|Year : 2022 | Volume
| Issue : 4 | Page : 176-182
Management of acquired hemophilia: Consensus recommendations for the United Arab Emirates practitioners
Mahmoud Marashi1, Ahmed Aly Basha2, Amar Lal3, Hani Osman3, Hasan Aal Yaseen1, Hasan Ghazal4, Sharukh Hashmi5, Muhammad Khanani6
1 Department of Hematology/Oncology, Dubai Hospital, Al Ain, UAE
2 Department of Hematology/Oncology, Saudi German Hospital, Al Ain, UAE
3 Department of Hematology/Oncology, Tawam Hospital, Al Ain, UAE
4 Department of Hematology/Oncology, King's College Hospital, Al Ain, UAE
5 Department of Hematology/Oncology, Sheikh Shakhbout Medical, Al Ain, UAE
6 City Abu Dhabi, Pediatric Hematology/Oncology Department, Tawam Hospital, City Abu Dhabi, Al Ain, UAE
|Date of Submission||13-Mar-2022|
|Date of Decision||08-May-2022|
|Date of Acceptance||17-May-2022|
|Date of Web Publication||03-Oct-2022|
Prof. Mahmoud Marashi
Dubai Hospital, Dubai
Source of Support: None, Conflict of Interest: None
Acquired hemophilia A (AHA) is a rare autoimmune condition characterized by spontaneous antibodies formation against coagulation factor VIII (FVIII). In the United Arab Emirates (UAE), the treatment paradigm of AHA varies, leading to heterogeneous patient outcomes. Because AHA cases often present to clinical practitioners with insufficient experience in the disease, diagnosis is sometimes delayed. This document aims to provide recommendations to clinical practitioners in the UAE to bridge the gap of heterogeneous practice in the clinical management of AHA. Structured literature searches in PubMed and Google Scholar with a three-stage Delphi method were conducted. Evidence suggests that prolonged activated partial thromboplastin time before surgery or coupled with acute or recent onset of bleeding is a hallmark of AHA. Treatment using bypassing agents is recommended in AHA patients with bleeding. Corticosteroids and rituximab with (out) a cytotoxic agent represent the first-line treatment in patients with FVIII: C <1 IU/dL. Second-line therapy involves agents not utilized in the first round of treatment. Thromboprophylaxis is recommended if FVIII: C has returned to normal levels. These recommendations are intended to improve the clinical practice and awareness of this disorder among hematologists and nonhematologists in the UAE and provide practical diagnosis and treatment advice.
Keywords: Acquired hemophilia A, activated partial thromboplastin time, factor VIII
|How to cite this article:|
Marashi M, Basha AA, Lal A, Osman H, Yaseen HA, Ghazal H, Hashmi S, Khanani M. Management of acquired hemophilia: Consensus recommendations for the United Arab Emirates practitioners. J Appl Hematol 2022;13:176-82
|How to cite this URL:|
Marashi M, Basha AA, Lal A, Osman H, Yaseen HA, Ghazal H, Hashmi S, Khanani M. Management of acquired hemophilia: Consensus recommendations for the United Arab Emirates practitioners. J Appl Hematol [serial online] 2022 [cited 2022 Nov 30];13:176-82. Available from: https://www.jahjournal.org/text.asp?2022/13/4/176/357780
| Introduction|| |
Hemophilia is a common and severe hemorrhagic disorder that is classified into Types A (caused by deficiency or dysfunction of factor VIII [FVIII]), B (due to deficiency or dysfunction of factor IX), and C (from deficiency or dysfunction of factor XI). While hemophilia is more commonly a hereditary condition, it is sometimes acquired. Acquired hemophilia results from immune dysfunction that leads to the formation of coagulation factor autoantibodies. Acquired hemophilia A (AHA), or acquired FVIII inhibitor disorder, is a rare bleeding disease in which patients without a history of bleeding conditions present with spontaneous and severe bleeding.
