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  Bleeding Disorders AssociatedBleeding Disorders AssociatedBleeding Disorders AssociatedBleeding Disorders AssociatedBleeding Disorders Associatedwith Menorrhagiawith Menorrhagiawith Menorrhagiawith Menorrhagiawith Menorrhagia Volume 17 , Number 1Volume 17 , Number 1Volume 17 , Number 1Volume 17 , Number 1Volume 17 , Number 1 January 2003 January 2003 January 2003 January 2003 January 2003Dorothy M. Adcock, MD Objective: The reader will be ableto discuss the various bleedingdisorders associated withmenorrhagia and the laboratoryevaluation used to distinguishamong these disorders. INTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTION Women with an underlying bleedingdisorder are at increased risk of a numberof untoward complications directly relatedto menorrhagia. Women with undiag-nosed bleeding disorders are also at riskof suffering significant hemorrhage withsurgical procedures, trauma, and child-birth. This may lead to prolonged hospi-talizations and unnecessary transfusiontherapy. A study by Ragni, et al. reportedthat post-operative bleeding in a cohort ofwomen could have been avoided in greaterthan 85% of cases if proper history andlaboratory studies had been applied pre-surgically.Menorrhagia frequently impacts awoman’s quality of life (QOL). Womenwho suffer from menorrhagia frequentlyreport diminished QOL due to the exces-sive bleeding. In a study performed byKouides et al., women with an underlyinghereditary bleeding disorder, specificallyvon Willebrand Disease (vWD), were pro-vided a questionnaire which evaluatedseven QOL parameters rated from 1-10with 0 referring to “no impact” and 10describing “complete interference”.Women with vWD were compared to asimilar cohort of otherwise healthy men-struating females. Results from theKouides questionnaire are listed in Table1. QOL was statistically poorer in thegroup with a bleeding disorder who suf-fered menorrhagia. Although thesewomen described their general health asvery good, 39% reported lost time fromwork or school secondary to heavy mensesand 47% reported accomplishing lessthan their normal capability during thistime. Over 50% of women with a bleedingdisorder also complained of dysmenor-rhea or painful menses, ranging in inten-sity from moderate to very severe. Anemiaand resultant fatigue is reported in 64% ofwomen with vWD. Diminished QOL inwomen with menorrhagia has also beenassociated with a greater incidence ofpsychological disturbances, most com-monly generalized as anxiety disorders.The Centers for Disease Control(CDC) has initiated a research and edu-cation program to increase both knowl-edge and awareness of bleeding disor- Heavy or prolonged menstrual bleeding or menorrhagia is defined as bloodloss of greater than 80cc per menstrual period. During their reproductiveyears, as many as 5%–10% of all women consult a physician complainingof menorrhagia. Menorrhagia is the primary reason for approximately30,000 hysterectomies every year. The incidence of menorrhagia ishigher in women with an underlying bleeding disorder and in fact, heavymenses are frequently the first manifestation of a hemostatic disorder inwomen.  CLINICAL HEMOSTASIS REVIEWCLINICAL HEMOSTASIS REVIEWCLINICAL HEMOSTASIS REVIEWCLINICAL HEMOSTASIS REVIEWCLINICAL HEMOSTASIS REVIEW7700 E. Wrightstown Rd., Ste. 106 Tucson, Arizona 85715chr@coagulation.com520.722.0797EDITOR IN CHIEFEDITOR IN CHIEFEDITOR IN CHIEFEDITOR IN CHIEFEDITOR IN CHIEFRebecca Jensen, MT(ASCP)CCCCCLINICAL ADVISORSLINICAL ADVISORSLINICAL ADVISORSLINICAL ADVISORSLINICAL ADVISORSDorothy M. Adcock, MDAlexander Duncan, MD, ChBH. James Day, MD, FACPDon W. Hill, MD, FACPCONTRIBUTORCONTRIBUTORCONTRIBUTORCONTRIBUTORCONTRIBUTORLynne Stevens, MT(ASCP)ASSISTANT TO THE EDITORASSISTANT TO THE EDITORASSISTANT TO THE EDITORASSISTANT TO THE EDITORASSISTANT TO THE EDITORKendra Sagar Clinical Hemostasis Review, is publishedby Esoterix Coagulation, Inc. and is circulatedto selected physicians and laboratorians.Copyright 2002. Esoterix Coagulation is partof the ESOTERIX, Inc family of laboratories pro-viding esoteric testing in numerous diseasecorridors. The opinions expressed in the ar-ticles are those of the author(s) and do notnecessarily reflect the opinions or recommen-dations of the advertisers, editors, or pub-lisher. The Publisher reserves copyright andrenewal on all published material and suchmaterial may not be reproduced in whole orin part without written permission from thepublisher. Consult the full prescribing infor-mation on any drugs or devices discussed.All correspondence should be directedto the attention of the Editor, Clinical Hemo-stasis