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Hematology 2006
© 2006 The American Society of Hematology

Bleeding Disorders in Premenopausal Women: (Another) Public Health Crisis for Hematology?

Andra H. James, Margaret V. Ragni and Vincent J. Picozzi

Correspondence: Vincent Picozzi, MD, Virginia Mason Clinic, 1100 Ninth Ave., Seattle WA 98101-2799; Phone 206-223-6193; Fax 206-223-691; Email hemvjp{at}vmmc.org

Session Chair: Vincent J. Picozzi, MD, MMM
Speakers: Andra H. James, MD, MPH; Margaret V. Ragni, MD, MPH; and Vincent J. Picozzi, MD, MMM

Abstract

Premenopausal women with bleeding disorders represent a major public health problem. Estimates suggest up to 20% of women with menorrhagia have an underlying bleeding disorder (corresponding to a prevalence of 1.5–4 million American women). Von Willebrand disease (VWD) is the most common bleeding disorder among women with menorrhagia, affecting up to 20% of such patients. Besides menorrhagia, important consequences of bleeding disorders in premenopausal women include iron deficiency anemia, miscarriage, postpartum bleeding, uterine bleeding and hysterectomy. These patients face many obstacles in achieving optimum care. Recognition is difficult as women may consider their symptoms "normal" and come to attention only after serious bleeding events. Symptoms of VWD may also overlap with benign conditions, primary providers may not suspect the diagnosis, and convenient hematologic input may be unavailable. Diagnosis is difficult as there is no single definitive test for VWD, and test results are variable, often being affected by extragenic factors, including stress, contraceptives, hormones, and pregnancy. Hemostatic treatment is limited by DDAVP tachyphylaxis, the lack of recombinant VWD concentrates, and the ineffectiveness of hormonal therapy, leading to unnecessary procedures and early hysterectomy. Finally, significant controversy exists regarding classification of type 1 VWD as a disease: given the overlap in symptoms and laboratory assays within the normal population, evaluation for those with VWD might be seen as identification of potential bleeding risk rather than detection of a disease. This symposium seeks to explore these issues in greater detail from the combined perspectives of the obstetrician-gynecologist and the hematologist to promote a better public health approach to this problem.

On behalf of the Committee on Practice (COP) for the American Society of Hematology, the Quality Subcommittee wishes to highlight major public health issues in hematology for our practice community. Last year, the subject of anemia in the elderly (a condition that affects 3 million Americans) was reviewed. This year, the COP wishes to examine a second important public health issue in hematology, specifically, that of bleeding disorders in premenopausal women. It is estimated that these disorders affect a like number of our citizens and, like anemia in the elderly, frequently go unrecognized and/or untreated. As patients with these disorders most commonly present initially to our colleagues in obstetrics and gynecology, we will examine this problem from the perspectives of the obstetrician/gynecologist, the hematologist, and from society as a whole.

Overview

Menorrhagia represents a major public health problem in women. As many as 10–15% of women experience menorrhagia during their lifetime. These patients account for 15% of all referrals to gynecologists and over 300,000 hysterectomies annually.1 The prevalence of bleeding disorders among women with menorrhagia is high; up to 20% (which equates to approximately 2–3 million American women) have an underlying bleeding disorder, most commonly von Willebrand disease (VWD).2 Conversely, menorrhagia is the most common presenting symptom among women with VWD, occurring in over 90% of patients.3 The morbidity of this condition is also high, and includes a variety of medical complications, lost work time, lifestyle and psychological disruption, poor quality of life and increased health costs.4 Although quantitatively defined as bleeding exceeding 80 cc per month based on its association with anemia,5 menorrhagia is generally a subjective diagnosis.

