- A 55-year-old male presented with soft tissue bleeding and a prolonged activated partial thromboplastin time. He was diagnosed with acquired hemophilia caused by autoantibodies against factor VIII. - Acquired hemophilia is a rare but serious condition typically treated initially with prednisolone and possibly cyclophosphamide. However, up to a third of patients may be refractory to this first-line treatment. - Rituximab, a monoclonal antibody against CD20, shows promising evidence as an alternative treatment with similar remission rates to standard therapy and possible additional benefits, but randomized studies are still needed.

2. Overview
• Case Example
• Acquired Haemophilia
• Factor VIII Inhibitors and coagulation
• Inhibitor elimination: the debate

3. Case Study
55 year old male
• Swollen, bruised left arm
• No trauma
• Increased bleeding on tooth brushing
Presenting
Complaint
• IV drug use as a teenager
• Diagnosis hepatitis C in 1990
Past Medical
History
• IFN-α and Ribavirin for hepatitis CDrug History
Soft tissue bleed in
acquired haemophilia 1

4. Investigations
FBC: Hb 12.4
LFT: Bilirubin 22
Clotting: INR 0.9,
Fibrinogen 2.8, aPTT 76s
Bethesda Assay: Factor VIII
1.8%

5. Acquired haemophilia
Key Features: 2
• Anaemia
• Prolonged aPTT
• Factor VIII
inhibitors
Epidemiology: 3
• 1.48 per million
• Median age 78 years
• Autoimmune disorders &
malignancies
• High morbidity & mortality

6. What are Factor VIII
Inhibitors?
IgG autoantibodies (Type 2 kinetics)
Action: 4,5
1.) Bind factor VIII at A2,A3,C2 domains
2.) Alter binding of vWF and Factor IXa
3.) Prevent thrombin generation
Kinetics of Factor VIII Inhibitors 2

7. Pathophysiology
Figure 1: Life cycle of factor VIII 6
Inhibitor binding
at C2 domain
disrupts vWF
binding.3
Inhibitor binding at
A2 and A3 domains
disrupts FIXa and FX
binding.3

8. Inhibitor elimination:
The debate
Prednisolone +/- cyclophosphamide
• 1st line treatment (UKHCDO)7
Efficacy:
Prospective randomised trial 31 patients:8
1/3 respond prednisolone
50% of non-responders respond to cyclophosphamide
1/3 fail to respond

9. Rituximab vs. standard
therapy
Efficacy:
78.6% remission in analysis of 42 cases
66% sustained remission for 2 years9
No randomised studies to date
Advantages Disadvantages
Avoid steroid use Cost vs. 1st line
Similar remission
to 1st line therapy10
Risk of neutropenic
sepsis 10
Possible dual
benefit -
autoimmune
comorbidities 10
Monoclonal antibody against CD20

10. Summary
• Acquired haemophilia is a rare cause of severe bleeding
• Caused by autoantibodies to factor VIII
• Associated with high morbidity and mortality
• Up to 1/3 fail to respond to 1st line treatment
• Promising evidence for use of Rituximab but randomised trials
needed

11. References
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patient with bullous pemphigoid, rheumatoid arthritis, and vitiligo. Postgrad Med J 2006;82:
2.) Ma AD, Carrizosa D. Acquired Factor VIII Inhibitors: Pathophysiology and Treatment. American Society of Hematology. 2006.
432-437
3.) Collins PW, Hirsch S, Baglin TP, Dolan G, Hanley J, Makris M, Keeling DM, Liesner R, Brown SA, Hay RM. Acquired hemophilia
A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors'
Organisation. Blood. 2007. 109: 1870-1877
4.) Fay PJ, Scandella D. Human inhibitor antibodies specific for the factor VIII A2 domain disrupt the interaction between the
subunit and factor IXa. J Biol Chem . 1999 Oct 15;274(42):
5.) Scandella DH. Properties of anti-factor VIII inhibitor antibodies in haemophilia A patients. Semin Thromb Hemost. 2000:
26(2):137-142.
6.) Lenting, P.J., Mourik, J.A., Mertens, K. The Life Cycle of Coagulation Factor VIII in View of Its Structure and Function. Blood.
1998. 92 (11):3983-3996.
7.) Hay CRM. The 2000 United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) Inhibitor Guidelines.
Pathophysiol Haemost Thromb. 2002; 32(suppl 1): 19-21.
8.) Green D, Rademaker AQ, Bret E. A Prospective Randomised Control Trial of prednisone and cyclophosphamide in the
treatment of patients with factor VIII autoantibodies. Throm Haemost. 1993: 70: 753-757
9.) Sperr WR, Lechner K, Pabinger I. Rituximab for the treatment of acquired antibodies to factor VIII. Haematologica. 2007;
92:66-71.
10.) Machado P, Raya JM, Martin T, Morabito L, Brito ML, Rodriguez-Martin JM. Successful response to rituximab in two cases of
acquired haemophilia refractory to standard therapy. Int J Hematol. 2008. 87:545-549.