AHA is estimated to have an incidence rate of around 1.5/million cases annually. The incidence rate increases with age, reaching 14.7/million cases per year in elderly patients aged 85 years and above. Data from the European Acquired Hemophilia Registry have shown that the median age at the time of AHA diagnosis is 73.9 years., In addition, AHA is more prominent among women aged 20–40 years than men because it can occur during pregnancy or in the postpartum period, especially the first 6–12 months after birth., Despite its rarity, AHA is a severe disorder that can be fatal in 5%–10% of cases. The mortality rate increases to exceed 40% in cases where the diagnosis is delayed, treatment is inadequate, or as a result of surgery-related hemorrhagic complications. Acquired inhibition of clotting factors results from autoantibodies activity. The interaction between autoantibodies and FVIII is nonlinear and unpredictable, causing severe bleeding despite small residual amounts of FVIII activity. Antibodies often bind to the A2 and C2 domains of FVIII, preventing its interaction with phospholipids and von Willebrand factor. AHA is a typical autoimmune disease caused by the production of neutralizing immunoglobulin G autoantibodies that target and inhibit FVIII. The reason for autoantibody production is unknown but hypothesized to result from an interplay of genetic and environmental factors.
In around half of AHA cases, the autoantibody development against FVIII is idiopathic in nature, while underlying conditions are found in the other half. These conditions include autoimmune disorders, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, thyroid dysfunction, inflammatory bowel diseases, pemphigus, autoimmune hemolytic anemia, graft versus host disease, pregnancy, and malignancies. Medical agents as penicillin antibiotics, antihypertensives, anticonvulsants, sulfonamides, chloramphenicol, and Bacillus Calmette–Guérin vaccine can contribute to AHA pathogenesis. The most common bleeding patterns in AHA are muscle hematomas and bleeding into subcutaneous, soft tissues, or mucous membranes. Bleeding can vary in severity ranging from mild-to-organ/limb/life-threatening.
Unfortunately, health-care providers not specialized in hemostatic disorders are not well-informed about AHA. This results in delayed diagnosis or even misdiagnosis. This puts patients at an increased risk of bleeding. In addition, limited data from comparative studies means that the guidelines for AHA management are developed based on registry findings and authors' experiences.
AHA is usually suspected when a patient presenting with bleeding has a normal prothrombin time and a prolonged activated partial thromboplastin time (aPTT).
An aPTT mixing test is recommended for AHA diagnosis. Measuring FVIII: C and determination of inhibitor titer are crucial. Other laboratory tests that detect and measure lupus anticoagulants, in addition to the Bethesda assays, are also employed in AHA diagnosis. The presence of autoantibodies can be confirmed by enzyme-linked immunosorbent assay (ELISA).
The clinical management of AHA focuses on hemostatic therapy for the acute bleeding episodes, rapid suppression of inhibitory titers to facilitate hemostatic therapy, control of the underlying autoimmune dysfunction, and providing adequate personalized therapy.
Hemostatic treatment includes the replacement therapy by human FVIII or porcine FVIII (pFVIII) and bypassing agents such as activated prothrombin complex concentrate (aPCC) and recombinant FVIIa (rFVIIa). Desmopressin is occasionally used in patients with minor bleeding and low inhibitor titers; in addition, tranexamic acid in combination with rFVIIa, or aPCC can be considered. Immunosuppressive therapy (IST) has been suggested as the treatment of choice for AHA patients. It eliminates coagulation FVIII autoantibodies; however, data from multiple registries have highlighted that IST is associated with adverse events, such as infections. The main goal of IST is to achieve rapid AHA remission and reduce the risk of further bleeding. IST can be achieved by utilizing immunosuppressive agents such as cyclophosphamide, rituximab, corticosteroids, or a combination of them. Immunoadsorption (IA) is a method that is used to remove circulating immunoglobulins from the patient's plasma, and, in turn, the blood, thus considerably lowering the autoantibodies' inhibitor titers. The Bonn‒Malmö Protocol is another strategy that combines intravenous immunoglobulin, immunosuppression, and IA with FVIII replacement. Although this treatment is not available in most centers, it was reported to provide safe and prompt control of acute bleeding.
Monitoring the decrease of inhibitor titers, stopping bleeding, and improving hemoglobin levels and stability are used to assess treatment response. Monitoring is also recommended to ensure that relapse does not occur. Usually, remission of AHA can be determined by high FVIII levels. Pharmacologic thromboprophylaxis is indicated after achieving clinical remission, as many patients have risk factors linked to other comorbidities. Long-term follow-up by laboratory tests is recommended to ensure that remission has been achieved and maintained. Monthly monitoring of aPTT is also recommended. In addition, a monthly assessment of FVIII activity for the first 6 months, followed by every 2 to 3 months during the 1st year, then every 6 months in the 2nd year and beyond is recommended. In addition, health-care providers need to educate patients about the signs and symptoms of recurrence, and patients should be encouraged to report bruising or bleeding.
| Methods|| |
From September 2021 to November 2021, a pre-Delphi search and a three-step modified Delphi technique were used to reach the current consensus. The consensus statements were developed through two cycles of blinded voting and an expert discussion meeting.
