Bleeding before prophylaxis in severe hemophilia: paradigm shift over two decades

Prophylaxis for hemophilia is the scheduled infusion of the missing clotting factor with pre-specified dose, with the intention of preventing bleeds and subsequent hemophilic arthropathy. It is the treatment of choice for patients with severe hemophilia A in countries with available resources.1 Around the year 2000 it was reported that prophylaxis is most efficient when initiated early: before 3 years of age2 or directly after the first joint bleed.43 These strategies are reflected in the two most frequently used definitions of primary prophylaxis. The European Pediatric Network for Hemophilia Management (PedNet) first specified primary prophylaxis as starting before two years of age OR before the second joint bleed,5 and The World Federation of Hemophilia (WFH) as starting before the age of three years AND before the second joint bleed, in the documented absence of osteochondral joint disease.1

Early prophylaxis may require placing a central venous access device (CVAD) to facilitate frequent venous access, but these devices carry a risk of infections and thrombotic complications.6 In an attempt to reduce the need for CVADs while initiating early prophylaxis, Petrini and colleagues started prophylaxis with once-weekly infusions;72 many authors have subsequently published or recommended protocols starting with once-weekly infusions.108

The present study assesses how the increasing awareness of the importance of early prophylaxis affected bleeding before prophylaxis, CVAD use, initial prophylactic regimens, and achievement of primary prophylaxis.

Data on 919 patients with severe hemophilia A (FVIII<0.01 IU/mL), born 1990–2010, collected for the CANAL study11 (n=313) and the PedNet registry12 (n= 606) were used. Nine and 16 patients were excluded from CANAL and PedNet, respectively, because no treatment data were available.

Case report forms and inclusion and exclusion criteria were the same for both datasets.1211 Anonymized data on patients’ demographics, bleeding, and details on all factor administrations were collected by the participating centers until 1 May 2013. For the present analysis, patients were followed from birth until the 50 treatment day with FVIII or the development of a clinically relevant inhibitor, defined as at least two positive inhibitor titers, combined with a decreased in vivo Factor VIII recovery. Start of prophylaxis was defined as the regular infusion of FVIII at least once-weekly and continued for at least two months. Data were analyzed in 5-year birth cohorts. Most parameters had a skewed distribution and were, therefore, presented as medians and interquartile range (IQR). Trends over time were analyzed using univariable linear or logistic regression. Kaplan-Meier survival analysis was used to assess the occurrence of the first joint bleed and cumulative incidences of start of prophylaxis and CVAD use, while accounting for differences in follow up due to inhibitor development. Differences in survival curves across birth cohorts were assessed using the log rank test.