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 Table of Contents  
Year : 2022  |  Volume : 13  |  Issue : 4  |  Page : 285-287

Immune tolerance induction in a severe hemophilia B child with low titer inhibitors

Hematology Oncology Unit, Tawam Hospital, SEHA, Al Ain, UAE

Date of Submission26-Nov-2021
Date of Decision03-Apr-2022
Date of Acceptance03-Jun-2022
Date of Web Publication18-Oct-2022

Correspondence Address:
Dr. Asia Almulla
Hematology Oncology Unit, Tawam Hospital, SEHA, Al Ain
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joah.joah_165_21

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Hemophilia B is an X-linked inherited bleeding disorder caused by either the absence or reduced biosynthesis of clotting factor IX (FIX). This disorder affects approximately 1 in 30,000 male individuals worldwide. Patients with severe form (FIX <1%) account for 30%–45% of hemophilia B cases and usually report of spontaneous bleeds. Treatment includes FIX replacement prophylactically to prevent complications. However, the patient may develop inhibitors against FIX, which is rare and a serious complication, reported to occur in 1.5%–3% of hemophilia B patients. Immune tolerance induction is a therapeutic strategy to eliminate inhibitors. We report a 14-month-old-male child with severe hemophilia B on primary prophylaxis, presented with right knee swelling. He developed anaphylactic reaction while receiving recombinant FIX concentrate. Investigation revealed that FIX inhibitor titers were 1.0 Bethesda Units. He was managed with immune tolerance induction successfully.

Keywords: Bleeding disorder, Hemophilia b, immune tolerance induction, immunosuppressive therapy, inhibitor[/TAG:2]

How to cite this article:
Almulla A, Awan N, Khanani F. Immune tolerance induction in a severe hemophilia B child with low titer inhibitors. J Appl Hematol 2022;13:285-7

How to cite this URL:
Almulla A, Awan N, Khanani F. Immune tolerance induction in a severe hemophilia B child with low titer inhibitors. J Appl Hematol [serial online] 2022 [cited 2022 Dec 4];13:285-7. Available from: https://www.jahjournal.org/text.asp?2022/13/4/285/358705

  Introduction Top

Hemophilia B is an X-linked recessive blood coagulation disorder caused due to deficiency of factor IX (FIX).[1] Globally, it is the second most common form of hemophilia, affecting 1 in 30,000 live male births.[1],[2] Bleeding tendency correlates with factor deficiency severity, wherein 5%–40% of the activity is classified as mild form, 1% to 5% as moderate, and <1% severe.[3] Patients with severe form (FIX <1%) account for 30%–45% of hemophilia B cases, and usually report of spontaneous bleeds and suffer from recurrent soft-tissue hematomas and hemarthroses.[4] Treatment of hemophilia B involves the replacement of FIX with plasma-derived or recombinant FIX concentrates, either given as scheduled infusions per week prophylactically or to manage a bleeding episode.[2] The development of inhibitors against FIX is a rare and serious complication reported to occur in 1.5%–3% of hemophilia B patients.[5] Inhibitor development is associated with a significant risk of morbidity, related not only to uncontrollable bleeding, but also to the frequent occurrence of anaphylaxis and nephrotic syndrome.[4] Immune tolerance induction (ITI) is a therapeutic strategy to eliminate inhibitors through regular high doses of FIX infusions.[6] ITI is less likely to be effective in hemoglobin (HB) patients as compared to hemophilia A patients.[7] Immunosuppressive therapy along with ITI is considered beneficial in increasing the proportion of success and decreasing the length of time for tolerance induction. Rituximab an anti-CD 20 is used as adjuvant therapy for ITI treatment.[6],[7] Since hemophilia B is less common than hemophilia A and inhibitor development in HB being rare and very challenging. The objective of this work is to report a case of a 14-month-old child diagnosed with severe hemophilia B along with the development of low titer inhibitor in early childhood and managed with ITI.

  Case Report Top

An 8-month-old male child of Palestinian origin with hemophilia B was referred to our center for follow-up and management. At 1 month of age, when he presented with a prolonged bleeding episode of 9 days following circumcision. There is no family history of any bleeding disorder. He received fresh-frozen plasma and packed red blood cells and underwent several investigations to rule out bleeding diathesis. The results revealed FIX activity of <1%, confirming the diagnosis of severe hemophilia B. Initially, the patient did not show any signs of frequent bleeding, but at 8 months of age, spontaneous bruises were observed, so he was referred to our center for further management. He was started on primary prophylaxis with long-acting recombinant FIX every 2 weeks and the occurrence of spontaneous bruises reduced subsequently. He remained symptom-free for 6 months on prophylaxis, but at 14 months of age, he presented with the right knee swelling. He received recombinant FIX concentrate to treat acute bleeding, but the patient developed an anaphylactic reaction with suspicion of inhibitor development to recombinant FIX. Acute bleeding was managed with recombinant factor VII replacement. Investigation revealed that FIX inhibitor titers were 1.0 Bethesda units (BU) and FIX recovery <0.5%.

