von Willebrand's disease:
A common cause of menorrhagia

Dawanda R. Pesicka, PA-C

Ms. Pesicka is a gynecologic oncology physician assistant at Virginia Mason Medical Center in Seattle, Wash. The author has indicated no relationships to disclose relating to the content of this article.

As many as 25% of women who complain of heavy menstrual periods have this inherited bleeding disorder.

 

Earn Category I CME credit by reading this article and the associated article and successfully completing the post-test. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of February 2004.

Learning objectives Describe the types of von Willebrand's disease and how they differ, based on unique genetic mutations Recognize the typical bleeding manifestations of this condition Discuss how definitive diagnosis relies on measurement of factor levels and function Understand choices of therapy and how they are based on the underlying pathophysiology

Disclosure of conflict of interest The author has indicated no relationships to disclose relating to the content of this article.

An estimated 1.5% of the populations of Europe and the United States and 25% of women who are referred for evaluation of menorrhagia have von Willebrand's disease (vWD),¹ the most common inherited bleeding disorder worldwide.² First described in 1926 by the Finnish internist Erik von Willebrand, the disorder is caused by a defect of von Willebrand's factor (vWF), resulting in inadequate platelet adhesion and thrombus formation.^3-5 Common symptoms include easy bruising, frequent nosebleeds, bleeding gums, heavy menstrual periods, and prolonged bleeding after cuts or surgery. Four types of the disease have been identified—types I, II, III, and acquired (see Table 1)—and the severity of the bleeding episodes varies depending on which of the four types of the disorder is involved.^2,6 Symptoms are often mild or go unnoticed, and estimates are that the disorder is undiagnosed in 99% of patients who have it.⁶

 

TABLE 1 Types of von Willebrand’s disease
Type	Patients with vWD, %	Abnormality	Comment
I	70-80	Decreased vWF and factor VIII procoagulant activity	Can cause mild or moderate bleeding
II	15-30	Altered glycoprotein structure renders vWF functionally defective	Can cause mild or moderate bleeding; includes several subtypes
III	<1	Severe deficiency of vWF	Can cause severe bleeding
Acquired	<1	Same deficiency as in type I, but caused by autoimmune or neoplastic disease	Severity of bleeding depends on underlying disease
Key: vWD, von Willebrand’s disease; vWF, von Willebrand’s factor.

What happens in vWD

A heterogeneous multimeric plasma glycoprotein that mediates platelet adhesion and platelet aggregation at localized sites of vascular injury,^3,5 vWF serves as the plasma carrier for factor VIII, an essential blood coagulation protein. When one or both factor levels are insufficient because of reduced synthesis, as in types I and III, or their function is impaired by structural abnormality, as in type II, binding to specific platelet membrane receptors and endothelial structures such as collagen fails to occur.³ Thus, a prolonged bleeding time may result from dysfunctional platelet adhesion and aggregation, an upset in the coagulation cascade, or both.^3,5

The four types of vWD differ primarily by the genetic mutation unique to that type (see Table 1).³ Type I accounts for approximately 70% to 80% of cases and is inherited in an autosomal dominant fashion.³ It is a quantitative problem that results in a vWF deficiency as well as a parallel decrease in factor VIII procoagulant activity. Typically, concentrations of vWF in type I vWD are 5% to 30% of normal and result in mild or moderately severe bleeding events.

Type II vWD is an autosomal dominant abnormality accounting for 15% to 30% of vWD cases. It is characterized by qualitative or functional abnormalities of the vWF that change the structure of the glycoprotein molecule.³ Functional defects are present, although plasma concentration of vWF and factor VIII levels are normal or only modestly reduced. Although several subtypes of type II vWD have been identified, affected patients have impaired platelet function, regardless of subtype.

Type III vWD is rare, affecting only 1 in 1 million persons.³ In type III disease, there is little or no detectable vWF. This bleeding diathesis is transmitted as an autosomal recessive trait and has varying genetic abnormalities.³ Patients who have this type are typically the offspring of two parents who have mild or asymptomatic type I vWD.⁵ Catastrophic clinical consequences, such as spontaneous bleeding into the stomach, muscles, intestines, and joints, result from this severe deficiency of vWF.⁷

Acquired, or autoimmune, vWD is a rare complication of an autoimmune or neoplastic disease and is generally associated with a lymphoid or plasma cell proliferative disorder, most commonly with monoclonal gammopathy.⁸ Only 200 cases have been reported since 1968.⁹ Acquired vWD may be suspected when a patient with one of these underlying diseases presents with bleeding symptoms and no medical or family history of bleeding problems.⁸ Presentation is similar to that of inherited forms of vWD; severity depends on the underlying disease.

vWD affects men, women, and children and all ethnic groups equally,⁷ although women with vWD tend to have more symptoms and frequently have more easily recognizable symptoms, such as heavy menstrual bleeding and prolonged bleeding after childbirth.⁶ Type O blood is associated with lower plasma levels of vWF than other types, and patients with type O blood have a greater prevalence of vWD.¹⁰

