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Diagnosis and treatment of acquired hemophilia A
and non-linear type 2 kinetics and so the assay may not be able to estimate the true potency of the autoantibody.27 By consensus, the dilution closest to a 50% inhibition of FVIII in normal plasma is selected to estimate the inhibitor titer:28 1 Bethesda unit (BU) = the amount of inhibitor that neutralizes 50% of FVIII:C in normal plasma after incuba- tion for 2 h at 37°C. Sometimes several dilutions are close to 50%, introducing some uncertainty in assigning the inhibitor titer. LA may interfere with the Bethesda assay and cause low-positive results. Immunoassays to detect anti-FVIII antibodies may help to distinguish LA from FVIII inhibitors in such cases.13,29 The Nijmegen modifica- tion has been developed to improve specificity in the detection of low-titer inhibitors.30 Pre-analytical heat inac- tivation of test plasma may improve assay accuracy/sensi- tivity.31,32
Anti-porcine inhibitor titer
The porcine FVIII inhibitor titer should be quantified if rpFVIII is considered as a treatment option. The assay is performed in the same way as the Bethesda assay, but with rpFVIII as the substrate instead of normal human plasma. In the rpFVIII OBI-1 pivotal clinical trial, patients with an anti-porcine titer of >20 BU were excluded.15 Lower, albeit detectable, anti-porcine titers had implica- tions for dosing of rpFVIII (see the ‘Recombinant porcine FVIII’ section for more details).
Anti-factor VIII enzyme-linked immunosorbent assay
A commercial anti-FVIII ELISA was shown to be sensi- tive and specific for diagnosing AHA.13 It may be particu- larly helpful when interference with LA is suspected in a positive Bethesda assay, or if the Bethesda assay cannot be performed because rpFVIII has already been given. In addition, determining the anti-FVIII isotype may have prognostic implications, as shown for anti-FVIII IgA.11
We recommend confirming a diagnosis of AHA by testing FVIII activity and inhibitor concentration using the Bethesda assay and/or an anti-FVIII ELISA (GRADE 1B).
We recommend testing for anti-porcine inhibitors using a mod- ified Bethesda assay, if treatment with rpFVIII is an option (GRADE 1B).
Hemostatic treatment
Treatment of bleeds in patients with AHA should be car- ried out in a specialist center; if immediate referral is not possible, expert advice should be sought. The first priority is to control acute bleeds and to prevent injury, including iatrogenic, that may provoke further bleeding. Surgical interventions and other invasive procedures should be per- formed only at specialist centers, or with expert advice. If a central venous line is required, it may be preferable to use the femoral vein. Venipuncture should be performed by experienced staff, and blood pressure measured only as often as deemed clinically relevant. Fasciotomy for intra- muscular bleeds should be avoided because this can result in uncontrolled bleeding.33,34 Early hemostatic therapy may prevent compartment syndrome in most patients or even reverse symptoms of developing compartment syn- drome.35 In the EACH2 registry, the only parameter that differed between patients who responded to treatment and those who did not was a delay in time to treatment.8
The decision to initiate treatment is guided by the clini-
cal relevance of acute bleeds. Overall, approximately 70% of patients with AHA need hemostatic treatment. According to data from the UK and the EACH2 registry, approximately 30% of patients were untreated,2,8 appar- ently because they had no bleeds or only non-severe sub- cutaneous bleeds. However, close observation may be warranted because even fatal bleeding can occur up to 5 months after first presentation in patients with persistent inhibitors.2
A lack of correlation between FVIII:C or inhibitor titer and bleeding phenotype in AHA has been described in many studies.2,3,36 Inhibitor titer and FVIII:C should not therefore influence the decision to initiate treatment for clinically relevant bleeding.
Any hemostatic treatment is associated with a risk of arterial and thrombotic events, particularly in elderly patients and those with risk factors or recent thromboem- bolic events. Acute illness and immobility in bleeding patients with AHA is a risk factor for thromboembolism; however, controlling acute bleeds should usually be prior- itized.
We recommend that hemostatic treatment be initiated in patients with AHA and clinically relevant bleeding irrespective of inhibitor titer and residual FVIII activity (GRADE 1B).
Choice of first- and second-line treatment for acute bleeds
Parallel-group, comparative-treatment studies are not available in AHA. Propensity score-matched analysis of registry data on bypassing agents, including recombinant activated factor VII (rFVIIa; NovoSeven®) and activated prothrombin concentrate complex (APCC; FEIBA®), as well as a single-arm clinical trial on rpFVIII did not show a clear efficacy or safety benefit of one drug over the others.8,15,37 A similar analysis showed that the efficacy of human FVIII concentrates and desmopressin was clearly lower than that of bypassing agents in EACH2.8 Therefore, APCC, rFVIIa and rpFVIII can all be considered appropriate first-line treatments (Figure 2). The final choice will be influenced mostly by the anti-porcine titer, as well as availability, cost and ability to monitor rpFVIII.
We recommend the use of rFVIIa, APCC or rpFVIII instead of human FVIII concentrates or desmopressin for the treatment of clinically relevant bleeding in patients with AHA (GRADE 1B).
Patients should be closely monitored for treatment effi- cacy. Such monitoring is based mainly on clinical judg- ment. Depending on the bleeding site, serial blood count measurements, inspection and palpation of bleeding sites, patient-reported changes in pain or mobility, as well as imaging studies should be taken into consideration.38 When using rpFVIII treatment, monitoring of FVIII:C can also help to guide subsequent dosing, although clinical efficacy may not always correlate with FVIII:C.15 Depending on the severity of the condition, failure to improve bleeding symptoms or the appearance of new symptoms may indicate the need for treatment intensifi- cation or switching to one of the alternative therapies.
We recommend that alternative treatment strategies from among the first-line agents be used if appropriate initial treatment fails (GRADE 1C).
Recombinant activated factor VII
The efficacy of rFVIIa [eptacog alfa (activated)] in AHA was recently addressed in a systematic literature review.37 A total of 12 studies, reporting on 671 patients and 1,063
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