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Laboratory, clinical and therapeutic aspects of acquired hemophilia A
Clinica Chimica Acta 395 (2008) 14–18
Contents lists available at ScienceDirect
Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m
Invited critical review
Laboratory, clinical and therapeutic aspects of acquired hemophilia A Massimo Franchini a,⁎, Giovanni Targher b, Martina Montagnana c, Giuseppe Lippi c a b c
Servizio di Immunoematologia e Trasfusione, Centro Emofilia, Azienda Ospedaliera di Verona, Italy Sezione di Endocrinologia e Malattie del Metabolismo, Dipartimento di Scienze Biomediche e Chirurgiche, Università di Verona, Italy Istituto di Chimica e Microscopia Clinica, Dipartimento di Scienze Morfologico-Biomediche, Università di Verona, Verona, Italy
A R T I C L E
I N F O
Article history: Received 25 January 2008 Received in revised form 24 March 2008 Accepted 1 May 2008 Available online 8 May 2008 Keywords: Acquired hemophilia Factor VIII Inhibitor Hemorrhage
A B S T R A C T Acquired hemophilia A is a rare bleeding diathesis caused by autoantibodies directed against clotting factor VIII and associated with an increased morbidity and mortality. This disease occurs most commonly in the elderly, and although it may be associated with a variety of underlying pathological conditions, up to 50% of reported cases remain idiopathic. In this review, we report the present knowledge on the most important laboratory, diagnostic and clinical aspects of acquired hemophilia A. Moreover, we focus on the most recent advances in the treatment of this disorder, which is primarily aimed to control bleeding episodes and to eradicate the autoantibody production. © 2008 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . 2. Laboratory diagnosis and immunological aspects 3. Clinical manifestations of acquired hemophilia A 4. Treatment of acquired hemophilia A . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .
. . . . . . of acquired . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . hemophilia A. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Acquired hemophilia A (AHA) is an uncommon but life-threatening hemorrhagic disorder caused by the presence of autoantibodies directed against the coagulation factor VIII (FVIII) [1–7]. Patients with AHA represent a demanding clinical challenge. Indeed, the mortality rate in this condition is extremely high, ranging from 8 to 22%, and severe bleeds have been reported to occur in more than 85% of the patients [4].
⁎ Corresponding author. Servizio di Immunoematologia e Trasfusione, Centro Emofilia, Ospedale Policlinico, Piazzale L. Scuro, 10, 37134 Verona, Italy. Tel.: +39 045 8124321; fax: +39 045 8124626. E-mail address: [email protected] (M. Franchini). 0009-8981/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2008.05.003
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The incidence of AHA has been reported as 1.48 and 1.34 per million/year in two recent large studies from the UK [8,9]. It increases with advancing age, being a very uncommon condition in children [10]. Indeed its incidence in children under 16 years has been estimated to be 0.045 per million/year compared with 14.7 per million/year in elderly aged over 85 years [9]. However, it is also likely that this autoimmune disorder is underestimated, especially in elderly patients. The age distribution of autoantibodies is typically biphasic with a small peak between 20 and 30 years (post-partum inhibitors) and a major peak in patients aged 68–80 years. The incidence in males and females is similar except in 20–40 year olds where the effect of pregnancy results in a preponderance of females [5]. In approximately 50% of cases, FVIII autoantibodies occur in patients lacking of relevant concomitant diseases, while the remaining cases may
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be associated with post-partum period, underlying malignancies, medications use or autoimmune diseases (see Table 1) [11–32]. In this review we will summarize the most important laboratory, clinical and therapeutic aspects of this autoimmune hemorrhagic disorder. 2. Laboratory diagnosis and immunological aspects of acquired hemophilia A The diagnosis of AHA is based on demonstrating an isolated prolongation of activated prothrombin thromboplastin time (APTT), not corrected by incubating for 2 h at 37 °C patient's plasma with equal volumes of normal plasma (mixing study), associated with a reduced FVIII level and evidence of FVIII inhibitor activity in a patient with no previous personal or family history of bleeding [33]. Fig. 1 reports the laboratory algorithm for the diagnosis of AHA. Factor VIII inhibitor can be titrated using the Bethesda assay, which measures residual FVIII activity after incubation of patient plasma with normal plasma for 2 h at 37 °C, or its Nijmegen modification, which uses a buffered normal plasma and FVIII-deficient plasma, instead of buffer, to dilute normal and patient plasmas. This modification, stabilizing FVIII activity, gives fewer false positive results, although it is more expensive [34]. According to the Bethesda assay, inhibitors are classified at low (b5 Bethesda units [BU]/mL) or high (N5 BU/mL). However, before confirming the presence of FVIII inhibitor, the possible coexistence of heparin or lupus anticoagulant should be ruled out. The presence of heparin is suggested by a prolonged thrombin time with normal reptilase time, while a similar APTT prolongation of the mixture patient/normal plasma at time 0 and after incubation is indicative for lupus anticoagulant. Like the alloantibodies occurring in congenital hemophilia A, FVIII autoantibodies are characterized as being predominantly polyclonal, belonging predominantly to IgG1 and IgG4 subclasses. Moreover, both auto- and alloantibodies appear to react with the same regions on the factor VIII molecule (i.e., A2, A3 and C2 domains) thus interfering with its interaction with FIXa, phospholipids and von Willebrand factor [1]. The possible biological mechanisms explaining the inhibitor production in AHA have been recently elucidated and is has become evident that autoantibodies arise from failure of the immune tolerance mechanisms which regulate a normal immune response to FVIII [35]. In this context, FVIII-specific CD4+ T cells play a central role in the anti-FVIII antibody synthesis, as documented by the observation that inhibitors may spontaneously disappear in conjunction with an HIV-associated decline in CD4+ counts [36]. In particular, a complex
