Acquired hemophilia A: Diagnosis, etiology, clinical spectrum and treatment options Shrimati Shetty , Manali Bhave , Kanjaksha Ghosh Autoimmunity Reviews 10 (2011) 311–316 R4 신재령

Introduction AHA is a rare bleeding disorder - autoantibodies against endogenous factor VIII (FVIII) The reported incidence of AHA is 1.34–1.48 cases per million Year The reported mortality rate in AHA ranges from 9.7% to 33% The age distribution of autoantibodies is typically biphasic - small peak between 20 and 30 years, due to postpartum inhibitors, and a major peak in patients 68 to 80 years of age The incidence in men and women is similar except in the age ranges 20 to 40 years where the effect of pregnancy results in a tilt in the ratio with higher number in women

Etiology In 50% of cases, FVIII autoantibodies occur in patients lacking any relevant concomitant disease The remaining cases may be associated with postpartum period, autoimmune diseases (SLE, rheumatoid arthritis, thyroid disorders and so on), underlying hematologic or solid cancers, infections, vaccination or use of medications In malignancy associated AHA, there is no clear relationship between the type and extent of the tumor and the occurrence or severity of AHA

Genetic basis The study by Oldenberg et al. in 57 patients with AHA, shows significantly higher frequencies of the HLA class II alleles DRB*16 (OR 10.2) and DQB1*0502 (OR 2.5) when compared with controls Haemophilia 2010;16:41–5 In another study, the CTLA-4+49G allele was found to be increased in patients with AHA (OR 2.17) Haemophilia 2010;16:107–12

Characteristics of Inhibitor Antibodies Factor VIII Inhibitors are classically divided into Types I or II depending upon the kinetics of the inhibitor Type I FVIII inhibitors exhibit linear inhibition kinetics that are both time and concentration dependent Type II inhibitors show more complex kinetics and commonly seen with autoantibodies – seen in acquired haemophilia A Two patterns of reaction kinetics are seen. Inhibitors with “Type 1” or “simple” kinetics completely neutralize factor VIII and are neutralized themselves in the reaction. Most inhibitors in patients with hemophilia are Type 1. Inhibitors with “Type 2” or “complex” kinetics do not completely neutralize factor VIII and, after reaction, retain some ability to neutralize additional factor VIII. Although some factor VIII may remain measurable in the presence of type 2 inhibitors, the patient may bleed as profusely as if he had no factor VIII at all. The reason for this confusing presentation is unknown. Type 2 reaction kinetics are more common in autoantibodies than in allo-antibodies. The Bethesda assay is widely used to quantitate the concentration of a factor VIII inhibitor. 1 Bethesda Unit (Bu) is defined as the amount of an inhibitor that will neutralised 50% of 1 unit of FVIII:C in normal plasma after 120 minutes incubation at 37°C. Factor VIII inhibitors are time dependent (e.g. factor VIII) whilst others are immediate acting (e.g. factor IX) and there is no requirement for an incubation step. However, the basic principles are the same.

Characteristics of Inhibitor Antibodies FVIII inhibitors in AHA are mostly IgG1 and IgG4 autoantibodies acting with second-order kinetics and reacting with the same regions of the FVIII molecule (i.e., A2 and C2 domains) targeted by FVIII alloantibodies Most antibodies bind to the 44-kD A2 domain and/or the 72-kD C2 domain of factor VIII, and do not fix complement

