International Journal of Laboratory Hematology The Official journal of the International Society for Laboratory Hematology

REVIEW

INTERNAT IONAL JOURNAL OF LABORATO RY HEMATO LOGY

Acquired hemophilia: a case report and review of the literature S. M. N. MULLIEZ*, A. VANTILBORGH † , K. M. J. DEVREESE*

*Coagulation Laboratory, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium † Department of Hematology, Ghent University Hospital, Ghent, Belgium Correspondence: Prof. Dr Katrien Devreese, Coagulation Laboratory, Laboratory for Clinical Biology, Ghent University Hospital, De Pintelaan, 185 (2P8), B-9000 Ghent, Belgium. Tel.: 00 32 9 332 65 67; Fax: 00 32 9 332 49 85; E-mail: katrien.devreese@ uzgent.be doi:10.1111/ijlh.12210

Received 27 December 2013; accepted for publication 24 February 2014 Keywords Acquired hemophilia A, factor VIII inhibitor, autoantibodies, bleeding, diagnosis

S U M M A RY

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). FVIII autoantibody is characterized as polyclonal immunoglobulin G directed against the FVIII procoagulant activity. This disease occurs most commonly in the elderly population and with preponderance of men in nonpregnancy-related AHA. There are well-established clinical associations with AHA such as malignancy, other autoimmune diseases and pregnancy. However, up to 50% of reported cases remain idiopathic. The clinical manifestation of AHA includes mostly spontaneous hemorrhages into skin, muscles and soft tissues, or mucous membranes. AHA should be suspected when a patient with no previous history of bleeding presents with bleeding and an unexplained prolonged activated partial thromboplastin time. The diagnosis is confirmed in the laboratory by the subsequent identification of reduced FVIII levels and FVIII inhibitor titration. There is a high mortality, making prompt diagnosis and treatment vitally important. The principles of treatment consist in controlling the bleeding and eradicating the inhibitor. Because of the overall high relapse rate (15–33%), it is also recommended to follow up these patients. The review summarizes what is currently known about the epidemiology, pathogenesis, clinical features, diagnosis, treatment and prognosis of AHA and starts with a case report.

CASE A 87-year-old woman was admitted for spontaneous development of hematomas on the right leg and both feet since 5 weeks. She also complained of tiredness and dizziness. We noticed in her medical history atrial fibrillation, myocardial infarction, gastrointestinal bleeding based on prepyloric ulcers, thrombosis of A. poplitea, and serious osteoporosis. 398

At presentation, the complete blood count revealed a white blood cell (WBC) count of 8.6*109/L (normal range, 4–10*109/L), platelet count of 185*109/L (normal range, 149–409*109/L), and hemoglobin of 58 g/L (normal range, 117–157 g/L). The coagulation results showed a prolonged activated partial thromboplastin time (aPTT) of 87.3 s (normal range, 28.9–38.1 s), and prolonged prothrombin time of 46% (normal range, 70–120%) with an INR of 1.78 (normal range, © 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 398–407

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09–1.1). The temporarily deregulated INR is due to the recently stopped oral anticoagulants. The nature of aPTT prolongation was studied by mixing the patient’s plasma with normal pooled plasma (NPP). Failure of correction on aPTT mixing study supported the presence of an inhibitor and prompted further evaluation of individual clotting factors. There was reduced factor VIII activity (1%) and a high titer of factor VIII inhibitor [150 Bethesda Units (BU)]. The patient was initially transfused with four units packed cells (PC) to correct her anemia. During hospitalization, the patient was syncopal, with low blood pressure, and developed spontaneous large muscular bleeding in the gluteal region. Once the diagnosis of acquired hemophilia A (AHA) was made, the patient was treated with recombinant activated factor VII (rFVIIa, Novosevenâ RT; Novo Nordish Inc., Plainsboro, NJ, USA) and Factor Eight Inhibitor Bypassing Agent (FEIBAâ; Baxter Healthcare Corporation, Westlake Village, CA, USA) to control the active bleeding. Corticosteroids (Medrol 32 mg 29/day) were initiated to eliminate the inhibitor. After 55 days, the inhibitor had disappeared, FVIII activity was 180%, and aPTT normalized (30.5 s). The corticosteroid dose was tapered and completely stopped 4 months after disappearance of the inhibitor. One year and 4 months later, the woman was readmitted with melena since 3 days. She was also syncopal and had a low blood pressure. The laboratory tests revealed WBC 7.1*109/L, platelets count of 324*109/L, hemoglobin of 75 g/L, and aPTT of 73.9 s. The patient relapsed, with FVIII activity of 2%, and

