Whole clotting assessment as predictor of clinical phenotype in aged patients with 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.

Currently, a study is performed to find a correlation between the results of
these coagulation tests and bleedingsfenotype in young patients with servere
hemophilia (the Haemotype study). In older (>60 years) hemophiliacs it seems
there is a reduced bleedingsfenotype. In this study, we assess whether the new
clotting tests change with age.

As a result of the severity of the disease, there are very few aged haemophilia
patients with the severe form. As a result, this study, in contrast to the
Haemotype study, does not consist of patients with severe haemophilia

The results of the older patients (> 60 years) and younger patients (20-30
years) may be correlated with age. This can lead to new insights into the
coagulation system in older age and can possibly lead to improved
patient-oriented treatment.

The aim of this study is to investigate if there is a correlation between the
clinical phenotype (defined as age of first bleeding) of patients with
haemophilia A and the results of the whole clotting assessment (TMETP + 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 of 12 patients, of which 6 are aged between 20-30 years,
and 6 are aged older than 60 years. It concerns patients with a mild form of
haemophilia A.

The whole clotting assessments will be compared between both patient
populations, so a correlation can be made with age.

Patients with severe haemophilia visit the outpatient clinic every 8 to 12
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.