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Recent evidence suggests that patients with severe hemophilia B may have a less severe disease compared to severe hemophilia A. To investigate clinical, radiological, laboratory and histological differences in the arthropathy of severe hemophilia A and hemophilia B, 70 patients with hemophilia A and 35 with hemophilia B with at least one joint bleeding were consecutively enrolled. Joint bleedings (<10, 10-50, >50), regimen of treatment (prophylaxis/on demand), World Federation of Hemophilia, Pettersson and ultrasound scores, serum soluble RANK ligand and osteoprotegerin were assessed in all patients. RANK, RANK ligand and osteoprotegerin expression was evaluated in synovial tissue from 18 hemophilia A and 4 hemophilia B patients. The percentage of patients with either 10-50 or more than 50 hemarthrosis was greater in hemophilia A than in hemophilia B (P<0.001 and P=0.03, respectively), while that with less than 10 hemarthrosis was higher in hemophilia B (P<0.0001). World Federation of Hemophilia (36.6 vs. 20.2; P<0.0001) and ultrasound (10.9 vs. 4.3; P<0.0001) score mean values were significantly higher in hemophilia A patients. Serum osteoprotegerin and soluble RANK ligand were decreased in hemophilia A versus hemophilia B (P<0.0001 and P=0.006, respectively). Osteoprotegerin expression was markedly reduced in synovial tissue from hemophilia A patients. In conclusion, the reduced number of hemarthrosis, the lower World Federation of Hemophilia and ultrasound scores, and higher osteoprotegerin expression in serum and synovial tissue in hemophilia B suggest that hemophilia B is a less severe disease than hemophilia A. Osteoprotegerin reduction seems to play a pivotal role in the progression of arthropathy in hemophilia A., (Copyright© Ferrata Storti Foundation.)

Background and Objectives: Unlike patients with hemophilia, those with von Willebrand's disease (VWD) have a mild to moderate bleeding tendency requiring a lower rate of transfusion: moreover, the use of blood products in most Italian patients with VWD was greatly reduced following the introduction of desmopressin in 1977. The main objective of this study was to compare the prevalence and outcome of hepatitis C virus (HCV) infection in multi-transfused patients with VWD and in those with hemophilia A or B., Design and Methods: In a large cohort of 356 patients with VWD (41% type 1, 53% type 2 and 6% type 3) and 340 with hemophilia A (85%) or B (15%), all of whom were negative for human immunodeficiency virus (HIV) serum HCV markers, liver function tests and abdominal ultrasound were performed every 6 months for 6 years., Results: VWD patients were less often transfused with any type of blood products than were hemophiliacs (40% versus 96%) and were, therefore, less frequently infected with HCV (39% versus 82%). HCV infection in patients with VWD occurred at an older mean age (22 versus 7 years), was of shorter duration (20 versus 31 years), and manifested less often with elevated transaminases (58% versus 83%). The risk of infection by HCV genotype 1a was significantly lower in patients with VWD than in hemophiliacs. Despite these differences in the features of HCV infection, the cumulative incidences of advanced liver disease (11% versus 10 %) and hepatocellular carcinoma (2% versus 4%) were very similar in the two groups of patients., Interpretation and Conclusions: VWD patients had lower prevalences of HCV infection with HCV and genotype 1a infections than did hemophiliacs, reflecting the different source and type of transfused blood products. HCV infection in both groups seems to run a relatively mild course, until now, but the high prevalence of genotypes resistant to curative antiviral therapies is of concern.

Background and Objectives: Since venous access in small children can be difficult to obtain, implantable venous access devices (IVAD) are used to administer clotting factor in such patients with severe hemophilia. The aim of our study was to evaluate how many children in our center needed an IVAD in order to be able to start early prophylaxis, what the differences were between children who needed an IVAD and those who did not and what the complications of the IVAD were., Design and Methods: All 70 patients with severe hemophilia born between January 1987 and October 2000 treated at our center before they were 6 years old were studied., Results: An IVAD was placed in 23 children (33%). Children with an IVAD started prophylactic treatment at a mean age of 2 years (SD 1.3), those without at a mean age of 3.6 years (SD 1.6) (p< 0.001). Home treatment was feasible at a mean age of 2.8 years (SD 1.3) in children with an IVAD and at 4.5 years in those without an IVAD (SD 1.8) (p = 0.001). Infection was the most frequent complication; the mean number of infections per IVAD was 0.61. Thrombosis was more common than initially thought (15%). The infection rate in children with inhibitory antibodies was 3.1 per 1000 patient-days; in children without an inhibitor it was 0.72 per 1000 patient-days., Interpretation and Conclusions: In 33% of the children in our cohort an IVAD was needed in order to start early prophylaxis. IVAD are needed more frequently when prophylaxis is started at an early age, but have the advantage that home treatment is feasible earlier. Infection is the most common complication, particularly in children with inhibitors.

Hemophilia B (factor IX deficiency) is an X-linked recessive disorder with a prevalence of 1:30,000 male births, which rarely affects females. A missense mutation T38R (6488C>G) of the factor IX (FIX) gene was characterized in a young female with moderate-to-severe hemophilia B. She is heterozygous for this mutation, which she inherited from her carrier mother. Analysis of the methyl-sensitive HpaII sites in the first exon of the human androgen-receptor locus indicated a de novo skewed X-chromosomal inactivation. This indicates that the paternal X-chromosome carrying her normal FIX gene is the inactive one, which has led to the phenotypic expression of hemophilia B in this patient.

The Malmö protocol for immune tolerance induction includes high doses of Factor VIII/IX, intravenous IgG and cyclophosphamide. If the inhibitor titer exceeds 10 Bethesda units at start, extracorporeal adsorption of IgG is performed using protein A. The protocol sometimes has to be repeated. A successful response may occur within a few weeks. In hemophilia A the success rate so far is 10/17 patients (15 high-responders, 2 low-responders) or 59%, whereas in hemophilia B 6/9 patients (8 high-responders, 1 low-responder), or 67%, have become tolerant. In one hemophilia B patient, a relapse occurred after 6 months. During a second treatment episode he developed an acute myocardial infarction, probably caused by replacement with prothrombin complex concentrate. We conclude that the Malmö protocol is efficient for induction of immune tolerance but the patients must be selected particularly with regard to inhibitor duration and time of last booster.