Table 1 Conditions associated with acquired hemophilia A Pregnancy Autoimmune disorders
Systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, temporal, arteritis, Sjögren's syndrome, autoimmune hemolytic anemia, Goodpasturesyndrome, myastenia gravis, Graves' disease, autoimmune hypotyroidism Solid cancers Prostate, lung, colon, pancreas, stomach, choledochus, head, neck, cervix, breast, melanoma, kidney Hematologic Chronic lymphocytic leukemia, non-Hodgkin's lymphoma, malignancies multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic syndrome, myelofibrosis, erythroleukemia Inflammatory bowel Ulcerative colitis diseases Dermatologic Psoriasis, pemphigus disorders Respiratory diseases Asthma, chronic obstructive pulmonary disease Diabetes Acute hepatitis B and C infection Drug-associated Penicillin and its derivatives, sulfa antibiotics, phenytoin, cloramphenicol, methyldopa, depot thyoxanthene, interferonalpha, fludarabine, levodopa, clopidogrel
Fig. 1. Diagnostic algorithm of acquired hemophilia A.
interaction between different CD4+ subsets, i.e. Th1 (stimulating B cells to produce IgG1 antibodies) and Th2 (stimulating B cells to produce IgG4 antibodies) cells, is implicated in the synthesis of antiFVIII antibodies. Indeed, a strong positive association between inhibitor titer and the proportion of Th2-driven IgG4 anti-FVIII antibody has been observed [37]. Thus, a predominance of Th2-driven IgG4 anti-FVIII antibody is correlated with a more intense anti-FVIII antibody response, with a high inhibitor titer and ultimately with a failure to eradicate the inhibitor. On the other hand, successful immunosuppressive therapy in acquired hemophilia correlates with a predominance of Th1-driven anti-FVIII antibody. Finally, the lack of recognition of certain immunodominant CD4+ epitopes on the FVIII A3 (sequence regions 1691–1710 and 1941–1960) and C2 (sequence region 2191–2210) domains seems also to correlate with inhibitor formation [38]. The most striking differences between auto- and alloantibodies are in their inactivation patterns. Most inhibitors in congenital hemophilia are “type 1”, in that there is linear inactivation when the logarithm of the residual FVIII:C activity is plotted against plasma concentration. These antibodies completely destroy all FVIII when present in high concentrations. A few autoantibodies have this pattern, but most have different “type 2” properties. “Type 2” inhibitors have a non-linear inactivation pattern and they do not completely inactivate FVIII, even at the highest concentrations of inhibitor plasma [39]. Thus, the Bethesda assay, which quantities the in vitro inhibitor titer, may underestimate the in vivo inhibitor potency, due to the non-linear complex reaction kinetics, and may complicate the therapeutic choice and monitoring. Consequently, particular care should be taken to not underestimate the inhibitor potency, since residual FVIII activity levels
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of up to 10% of normal can be observed in the presence of a severe hemorrhagic picture. 3. Clinical manifestations of acquired hemophilia A The clinical picture of AHA differs from that of “classical” hereditary hemophilia A. In fact, more than 80% of patients with FVIII autoantibodies have hemorrhages into the skin, muscles or soft tissues and mucous membranes (e.g. epistaxis, gastrointestinal and urological bleeds, retroperitoneal hematomas), whereas hemarthroses, a typical feature of congenital factor VIII deficiency, are unusual [4,9]. Not rarely the hemorrhages in AHA are serious or lifethreatening, such as in the case of rapidly progressive retroperitoneal hematomas or compartment syndrome due to intramuscular bleeds. Sometimes the disease becomes manifest dramatically by excessive bleeding following trauma or surgery or by cerebral hemorrhage [4]. In the study conducted by Collins et al. for the UK Haemophilia Centre Doctors' Organisation [9], the majority of the 149 patients with information on the presence or absence of bleeding symptoms, had subcutaneous, mucosal or soft tissue bleeds. In a recent study, we observed that the prognosis was worse in patients with a high inhibitor titer, low FVIII plasma levels and transfusional requirements [40]. The presence of an underlying condition different from post-partum, an age at diagnosis higher than 65 years, and the lack of achievement of a complete remission were the three independent worse prognostic factors identified by Delgado and colleagues in their meta-analysis [33]. Other clinical manifestations of AHA include prolonged postpartum bleeding. Post-partum AHA occurs most frequently after the first delivery. The majority of autoantibody inhibitors, especially those at low titer, disappear spontaneously after a median period of 30 months and usually does not recur with subsequent pregnancies. However, in a few cases the autoantibody may persist and cause lifethreatening hemorrhages in the subsequent fetus because of transplacental transfer of the IgG antibodies. The most serious clinical presentation is severe uterine bleeding during labor or delivery, although more frequently bleeding occurs during the post-partum period, between 3 and 150 days after delivery. A persisting autoantibody