Expert panel recruitment
A total of eight specialized hematologists from the United Arab Emirates (UAE) were selected. The selected advisors have established research profiles in the field of hematology. Eligible experts were contacted through email and asked to participate in the three stages of this Delphi method-based study.
To gather relevant material for survey development with the committee, a literature search was conducted on Google Scholar and PubMed. The following keywords were used to find potentially eligible literature: (“AHA” OR “Diagnosis, Management [MeSH Terms]” OR “(aPTT [MeSH Terms])”) and “(aPTT [MeSH Terms])” (“IST” OR “Treatment” OR “ AHA” OR “diagnosis”). The claims mainly were taken from research having an evidence quality level of 5 (expert opinion). The committee gathered all of the statements onto an Excel sheet and met to approve the proposed consensus statements.
Three stages were involved in the creation of the consensus document. A draft questionnaire was circulated to experts through email in the first step. The experts were asked to select between “agree” and “disagree” alternatives for statements. Each expert was allowed to respond to each statement and offer solutions. If an agreement level of 80% was obtained on each statement that means these statements are submitted directly to the consensus. The experts kept the statements that did not meet the agreement threshold for stage 2 and amended or omitted them. On October 22, 2021, a hybrid advisory board meeting (virtual and on-site) representing stage 2 was held and was attended by the eight experts. The panel provided the statements with 80% agreement for complete consensus, whereas the remaining items were presented for adjustment or deletion. The list of changed statements was sent to the experts for voting in the last phase, which followed the same voting process as step 1.
| Results and Discussion|| |
The results of the Delphi consensus process are presented in [Table 1], [Table 2], [Table 3].
|Table 1: Consensus statements regarding the diagnosis of acquired hemophilia A|
Click here to view
|Table 2: Consensus statements regarding the treatment of acquired hemophilia A-related bleeding|
Click here to view
|Table 3: Consensus statements regarding the immunosuppressive treatment of acquired hemophilia A|
Click here to view
The panel agreed that any nonresolving new onset of bleeding, commonly observed in older adults and females during the postpartum period, coupled with isolated prolonged aPTT should be suspected of AHA. Soft-tissue hematoma is the most common symptom of acquired hemophilia. Other places where bleeding can occur include the gastrointestinal and genitourinary tracts, as well as bleeding during invasive operations. Unexplained aPTT prolongation before surgery should be resolved before surgery.
Differential diagnosis of AHA includes the antiphospholipid antibody syndrome (APS). A correction of the aPTT after the addition of phospholipids supports the suspicion of APS. However, antiphospholipid antibodies can also occur in patients with AHA, and specialist consultation may be required. Usually, patients with APS have no bleeding tendency but rather signs of thrombosis. In bleeding patients, AHA should be strongly suspected.
The Bethesda assay is used to verify and quantify FVIII inhibitor titer if the aPTT is not corrected after introducing phospholipids. Moreover, the assay could be used to show and quantify inhibitory anti-FVIII antibodies depending on their capacity to block FVIII: C activity. It is important to note that this test will not discover nonneutralizing antibodies directed against FVIII, which are only detected in anti-FVIII ELISA. Additional diagnostic tests include the mixing test, which shows the lack of aPTT correction when a mixture of equal amounts of patient and normal plasma is incubated at 37° for 2 h or longer, confirming the existence of circulating inhibitors.
