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Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding
Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding Peter A. Kouides, M.D.,a Jacqueline Conard, Ph.D.,b Flora Peyvandi, M.D., Ph.D.,c Andrea Lukes, M.D.,d and Rezan Kadir, M.D.e a
Mary M. Gooley Hemophilia Treatment Center and the University of Rochester School of Medicine, Rochester, New York; Hôpital Hotel Dieu, Paris, France; c Angelo Bianchi Bonomi Hemophilia Thrombosis Center, Department of Internal Medicine, IRCCS Maggiore Hospital and University of Milan, Milan, Italy; d Women’s Hemostasis and Thrombosis Clinic, Duke University Medical Center, Durham, North Carolina; and e Royal Free Hospital and the Katharine Dormandy Haemophilia Centre, London, United Kingdom
b
The evaluation of excessive menstrual bleeding carries a relatively high yield of discovering an underlying disorder of hemostasis in females. This review highlights important components in a structured history and outlines primary and secondary hematologic testing that should be considered in the evaluation of excessive menstrual bleeding. (Fertil Steril威 2005;84:1345–51. ©2005 by American Society for Reproductive Medicine.)
Excessive menstrual bleeding (EMB), or menorrhagia, in women with an underlying bleeding disorder is likely, but not exclusively, to be due to a defect in hemostatic function. As such, standard gynecologic evaluation should be performed first with causes of uterine pathology excluded, particularly the possibility of malignancy in older women. Excessive menstrual bleeding may indeed be multifactorial in a woman with an underlying bleeding disorder. In a study of women undergoing hysterectomy for control of menorrhagia in the setting of von Willebrand disease (VWD), approximately half of them had concurrent fibroids (1). Consequently, it has been hypothesized that VWD may “unmask” underlying uterine pathology (2). Recently, the Royal College of Obstetricians and Gynecologists outlined investigations used for females with menorrhagia in general and the level of evidence to support their usefulness (Table 1) (3). Most of these investigations have not been assessed in menorrhagia related to an underlying disorder of hemostasis and the majority of recommendations are based on small observational studies. For best clinical practice, the results of general menorrhagia patients can be extrapolated. However, prior to any invasive investigations, the risk of bleeding complications and the need for blood products must always be assessed against the possible benefit. PRIMARY EVALUATION FOR AN UNDERLYING DISORDER OF HEMOSTASIS IN WOMEN WITH EMB Laboratory investigation for an underlying disorder of hemostasis in a woman with EMB cannot be carried out by the practitioner who is oblivious to the clinical history. Conse-
Received January 23, 2005; revised and accepted May 5, 2005. Reprint requests: Peter A. Kouides, M.D., Rochester General Hospital, 1425 Portland Avenue, Rochester, New York 14621 (FAX: 585-9224622; E-mail: [email protected]).
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.05.035
quently, the first step is not venipuncture but a focused history for a family history of bleeding and a personal history of bleeding symptoms (Table 2). These symptoms for all women include easy bruising of ⬎5 cm 1–2 times/month, frequent gum bleeding when flossing or brushing teeth, and epistaxis 1–2 times per month. In addition, for those having already undergone invasive interventions with the subsequent risk for hemorrhage, inquiry should be made for excessive bleeding with childbirth, dental tooth extraction, and/or surgery. These discriminatory symptoms are derived from case-control studies of ⬃200 women with previously diagnosed VWD compared to women without VWD. A limitation of such data is that the symptoms are self-reported; consequently there can be a recall bias. All the symptoms described above occurred to a degree of statistical significance more frequently in the females with VWD compared to normally menstruating controls (1, 4). Furthermore, in the Kadir et al. (5) Royal Free London study on the prevalence of VWD in menorrhagia patients, those with VWD were more likely to report the following: menorrhagia since menarche (65% vs. 9%), bleeding after dental extraction (46% vs. 7%), postoperative bleeding (62% vs. 8%), and postpartum hemorrhage (62% vs. 21%). These comparisons are particularly notable as the control group also had menorrhagia and the symptoms were queried prior to the diagnosis of a bleeding disorder so there would appear to be less of a recall bias. Both primary and secondary evaluations are summarized in Tables 2 and 4. Note that the positive screen for structured history is intended to help avoid unnecessary testing on females less likely to have an underlying disorder of hemostasis. The secondary evaluation is for females with a positive screen and for consideration in those females considering major surgical intervention. Because there will be instances where a history will not be helpful in terms of the unprovoked or unreliable or forgetful patient, hemostasis
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TABLE 1 Summary of levels of evidence of menorrhagia investigations. Level of evidence in menorrhagia in general
Investigations Pictorial blood assessment chart Complete blood cell count Thyroid function test Other endocrine tests Pelvic scan Endometrial biopsy Hysteroscopy ⫹ endometrial biopsy Dilatation and curettage
C—in favor B—in favor C—in favor (only when clinically indicated) B—against B—in favor C—in favor (only if persistent) A—in favor (only when abnormal pelvic scan) B—against
Level of evidence in menorrhagia with bleeding disorders C—in favor Insufficient data C—in favor Insufficient data Insufficient data Insufficient data Insufficient data Insufficient data
Note: A ⫽ randomized trial; B ⫽ robust observational; C ⫽ case series. Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
testing in terms of von Willebrand factor (VWF) analysis should be considered in those women scheduled for surgical management of excessive menstrual bleeding. Along those lines, Kadir et al. (5) reported that 8% of the VWD patients identified in their prevalence study had no additional bleeding symptoms.
rhagia are iron deficient (6), as has also been noted in a study of women with VWD (1). There also appears to be an inverse relationship between subnormal VWF levels and the prevalence of iron deficiency, as reported by Beck and Limoni (7).
The initial laboratory evaluation for an underlying disorder of hemostasis should be the complete blood cell count (CBC). This will rule out thrombocytopenic bleeding. The further evaluation of thrombocytopenia is outlined in Table 3. The CBC also assesses for the degree, if any, of anemia. At least two-thirds of women in the general population with menor-
SECONDARY EVALUATION FOR AN UNDERLYING DISORDER OF HEMOSTASIS IN WOMEN WITH EMB Those women with a “positive” screen and normal platelet count should then undergo a logical, stepwise sequence of testing for various disorders of hemostasis. Accurate hemostasis testing is crucial because the specificity of bleeding symptoms is poor and many “normal” patients without an identifiable disorder of hemostasis will report bleeding symptoms (1). Hemostasis testing ideally should be done on site with immediate on-site processing, given the frequent misdiagnosis of von Willebrand factor (VWF) deficiency when analysis is sent out over long travel to another site far from where the blood was drawn with subsequent activation/ degradation of the sample (8).
