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The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

Bleeding into the joints is common in patients with hemophilia. After total knee or elbow replacement, profuse intraarticular bleeding unresponsive to high-dose clotting factor replacement sometimes occurs. In some patients who have severely damaged elbow or knee joints the same profuse bleeding pattern can be seen. To control bleeding in these patients, selective catheterization with a microcatheter and therapeutic embolization with microcoils was performed whenever a severe blush or microaneurysm was observed on angiography. Over 12 years, in 23 cases of massive joint bleeding in 18 patients with hemophilia selective catheterization was performed. In 15 cases the bleeding was postoperative and in 8 spontaneous. Results of angiographic imaging revealed vascular blush, false aneurysm, true aneurysm, and arteriovenous shunt in combination with an aneurysm as cause of bleeding. In 2 patients, the cause of bleeding was not found. In 21 cases an embolization procedure was performed, in which the bleeding was completely controlled by a single procedure in 14 cases. Recurrence of the bleeding occurred in 7 cases and required a second embolization procedure; in one patient even a third embolization was required to stop the bleeding completely. No difference in the outcome, that is, clinical end of bleeding and joint range of motion, was observed, when comparing postoperative and spontaneous bleeding.

Objective: To investigate the effect of a limited number of experimental joint bleedings, combined with loading of the affected joint, on the development of progressive degenerative joint damage., Methods: The right knee of 8 mature beagle dogs was injected with freshly collected autologous blood 3 times per week for 4 weeks, to mimic a limited number of joint hemorrhages occurring over a short period. To ensure loading of the experimental joint, the contralateral control knee of the animals was fixed to the trunk 4 hours per day, 3 days per week. Ten weeks after the last injection, cartilage tissue and synovium were collected from both knees to analyze features of joint degeneration. Cartilage was prepared for analysis of proteoglycan turnover (synthesis, retention, release, and content) and histologic features. Synovium was prepared for histologic analysis., Results: The rate of proteoglycan synthesis was significantly increased, characteristic of degenerative cartilage damage as seen in osteoarthritis. Release of newly formed proteoglycans (as a measure of retention) and total loss of proteoglycans from the cartilage matrix were increased. Cartilage matrix integrity was adversely altered, as shown by histologic damage. Histologic analysis also revealed signs of synovial inflammation. These effects were not observed 10 weeks after the experimental bleedings in joints that did not undergo forced loading., Conclusion: Experimental joint bleedings when combined with loading of the affected joint resulted in features of progressive degenerative joint damage, whereas similar joint hemorrhages without joint loading did not. This might reflect a possible mechanism of joint damage in hemophilia.

Phenotypic variability is well recognized in severe hemophilia A. A few studies, mainly in adults treated lifelong on demand, suggest that bleeding phenotype correlates with factor VIII gene (F8) mutation type. Because treatment regimens influence outcomes to a large extent, examining bleeding phenotype during the first years of life may be the most suitable way to define this variability. We set out to analyze the very early phenotypic expression of severe hemophilia A in 621 consecutively enrolled, well-characterized previously untreated patients and to correlate this with patients' F8 mutation. Detailed information was collected on bleeds and treatment of the first 75 exposure days or until inhibitor development. F8 mutation type was known for 531 patients; 402 had null mutations and 129 had non-null mutations. Considering only patients who had not started prophylaxis or developed an inhibitor before select bleeding events, we found that patients with null mutations experienced their first bleed and first joint bleed at younger median ages than patients with non-null mutations (9.7 vs 10.9 months and 13.8 vs 16.1 months, respectively). We conclude that F8 mutation type accounts for only a small component of the significant phenotypic variability found among patients with severe hemophilia A. [ABSTRACT FROM AUTHOR]

Prophylactic treatment in severe hemophilia is very effective but limited by cost-issues. The implementation of two different prophylactic regimens in the Netherlands and Sweden since the 1970s may be considered as a 'natural experiment'. We compared costs and outcome of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (FVIII/IX <1IU/dl) born 1970-1994 using prospective standardised outcome assessment and retrospective collection of cost data. 78 Dutch and 50 Swedish patients, median age 24 (range14-37) were included. Intermediate-dose prophylaxis used less factor concentrates [median (IQR) Netherlands 2100 IU/kg/yr (1400-2900) vs Sweden 4000 IU/kg/yr (3000-4900); p<0.01]. Clinical outcome was slightly inferior for the intermediate-dose regimen (p<0.01): 5-year bleeding [median 1.3 (0.8-2.7) vs 0 (0.0-2.0) joint bleeds/yr] and joint health [HJHS score over 10/144 points in 46% vs 11%], while social participation and quality of life (EQ-5D) were similar. Annual total costs were 66% higher for high-dose prophylaxis: mean 180 (95%CI 163-196) × US$1000 USD for Dutch vs 298 (95%CI 271-325) × US$1000 USD for Swedish patients (p<0.01). At group level, the incremental benefits of high dose prophylaxis appear limited. At patient level, prophylaxis should be tailored individually and many patients may do well on lower doses of concentrate without compromising safety. [ABSTRACT FROM AUTHOR]