To cite this article: Konkle BA, Ebbesen LS, Erhardtsen E, Bianco RP, Lissitchkov T, Rusen L, Serban MA. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007; 5: 1904-13. Summary. Background: Hemophilic patients with factor VIII (FVIII) and FIX inhibitors suffer from frequent bleeding episodes and reduced quality of life. Objectives: To evaluate whether secondary prophylaxis with activated recombinant factor VII (rFVIIa) can safely and effectively reduce bleeding frequency as compared to conventional on-demand therapy. Methods: Thirty-eight male patients entered a 3-month preprophylaxis period to confirm high baseline bleeding frequency (mean ‡ 4 bleeds per month). Twenty-two patients were randomized 1:1 to receive daily rFVIIa prophylaxis with either 90 or 270 lg kg )1 for 3 months, followed by a 3-month postprophylaxis period. Results: Bleeding frequency was reduced by 45% and 59% during prophylaxis with 90 and 270 lg kg , respectively (P < 0.0001); however, there was no significant difference detected between doses. The majority of this reduction was maintained during the postprophylaxis period. Although all types of bleed were similarly reduced, the effect was most pronounced for spontaneous joint bleeds. Patients reported significantly fewer hospital admissions and days absent from work/school during prophylaxis as compared to the preprophylaxis period. No thromboembolic events were reported during prophylaxis. Conclusion: Clinically relevant reductions in bleeding frequency during prophylaxis as compared to conventional on-demand therapy were achieved without raising safety concerns. These results provide evidence for the concept of secondary rFVIIa prophylaxis in inhibitor patients with frequent bleeds.

In order to investigate hepatitis C virus (HCV) persistence and replication in peripheral blood mononuclear cells (PBMC) from a group of haemophilic individuals, HCV production and release to PBMC culture supernatants (SNs) from HCV singly infected patients and HIV/HCV co-infected patients was studied. HCV RNA + SNs were found more frequently from HIV/HCV co-infected individuals (89?5 %) with poor reconstitution of their immune status than from singly HCV-infected patients (57 %) or from HIV/HCV co-infected individuals with a good response to highly active anti-retroviral therapy (50 %). The presence of the HCV genome in culture SNs was associated with lower CD4 + T-cell counts and with a more severe clinical picture of HIV infection. In spite of prolonged negative HCV viraemia, PBMC from HIV/HCV co-infected patients released the HCV genome after culture. HCV permissive PBMC allowed generation of HCV productive B cell lines with continuous HCV replication. These findings add further weight to the involvement of PBMCs in persistence of HCV infection and emphasize the role of B lymphocytes as HCV reservoirs.

With the introduction of safe and effective factor VIII/IX-bypassing agents--recombinant activated factor VII (rFVIIa) and plasma-derived activated prothrombin complex concentrates (pd-APCC)--elective orthopaedic surgery (EOS) is a viable option for haemophilia patients with inhibitors. We report a series of patients with haemophilia and inhibitors undergoing EOS between 1997 and 2008 using bypassing agents to provide haemostatic cover. All inhibitor patients undergoing EOS and receiving rFVIIa, plasma-derived prothrombin complex concentrates (pd-PCC) or pd-APCC as haemostatic cover were included. Patients were operated on by the same surgeon and were managed by the same haemophilia treatment centre. Forty procedures (25 minor and 15 major) were conducted in 18 patients. Twenty-one minor cases were covered using rFVIIa, three with pd-PCC, and one with pd-APCC; all major cases were covered using rFVIIa. Bleeding was no greater than expected compared with a non-haemophilic population in all 25 minor procedures. In the major procedure group, there was no excessive bleeding in 40% of cases (6/15) and bleeding completely stopped in response to rFVIIa. For the remaining nine cases, bleeding response to rFVIIa was described as 'markedly decreased' or 'decreased' in 4/15 cases and 'unchanged' in 5/15 cases. Overall, efficacy of rFVIIa, based on final patient outcome, was 85%. One death occurred as a result of sepsis secondary to necrotizing fasciitis. Good control of haemostasis can be achieved with bypassing agents in haemophilia patients with inhibitors undergoing minor EOS; rFVIIa was used as an effective bypassing agent, enabling EOS in patients undergoing minor and major procedures.

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