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References 1 Buckner TW, Nielsen BI, Key NS, Ma A. Factor VIII inhibitory antibody in a patient with combined factor V/factor VIII deficiency. Haemophilia 2015; 21: e77–80. 2 Astermark J. Why do inhibitors develop? Principles of and factors influencing the risk

for inhibitor development in haemophilia. Haemophilia 2006; 12(Suppl. 3): 52–60. 3 Lee CA, Lillicrap D, Astermark J. Inhibitor development in hemophiliacs: the roles of genetic versus environmental factors. Semin Thromb Hemost 2006; 32(Suppl. 2): 10–4. 4 Iorio A, Puccetti P, Makris M. Clotting factor concentrate switching and inhibitor

development in hemophilia A. Blood 2012; 120: 720–7. 5 Soucie JM, Miller CH, Kelly FM, Oakley M, Brown DL, Kucab P. A public health approach to the prevention of inhibitors in hemophilia. Am J Prev Med 2014; 47: 669– 73.

Haemophilia B acquired from liver transplantation: a case report and literature review K . B E R G S T R O M , * A . S T E V E N S , * L . S R I V A T H S , * J . E C O N O M I D E S † ‡ and D . L . Y E E * *Department of Pediatrics: Hematology-Oncology Section, Texas Children’s Hematology and Cancer Centers, Baylor College of Medicine; †Department of Surgery, Transplant Services, Texas Children’s Department of Gastroenterology Hepatology, and Nutrition; and ‡Texas Children’s Hospital, Houston, TX, USA

Acquired haemophilia is a rare disorder and is almost universally mediated through autoantibodies, usually as acquired haemophilia A [1]. Although even less common, autoantibody-mediated acquired haemophilia B has been described [2]. We report here an unusual case of haemophilia B acquired via orthotopic liver transplantation (OLT). OLT is an established therapy for the advanced liver disease that was once a frequent treatment sequela in haemophiliacs. Additionally, although undertaken for liver disease, OLT cures underlying haemophilia [3]. Here, we report the converse, a case of acquired haemophilia B following OLT, confirmed by genetic testing. A 28-month-old Caucasian male was referred to the haematology service for consultation due to a persistently prolonged activated partial thromboplastin time (aPTT), of 61 s (normal 24–35 s) identified during a hospital stay for gastroenteritis. Prothrombin time was normal at 14.3 s (normal 11.5–14.5 s). Factor VIII (FVIII) and FXI were normal, but FIX was measured at 8% and no inhibitor (including lupus anticoagulant) was identified. The past medical history was significant for circumcision in the neonatal period and a Kasai procedure at age 1 month, both without bleeding complications, and an OLT at age 19 months for biliary atresia. In the postoperative period following the OLT, there was mild oozing from the surgical scar, which required resuturing. He subsequently experienced episodes of prolonged bleeding following venipuncture, and Correspondence: Donald L. Yee, Texas Children’s Clinical Care Center, 6701 Fannin St. Suite 1580, Houston, TX 77030, USA. Tel.: 832 822 1570; fax: 832 825 0285; e-mail: [email protected] Accepted after revision 16 April 2015 Haemophilia (2015), 21, e322--e343

several bruising incidents that were slow to heal. Abdominal bruising was noted following routine liver biopsies. His mother reported a black eye lasting 1 month. Of note, the patient had a normal aPTT (29.5 s) and no bleeding (spontaneous or posttrauma/surgery) or bruising problems prior to OLT. There was no family history of haemophilia or other bleeding disorders. The patient was diagnosed with mild haemophilia B, presumed to be acquired from his OLT, but due in part to his mild bleeding symptoms, maintained only sporadic follow-up with the haemophilia treatment centre. Over the next few years, baseline FIX levels varied from 5% to 12%. Bleeding episodes were infrequent and usually trauma induced, including occasional nosebleeds, bleeding that occurred following a tonsillectomy and adenoidectomy at age three, bruising related to sports activity and a bleed associated with trauma from a dirt bike accident. Now an adolescent, the patient is an active baseball player. He does not require FIX prophylaxis, but receives FIX infusions as needed for his infrequent trauma-related bleeds. At age 10, F9 gene sequencing followed by deletion/ duplication testing was performed on the patient’s leucocytes using direct DNA sequence analysis with fluorescent detection and multiplex ligation-dependent probe amplification (MLPA) techniques. An abnormality in the F9 gene was not identified. At age 13, the patient had a liver biopsy performed for reasons unrelated to his haemophilia diagnosis, and DNA was extracted from a sample of the transplanted liver tissue. F9 gene sequencing was performed on this sample and revealed a g.10415C>G (p.Pro55Ala) mutation, which had not been detected in the patient’s peripheral blood leucocytes. © 2015 John Wiley & Sons Ltd

LETTERS TO THE EDITORS

This F9 mutation has been identified previously in other patients with mild haemophilia B [4] and appears to be more common in the African American population. Of note, the liver donor was a 14-yearold African American male who died of a subdural haematoma after a fall. Although his family denied a family history of bleeding disorders on the donor questionnaire, they described a donor history of bleeding after tonsillectomy requiring three units of transfused blood 2 months prior to his death. Moreover, during organ recovery, the donor’s aPTT was measured at 38.5 s and he received another three units of transfused blood. Part of the donor’s liver also went to an adult female recipient, who was lost to followup after she moved out of the country. Prior to her relocation, there were no records of bleeding issues or health concerns. Since infectious hepatitis and consequent end stage liver disease were common complications of therapy for haemophilia in the prerecombinant factor era, cases of OLT leading to improvement or cure of congenital haemophilia are well documented [3]. However, to our knowledge, this is the first reported case of haemophilia B transmitted via liver transplantation. Given the liver’s role in the synthesis of proteins critical to haemostasis and its regulation, it is perhaps not surprising that transmission of other haemostatic deficiencies via OLT has been reported, especially involving proteins thought to be produced exclusively by the liver (see Table 1). In some rare cases, the grafts were knowingly transplanted from affected donors to previously unaffected recipients because the benefit of OLT was felt to outweigh the risk from the haemostatic disorder. Interestingly, each organ donor in the previously described cases died after trauma, most after intracranial haemorrhage. In our patient’s case, however, mild haemophilia B was not reported, and likely not previously diagnosed in the donor, but only became recognized as an acquired disorder in the liver recipient after he developed mild bleeding symptoms and laboratory abnormalities. Prothrombotic disorders with a genetic basis have also rarely been reported as transmitted via OLT [5]. Currently, donor screening for bleeding disorders does not mandate any routine laboratory testing but only requires answering

References 1 Coppola A, Favaloro EJ, Tufano A, Di Minno MN, Cerbone AM, Franchini M. Acquired inhibitors of coagulation factors: part I-acquired hemophilia A. Semin Thromb Hemost 2012; 38: 433–46. 2 Franchini M, Lippi G, Favaloro EJ. Acquired inhibitors of coagulation factors: part II. Semin Thromb Hemost 2012; 38: 447–53.

© 2015 John Wiley & Sons Ltd

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Table 1. Transmission of haemostatic factor deficiencies via OLT. Haemostatic factor deficiency

Age of recipient (years)

Recipient pretransplant factor level (%)

Recipient posttransplant factor level (%)

FVII FVIII

29 62

NR >100

12 100

22 2

FXII

62

NR