Clinical Aspects of and Therapy for Hemophilia A. Incidence. Clinical Severity, страница 13

Recombinant Factor VIII

Currently, there are three recombinant factor VIII products approved for clinical use, Recombinate (Baxter), Kogenate (Miles), and Bioclate (Armour). The final products are highly purified factor VIII, with a specific activity of approximately 7,000 U/mg protein prior to the addition of human albumin. Recombinant factor VIII has been shown to be safe and as efficacious as plasma-derived factor VIII concentrate, with similar recovery and half-life. MLID91061845  13,14,85 Major surgery has been performed using the concentrate, with excellent hemostasis.

Two ongoing clinical trials are evaluating inhibitor development in persons with hemophilia treated with recombinant factor VIII. The patients in these trials are those most at risk of inhibitor development: persons who have previously been untransfused, mostly infants. To date, 16 of 64 patients developed an inhibitor after a median of 9 exposure days. MLID93133254  86 Although this prevalence is high, in 9 of the 16 patients, inhibitors remained at low titer. In another study, 17 of 69 previously untransfused patients given recombinate by infusion developed inhibitors. MLID94220686  87 It is not clear whether recombinant factor concentrate leads to increased inhibitor development or inhibitor development at an earlier time. Previous studies showing inhibitor prevalences of 10–15% were cross-sectional cohort, not prospective studies in a high-risk group. Also, the patients were not monitored as closely for inhibitor development. Thus, these studies are difficult to compare.

Factor VIII: Recombinant Versus Plasma Derived

Who should receive recombinant factor concentrate?  There are many different opinions; ours is that this  product should be reserved for those persons with  hemophilia who are HIV-1 seronegative as well as HCV  seronegative (i.e., mostly young children). The product is  E$0.10/unit more expensive than the most expensive  plasma-derived high-purity product. In this era of  medical cost containment, price is a large issue. In addition,  the possibility of inhibitor development must be  discussed with the family or patient who will receive  recombinant factor VIII.

Cure of Hemophilia A

Liver transplantation currently offers a cure for hemophilia, albeit an impractical one. Persons with hemophilia A have undergone liver transplantation because of end-stage liver disease caused by HBV or HCV. In one of the first series (four patients with hemophilia A), three survived the initial surgery and then normalized their factor VIII levels, requiring no further replacement. MLID87214539  88 Additional patients with hemophilia A have since undergone liver transplantation; of those who survived, factor VIII levels have been normalized. In the future, gene replacement therapy may offer a hope of cure to all persons with hemophilia.

Genetic Counseling and Prenatal Diagnosis

The cloning of the factor VIII gene and the determination of its molecular structure allow detection of carriers and accurate prenatal diagnosis. Female relatives of individuals with hemophilia may be carriers of the abnormal gene, and therefore may be at risk of having children with hemophilia. Women who are considered obligate carriers are daughters of individuals with hemophilia and women who have one son and another relative with hemophilia. These women have a 50% risk of each newborn son having hemophilia. Women who have two sons with hemophilia are obligate heterozygotes. However, a small proportion of these women may be either somatic mosaics or germline mosaics. MLID90368079  89 Reproductive risk in these circumstances is difficult to assess and depends on the proportion of ova carrying the abnormal gene.