Figure 1. Results of activated partial thromboplastin time (aPTT – seconds) and factor VIII activity (FVIII -%) of the patient over a period of almost 3 years. On day 0, she was first diagnosed with acquired hemophilia A; 1 year and 4 months later, she relapsed (day 498).

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presence of FVIII inhibitor (4.6 BU). Initially, she was treated with PC, rFVIIa, and corticosteroids. The corticosteroids were continued until eradication of the inhibitor (after 14 days). Figure 1 presents the results of the patient’s aPTT and FVIII level over a period almost 3 years including the two periods of AHA.

EPIDEMIOLOGY Acquired hemophilia A (AHA) is a rare but clinical significant entity. The reported incidence ranges between 1.20 and 1.48 cases per million/years and was reported from three cohorts: a large Australian hemophilia center cohort collected over 12 years (1997–2008) based in South Australia, a cohort of patients diagnosed with AHA in South and West Wales between 1996 and 2002, and 2-years (2001– 2003) national surveillance in the UK Haemophilia Centre Doctor’s Organisation [1–3]. But these data are likely to be underestimated because of undiagnosed and unreported cases, particularly in elderly patients. The incidence increases with age and is a rare occurrence in children [2, 4, 5]. However, the outcome in children seems more favorable than in adults because the inhibitors usually resolve more quickly and in a higher number of patients [5].

PAT H O G E N E S I S Factor VIII is a protein with a molecular weight of 265 kDa, and the sequence is composed of amino

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acids grouped into domains A1-A2-B (heavy chain) -A3-C1-C2 (light chain). The A2 and A3 domains have binding sites for activated factor IX, whereas the C2 domain binds von Willebrand Factor (vWF) and attaches the factor VIII molecule to the phospholipid membrane. Autoantibody inhibitors are most commonly directed against A2, A3, or, more frequently, C2 domain, while alloantibodies developing in congenital hemophilia are often directed against more than one site. Binding of antibody to these sites disrupts the function of the molecule [6]. Factor VIII autoantibody is usually characterized as polyclonal immunoglobulin (Ig) G and belongs mostly to IgG1 and IgG4 subclasses. However, monoclonal IgA or IgM antibodies have also been rarely described in patients with acquired hemophilia A [6–8]. CD4+ T cells play a central role in the humoral immune response to FVIII. The immune response to FVIII depends on a complex interaction between CD4+ T-cells subsets, Th1 (stimulate B cells to produce IgG1 and IgG2 antibodies) and Th2 cell (stimulate B cells to produce IgG4 antibodies). A predominance of Th2-driven anti-FVIII antibody is correlated with a more intense anti-FVIII antibody response and higher inhibitor titers, while successful immunosuppressive therapy in acquired hemophilia patients correlate with a predominance of Th1-driven inhibitor [9, 10]. Also the lack of recognition of certain immune-dominant CD4+ epitopes on FVIII domains seems to correlate with inhibitor formation [11]. A combination of genetic and environmental factors might lead to failure in immune tolerance and cause development of autoantibodies against FVIII. Some human leukocyte antigen (HLA) class II alleles and single-nucleotide polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA-4) have been observed in a higher frequency in AHA [12, 13]. The reaction kinetic of the interaction between factor VIII and the inactivating antibody in acquired hemophilia (autoantibodies) differs from the pattern seen in congenital hemophilia complicated by inhibitor development (alloantibodies). Most alloantibodies inactivate FVIII in linear proportion to their concentration (‘Type I’ or 1st order kinetics), whereas FVIII is completely inactivated if the inhibitor is present in excess and is saturated with FVIII. While most acquired autoantibodies have a nonlinear inactivation kinetic (‘Type II’ or 2nd order kinetics) with a rapid

initial inactivation phase followed by a slower phase and usually they do not completely inactivate FVIII, even at the highest concentration of inhibitor plasma. Consequently, the antibody and measurable levels of FVIII may be found simultaneously in circulation. There is a poor correlation between the factor VIII level and bleeding severity in AHA, as opposed to what is seen with congenital hemophilia [14]. Thus, when residual FVIII activity levels of up to 10% of normal range was observed in combination with a severe hemorrhagic picture, care should be taken not to underestimate the inhibitor [15].