TABLE 2 Primary evaluation for an underlying disorder of hemostasis in females with excessive menstrual bleeding. 1. Structured history—positive screen if a. Excessive menstrual bleeding since menarche, or b. History of one of the following—postpartum hemorrhage, surgery-related bleeding, or bleeding associated with dental work, or c. History of two or more of the following— bruising greater than 5 cm once or twice/ month, epistaxis once or twice/month, frequent gum bleeding, family history of bleeding symptoms. 2. Initial laboratory evaluation: Complete blood cell count Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
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This phase of hemostasis testing, outlined in Table 4, should include prothrombin time (PT) and activated partial thromboplastin time (APTT) (if not already performed), VWF antigen, ristocetin cofactor, factor VIII (FVIII), ABO type, and Ivy bleeding time (BT) and/or platelet function analyzer (PFA)–100 closure time (CT) (9). The tests and the rationale for performing them in this phase of evaluation in women with extensive menstrual bleeding are described in further detail. Prothrombin Time and Activated Partial Thromboplastin Time These are standard readily available tests of hemostasis carried out in the evaluation of the bleeding patient. HowVol. 84, No. 5, November 2005
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TABLE 3 Approach to the patient with thrombocytopenia based on four possible underlying mechanisms. Relevant aspects to consider in the history, physical, and laboratory exam Mechanism 1. Bone marrow suppression (a) Exogenous
History Query for:
Physical
Laboratory
—
—
—
1. Examine blood smear for abnormal cells 2. Is rest of the full blood cell count normal? If not, then bone marrow examination likely needed
● Alcohol use ● Sulfa-containing medications
(b) Endogenous (bone marrow disease–aplastic anemia, leukemia, lymphoma, metastatic cancer) 2. Consumption (a) Hypersplenism (b) DIC
(c) HUS-TTP
(d) VWD, Type 2B 3. Pseudothrombocytopenia
4. Immune-mediated destruction (a) ITP, primary (b) ITP, secondary
—
Query for history for occult liver disease/alcohol use, hepatitis Query for acute symptoms for sepsis or chronic symptoms for malignancy Query for acute neurological symptoms
Query for family history of bleeding —
— Query for: ● history of HIV risks ● history of hyperthyroidism ● history of medication use (e.g., valproic acid, quinidine)
Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
Assess for splenomegaly —
Check neurological exam
— —
— ? signs of thyroid disease
Consider abdominal ultrasound to assess for splenomegaly 1. Check PT, APTT, and fibrinogen level 2. Examine smear for red blood cell fragments 1. Check PT, APTT, and fibrinogen level 2. Examine smear for red blood cell fragments 3. Check serum chemistries for hemolysis and renal failure VWF levels Examine blood smear for clumping; if present, repeat the platelet count in non EDTA-containing tube
Consider HIV test TSH, T3, T4
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TABLE 4
TABLE 5
Secondary evaluation for an underlying disorder of hemostasis in females with excessive menstrual bleeding. 1. Additional hematologic testing performed for females with positive screen from structured history (as noted in primary evaluation, ideally done with on-site analysis with consultation with hematologist): a. PT and APTT (if APTT prolonged, do mixing assay for inhibitor or factor deficiency) b. VWF antigen c. ristocetin cofactor d. Factor VIII e. ABO type f. Ivy bleeding time and/or PFA-100 closure time g. Nonhematologic testing: Consider TSH, especially if VWF levels reduced, and baseline iron profile if anemic prior to intervention. 2. If #1 is normal, then consider platelet aggregation and release studies. 3. If #2 is normal, then consider specific factor levels (e.g., FXI, FXIII), and euglobuin clot lysis and other measures of fibrinolysis (␣2-antiplasmin level, plasminogen activator inhibitor level). 4. For females without positive screen as noted in structured history above, but who are considering major surgical intervention, consider secondary evaluation. Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
ever, in general, these tests carry a very low positive and negative predictive value for an underlying bleeding disorder (10). In consideration of acquired disorders of hemostasis, the PT screens for bleeding are most commonly due to chronic liver disease or vitamin K deficiency. Historically, practitioners have often ordered only a CBC and PT/APTT in evaluation of a patient who may have an underlying bleeding disorder with the erroneous assumption that normal PT/APTT values rule out an underlying bleeding disorder. However, the sensitivity of a prolonged APTT for VWD is less than 40% (11). On the other hand, in consideration of the severe, albeit rare, nonX-linked hemophilia disorders (deficiencies of factors I, II, V, VII, X, and XI), a PT and APTT should be an adequate screen for the severely deficient, and hence likely to be symptomatic, homozygous cases (12). A prolonged APTT necessitates a mixing study with pooled normal plasma to distinguish further between a deficiency state such as hemophilia or an inhibitor. An inhibitor may be an incidental finding in terms of a lupus anticoagu1348
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Logistical issues to be considered in VWF testing. 1. Laboratory artifact and interpretation—VWF testing should be performed with: a. On-site laboratory processing and analysis b. Interpretation of results by clinical pathologist/hematologist. 2. Potential effect of OC and timing—ideally, the patient should be: a. Off oral contraceptive (OC) ⫻ 1 month b. Testing should be during menses. 3. In cases of results in the normal range, repeat testing off OC and during menses is advisable if: a. The first sample was obtained while the patient was still on OC or was tested in the nonmenses time frame b. The VWF levels were drawn in the appropriate time frame and off OC but the VWF levels returned in the lower half of the normal range. 4. ABO blood type—since the VWF level may be a continuous inverse variable for bleeding risk, stringent adjustment of the VWF levels for the blood type is not necessary. Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
lant or a potentially life-threatening condition in terms of acquired hemophilia A due to an autoantibody. VWF (VWF Antigen, Ristocetin Cofactor) and Factor VIII Levels The ⬃13% prevalence (95% confidence intervals 11.1%– 15.6%) (5, 13–16) of VWD in EMB patients warrants VWF and FVIII levels as part of the initial hemostasis evaluation. The FVIII level can be reduced in VWD because VWF protects FVIII from proteolytic cleavage (17). Factor VIII deficiency can stand alone with normal VWF levels as a cause of menorrhagia (i.e., mild hemophilia A) (18). In ordering VWF and FVIII levels, the clinician must be aware that VWF and FVIII levels can fluctuate (19). Hormonal factors, both exogenous and endogenous, are a potential mechanism in part for such fluctuation (20). Consequently, there are several subtleties (Table 5) in the laboratory diagnosis of VWD that warrant clarification. Testing in Relation to the Menstrual Cycle. Historically, there have been reports, albeit of a relatively small total number of patients (21, 22) that overall point to a decrease in VWF levels during menstruation. However, this has not been confirmed in two recent studies. In one study of 95 normal menstruating females sampled serially at days 4 –7, 11–15, and 21–28, there was no variation (23). In another study of Vol. 84, No. 5, November 2005