He was initially kept on factor VII on-demand treatment. As he was a very active toddler and started frequent bruising, so he was kept on factor VII prophylaxis 90 mcg/kg daily for few weeks. Due to the increasing frequency of significant bleeds and persistent low titer FIX inhibitors, international experts' consultation was done and was planned to start ITI with immunomodulation (modified Beutel protocol). He received four doses of rituximab at 375 mg/m2 although it was interrupted due to central line infections requiring removal of Port a Cath and then reinsertion. ITI with long-acting recombinant FIX was started after the second dose of rituximab at 50 units/kg q 48 h. He was initially kept on daily factor VII, but later on, switched to on-demand as he improved with no clinically significant bleeding [Table 1] and [Table 2]. With ITI and immunomodulation, FIX recovery improved and inhibitor titers became negative. No anaphylactic reactions or renal complications were witnessed during the therapy. Currently, the patient is on ITI therapy for 6 months and we recorded a good clinical and paraclinical response [Figure 1].
Table 1: Factor IX inhibitor and Factor IX recovery

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Table 2: Immune tolerance induction with immunomodulation and factor VII

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Figure 1: Study flowchart

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  Discussion Top

Inhibitors are the high-affinity polyclonal antibodies, neutralizing the procoagulant activity of a coagulation factor. Inhibitor development to FIX is a rare complication and its management corresponds to the titer of the inhibitor, where less than <5 BU/ml is considered low titer and ≥5 BU/ml as high titer.[8] In the present case, inhibitors developed to recombinant FIX after several doses of prophylactic therapy. The incidence of inhibitor development is approximately 30% in HA and 3% in hemophilia B. They tend to develop early in the course of replacement therapy and relatively more early in childhood, which makes the management more challenging.[1]

ITI therapy is the mainstay for treatment, where the patient is given regular high doses of factor infusion.[6] However, ITI carries a significant risk of developing anaphylactic reaction and nephrotic syndrome which corresponds to its low success rates in hemophilia B patients.[7] Since the development of antibodies depends on the immune system, it has been postulated that immune system modulation may improve ITI response.[1] Several reports have been published, investigating ITI with rituximab, and other immunosuppressive agents such as mycophenolate mofetil (MMF) and intravenous immunoglobulins (IVIG).[7],[9] Rituximab is an anti-CD20 lymphocyte antibody, and its successful use in treating hemophilia B patients with inhibitors has been documented in the literature.[7],[10] No clear consensus guidelines are present, as to which method is optimal for the management of hemophilia B patients with inhibitors.

Beutel protocol – 50-day course includes ITI along with immunosuppressive agents (FIX 100 IU/kg twice daily, rituximab 375 mg/m2 × 4 doses, MMF 300 mg/m2/dose daily, dexamethasone 6 mg/m2/dose in a pulsed manner, and IVIG 1 g/kg × 6 doses).[11] As our patient has low titer inhibitors but with frequent and clinically significant bleeds, so we managed him as per modified Beutel protocol. The patient was treated with IV infusion of rituximab along with long-acting FIX concentrate to reduce the chances of nephrotic syndrome and anaphylaxis. Our patient did not develop any adverse reactions throughout the ITI. Rituximab in combination with ITI helped in achieving negative FIX inhibitor and good FIX recovery with no adverse events in severe hemophilia patients with low titer inhibitor.

Findings from the present case report determine the efficacy of ITI with rituximab and it can be concluded that immunomodulation with rituximab is a helpful adjuvant to ITI to achieve success and decreases the risks of complications. Therefore, simultaneous administration of FIX concentrate and rituximab is emphasized. However, the risk of allergic reaction during ITI should be closely monitored in a well-equipped clinical setting to manage emergency conditions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Karim MA, Jamal CY. A review on hemophilia in children. Bangladesh J Child Heal 2013;371:27-40.  Back to cited text no. 1
Franchini M, Frattini F, Crestani S, Sissa C, Bonfanti C. Treatment of hemophilia B: Focus on recombinant factor IX. Biologics 2013;7:33-8.  Back to cited text no. 2
Simões R, Adnet G, Quintans M, Costa Bueno A. When to consider hemophilia in the neonatal period? A case report. Residência Pediátrica 2018;8:134-6.  Back to cited text no. 3
Santoro C, Quintavalle G, Castaman G, Baldacci E, Ferretti A, Riccardi F, et al. Inhibitors in hemophilia B. Semin Thromb Hemost 2018;44:578-89.  Back to cited text no. 4
DiMichele D. Inhibitor development in haemophilia B: An orphan disease in need of attention. Br J Haematol 2007;138:305-15.  Back to cited text no. 5
Mariani G, Siragusa S, Kroner BL. Immune tolerance induction in hemophilia a: A review. Semin Thromb Hemost 2003;29:69-76.  Back to cited text no. 6
Kobayashi R, Sano H, Suzuki D, Kishimoto K, Yasuda K, Honjo R, et al. Successful treatment of immune tolerance induction with rituximab in a patient with severe hemophilia B and inhibitor. Blood Coagul Fibrinolysis 2015;26:580-2.  Back to cited text no. 7
Bertamino M, Riccardi F, Banov L, Svahn J, Molinari AC. Hemophilia care in the pediatric age. J Clin Med 2017;6:54.  Back to cited text no. 8
Klarmann D, Martinez Saguer I, Funk MB, Knoefler R, von Hentig N, Heller C, et al. Immune tolerance induction with mycophenolate-mofetil in two children with haemophilia B and inhibitor. Haemophilia 2008;14:44-9.  Back to cited text no. 9
Alexander S, Hopewell S, Hunter S, Chouksey A. Rituximab and desensitization for a patient with severe factor IX deficiency, inhibitors, and history of anaphylaxis. J Pediatr Hematol Oncol 2008;30:93-5  Back to cited text no. 10
Abajas YL, Monahan PE, Nielsen B, Petrini P, Ranta S, Allen GA, et al. Immune tolerance induction for FIX inhibitors using combined B and T cell immune modulation therapy in severe hemophilia B. Blood 2018;132 Suppl 1:1193.  Back to cited text no. 11


  [Figure 1]

  [Table 1], [Table 2]


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