PAT I E N T ’ S C H A R AC T E R I S T I C S Age, gender and seasonal variation The age distribution of autoantibodies is biphasic, with a large peak (>80%) of patients aged over 60 years but also a small population of younger women mainly because of the postpartum context [1, 2, 16]. The median age of 154 diagnosed patients in the prospective UK study was 78 years and 74 years in the largest available European cohort, the European Acquired Haemophilia (EACH2) Registry [2, 4, 16]. Overall, acquired factor VIII autoantibodies in non-hemophiliacs affect both sexes equally, although females constitute the majority of patients in the younger age group while males predominates over the age of 65 [2, 16– 19]. In the cohort from the EACH2 Registry, a marked excess of men presenting with nonpregnancy-related AHA is observed, with a male/female ratio of 1 : 0.73 and a median age of 74 years [16]. Also a monocentric cohort of 39 patients with AHA in France showed a predomination of males, with a male/female ratio of 1 : 0.44 [20]. There is no seasonal variation in the presentation of AHA reported [2, 16]. Underlying diagnosis According to recent data, in about 50% of cases, no underlying diagnosis that might have been associated with the development of factor VIII autoantibodies was identified (‘idiopathic AHA’) [2, 16, 17]. The likelihood of having an underlying disorder is inversely related to age [2]. There are well-established clinical associations with AHA such as malignant diseases (solid tumors and lymphoproliferative malignancies) © 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 398–407

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[21–23], other autoimmune diseases [24–27] and pregnancy. Other potential risk factors include exposure to drugs, blood transfusions, or infections [16, 28, 29]. These conditions are common in elder patients; it remains unclear whether these were causative or coincidental. The association between pregnancy and AHA is well known, and rates range from 2% to 21% [30]. The wide interval may reflect referral of this patient subgroup to specialist centers [16]. It occurs most frequently after the first delivery, in the EACH2 Registry was AHA associated with the first pregnancy in 31 of the 42 women (74%), in seven women with the second pregnancy (17%) and with the third and fourth pregnancy in two women each (5% each) [31]. Recurrence of the inhibitor in subsequent pregnancies is rare [19, 30, 32]. But in a cohort of 14 patients of United States and Canadian hemophilia centers, three patients had six subsequent pregnancies, and four of these pregnancies (66%) had an anamnestic response of the inhibitor [18]. Therefore, accurate follow-up and counseling of subsequent pregnancies is needed to identify recurrence of inhibitors because of risk of transplacental transfer of the IgG antibody (inhibitor) and potential fatal neonatal hemorrhage [33]. Most commonly, the inhibitor arises between 1 to 4 months after delivery, but cases have been reported to occur over a year after [30]. In the EACH2 Registry, the median interval between delivery and reported onset of bleed was 77 days [31]. In most cases, the potency of the inhibitor is low, with a relatively low inhibitor titer [18, 30]. This may explain why in the majority of cases the inhibitor disappears spontaneously after a mean period of 30 months making the prognosis of postpartum AHA is good in comparison with other forms of AHA, with low mortality rates (0–6%) [18, 30, 31, 34]. Bleeding pattern A major characteristic of AHA is the difference in bleeding pattern compared with congenital hemophilia. Bleeding symptoms in AHA may be spontaneous or occur after trauma. Most patients with autoantibodies against FVIII have hemorrhages into skin, muscles and soft tissues, or mucous membranes (e.g., epistaxis, gastrointestinal or urogenital bleeds). Cases of intracerebral bleeding are rare, about 1.1% reported in the EACH2 Registry [16]. From the © 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 398–407

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EACH2 Registry, a minority of patients (6.6%) was reported with no clinically significant bleeding at presentation, and severe bleeds occurred in 70.3% [16]. By contrast, hemarthroses, the hallmark of congenital hemophilia, is uncommon in AHA [2]. The reason for the difference in bleeding features between acquired and congenital hemophilia is not known [35].

