Inhibitor Development in Patients With Hemophilia A Undergoing Surgery

Status:	Active, not recruiting
Conditions:	Anemia, Hematology
Therapuetic Areas:	Hematology
Healthy:	No
Age Range:	Any
Updated:	4/21/2016
Start Date:	November 2011
End Date:	March 2017

Hemophilia A is a genetic deficiency of factor VIII that causes blood to clot too slowly.
The disease is classified based on how much factor VIII is in the blood. People with mild or
moderate hemophilia A have low, but detectable, blood levels of factor VIII and bleed with
trauma or surgery. At the time of surgery, they need to receive factor VIII replacement by
infusion into the vein so that blood can clot normally and abnormal bleeding can be avoided.
A complication of hemophilia A is the development of an antibody that binds factor VIII and
makes the factor VIII infused for treatment not work properly. This antibody is called an
inhibitor. In mild and moderate hemophilia A, inhibitors are not common, but have been
reported to occur after intensive factor VIII infusions, as may occur at the time of
surgery. This study is designed to observe people with mild and moderate hemophilia A who
are having surgery. Information on the surgery, treatments given, bleeding, and infection
will be gathered. Also, blood will be drawn to determine how the immune system is reacting
to the factor VIII. No specific treatments will be given as part of this study. We will use
the information to determine what influences inhibitor development. A better understanding
of inhibitor development will help medical providers do things to avoid inhibitor
development in this population or researchers to design new treatments.

The development of neutralizing anti-factor VIII (fVIII) antibodies, fVIII inhibitor, is the
most significant complication affecting patients with hemophilia A (HA). Once an inhibitor
develops, treatment is less effective and costly. Although inhibitors occur most commonly in
those with severe HA, 25% of new inhibitors occur in those with non-severe HA. In patients
with non-severe HA, the development of a fVIII inhibitor can change the course of disease
from one that is easily managed to one with the potential for spontaneous life-threatening
difficult to treat bleeding. Although significant advances have been made in understanding
risk factors for fVIII inhibitor development in patients with severe HA, studies that seek
to understand the risk for fVIII inhibitor development in those with non-severe disease have
been limited to retrospective analyses. In these retrospective analyses, intensive fVIII
treatment and surgery have been identified as risk factors for fVIII inhibitor development
in non-severe HA. Additionally, receiving fVIII by continuous infusion has been associated
with fVIII inhibitor development in non-severe HA in some but not all studies and may be due
in part to a more robust proinflammatory response during continuous infusion. Accordingly,
the next logical step to evaluate the risk of inhibitor development associated with
continuous fVIII infusion is a prospective observational cohort study. Additionally,
knowledge of the immune response to fVIII in the surgical setting is essential for
identification of patients at high risk for inhibitor development and development of
strategies to prevent inhibitor development and is best evaluated in the setting of an
prospective cohort study.

This multicenter prospective observational cohort study will enroll a total of 140 subjects
at 10 centers who have mild or moderate hemophilia a (fVIII activity 1-40%) who are
scheduled to undergo surgery for which at least 5 consecutive days of fVIII replacement
therapy is required. The study will gather clinical data and collect blood specimens on 4
occasions over a 3 month period. Outcomes include: inhibitor development, total fVIII usage,
bleeding, and markers of T cell activation.

Inclusion Criteria:

- Males with mild/moderate hemophilia A (fVIII activity 1-40%)

- Planned surgical intervention which is anticipated to require 5 consecutive days of
fVIII replacement therapy (These can be outpatient or inpatient treatment days.)

- Weight >22.5 kg (To assure that volumes of blood to be drawn for study purposes are
safe.)

Exclusion Criteria:

- Past history of an inhibitor (inhibitor titer >0.4 BU/ml)

- HIV infection with CD4 count <400/ul

- Currently receiving immunosuppressive medication(s)

- Unable to tolerate quantity of blood to be drawn

- Current or past diagnosis autoimmune disorder

- Current or past diagnosis of immune deficiency disorder other than HIV

We found this trial at

sites

University of Colorado, Hemophilia and Thrombosis Center

Aurora, Colorado 80045

Principal Investigator: Jorge Di Paola

Phone: 303-724-0363

from

Aurora, CO