may precede the development of an overt autoimmune disorder [41]. Hauser and colleagues [42] reviewed 51 cases of post-partum inhibitors and found a considerable heterogeneity in the interval between delivery and onset of symptoms (most being within the first 3 months), the titer of inhibitors (between 5 and 200 BU/mL) and the severity of hemorrhages. Although there were 3 deaths, in 76.5% of cases the autoantibody disappeared. In a recent description of the results of the Italian register of acquired factor VIII inhibitors, Baudo and colleagues reported a median time of 60 days between delivery and the onset of significant bleeding and/or the identification of the inhibitor [43]. The authors observed a high rate of complete remission: in fact the autoantibody was eradicated from 14 out of the 18 patients (78%) who were treated with steroids alone or in association with other agents (cyclophosphamide, azathioprine or high-dose immunoglobulins). The good prognosis of pregnancyassociated AHA was also confirmed by Delgado and colleagues in their meta-analysis of data from 20 retrospective and prospective surveys of patients with acquired inhibitors against factor VIII [33]. In fact, these authors recorded only 1 death in the 34 cases of postpartum inhibitors collected. In the majority of the reported cases, the potency of the inhibitors was low and this accounted for the high percentage of spontaneous remissions and, thus, the good outcome of the post-partum inhibitor syndrome. 4. Treatment of acquired hemophilia A The appropriate pharmacological treatment of patients with AHA essentially depends on the natural history of any concomitant pathology
and the clinical presentation of coagulopathy [44–46]. Some patients, for instance those with post-partum or drug induced inhibitors, may require no treatment additional to close clinical observation, since these inhibitors tend to disappear spontaneously within a few months after delivery or drug discontinuation [47]. Conversely, in other cases the eradication of the associated disease may lead to the disappearance of the inhibitor [48]. The fundamental aspects of therapeutic strategy in patients with AHA are the treatment of bleeding episodes and the eradication of the autoantibody [44]. Two options are currently available for hemostatic control: the use of bypassing agents and strategies to raise the level of circulating FVIII. The choice of the most appropriate therapeutic strategy will depend on the site and severity of the bleed and patient characteristics [49]. Bypassing agents are currently the most used first-line treatment and both recombinant factor VIIa (rFVIIa) and factor eight inhibitor bypassing activity (FEIBA) have been shown to be effective in the treatment of AHA [5,50,51]. Indeed, in a retrospective analysis of 38 patients, Hay and colleagues [50] reported a good response in 100% of patients when rFVIIa was used as a first-line treatment, and a good response in 75% of patients when it was used as non-first-line treatment. In a retrospective study with FEIBA, Sallah reported a 100% of hemostatic efficacy for moderate bleeds and a 75% hemostatic control for severe bleeds [51]. Recently, Sumner and colleagues [52] collected the available data on the use of rFVIIa in acquired hemophilia patients from compassionate use programs, the Hemophilia and Thrombosis Research Society (HTRS) Registry and from the published literature. A total of 139 patients were treated with rFVIIa for 204 bleeding episodes. The overall efficacy rate (complete or partial) of rFVIIa was 88% (161/182 bleeding episodes valuable). rFVIIa as a first-line treatment was effective overall in 95% of bleeding episodes compared with 80% when it was used as salvage therapy after failure of other hemostatic agents. Regarding the possible therapeutic strategies aimed to raise the levels of circulating FVIII, human FVIII concentrate is usually an inadequate hemostatic therapy unless the inhibitor titer is low. Thus, patients with a low titer of inhibitor can be treated with human FVIII concentrates, which should be administered at a dose great enough to overwhelm the inhibitor so that hemostatic levels of factor VIII can be achieved [53]. While a number of formulae have been proposed for calculating the optimal dose of FVIII to administer, the inaccuracy inherent in the laboratory measurement of inhibitor titer in acquired hemophilia makes it a very approximate tool and a regular monitoring of plasma FVIII levels and clinical response are required. Similarly, Desmopressin alone or in association with FVIII concentrates may also be effective in patients with a low titer of inhibitor for the treatment of minor bleeding episodes [54]. In patients with a high titer of inhibitor and severe hemorrhages, the extracorporeal removal of the autoantibody by therapeutic plasmapheresis, or immunoadsorption of immunoglobulins to staphylococcal protein A or to polyclonal sheep antibodies against human immunoglobulins, can be used prior to factor concentrate treatment [55–57]. The eradication of inhibitor may also be obtained with immunosuppressive agents including corticosteroids and cytotoxic drugs such as cyclophosphamide, azathioprine, 6-mercaptopurine and vincristine [58–62]. In their meta-analysis combining data from 20 reports, Delgado and colleagues concluded that cyclophosphamide use was superior to that of prednisone in terms of inhibitor eradication but not in terms of overall survival [33]. The combined data available from uncontrolled cohort studies recently reviewed by Collins, suggested a benefit for combined steroids and cytotoxic agents) [47]. Also high-dose immunoglobulins and cyclosporin, alone or in combination with prednisone, have shown to be effective in acquired hemophilia and can be considered as a second-line therapy for those patients nonresponders to standard immunosuppressive regimens [63–66].