Despite their high prevalence in premenopausal women, bleeding disorders (and particularly VWD) often remain undiagnosed, and particularly so unless significant iron deficiency anemia, postoperative bleeding and/or transfusion occurs. Why is this so? Major reasons include 1) the failure to recognize or even consider a diagnosis of a bleeding disorder either by patients or providers; 2) the limitation of available diagnostic tests, which are complex and frequently inexact, and 3) the lack of available therapeutic agents with which to treat such patients chronically. Diagnosing VWD is especially difficult: although it is caused by deficient or defective von Willebrand factor (VWF), there is no single definitive test that confirms the diagnosis. Laboratory assays are difficult to perform and influenced by extragenic factors, sampling and storage conditions. The genetics are complex, and the presence of low VWF levels does not correlate with symptoms, suggesting that VWF may be a marker for bleeding risk rather than a diagnostic test. The link between specific molecular defects leading to VWD and the natural history of the disease is poorly defined, and despite ongoing clinical and biochemical studies to improve our understanding of the clinical aspects of VWD, treatment is suboptimal, with invasive, inconvenient, short-duration protein-based or high-cost plasma-derived products.

Despite these limitations, a number of exciting new developments are on the horizon, including 1) a new diagnostic clinical scoring system for VWD based on bleeding symptoms; 2) genotype-phenotype studies in VWD kindreds to determine markers for bleeding risk; 3) standardization of VWD assays among laboratories; and 4) clinical trials of new, less invasive recombinant agents.

Based on the magnitude of health problems associated with menorrhagia in women with bleeding disorders, the National Heart, Lung & Blood Institute (NHLBI) convened two separate panels in the spring of 20041: a Consensus Panel of 10 experts in hematology, family medicine, obstetrics and gynecology, pediatrics, laboratory medicine, and basic science, to develop guidelines for VWD diagnosis, treatment, and management,6 and 2) a Working Group of 15 scientific experts in hematology, obstetrics and gynecology to identify key research objectives to reduce VWD morbidity.7 This review emphasizes recommendations of these expert panels.

Bleeding Disorders in Premenopausal Women—The View of the Obstetrician-Gynecologist ~Andra H. James

Significance and magnitude of the problem
Women bleed. They bleed with menstruation and they bleed with childbirth or miscarriage. Due to these bleeding challenges, premenopausal women (females in their childbearing years) are more likely to manifest a bleeding disorder than premenarchal females, postmenopausal females, or men. The prevalence of undiagnosed bleeding disorders among women with menorrhagia is high, with estimates ranging anywhere from 5–20%8–14 (Table 1Go). Higher estimates have been reported for platelet dysfunction, but these were based on nonspecific tests such as platelet aggregometry.15


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  		Table 1. Previously undiagnosed bleeding disorders in patients with menorrhagia.8–14
 
As can be seen from Table 1Go, the most common inherited bleeding disorder in women is VWD although it represents only about one-half of all bleeding disorders among women. The diagnosis of VWD is based on a personal bleeding history, a positive family history and a low VWF level. Estimates of the prevalence of VWD among females with menorrhagia are as high as 20%. This is in contrast to estimates of the prevalence of VWD in the general population, which depend on the population studied and the definition of the disease used. Estimates of VWD prevalence based on the number of individuals registered in hemophilia treatment centers range from 0.002% to 0.01% of the population.16 However, estimates based on identification of individuals with classic criteria for the diagnosis of VWD (i.e., bleeding symptoms, a positive family history and a low VWF level) are much higher, ranging from 0.6% to 1.3% of the population.17,18 While few individuals have severe symptoms, many with mild symptoms are potentially affected. Also, while both women and men should be seen as "at risk" for a bleeding disorder from a positive family history or low VWF level, women are more likely to have a personal bleeding history and thus more likely to be diagnosed with VWD.19 In fact, in Erik von Willebrand’s original paper published in 1926, he stated that the hereditary hemorrhagic condition he described as "hereditary pseudohemophilia" appeared to affect women twice as often as men.20 Thus, the presence of abnormal bleeding in a pre-menopausal female should markedly increase clinical suspicion that a bleeding disorder exists.

