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2124 Part XII: Hemostasis and Thrombosis Chapter 123: Hemophilia A and Hemophilia B 2125

laboratory diagnosis is required for confirmation. Factor VIII inhibitors doses of 90 to 120 mcg per kilogram of body weight or higher every 2 to
are time and temperature dependent in vitro. The prolonged aPTT of 3 hours is safe and effective in most hemorrhagic episodes. The dosing
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the plasma of a patient without an inhibitor is corrected when mixed frequency is based on a factor VIIa plasma half-life of approximately
1:1 with normal plasma even after incubation at 37°C for 1 to 2 hours. 2 to 3 hours. The mechanisms of action of factor VIIa have been inves-
In contrast, the aPTT of a 1:1 mixture of plasma from a patient with an tigated using in vitro techniques. After coagulation is initiated by the
inhibitor and normal plasma is significantly prolonged after incubation tissue factor–factor VIIa pathway, factor VIIa at recommended doses
at 37°C for 1 to 2 hours. Specific diagnosis rests upon demonstrating that is hypothesized to activate factor X on the surface of activated plate-
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an appropriate dilution of the patient’s plasma, when added to normal lets, even in the absence of additional tissue factor activity. Factor Xa
plasma, specifically neutralizes factor VIII and not other blood clotting then can associate with factor Va and convert prothrombin to thrombin.
factors that influence the aPTT (i.e., factors IX, XI, XII, prekallikrein, Because activated platelets are localized to the site of vessel injury,
high-molecular-weight kininogen). The demonstration that the inhib- thrombin generation by factor VIIa is localized to the site of bleed-
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itor is specific for factor VIII distinguishes it from inhibitors of other ing. This process may account for the reported safety of factor VIIa.
clotting factors, for example, the lupus anticoagulant, and nonspecific Factor VIII inhibitor bypassing activity (FEIBA), a plasma-derived
inhibitors. A common assay used for inhibitor detection and quantifica- agent, has also been used successfully to treat bleeding episodes in
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tion is the Bethesda assay. In the Bethesda assay, the patient’s plasma inhibitor patients and is both safe and effective given at a recom-
is diluted such that, when the plasma is mixed with an equal volume of mended dose of 50 to 100 U per kilogram body weight every 8 to
normal pooled human plasma and incubated for 2 hours at 37°C, the 12 hours (not to exceed 200 U per kilogram per day).
factor VIII activity in the mixture is decreased by 50 percent. A modi- High-responder patients whose initial inhibitor titer is greater
fication of the Bethesda assay is the Nijmegen assay, in which buffer is than 5 BU usually do not respond to even very high doses of human
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used instead of factor VIII–deficient plasma. This method has shown factor VIII. Thus, recombinant factor VIIa or FEIBA should be used. If
to be more dependable at detecting low concentration of inhibitors. 78 these agents are not available, nonactivated prothrombin complex con-
Several approaches to treatment of factor VIII inhibitors are centrates or plasma exchange with high dose replacement factor VIII
available (Table 123–5). Use of these treatments requires knowledge of can be considered.
whether the patient with an inhibitor is a “high” or “low” responder and Low-Responder Patients Low-responder patients are arbitrarily
whether the bleeding episode requiring treatment is minor or major. 67 defined as patients whose inhibitor titer is less than 5 BU even after
High-Responder Patients Approximately 60 percent of patients a challenge with factor VIII. For major bleeding episodes, high doses
who have inhibitors are high responders. High responders are defined of human factor VIII can be used as recommended above. For minor
as patients whose inhibitor titer is higher than 5 Bethesda units (BU) bleeds, recombinant factor VIIa or FEIBA are recommended because
at baseline or whose initial inhibitor titer is less than 5 BU but rises some “low” responders may convert to high responders when they are
to greater than 5 BU after administration of factor VIII. Thus, high challenged repeatedly with factor VIII.
responders who are not treated with factor VIII for long periods may Nonactivated or activated prothrombin complex concentrates both
have a sustained high level of inhibitor, or they may have a very low to contain variable amounts of activated factors, including factors VIIa,
undetectable level of inhibitor until they are challenged with factor VIII. IXa, and Xa. The activated products have higher concentrations of acti-
Major bleeding episodes in a high-responder patient whose vated factors than do nonactivated products. FEIBA contains a complex
initial inhibitor titer is less than 5 BU can be treated with human of prothrombin and factor Xa that can bind to membrane surfaces and
factor VIII concentrate (see Table 123–5). When the initial titer is low, enhance thrombin generation in the absence of factors VIII or IX. 80,81
sufficient factor VIII can be administered in high doses to neutralize the Surgery in Inhibitor Patients The question of whether major sur-
inhibitor and attain adequate factor VIII levels for hemostasis. Although gery can be performed in patients with hemophilia A or B with inhib-
factor VIII inhibitor bypassing agents can be used (see below), they itors arises now that joint replacement is possible. Knee, ankle, hip,
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are not as reliable as factor VIII in achieving hemostasis, and their and elbow replacements have been carried out successfully in patients
effect cannot be adequately monitored with specific laboratory tests. If with inhibitor antibodies using bypassing agents. Basically, the patient is
factor VIII is used, a loading dose of 10,000 to 15,000 U may be required, given a loading dose of factor VIIa followed by bolus doses of factor VIIa
followed by up to 1000 U of factor VIII per hour, depending upon the and use of fibrin sealant and antifibrinolytic therapy until healing is
factor VIII level. One can expect an anamnestic response approximately complete. FEIBA has also been successfully used in surgery in hemo-
5 days after administration of factor VIII. philic patients with inhibitors. 83
In high-responder patients whose initial inhibitor titer is less than Immune Tolerance Removal of the antibody is the definitive goal
5 BU and who experience a minor bleeding episode, the agent of choice of inhibitor management. Plasmapheresis, adsorption of the antibody
is a factor VIII inhibitor bypassing agent. Recombinant factor VIIa in on an affinity column during plasma exchange, and administration of

TABLE 123–5. Treatment of Inhibitors in Hemophilia A Patients
Type of Patient Initial Titer Minor Hemorrhage* Major Hemorrhage*
High responder <5 BU Recombinant factor VIIa; FEIBA Factor VIII ; recombinant factor VIIa; FEIBA
†
High responder >5 BU Recombinant factor VIIa; FEIBA Recombinant factor VIIa; FEIBA; plasma exchange
Low responder <5 BU Recombinant factor VIIa; FEIBA High-dose factor VIII; recombinant factor VIIa; FEIBA

BU, Bethesda unit; FEIBA, factor VIII inhibitor bypassing activity.
*Choice of agents for treatment of major and minor hemorrhage are listed. Some physicians will choose the first product listed as the agent of
choice, but the choice varies among physicians.
† High dose of factor VIII may overcome an initial low-titer inhibitor, although an anamnestic response can be expected in high responders.
Data from Hoffman M, Dargaud Y: Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost 10(8):1478–1485, 2012.

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