acquired hemophilia CME medical JAN 2024.pptx

acquired hemophilia

1. Diagnosis and Management of Acquired Haemophilia (A)

2. Introduction Acquired hemophilia A (AHA) is an acquired bleeding disorder caused by neutralizing autoantibodies (inhibitors) against coagulation factor VIII (FVIII) Rare disease- 1.5 cases per million person per year 50% has underlying medical condition. Eg. elderly, usually has malignancy ; young female, due to autoimmune disorder or pregnancy ; Medications Knoebl  P, Marco P,  Baudo  F, et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost . 2012;10 (4):622‒63 Tiede A, Collins P, Knoebl P, et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica 2020; 105:1791

3. The differences Congenital Hemophilia  Acquired Hemophilia Pattern of inheritance Inherited or sporadic Acquired History History of bleeding, including family Hx Previously no history of bleeding No family Hx of bleeding Age distribution Usually diagnosed since young Usually, elderly Pathophysiology Due to deficiency, although some will produce alloantibody  Due to autoantibody Mixing test Mixing test- Correctable unless develop inhibitor Mixing test-  Not correctable, time dependent Bleeding site Joints, soft tissues Subcutaneous or Visceral bleeding. Hemathrosis rare Meera S, Rajiv KP. Autoimmune (Acquired) Hemophilia: Updates in Diagnosis and Therapy The Hematologist (2022) 19 (2) https:// doi.org /10.1182/hem.V19.2.2022214

4. Coagulation cascade: Acquired Hemophilia Autoantibody – impair function – reduce half life Factor Va Dammann, Kyle & Gifford, Amanda & Kelley, Kathryn & Stawicki, Stanislaw. (2020). Operative Hemostasis in Trauma and Acute Care Surgery: The Role of  Biosurgical  Agents. 10.5772/intechopen.94100.​ Arai M, Scandella D, Hoyer LW. Molecular basis of factor VIII inhibition by human antibodies. Antibodies that bind to the factor VIII light chain prevent the interaction of factor VIII with phospholipid. J Clin Invest 1989; 83:1978.https://doi.org/10.1182/hem.V19.2.2022214

5. Clinical manifestation Spontaneous bleeding (80-90%) Sudden presence of hematoma or extensive ecchymosis. Hemarthrosis rare. No history of bleeding & trauma Elderly Cancer, Autoimmune, Postpartum, Drugs Sometimes associated with skin lesion , eg. Pemphigus Asymptomatic/incidental in 10-20% Knoebl P, Marco P, Baudo F, et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost 2012; 10:622

6. Diagnosis History and Examination – Acute BLEEDING tendencies, FBC- low Hb if significant bleeding Coagulation – Prolonged APTT , normal PT in absence of OTHER causes including DIVC or medication Mixing test- not correctable +/- at 0 hr and definitely at 2 hr Rosner index – >15% ( not correctable) Factor level – very low , Inhibitor level - Positive in Bethesda Unit (Bu) More than 75-80% targets Factor 8  Acquired Haemophilia A Franchini M, Zaffanello M, Lippi G. Acquired hemophilia in pediatrics : a systematic review. Pediatr Blood Cancer 2010; 55:606 Baudo F, Collins P, Huth-Kühne A, et al. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012; 120:39

7. Differential Diagnosis Acquired bleeding disorders – Other acquired bleeding disorders include disseminated intravascular coagulation, acquired von Willebrand syndrome, and various causes of thrombocytopenia. Factor IX inhibitor, Factor XI inhibitor Heritable bleeding disorders – Heritable bleeding disorders include congenital hemophilia , von Willebrand disease, rare factor disorders, and vascular disorders such as hereditary hemorrhagic telangiectasia (HHT) or Ehlers-Danlos syndrome. Prolonged PT or aPTT – Other causes of prolonged clotting times include anticoagulants, vitamin K deficiency, and a lupus anticoagulant caused by antiphospholipid antibodies ( aPL ).

