hemophilic boys and adolescents. These abnormalities might serve as indicators of the presence of HIV infection in this at-risk population. Since thyroid function tests and IGF-1 levels were normal, the etiology of growth impairment in HIV infection does not appear to be secondary to inadequate caloric intake or acquisition, or severe illness such as that caused by recurrent or persistent infection. Rather, HIV infection appears to lead to diminished growth hormone production or release and decreased androgen secretion, even before the development of AIDS and immunocompromise. These results provide a rationale for trials of treatment with growth hormone or androgens in patients with abnormalities of endocrine function.

Vox SanguinisVolume 70, Issue s1 p. 60-65 Protocols, Dosages and Clinical Aspects of Immune Tolerance J. Lusher, J. Lusher DMC Children's Hospital of Michigan Dept. of Pediatrics, Detroit MI, USASearch for more papers by this authorG. Mariani, Corresponding Author G. Mariani Department of Biopathology, La Sapienza University, Rome, ItalyLa Sapienza University, Department of Biopathology, Haematology Section, Via Chieti 7, 1–00161 Rome (Italy)Search for more papers by this author J. Lusher, J. Lusher DMC Children's Hospital of Michigan Dept. of Pediatrics, Detroit MI, USASearch for more papers by this authorG. Mariani, Corresponding Author G. Mariani Department of Biopathology, La Sapienza University, Rome, ItalyLa Sapienza University, Department of Biopathology, Haematology Section, Via Chieti 7, 1–00161 Rome (Italy)Search for more papers by this author First published: February 1996 https://doi.org/10.1111/j.1423-0410.1996.tb01351.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume70, Issues1February 1996Pages 60-65 RelatedInformation

Monoclonal antibody purified factor IX concentrate, Mononine (Armour Pharmaceutical Company, Kankakee, Illinois, USA), is a recently developed replacement factor concentrate for the treatment of patients with hemophilia B. The pharmacokinetic properties of monoclonal antibody purified factor IX concentrate (MAb Factor IX concentrate) have been evaluated in only small samples of patients, and little is known about those factors that might influenced in vivo recovery of factor IX after infusion is a larger patient population. In vivo recovery of factor IX was therefore evaluated for 80 different indications in 72 patients who received MAb Factor IX concentrate for the management of spontaneous or trauma-induced bleeding, or as prophylaxis with surgery. The average recovery after infusions for presurgical pharmacokinetic analysis (mean +/- standard deviation) was 1.28 +/- 0.56 U/dl rise per U/kg infused (range 0.41-2.80), and the average recovery after all infusions for treatment was 1.23 +/- 0.49 U/dl rise per U/kg infused (range - 0.35-2.92). Recovery values for multiple MAb Factor IX doses in a given patient were also variable; the average recovery was 1.22 +/- 0.53 U/dl rise per U/kg given, and standard deviations ranged from 0.03 to 1.26. Patient age, weight, and MAb Factor IX concentrate dose minimally but significantly influenced factor IX recovery. There was no significant effect of either race, history of previous thrombotic complications during treatment with other replacement factor concentrates, or bleeding state on recovery. All of the patients treated with this preparation experienced excellent hemostasis, and no thrombotic complications were observed.

Whether a shift from a type I (cell mediated) immune profile occurs with progressive HIV-related immune dysfunction is a matter of heated debate. We analyzed data for 333 HIV antibody-positive (HIV+) and -negative (HIV-) hemophilic children/adolescents, to examine whether the relationships among immunologic parameters and vaccine-related serology supported a shift with advancing HIV infection. In stepwise logistic regression analysis of HIV+ children's data, anergy to a panel of delayed hypersensitivity skin test antigens was positively associated with serum immunoglobulin A (IgA) levels (p = 0.012) and CD8+ cell counts (p = 0.021) and negatively associated with CD4+ cell counts (p = 0.002). Modeling supported anergy as a positive correlate of log IgA level (p = 0.046) and CD4+ lymphocyte count as a negative correlate, for HIV+ participants only (p < 0.0001). For mumps, the proportion of vaccinated HIV+ participants with protective IgG antibody titers was higher among those with CD4+ lymphocyte counts < 200 cells/mm3 (p = 0.058). For HIV+ participants < 14 years of age, this same trend was seen for measles and rubella, but was not seen in any age group for bacterial vaccine antigens. The intercorrelations among skin test anergy, CD4+ lymphocyte counts, serum IgA levels, and viral vaccine antigen-related serologic titers for HIV+ participants are consistent with an association between progressive HIV-related immune dysfunction and a predominance of type II (humoral immunity) or Type 0 (mixed immunity), relative to type I, lymphocyte profiles.

Many rapid advances have been made in the diagnosis and therapy of haemophilia. Nevertheless, the condition still poses problems and challenges (e,g,, joint disease, transfusion-transmitted diseases, inhibitors, provision of care in developing countries, and education and cost issues), WHO and the World Federation of Hemophilia held a joint meeting in Geneva, on 21-23 March 1994, to discuss and review current and future approaches to the management of haemophilia and its complications, including prospects for genetic technology and gene therapy in developed and developing countries, The present review article summarizes the discussions and recommendations made by the participants.