40 volunteers, by cross-sectional analysis there was no difference (24). But in that study, interestingly, analysis of samples longitudinally showed a decrease in VWF antigen during menstruation. In another recently published study, using cross-sectional analysis, the lowest levels of VWF were found on days 1– 4, whereas the highest were identified on days 9 –10 (25). Conceivably, these groups were more finely divided than the other studies. In sum, in light of these conflicting results, recommendations for testing exclusively during menses cannot be made. However, the practitioner should note when in the menstrual cycle the patient had VWF testing and if those results are at the mean or below the normal reference range. If so, then repeat testing during the first 4 days of menstruation would be reasonable. Testing in Relation to Combination Oral Contraceptive (OC) Use. Historically, it has been felt that OC use can obscure the diagnosis of VWD, based on an observation that estrogen can raise VWF levels in VWD patients (26). However, the dose of estrogen used was 10 times the dose of estrogen in present third-generation formulations. There have also been reports of patients diagnosed postpartum with VWD having been started empirically years before OC for menorrhagia wherein it is postulated that the OC “masked” the diagnosis of VWD (27). Interestingly, however, a recent study in normal volunteers taking third-generation OC (⬍30 g) actually showed a decrease in the VWF levels though this did not approach statistical significance (24). In summary, given lack of evidence presently demonstrating a definite effect of combination OC on VWF levels, a practical approach would be to still test women when on OC, particularly if they are indeed still experiencing menorrhagia or other mucocutaneous bleeding symptoms as intuitively if the subnormal VWF levels are contributing to the bleeding, at that point in time, then the OC should not be raising the VWF and FVIII levels. Adjustment for the ABO Blood Type. It is well known that patients with blood type O have 25% lower VWF and FVIII levels (28). Obviously, adjusting for the ABO blood type would require a lower VWF and FVIII level for blood type O patients with bleeding symptoms. This would exclude those blood type O patients who have a subnormal level defined as two standard deviations below the mean of the total population, e.g., ⬍50%, but a level not lower than the range of blood type O patients, e.g., ⬎35%. However, NituWhalley et al. (29) showed that type O patients with ristocetin cofactor levels between 35% and 50% had similar bleeding symptoms as non-O patients in that range. It seems that this may be more of an academic issue whether the laboratory diagnosis of VWD should necessitate ABO adjustment. Probably a significant proportion of cases that have been diagnosed as mild “VWD” are nongenetic and related to the blood type (30). Perhaps, in the future, in consideration of these “nongenetic” cases, a better descriptive term of patients with subnormal VWF levels and bleeding symptoms would be the simple descriptive classification as von Willebrand deficiency based on the demonstration of a subnormal Fertility and Sterility姞
VWF antigen and/or ristocetin cofactor compared to the local laboratory range, non–ABO adjusted (31). ABO typing is still advisable, because the finding of blood type O allows the clinician to emphasize to the patient that their subnormal VWF level is most likely secondary, at least, in part to being blood type O and not a “disease” state per se or due to a genetic mutation. This is particularly the case because patients who have mild depression of VWF levels intuitively have a normal life expectancy. Consequently, the term “disease” with the connotation that they have a disorder that could shorten the life expectancy is perhaps too restrictive. It may also have a negative connotation when such a patient seeks insurance coverage. Perhaps, the term von Willebrand syndrome could be used if the patient has mucocutaneous bleeding symptoms in addition to VWF deficiency. In those patients with a subnormal VWF antigen and/or ristocetin cofactor, i.e., VWF deficiency, subsequent VWF multimer analysis and ristocetin-induced platelet aggregation should be carried out (20). However, prior to embarking on those relatively costly and time consuming tests, the patient should be screened for hypothyroidism. This is because of the association of hypothyroidism with acquired VWD (32, 33). In such cases, thyroid replacement can result in resolution of the VWF deficiency (34). In this phase of testing, if not done already, in addition to a TSH test, a serum creatinine test should be done to rule out, in part, uremic bleeding. An iron profile should also be done as a baseline prior to any intervention. Bleeding Time and/or Platelet Function Analyzer–100 Closure Time Concurrent with VWF testing, a BT and/or PFA-100 CT test could also be done as a baseline, because if such a test is prolonged in a VWF-deficient excessive menstrual bleeding patient, it could be followed postintervention for shortening of the time in ensuring adequate hemostasis. Neither BT nor CT is advisable “up front” for screening in lieu of VWF levels nor for screening for a platelet function disorder, given the relatively poor sensitivity of these tests for mild VWF deficiency (35) and platelet function disorders (35–37). Platelet Aggregation and Release Studies If initial hemostasis testing above is normal, and gynecologic evaluation is completely normal, then further hemostasis testing can be considered in terms of platelet aggregation and release (preferably off all medications [38]) as would normally be done in the investigation of a bleeding disorder in a patient with bleeding symptoms and a normal PT, APTT, CBC, and VWF profile, because platelet function is a critical component of normal hemostasis (10). Recently, Philipp et al. reported a relatively high prevalence of platelet function abnormalities in patients with extensive menstrual bleeding (39 – 41). The abnormalities were far more prevalent in the black population (39). The practical value of 1349
testing such a patient is that she may respond to desmopressin (42). If platelet aggregation and release studies are within normal limits, then based on the degree and severity of additional personal bleeding symptoms and the family history, the practitioner may consider additional coagulation studies such as a factor XIII level in consideration of factor XIII deficiency (12) and tests for fibrinolysis in terms of the screening euglobulin lysis test (43) and more specific fibrinolytic defects in terms of deficiencies of ␣2-antiplasmin or plasminogen activator inhibitor. The latter two tests may specify a fibrinolytic state. Increased fibrinolysis, in general, has been reported in menorrhagia patients (44 – 46), but whether fibrinolysis is localized to the uterus or present systemically has not been fully studied. FUTURE RESEARCH IN THE INVESTIGATION OF UNDERLYING DISORDERS IN WOMEN WITH EMB Finally, future clinical trials of hemostasis testing in the women with excessive menstrual bleeding should include the following: 1. In the light of the preliminary data cited above showing a relatively high prevalence of platelet function abnormalities in menorrhagia, further study of the potential role of subtle platelet aggregation and release abnormalities with concurrent study of platelet aggregation and release in normally menstruating women in determining if these abnormalities are a cause of heavy menstruation or an effect of normal and/or heavy menstruation. 2. Because there appears to be a high prevalence of platelet function abnormalities in black women, delineating further the platelet function defect in black women with excessive menstrual bleeding. 3. Given emerging data suggesting a role for the PFA-100 in the evaluation of an underlying bleeding disorder in menorrhagia (9), pooling of data and cost-effectiveness analysis of the PFA-100 versus “up front” VWF analysis in screening for VWD in the setting of women with EMB. 4. Given the presumed role of increased fibrinolysis in the pathogenesis of menorrhagia, prevalence studies of increased systemic fibrinolysis in terms of the euglobulin clot lysis as well as ␣2-antiplasmin, and plasminogen activator inhibitor levels. It is hoped that such research will lead to further improvement in the recognition and proper management of women with excessive menstrual bleeding who have primarily an underlying disorder of hemostasis. REFERENCES 1. Kouides PA, Burkhart P, Phatak P, Porter J, Peacock L, Braggins C, et al. Gynecological and obstetrical morbidity in women with type i von Willebrand disease: results of a patient survey. Haemophilia 2000;6: 643– 8. 2. Kouides PA. Obstetric and gynaecological aspects of von Willebrand disease [review]. Bailliere’s Best Pract Clin Haematol 2001;14:381–99.
