Exercise Versus DDAVP in Patients With Mild Hemophilia A

Persons with mild hemophilia A (MHA) (defined as having a FVIII level of >5% to ≈50%) bleed
infrequently but can in the setting of trauma which can often is in the context of
participating in sports/exercise. FVIII levels temporarily rise with stress, exercise and
with DDAVP (1-desamino-8-Darginine vasopressin, desmopressin). In the case of DDAVP, the
Hospital for Sick Children (SickKids) Hemophilia Team and others have shown that FVIII and
VWF levels rise by 2-4 fold with DDAVP. Consequently many persons with MHA in an attempt to
reduce their risk of bleeding take intranasal (IN) DDAVP prior to sports activities/exercise.
IN DDAVP is reasonably expensive ($300/bottle of Octistim® in Canada and $700/bottle of
Stimate® in USA), requires fluid restriction, and may be associated with nausea, vomiting,
seizures and tachyphylaxis.

Recently, our group completed a pilot/feasibility study to evaluate the impact of a
prescribed, moderate intensity aerobic exercise regimen on hemostatic indices in 30 children
with hemophilia A [HA] or B [HB] (all severities) and documented a significant improvement in
multiple coagulation parameters (platelet count, FVIII:C and von Willebrand factor [VWF])
with exercise. This improvement was particularly pronounced in 13 post-adolescent males with
mild-moderate HA. In this sub-cohort, the investigators noted a mean 2.3 fold increase in
FVIII:C immediately after exercise, which remained significantly elevated at 1.9 fold,1 hour
after completion of exercise

These changes in hemostatic variables associated with aerobic exercise may be protective
against bleeding, and may negate the need to administer IN DDAVP immediately prior to sports
participation.

Although both exercise and DDAVP can raise FVIII/VWF levels, it is not clear whether the
pathophysiological mechanism in which they do this is the same. Consequently it is not known
if DDAVP and exercise would augment each other's effects in raising FVIII:C and VWF levels or
if one would one negate the effect of the other. Herein, the investigators propose a
prospective, interventional study of exercise vs IN DDAVP in 40-50 post adolescent (13-21 yr)
males with MHA to compare their impact on hemostasis and also to investigate the impact of
sequentially administering these interventions on hemostatic indices.

Inclusion Criteria:

- 1) Patients of ≥13 years of age and ≤21 years of age with MHA (FVIII:C level of ≥6% to
≤50%).

Exclusion Criteria:

1. A currently circulating or a history of inhibitor (0.5 BU on two or more occasions).
Inhibitor development is rare in MHA.

2. History of FVIII infusion (both standard-acting and extended half-life products) or
DDAVP use in preceding 1 week. Patients will be instructed to hold factor use or DDAVP
for 1-week prior to participation in study, except for management of acute bleeds, in
which case they will be instructed to inform the PI via telephone or e-mail.

3. Patients with severe arthropathy (as determined by the principal investigator)
interfering with ability to exercise. Severe arthropathy is rare in MHA.

4. Patients on beta-blockers, anti-platelet agents or regular non-steroidal
anti-inflammatory medications (e.g. Celebrex).

5. Patients who are active smokers (cigarettes, marijuana).

6. Patients with a history of a recent bleed (in preceding 2 weeks) in any location or a
joint/muscle bleed in the lower limbs in the preceding 4 weeks.

7. Co-existence of a congenital bleeding disorder other than MHA (e.g. VWD).

8. Patients with an active infectious or inflammatory condition. This includes previously
identified HIV, active hepatitis B or C as reflected in elevated AST, ALT, RNA
positivity for hepatitis B or C. HIV, hepatitis B and C are very rare in the age group
(13-21 years) we hope to accrue in the proposed study.

9. Patients who for medical reasons should not receive DDAVP [those with renal or CNS
disease (e.g. brain tumor)] or have previously experienced adverse events with DDAVP
(e.g. hypotensive event, seizure).