HEMOLEVEN® Expanded Access Program Prevention of Surgical/Postpartum Hemorrhage Severe Inherited Factor XI Deficiency

Many patients are asymptomatic until hemostatically challenged by surgery or trauma; so, the
diagnosis is often made in late childhood or early adulthood but always after full liver
maturation (i.e. 6 months) as reported by Andrew et al.

Spontaneous bleeding is rare, except menorrhagia, and bleeding occurs mainly after surgery
or injury. Bleeding is observed mainly in surgical sites with high fibrinolytic activity
such as mouth, nose, or the genitourinary tract.

Pregnancy, labor and delivery can also be challenging for women with FXI deficiency. In 1999
a study published in the American Journal of Hematology revealed that FXI levels are
inconsistent during pregnancy. The incidence of postpartum hemorrhage is increased in women
with factor XI deficiency. The incidence is 16% for the primary postpartum hemorrhage in FXI
patients, compared with 5% in the general population. Moreover, the incidence is 24% for the
secondary postpartum hemorrhage in comparison with that in the general obstetric population
(0.7%). The authors recommend that FXI levels be obtained during the initial visit and
monitored during the woman's third trimester. For all of these reasons it is important for
women who suspect they might have a FXI deficiency to be tested and diagnosed before
pregnancy.

Severe factor XI deficiency is defined by levels of <0.20 IU/mL. Such individuals have a
high probability of post-operative hemorrhage. Individuals with levels between 0.20 IU/mL
and the lower limit of the normal range, generally 0.65-0.80 IU/mL, are generally classified
as having partial or mild deficiency with a lower risk of post-operative bleeding. Partial
deficiency is being increasingly recognized following pre-operative tests or as a result of
family screening. Thus partial factor XI deficiency is often diagnosed in asymptomatic
individuals, creating management dilemmas because of the unpredictability of the bleeding
risk. To differentiate an isolated or combined bleeding disorder in a patient with factor XI
deficiency, other causes of bleeding should be investigated and excluded (e.g. von
Willebrand disease, platelet disorders).

Inclusion Criteria:

1. Severe inherited factor XI deficiency (FXI:C < 0.20 IU/mL i.e. <20 %)

2. Patient older than 6 months old and weight at least 8 kg

3. Known personal bleeding history

4. Patient requiring FXI replacement therapy when oral antifibrinolytic agents alone or
other means are ineffective or are contraindicated

5. Scheduled to undergo an elective surgical procedure (including caesarean section) for
which the patient requires hemostasis prophylaxis, which in the case of caesarean
section is due to a history of postpartum bleeding, OR vaginal delivery for which the
patient requires hemostasis prophylaxis due to a history of postpartum hemorrhage

6. Patient/guardian provides signed and dated Informed Consent for 'HEMOLEVEN Expanded
Access Program' prior to entry into the program

Exclusion Criteria:

1. Personal history of thromboembolic events

2. Underlying cardiopulmonary disease of NYHA Class III or greater

3. History of severe reaction to any component of HEMOLEVEN notably to heparin or to its
derivatives,including LMWH. Past history of serious type II heparin-induced
thrombocytopenia (HIT)

4. Presence of antibody to FXI in the past or currently

5. Presence of any other condition that could contraindicate treatment with factor XI
concentrate or lead the Physician/Investigator to believe treatment would not be in
the best interest of the patient

6. Positive, confirmed pregnancy test for patients undergoing elective surgery (not
applicable for caesarean section and prevention in vaginal delivery)

7. Lactating woman.

Of the seven exclusion criteria, the first four are included as a precautionary safety
measure; the fifth is included to avoid a lack of efficacy.

The two last criteria are included to minimize confounding influences on the evaluation of
patient safety. Oral contraception is not mandatory as a pregnancy test is scheduled at
inclusion visit and before surgery.