Clinical presentation
The most common bleeding symptom among women with bleeding disorders, at least among women with VWD, is menorrhagia. Menorrhagia is defined as heavy, regular menstrual bleeding as opposed to metrorrhagia, which is defined as irregular menstrual bleeding. In a survey conducted by the United States Centers for Disease Control and Prevention (CDC), 84% of women with VWD reported menorrhagia, the highest prevalence for any bleeding symptom21 (Table 2Go). Menorrhagia is commonly reported in other bleeding disorders as well, including hemophilia carriers, women with afibrinogenemia, combined factors V and VIII deficiency, factors XI and XIII deficiency, Bernard-Soulier syndrome and Glanzmann thrombasthenia.


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  		Table 2. Bleeding symptoms in women with von Willebrand disease.21
 
Women with bleeding disorders may experience even heavier menstrual bleeding in cycles in which ovulation does not occur. During a normal cycle, the endometrium, or lining of the uterus, is first exposed to estrogen, then a combination of both estrogen and progesterone, and finally, to falling levels of estrogen and progesterone. In the absence of ovulation (anovulation), a corpus luteum, which is necessary for the production of progesterone, does not form. In a female of reproductive age, with anovulation, estrogen continues to be produced and the endometrium continues to proliferate, but without the secretory changes induced by progesterone. Eventually, growth becomes unstable and the endometrium begins to bleed.22 Unlike the synchronized shedding of the endometrium that occurs in a normal cycle, the bleeding may be irregular and prolonged. Anovulation is more likely to occur in adolescence and during the premenopausal years. Not surprisingly, in women with VWD, menorrhagia has been reported to be most severe during the first few years after menarche,23 but may increase in severity again toward the end of the child-bearing years.24

Complications of bleeding disorders in premenopausal women
Although menorrhagia may be the most common manifestation of a bleeding disorder in premenopausal women, it is far from the only one. Women with bleeding disorders are vulnerable to chronic anemia from iron deficiency,25 endometriosis,26 bleeding from benign pathology such as fibroids, endometrial hyperplasia and polyps, and hemorrhagic ovarian cysts.27 Hemorrhagic cysts are particularly suggestive of a bleeding disorder. Women with bleeding disorders are also at risk for a variety of obstetrical complications, including miscarriage26 and obstetrical bleeding, especially secondary or delayed postpartum bleeding.27 Vaginal or vulvar hematomas, while extremely rare in the general population, are not uncommon in patients with bleeding disorders and their detection should immediately trigger pursuit of such a diagnosis.27

However, most manifestations of bleeding in women are not unique to women with bleeding disorders; they are simply more common and severe. In particular, both the risk of life-threatening hemorrhage and the likelihood of hysterectomy appear to be greater. With respect to the latter, women with bleeding disorders also undergo hysterectomy at an earlier age.26 Premenopausal women with bleeding disorders can, of course, also display the full range of bleeding complications displayed by their male counterparts.

Barriers to hematologic referral
Why are bleeding disorders in women so difficult to recognize, and in particular, why are hematologists so infrequently consulted for this problem? A variety of reasons exists. First, from the patient’s point of view, it is difficult to distinguish "normal" from pathological bleeding. In studies comparing women with bleeding disorders to those without, even women without bleeding disorders report an incidence of menorrhagia ranging from 23–69%.23,26

Second, from the obstetrician-gynecologist’s point of view, a certain amount of bleeding is normal with menstruation, childbirth and miscarriage, and there is a wide variation in the amount of bleeding experienced in these situations among normal individuals. Even an abnormally large amount of bleeding is usually not due to a disorder of hemostasis. For example, most abnormal bleeding in menstruation is explained by anovulation or by an anatomic problem. Most abnormal bleeding with miscarriage is due to retained tissue, and most abnormal bleeding after childbirth is due to failure of the uterus to contract.