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3. Royal College of Obstetricians and Gynaecologists. The management of menorrhagia in secondary care. Evidence-based clinical guidelines. Br J Obstet Gynaecol 1999;5. 4. Kirtava A, Drews C, Lally C, Dilley A, Evatt B. Medical, reproductive and psychosocial experiences of women diagnosed with von Willebrand’s disease receiving care in haemophilia treatment centres: a case-control study. Haemophilia 2003;9:292–7. 5. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet 1998;351:485–9. 6. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood loss and iron deficiency. Acta Med Scand 1966;180:639 –50. 7. Beck EA, Limoni C. Subnormal plasma von Willebrand factor (ristocetin cofactor) and iron deficiency anaemia in menstruating women [letter]. Thromb Haemost 1996;75:693. 8. Lipton RA. Misdiagnosis by milk box. Haemophilia 2003;9:235. 9. James AH, Lukes AS, Brancazio LR, Thames E, Ortel TL. Use of a new platelet function analyzer to detect von Willebrand disease in women with menorrhagia. Am J Obstet Gynecol 2004;191:449 –55. 10. Fricke W, Kouides P, Kessler C, Schmaier AH, Krijanovski Y, Jagadeesan K, et al. A multicenter clinical evaluation of the Clot Signature Analyzer. J Thromb Haemost 2004;2:763– 8. 11. Montgomery RR, Coller BS. Von Willebrand disease. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, editors. Hemostasis and thrombosis: basic principles and practice. 3rd ed. Philadelphia: J. B. Lippincott, 1994:134 – 68. 12. Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood 2004;104:1243–52. 13. Edlund M, Blomback M, von Schoultz B, Andersson O. On the value of menorrhagia as a predictor for coagulation disorders. Am J Hematol 1996;53:234 – 8. 14. Dilley A, Drews C, Miller C, Lally C, Austin H, Ramaswamy D, et al. von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia. Obstet Gynecol 2001;97:630 – 6. 15. Woo YL, White B, Corbally R, Byrne M, O’Connell N, O’Shea E, et al. Von Willebrand’s disease: an important cause of dysfunctional uterine bleeding. Blood Coagul Fibrinolysis 2002;13:89 –93. 16. Shankar M, Lee CA, Sabin CA, Economides DL, Kadir RA. Von Willebrand disease in women with menorrhagia: a systematic review. BJOG 2004;111:734 – 40. 17. Federici AB. The factor VIII/von Willebrand factor complex: basic and clinical issues [review]. Haematologica 2003;88(6): 18. Kadir RA, Economides DL, Sabin CA, Pollard D, Lee CA. Assessment of menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders. Haemophilia 1999;5:40 – 8. 19. Abildgaard CF, Suzuki Z, Harrison J, Jefcoat K, Zimmerman TS. Serial studies in von Willebrand’s disease: variability versus “variants.” Blood 1980;56:712– 6. 20. Federici AB. Mild forms of von Willebrand disease: diagnosis and management. Curr Hematol Rep 2003;2:373– 80. 21. Mandalaki T, Louizou C, Dimitriadou C, Symeonidis P. Variations in factor VIII during the menstrual cycle in normal women [letter]. N Engl J Med 1980;302:1093– 4. 22. Blomback M, Eneroth P, Landgren BM, Lagerstrom M, Anderson O. On the intraindividual and gender variability of haemostatic components. Thromb Haemost 1992;67:70 –5. 23. Onundarson PT, Gumundsdottir BR, Arnfinnsdottir AV, Kjeld M, Olafsson O. Von Willebrand factor does not vary during the normal menstrual cycle [letter]. Thromb Haemost 2001;85:183– 4. 24. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive. Thromb Haemost 1999;82: 1456 – 61. 25. Miller CH, Dilley A, Drews C, Richardson L, Evatt B. Changes in von Willebrand factor and Factor VIII levels during the menstrual cycle [letter]. Thromb Haemost 2002;2002–3. 26. Alperin JB. Estrogens and surgery in women with von Willebrand’s disease. Am J Med 1982;73:367–71.
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27. Mangal AK, Naiman SC. Oral contraceptives and von Willebrand’s disease [letter]. Can Med Assoc J 1983;128:1274. 28. Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ Jr, Montgomery RR. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987;69:1691–5. 29. Nitu-Whalley IC, Lee CA, Griffioen A, Jenkins PV, Pasi KJ. Type 1 von Willebrand disease—a clinical retrospective study of the diagnosis, the influence of the ABO blood group and the role of the bleeding history. Br J Haematol 2000;108:259 – 64. 30. Bauduer F, Ducout L. Is the assessment of von Willebrand disease prevalence an achievable challenge? The example of the French Basque Country where blood group O and factor XI deficiency are highly prevalent. J Thromb Haemost 2004;2:1724 – 6. 31. Sadler JE. Slippery criteria for von Willebrand disease type 1. J Thromb Haemost 2004;2:1720 –3. 32. Coccia MR, Barnes HV. Hypothyroidism and acquired von Willebrand disease. J Adolesc Health 1991;12:152– 4. 33. Blesing NE, Hambley H, McDonald GA. Acquired von Willebrand’s disease and hypothyroidism: report of a case presenting with menorrhagia. Postgrad Med J 1990;66:474 – 6. 34. Michiels JJ, Schroyens W, Berneman Z, Van der PM. Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine. Clin Appl Thromb Hemost 2001;7:113–5. 35. Posan E, Nichols WL, McBane RD, Grill DE, Motsko D. Comparison of the PFA-100 testing and the bleeding time for detecting platelet hypofunction and von Willebrand disease. J Thromb Haemost 2003; 90:483–90. 36. Philipp CS, Miller CH, Faiz A, Dilley A, Michaels LA, Ayers C, et al. Screening women with menorrhagia for underlying bleeding disorders: the utility of the platelet function analyser and bleeding time. Haemophilia 2005;11(5):497–503.
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37. Quiroga T, Goycoolea M, Munoz B, Morales M, Aranda E, Panes O, et al. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients. J Thromb Haemost 2004 June 1;2:892– 8. 38. Bick RL. Platelet function defects: a clinical review [review]. Sem Thromb Hemost 1992;18:167– 85. 39. Philipp CS, Dilley A, Miller CH, Evatt B, Baranwal A, Schwartz R, et al. Platelet functional defects in women with unexplained menorrhagia. J Thromb Haemost 2003;1:477– 84. 40. Philipp CS, Faiz A, Dowling N, Dilley A, Michaels LA, Ayers C, et al. Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol 2005;105:61– 6. 41. Gulbas Z, Akay M, Akin A. Platelet dysfunction and other hemostatic abnormalities in iron deficient women with unexplained menorrhagia. Blood 2001; [abstract]1056. 42. DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunction. Am J Hematol 1990;33:39 – 45. 43. Smith AA, Jacobson LJ, Miller BI, Hathaway WE, Manco-Johnson MJ. A new euglobulin clot lysis assay for global fibrinolysis. Thromb Res 2003;112:329 –37. 44. Hahn L, Cederblad G, Rybo G, Pehrsson NG, Bengtsen KK. Blood coagulation, fibrinolysis and plasma proteins in women with normal and with excessive menstrual blood loss. Br J Obstet Gynaecol 1976; 83:974 – 80. 45. Winkler UH. Menstruation: extravascular fibrinolytic activity and reduced fibrinolytic capacity. Ann N Y Acad Sci 1992;667:289 –90. 46. Edlund M, Blomback M, He L. On the correlation between local fibrinolytic activity in menstrual fluid and total blood loss during menstruation and effects of desmopressin. Blood Coagul Fibrinolysis 2003;14:593– 8.
