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Diagnosis and treatment of acquired hemophilia A
titer >20 BU. rpFVII was administered at an initial dose of 200 U/kg. Subsequent doses and dosing intervals were assigned by the treating physician based on the clinical response and FVIII:C measured, with the aim of maintain- ing FVIII:C >80% for severe bleeds of particular concern“ (e.g. severe mucous, intracranial, retro- or intra-abdominal, genitourinary, neck, traumatic or postoperative bleeds), and >50% for all other bleeds. Clinical assessment after 24 h indicated an effective response in 24/28 patients and a par- tial response in 4/28 patients. The bleeding was controlled at the time of the final dose in 24/28 (86%) patients. FVIII levels measured immediately after the first dose and 24 h later were 22−540% and 2−369% of normal, respectively. The presence of cross-reacting antibodies did not appear to affect the clinical response after 24 h, but patients with cross-reactivity needed higher doses in the first 24 h than patients without cross-reactivity (median 1,400 and 300 U/kg, respectively). Cross-reacting anti-rpFVIII inhibitors were found in 44% of patients in a recent study.49 A retro- spective study used a lower starting dose of 100 U/kg in six of seven patients given rpFVIII as second-line therapy, with five of these six patients achieving FVIII:C >100% after infusion (one patient had unmeasurable FVIII:C).50 Overall, treatment was effective in five of the seven patients. These data suggest that, although the approved initial dose for rpFVIII is 200 U/kg, an initial dose of 100 U/kg appears to be sufficient for most patients, and FVIII:C should be close- ly monitored to prevent excess FVIII:C. The baseline anti- rpFVIII titer may help to identify those patients for whom rpFVIII is unlikely to be efficacious.
In the pivotal trial, rpFVIII was well-tolerated in all patients.15 A total of 5/18 patients who did not have anti- rpFVIII inhibitors at baseline developed de novo anti- rpFVIII antibodies after 8−85 days, prompting discontinu- ation of the drug in two patients. No patient developed thromboembolic events.
For initial treatment with rpFVIII, we recommend the approved dose of 200 U/kg, followed by further doses to maintain trough levels >50% (GRADE 1B).
We recommend close monitoring of FVIII activity during thera- py with rpFVIII (GRADE 1B).
Human factor VIII concentrates and desmopressin
The 2009 international AHA recommendations suggest- ed the use of human FVIII concentrates or desmopressin only if therapy with bypassing agents was not available.1 In the EACH2 registry, an efficacy assessment of the treat- ment of first bleeding episodes could be performed in 288 patients, of whom 219 (76%) received bypassing agents and 69 (24%) received human FVIII or desmopressin.8 Patients administered human FVIII concentrates or desmo- pressin had higher initial FVIII levels, lower inhibitor titers, less severe bleeds and received tranexamic acid more often. When comparing propensity score-matched groups (n=60 per group), significantly lower efficacy rates were observed for treatment with FVIII or desmopressin (68%) compared with bypassing agents (93%). Of note, there was no matching for tranexamic acid use in this comparison. There may be a risk of fluid overload, heart failure and severe hyponatremia with desmopressin and it should not, therefore, be used in elderly patients.51
We suggest the use of recombinant or plasma-derived human FVIII concentrates only if bypassing agents or rpFVIII are unavailable or ineffective and the inhibitor titer is low. We recom- mend against the use of desmopressin (GRADE 1B).
Anti-fibrinolytics and other treatments
Some controversy persists regarding the use of anti-fib- rinolytic agents in conjunction with bypassing agents. Anti-fibrinolytic agents should be used with caution in patients treated with APCC.52 However, in a small case series of combination therapy of tranexamic acid with APCC, which included one patient with AHA, no throm- boembolic events or disseminated intravascular coagula- tion were reported.53 Combining tranexamic acid with rFVIIa has been of less concern traditionally.54 In the EACH2 registry, 17% of rFVIIa patients received ancillary anti-fibrinolytic therapy compared with only 5% of patients treated with APCC.8 In the GTH study, 32/102 (31%) patients received tranexamic acid, 63/102 (62%) received rFVIIa, and 21 (21%) received both concomitant- ly.10 Of the three fatal thromboembolic events observed in relation to rFVIIa, two occurred in the 21 patients receiv- ing concomitant tranexamic acid and rFVIIa.10 We, there- fore, suggest caution when combining tranexamic acid with bypassing agents. Topical tranexamic acid may be used as an alternative for some types of bleeding.
A plasma-derived, purified FVIIa/factor X concentrate (MC710, Byclot) is approved in Japan for the treatment of acute bleeds in patients with inhibitors against FVIII or FIX.55 Studies in AHA are not available.
Emicizumab is a recombinant, humanized, bispecific monoclonal antibody with FVIII-mimetic activity. It was recently licensed for prophylaxis in patients with hemo- philia A with or without inhibitors.56 The drug has been used in a few patients with AHA with severe bleeding.57,58 However, the safety and efficacy of emicizumab in AHA is unknown and so this antibody should not be used in this group of patients outside of clinical trials. This is par- ticularly relevant for elderly patients, in whom cardiovas- cular events are more common, and in women who are considering use of hormonal therapy or future pregnancy, as emicizumab is an IgG4 antibody and may therefore be transferred across the placenta. Given its long half-life of approximately 1 month, patients treated with emicizum- ab are exposed for up to 6 months after their last dose.
Invasive procedures
In patients with AHA, even minor invasive procedures can result in significant bleeding;36,59 therefore, particular caution should be exercised during all procedures and sur- gery and, if possible, they should be delayed until after the inhibitor has been eradicated. Use of a bypassing agent or rpFVIII is usually required for central venous access, taking biopsies or performing other invasive procedures.
We recommend the prophylactic use of bypassing agents or rpFVIII to cover minor or major invasive procedures (GRADE 1B).
Immunosuppressive therapy
Goals of immunosuppressive therapy and definition of remission
The goal of immunosuppressive therapy (IST) is to reduce the risk of bleeding by shortening the time to achieve remission of AHA. Spontaneous remissions have been observed in patients not treated with IST, but this outcome is unpredictable.60 Definitions of remission vary across studies and registries. The UK surveillance study defined complete remission as: FVIII normal, inhibitor undetectable, and immunosuppression stopped or
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