Third, as previously stated, there is a spectrum of severity of bleeding among premenopausal patients with bleeding disorders.28 Previously undiagnosed women with a bleeding disorder who present to an obstetrician-gynecologist may be far less symptomatic than those that present themselves to a hematologist or a hemophilia referral center. Failure to diagnose a patient with a mild disorder may be of little consequence.29 Even surgery may pose a low risk. There are almost no data to allow estimation of the degree to which VWD increases the risk of bleeding complications at surgery in women with menorrhagia.30 In a study of women with menorrhagia, among 17 individuals who were found to have previously unreported VWD, none reported a history of postoperative bleeding, and the rate of postpartum bleeding was the same as in controls.10

Fourth, most reproductive tract bleeding can be managed by the obstetrician-gynecologist using hormonal or surgical therapy. Combined oral contraceptives,31 depot medroxyprogesterone acetate injections,32 and the levonogestrel intrauterine device33 reduce menstrual blood loss. After childbearing is complete, other options available include ablation and hysterectomy.

Given the above, perhaps coupled with limited knowledge and experience with hemostatic disorders, obstetrician-gynecologists and other practitioners who see women with reproductive tract bleeding, often fail to consider a bleeding disorder as a contributing factor to symptomatology. In a survey of obstetrician-gynecologists, only 4% responded that they would consider VWD as an explanation for menorrhagia. (Previous guidelines for the management of VWD have been rescinded due to lack of supporting evidence.34) In one study in VWD, the delay in onset of bleeding symptoms until diagnosis was an average of 4 years;5 in another, 16 years.21 Women with mild as well as those with severe significant bleeding disorders, thus, are deprived of optimal management, including hemostatic therapies.

Finally, obstetrician-gynecologists may well experience a dearth of ready access to the community of hematologists. There is a recognized shortage of hematologists with expertise in hemostasis and thrombosis.35 In some regions of the country, it may not even be known who the appropriate hematology referral contact is, yet there are situations that absolutely require hematology expertise:

Bleeding Disorders in Premenopausal Women—The View of the Hematologist ~Margaret V. Ragni

Epidemiology
As many as 20% of women with menorrhagia have an underlying bleeding disorder, of which VWD is the most common. The disease was described by Eric von Willebrand in 1926 in a 5-year-old girl from a large kindred in the Åland Islands, who subsequently died from severe menorrhagia.28 Type 1 VWD, accounting for 70% of diagnosed individuals, is an autosomal dominant disorder caused by a partial quantitative deficiency of von Willebrand factor (VWF), a multimeric plasma glycoprotein that mediates platelet adhesion to damaged vascular endothelium following injury and serves as a carrier for factor VIII. The bleeding in VWD is primarily mucosal, including epistaxis, easy bruising, gastrointestinal bleeding, oropharyngeal bleeding, and prolonged bleeding after trauma and surgery. In women with VWD, menorrhagia is the most common symptom, occurring in up to 93% of patients.5 Menorrhagia in VWD patients typically presents at menarche,5 in contrast to other causes of menorrhagia, e.g., endometriosis, uterine cancer, polyps, and hypothyroidism, which tend to present later in life. Yet, from the perspective of the consulting hematologist, a diagnosis of VWD diagnosis is often not considered until after invasive testing is unrevealing or postprocedure bleeding occurs.5 In clinical practice, menorrhagia is a subjective diagnosis and even in affected families may be considered "normal" and VWD overlooked. VWF levels do not correlate with bleeding symptoms and overlap those in healthy individuals.29 Thus, failure to diagnose VWD or other bleeding disorder in women with menorrhagia constitutes a major public health problem.

Diagnosis and evaluation
Bleeding during the menstrual cycle is regulated by normal hemostatic mechanisms. Vessel injury is precipitated by the monthly sloughing of the vascular, outer layer of the lining of the uterus or endometrium, leading to vasoconstriction of endometrial vessels, platelet plug formation (primary hemostasis), activation of coagulation, subsequent fibrin clot formation (secondary hemostasis) and gradual cessation of bleeding. When VWF is reduced as in type 1 VWD, platelet plug formation is delayed and defective, and primary hemostasis fails, leading to clinical bleeding. Although VWD is the most common inherited bleeding disorder underlying menorrhagia, other disorders of primary or secondary hemostasis or of the vascular wall, congenital or acquired, may underlie menorrhagia.36 Thus, women with menorrhagia should be screened for defects in primary or secondary hemostasis or vessel wall abnormalities (Table 3Go).