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More recently, biotherapy with the anti-CD20 monoclonal antibody rituximab has been also used to treat cohorts of patients with acquired hemophilia. The largest published study performed on 10 patients, documented a complete remission in 8 patients whereas the 2 non-remitters responded to subsequent intravenous cyclophosphamide [67]. A 100% of complete remission was observed in two other studies [68,69]. From then, several other reports on small cohorts of patients have documented the benefit of rituximab in acquired hemophilia [70–72]. We have recently reviewed the literature data and collected 65 patients with AHA treated with this agent [70]. A complete or partial response was reached in more than 90% of cases. The presence of high inhibitor titers (N100 BU/mL) was a negative prognostic factor for the response to rituximab. However, the concomitant immunosuppressive therapy in most cases reported limited the evaluation of the real effectiveness of this agent. Based on these results, Aggarwal and colleagues proposed a treatment algorithm with the use of rituximab in association with immunosuppressive agents [71]. Finally, immune tolerance induction (ITI) protocols, like these used for the treatment of alloantibody inhibitors against factor VIII or IX in patients with congenital hemophilia A or B, have been proposed also for the eradication of autoantibodies against coagulation factors [72]. In particular, a protocol consisting of a combination of human factor VIII, cyclophamide and methylprednisolone was highly effective for the eradication of FVIII autoantibodies in patients presenting with severe bleeding [73]. 5. Conclusions AHA is a heterogeneous condition from a pathogenic, clinical and therapeutic point of view. The progresses in the understanding of the biology of the disease and the development of novel treatment protocols have greatly contributed to the improvement of patient's prognosis. References [1] Cohen AJ, Kessler CM. Acquired inhibitors. Baillere's Clin Haematol 1996;9:331–54. [2] Morrison AE. Acquired haemophilia and its management. Br J Haematol 1995;89:231–6. [3] Hay CRM. Acquired haemophilia. Baillere's Clin Haematol 1998;11:287–303. [4] Boggio LN, Green D. Acquired hemophilia. Rev Clin Exp Hematol 2001;5:389–404. [5] Franchini M, Gandini G, Di Paolantonio T, Mariani G. Am J Hematol 2005;80:55–63. [6] Pruthi RK, Nichols WL. Autoimmune factor VIII inhibitors. Curr Opin Hematol 1999;6:314–22. [7] Hay CRM, Baglin TP, Collins PW, Hill FGH, Keeling DM. The diagnosis and management of factor VIII and IX inhibitors: A guideline from the UK haemophilia Centre doctors' organization (UKHCDO). Br J Haematol 2000;111:78–90. [8] Collins P, Macartney N, Davies B, Lees S, Giddings J, Maier R. A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br J Haematol 2004;124:86–90. [9] Collins PW, Hirsch S, Baglin TP, et al. UK Haemophilia Centre Doctors' Organisation. Acquired hemophilia A in the United Kingdom: A 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood 2007;109:1870–7. [10] Moraca RJ, Ragni MV. Acquired anti-FVIII inhibitors in children. Haemophilia 2002;8:28–32. [11] Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981;45:200–3. [12] Bossi P, Cabane J, Ninet J, et al. Acquired haemophilia due to factor VIII inhibitors in 34 patients. Am J Med 1998;105:400–8. [13] Yee TT, Pasi KJ, Lilley PA, Lee CA. Factor VIII inhibitors in haemophiliacs: A singlecentre experience over 34 years, 1964–97. Brit J Haematol 1999;104:909–14. [14] Solymoss S. Postpartum acquired factor VIII inhibitors: Results of a survey. Am J Haematol 1998;59:1–4. [15] Kashyap R, Choudhry VP, Mahapatra M, Chumber S, Saxena R, Kaul HL. Postpartum acquired haemophilia: Clinical recognition and management. Haemophilia 2001;7:327–30. [16] Trotta F, Baiocchi G, La Corte R, Moratelli S, Sun LY. Long-lasting remission and successful treatment of acquired factor VIII inhibitors using cyclophosfamide in a patient with systemic lupus erythematosus. Rheumatology 1999;38:1007–9. [17] Soriano RM, Mathews JM, Guerado-Parra E. Acquired haemophilia and rheumatoid arthritis. Brit J Rheumatol 1987;26:381–3. [18] Vignes S, Le Moing V, Meekel P, et al. Acquired hemophilia: A rare complication of Sjögren's syndrome. Clin Exp Rheumatol 1996;14:559–60.
