Changes in Bleeding and Clotting During the Menstrual Cycle

Von Willebrand disease (VWD) is the most common hereditary bleeding disorder, occurring in
1-2% of the population. Menorrhagia, or heavy menstrual bleeding, occurs in the majority of
women with von Willebrand disease (VWD) and adversely affects quality of life. The American
College of Obstetrics and Gynecology has recommended that women with heavy menstrual
bleeding have diagnostic testing for VWD. Unfortunately, the diagnosis of VWD in women with
menorrhagia can be difficult due to fluctuations in hemostatic protein levels during the
menstrual cycle. The lack of useful coagulation assays has also limited the scope of
pharmacokinetic studies and comparative clinical trials needed to determine best clinical
practices in women with VWD.

Two new assay systems offer a possibility of increased sensitivity to physiologic variations
in coagulation and fibrinolysis. The calibrated automated thrombin generation assay (TG),
an estimation of endogenous thrombin potential (ETP), measures generation of thrombin
throughout the entire process of coagulation and has appears to be very sensitive to small
changes in levels of coagulation proteins. Thromboelastography (TEG) records clot
formation and dissolution in whole blood samples providing a good marker for fibrinolysis.
We propose that TG and TEG will be more sensitive than traditional coagulation assays to
detect physiologic variations in hemostasis during the menstrual cycle and can accurately
diagnose VWD. This is a single-institution pilot study to identify trends which are worthy
of further exploration in a larger multi-institutional study. Our primary objective is to
describe characteristics of TG and TEG at 4 time points during the menstrual cycle (days
0-3, 7-10, 14-17, and 21-24). Our secondary goal is to quantify the effects of VWD on TG
and TEG at the same time points during the menstrual cycle and compare these to traditional
coagulation assays.

This will be a single-institution pilot study of a total of 40 subjects: 20 healthy women
and 20 women with VWD. Subjects must be female between the ages of 18 and 50 years, have
regular menstrual periods, and not be pregnant. Women who are taking hormonal therapy,
anti-fibrinolytic therapy, hemostatic agents or anti-platelet agents, will not be eligible
for participation. Subjects will be given tampons and/or pads to use during one menstrual
cycle. Study participation will involve a brief interview, completion of a questionnaire
and a pictorial chart of one menstrual cycle, and having blood drawn at 4 time points during
one menstrual cycle. Blood samples will be collected for TG and TEG and standard assays of
coagulation and fibrinolysis. TG and TEG measurements will be compared to standard measures
of coagulation, fibrinolysis, and platelet activation markers. Serum from the visit on day
21-24 will be tested for progesterone and Bhcg to confirm ovulation and exclude pregnancy.
All assays will be performed at the Gulf States Hemophilia & Thrombophilia coagulation
laboratory.

This study will result in an improved capability to diagnose women with VWD during the
menstrual cycle. These new assays may be useful in the rational design of therapeutic
agents and clinical trials. In addition, the physiologic basis of variations in coagulation
during the menstrual cycle can be explored in future studies using this assay system.

Inclusion Criteria:

- Must be female

- Aged 18 to 50 years, with regular menstrual cycles.

- Healthy volunteers and women with von Willebrand's disorder are both being recruited.

Exclusion Criteria:

- Pregnancy

- Use of hormonal therapy including birth control pills

- Use of hemostatic agents such as DDAVP or anti-platelet agents.