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Background: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors., Methods: This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102., Findings: Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported., Interpretation: Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia., Funding: Sanofi., Competing Interests: Declaration of interests GY reports grants from Genentech/Roche, Grifols, and Takeda; and speaking and consultancy fees from Apcintex, BioMarin, Genentech/Roche, Grifols, Hema Biologics/ Laboratoire français du Fractionnement et des Biotechnologies biomedicaments, Novo Nordisk, Pfizer, Rani, Sanofi, Spark, Takeda, and UniQure. AS reports membership on advisory committees or grant review committees for Sanofi, Takeda, Novo Nordisk, Roche, Pfizer, and Bayer Healthcare and reports research funding from Roche, Novo Nordisk, Sanofi, and Pfizer. KK reports grants and consultancy fees from Novo Nordisk, Roche, and Takeda. JSa is the president of the Malaysian Society of Patient Blood Management. HT reports grants or honorarium from Sanofi, Takeda, Roche, and CSL Behring. SP, ZQ, and SK are employees and equity holders in Sanofi. BM was an employee and equity holder in Sanofi at the time of the study and has divested equity in Sanofi in the past 24 months; he is an employee of Editas Medicine. SA is an employee and equity holder in Sanofi, and a member of the WEST advisory committee. SR reports consultancy fees from Reliance Life Sciences; grants for conference attendance from Takeda; and fees for attendance at advisory board meetings from Pfizer, Sanofi, Sigilon, and Takeda. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Spontaneous bleeding into the joints is common in haemophilia. Recurrent intra-articular bleeding leads to joint destruction. In the past 4 years we have carried out sixteen total knee replacements for haemophilic arthropathy. In three patients there was persistent bleeding with haemarthrosis, manifest skin discolouration, severe pain, and swelling, which was caused by a periarticular aneurysm., Methods: Using angiography as part of the preoperative preparation, we initiated a prospective study. Ten angiographic examinations (six preoperative, two postoperative, one both) were carried out in seven patients without major complications., Findings: In seven of the ten angiographic examinations, three preoperative and four postoperative, we found aneurysms around the knee. Since the patients with a positive postoperative finding did not have preoperative studies, we do not know whether the aneurysms existed before surgery., Interpretation: Aneurysms can cause increased bleeding and other complications. The occurrence of spontaneous periarticular aneurysms in haemophilia has not been explored. In these cases, the resultant bleeding led to serious clinical symptoms that were not responsive to conservative measures. This new finding is relevant to those who surgically treat haemophilia patients. Angiography--and, when indicated, embolisation--before total knee replacement proved simple and effective as a diagnostic and therapeutic procedure.

A radioimmunoassay was used to detect antibodies to hepatitis C virus (anti-HCV) in 154 patients with haemophilia. Prevalence of anti-HCV was associated with exposure to clotting factor concentrates. 76 of 129 (59%) who had received factor VIII or IX had anti-HCV: 42 of 55 (76%) who required over 10,000 units of concentrate annually had anti-HCV, compared with 34 of 74 (46%) who required less, and 0 of 25 patients who had never received concentrates. Anti-HCV were significantly more common in patients seropositive for antibodies against human immunodeficiency virus (anti-HIV) or with markers of previous hepatitis B infection than in those without anti-HIV or hepatitis B markers (88% vs 39% and 75% vs 46%, respectively). 5 of 23 (22%) haemophiliacs treated only with heated concentrates had anti-HCV compared with 71 of 106 (67%) patients who received unmodified products. 35 patients with chronic liver disease underwent liver biopsy: histological examination showed features associated with post-transfusion hepatitis in 24, all of whom were anti-HCV-positive; of the other 11 patients with no histological features of non-A, non-B hepatitis, 5 were anti-HCV-positive. HCV appears to be the major predisposing factor for most non-A, non-B hepatitis and chronic liver disease in haemophilia.

A questionnaire concerning the occurrence of acquired immunodeficiency syndrome (AIDS) and possible related clinical syndromes in treated haemophiliacs was sent to directors of 201 European haemophilia centres. 135 replies were received from eighteen countries, covering 8928 patients with haemophilia A, 1889 with haemophilia B, and 2330 with von Willebrand's disease treated with blood products per year; 8 cases of AIDS were identified, one of which was in a patient with haemophilia B; 7 suffered from infections and 1 from pleomorphic non-Hodgkin's lymphoma. 3 other patients with lymphoma were recorded. The median age was 20 years with range 12-57 years and 3 were aged 14 years or less; 3 of the patients had died. 179 patients with other possible immunological disorders were recorded including 86 with lymphadenopathy but 70 of these occurred at one centre. At least 48 patients with thrombocytopenia were identified, suggesting that this condition is more common in treated haemophiliacs than is "idiopathic thrombocytopenic purpura" in the general population. None of the abnormalities could be related to use of any particular type of factor VIII concentrates. These results, together with 3 cases of AIDS previously reported and not returned in this study, point to an incidence of 11 cases in 13 000 treated haemophiliacs.