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Contents lists available at ScienceDirect
Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m
Invited critical review
Laboratory, clinical and therapeutic aspects of acquired hemophilia A Massimo Franchini a,⁎, Giovanni Targher b, Martina Montagnana c, Giuseppe Lippi c a b c
Servizio di Immunoematologia e Trasfusione, Centro Emofilia, Azienda Ospedaliera di Verona, Italy Sezione di Endocrinologia e Malattie del Metabolismo, Dipartimento di Scienze Biomediche e Chirurgiche, Università di Verona, Italy Istituto di Chimica e Microscopia Clinica, Dipartimento di Scienze Morfologico-Biomediche, Università di Verona, Verona, Italy
A R T I C L E
I N F O
Article history: Received 25 January 2008 Received in revised form 24 March 2008 Accepted 1 May 2008 Available online 8 May 2008 Keywords: Acquired hemophilia Factor VIII Inhibitor Hemorrhage
A B S T R A C T Acquired hemophilia A is a rare bleeding diathesis caused by autoantibodies directed against clotting factor VIII and associated with an increased morbidity and mortality. This disease occurs most commonly in the elderly, and although it may be associated with a variety of underlying pathological conditions, up to 50% of reported cases remain idiopathic. In this review, we report the present knowledge on the most important laboratory, diagnostic and clinical aspects of acquired hemophilia A. Moreover, we focus on the most recent advances in the treatment of this disorder, which is primarily aimed to control bleeding episodes and to eradicate the autoantibody production. © 2008 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . 2. Laboratory diagnosis and immunological aspects 3. Clinical manifestations of acquired hemophilia A 4. Treatment of acquired hemophilia A . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .
. . . . . . of acquired . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . hemophilia A. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Acquired hemophilia A (AHA) is an uncommon but life-threatening hemorrhagic disorder caused by the presence of autoantibodies directed against the coagulation factor VIII (FVIII) [1–7]. Patients with AHA represent a demanding clinical challenge. Indeed, the mortality rate in this condition is extremely high, ranging from 8 to 22%, and severe bleeds have been reported to occur in more than 85% of the patients [4].
⁎ Corresponding author. Servizio di Immunoematologia e Trasfusione, Centro Emofilia, Ospedale Policlinico, Piazzale L. Scuro, 10, 37134 Verona, Italy. Tel.: +39 045 8124321; fax: +39 045 8124626. E-mail address: [email protected] (M. Franchini). 0009-8981/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2008.05.003
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The incidence of AHA has been reported as 1.48 and 1.34 per million/year in two recent large studies from the UK [8,9]. It increases with advancing age, being a very uncommon condition in children [10]. Indeed its incidence in children under 16 years has been estimated to be 0.045 per million/year compared with 14.7 per million/year in elderly aged over 85 years [9]. However, it is also likely that this autoimmune disorder is underestimated, especially in elderly patients. The age distribution of autoantibodies is typically biphasic with a small peak between 20 and 30 years (post-partum inhibitors) and a major peak in patients aged 68–80 years. The incidence in males and females is similar except in 20–40 year olds where the effect of pregnancy results in a preponderance of females [5]. In approximately 50% of cases, FVIII autoantibodies occur in patients lacking of relevant concomitant diseases, while the remaining cases may
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be associated with post-partum period, underlying malignancies, medications use or autoimmune diseases (see Table 1) [11–32]. In this review we will summarize the most important laboratory, clinical and therapeutic aspects of this autoimmune hemorrhagic disorder. 2. Laboratory diagnosis and immunological aspects of acquired hemophilia A The diagnosis of AHA is based on demonstrating an isolated prolongation of activated prothrombin thromboplastin time (APTT), not corrected by incubating for 2 h at 37 °C patient's plasma with equal volumes of normal plasma (mixing study), associated with a reduced FVIII level and evidence of FVIII inhibitor activity in a patient with no previous personal or family history of bleeding [33]. Fig. 1 reports the laboratory algorithm for the diagnosis of AHA. Factor VIII inhibitor can be titrated using the Bethesda assay, which measures residual FVIII activity after incubation of patient plasma with normal plasma for 2 h at 37 °C, or its Nijmegen modification, which uses a buffered normal plasma and FVIII-deficient plasma, instead of buffer, to dilute normal and patient plasmas. This modification, stabilizing FVIII activity, gives fewer false positive results, although it is more expensive [34]. According to the Bethesda assay, inhibitors are classified at low (b5 Bethesda units [BU]/mL) or high (N5 BU/mL). However, before confirming the presence of FVIII inhibitor, the possible coexistence of heparin or lupus anticoagulant should be ruled out. The presence of heparin is suggested by a prolonged thrombin time with normal reptilase time, while a similar APTT prolongation of the mixture patient/normal plasma at time 0 and after incubation is indicative for lupus anticoagulant. Like the alloantibodies occurring in congenital hemophilia A, FVIII autoantibodies are characterized as being predominantly polyclonal, belonging predominantly to IgG1 and IgG4 subclasses. Moreover, both auto- and alloantibodies appear to react with the same regions on the factor VIII molecule (i.e., A2, A3 and C2 domains) thus interfering with its interaction with FIXa, phospholipids and von Willebrand factor [1]. The possible biological mechanisms explaining the inhibitor production in AHA have been recently elucidated and is has become evident that autoantibodies arise from failure of the immune tolerance mechanisms which regulate a normal immune response to FVIII [35]. In this context, FVIII-specific CD4+ T cells play a central role in the anti-FVIII antibody synthesis, as documented by the observation that inhibitors may spontaneously disappear in conjunction with an HIV-associated decline in CD4+ counts [36]. In particular, a complex
