Dr. Paul GiangrandeGreen 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 beingused in clinical studies to include both patientswith 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 nonseverehaemophilia:

• 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 mildhaemophilia:

One stage clotting ChromogenicPatient sample

• Factor deficient plasma• aPTT reagent & Ca++

Met

hod

Goa

lM

etric

• Purified proteins• Ca++

• Fibrin formation

• Turbidity

• FXa generation

• Colorimetric

Relevance to diagnosis:• Significant discrepancy between results of

one stage and two stage/chromogenic FVIIIassays in large proportion of patients withmild and moderate haemophiliaPoulsen Al et al. Haemophilia 15: 285-289 (2009)

• One stage result may be normal whilst twostage/chromogenic assay result is low

• Bleeding tendency correlates best withlower two stage/chromogenic result

• No discrepancy in severe haemophilia

Relevance to diagnosis:

• Some reports of reverse discrepancy (low onestage/normal chromogenic) but these patientsgenerally 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 mutationStoof SCM et al. Thromb Haemostas 109: 440-449 (2013)

– Poor response with R2169H and P149R• Lower absolute increase in factor VIII level

observed in patients with blood group OMauser-Bunschoten EP et al. J Thromb Haemostas 11: 2179-2181 (2013)

• Safe to use during pregnancy in carriersTrigg DE et al. Haemophilia 18: 25-33 (2012)

• May be of therapeutic benefit in somecases of type 2 VWD (not just type 1)

Inhibitor development innonsevere haemophilia:

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

• 1112 nonsevere haemophilia A patientsfrom 14 centres in Europe and Australiathat had genotyped ≥ 70% of their patients

• During 44,800 exposure days (median, 24per patient), 59 of the 1112 patientsdeveloped an inhibitor:– Cumulative incidence of 5.3%– After a median of 28 exposure days

Inhibitor development innonsevere haemophilia:

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

• The inhibitor risk after 50 exposure dayswas 6.7% (95% CI, 4.5-8.9)

• The risk increased to 13.3% after 100exposure days (95% CI, 9.6-17.0)

• Among a total of 214 different F8missense mutations, 19 were associatedwith inhibitor development

• These results emphasize the importanceof 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 sourcepopulation 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 rechallengein 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 sustainedsuccess (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