Follow-up
The patient has been followed for three years since discontinuing immunosuppressive therapy and continues to do well. She has not had any additional abnormal bleeding events, FVIII activity has remained normal, and FVIII inhibitor levels remain undetectable.

DISCUSSION

AHA is rare in pediatric patients. A systematic literature review identified 42 cases of de novo acquired coagulation factor inhibitors in pediatric patients, including 29 cases of acquired hemophilia A12. Of the reported cases, 14/29 were idiopathic, 5/29 were associated with prior penicillin/ampicillin use, 5/29 with prior infection, and 3/29 with autoimmune disease. Bleeding episodes typically were mucosal bleeds, bleeding into muscles and soft tissues, and subcutaneous bleeds. Hemarthrosis was observed in only one patient. Resolution of disease was reported in 22/29 cases.
AHA treatment entails achieving hemostasis with factor replacement therapy, reduction of the autoantibody via immunosuppression, and supportive care. Due to the rarity of the condition, there is no data from randomized clinical trials to guide management. Control of bleeding by FVIII replacement or desmopressin (DDAVP) to increase FVIII levels is typically not recommended, even if inhibitor titers are low13,14. Control of bleeding with such bypassing agents as rFVIIa or prothrombin complex concentrates appears to be more effective, and there does not appear to be a significant difference in efficacy between the two13,15–17. Emicizumab is a manufactured bispecific antibody that mimics the effects of activated factor VIII by bridging factors IX and X. Emicizumab successfully prevents bleeding in patients with congenitally acquired hemophilia A18. Several case reports describe successful bleeding control in adult onset AHA, but its efficacy has not been evaluated in prospective trials19,20.
Immunosuppressive therapy is typically employed to eliminate the inhibitor, although spontaneous loss of the inhibitor may occur in one-third of patients21. A retrospective study of 331 adult patients with AHA observed improved rates of complete remission with cyclophosphamide combined with steroids (70%) compared to steroids alone (48%) or rituximab-based regimens (59%)13. Given the scarcity of pediatric cases, little evidence exists regarding the optimal immunosuppressive regimen in children.
In summary, we present two cases of acquired hemophilia A with hemarthrosis as the sentinel bleeding event. AHA should thus be considered in pediatric patients presenting with sudden onset hemarthrosis. It is notable that both cases also had a possible triggering event — recent infection or vaccination — that may have been related to development of AHA. Finally, as demonstrated with these two cases, immunosuppression with steroids +/- IVIG may be curative in pediatric AHA.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ACKNOWLEDGMENTS

L.H.D. was supported by the Stanford Medical Scientist Training Program NIH training grant T32GM007365.

REFERENCES

1. Collins PW, Hirsch S, Baglin TP, Dolan G, Hanley J, Makris M, Keeling DM, Liesner R, Brown SA, Hay CRM, 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(5):1870-1877.
2. 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(1):86-90.
3. Tay L, Duncan E, Singhal D, Al-Qunfoidi R, Coghlan D, Jaksic W, Szabo F, McRae S, Lloyd J. Twelve years of experience of acquired hemophilia A: trials and tribulations in South Australia. Semin Thromb Hemost . 2009;35(8):769-777.
4. Söhngen D, Specker C, Bach D, Kuntz BM, Burk M, Aul C, Kobbe G, Heyll A, Hollmig KA, Schneider W. Acquired factor VIII inhibitors in nonhemophilic patients. Ann Hematol . 1997;74(2):89-93.
5. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, Tiede A, Kessler CM. Acquired hemophilia A: Updated review of evidence and treatment guidance. Am J Hematol . 2017;92(7):695-705.
6. O’Connor CR. Systematic review of the presentation of coagulation factor VIII inhibitors in rheumatic diseases: A potential cause of life-threatening hemorrhage. Semin Arthritis Rheum . 2015;44(6):695-709.
7. Cao X-Y, Li M-T, Zhang X, Zhao Y, Zeng X-F, Zhang F-C, Hou Y, Zhu L-X. Characteristics of Acquired Inhibitors to Factor VIII and Von Willebrand Factor Secondary to Systemic Lupus Erythematosus: Experiences From a Chinese Tertiary Medical Center. J Clin Rheumatol . 2021;27(5):201-205.
8. Franco-Moreno AI, Santero-García M, Cabezón-Gutiérrez L, Martín-Díaz RM, García-Navarro MJ. Acquired hemophilia A in a patient with hepatocellular carcinoma: a case report and literature review. Ann Hematol . 2016;95(12):2099-2100.
9. Sallah S, Wan JY. Inhibitors against factor VIII in patients with cancer. Analysis of 41 patients. Cancer . 2001;91(6):1067-1074.
10. Reeves BN, Key NS. Acquired hemophilia in malignancy. Thromb Res . 2012;129 Suppl 1:S66-S68.
11. 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(1):21-35.
12. Franchini M, Zaffanello M, Lippi G. Acquired hemophilia in pediatrics: a systematic review. Pediatr Blood Cancer . 2010;55(4):606-611.
13. Baudo F, Collins P, Huth-Kühne A, Lévesque H, Marco P, Nemes L, Pellegrini F, Tengborn L, Knoebl P, EACH2 registry contributors. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood . 2012;120(1):39-46.
14. Huth-Kühne A, Baudo F, Collins P, Ingerslev J, Kessler CM, Lévesque H, Castellano MEM, Shima M, St-Louis J. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A.Haematologica . 2009;94(4):566-575.
15. Hay CR, Negrier C, Ludlam CA. The treatment of bleeding in acquired haemophilia with recombinant factor VIIa: a multicentre study.Thromb Haemost . 1997;78(6):1463-1467.
16. Sallah S. Treatment of acquired haemophilia with factor eight inhibitor bypassing activity. Haemophilia . 2004;10(2):169-173.
17. Tiede A, Worster A. Lessons from a systematic literature review of the effectiveness of recombinant factor VIIa in acquired haemophilia.Ann Hematol . 2018;97(10):1889-1901.
18. Knöbl P. Prevention and Management of Bleeding Episodes in Patients with Acquired Hemophilia A. Drugs . 2018;78(18):1861-1872.
19. Tiede A, Kemkes-Matthes B, Knöbl P. Should emicizumab be used in patients with acquired hemophilia A? J Thromb Haemost . 2021;19(3):637-644.
20. Knoebl P, Thaler J, Jilma P, Quehenberger P, Gleixner K, Sperr WR. Emicizumab for the treatment of acquired hemophilia A. Blood . 2021;137(3):410-419.
21. Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to Factor VIII. Thromb Haemost . 1981;45(3):200-203.

LEGENDS

FIGURE 1: FVIII inhibitor levels and FVIII activity versus time since diagnosis in case #1. Bleeding events are indicated with an asterix. IVIG doses are indicated with an arrowhead. a, prednisone started at 1mg/kg/dose twice daily; b, prednisone taper initiated; c, prednisone discontinued.
FIGURE 2: FVIII inhibitor levels and FVIII activity versus time since diagnosis in case #2. Bleeding events are indicated with an asterix. a, prednisone started at 1 mg/kg/dose twice daily; b, prednisone taper initiated with 5 mg/dose decrease each week; c, prednisone discontinued.