MASAC Recommendations

MASAC Recommendations #172: Regarding Women with Inherited Bleeding Disorders

The following recommendations were approved by the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation on October 14, 2006, and adopted by the NHF Board of Directors on October 15, 2006.

Inherited bleeding disorders are under recognized as causes of bleeding in women. However, recent data have documented that 50% of women who are carriers for hemophilia A or B have factor VIII or IX levels below 50%, putting them in the category of mild hemophilia and causing them to have an increased risk of bleeding, especially during menstruation and at the time of an accident or surgery. Moreover, 1%-2% of the general population may have laboratory evidence of von Willebrand disease. Thus 1%-2% of all women may have inherited this bleeding tendency and may also have heavy bleeding during menstruation or surgery.

With this information in mind, MASAC recommends the following:

A. Management

1. von Willebrand disease (VWD) and other inherited bleeding disorders should be considered in the differential diagnosis of all females presenting with menorrhagia, and an appropriate workup should be undertaken. Initial testing should include a CBC, PT, PTT, and a TT or fibrinogen. Additional testing specifically for VWD should include factor VIII activity, ristocetin cofactor, von Willebrand antigen, and factor VIII-related multimers. This workup should be done in consultation with a hematologist who is well versed in the diagnosis of inherited bleeding disorders.

2. The above laboratory evaluation should be considered in all females scheduled for endometrial ablation and/or hysterectomy for menorrhagia or dysfunctional uterine bleeding who also have mucous membrane bleeding and/or a family history of bleeding.

3. If there is a positive family history of hemophilia, females should have a factor VIII or factor IX activity level determined as soon as feasible and definitely prior to any planned surgical procedure regardless of age.

4. For bleeding, trauma, and before and after any surgical procedure, females with a low factor VIII level (less than 50%) may be treated with recombinant factor VIII or DDAVP (if DDAVP challenge has shown her to be responsive). Females with a low factor IX level (below 50%) should be treated with recombinant factor IX. Females with abnormal von Willebrand studies should be treated with DDAVP or a virally inactivated factor VIII product that contains von Willebrand factor (AlphaNate, Humate P, Koate HP). Humate P is currently the only product approved by the FDA for treatment of VWD. (See MASAC Document #173, MASAC Recommendations Regarding the Treatment of von Willebrand Disease, for specific details.) Cryoprecipitate and fresh frozen plasma should not be used unless the patient is at risk of life-threatening bleeding. (See MASAC Document #177, MASAC Recommendations Concerning the Treatment of Hemophilia and Related Bleeding Disorders, Revised October 2006).

B. Outreach, Education, and Research

1. Because women's bleeding disorders are under recognized by both the general public and clinicians who are primary care providers for girls and women, a national outreach and education program should be mounted. The target audiences should be health care professionals (e.g. pediatricians, hematologists/oncologists, internists, OB/GYN, family practitioners, and dentists as well as nurse practitioners in these fields), women's health advocates, and the general public.

2. NHF should continue to work with NHLBI and CDC to develop a national research agenda on women's bleeding disorders.

MASAC Recommendations #173: Regarding the Treatment of von Willebrand Disease

The following recommendations were approved by the Medical and Scientific Advisory Council (MASAC) on October 14, 2006, and adopted by the NHF Board of Directors on October 15, 2006.

Von Willebrand disease is the most common inherited bleeding disorder. Recent studies estimate the incidence at 1-2% of the general population. Since it is inherited in an autosomal dominant fashion, males and females are equally affected. Von Willebrand disease is associated with mucous membrane bleeding, excessive bruising, and bleeding from cuts. It can result in excessive bleeding with invasive dental work, during surgical procedures, and after accident or injury. In women, excessive menstrual bleeding is often the major symptom. Women with von Willebrand disease are also at risk of postpartum hemorrhage, particularly delayed postpartum hemorrhage.

Recently developed products have changed the treatment options for individuals with von Willebrand disease. The following are current recommendations for treating bleeding in these individuals.

1. Persons with type 1 von Willebrand disease should be treated with the synthetic agent desmopressin (DDAVP Injectable or Stimate Nasal Spray for Bleeding, 1.5 mg/ml), and their response at first use should be documented for future reference. For surgery, trauma, or other serious bleeding episodes, if hemostasis is not achieved with DDAVP, a factor VIII concentrate rich in the high molecular weight multimers of von Willebrand factor should be used (see #3 below).

2. Persons with type 2A, 2M, and 2N von Willebrand disease should be treated with DDAVP if they have been shown by a DDAVP trial to be responsive.

3. Persons with type 2B and type 3 von Willebrand disease, and those with type 1, 2A, 2M, and 2N who have been shown to be nonresponsive to DDAVP, should be treated with a factor VIII concentrate that is known to contain the higher molecular weight multimers of von Willebrand factor and that has been virally attenuated to eliminate transmission of HIV and hepatitis A, B, and C. Humate P (ZLB-Behring) has been approved by the FDA for use in VWD. Two other products, AlphaNate (Grifols) and Koate DVI (Talecris), may also be effective in these patients, but have not been approved by the FDA for use in von Willebrand disease.

4. Because of the increased risk of HIV and hepatitis A, B, and C transmission, cryoprecipitate should not be used except in an emergency situation where one of the above-mentioned products is not available and delay of treatment would be life- or limb-threatening.

5. Desmopressin is a potent antidiuretic agent, and fluid retention is a potential complication of this drug. Both parenterally administered DDAVP and Stimate Nasal Spray have been associated with the development of hyponatremia and seizures. To minimize this risk, the following precautions should be observed when this drug is used at home:
a. DDAVP and Stimate should be administered no more often than once every 24 hours.
b. DDAVP and Stimate should be used for no more than three consecutive days unless directed to do so by Hemophilia Treatment Center medical staff.
c. DDAVP and Stimate should not be used in children under the age of two years.
d. DDAVP and Stimate should be used with caution in the elderly and in individuals with a history of heart disease, hypertension, or stroke.
e. If a patient is treated with DDAVP before surgery, the anesthesiologist should be advised to avoid fluid overload and dilutional hyponatremia.
f. DDAVP should be used with extreme caution in pregnant women and in women who are immediately postpartum.

6. An adjunctive treatment for mucous membrane bleeding is the antifibrinolytic agent amino- caproic acid (Amicar). This agent can be given orally or intravenously.

7. Prior to surgery in a patient with von Willebrand disease, consultation should be obtained with a pediatric or adult hematologist who specializes in the management of individuals with inherited bleeding disorders. This consultation should cover such issues as the need for a DDAVP stimulation test; type of fluid replacement/fluid restriction; dose and duration if DDAVP is to be used; appropriate dose, timing, and duration of factor replacement therapy; and use of adjunctive medications (Amicar).

References:
1. Mannucci PM. Desmopressin (DDAVP) for treatment of disorders of hemostasis. Prog Hemost Thromb 1986; 8: 19-45.
2. Mannucci PM, Canciani MT, Rota L, Donovan BS. Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand disease. Br J Haematoli 1981; 47: 283-93.
3. Mannucci PM, Lusher JM. Desmopressin and thrombosis. Lancet 1989; 2: 675-6.
4. Nilsson IM, Hethagen S. Current status of DDAVP formulations and their use. In Lusher JM, Kessler CM, eds. Hemophilia and von Willebrand disease in the 1990's. International Congress Series/Excerpta Medica 1991; 943: 443-53.