Inhibitor incidence after intensive FVIII replacement for surgery in mild and moderate haemophilia A: a prospective national study in the Netherlands

Abstract

SummaryInhibitor development is currently the most severe complication in mild/ moderate haemophilia A patients, causing increased bleeding tendency, hospitalization and mortality. It has been suggested that receiving high doses of factor VIII (FVIII) concentrates for surgical procedures is an important risk factor for inhibitor development in these patients. The current multicentre study aimed to determine prospectively the incidence of inhibitor development after intensive FVIII replacement therapy for surgical procedures in patients with mild/moderate haemophilia A. All consecutive patients with mild/moderate haemophilia A were included when they required at least 10 000 iu of FVIII concentrates (or 250 iu/kg) for 5 or more days for a surgical procedure. Potential clinical risk factors for inhibitor development and results of inhibitor tests were collected. Forty-six patients with a median age of 54 years (interquartile range, 40-59 years) were included in the study. F8 genotyping revealed 20 different missense mutations. Patients received either recombinant (65%) or plasma-derived FVIII concentrates (35%) by intermittent bolus injections (41%) or continuous infusion (57%). Two patients developed a low titre inhibitor postoperatively. The incidence of inhibitor development following intensive treatment for surgery in this unselected prospective cohort of mild/moderate haemophilia A patients was 4% (95% confidence interval, 0·5-14·8).

Bolnik S Hemofilijo v Sloveniji: Od Leta 1967 Do Danes

“…Še posebej moramo premisliti o umestnosti nadomestnega zdravljenja pri bolnikih z lahko HA, pri katerih hemofilijo povzroča t. i. rizična mutacija za pojav inhibitorjev. 10 Naloga vsakega HCCC, kar je v Sloveniji NCH, je tudi organiziranje celostne obravnave bolnikov s hemofilijo: testi za ugotavljanje prirojenih motenj strjevanja krvi, takojšen dostop do ustreznega nadomestnega zdravljenja, samozdravljenje oz. zdravljenje na domu, profilaktično zdravljenje, obravnava pri zobozdravniku, reševanje čustvenih, psihičnih in socialnih težav, genetsko testiranje in genetsko svetovanje, ugotavljanje inhibitorjev proti faktorjem strjevanja krvi in obravnava bolnikov z inhibitorji, zdravljenje pri drugih specialistih npr.…”

Inhibitors to Factor VIII: Mild and Moderate Hemophilia

“…In a prospective study in the Netherlands, the incidence of inhibitor development following intensive treatment with FVIII for surgery was 4% in 56 unselected patients with mild/moderate hemophilia [8].…”

“…Missense mutations in the light chain are more often (12%) associated with inhibitors than are missense mutations in other parts of the FVIII gene (3.9%) [16]. Clustering of the mutations in these regions has been confirmed in most other reported cases of mild/moderate hemophilia with inhibitor and some particular mutations such as Arg2150His and Arg593Cys seem to be overrepresented [1,8,9,11,12,[17][18][19][20]. In the series of Hay et al [1] seven out of nine mutations were clustered in a region at the junction between the C1 and C2 domain.…”

“…In the series of Hay et al [1] seven out of nine mutations were clustered in a region at the junction between the C1 and C2 domain. Other reported treatments have included immunomodulatory drugs such as corticosteroids, cyclophosphamide, anti-CD20 monoclonal antibody rituximab [8,[31][32][33][34], and avoidance of re-exposure to FVIII using desmopressin and bypassing agents to treat bleeding episodes [35]. Clustering of the mutations in these regions has been confirmed in most other reported cases of mild/moderate hemophilia with inhibitor and some particular mutations such as Arg2150His and Arg593Cys seem to be overrepresented [1,8,9,11,12,[17][18][19][20].…”

Current dosing practices for perioperative factor VIII concentrate treatment in mild haemophilia A patients result in FVIII levels above target

“…Known predictive factors for inhibitor development in mild haemophilia A patients include F8-mutation, total exposure to FVIII concentrates and a period of intensive FVIII concentrate treatment 3,5,[23][24][25]. Known predictive factors for inhibitor development in mild haemophilia A patients include F8-mutation, total exposure to FVIII concentrates and a period of intensive FVIII concentrate treatment 3,5,[23][24][25].…”