Mixing tests at 0.1 and 2 h, specific factor assays, and the Bethesda assay for inhibitor quantification should all be included in the laboratory tests. [Figure 1] suggests an algorithm for diagnosing AHA. The first four statements for AHA diagnosis and the agreement level of the voting experts are listed in [Table 1].
|Figure 1: AHA diagnosis flowchart (adapted from Tiede et al. 2020). aPTT, activated partial thromboplastin time; FVII, Factor VIII; AHA, acquired hemophilia A; ELISA, enzyme-linked immunoassay. AHA: Acquired hemophilia A, aPTT: Activated partial thromboplastin time, ELISA: Enzyme-linked immunosorbent assay|
Click here to view
Management of acute bleeds
The best way to manage AHA is to have specialized centers that provide hematologists with hemostatic medications and the flexibility to perform frequent FVIII monitoring tests., Treatments employed in AHA include hemostatic medications to prevent hemorrhage and immunological therapy to eliminate inhibitors. Bypassing medications, such as recombinant activated FVII concentrate (rFVIIa) and aPCC are first-line treatments for bleeding episodes. The use of bypassing drugs aims at stimulating the hemostatic process by overcoming inhibitor's interference and replacement therapy; the latter is involved in restoring hemostatic levels of FVIII., rFVIIa amplifies the process of the initial generation of tissue factor-dependent thrombin and directly activates factor X on activated platelets. Salaj et al. highlighted that rFVIIa doses of <120–>250 μg/kg provide similar efficacy if treatment is given within 2 h of bleeding initiation and that the higher dose of rFVIIa is the most effective if the treatment is initiated after the 2-h mark. rFVIIa has been shown to have high success rates as a first-line treatment. In a study, rFVIIa was successful in controlling 95% of bleeding episodes. These results were further supported by data from the European Acquired Hemophilia Registry, where the success rate was as high as 92%. Moreover, information from the registry highlighted that it was the most widely used hemostatic agent, where more than 56% of cases received it., In patients with AHA and inhibitors to FVIII, the National Hemophilia Foundation's Medical and Scientific Advisory Council recommends prophylaxis with bypassing agents; however, these recommendations do not specify the initiation time, the regimen, or the dose that should be used with either bypassing agents. Both bypassing agents can be administered as a first-line treatment for AHA bleeding, with the choice based on dosing convenience, the need for early redosing, preference for plasma-derived or recombinant products, availability, and patient's historical response to treatment. Despite strong anti-FVIII inhibitor titers, using a high dose of human FVIII (100 IU/kg/day) in combination with IA may result in hemostatic FVIII levels and quick management of severe bleeding. Although it is only available in a few centers, this treatment method may be useful as first-line therapy if bypassing drugs have failed. [Figure 2] summarizes the suggested methods for treating AHA-related bleeding. [Table 2] lists the statements for treating AHA-related bleeding and the level of agreement of the voting experts.
|Figure 2: Treatment of bleeds (adapted from Tiede et al. 2022). rFVIIa, recombinant activated factor VII; aPCC, activated prothrombin complex concentrates. rFVIIa: Recombinant factor VIIa, aPCC: Activated prothrombin complex concentrate|
Click here to view
Patients with AHA receive IST to inhibit and eliminate autoantibodies to coagulation FVIII. In addition to the previous, IST decreases bleeding by reducing the time it takes to attain AHA remission. Corticosteroids alone or combined with cytotoxic drugs, rituximab, or FVIII immune tolerance have been documented as immunosuppressive regimens. Complete remission (CR) is considered to be achieved when FVIII is normal, inhibitors are undetectable, and the patient is either of therapy or on a low-dose treatment, yet without relapse. Three prognostic factors are independently linked to a variable clinical outcome: achievement of CR (yes vs. no), related conditions (malignancy vs. postpartum vs. others), and age (<65 years vs. ≥65 years). In 102 patients treated with a homogeneous IST procedure, prognostic variables were studied prospectively, and FVIII: C at presentation was viewed as the most important predictive factor. Partial remission (PR) is defined as the lack of bleeding, restored FVIII to levels >50 IU/dL, and cessation of hemostatic treatment for >24 h. Eighty-three percent of patients achieved PR after a median of 31 days. Patients with baseline FVIII <1 IU/dL achieved PR less often (77%) and later than (43 days) patients with ≥1 IU/dL (89%, 24 days).
