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2184 Part XII: Hemostasis and Thrombosis Chapter 127: Antibody-mediated Coagulation Factor Deficiencies 2185

or absent factor VIII activity in the intrinsic pathway of blood coag- whereas those with titers greater than 10 BU/mL generally do not
ulation. The autoantibody inhibits the factor VIII in the plasma from respond. Formulas exist to calculate the amount of factor VIII needed
normal individuals, which forms the basis of mixing study that is used to treat a patient, but these are rough estimates at best. The efficacy of
to screen for inhibitors. The presence of a prolonged aPTT in a mixing factor VIII concentrates was lower than that of bypassing agents in a
study establishes the diagnosis of a circulating anticoagulant. Specific large registry study, which was likely secondary to challenges in appro-
factor assays then are performed to determine whether a specific coag- priately dosing the factor VIII concentrate. 48
ulation factor inhibitor or a lupus anticoagulant is present. The activity Desmopressin can be administered by intravenous, subcutaneous,
of other intrinsic pathway coagulation factors may be decreased in the or intranasal routes and results in an increase in plasma von Willebrand
presence of high titer factor VIII inhibitors. However, the levels of these factor levels and factor VIII activity. Its potential use is in patients with
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factors normalize at increasing dilutions of patient plasma, whereas fac- baseline factor VIII levels greater than 5 IU/dL and minor bleeding.
tor VIII activity remains decreased. However, like factor VIII concentrates, response is not predictable and
Once the identity of an inhibitor has been established, its titer is close monitoring of hemostatic efficacy and factor VIII levels is needed.
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determined using the Bethesda assay. Inhibitors frequently take min- Factor VIII bypassing agents, which drive the coagulation mecha-
utes to hours to maximally inhibit factor VIII. Therefore, dilutions of nism through the extrinsic pathway, are the mainstays of management
patient plasma are preincubated with normal plasma for 2 hours at of patients with a high titer of an inhibitor. Two agents, recombinant
37°C. The inhibitor titer is defined as the dilution of patient plasma activated factor VII (rFVIIa; NovoSeven RT) and plasma-derived anti-
that produces 50 percent inhibition of the factor VIII activity and is inhibitor coagulant complex (AICC; FEIBA VH Immuno, also called
expressed in Bethesda units per milliliter (BU/mL). Inhibitors are clas- activated prothrombin complex concentrate [aPCC]) are commercially
sified informally as low titer or high titer when the titers are less than available and approved by the U.S. Food and Drug Administration for
5 BU/mL or greater than 5 to 10 BU/mL, respectively. The Bethesda treatment of acquired hemophilia A. Although no comparative tri-
assay has been modified by the addition of 0.1 M imidazole, pH 7.4, and als have been done, analysis of the European Acquired Haemophilia
by diluting test plasma into factor VIII–deficient plasma during the pre- (EACH2) Registry showed similar hemostatic efficacy between rFVIIa
incubation phase to prevent assay variation resulting from pH changes and aPCC at approximately 90 percent. Similar hemostatic efficacy
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and adsorptive losses of factor VIII. This “Nijmegen” modification between rFVIIa and aPCC has been seen in the treatment of congen-
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of the Bethesda assay decreases false-positive low-titer inhibitors. ital hemophilia A with inhibitors. The recommended dose range of
Patients with acquired hemophilia often have measurable residual fac- rFVIIa for the treatment of patients with acquired hemophilia is 70 to
tor VIII activity. This activity may cause an underestimate of the inhib- 90 mcg/kg repeated every 2 to 3 hours until hemostasis is achieved.
itory titer. Preanalytical heat treatment has been proposed as a simple aPCC is given at doses of 50 to 100 U/kg every 8 to 12 hours, but should
way to denature factor VIII to allow for more accurate determination not exceed 200 U/kg per day. Lower doses (50 to 75 U/kg) are used for
of titer in both patients with acquired hemophilia A and patients with mild bleeding, whereas higher doses (100 U/kg) are given for severe
congenital hemophilia A who may have infused factor VIII. 53,54 limb or life-threatening bleeding. Treatment should be continued until
Factor VIII inhibitors are classified based on the kinetics and there are clear signs of clinical improvement.
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extent of inactivation of factor VIII in plasma. Type I inhibitors follow Although there are similar rates of efficacy between the two avail-
second-order kinetics and inactivate factor VIII completely, which able bypassing agents, not all patients respond. Additionally, there are
would be expected for a simple bimolecular antigen-antibody reaction. no widely accepted methods available for predicting response to ther-
Type II inhibitors inactivate factor VIII incompletely and display more apy or monitoring patients on therapy. The use of thromboelastography
complex kinetics of inhibition. Hemophilia A inhibitor patients and and the thrombin generation assays as a predictor of response to ther-
acquired hemophilia A patients tend to have type I and type II inhibi- apy in congenital hemophilia A and inhibitors has been reported but
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tors, respectively. However, the borderline between type I and type II large clinical studies linking clinical data to outcome are lacking, leaving
inhibitors is not always clear and the distinction is not useful clinically. clinical response as the only available monitoring option. 60
Additionally in a recent observational study of patients with acquired The major serious adverse event associated with bypassing agents
hemophilia in the United Kingdom, factor VIII levels and inhibitor is thrombosis. The EACH2 Registry reported similar rates in patients
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titers at presentation were not predictive of the severity of bleeding treated with rFVIIa or aPCC. However, the risk of thrombosis is con-
events. The median factor VIII level and inhibitory titers were nearly sidered low when used for approved indications at the recommended
identical for patients with fatal bleeding events compared to those who doses. The incidence of thrombosis in patients with acquired hemo-
did not require treatment for their bleeding symptoms. 2 philia A treated with bypassing agents appears higher than that for
patients with congenital hemophilia. This is probably because of car-
TREATMENT diovascular risk factors in the acquired hemophilia population given
their age and associated medical conditions. Escalating doses of either
The severe bleeding that often is the presenting feature of this disorder bypassing agent or combination of the two agents should be done with
requires urgent action to establish a diagnosis and initiate therapeutic caution, especially in older patients.
measures. Ideally, this is carried out in a setting where factor VIII inhib- Factor VIII inhibitors usually cross-react poorly with porcine fac-
itors can be identified and quantitated and where there is subspecialty tor VIII. A commercial plasma-derived porcine factor VIII concen-
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expertise in the management of bleeding disorders. Invasive procedures trate was useful in the treatment of factor VIII inhibitor patients for
should be performed only if absolutely necessary and venipuncture approximately 20 years, but was discontinued in 2004 because of viral
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should be kept to a minimum given the risk of significant bleeding. 57 contamination of the product. Porcine factor VIII has the advantage of
Treatment of patients with acquired hemophilia A depends on the potentially being guided by laboratory monitoring of recovery of factor
inhibitor titer. Although no prospective trials are available, clinical expe- VIII activity in plasma. However, the development of antiporcine factor
rience indicates that patients with a factor VIII inhibitor titer of less than VIII antibodies may preclude its long-term use. A phase II/III clinical
5 BU/mL often are treated successfully with sufficient doses of recombi- trial of a recombinant porcine factor VIII product has been completed
nant or plasma-derived factor VIII to neutralize the inhibitor. Patients in patients with acquired hemophilia A and a phase II trial has been
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with titers between 5 and 10 BU/mL also may respond to factor VIII, completed in congenital hemophilia inhibitor patients. 64

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