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Mary M. Gooley Hemophilia Treatment Center and the University of Rochester School of Medicine, Rochester, New York; Hôpital Hotel Dieu, Paris, France; c Angelo Bianchi Bonomi Hemophilia Thrombosis Center, Department of Internal Medicine, IRCCS Maggiore Hospital and University of Milan, Milan, Italy; d Women’s Hemostasis and Thrombosis Clinic, Duke University Medical Center, Durham, North Carolina; and e Royal Free Hospital and the Katharine Dormandy Haemophilia Centre, London, United Kingdom
b
The evaluation of excessive menstrual bleeding carries a relatively high yield of discovering an underlying disorder of hemostasis in females. This review highlights important components in a structured history and outlines primary and secondary hematologic testing that should be considered in the evaluation of excessive menstrual bleeding. (Fertil Steril威 2005;84:1345–51. ©2005 by American Society for Reproductive Medicine.)
Excessive menstrual bleeding (EMB), or menorrhagia, in women with an underlying bleeding disorder is likely, but not exclusively, to be due to a defect in hemostatic function. As such, standard gynecologic evaluation should be performed first with causes of uterine pathology excluded, particularly the possibility of malignancy in older women. Excessive menstrual bleeding may indeed be multifactorial in a woman with an underlying bleeding disorder. In a study of women undergoing hysterectomy for control of menorrhagia in the setting of von Willebrand disease (VWD), approximately half of them had concurrent fibroids (1). Consequently, it has been hypothesized that VWD may “unmask” underlying uterine pathology (2). Recently, the Royal College of Obstetricians and Gynecologists outlined investigations used for females with menorrhagia in general and the level of evidence to support their usefulness (Table 1) (3). Most of these investigations have not been assessed in menorrhagia related to an underlying disorder of hemostasis and the majority of recommendations are based on small observational studies. For best clinical practice, the results of general menorrhagia patients can be extrapolated. However, prior to any invasive investigations, the risk of bleeding complications and the need for blood products must always be assessed against the possible benefit. PRIMARY EVALUATION FOR AN UNDERLYING DISORDER OF HEMOSTASIS IN WOMEN WITH EMB Laboratory investigation for an underlying disorder of hemostasis in a woman with EMB cannot be carried out by the practitioner who is oblivious to the clinical history. Conse-
Received January 23, 2005; revised and accepted May 5, 2005. Reprint requests: Peter A. Kouides, M.D., Rochester General Hospital, 1425 Portland Avenue, Rochester, New York 14621 (FAX: 585-9224622; E-mail: [email protected]).
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.05.035
quently, the first step is not venipuncture but a focused history for a family history of bleeding and a personal history of bleeding symptoms (Table 2). These symptoms for all women include easy bruising of ⬎5 cm 1–2 times/month, frequent gum bleeding when flossing or brushing teeth, and epistaxis 1–2 times per month. In addition, for those having already undergone invasive interventions with the subsequent risk for hemorrhage, inquiry should be made for excessive bleeding with childbirth, dental tooth extraction, and/or surgery. These discriminatory symptoms are derived from case-control studies of ⬃200 women with previously diagnosed VWD compared to women without VWD. A limitation of such data is that the symptoms are self-reported; consequently there can be a recall bias. All the symptoms described above occurred to a degree of statistical significance more frequently in the females with VWD compared to normally menstruating controls (1, 4). Furthermore, in the Kadir et al. (5) Royal Free London study on the prevalence of VWD in menorrhagia patients, those with VWD were more likely to report the following: menorrhagia since menarche (65% vs. 9%), bleeding after dental extraction (46% vs. 7%), postoperative bleeding (62% vs. 8%), and postpartum hemorrhage (62% vs. 21%). These comparisons are particularly notable as the control group also had menorrhagia and the symptoms were queried prior to the diagnosis of a bleeding disorder so there would appear to be less of a recall bias. Both primary and secondary evaluations are summarized in Tables 2 and 4. Note that the positive screen for structured history is intended to help avoid unnecessary testing on females less likely to have an underlying disorder of hemostasis. The secondary evaluation is for females with a positive screen and for consideration in those females considering major surgical intervention. Because there will be instances where a history will not be helpful in terms of the unprovoked or unreliable or forgetful patient, hemostasis
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TABLE 1 Summary of levels of evidence of menorrhagia investigations. Level of evidence in menorrhagia in general
Investigations Pictorial blood assessment chart Complete blood cell count Thyroid function test Other endocrine tests Pelvic scan Endometrial biopsy Hysteroscopy ⫹ endometrial biopsy Dilatation and curettage
C—in favor B—in favor C—in favor (only when clinically indicated) B—against B—in favor C—in favor (only if persistent) A—in favor (only when abnormal pelvic scan) B—against
Level of evidence in menorrhagia with bleeding disorders C—in favor Insufficient data C—in favor Insufficient data Insufficient data Insufficient data Insufficient data Insufficient data
Note: A ⫽ randomized trial; B ⫽ robust observational; C ⫽ case series. Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
testing in terms of von Willebrand factor (VWF) analysis should be considered in those women scheduled for surgical management of excessive menstrual bleeding. Along those lines, Kadir et al. (5) reported that 8% of the VWD patients identified in their prevalence study had no additional bleeding symptoms.
rhagia are iron deficient (6), as has also been noted in a study of women with VWD (1). There also appears to be an inverse relationship between subnormal VWF levels and the prevalence of iron deficiency, as reported by Beck and Limoni (7).
The initial laboratory evaluation for an underlying disorder of hemostasis should be the complete blood cell count (CBC). This will rule out thrombocytopenic bleeding. The further evaluation of thrombocytopenia is outlined in Table 3. The CBC also assesses for the degree, if any, of anemia. At least two-thirds of women in the general population with menor-
SECONDARY EVALUATION FOR AN UNDERLYING DISORDER OF HEMOSTASIS IN WOMEN WITH EMB Those women with a “positive” screen and normal platelet count should then undergo a logical, stepwise sequence of testing for various disorders of hemostasis. Accurate hemostasis testing is crucial because the specificity of bleeding symptoms is poor and many “normal” patients without an identifiable disorder of hemostasis will report bleeding symptoms (1). Hemostasis testing ideally should be done on site with immediate on-site processing, given the frequent misdiagnosis of von Willebrand factor (VWF) deficiency when analysis is sent out over long travel to another site far from where the blood was drawn with subsequent activation/ degradation of the sample (8).