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  		Table 3. Women with bleeding disorders: differential diagnosis.45
 
Disorders of primary hemostasis include congenital diseases, e.g., Bernard-Soulier syndrome, Glanzmann thrombasthenia, storage pool disease, congenital thrombocytopenias, and disorders of platelet dysfunction; and acquired disease, i.e., drug-induced thrombocytopenia or platelet dysfunction, and systemic diseases with thrombocytopenia or platelet dysfunction, such as renal or hepatic disease. Menorrhagia is rare in the latter disorders, unless another defect exists, for example, use of aspirin (ASA) or nonsteroidal anti-inflammatory agents (NSAIDs).

Disorders of secondary hemostasis include congenital diseases, e.g., hemophilia A, B carriers, factor XI deficiency, other factor deficiencies; and acquired diseases, e.g., anti-VIII inhibitors, Vitamin K deficiency, liver disease, and disseminated intravascular coagulation. Menorrhagia is a recognized symptom in women with congenital factor I, II, V, VII, X, and XI deficiencies, although the latter disorders are rare, < 1 in 500,000, but has not been reported in women with factor XII, prekallikrein, or high-molecular-weight kininogen deficiency, as these disorders are not associated with clinical bleeding.

Congenital disorders of the vessel wall including hereditary hemorrhagic telangiectasia and Ehlers-Danlos syndrome may have clinical menorrhagia, while acquired disorders of the vessel wall, e.g., vasculitis, dysproteinemias, infections, or drug-induced vascular necrosis, may be associated with purpura, but not typically with menorrhagia.

Genetics
The VWF gene is located on chromosome 12, and the VWF mRNA encodes for the large VWF polypeptide, which is composed of four domains linked by disulfide bonds and containing receptors for platelet glycoproteins Ib/IIa and IIb/IIIa, heparin, collagen, and factor VIII. Because type 1 VWD is autosomal dominant with variable penetrance, bleeding tendency even within families may vary widely, unrelated to VWF levels. Studies in twins have determined that up to 60% of the variation in VWF levels is inherited, 30% of which is due to ABO blood type,37 resulting in 25–35% lower VWF levels in blood group O.38 Genetic defects have been identified in more severe forms of type 1 VWD, primarily single amino acid substitutions in the D3 domain, resulting in defective VWF secretion or clearance.39,40 Because the multimeric structure is normal, mutations are suspected in the promoter region or in genes outside the VWF gene, as demonstrated in the type 1 VWD mouse model. As defects are identified in ongoing US and European phenotype-genotype studies, the database of VWF mutations set up by International Society on Haemostasis and Thrombosis (http://www.shef.ac.uk/vwf/index/html) will expand, the classification system will be revised, and it is anticipated that more precise diagnostic tests will be developed.

Clinical history
Deficiency of VWF may lead to clinical bleeding, but not all affected patients bleed, and there is overlap with bleeding reported in normal healthy individuals (Table 3Go). The bleeding is primarily mucosal, may not occur consistently, and may be worsened by medications, such as aspirin or NSAIDs. Despite the variability, studies have shown that if a bleeding history were taken prior to surgery among women with menorrhagia, two-thirds of postoperative bleeding might be avoided.5 Clinical evaluation of an individual suspected of having an underlying bleeding disorder should include a history, physical examination, and laboratory screening tests (Table 4Go). The clinical history should include a personal bleeding history, a family history of bleeding, and history of medications. The bleeding history should include the site, severity, and frequency of bleeding, whether it is spontaneous, mucosal, involves mucosa of the gastrointestinal, genitourinary, or oral cavity, nares, dental tissue, or respiratory tract. Such symptoms as epistaxis lasting 10 minutes, bruising without trauma, prolonged bleeding after dental work, or heavy postoperative bleeding are highly suggestive of a bleeding disorder.41,42 Questions should also determine if there is bruising with minimal trauma or prolonged bleeding following surgery or procedures, medical or dental. If there is a history of menorrhagia, the number of pads or tampons per day, duration, and presence of anemia or iron replacement should be determined. Of these, the three best predictors of abnormal menstrual blood flow43 include: 1) clots greater than 1" in diameter, 2) changing pads more frequently than hourly, and 3) a low ferritin. A history of transfusions, postpartum bleeding, and other medical conditions including thyroid, liver, kidney or bone marrow disorders should be determined. The family history should establish if bleeding occurs in males and/or females and if symptoms are variable in family members. A medication history should determine use of aspirin, NSAIDs, antiplatelet or anticoagulant drugs, and hormones.