First-line treatment with corticosteroid monotherapy consists of oral prednisone with a dose of 1 mg/kg every day (the alternative is oral dexamethasone 40 mg daily for 4–7 days). This choice is ineffective if used for <3 weeks in patients with FVIII <1 IU/dL or inhibitor >20 BU/mL at presentation. Furthermore, this choice requires close monitoring of adverse events such as infection, elevated glucose levels, and psychiatric disorders. On using combination therapy, the dose of corticosteroids remains the same, and oral cyclophosphamide with a dose of 1–2 mg/kg/day is added. According to the results from the European Acquired Hemophilia Registry, steroids with cyclophosphamide produced more sustained full remission (70%) than steroids alone (48%) or rituximab-based regimens (59%). These findings are aligned with several other reports showing that first-line management with steroids plus cyclophosphamide is more likely to achieve a CR than the former alone. The median time to remission with corticosteroids is about 5 weeks, but if FVIII level does not rise and the inhibitor titer does not decrease after 2–3 weeks, an alternative immunosuppressive regimen should be sought. If corticosteroid treatment fails to achieve remission, cyclophosphamide or rituximab is routinely administered; however, rituximab is not approved for this indication. If rituximab has not been tried at this stage, second-line therapy includes combinations of cytotoxic drugs or cyclosporine., The negative effects of these medications must be considered, especially in the context of the patient's age. [Figure 3] illustrates the current international recommendations for immunosuppressive treatment of AHA. [Table 3] lists the statements regarding the immunosuppressive treatment of AHA and the level of agreement of the voting experts.
|Figure 3: Immunosuppressive treatment (adapted from Tiede et al. 2020). FVIII: Factor VIII; CTX: Cyclophosphamide|
Click here to view
| Conclusions|| |
This consensus statement was developed based on the most recent scientific evidence from the available data on AHA in the UAE and on a global stage at the time of publication. The board agreed on screening patients for AHA in cases presenting with an acute or recent onset of bleeding accompanied by unexplained prolonged aPTT. The advisors agreed on the necessity of initiating a personalized, professionally guided hemostatic treatment for AHA patients with clinically relevant bleeding regardless of other factors. FVIII: C monitoring is strongly recommended even after remission. This document will provide health-care professionals in the UAE with an expert consensus to aid them in making the best clinical decisions when managing AHA patients.
The authors acknowledge Professor Andreas Tiede for his revision of this manuscript. Medical writing and editorial assistance were provided by PDC FZ-LLC and financially funded by Novo Nordisk UAE. The authors take full responsibility for the content and conclusions stated in this manuscript.
Financial support and sponsorship
This consensus received funding support from Novo Nordisk UAE. Novo Nordisk neither influenced the content of this publication nor was it involved in the study design, data collection, interpretation, and review.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Haider MZ, Anwer F. Acquired hemophilia. Treasure Island (FL): StatPearls; 2022.
Yousphi AS, Bakhtiar A, Cheema MA, Nasim S, Ullah W. Acquired hemophilia A: A rare but potentially fatal bleeding disorder. Cureus 2019;11:e5442.
Collins PW, Hirsch S, Baglin TP, Dolan G, Hanley J, Makris M, et al.
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.
Knoebl P, Marco P, Baudo F, Collins P, Huth-Kühne A, Nemes L, et al.
Demographic and clinical data in acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost 2012;10:622-31.
Windyga J, Baran B, Odnoczko E, Buczma A, Drews K, Laudanski P, et al.
Treatment guidelines for acquired hemophilia A. Ginekol Pol 2019;90:353-64.
Pandey Y, Atwal D, Konda M, Roy A, Sasapu A. Acquired hemophilia A. Proc (Bayl Univ Med Cent) 2020;33:71-4.
Elezović I. Acquired haemophilia syndrome: Pathophysiology and therapy. Srp Arh Celok Lek 2010;138 Suppl 1:64-8.
Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, et al.
Acquired hemophilia A: Updated review of evidence and treatment guidance. Am J Hematol 2017;92:695-705.
Dolan G, Benson G, Bowyer A, Eichler H, Hermans C, Jiménez-Yuste V, et al.
Principles of care for acquired hemophilia. Eur J Haematol 2021;106:762-73.
Mingot-Castellano ME, Pardos-Gea J, Haya S, Bastida-Bermejo JM, Tàssies D, Marco-Rico A, et al.
Management of acquired hemophilia A: Results from the Spanish registry. Blood Adv 2021;5:3821-9.
Sakurai Y, Takeda T. Acquired hemophilia A: A frequently overlooked autoimmune hemorrhagic disorder. J Immunol Res 2014;2014:320674.