D I AG N O S I S The diagnosis of AHA is most frequently suggested by the clinical picture and confirmed by laboratory investigation, although occasionally patients with no prior clinical evidence of bleeding are diagnosed on the basis of coagulation abnormalities during routine blood screens [2]. Therefore, a good communication and collaboration between clinicians and laboratory staff is important [36]. The most common laboratory abnormality is an isolated prolonged aPTT, with a normal prothrombin time (in absence of oral anticoagulant use, liver disease,. . .), normal thrombin time, and normal platelet count. The isolated prolonged aPTT may be due to a deficiency of one of the intrinsic coagulation factors (FVIII, IX, XI or XII) or indicate the presence of an inhibitor. It is also important to rule out nonspecific inhibitors (lupus anticoagulant (LA) or heparin) that could prolong the aPTT. The most common way to further investigate the cause of the prolonged aPTT and distinguish a factor deficiency from an inhibitor is to perform a mixing study. Mixing of the patient’s plasma with normal pooled plasma in a ratio of 1 : 1 will correct the aPTT to the normal range in the presence of a factor deficiency. But if the patient has an inhibitor to factor VIII, then the FVIII in het normal plasma will be inhibited and the aPTT will not be correct. There is no international consensus about the percentage of correction need to exclude the presence of an inhibitor [37]. The FVIII inhibitor does not normally inhibit FVIII in the normal plasma immediately, because FVIII inhibitor is a slow antibody and is time and temperature dependent. Therefore, mixtures should be incubated for 1–2 h at 37 °C, and immediate correction of the aPTT with normal plasma does not exclude AHA [36, 38]. If mixing test is compatible with an inhibitor, the FVIII activity should be measured. Of note, FVIII is the most labile of the procoagulant factors; therefore,

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correct preanalytical processing of the blood sample is very important [39]. If the FVIII activity is low, a FVIII inhibitor should be established. The inhibitor can be quantified using the Bethesda assay, which measures residual FVIII activity after incubation of normal plasma with serial dilutions of patient plasma for 2 h at 37°. The inhibitor titer in Bethesda units represents the reciprocal of the dilution of the patient’s plasma that produces 50% inhibition of FVIII [40]. The Bethesda assay was developed to quantitate the in vitro activity of FVIII alloantibodies, which have linear type I kinetics. Due to the nonlinear inactivation kinetic of the FVIII autoantibodies (‘Type II’), the use of Bethesda assay for titer determination for FVIII can cause problems [39, 41]. Experts recommend to report the inhibitor titer for dilutions of patient’s plasma that is closest to 50% inhibition of the normal plasma FVIII activity after a 2-h incubation [36]. The Nijmegen modification of the Bethesda assay uses a buffered normal plasma and FVIII-deficient plasma, instead of buffer, for diluting the normal and patient plasma. This modification is more expensive, but results in fewer false-positive results, because this assay avoids the pH shift and consequently avoids reducing protein concentration and the loss of FVIII activity [42]. The sensitivity of inhibitor testing may be improved, especially in patients with higher FVIII activity, by heating the plasma at 58 °C for 90 min. This procedure inactivates residual FVIII, without destroying antibodies, because inhibitor is more stable than FVIII [43, 44]. Nevertheless, the between-laboratory variation of FVIII inhibitor test in external quality surveys remains very high (variation coefficient of 40–60%) [45]. This shows the various problems encountered with the assays used in the quantitation of functional FVIII inhibitors. Several factors influence the results of inhibitors assays: the assay characteristics (pH, time, and temperature), the von Willebrand factor content of the test system, the nature of the control sample, and the possible presence of interfering factor (LA and heparin) [44]. Improvement of FVIII inhibitor assay results can only be reached when further standardization is implemented [45]. Figure 2 summarizes a diagnostic algorithm for the laboratory diagnosis of AHA. Remark, sometimes if high-titer FVIII inhibitors are present, activity of factors IX, XII and XII may be artificially reduced but, when the assays are repeated in