TABLE 2 Primary evaluation for an underlying disorder of hemostasis in females with excessive menstrual bleeding. 1. Structured history—positive screen if a. Excessive menstrual bleeding since menarche, or b. History of one of the following—postpartum hemorrhage, surgery-related bleeding, or bleeding associated with dental work, or c. History of two or more of the following— bruising greater than 5 cm once or twice/ month, epistaxis once or twice/month, frequent gum bleeding, family history of bleeding symptoms. 2. Initial laboratory evaluation: Complete blood cell count Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
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This phase of hemostasis testing, outlined in Table 4, should include prothrombin time (PT) and activated partial thromboplastin time (APTT) (if not already performed), VWF antigen, ristocetin cofactor, factor VIII (FVIII), ABO type, and Ivy bleeding time (BT) and/or platelet function analyzer (PFA)–100 closure time (CT) (9). The tests and the rationale for performing them in this phase of evaluation in women with extensive menstrual bleeding are described in further detail. Prothrombin Time and Activated Partial Thromboplastin Time These are standard readily available tests of hemostasis carried out in the evaluation of the bleeding patient. HowVol. 84, No. 5, November 2005
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TABLE 3 Approach to the patient with thrombocytopenia based on four possible underlying mechanisms. Relevant aspects to consider in the history, physical, and laboratory exam Mechanism 1. Bone marrow suppression (a) Exogenous
History Query for:
Physical
Laboratory
—
—
—
1. Examine blood smear for abnormal cells 2. Is rest of the full blood cell count normal? If not, then bone marrow examination likely needed
● Alcohol use ● Sulfa-containing medications
(b) Endogenous (bone marrow disease–aplastic anemia, leukemia, lymphoma, metastatic cancer) 2. Consumption (a) Hypersplenism (b) DIC
(c) HUS-TTP
(d) VWD, Type 2B 3. Pseudothrombocytopenia
4. Immune-mediated destruction (a) ITP, primary (b) ITP, secondary
—
Query for history for occult liver disease/alcohol use, hepatitis Query for acute symptoms for sepsis or chronic symptoms for malignancy Query for acute neurological symptoms
Query for family history of bleeding —
— Query for: ● history of HIV risks ● history of hyperthyroidism ● history of medication use (e.g., valproic acid, quinidine)
Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
Assess for splenomegaly —
Check neurological exam
— —
— ? signs of thyroid disease
Consider abdominal ultrasound to assess for splenomegaly 1. Check PT, APTT, and fibrinogen level 2. Examine smear for red blood cell fragments 1. Check PT, APTT, and fibrinogen level 2. Examine smear for red blood cell fragments 3. Check serum chemistries for hemolysis and renal failure VWF levels Examine blood smear for clumping; if present, repeat the platelet count in non EDTA-containing tube
Consider HIV test TSH, T3, T4
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TABLE 4
TABLE 5
Secondary evaluation for an underlying disorder of hemostasis in females with excessive menstrual bleeding. 1. Additional hematologic testing performed for females with positive screen from structured history (as noted in primary evaluation, ideally done with on-site analysis with consultation with hematologist): a. PT and APTT (if APTT prolonged, do mixing assay for inhibitor or factor deficiency) b. VWF antigen c. ristocetin cofactor d. Factor VIII e. ABO type f. Ivy bleeding time and/or PFA-100 closure time g. Nonhematologic testing: Consider TSH, especially if VWF levels reduced, and baseline iron profile if anemic prior to intervention. 2. If #1 is normal, then consider platelet aggregation and release studies. 3. If #2 is normal, then consider specific factor levels (e.g., FXI, FXIII), and euglobuin clot lysis and other measures of fibrinolysis (␣2-antiplasmin level, plasminogen activator inhibitor level). 4. For females without positive screen as noted in structured history above, but who are considering major surgical intervention, consider secondary evaluation. Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
ever, in general, these tests carry a very low positive and negative predictive value for an underlying bleeding disorder (10). In consideration of acquired disorders of hemostasis, the PT screens for bleeding are most commonly due to chronic liver disease or vitamin K deficiency. Historically, practitioners have often ordered only a CBC and PT/APTT in evaluation of a patient who may have an underlying bleeding disorder with the erroneous assumption that normal PT/APTT values rule out an underlying bleeding disorder. However, the sensitivity of a prolonged APTT for VWD is less than 40% (11). On the other hand, in consideration of the severe, albeit rare, nonX-linked hemophilia disorders (deficiencies of factors I, II, V, VII, X, and XI), a PT and APTT should be an adequate screen for the severely deficient, and hence likely to be symptomatic, homozygous cases (12). A prolonged APTT necessitates a mixing study with pooled normal plasma to distinguish further between a deficiency state such as hemophilia or an inhibitor. An inhibitor may be an incidental finding in terms of a lupus anticoagu1348
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Logistical issues to be considered in VWF testing. 1. Laboratory artifact and interpretation—VWF testing should be performed with: a. On-site laboratory processing and analysis b. Interpretation of results by clinical pathologist/hematologist. 2. Potential effect of OC and timing—ideally, the patient should be: a. Off oral contraceptive (OC) ⫻ 1 month b. Testing should be during menses. 3. In cases of results in the normal range, repeat testing off OC and during menses is advisable if: a. The first sample was obtained while the patient was still on OC or was tested in the nonmenses time frame b. The VWF levels were drawn in the appropriate time frame and off OC but the VWF levels returned in the lower half of the normal range. 4. ABO blood type—since the VWF level may be a continuous inverse variable for bleeding risk, stringent adjustment of the VWF levels for the blood type is not necessary. Kouides. Hemostasis and thrombosis: laboratory. Fertil Steril 2005.
lant or a potentially life-threatening condition in terms of acquired hemophilia A due to an autoantibody. VWF (VWF Antigen, Ristocetin Cofactor) and Factor VIII Levels The ⬃13% prevalence (95% confidence intervals 11.1%– 15.6%) (5, 13–16) of VWD in EMB patients warrants VWF and FVIII levels as part of the initial hemostasis evaluation. The FVIII level can be reduced in VWD because VWF protects FVIII from proteolytic cleavage (17). Factor VIII deficiency can stand alone with normal VWF levels as a cause of menorrhagia (i.e., mild hemophilia A) (18). In ordering VWF and FVIII levels, the clinician must be aware that VWF and FVIII levels can fluctuate (19). Hormonal factors, both exogenous and endogenous, are a potential mechanism in part for such fluctuation (20). Consequently, there are several subtleties (Table 5) in the laboratory diagnosis of VWD that warrant clarification. Testing in Relation to the Menstrual Cycle. Historically, there have been reports, albeit of a relatively small total number of patients (21, 22) that overall point to a decrease in VWF levels during menstruation. However, this has not been confirmed in two recent studies. In one study of 95 normal menstruating females sampled serially at days 4 –7, 11–15, and 21–28, there was no variation (23). In another study of Vol. 84, No. 5, November 2005