Table 1 Conditions associated with acquired hemophilia A Pregnancy Autoimmune disorders
Systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, temporal, arteritis, Sjögren's syndrome, autoimmune hemolytic anemia, Goodpasturesyndrome, myastenia gravis, Graves' disease, autoimmune hypotyroidism Solid cancers Prostate, lung, colon, pancreas, stomach, choledochus, head, neck, cervix, breast, melanoma, kidney Hematologic Chronic lymphocytic leukemia, non-Hodgkin's lymphoma, malignancies multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic syndrome, myelofibrosis, erythroleukemia Inflammatory bowel Ulcerative colitis diseases Dermatologic Psoriasis, pemphigus disorders Respiratory diseases Asthma, chronic obstructive pulmonary disease Diabetes Acute hepatitis B and C infection Drug-associated Penicillin and its derivatives, sulfa antibiotics, phenytoin, cloramphenicol, methyldopa, depot thyoxanthene, interferonalpha, fludarabine, levodopa, clopidogrel
Fig. 1. Diagnostic algorithm of acquired hemophilia A.
interaction between different CD4+ subsets, i.e. Th1 (stimulating B cells to produce IgG1 antibodies) and Th2 (stimulating B cells to produce IgG4 antibodies) cells, is implicated in the synthesis of antiFVIII antibodies. Indeed, a strong positive association between inhibitor titer and the proportion of Th2-driven IgG4 anti-FVIII antibody has been observed [37]. Thus, a predominance of Th2-driven IgG4 anti-FVIII antibody is correlated with a more intense anti-FVIII antibody response, with a high inhibitor titer and ultimately with a failure to eradicate the inhibitor. On the other hand, successful immunosuppressive therapy in acquired hemophilia correlates with a predominance of Th1-driven anti-FVIII antibody. Finally, the lack of recognition of certain immunodominant CD4+ epitopes on the FVIII A3 (sequence regions 1691–1710 and 1941–1960) and C2 (sequence region 2191–2210) domains seems also to correlate with inhibitor formation [38]. The most striking differences between auto- and alloantibodies are in their inactivation patterns. Most inhibitors in congenital hemophilia are “type 1”, in that there is linear inactivation when the logarithm of the residual FVIII:C activity is plotted against plasma concentration. These antibodies completely destroy all FVIII when present in high concentrations. A few autoantibodies have this pattern, but most have different “type 2” properties. “Type 2” inhibitors have a non-linear inactivation pattern and they do not completely inactivate FVIII, even at the highest concentrations of inhibitor plasma [39]. Thus, the Bethesda assay, which quantities the in vitro inhibitor titer, may underestimate the in vivo inhibitor potency, due to the non-linear complex reaction kinetics, and may complicate the therapeutic choice and monitoring. Consequently, particular care should be taken to not underestimate the inhibitor potency, since residual FVIII activity levels
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of up to 10% of normal can be observed in the presence of a severe hemorrhagic picture. 3. Clinical manifestations of acquired hemophilia A The clinical picture of AHA differs from that of “classical” hereditary hemophilia A. In fact, more than 80% of patients with FVIII autoantibodies have hemorrhages into the skin, muscles or soft tissues and mucous membranes (e.g. epistaxis, gastrointestinal and urological bleeds, retroperitoneal hematomas), whereas hemarthroses, a typical feature of congenital factor VIII deficiency, are unusual [4,9]. Not rarely the hemorrhages in AHA are serious or lifethreatening, such as in the case of rapidly progressive retroperitoneal hematomas or compartment syndrome due to intramuscular bleeds. Sometimes the disease becomes manifest dramatically by excessive bleeding following trauma or surgery or by cerebral hemorrhage [4]. In the study conducted by Collins et al. for the UK Haemophilia Centre Doctors' Organisation [9], the majority of the 149 patients with information on the presence or absence of bleeding symptoms, had subcutaneous, mucosal or soft tissue bleeds. In a recent study, we observed that the prognosis was worse in patients with a high inhibitor titer, low FVIII plasma levels and transfusional requirements [40]. The presence of an underlying condition different from post-partum, an age at diagnosis higher than 65 years, and the lack of achievement of a complete remission were the three independent worse prognostic factors identified by Delgado and colleagues in their meta-analysis [33]. Other clinical manifestations of AHA include prolonged postpartum bleeding. Post-partum AHA occurs most frequently after the first delivery. The majority of autoantibody inhibitors, especially those at low titer, disappear spontaneously after a median period of 30 months and usually does not recur with subsequent pregnancies. However, in a few cases the autoantibody may persist and cause lifethreatening hemorrhages in the subsequent fetus because of transplacental transfer of the IgG antibodies. The most serious clinical presentation is severe uterine bleeding during labor or delivery, although more frequently bleeding occurs during the post-partum period, between 3 and 150 days after delivery. A persisting autoantibody may precede the development of an