8. Mixing test

9. Evaluation for suspected acquired hemophilia A in adults

10. Management

11. Management STOP BLEEDING Assess severity of bleeding Conservative management in non severe bleeding (compression, tranexamic acid, avoid invasive procedure) Close observation and monitoring of Hb If acute, severe bleeding need pharmacological +/- surgical intervention ERADICATE ANTIBODY/INHIBITOR Steroid Immunosuppressive agent Start promptly upon diagnosis , taper down slowly over weeks to months Watch out for side effects, esp in frail patients Collins PW. Treatment of acquired hemophilia A. J Thromb Haemost 2007; 5:893. Tiede A, Collins P, Knoebl P, et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica 2020; 105:1791

12. Management of acute bleed Supportive: Packed cell transfusion, tranexamic acid, compression, avoidance of invasive procedure, source control Haemostatic agents Recombinant factor VIIa ( rFVIIa ) - 90mcg/kg every 2 hour 2. Factor eight inhibitor bypassing activity (FEIBA) • Activated factor VII, non-activated factors II, IX, X • 50U-100U/kg every 6-12hours with max 200U/kg/day Effectiveness • rFVIIa : 95% (Sumner et al, 2007), 92% ( Baudo et al, 2012) • FEIBA: 93% ( Baudo et al, 2012), 100% in moderate bleed, 76% in severe bleed within 48 hours ( Sallah , 2004)

13. INDIRECT COMPARISON Recombinant Activated Factor VII ( rFVIIa ) Activated Prothrombin Complex Concentrate (APCC) Recombinant Plasma derived, hence infusion reaction rFVIIa Non activated FII, FIX, FX, activated FVII Binds to Tissue Factor and activates FX, generates thrombin burst Replacing factor Dosing 90 mcg/kg every 2 to 3 hour until hemostasis secure 50 to 100 unit/kg max 200 unit/kg Infusion volume 2-8 ml 132ml Administration time 2-5 min slow bolus 2unit/kg/min  Redosing time/Frequency 2-3 hourly 8-12 hourly Duration of action  Half life: 2.3h; Mean peak coagulant activity occurred within 2–5 minutes 8 to 12 hour (based on thrombin generation) peak at 15 to 30 min Tissue targeted Systemic Less thrombotic risk Higher thrombotic risk Reference: NovoSeven Malaysia PI; FEIBA Malaysia PI; Bysted  BV et al. Haemophilia  2007;13:527 – 32

14. Eradication of inhibitor/antibody Steroid- Prednisolone 1mg/kg or equivalent taper in 4-6 weeks Cyclophosphamide- 1.5 to 2mg/kg/day taper in 4-6 weeks Tiede A, Collins P, Knoebl P, et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica 2020; 105:1791 Schep SJ, van Dijk WEM, Beckers EAM, et al. Treatment of acquired hemophilia A, a balancing act: results from a 27-year Dutch cohort study. Am J Hematol 2021; 96:51  Collins P, Baudo F, Knoebl P, et al. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). Blood 2012; 120:47 EACH2  STUDY Steroid Steroid + cyclophosphamide Complete remission 58% 80% Median time to remission 40 days 32 days Median time to stop  IST 108 days 74 days Adverse event 25% 41%

15. What’s new in the treatment of acquired hemophilia? Emicizumab - off label use In a series of 11 acquired hemophilia A patients treated with emicizumab (3 mg/kg weekly subcutaneously for four weeks in conjunction with rituximab-based immunosuppression), only one had breakthrough bleeding. In another series of 12 patients with acquired hemophilia A treated with emicizumab , breakthrough bleeding ceased and the aPTT normalized within one to three days Chen EC, Gibson W, Temoczko P, et al. Emicizumab for the treatment of acquired hemophilia A: Retrospective review of a single-institution experience. Haemophilia 2023; 29:84   Knoebl P, Thaler J, Jilma P, et al. Emicizumab for the treatment of acquired hemophilia A. Blood 2021; 137:410 Disclaimer: This is for scientific education purposes only and may contain information on unapproved products/ indications. Please follow Malaysia PI for full details.

16. THE END Thank you