Making the diagnosis

Making a precise diagnosis is often difficult. Measurements of plasma and platelet vWF, the ability of vWF to interact with platelet receptors, and structural analysis of vWF are key to making an accurate diagnosis.⁹ Initial laboratory tests useful in determining whether a disease of primary hemostasis exists are a platelet count and a bleeding time test.⁵ A normal platelet count is 150,000 to 400,000/mm³ of blood, and patients are usually asymptomatic with a normal bleeding time with counts higher than 100,000/mm³. Mildly prolonged bleeding is often seen with platelet counts between 50,000 and 100,000/mm³. Spontaneous bleeding can occur when platelet counts are below 20,000/mm³.⁵ Bleeding times longer than 10 minutes suggest a risk of increased bleeding, and the risk grows with bleeding times that are longer than 15 to 20 minutes.⁵

The diagnosis of vWD requires specific tests, including assays for factor VIIIc and vWF, tests for ristocetin cofactor activity and ristocetin-induced platelet aggregation, measures of membrane glycoproteins, and tests for platelet granule content. The combination of a prolonged bleeding time, reduced plasma vWF concentration, parallel reduction in ristocetin cofactor activity, and reduced factor VIII activity suggests vWD.⁵ These laboratory tests, however, often correlate poorly with one another and with the severity of the hemorrhagic manifestation(s).⁷ Often one or more lab test results are within normal limits, and when vWD is mild, multiple lab test results can fluctuate between normal and abnormal levels. Blood tests under development include the commonly used bleeding time test—which, despite its value in estimating the degree of functional abnormality, is not fully reliable. More accurate and less intrusive tests, which are currently under study, are an important research goal.¹⁰

Treating the deficiency

Desmopressin acetate (DDAVP), a synthetic analogue of arginine vasopressin, is the treatment of choice for acute bleeding and for prophylaxis in type I vWD. It works by stimulating the endogenous release of vWF and factor VIII, increasing platelet adhesion and shortening bleeding time.^9,11 Approximately 80% of patients with bleeding respond well to DDAVP, and adverse reactions tend to be minimal and include flushing, headache, nausea, dizziness, and abdominal pain.⁹ Although the drug can be administered IV or SC, the most practical mode of administration is intranasal, particularly for home treatment.¹¹ (Intranasal use, however, may cause rhinitis or epistaxis.) The dosage for patients aged 3 months through adulthood is 0.3 mcg/kg SC or IV, repeated in 8 to 24 hours if needed. The same dosage is used for preoperative prophylaxis and is given 30 minutes before the procedure. Recent findings have shown that patients who have type II disease may also benefit from use of DDAVP, but it is ineffective for type III vWD and for unusually severe cases of types I and II vWD.¹² Patients with severe types I and II disease often require plasma concentrates including both vWF and factor VIII, which are safe and effective. This therapy does not, however, always correct bleeding time, and in these cases, plasma concentrates may be used first with either platelet concentrates or DDAVP.¹²

In patients with known bleeding disorders, plasma concentrates may be infused after major trauma or during surgery; usually, two infusions are given daily for 2 or 3 days.⁵ A single infusion may be effective for minor bleeding episodes such as menorrhagia or prolonged epistaxis. Oral contraceptives are an effective treatment for repeated, severe menorrhagia due to vWD.

In all bleeding episodes associated with acquired vWD, addressing the underlying disease is the most important part of management.⁵ No single therapy has been identified for bleeding events with this type of vWD, although DDAVP and plasma derivatives have been effective in some patients.⁵ Some success has been reported with corticosteroids, plasma exchange, high-dose gamma globulin, vWF and factor VIII concentrates, and IV DDAVP.¹³

Cryoprecipitate, once a commonly used clotting factor concentrate, is now used only in severe bleeding and when all other therapies fail.⁹ Its use has been linked to infection with the hepatitis B and C viruses and with HIV.¹⁴

 