Tiede A, Collins P, Knoebl P, Teitel J, Kessler C, Shima M, et al.
International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica 2020;105:1791-801.
Knöbl P. Prevention and management of bleeding episodes in patients with acquired hemophilia A. Drugs 2018;78:1861-72.
Dobbelstein C, Moschovakis GL, Tiede A. Reduced-intensity, risk factor-stratified immunosuppression for acquired hemophilia A: Single-center observational study. Ann Hematol 2020;99:2105-12.
Esteves Pereira M, Bocksrucker C, Kremer Hovinga JA, Mueller M, Daskalakis M, Mansouri Taleghani B, et al.
Immunoadsorption for the treatment of acquired hemophilia: New observational data, systematic review, and meta-analysis. Transfus Med Rev 2021;35:125-34.
Zeitler H, Ulrich-Merzenich G, Hess L, Konsek E, Unkrig C, Walger P, et al.
Treatment of acquired hemophilia by the Bonn-Malmo Protocol: Documentation of an in vivo
immunomodulating concept. Blood 2005;105:2287-93.
Janbain M, Leissinger CA, Kruse-Jarres R. Acquired hemophilia A: Emerging treatment options. J Blood Med 2015;6:143-50.
Wright JG, Swiontkowski MF, Heckman JD. Introducing levels of evidence to the journal. J Bone Joint Surg Am 2003;85:1-3.
Shetty S, Bhave M, Ghosh K. Acquired hemophilia a: Diagnosis, aetiology, clinical spectrum and treatment options. Autoimmun Rev 2011;10:311-6.
Mavroeidis L, Vassou A, Zarkavelis G, Papadaki A, Mouzaki I, Ntellas P, et al.
Acquired hemophilia in an elderly patient with carcinoma of the ampulla of vater. Case Rep Oncol 2020;13:1-6.
Tufano A, Coppola A, Guida A, Cimino E, De Gregorio AM, Cerbone AM, et al.
Acquired haemophilia a in the elderly: Case reports. Curr Gerontol Geriatr Res 2010;2010:927503.
Saito M, Kanaya M, Izumiyama K, Mori A, Irie T, Tanaka M, et al.
Treatment of bleeding in acquired hemophilia A with the proper administration of recombinant activated factor VII: Single-center study of 7 cases. Int J Gen Med 2016;9:393-9.
Franchini M, Schiavulli M, Liumbruno GM. Hemostatic therapy as a management strategy for acquired hemophilia: What does the future hold? Expert Rev Hematol 2021;14:263-70.
Salaj P, Brabec P, Penka M, Pohlreichova V, Smejkal P, Cetkovsky P, et al.
Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: Analysis of HemoRec registry data from the Czech Republic. Haemophilia 2009;15:752-9.
Holstein K, Liu X, Smith A, Knöbl P, Klamroth R, Geisen U, et al.
Bleeding and response to hemostatic therapy in acquired hemophilia A: Results from the GTH-AH 01/2010 study. Blood 2020;136:279-87.
Carpenter SL, Khair K, Gringeri A, Valentino LA. Prophylactic bypassing agent use before and during immune tolerance induction in patients with haemophilia A and inhibitors to FVIII. Haemophilia 2018;24:570-7.
Collins PW, Chalmers E, Hart D, Jennings I, Liesner R, Rangarajan S, et al.
Diagnosis and management of acquired coagulation inhibitors: A guideline from UKHCDO. Br J Haematol 2013;162:758-73.
Franchini M, Vaglio S, Marano G, Mengoli C, Gentili S, Pupella S, et al.
Acquired hemophilia A: A review of recent data and new therapeutic options. Hematology 2017;22:514-20.
Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, Villar A. Acquired haemophilia: Review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003;121:21-35.
Tiede A, Klamroth R, Scharf RE, Trappe RU, Holstein K, Huth-Kühne A, et al.
Prognostic factors for remission of and survival in acquired hemophilia A (AHA): Results from the GTH-AH 01/2010 study. Blood 2015;125:1091-7.
Collins P, Baudo F, Knoebl P, Levesque H, Nemes L, Pellegrini F, et al.
Immunosuppression for acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2). Blood 2012;120:47-55.
Au WY, Lam CC, Kwong YL. Successful treatment of acquired factor VIII inhibitor with cyclosporin. Haemophilia 2004;10:98-100.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]