AHA는 isolated Aptt prolongation과 factir VIII의 감소가 특징적인 소견으로, 이의 diagnosis를 위해 mixing study를 진행하게 됩니다. Mixing study는 time-dependent한 factor VIII inhibitor의 존재하는지 단순히 factor deficiency만 있는지 감별하게 되는데 환자의 plasma에 정상 plasma를 mixing해서 correction이 되면 factor deficiency로 생각할 수 있겠습니다. AHA에서 Inhibitors은 항상 time dependent하게 작용하지 않으며, immediate하게 작용할수 있는데 Lupus anticoagulant- mimic like FVIII inhibitors로 작용하여 coagulation factor의 감소를 가져오고, no correction of the baseline APTT will be seen immediately after mixing text plasma with normal plasma High phospholipid 시약을 사용하여 Aptt의 감소는 antiphospholipid antibody를 의미한다. Lupus anticoagulant (LA)는 phospholipid에 대한 항체의 일종으로서, 응고검사에서 phospholipid의 작용 억제하는 성질을 이용하여 phospholipid에 의존하는 응고검사의 응고시간을 연장시킴을 보임으로서 증명한다. It is important to distinguish anti-factor VIII inhibitors from the more commonly encountered antiphospholipid antibodies (or “lupus anticoagulant”). In such cases, no correction of the baseline APTT will be seen immediately after mixing text plasma with normal plasma. LA 진단은 (1) phospholipids 의존성 응고검사에서 연장소견을 보이고, (2) mixing test에서 억제효과 (연장된 응고시간이 mixing에서 교정되지 않음)가 있고, (3) phospholipids 의존성이 있어야 하고 (phospholipids 첨가시 연장된 응고시간이 교정됨), (4) 다른 응고인자를 억제하는 소견이 없어야 한다.

Bleeding manifestation Life-threatening hemorrhage occurs in about 9–22% of cases while mild bleeding, requiring no treatment, is seen in about 30% of cases Most patients have hemorrhages into the skin, muscles, or soft tissues and mucous membranes (e.g., epistaxis, GI and urological bleeds, retroperitoneal hematomas, and postpartum bleeding) Hemarthrosis, a typical feature of congenital FVIII deficiency, are uncommon The clinical phenotype in AHA does not correlate with the FVIII level or inhibitor titer The age and associated comorbidities generally influence the clinical phenotype and the risk of treatment-induced side effects

Haemostatic agents Recombinant factor VIIa (rFVIIa) Novoseven® By directly activating FX on the surface of activated platelets at the site of injury (thereby bypassing FVIII and FIX) A retrospective analysis by Hay et al. shows that 100% response in patients with AHA when rFVIIa was used as a first-line treatment and approximately about 75% response was observed when it was used at a late stage Thromb Haemost 1997;78:1463–7 rFVIIa is 90 mcg/kg every 2 h until the bleeding has been controlled

Recombinant factor VIIa (rFVIIa) Novoseven® Short half-life of 2.9 hours and dosing at intervals of 2–3 hours is necessary to maintain hemostasis The initial dose should be high enough to maintain a plasma level of FVII-coagulant activity (FVII:C) of > 6 U/mL for several hours Higher bolus doses of rFVIIa(> 200 µg/kg) may be more efficacious for the treatment of acute bleeding, further studies are needed to test this in a prospective manner and to clarify that thrombotic side-effects are, indeed, minimal

Recombinant factor VIIa (rFVIIa) Novoseven® In surgical cases, complicated bleeds or those bleeds in which treatment has been delayed, continuous infusion of rFVIIa can be considered Initial bolus dose of 90-120 µg/kg followed by continuous rFVIIa administration at an initial rate of 14-16.5 µg/kg/h Adjusting rates to the individual patient’s clearance rate, in order to maintain FVII:C levels above the presumed hemostatic trough of 10 U/mL The incidence of thrombotic events with the use of rFVIIa is extremely low. It appears to be lower than the thrombotic risk seen with other clotting factor concentrates, such as prothrombin complex con-centrates and FEIBA®

Activated prothrombin complex concentrates (aPCC) The only aPCC available is FEIBA®, which is a plasma-derived concentrate containing activated clotting factors (factors II, IX, and X) A retrospective study of 34 patients with AHA showed an overall complete response rate of 86% with a dosing regimen of FEIBA at 75 U/kg every 8–12 h with a median number of 10 doses to control severe bleeding Haemophilia 2004;10:169–73 FEIBA is given at a dosage of 50–100 U/kg every 8–12 h with a maximum dose of 200 U/kg/day until the bleeding has been controlled Currently, no assay is available to monitor response to FEIBA, making the duration of treatment dependent on clinical judgment

1-deamino-8-D-arginine vasopressin (DDAVP) DDAVP can provide a transient rise in factor VIII levels, most patients with mild hemophilia A Patients with AHA who have very low titer inhibitors (<3 BU) may have sufficient FVIII released to neutralize their autoantibodies In most patients with AHA, however, DDAVP treatment alone is insufficient to provide hemostasis. DDAVP at a dose of 0.3 mcg/kg intravenously may be useful in the context of minor bleeding episodes and very low titer inhibitors