overt autoimmune disorder [41]. Hauser and colleagues [42] reviewed 51 cases of post-partum inhibitors and found a considerable heterogeneity in the interval between delivery and onset of symptoms (most being within the first 3 months), the titer of inhibitors (between 5 and 200 BU/mL) and the severity of hemorrhages. Although there were 3 deaths, in 76.5% of cases the autoantibody disappeared. In a recent description of the results of the Italian register of acquired factor VIII inhibitors, Baudo and colleagues reported a median time of 60 days between delivery and the onset of significant bleeding and/or the identification of the inhibitor [43]. The authors observed a high rate of complete remission: in fact the autoantibody was eradicated from 14 out of the 18 patients (78%) who were treated with steroids alone or in association with other agents (cyclophosphamide, azathioprine or high-dose immunoglobulins). The good prognosis of pregnancyassociated AHA was also confirmed by Delgado and colleagues in their meta-analysis of data from 20 retrospective and prospective surveys of patients with acquired inhibitors against factor VIII [33]. In fact, these authors recorded only 1 death in the 34 cases of postpartum inhibitors collected. In the majority of the reported cases, the potency of the inhibitors was low and this accounted for the high percentage of spontaneous remissions and, thus, the good outcome of the post-partum inhibitor syndrome. 4. Treatment of acquired hemophilia A The appropriate pharmacological treatment of patients with AHA essentially depends on the natural history of any concomitant pathology
and the clinical presentation of coagulopathy [44–46]. Some patients, for instance those with post-partum or drug induced inhibitors, may require no treatment additional to close clinical observation, since these inhibitors tend to disappear spontaneously within a few months after delivery or drug discontinuation [47]. Conversely, in other cases the eradication of the associated disease may lead to the disappearance of the inhibitor [48]. The fundamental aspects of therapeutic strategy in patients with AHA are the treatment of bleeding episodes and the eradication of the autoantibody [44]. Two options are currently available for hemostatic control: the use of bypassing agents and strategies to raise the level of circulating FVIII. The choice of the most appropriate therapeutic strategy will depend on the site and severity of the bleed and patient characteristics [49]. Bypassing agents are currently the most used first-line treatment and both recombinant factor VIIa (rFVIIa) and factor eight inhibitor bypassing activity (FEIBA) have been shown to be effective in the treatment of AHA [5,50,51]. Indeed, in a retrospective analysis of 38 patients, Hay and colleagues [50] reported a good response in 100% of patients when rFVIIa was used as a first-line treatment, and a good response in 75% of patients when it was used as non-first-line treatment. In a retrospective study with FEIBA, Sallah reported a 100% of hemostatic efficacy for moderate bleeds and a 75% hemostatic control for severe bleeds [51]. Recently, Sumner and colleagues [52] collected the available data on the use of rFVIIa in acquired hemophilia patients from compassionate use programs, the Hemophilia and Thrombosis Research Society (HTRS) Registry and from the published literature. A total of 139 patients were treated with rFVIIa for 204 bleeding episodes. The overall efficacy rate (complete or partial) of rFVIIa was 88% (161/182 bleeding episodes valuable). rFVIIa as a first-line treatment was effective overall in 95% of bleeding episodes compared with 80% when it was used as salvage therapy after failure of other hemostatic agents. Regarding the possible therapeutic strategies aimed to raise the levels of circulating FVIII, human FVIII concentrate is usually an inadequate hemostatic therapy unless the inhibitor titer is low. Thus, patients with a low titer of inhibitor can be treated with human FVIII concentrates, which should be administered at a dose great enough to overwhelm the inhibitor so that hemostatic levels of factor VIII can be achieved [53]. While a number of formulae have been proposed for calculating the optimal dose of FVIII to administer, the inaccuracy inherent in the laboratory measurement of inhibitor titer in acquired hemophilia makes it a very approximate tool and a regular monitoring of plasma FVIII levels and clinical response are required. Similarly, Desmopressin alone or in association with FVIII concentrates may also be effective in patients with a low titer of inhibitor for the treatment of minor bleeding episodes [54]. In patients with a high titer of inhibitor and severe hemorrhages, the extracorporeal removal of the autoantibody by therapeutic plasmapheresis, or immunoadsorption of immunoglobulins to staphylococcal protein A or to polyclonal sheep antibodies against human immunoglobulins, can be used prior to factor concentrate treatment [55–57]. The eradication of inhibitor may also be obtained with immunosuppressive agents including corticosteroids and cytotoxic drugs such as cyclophosphamide, azathioprine, 6-mercaptopurine and vincristine [58–62]. In their meta-analysis combining data from 20 reports, Delgado and colleagues concluded that cyclophosphamide use was superior to that of prednisone in terms of inhibitor eradication but not in terms of overall survival [33]. The combined data available from uncontrolled cohort studies recently reviewed by Collins, suggested a benefit for combined steroids and cytotoxic agents) [47]. Also high-dose immunoglobulins and cyclosporin, alone or in combination with prednisone, have shown to be effective in acquired hemophilia and can be considered as a second-line therapy for those patients nonresponders to standard immunosuppressive regimens [63–66].