40 volunteers, by cross-sectional analysis there was no difference (24). But in that study, interestingly, analysis of samples longitudinally showed a decrease in VWF antigen during menstruation. In another recently published study, using cross-sectional analysis, the lowest levels of VWF were found on days 1– 4, whereas the highest were identified on days 9 –10 (25). Conceivably, these groups were more finely divided than the other studies. In sum, in light of these conflicting results, recommendations for testing exclusively during menses cannot be made. However, the practitioner should note when in the menstrual cycle the patient had VWF testing and if those results are at the mean or below the normal reference range. If so, then repeat testing during the first 4 days of menstruation would be reasonable. Testing in Relation to Combination Oral Contraceptive (OC) Use. Historically, it has been felt that OC use can obscure the diagnosis of VWD, based on an observation that estrogen can raise VWF levels in VWD patients (26). However, the dose of estrogen used was 10 times the dose of estrogen in present third-generation formulations. There have also been reports of patients diagnosed postpartum with VWD having been started empirically years before OC for menorrhagia wherein it is postulated that the OC “masked” the diagnosis of VWD (27). Interestingly, however, a recent study in normal volunteers taking third-generation OC (⬍30 g) actually showed a decrease in the VWF levels though this did not approach statistical significance (24). In summary, given lack of evidence presently demonstrating a definite effect of combination OC on VWF levels, a practical approach would be to still test women when on OC, particularly if they are indeed still experiencing menorrhagia or other mucocutaneous bleeding symptoms as intuitively if the subnormal VWF levels are contributing to the bleeding, at that point in time, then the OC should not be raising the VWF and FVIII levels. Adjustment for the ABO Blood Type. It is well known that patients with blood type O have 25% lower VWF and FVIII levels (28). Obviously, adjusting for the ABO blood type would require a lower VWF and FVIII level for blood type O patients with bleeding symptoms. This would exclude those blood type O patients who have a subnormal level defined as two standard deviations below the mean of the total population, e.g., ⬍50%, but a level not lower than the range of blood type O patients, e.g., ⬎35%. However, NituWhalley et al. (29) showed that type O patients with ristocetin cofactor levels between 35% and 50% had similar bleeding symptoms as non-O patients in that range. It seems that this may be more of an academic issue whether the laboratory diagnosis of VWD should necessitate ABO adjustment. Probably a significant proportion of cases that have been diagnosed as mild “VWD” are nongenetic and related to the blood type (30). Perhaps, in the future, in consideration of these “nongenetic” cases, a better descriptive term of patients with subnormal VWF levels and bleeding symptoms would be the simple descriptive classification as von Willebrand deficiency based on the demonstration of a subnormal Fertility and Sterility姞
VWF antigen and/or ristocetin cofactor compared to the local laboratory range, non–ABO adjusted (31). ABO typing is still advisable, because the finding of blood type O allows the clinician to emphasize to the patient that their subnormal VWF level is most likely secondary, at least, in part to being blood type O and not a “disease” state per se or due to a genetic mutation. This is particularly the case because patients who have mild depression of VWF levels intuitively have a normal life expectancy. Consequently, the term “disease” with the connotation that they have a disorder that could shorten the life expectancy is perhaps too restrictive. It may also have a negative connotation when such a patient seeks insurance coverage. Perhaps, the term von Willebrand syndrome could be used if the patient has mucocutaneous bleeding symptoms in addition to VWF deficiency. In those patients with a subnormal VWF antigen and/or ristocetin cofactor, i.e., VWF deficiency, subsequent VWF multimer analysis and ristocetin-induced platelet aggregation should be carried out (20). However, prior to embarking on those relatively costly and time consuming tests, the patient should be screened for hypothyroidism. This is because of the association of hypothyroidism with acquired VWD (32, 33). In such cases, thyroid replacement can result in resolution of the VWF deficiency (34). In this phase of testing, if not done already, in addition to a TSH test, a serum creatinine test should be done to rule out, in part, uremic bleeding. An iron profile should also be done as a baseline prior to any intervention. Bleeding Time and/or Platelet Function Analyzer–100 Closure Time Concurrent with VWF testing, a BT and/or PFA-100 CT test could also be done as a baseline, because if such a test is prolonged in a VWF-deficient excessive menstrual bleeding patient, it could be followed postintervention for shortening of the time in ensuring adequate hemostasis. Neither BT nor CT is advisable “up front” for screening in lieu of VWF levels nor for screening for a platelet function disorder, given the relatively poor sensitivity of these tests for mild VWF deficiency (35) and platelet function disorders (35–37). Platelet Aggregation and Release Studies If initial hemostasis testing above is normal, and gynecologic evaluation is completely normal, then further hemostasis testing can be considered in terms of platelet aggregation and release (preferably off all medications [38]) as would normally be done in the investigation of a bleeding disorder in a patient with bleeding symptoms and a normal PT, APTT, CBC, and VWF profile, because platelet function is a critical component of normal hemostasis (10). Recently, Philipp et al. reported a relatively high prevalence of platelet function abnormalities in patients with extensive menstrual bleeding (39 – 41). The abnormalities were far more prevalent in the black population (39). The practical value of 1349
testing such a patient is that she may respond to desmopressin (42). If platelet aggregation and release studies are within normal limits, then based on the degree and severity of additional personal bleeding symptoms and the family history, the practitioner may consider additional coagulation studies such as a factor XIII level in consideration of factor XIII deficiency (12) and tests for fibrinolysis in terms of the screening euglobulin lysis test (43) and more specific fibrinolytic defects in terms of deficiencies of ␣2-antiplasmin or plasminogen activator inhibitor. The latter two tests may specify a fibrinolytic state. Increased fibrinolysis, in general, has been reported in menorrhagia patients (44 – 46), but whether fibrinolysis is localized to the uterus or present systemically has not been fully studied. FUTURE RESEARCH IN THE INVESTIGATION OF UNDERLYING DISORDERS IN WOMEN WITH EMB Finally, future clinical trials of hemostasis testing in the women with excessive menstrual bleeding should include the following: 1. In the light of the preliminary data cited above showing a relatively high prevalence of platelet function abnormalities in menorrhagia, further study of the potential role of subtle platelet aggregation and release abnormalities with concurrent study of platelet aggregation and release in normally menstruating women in determining if these abnormalities are a cause of heavy menstruation or an effect of normal and/or heavy menstruation. 2. Because there appears to be a high prevalence of platelet function abnormalities in black women, delineating further the platelet function defect in black women with excessive menstrual bleeding. 3. Given emerging data suggesting a role for the PFA-100 in the evaluation of an underlying bleeding disorder in menorrhagia (9), pooling of data and cost-effectiveness analysis of the PFA-100 versus “up front” VWF analysis in screening for VWD in the setting of women with EMB. 4. Given the presumed role of increased fibrinolysis in the pathogenesis of menorrhagia, prevalence studies of increased systemic fibrinolysis in terms of the euglobulin clot lysis as well as ␣2-antiplasmin, and plasminogen activator inhibitor levels. It is hoped that such research will lead to further improvement in the recognition and proper management of women with excessive menstrual bleeding who have primarily an underlying disorder of hemostasis. REFERENCES 1. Kouides PA, Burkhart P, Phatak P, Porter J, Peacock L, Braggins C, et al. Gynecological and obstetrical morbidity in women with type i von Willebrand disease: results of a patient survey. Haemophilia 2000;6: 643– 8. 2. Kouides PA. Obstetric and gynaecological aspects of von Willebrand disease [review]. Bailliere’s Best Pract Clin Haematol 2001;14:381–99.