increasing dilutions of patient plasma, the true level of this factors will be found while the FVIII activity will remain low at all dilutions [39]. FVIII inhibitors can also be identified by immunoassays. Several immunoassays have been developed and have been used for FVIII inhibitor research but are generally not used for clinical diagnosis; however, the information they can provide may be useful. Different studies demonstrate a strong correlation between the Bethesda assay and an enzyme-linked immune sorbent assay (ELISA) [46–48]. In these studies, the ELISA assay found additional cases to be positive, which, however, were negative in Bethesda assay. The positive ELISA may be either due to the presence of natural antibodies without inhibiting activity or pick up lower-level inhibitors [46]. The clinical significance of noninhibitory antibodies that would be missed or underestimated by the Bethesda assay is not fully understood, but may be clinically significant, as they may shorten the survival of infused FVIII [48]. In contrast, immunoassays do not provide functional information (the capacity of the antibody to inhibit FVIII activity), and they can only detect the presence of the antibody. Some antibodies could be stronger neutralizing species even at lower levels binding IgG in the ELISA [39, 48]. The ELISA used in the studies detects IgG and will miss the rare cases where FVIII activity is blocked by an IgM or IgA antibody [46, 48]. An ELISA assay may be useful if a lupus anticoagulant is present [46]. Lupus anticoagulant may interfere with coagulation factor assays and potentially leading to misdiagnosis [49, 50]. Further study is needed to evaluate the utility of ELISA assays in detecting FVIII inhibitors for clinical diagnosis and to determine whether it is useful in following patients over time in response to therapy. The data from EACH2 Registry showed an inverse correlation between the inhibitor titer and the residual FVIII activity (Spearman, r = 0.47, P < 0.0001). Patients administrated with a bleeding effect had a significant lower FVIII activity and higher inhibitor titers at presentation than patient who were diagnosed by abnormalities of coagulation on routine blood screens [16]. However, the inhibitor titer or residual FVIII activity is not directly related to the severity of bleeding symptoms or mortality. Consequently, they are not useful as predicting factor, but the titers are useful to follow during treatment as a measure of efficacy of inhibitor eradication [2, 16]. © 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 398–407

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Isolated, prolonged aPTT

Confirm prolonged aPTT and exclude heparin contaminaon

Mixing test, 1:1 PP:NPP (37°C at me 0 and 2 h)

(at both intervals)

Weak or no aPTT correction

Suspect factor deficiency

Suspect inhibitor (LA or other)

Measure FVIII, IX, XI, XII

Assay for LA and FVIII, IX, XI

aPTT correction

Figure 2. A diagnostic algorithm for the laboratory diagnosis of acquired hemophilia A. An isolated, prolonged activated partial thromboplastin time (aPTT) is the key to the diagnosis of acquired hemophilia A and should be further evaluated. Heparin effect, factor deficiency (with a mixing test) and a lupus anticoagulant should be excluded. aPTT, activated partial thromboplastin time; PP, patient plasma; NPP, normal pooled plasma; LA, lupus anticoagulant; and F, coagulant factor.

Single factor deficiency

T R E AT M E N T The fundamental principles of treating AHA are to control bleeding and initiate immunosuppression to eradicate the inhibitor. Treatment of hemorrhage It is recommended to immediately initiate antihemorrhagic treatment in patients with AHA and active severe bleeding symptoms, but not all types of bleeding require intervention. Factor VIII levels or inhibitor titers do not help in guiding bleeding treatment [37, 51]. The first-line treatment of bleeding in AHA is with a bypassing agent. The two available treatments are recombinant activated factor VII (rFVIIa, Novosevenâ) and the activated prothrombin complex concentrate (aPCC, Factor Eight Inhibitor Bypassing Activity – FEIBAâ) [52–54]. Retrospective studies in AHA © 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 398–407

