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. 2022 May;20(3):245-262.
doi: 10.2450/2022.0238-21. Epub 2022 Jan 20.

Acquired haemophilia A: Italian Consensus Recommendations on diagnosis, general management and treatment of bleeding

Antonio Coppola  1 , Massimo Franchini  2 , Armando Tripodi  3 , Rita C Santoro  4 , Giancarlo Castaman  5 , Renato Marino  6 , Ezio Zanon  7 , Cristina Santoro  8 , Gianna F Rivolta  1 , Laura Contino  9 , Raimondo De Cristofaro  10 , Angelo C Molinari  11 , Paolo Gresele  12 , Angiola Rocino  13 ; ad hoc Working Group (Appendix 1)
Affiliations

Acquired haemophilia A: Italian Consensus Recommendations on diagnosis, general management and treatment of bleeding

Antonio Coppola et al. Blood Transfus. 2022 May.

Abstract

Background: Acquired haemophilia A (AHA) is a rare bleeding disorder due to autoantibodies to coagulation factor VIII that may be secondary to autoimmune diseases, cancer, drugs, pregnancy, infections, or be idiopathic. Recurrent bleeding, often severe, mostly in muscles and soft tissues, and isolated prolonged activated partial thromboplastin time (aPTT), in the absence of personal and family history of bleeding, are typical features that should raise the suspicion of AHA. Poor awareness of the disease results in diagnostic delays and inappropriate treatment.

Materials and methods: The Italian Association of Haemophilia Centres (AICE) developed consensus recommendations in cooperation with the Italian Society on Thrombosis and Haemostasis (SISET). The document was shared with scientific societies of specialist physicians, laboratory professionals and pharmacists to spread knowledge about AHA and promote appropriate diagnosis/treatment.

Results: Ready availability of the aPTT mixing test is crucial, although diagnostic confirmation and optimal management require prompt referral of patients to specialised centres with rapidly available diagnostic and therapeutic facilities. If immediate referral is unfeasible, treatment must be undertaken early, under guidance of specialised centres or based on shared protocols. Recommendations about diagnosis, general management and, in bleeding patients, haemostatic therapy using bypassing agents or replacement treatment, including the recently available recombinant porcine factor VIII, are provided, considering the different clinical settings and laboratory facilities.

Discussion: This consensus document aims to improve the overall healthcare pathways for AHA, harmonise the management and therapeutic approaches to newly diagnosed patients and reduce the still relevant complications and mortality in this setting.

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Conflict of interest statement

CONFLICT OF INTEREST DISCLOSURE

AC has acted as a paid consultant or speaker for Bayer, Kedrion, Novo Nordisk, Roche and Werfen. MF has acted as a paid consultant or speaker for Bayer and Novo Nordisk. AT has received speaker fees from Roche, Stago, Sobi and Werfen. GC has participated as a speaker or in advisory boards for Alexion, CSL Behring, Kedrion, Novo Nordisk, Pfizer, Sanofi, Sobi, Takeda, Uniqure and Werfen, acted as a consultant to Roche, and received research funding directly to his Institution from CSL Behring, Pfizer and Sobi. CS has acted as a paid consultant/advisor/speaker for Amgen, Bayer, Biomarin, CSL Behring, Novo Nordisk, Roche, Sobi and Takeda. LC has received speaker fees from Bayer and Novo Nordisk. RDC has received speaker fees from Bayer, Sanofi, Roche, Takeda, and Sobi and participated in scientific advisory boards for Bayer, Sanofi, Pfizer, Werfen, Sobi and Kedrion. ACM has acted as an advisor for Bayer, CSL Behring, Roche, SOBI and Takeda and has received speaker fees from Bayer, CSL Behring, Kedrion, Novo Nordisk, Pfizer, Roche, SOBI and Takeda. PG has received speaker fees from Sanofi. AR has acted as a paid consultant/advisor/speaker for Bayer, CSL Behring, Shire/Takeda, Novo Nordisk, Kedrion, Pfizer, Roche and Sobi. RCS, RM, EZ and GFR declare that they have no interests which might be perceived as conflicts or bias.

Figures

Figure 1*
Figure 1*. Distribution of the idiopathic forms of acquired haemophilia A and those “secondary” to associated conditions, as reported in the largest published series of patients
Green bars: UKHCDO survey, 2007 (n=172)3; purple bars: EACH2 Registry, 2012 (n=501)4; yellow bars: GTH-AH study, 2015 (n=102)5; red bars: HTRS Registry, 2016 (n=166)18; blue bars: CARE Registry, 2019 (n=187)19. The absence of a bar indicates that the data were not reported in the study. *The coloured figure is published online.
Figure 2*
Figure 2*. Rates of main sites of bleeding and of those resulting in death or not requiring haemostatic treatment in patients with acquired haemophilia A, as reported in the largest published series of patients
Green bars: UKHCDO survey, 2007 (n=172)3; purple bars: EACH2 Registry, 2012 (n=501)4; yellow bars: GTH-AH study, 2015 (n=102)5; red bars: HTRS Registry, 2016 (n=166)18; blue bars: CARE Registry, 2019 (n=187)19. The absence of a bar indicates that the data were not reported in the study. Mucosal: gastrointestinal and genitourinary tract. Deep sites: muscles and retroperitoneum. No treatment: bleeding episodes in which anti-haemorragic drugs were not used. *The coloured figure is published online.
Figure 3
Figure 3. Diagnostic algorithm for acquired haemophilia A
*Measurement of FXII levels is not indicated in the presence of bleeding symptoms, because even severe deficiencies of this factor, which causes prolongation of the aPTT, are not associated with bleeding tendency. aPTT: activated partial thromboplastin time; PT: prothrombin time; FVIII: factor VIII; FIX: factor IX; FXI: factor XI; VWF: von Willebrand factor.
Figure 4*
Figure 4*. Algorithm for the management of the patient with acquired haemophilia A at diagnosis, with emphasis on haemostatic treatment, depending on whether the patient is managed outside a specialised centre (A) or at a centre with clinical and laboratory expertise in the diagnosis and treatment of haemophilia and other coagulopathies (B)
AHA: acquired haemophilia A; CV: cardiovascular; FVIII: factor VIII; BU: Bethesda unit; rpFVIII: recombinant porcine factor VIII; FVIII:C: factor VIII clotting activity. *The coloured figure is published online.
Figure 4*
Figure 4*. Algorithm for the management of the patient with acquired haemophilia A at diagnosis, with emphasis on haemostatic treatment, depending on whether the patient is managed outside a specialised centre (A) or at a centre with clinical and laboratory expertise in the diagnosis and treatment of haemophilia and other coagulopathies (B)
AHA: acquired haemophilia A; CV: cardiovascular; FVIII: factor VIII; BU: Bethesda unit; rpFVIII: recombinant porcine factor VIII; FVIII:C: factor VIII clotting activity. *The coloured figure is published online.
See this image and copyright information in PMC

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Supplementary concepts