NEWER APPROACHES TO TREATMENT OF HEMOPHILIA AND VON WILLEBRAND’S DISEASE

Margaret V. Ragni, M.D., Director, Hemophilia Center Of Western Pennsylvania

INTRODUCTION

Hemophilia is an X-linked recessive disorder occurring one in 5,000 male births.  It is characterized by deficiency of coagulation factor VIII (hemophilia A) or coagulation factor IX (hemophilia B).  Clinical symptoms include hemorrhage, either spontaneous or traumatic, primarily in joints (hemarthrosis) or in muscles (hematoma).  In order to prevent chronic joint damage, pain, and disability, hemorrhages are treated early and often with repeat doses of factor VIII or IX concentrate therapy.  An individual with hemophilia typically has three or four hemorrhages per month and uses several hundred thousand units of factor replacement per year.  The goal of treatment has been to enhance safety while maintaining efficacy.

Since 1986, there has been no new HIV infection in the hemophilia population because of newer techniques of viral inactivation; these techniques include high temperature heating, vaor-heating, sp;vemt-detergent treatment, and monoclonal-antibody purification techniques.  Rare instances of hepatitis C have occurred with some of the heat-inactivated products.  This update summarizes what is known about (1) recombinant factor VIII contentrate, (2) solvent-detergent and monoclonally-repared factor IX concentrates, and (3) a factor VIII concentrate for von Willebrand’s disease.

recombinant factor VIII concentrate

A recently published study (Schwartz et al, NEJM, 323:800-5; 1990) has shown recombinant factor VIII (non-plasma derived) to be safe and efficacious in the treatment of hemophilia A.  Because the frequency of inhibitor formation to the infused factor was 12-15%, the product is still under review by the FDA.  Most of those who developed inhibitors have shown a reduction or disappearance of the inhibitor with cessation of the treatment.  Continued study of clinical inhibitor formation is recommended and will be necessary to resolve this safety issue.

factor ix concentrate products

Until recently, the only viral inactivation technique employed in the manufacture of factor IX concentrates was high-temperature heating at 50°C for 72 hours or vapor heating at 60°C for 20 hours in n-heptane.  However, in August, 1992, the FDA approved two new products for treatment of hemophilia B, Mononine and Alphanine-SD.  Mononine is a monoclonal-antibody purified factor IX concentrate.  The viral inactivation process for Mononine combines affinity-chromatography with ultrafiltration plus chemical inactivation.  It is similar to the process employed in the manufacture of the already marketed “monoclonal” factor VIII.  By virture of the affinity chromatography purification step, the product is “purer” with inactivation of all known viruses and only minimal levels of other clotting factors.  Thus, it is “safer” with regard to viral transmission and is preferred over the various heat-inactivated factor IX products.

A second factor IX product “Alphanine-SD” was also licensed in August 1992.  It is a solvent-detergent inactivated factor IX.  By virtue of the detergent inactivation step, Alphanine-SD prevents HIV and hepatitis C transmission.  In addition, it also prevents the rare complication of thrombosis, which has been attributed to activated factors present in standard factor IX concentrate.  Alphanine-SD is virtually devoid of activated factors and is the product of choice for factor IX deficient patients who require prolonged treatment, such as patients with a severe hemorrhage or those undergoing surgery.

It is important to note that, unlike the standard factor IX products, Mononine and Alphanine-SD products are not indicated for treatment of patients with inhibitors, replacement therapy for congenital factor II, VII, X deficiency states, or reversal of severe Vitamin K deficiency.  This is because the newer products lack coagulation factors other than factor IX.  For the latter conditions, the heat-activated (standard) factor IX complex concentrate which contains other activated factors is indicated.

factor VIII concentrate for von willebrand’s disease

In the past, patients with von Willebrand’s disease had only one choice for treatment, cryoprecipitate.  However, because cryoprecipitate undergoes only donor screening, but no viral inactivation step, it is a “less-preferred” product for factor replacement.  Safety can be increased by preparing cryoprecipitate from frequently retested, designated donors; however, this process is impractical for adult replacement requirements.  With the indroduction of desmopressin (DDAVP), mild and moderate von Willebrand’s patients (except those with IIB disease in whom DDAVP is contraindicated) may be treated with a non-plasma-derived treatment alternative.  Other than occasional flushing with infusion, DDAVP has been well-tolerated and efficacious.  Its use, however, is limited by tachyphylaxis with repeated dosing.  For von Willebrand’s patients who require surgery, a new factor VIII product, Humate P, which contains the high-molecular-weight von Willebrand’s multimers, is the preparation of choice.  Not only does Humate P markedly reduce the risk of viral transmission, through its chemical viral inactivation steps, it also allows for a significantly smaller volume of infusion than cryoprecipitate.

Copies of the Transfusion Medicine Update can be obtained by contacting Deborah Small at (412) 209-7320 or
by e-mail:  dsmall@itxm.org.