LA test negative AND isolated decreased FVIII (mostly time-dependent inhibion)

FVIII inhibitor titer (Bethesda method)

Acquired hemophilia A

LA test positive (immediate acting inhibion)

Lupus anticoagulant

Correlate with clinical presentation

Correlate with clinical presentaon

showed that the overall efficacy rate of both bypassing agents (rFVIIa and FEIBA) was about 90% [52, 54]. In the EACH2 Registry, rFVIIa was most frequently used as first-line therapy. But both bypassing agents showed similar (93%) rates of bleeding control [55]. Therefore, current guidelines support that initial bypass agent selection is based on availability and physician preference [36, 37, 51]. However, the use of bypassing agents is associated with risk of thrombotic events (myocardial infarction, stroke and venous thromboembolism) [56]. In EACH2 Registry, the incidence of thrombotic event is low, 2.9% and 4.8%, for rFVIIa and aPCC, respectively [55]. This risk is depending on patient co-morbidities; therefore, these drugs should be used with caution in the elderly and patients with underlying malignancy and cardiovascular disease. When the level of the inhibitor is very low and no bypassing agent is available, an alternative therapeutic

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strategy is the use of high doses of FVIII [37]. The response to this treatment is unpredictable and is more efficacious when used as a part of a multitreatment that includes immmunoadsorption to temporarily remove the inhibitor [56]. Desmopressin (DDAVP) may be useful in treating minor bleedings in patients with low inhibitor titer and basal FVIII levels above 5 IU/dL [57, 58]. But the use of desmopressin or factor FVIII should not delay the use of agents more likely to control bleeding. Data from the EACH2 Registry confirm a significant lower rate of bleeding control in patients receiving replacement therapy with FVIII concentrates or desmopressin than in those treated with bypassing agents (68.3% vs. 93.3%; P = 0.003) [55]. Antibody eradication Patients with AHA should receive immunosuppressive therapy to eradicate inhibitory autoantibodies immediately following the diagnosis, independent of bleeding severity [36, 37, 51]. The urgent treatment is needed because the risk of fatal bleeding persists until factor VIII antibody has been eradicated. The optimal therapeutic strategy to eradicate the inhibitor is unknown, but the current recommendations include immunosuppression with corticosteroids alone or corticosteroids in combination with cyclophosphamide [37]. Some meta-analyses reported a better response with steroid plus cyclophosphamide vs. steroid alone [59, 60]. However, no difference in overall survival was found, possibly due to the increased toxicity of cyclophosphamide [59, 60]. Therefore, it is necessary to consider the characteristics of the patient prior to initiating any antibody eradication therapy [56]. Alternative treatment options for inhibitor eradication are rituximab, immunoabsorbant or cytotoxic agents other than cyclophosphamide (calcineurin inhibitors, azathioprine, and vincristine). High-dose intravenous immunoglobulin (IVIG) alone or in combination with steroids is no longer recommended [36]. Immunoadsorption-containing protocols are only recommended in the context of life-threatening bleeding, especially in those unresponsive to bypassing therapy, or clinical research studies [36, 51]. Rituximab, anti-CD20 monoclonal antibody is suggested as a second-line treatment or salvage therapy,

when first-line treatment with steroids and cyclophosphamide is contraindicated [37]. Different studies of small cohorts of patients and a review demonstrated the usefulness of rituximab in the treatment of AHA [56, 61]. Two studies showed that only patients with a lower inhibitor titer (100 BU) achieved only complete response with addition of immunosuppressive agents [62, 63]. The recommendations indicate rituximab, when used in conjunction with steroid or cytotoxic therapy, as a safe and effective alternative first- or second-line therapy [56]. Calcineurin inhibitors (such as cyclosporine) are other potential second-line agents after cyclophosphamide failed to induce adequate response. Also studies from other alternate immunosuppressive treatment, such as azathioprine (mostly in combination with prednisone) or vincristine in a cyclophosphamide and prednisolone containing protocol, showed benefit for inhibitor eradiation, but data are limited [56]. Finally, immune tolerance induction protocols (ITI), like these used for the treatment of alloantibody inhibitors in patients with congenital hemophilia, have also been proposed for the eradication of autoantibodies. Different protocols are described for patients presenting with severe bleedings. The Budapest protocol, consisting of a combination of human FVIII, cyclophosphamide and methylprednisolone, resulted in eradication of the inhibitor in 13 of the 14 patients (93%) [64]. Similarly, the modified BonnMalmo protocol (MBMP), including FVIII, cyclophosphamide, prednisolone, large volume immunoadsorption, and IVIG, was highly effective in eradicating FVIII autoantibodies in about 90% of the cases [65, 66]. No relapse in 55 patients received MBMP was seen during a long-term follow-up of a median of 62 months, minimum 12 months [66]. Overall, the available data show potential, but it is not clear whether the addition of FVIII achieves any benefit. Therefore, immune tolerance is only recommended to be used in conjunction with clinical research trials to define the real benefit [36].