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More recently, biotherapy with the anti-CD20 monoclonal antibody rituximab has been also used to treat cohorts of patients with acquired hemophilia. The largest published study performed on 10 patients, documented a complete remission in 8 patients whereas the 2 non-remitters responded to subsequent intravenous cyclophosphamide [67]. A 100% of complete remission was observed in two other studies [68,69]. From then, several other reports on small cohorts of patients have documented the benefit of rituximab in acquired hemophilia [70–72]. We have recently reviewed the literature data and collected 65 patients with AHA treated with this agent [70]. A complete or partial response was reached in more than 90% of cases. The presence of high inhibitor titers (N100 BU/mL) was a negative prognostic factor for the response to rituximab. However, the concomitant immunosuppressive therapy in most cases reported limited the evaluation of the real effectiveness of this agent. Based on these results, Aggarwal and colleagues proposed a treatment algorithm with the use of rituximab in association with immunosuppressive agents [71]. Finally, immune tolerance induction (ITI) protocols, like these used for the treatment of alloantibody inhibitors against factor VIII or IX in patients with congenital hemophilia A or B, have been proposed also for the eradication of autoantibodies against coagulation factors [72]. In particular, a protocol consisting of a combination of human factor VIII, cyclophamide and methylprednisolone was highly effective for the eradication of FVIII autoantibodies in patients presenting with severe bleeding [73]. 5. Conclusions AHA is a heterogeneous condition from a pathogenic, clinical and therapeutic point of view. The progresses in the understanding of the biology of the disease and the development of novel treatment protocols have greatly contributed to the improvement of patient's prognosis. References [1] Cohen AJ, Kessler CM. Acquired inhibitors. Baillere's Clin Haematol 1996;9:331–54. [2] Morrison AE. Acquired haemophilia and its management. Br J Haematol 1995;89:231–6. [3] Hay CRM. Acquired haemophilia. Baillere's Clin Haematol 1998;11:287–303. [4] Boggio LN, Green D. Acquired hemophilia. Rev Clin Exp Hematol 2001;5:389–404. [5] Franchini M, Gandini G, Di Paolantonio T, Mariani G. Am J Hematol 2005;80:55–63. [6] Pruthi RK, Nichols WL. Autoimmune factor VIII inhibitors. Curr Opin Hematol 1999;6:314–22. [7] Hay CRM, Baglin TP, Collins PW, Hill FGH, Keeling DM. The diagnosis and management of factor VIII and IX inhibitors: A guideline from the UK haemophilia Centre doctors' organization (UKHCDO). Br J Haematol 2000;111:78–90. [8] Collins P, Macartney N, Davies B, Lees S, Giddings J, Maier R. A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br J Haematol 2004;124:86–90. [9] Collins PW, Hirsch S, Baglin TP, et al. UK Haemophilia Centre Doctors' Organisation. Acquired hemophilia A in the United Kingdom: A 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood 2007;109:1870–7. [10] Moraca RJ, Ragni MV. Acquired anti-FVIII inhibitors in children. Haemophilia 2002;8:28–32. [11] Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981;45:200–3. [12] Bossi P, Cabane J, Ninet J, et al. Acquired haemophilia due to factor VIII inhibitors in 34 patients. Am J Med 1998;105:400–8. [13] Yee TT, Pasi KJ, Lilley PA, Lee CA. Factor VIII inhibitors in haemophiliacs: A singlecentre experience over 34 years, 1964–97. Brit J Haematol 1999;104:909–14. [14] Solymoss S. Postpartum acquired factor VIII inhibitors: Results of a survey. Am J Haematol 1998;59:1–4. [15] Kashyap R, Choudhry VP, Mahapatra M, Chumber S, Saxena R, Kaul HL. Postpartum acquired haemophilia: Clinical recognition and management. Haemophilia 2001;7:327–30. [16] Trotta F, Baiocchi G, La Corte R, Moratelli S, Sun LY. Long-lasting remission and successful treatment of acquired factor VIII inhibitors using cyclophosfamide in a patient with systemic lupus erythematosus. Rheumatology 1999;38:1007–9. [17] Soriano RM, Mathews JM, Guerado-Parra E. Acquired haemophilia and rheumatoid arthritis. Brit J Rheumatol 1987;26:381–3. [18] Vignes S, Le Moing V, Meekel P, et al. Acquired hemophilia: A rare complication of Sjögren's syndrome. Clin Exp Rheumatol 1996;14:559–60.
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