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3. Royal College of Obstetricians and Gynaecologists. The management of menorrhagia in secondary care. Evidence-based clinical guidelines. Br J Obstet Gynaecol 1999;5. 4. Kirtava A, Drews C, Lally C, Dilley A, Evatt B. Medical, reproductive and psychosocial experiences of women diagnosed with von Willebrand’s disease receiving care in haemophilia treatment centres: a case-control study. Haemophilia 2003;9:292–7. 5. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet 1998;351:485–9. 6. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood loss and iron deficiency. Acta Med Scand 1966;180:639 –50. 7. Beck EA, Limoni C. Subnormal plasma von Willebrand factor (ristocetin cofactor) and iron deficiency anaemia in menstruating women [letter]. Thromb Haemost 1996;75:693. 8. Lipton RA. Misdiagnosis by milk box. Haemophilia 2003;9:235. 9. James AH, Lukes AS, Brancazio LR, Thames E, Ortel TL. Use of a new platelet function analyzer to detect von Willebrand disease in women with menorrhagia. Am J Obstet Gynecol 2004;191:449 –55. 10. Fricke W, Kouides P, Kessler C, Schmaier AH, Krijanovski Y, Jagadeesan K, et al. A multicenter clinical evaluation of the Clot Signature Analyzer. J Thromb Haemost 2004;2:763– 8. 11. Montgomery RR, Coller BS. Von Willebrand disease. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, editors. Hemostasis and thrombosis: basic principles and practice. 3rd ed. Philadelphia: J. B. Lippincott, 1994:134 – 68. 12. Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood 2004;104:1243–52. 13. Edlund M, Blomback M, von Schoultz B, Andersson O. On the value of menorrhagia as a predictor for coagulation disorders. Am J Hematol 1996;53:234 – 8. 14. Dilley A, Drews C, Miller C, Lally C, Austin H, Ramaswamy D, et al. von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia. Obstet Gynecol 2001;97:630 – 6. 15. Woo YL, White B, Corbally R, Byrne M, O’Connell N, O’Shea E, et al. Von Willebrand’s disease: an important cause of dysfunctional uterine bleeding. Blood Coagul Fibrinolysis 2002;13:89 –93. 16. Shankar M, Lee CA, Sabin CA, Economides DL, Kadir RA. Von Willebrand disease in women with menorrhagia: a systematic review. BJOG 2004;111:734 – 40. 17. Federici AB. The factor VIII/von Willebrand factor complex: basic and clinical issues [review]. Haematologica 2003;88(6): 18. Kadir RA, Economides DL, Sabin CA, Pollard D, Lee CA. Assessment of menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders. Haemophilia 1999;5:40 – 8. 19. Abildgaard CF, Suzuki Z, Harrison J, Jefcoat K, Zimmerman TS. Serial studies in von Willebrand’s disease: variability versus “variants.” Blood 1980;56:712– 6. 20. Federici AB. Mild forms of von Willebrand disease: diagnosis and management. Curr Hematol Rep 2003;2:373– 80. 21. Mandalaki T, Louizou C, Dimitriadou C, Symeonidis P. Variations in factor VIII during the menstrual cycle in normal women [letter]. N Engl J Med 1980;302:1093– 4. 22. Blomback M, Eneroth P, Landgren BM, Lagerstrom M, Anderson O. On the intraindividual and gender variability of haemostatic components. Thromb Haemost 1992;67:70 –5. 23. Onundarson PT, Gumundsdottir BR, Arnfinnsdottir AV, Kjeld M, Olafsson O. Von Willebrand factor does not vary during the normal menstrual cycle [letter]. Thromb Haemost 2001;85:183– 4. 24. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive. Thromb Haemost 1999;82: 1456 – 61. 25. Miller CH, Dilley A, Drews C, Richardson L, Evatt B. Changes in von Willebrand factor and Factor VIII levels during the menstrual cycle [letter]. Thromb Haemost 2002;2002–3. 26. Alperin JB. Estrogens and surgery in women with von Willebrand’s disease. Am J Med 1982;73:367–71.
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27. Mangal AK, Naiman SC. Oral contraceptives and von Willebrand’s disease [letter]. Can Med Assoc J 1983;128:1274. 28. Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ Jr, Montgomery RR. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987;69:1691–5. 29. Nitu-Whalley IC, Lee CA, Griffioen A, Jenkins PV, Pasi KJ. Type 1 von Willebrand disease—a clinical retrospective study of the diagnosis, the influence of the ABO blood group and the role of the bleeding history. Br J Haematol 2000;108:259 – 64. 30. Bauduer F, Ducout L. Is the assessment of von Willebrand disease prevalence an achievable challenge? The example of the French Basque Country where blood group O and factor XI deficiency are highly prevalent. J Thromb Haemost 2004;2:1724 – 6. 31. Sadler JE. Slippery criteria for von Willebrand disease type 1. J Thromb Haemost 2004;2:1720 –3. 32. Coccia MR, Barnes HV. Hypothyroidism and acquired von Willebrand disease. J Adolesc Health 1991;12:152– 4. 33. Blesing NE, Hambley H, McDonald GA. Acquired von Willebrand’s disease and hypothyroidism: report of a case presenting with menorrhagia. Postgrad Med J 1990;66:474 – 6. 34. Michiels JJ, Schroyens W, Berneman Z, Van der PM. Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine. Clin Appl Thromb Hemost 2001;7:113–5. 35. Posan E, Nichols WL, McBane RD, Grill DE, Motsko D. Comparison of the PFA-100 testing and the bleeding time for detecting platelet hypofunction and von Willebrand disease. J Thromb Haemost 2003; 90:483–90. 36. Philipp CS, Miller CH, Faiz A, Dilley A, Michaels LA, Ayers C, et al. Screening women with menorrhagia for underlying bleeding disorders: the utility of the platelet function analyser and bleeding time. Haemophilia 2005;11(5):497–503.
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37. Quiroga T, Goycoolea M, Munoz B, Morales M, Aranda E, Panes O, et al. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients. J Thromb Haemost 2004 June 1;2:892– 8. 38. Bick RL. Platelet function defects: a clinical review [review]. Sem Thromb Hemost 1992;18:167– 85. 39. Philipp CS, Dilley A, Miller CH, Evatt B, Baranwal A, Schwartz R, et al. Platelet functional defects in women with unexplained menorrhagia. J Thromb Haemost 2003;1:477– 84. 40. Philipp CS, Faiz A, Dowling N, Dilley A, Michaels LA, Ayers C, et al. Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol 2005;105:61– 6. 41. Gulbas Z, Akay M, Akin A. Platelet dysfunction and other hemostatic abnormalities in iron deficient women with unexplained menorrhagia. Blood 2001; [abstract]1056. 42. DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunction. Am J Hematol 1990;33:39 – 45. 43. Smith AA, Jacobson LJ, Miller BI, Hathaway WE, Manco-Johnson MJ. A new euglobulin clot lysis assay for global fibrinolysis. Thromb Res 2003;112:329 –37. 44. Hahn L, Cederblad G, Rybo G, Pehrsson NG, Bengtsen KK. Blood coagulation, fibrinolysis and plasma proteins in women with normal and with excessive menstrual blood loss. Br J Obstet Gynaecol 1976; 83:974 – 80. 45. Winkler UH. Menstruation: extravascular fibrinolytic activity and reduced fibrinolytic capacity. Ann N Y Acad Sci 1992;667:289 –90. 46. Edlund M, Blomback M, He L. On the correlation between local fibrinolytic activity in menstrual fluid and total blood loss during menstruation and effects of desmopressin. Blood Coagul Fibrinolysis 2003;14:593– 8.
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