PROGNOSIS Bleeding in AHA is often severe; however, the reported overall incidence of fatal bleeding has © 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 398–407

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decreased. The reported bleeding mortalities in earlier studies are 9–22%, and recently 4% and 4.5% were reported, from the prospective French registry (Surveillance des Auto antiCorps au cours de l’Hemophilie Acquise – SACHA) and from EACH2 Registry, respectively [2, 16, 17, 67]. In the 2-year national surveillance study of the UK, gastrointestinal bleeds and pulmonary hemorrhages are generally the cause of early deaths (within first week), while later deaths are predominantly secondary to soft tissue bleeds such as intracranial and retroperitoneal [2]. The overall mortality rate has been estimated with a range between 7.9% and 33% [3, 17, 53, 67]. The EACH2 Registry demonstrated a significant lower mortality rate of younger patients (76.3 years; 43%). Different groups demonstrated that higher age is a significant independent predictor of death [2, 16, 60], whereas gender, initial factor VIII level and inhibitor titer at diagnose had no influence [2, 16]. The UK cohort revealed no association of the underlying diagnosis with outcome, while other cohorts showed an association. Pregnancy-associated AHA has a better prognosis, and the presence of a malignant disease has a higher mortality rate [2, 16, 60]. Lower hemoglobin levels at diagnosis had also a worse prognosis in the EACH2 Registry [16]. If the inhibitor is eradicated, relapses may occur in about 15–33% of cases [2, 3, 59]. In the EACH2 cohort, relapses before 1 year were described relatively common after treatment with steroids, either alone (18%) or in combination with cyclophosphamide (12%), but

REFERENCES 1. Collins P, Macartney N, Davies R, Lees S, Giddings J, Majer R. A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br J Haematol 2004;124:86–90. 2. Collins PW, Hirsch S, Baglin TP, Dolan G, Hanley J, Makris M, Keeling DM, Liesner R, Brown SA, Hay CR. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre

appears to be less common after a rituximab-based regime (3%) [59]. The median time to relapse is being 3–7.5 months after stopping immunosuppression [2, 16]. However, in SACHA registry, no relapses (n = 55) were observed during 1-year follow-up period [17]. In pregnancy-related acquired hemophilia relapse appears to be relatively rare [19, 30, 32, 51]. Because of the overall high relapse rate, it is recommended to monitor monthly the aPTT and FVIII levels during the first 6 months, then every 2–3 months up to 12 months and every 6 months during the second year and beyond, if possible [36].

CONCLUSION Acquired hemophilia A is a rare disease associated with bleeding complications that can be severe or even life threatening. Therefore, correct and fast diagnosis is critical, as early therapy to control bleeding and to eradicate inhibitor can be life saving. Routine coagulation screening blood test is the key to the diagnosis in AHA: an isolated, prolonged aPTT. Further laboratory investigations to rule out other cases of prolonged aPTT (a mixing test to exclude factor deficiency, tests to exclude heparin effect and a lupus anticoagulant) and identification of reduced FVIII levels with evidence of FVIII neutralizing activity (inhibitor titration) confirm the diagnosis of AHA. Once the diagnosis is made, adequate treatment should immediately start. A good collaboration between clinicians and laboratory staff is therefore important, particularly in patients without clinical evidence of bleeding.

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