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  		Table 4. Laboratory diagnosis: women with bleeding disorders.45
 
Physical examination
The exam should evaluate for mucosal bleeding, bruising, petechiae, purpura, and oropharyngeal bleeding, which typify defects in primary hemostasis. Hematomas or hemarthroses suggest a defect in secondary hemostasis, while dermal or mucosal telangiectasias in the oral or nasal mucosa suggest a vascular wall abnormality. The size, location, and distribution of these bleeding signs should be determined, yet the absence of signs or symptoms of bleeding does not exclude a diagnosis of a bleeding disorder, nor does their presence confirm a diagnosis of a bleeding disorder.

Laboratory evaluation
Testing for VWD is complex, and should include FVIII, VWF:RCo, VWF:Ag, platelet function analyzer (PFA-100), multimers, and platelet ristocetin aggregation (Table 5Go). In type 1 VWD, the VWF:Ag and VWF:RCo are generally in a 1:1 ratio, and the FVIII and VWF:Ag (or VWF:RCo) are in a 2:1 ratio. Multimers, measured by sodium dodecyl sulfate agarose electropheresis, are qualitatively normal, and may be decreased. Platelet function testing by PFA-100, although nonspecific, may suggest VWD, platelet disorders, or platelet inhibitory drugs.44 Samples for VWD testing should be drawn fasting into 3.2% citrate, frozen at –40°C, and, after thawing at 37°C, tested at room temperature. The optimal time to test is the first 3 days of the menstrual cycle, when estrogen is lowest; ideally, testing should be repeated three times and delayed at least 6–8 weeks following delivery or cessation of estrogen.


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  		Table 5. Treatment of women with bleeding disorders.45
 
To evaluate for other bleeding disorders,45 a complete blood count, hemoglobin, hematocrit, platelet count, MCV, prothrombin time (PT), and activated partial thromboplastin time (APTT) mix, fibrinogen, and thrombin time should be obtained (Table 4Go). Prolongation of the PT indicates a deficiency in the extrinsic pathway, while prolongation of APTT indicates a deficiency in the intrinsic pathway, i.e., factor XII, XI, prekallikrein (PK), high-molecular-weight kininogen, VIII, IX, FVIII carrier, FIX carrier, and VWD. In up to 50% of those with VWD, the APTT is normal, which should not discourage VWD testing. Prolongation of both PT and APTT suggests a defect in the common pathway, including deficiency of factor X, V, II, or I, or acquired disorders, e.g., Vitamin K deficiency or liver disease. A prolonged APTT should be further evaluated by a mixing study to distinguish factor deficiency from clotting factor inhibition. A failure to correct the APTT upon mixing with normal plasma should be further pursued by a Bethesda assay to evaluate for an anti-VIII antibody or other inhibitor, a thrombin time to evaluate the possibility of heparin contamination and the hexagonal lipid assay to assess the potential presence of a lupus anticoagulant.

Tests for disorders of platelet function include platelet adhesion, aggregation, platelet count, and platelet function analyzer (PFA-100). Defects in platelet adhesion may suggest the congenital disorder Bernard-Soulier syndrome, or acquired platelet defects in ITP or myeloproliferative disorders. Defects in platelet aggregation suggest the congenital disorder Glanzmann thrombasthenia or acquired disorders, such as renal disease or cardiopulmonary bypass.

