Mild and moderate haemophilia: introduction Dr. Paul Giangrande - - PowerPoint PPT Presentation

• Dr. Paul Giangrande

Green Templeton College University of Oxford

paul.giangrande@gtc.ox.ac.uk

Mild and moderate haemophilia: introduction

ISTH definitions:

White GC et al. Thromb. Haemost. 85: 560 (2001)

Categories defined by factor VIII/IX level:

• Severe haemophilia: < 1% (0.01 IU/ml)
• Moderate haemophilia: 1-5%
• Mild haemophilia: > 5% - < 40%

The term “nonsevere” is increasingly being used in clinical studies to include both patients with mild and moderately severe haemophilia

den Uijl IEM et al. Haemophilia 17: 849-853 (2011)

den Uijl IEM et al. Haemophilia 17: 849-853 (2011)

Challenges of nonsevere haemophilia:

• Far more nonsevere than severe patients
• Diagnosis often delayed
• Patients generally far less engaged with

specialist haemophilia centres

• Danger of complacency: risk of bleeding

underestimated by patients and doctors

• Not trained to self-infuse concentrates
• Some of these patients develop inhibitors

– Dramatic impact on bleeding pattern

Sports-related injuries in mild haemophilia:

One stage clotting Chromogenic

Patient sample

• Factor deficient plasma
• aPTT reagent & Ca++

Method Goal Metric

• Purified proteins
• Ca++
• Fibrin formation
• Turbidity
• FXa generation
• Colorimetric

Relevance to diagnosis:

• Significant discrepancy between results of
• ne stage and two stage/chromogenic FVIII

assays in large proportion of patients with mild and moderate haemophilia

Poulsen Al et al. Haemophilia 15: 285-289 (2009)

• One stage result may be normal whilst two

stage/chromogenic assay result is low

• Bleeding tendency correlates best with

lower two stage/chromogenic result

• No discrepancy in severe haemophilia

Relevance to diagnosis:

• Some reports of reverse discrepancy (low one

stage/normal chromogenic) but these patients generally have no bleeding symptoms

• If you only use a one stage assay:

– Some cases of mild haemophilia will be missed – Some patients with moderate haemophilia will be incorrectly labelled as mild – Some normal subjects will be incorrectly labelled as having a bleeding disorder

Potgieter JJ et al. Eur J Haematology 94 (Suppl. 77): 38-44 (2015)

Type 2N VWD:

• Often mistaken for mild haemophilia A
• Defect is in N-terminal of VWF: factor VIII

binding to VWF is impaired

• Three mutations in exons 18-20 account for ≈

95% of cases: T791M, R816W, R854Q

• Factor VIII typically in range 3-15 iu/dl (%)
• VWF levels all normal (Ag/RCo/CB)
• Bleeding time is normal
• Autosomal recessive inheritance: both sexes

affected in family tree

• DNA-based studies will confirm diagnosis
• FVIII binding assay an alternative test

Lancet 309: 869-872 (1977)

DDAVP: what is new?

• Response improves with age

Revel-Vilk S et al. Br J Haematol 117: 847-951 (2002)

• Response dependent on F8 mutation

Stoof SCM et al. Thromb Haemostas 109: 440-449 (2013)

– Poor response with R2169H and P149R

• Lower absolute increase in factor VIII level
• bserved in patients with blood group O

Mauser-Bunschoten EP et al. J Thromb Haemostas 11: 2179-2181 (2013)

• Safe to use during pregnancy in carriers

Trigg DE et al. Haemophilia 18: 25-33 (2012)

• May be of therapeutic benefit in some

cases of type 2 VWD (not just type 1)

Inhibitor development in nonsevere haemophilia:

Eckhardt C and INSIGHT Study Group. Blood 122: 1954-1962 (2013)

• 1112 nonsevere haemophilia A patients

from 14 centres in Europe and Australia that had genotyped ≥ 70% of their patients

• During 44,800 exposure days (median, 24

per patient), 59 of the 1112 patients developed an inhibitor:

– Cumulative incidence of 5.3% – After a median of 28 exposure days

Inhibitor development in nonsevere haemophilia:

Eckhardt C and INSIGHT Study Group. Blood 122: 1954-1962 (2013)

• The inhibitor risk after 50 exposure days

was 6.7% (95% CI, 4.5-8.9)

• The risk increased to 13.3% after 100

exposure days (95% CI, 9.6-17.0)

• Among a total of 214 different F8

missense mutations, 19 were associated with inhibitor development

• These results emphasize the importance
• f F8 genotyping in nonsevere hemophilia

Outcome and eradication strategies:

van Velzen A and INSIGHT Study Group. Thromb Haemostas 114: 46-55 (2015)

• 101 inhibitor patients from a source

population of 2,709 nonsevere HA patients

– Median age 37 years; median peak titre 7 BU/ml

• Inhibitor disappeared in 72/101 (71%)

– Spontaneously 51/73 (70%) – After eradication treatment 21/28 (75%)

• Eradication strategies varied widely

– Conventional immune tolerance induction and immunosuppression

Outcome and eradication strategies:

van Velzen A and INSIGHT Study Group. Thromb Haemostas 114: 46-55 (2015)

• Anamnestic response seen after rechallenge

in 25/72 (35%) of patients who lost antibodies

– Disappearance does not always equal sustained response

• Sustained success was observed in 64 %

(30/47) of patients rechallenged

• In high-titre inhibitor patients, eradication

treatment was associated with sustained success (RR 2.3)

Principal conclusions:

• Need to improve engagement of nonsevere

patients with treatment centres

• Patients and health care professionals often

underestimate potential for bleeding

– Bleeds caused by sporting injuries can be severe

• Response to DDAVP linked to F8 mutations
• Patients can develop inhibitors after treatment

with coagulation factor concentrates

• Chromogenic assay best for reliable diagnosis
• Always exclude possibility of 2N VWD