Inhibitors in Hemophilia. Pathophysiology. Characterization and Properties of Inhibitors, страница 4

Although dosage is relatively arbitrary, in patients with inhibitor titers of <5 Bethesda units, 50 U of porcine factor VIII/kg should be given initially, and in patients with >5 Bethesda units, 50–150 U/kg MLID84080838 MLID89272459  60,63 (Kasper CK, personal communication). It is very important to monitor the level of factor VIII achieved in vivo following the infusion to determine the adequacy of the dose administered; if the initial dose is inadequate, rapid upward titration of the dose is important.

Several patients have had multiple courses of therapy with the porcine concentrate without loss of efficacy. In only the occasional patient have heterologous antibodies to porcine factor VIII developed. Classic anamnestic responses to porcine factor VIII occasionally occur, particularly in high responders who are infrequently treated. 61 In addition, a few cases of thrombocytopenia in response to the porcine concentrate have been reported, MLID89272459 MLID89116256  63,64 as has the occasional anaphylactic reaction. Mild febrile reactions are common and are easily modulated with prophylactic antihistamine and acetaminophen.

Management of Critical, Life-Threatening  Hemorrhages or Emergency Surgery In   Patients With Inhibitors

In an emergent situation with a critical hemorrhage or  with impending lifesaving surgery, both a high responder  and low responder should be initially treated with a bolus  infusion of the porcine factor VIII concentrate 100 U/kg.  Ten minutes after the infusion, blood should be drawn  for factor VIII assay in order to determine the adequacy  of the dose; if inadequate, the dose should be increased  by 50 U/kg, until the patient has a postinfusion factor VIII  level of 30–50%. Simultaneously, the preinfusion  antibody titer to both porcine and human factor VIII can be  determined. If the titer to porcine factor VIII is >10  Bethesda units and clinical efficacy has not been  established, plasmapheresis can be performed, followed by  a massive dose of porcine factor VIII. Once efficacy is  established, the patient should be treated at frequent  intervals or by continuous infusion at a dose of 1,000 U/ hr. Factor VIII levels should be monitored frequently. As  long as hemostatic levels are achieved, the porcine  concentrate should be continued for several days. If the  inhibitor titer begins to rise and hemostatic levels can no  longer be achieved, anti-inhibitor coagulant complex  concentrate or factor IX complex concentrate should be  used for several days.   

If the patient does not respond initially to porcine  factor VIII, anti-inhibitor complex concentrate may be  administered, starting at a dose of 100 U/kg. Factor VIIa is  currently available on a compassionate basis on research  protocol by the manufacturer.

Factor IX Complex Concentrate

If human factor VIII cannot be used because the inhibitor level is too high (>30 Bethesda units), an attempt may be made to bypass the need for factor VIII, by giving a factor IX complex concentrate. MLID79042000 MLID81270622 MLID80232757 MLID81270615 MLID84025044 MLID83075888  65–72 These concentrates contain phospholipids, prothrombin, and factors VII, IX, and X, but the substance(s) responsible for factor VIII bypassing activity remain(s) unknown. MLID79166675 MLID83283809  73,74 These concentrates are of two types: unactivated intermediate-purity factor IX complex concentrates; and activated concentrates, so-called anti-inhibitor coagulant complex. The activated concentrates (Autoplex [Baxter]; FEIBA [Immuno]), contain a greater amount of the factor VIII bypassing material and are specifically designed for patients with factor VIII inhibitors. Both types of concentrates have proved efficacious in controlled clinical trials, MLID81270615 MLID84025044  70,71 and no significant differences have been demonstrated. However, some patients have described successful use of anti-inhibitor coagulant complex in life-threatening situations in which the unactivated concentrates were ineffective. These concentrates should be distinguished from the highly purified factor IX concentrates used for the treatment of hemophilia B.