CASE REPORT Long-standing menorrhagia, and frustration At a routine physical examination, 28-year-old Ms. A voiced a complaint of menorrhagia (long, heavy periods). She was concerned about the volume of blood lost during her periods and with the inconvenience and embarrassment of frequent and untimely menstrual bleeding episodes. Consultations with gynecologists and internists had resulted in recommendations that ranged from a better diet to a hysterectomy. Her periods typically lasted 4 to 11 days, although 2 months earlier, her period had lasted 23 consecutive days. The patient was often anemic, with typical hematocrit levels of 30% to 33%. Fatigue and moderate lower abdominal cramps commonly accompanied the bleeding. Her menstrual cycle generally began with spotting, proceeded to heavy bleeding, and ended with spotting, with each stage lasting a few days. A heavy, longer cycle requiring 40 or more tampons occurred approximately three times a year. Blood loss during her normal cycles was more manageable because of their shorter duration. The patient's menarche had taken place at 11 years of age; she had experienced irregular cycles until her first episode of menorrhagia 4 years later, after which her cycle regularity improved somewhat. Activity exacerbated heavy bleeding. Episodes of menorrhagia had brought the patient to the emergency department three times in the preceding 7 years; in each episode, IM injections of progesterone in oil or medroxyprogesterone (Depo-Provera) stopped the bleeding after approximately 24 hours. The patient had never been pregnant and denied any sexually transmitted disease or pelvic infection. Pap smear screenings had been normal. Several years earlier, she had been given a prescription for an oral contraceptive (OC) to control the menorrhagia, but migraines complicated its use. She was now taking a combination OC containing 20 mcg of ethinyl estradiol and 0.1 mg of levonorgestrel, in addition to a multivitamin. She had recently stopped taking valproic acid, which was prescribed 18 months earlier for migraine prevention, because of ineffectiveness and a suspicion that it exacerbated menorrhagia. She denied use of aspirin products and of NSAIDs. She was allergic to penicillin and had no chronic illness. The patient said that she had had surface nasal vessels cauterized as a child to treat frequent nosebleeds, and she denied excessive gum bleeding with dental work. There was no history of blood transfusions. Although she had no known family history of a bleeding problem, the patient's mother had required blood transfusion with two major orthopedic surgeries. A nonsmoker, the patient drank little alcohol, followed a balanced diet, and exercised regularly. Resolution and discussion On a routine annual physical exam, a 4th-year resident physician initiated the testing that solved the mystery and confirmed a diagnosis of type I von Willebrand's disease (vWD). Diagnostic testing and laboratory results revealed a mildly decreased plasma von Willebrand's factor concentration, a reduced factor VIII activity, and a prolonged bleeding time that returned to normal after IV infusion of desmopressin acetate (DDAVP). The patient reported several years of difficulties with bleeding during her mid 20s, about the time she was taking valproic acid for migraine prevention. Studies have shown that valproate therapy can cause bone marrow suppression, leading to complications that may present as thrombocytopenia, abnormal platelet function, and an acquired form of type I vWD.1 These complications are typically seen only in patients who have valproate levels greater than 100 µg/mL or are taking consistent dosages of 250 to 1,000 mg/d; the complications usually resolve when the dosage is reduced.1 Whether valproic acid exacerbated this patient's bleeding is unclear; her concomitant OC use was inconsistent, and side effects (ie, migraines) frequently caused her to discontinue the pills and to try alternative combinations. This variability in itself may have created the frequent bleeding changes. Today, the patient's type I vWD is well controlled with a low-dose combination OC (20 mcg of ethinyl estradiol and 0.1 mg of levonorgestrel) taken daily for 21 days, followed by one filler pill daily for 4 days, giving her a shortened 25-day cycle and minimizing her menstrual bleeds. The patient has no unpredictable or unmanageable bleeding episodes. Should Ms. A need surgery or have a child, DDAVP, which has proven effective for her, would be used prophylactically and perioperatively to control bleeding. 1. Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol. January-February 2000;22:62-65.

 

KEY POINTS in this article The severity of the bleeding episodes in patients who have von Willebrand's disease depends on which of the four types of the disorder is involved—the most common, type I, usually causes mild or moderate bleeding. The combination of a prolonged bleeding time, reduced plasma von Willebrand's factor concentration, parallel reduction in ristocetin cofactor activity, and reduced factor VIII activity suggests von Willebrand's disease. Desmopressin acetate, a synthetic analogue of arginine vasopressin, is the treatment of choice for type I vWD.

REFERENCES

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4. Kertzscher F, Muller AE, Lenk H. Analysis of von Willebrand's factor in platelets of patients with various forms of von Willebrand's disease: is there a clinical relevance? Eur J Pediatr. 1999;158(suppl 3):S177-S179.

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9. Get to know von Willebrand disease. Allaboutbleeding.com [Web site]. Available at: http://www.allaboutbleeding.com . Accessed December 8, 2003.

10. Phillips MD, Santhouse A. von Willebrand disease: recent advances in pathophysiology and treatment. Am J Med Sci. August 1998;316:77-86.

11. Lethagen S. Desmopressin in the treatment of women's bleeding disorders. Haemophilia. July 1999;5:233-237.

12. Federici AB, Castaman G, Mannucci PM, et al. Guidelines for the diagnosis and management of von Willebrand disease in Italy. Haemophilia. 2002;8:607-621.

13. Tefferi A, Nichols WL. Acquired von Willebrand disease: concise review of occurrence, diagnosis, pathogenesis, and treatment. Am J Med. 1997;103:536-540.

14. Hambleton J. Advances in the treatment of von Willebrand disease. Semin Hematol. October 2001;38(4 suppl 9):7-10.

 

Dawanda Pesicka. von Willebrand's disease: A common cause of menorrhagia. JAAPA February 2004;17:40-44.

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