Factor VIII concentrates If the level of the inhibitor is very low and no bypassing agent is available, hemostasis can sometimes be achieved with high doses of FVIII The response to this treatment, however, is unpredictable FVIII is more efficacious when used as part of multimodal treatment regimens that include immunoadsorption to temporarily remove the inhibitor The effect of antifibrinolytics in acquired hemophilia has also been reported by a few authors; however there are no guidelines or consensus on the dosage of EACA or tranexamic acid in these patients J Postgrad Med 1996;42:88–90 However, allergic side effects and a temporary drop in platelet counts can occur with the use of this product, which is limited to serious often life or limb threatening bleeding episodes. It is not used for routine treatment of bleeding episodes in inhibitor patients at home or in a clinic.

Eradication of inhibitors Steroids alone (1mg/kg) or combined with cyclophosphamide (1-2mg /kg) Different combinations of azathioprine, rituximab, high-dose immunoglobulin, cyclosporine A, immunoadsorption, vincristine and combination chemotherapy Quickly eradicating the inhibitor

Intravenous immunoglobulin (IVIG) The study by Schwartz et al. in 16 patients using a total dosing of 2g/kg over 2 or 5 days showed a response rate of 30% Blood 1995;86:797–804 Maximum response time was 40 days, and patients with lower initial Bethesda titers showed a better response Of note, some of these patients were receiving immunoglobulin as second-line therapy reasonable option for those patients who do not initially respond to immunosuppression

Immunoadsorption / Plasmapheresis Extracorporeal means to remove the autoantibodies to FVIII with either plasmapheresis or immunoadsorption with staphylococcal protein A Protein A is a staphylococcal bacterial cell wall component that binds certain s ubclasses of IgG and immune complexes This modality may be useful in bleeding or presurgical patients with high titer inhibitors who have failed to respond to bypassing agents Following pheresis or immunoadsorption, these patients should be treated with FVIII replacement to achieve hemostasis Protein A is a staphylococcal bacterial cell wall component that binds certain subclasses of IgG, other classes of mammalian immunoglobulins and immune complexes. protein A-bearing staphylococci as an extracorporeal immunoadsorbent to remove IgG and immune complexes

Immune tolerance induction ITI protocols - the eradication of autoantibodies Evidence of its effectiveness and safety has been demonstrated in patients treated by the Budapest protocol Haematologica 2000;85:64–8 Human FVIII concentrates (30 U/kg/day for the 1st week, 20 U/kg/day for the 2nd, and 15 U/kg/day for the 3rd week) plus Cyclophosphamide (200 mg/day to a total dose of 2–3 g) plus Methylprednisolone (100mg/day iv. for one week and then tapering down the dose gradually over two weeks)

Immune tolerance induction Eradication of the inhibitor occurred in 13/14 patients in the ITI against 4/6 patients in the control group who were treated with traditional immunosuppressive therapy Haematologica 2000;85:64–8 Similar results (complete response of 88%) have been reported with a modified Malmo protocol (immunoadsorption, high doses of FVIII, high-dose immunoglobulin, cyclophosphamide, and corticosteroids) Blood 2005;105:2287–93

Rituximab Promising new agent for the eradication of inhibitors The usual dose is 375 mg/m2 each week for 4 weeks Most responses are seen within the first 2 weeks of therapy The largest published study reported 10 patients and documented a complete remission in 8 of them Blood 2004;103:4424–8 The presence of high inhibitor titers (>100 BU/mL) was a negative prognostic factor for responsiveness to rituximab Some groups propose that rituximab should be included as first-line therapy - Rituximab + prednisolone (5-30 BU/mL) - In addition to cyclophospamide (>30 BU/mL) Haemophilia 2005;11:13–9 However, the concomitant immunosuppressive therapy in most reported cases limited the evaluation of the real effectiveness of this agent. the general consensus is that it should be considered in patients who are resistant to first-line therapy or cannot tolerate standard immunosuppressive therapy