An exciting development in diagnosis has been the introduction of a quantitative scoring system43 that rates bleeding symptom severity from 0 to 3 (Table 6Go). The derived "bleeding score" has 96.8% specificity and 69.1% sensitivity for type 1 VWD.46 In a validation of the system in 177 members of 144 kindreds (http://www.shef.ac.uk/euvwd/bleed_score.htm), the "score" was found to correlate directly with surgical/procedural bleeding, and indirectly with VWF:RCo, VWF:Ag, and FVIII levels.47 This "score" thus appears to be a potentially useful quantitative predictor of bleeding risk. Further studies will be needed to confirm these findings. However, it should be recognized that, given the overlap of symptoms and laboratory findings with normal controls, and in the absence of a single definitive diagnostic test, the diagnosis of VWD remains difficult and controversial. Further studies are clearly needed to improve VWD diagnosis.


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  		Table 6. The bleeding score for von Willebrand disease.46,47
 
Management—general considerations
The consulting hematologist plays a pivotal role in the care of women with bleeding disorders (Table 7Go). In addition to taking a careful and complete history and obtaining coagulation testing, the hematologist should discuss with the affected woman a treatment plan for future bleeding problems and testing of family members, and communicate with the primary care provider. DDAVP testing should be performed to determine response for future surgeries, taking care to avoid testing within three weeks of anticipated surgery, to avoid depletion of VWF stores and subclinical DDAVP response. Hepatitis A and B vaccination, if not previously given, should be administered, as per current US Public Health guidelines for individuals with bleeding disorders. The potential risk for increased bleeding associated with the use of aspirin and NSAIDs in women with bleeding disorders should be discussed. The hematologist should also assure that menorrhagia or unexplained symptoms in a woman with a bleeding disorder are taken seriously, evaluated and treated in a timely fashion, avoiding unnecessary procedures. If surgery is planned, the treatment plan should be made available to surgical and anesthesia staff. In pregnancy, the VWF level increases and is often normal in the third trimester of pregnancy. VWF levels should be assessed in the 8th month to determine need for prophylaxis at delivery. Women should be made aware that postpartum bleeding may be delayed26,48 and seek treatment if needed. For surgery, heparin and antiplatelet drugs should be avoided, and hemostatic agents should be continued 10–14 days, and for minor surgery, 3–5 days.49,50 Cryoprecipitate cannot be virally inactivated without loss of activity and thus should be avoided.


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  		Table 7. Problems in diagnosis of von WIllebrand disease.
 
Treatment—hemostatic agents
There is no consensus on the treatment of menorrhagia (Table 8Go). Oral contraceptives (OCPs), the first-line treatment for menorrhagia,51 were reported to be ineffective in 76% of women with bleeding disorders referred to a hematologist,25 despite reported reduction in blood loss and iron deficiency anemia.52 Nonetheless, multiple formulations of combined hormonal contraceptives are available, and moderate-dose estrogen, if not used initially, may be tried if a low-dose estrogen pill fails to control menorrhagia. Continuous combined hormonal contraception may also be considered, in collaboration with a gynecologist, to induce temporary amenorrhea, although migraine headaches or cardiovascular disease may limit the use of estrogen. Whether the same incidence of long-term cardiovascular effects known to occur with hormonal therapy are reduced in women with VWD is not known.


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  		Table 8. How I treat women with bleeding disorders.
 
