Inhibitors in Hemophilia. Pathophysiology. Characterization and Properties of Inhibitors, страница 3

4.  If the level of inhibitor against human factor VIII is  >10 Bethesda units but the level of inhibitor against  porcine factor VIII is much <10 Bethesda units, a large  dose of porcine factor VIII should be tried.

5.  If a patient has a moderately high inhibitor level of  10–30 Bethesda units to both porcine and human  factor VIII, the inhibitor level may be lowered by about  50–66% by a 1.5-vol plasmapheresis56 or  extracorporeal immunoadsorption, MLID81208665 MLID91165179 57,58 after which a large  infusion of factor VIII concentrate may achieve hemostatic  levels. Alternatively, patients with moderately high  inhibitor levels can be treated with factor IX complex or  with the porcine factor VIII concentrate (particularly if  the level of inhibitor against porcine factor VIII is <10  Bethesda units).

6.  If a patient has a very high inhibitor level (>30  Bethesda units), the only alternatives are factor IX  complex concentrates or the porcine concentrate.

General Considerations

The presence of an inhibitor in a hemophiliac, the titer of that inhibitor, and whether the patient is a low responder or high responder are important determinants of immediate and future therapy. Minor hemorrhage may respond to conservative measures, such as immobilization and compression. For a hemorrhage requiring blood product therapy, two possible choices are available: (1) raise the factor VIII level by infusion of human or porcine factor VIII and, if the inhibitor titer is moderately high, precede this therapy by maneuvers to lower the titer; or (2) infuse an agent that bypasses the need for factor VIII, such as factor IX complex concentrates or factor VIIa.

High-Purity Human Factor VIII Concentrate

High-purity human factor VIII may be used successfully in the treatment of critical hemorrhages in either low or high responders with low inhibitor levels (<5 Bethesda units) and in patients with moderate inhibitor levels (10–30 Bethesda units) after reduction of the inhibitor level by plasmapheresis or immunoadsorption. In order to neutralize the inhibitor and achieve a hemostatic level of 30–50 U/ml, an adult patient is given an initial bolus of factor VIII of 5,000–10,000 U, followed by a continuous infusion of 300–1,000 U/hr. Alternatively, a large amount of factor VIII can be given every 1–4 hours (20 U of factor VIII for each Bethesda unit plus an additional 40 U/kg). MLID91221500  59 Since the dose of factor VIII concentrate needed to neutralize inhibitors and provide a hemostatic level of factor VIII cannot be predicted by the inhibitor level, factor VIII levels need to be assayed frequently in order to monitor the plasma factor VIII level achieved in vivo. However, although blood drawn for assay even a few minutes later may not have a measurable factor VIII level by the time the blood is processed and the assay completed, the infused factor VIII may achieve in vivo hemostasis before it is inactivated.

In patients who are high responders and who sustain a critical hemorrhage, hemostasis should be achieved early, before the anamnestic response occurs. As the factor VIII inhibitor level rises after several days of factor VIII therapy, factor VIII should be continued at a frequent interval or continuously—hemostasis can be maintained because of the slow neutralization rate of factor VIII. MLID67093871  32

Porcine Factor VIII Concentrate

The suitability of a patient for porcine factor VIII depends partially on the degree of cross-reactivity of the patient's inhibitor with porcine factor VIII. The level of inhibitor to porcine factor VIII can be determined in the Bethesda test or the Oxford test by substituting porcine factor VIII for human factor VIII. Although the degree of cross-reactivity can vary widely from 0% to 75%, MLID84080838 MLID85041086 MLID89272459  60–63 on average it is usually about 25% (i.e., about 1 U of antiporcine factor VIII equals 4 U of antihuman factor VIII MLID84080838  60 (Kasper CK, personal communication). After treatment with porcine factor VIII, the degree of cross-reactivity increases. Thus, measurements of cross-reactivity are useful in predicting efficacy before the use of the porcine concentrate.