Whole clotting assessment as predictor of clinical phenotype in patients with severe haemophilia A

Haemophilia A is a congenital coagulation disorder, caused by a decreased level
of clotting factor VIII (FVIII > 0.01 IU/mL, known as mild/moderate haemophilia
A) or a complete absence of FVIII (FVIII < 0.01 IU/mL, known as severe
haemophilia A).
Patients with severe haemophilia suffer from recurrent haemarthroses, resulting
in haemophiliac arthropathy, muscle bleeds and life threatening bleeding,
causing a decreased life expectancy.
Although all these patients have no FVIII plasma level, a heterogeneity in
clinical phenotype (age of first joint bleeding and/or bleeding frequency) is
observed.
Patients with severe haemophilia are treated with FVIII replacement therapy on
a prophylactic schedule, i.e. three times a week 25-40 IU/kg in order to
minimize the amount of joint bleeds. In general, these treatment regimens are
fixed regimens. If a patient on prophylaxis has no joint bleeds, it can be
caused by adequate treatment or by over-treatment.
Since haemophilia treatment is very costly (about 100,000-200,000 ¤/year), cost
awareness and measurements to reduce costs are important. Proper predictions of
the clinical phenotype will make it possible to individualize the haemophilia
treatment and hopefully to reduce the cost. Furthermore, the risk of
over-treatment (e.g. induction FVIII inhibiting antibodies) may be reduced.

Since the residual FVIII level is not able to predict the clinical phenotype
accurately, other haemostatic tests are needed, to serve as a more reliable
base for treatment regimens. Assessment of the whole clotting system, by using
a modified thrombin generation test (TM-ETP) in combination with the total
thrombus-formation analyzing system (T-TAS), is a promising candidate as it
provides information about different aspects of the haemostatic system. It is
hypothesized that assessment of the whole clotting system will have the ability
to predict the clinical severity more accurately, since more determinants of
the phenotype are included in the assessment.

The aim of this study is to investigate if there is a correlation between the
clinical phenotype (defined as age of first bleeding and bleeding score) of
patients with severe haemophilia A and the results of the whole clotting
assessment (TM-ETP + T-TAS).
The results will contribute to a better understanding of the interplay between
the coagulation system and the clinical severity, more accurate predictions of
the course of haemophilia and a more reliable base for prophylactic treatment
of haemophilia A.

A retrospective study, including 14 patients with severe haemophilia A at both
ends of the clinical spectrum, e.g. a mild phenotype (n= 7) or a severe
phenotype (n= 7). The whole clotting assessments of both groups will be
compared with the clinical severity parameters.

Patients with severe haemophilia visit the outpatient clinic every 3 to 6
months and refrain prophylactic administration of FVIII concentrate for at
least 3 days prior to the visit in order to test their nadir FVIII level and to
perform inhibitor testing. During this outpatient visit, extra blood (3 tubes
of 5 mL) for the whole clotting assessment will be drawn during the same
venapuncture used for regular blood testing. The total amount of drawn blood
will be less than 2.5 percent of the total circulating volume.

Several reasons make it unavoidable to include minors in this study.
Firstly, it is necessary to include patients who do not have developed
arthropathy yet to obtain a reliable correlation, because arthropathy
influences the bleeding pattern. Only minors and young adults have not
developed arthropathy yet.
Secondly, it is impossible to achieve clinical parameters in patients > 25
years in a reliable way, because these parameters (e.g. age of first joint
bleed) were not documented in the past.
Thirdly, prophylactic treatment starts at a young age and will be less
intensified after the patient reaches adulthood. As this study aims to predict
the clinical phenotype in children in advance, it is necessary to perform this
study in young patients.
Finally, as the incidence of severe haemophilia is estimated to be 9.5 births
per annum (see section 6.1) nationwide. The amount of patients with severe
haemophilia A aged >18 and <25 years is too small to perform a reliable study