The synthetic vasopressin analogue, DDAVP, or 1-desamino-8-D-arginine vasopressin, is the major hemostatic agent in type 1 VWD,53 which acts through cyclic AMP-mediated release of VWF from endothelial Weibel-Palade stores.54 Over 90% of patients respond to DDAVP at a dose of 0.3 µg per kilogram by intravenous infusion over 30 minutes, and although effective for mucosal bleeding, DDAVP may not reduce menorrhagia, as shown in a randomized placebo-controlled trial in women with bleeding disorders.55 The intranasal form of DDAVP, Stimate®, given at 150 µg, or 0.1 mL of 1.5 mg/mL solution, one puff in one nostril for those < 50 kg in weight, and one puff in each nostril, for those > 50 kg in weight, may also reduce menorrhagia when given as an adjunct to hormonal therapy.56 Use of these agents is limited by tachyphylaxis, after depletion of endothelial stores, and adverse effects include tachycardia, headache, flushing, and rarely, hyponatremia or volume overload, due to antidiuretic effects, which are prevented by avoiding excess fluid intake. Antifibrinolytic therapy, e.g., Amicar (epsilon aminocaproic acid), at a dose of 50 mg/kg every 6 hours for 5–7 days of the cycle, may reduce menorrhagia when used as an adjunct to hormonal therapy or DDAVP.52

The alternative to DDAVP for hemostasis in type 1 VWD is plasma-derived VWF-containing concentrate, which may reduce menorrhagia,52 when given intravenously during the first 3–5 days of the cycle at a dose of 40–70 U/kg based on VWF:RCo activity.49,50 Use of VWF-containing products, however, is limited by high cost, inconvenience, and potential transmissible infection risk. If blood products and hormonal therapy fail to control menorrhagia, surgical interventions may be considered, although the commonly attempted dilation and curettage (D&C) fails to reduce blood loss in women with bleeding disorders, and endometrial ablation, which induces temporary amenorrhea, may provide only short-term relief.57 For these procedures or hysterectomy, DDAVP or VWF-concentrates will be required.

A potential new therapeutic approach is interleukin 11 (Neumega®) rhIL-11), a gp-130 signaling cytokine with hematopoietic and anti-inflammatory activities, which has increased VWF levels in VWD mice58 and VWD dogs59 and is currently in clinical trials.

Bleeding Disorders in Premenopausal Women—The View from Society ~Vincent J. Picozzi

There can be no doubt that the millions of premenopausal women with bleeding disorders experience significant and numerous compromises in lifestyle as a result of their disease. Numerous improvements in our public health approach to this problem seem necessary in order to improve healthcare outcomes for these patients.

The first necessary improvement would seem to be improved patient self-awareness of the potential existence of a bleeding disorder. Based on a recent study in which 1410 teenage girls in Sweden were surveyed by questionnaire for their bleeding history,60 the prevalence of women in the population at risk for a bleeding disorder is far greater than the number that have actually been diagnosed. How best to educate and remind women as to the existence and characteristics of these disorders (e.g., health classes in school, public health messages) needs to be actively explored.

The second necessary improvement is for obstetrician-gynecologists and other primary care providers who see premenopausal women with bleeding disorders to become more aware of the possible existence of bleeding disorders in their patients. The mere existence of practice guidelines is inadequate for this purpose. Other forms of physician behavior modification (e.g., physician thought leaders, postgraduate education programs, practice benchmarks and reporting) will be necessary to accomplish this.

The third necessary improvement is for the hematology community to insure an adequate supply of well-trained, highly visible subspecialists willing and able to see such patients. An ongoing relationship between appropriate sub-specialty groups concerning this health care issue and a national directory (geographically organized) of appropriate hematology providers would provide steps in this direction.

The fourth necessary improvement would be the development of improved screening tools for the detection of pathological bleeding (especially in VWD) for premenopausal women. The absence of a quantitative, definitive predictor of bleeding among currently available laboratory tests represents a major clinical limitation. The laboratory and clinical tools cited in this symposium represent a step in this direction, but such tools require ongoing testing and refinement "in the field" to assess their true utility. A better understanding of the overall screening process and studies of the cost-effectiveness of screening (including the implications of false-positive results) are clearly needed. Also needed are well-designed clinical studies to help physicians define the optimal diagnostic algorithms and clinical management for women with menorrhagia.

Finally, improved therapeutic approaches to VWD and other bleeding disorders important to premenopausal patients are clearly needed. A widely available roster of clinical studies appropriate to this hemostatic disorder, coupled with a broader network of clinical collaborators, would assist in the expansion of knowledge surrounding this important public health issue.

References

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