Review, 7700 E. Wrightstown Road, Ste.106, Tucson, AZ 85715.Subscription Rate: $65.00/year, 14 issues,prepaid. Outside the USA additional postageis required: Canada and Mexico $20/year, allother destinations $50/year. Single copies$7.00. Subscriptions are to be paid in USAdollars only. Subscriptions not accompaniedby payment will be assessed a billing charge. To assure prompt delivery of your issues,please notify us of any address corrections. Sixweeks are required to effect a change. Miss-ing copies not received by mail will be pro-vided free of charge if we are notified no laterthan two months after the issue date. Afterthis deadline, we will charge subscribers$5.00 per issue.ISSN 0894-1025 ders in women. The primary goals ofthe CDC program are to decrease un-necessary surgeries, such as hyster-ectomies, in women with bleeding dis-orders and to improve QOL. As part ofthis initiative, the CDC surveyed a co-hort of obstetricians/gynecologists inGeorgia to determine the prevalence ofmenorrhagia in their patient popula-tions and to determine the etiologies ofheavy menses most often consideredby these physicians. There was a 54%response rate to the survey. The aver-age physician surveyed had been inpractice for 20 years and reported that8% of their patient population com-plained of menorrhagia. Respondentsreported that the most common etiol-ogy of the bleeding was likely anovula-tory in nature or secondary to a benignlesion of the uterus (e.g. fibroids). Anunderlying bleeding disorder such asvWD was entertained by only 4% of thephysicians surveyed. This survey sug-gests that physician awareness ofbleeding disorders, as a cause ofmenorrhagia, must be heightened asa number of studies suggest that theactual incidence of an underlying bleed-ing disorder is as high as 40% in thispopulation.Realizing that there are manywomen who go undiagnosed, and aretherefore at increased bleeding risk,the National Hemophilia Foundation(NHF) initiated “Project Red Flag.” Thispublic awareness program is designedto inform and educate both the generalpublic and healthcare providers aboutthe high prevalence of women’s bleed-ing disorders such as vWD. EVALUATION OF WOMENEVALUATION OF WOMENEVALUATION OF WOMENEVALUATION OF WOMENEVALUATION OF WOMENWITH MENORRHAGIAWITH MENORRHAGIAWITH MENORRHAGIAWITH MENORRHAGIAWITH MENORRHAGIA It is very difficult for most women todetermine the quantity of blood lostwith menses and attempts to assistquantitation through determining num-ber of pads or tampons soaked havenot been well standardized or acceptedby clinicians. A significant problem isthat “heavy bleeding” is a relative con-cept. This is compounded by the factthat bleeding disorders tend to run infamilies and families may considerheavy menses to be normal sincewomen frequently learn about men-struation from their mothers or sis-ters. One good indicator of menor-rhagia is the presence of iron defi-ciency anemia.Studies report that 17%-40% ofwomen with menorrhagia have an un-derlying bleeding disorder. Non-he-matologic causes of excessive uterinebleeding, however, are also commonand should be excluded in the evalua-tion of women complaining of menor-rhagia. The most common causes ofheavy menses are uterine fibroids(myomas) or hormonal disturbancesthat frequently occur in women at thebeginning or end of their reproductiveage. Hormonal disturbances com-monly lead to menometrorrhagia, whichrefers to irregular yet heavy bleeding.Menorrhagia is common in womenwith low levels of thyroid hormone.The American College of Gynecol-ogy (ACOG) published a CommitteeOpinion in December of 2001 statingthat inherited and acquired disordersof hemostasis should be consideredin women with menorrhagia, particu-larly those without obvious pelvic ab-normalities to account for the bleeding.While ACOG recommends screeningfor vWD only as the initial evaluation, acomplete evaluation would include thefollowing assays: complete blood count(CBC), activated partial thromboplas-tin time (APTT), prothrombin time (PT),and von Willebrand panel (factor VIIIactivity, VWF antigen and activity). SeeTable 2. A CBC is useful to screen foranemia as well as thrombocytopenia.APTT may be increased in women withvWD or due to a factor VIII, factor IX, orfactor XI deficiency. Factor XI levelsshould be evaluated in women withmenorrhagia to rule out hemophilia C(factor XI deficiency). APTT values,however, may be normal in women  TABLE 1. TABLE 1. TABLE 1. TABLE 1. TABLE 1. Quality of LIfe Assessment 2 2 2 2 2 CLINICAL HEMOSTASIS REVIEW / OCTOBER 2003  Controls n =150 vWD patients Type 1) n =81 P-value* Impact of menses on general activity 1.1 +1.8 4.1 +3.0 <0.0001 ability to work or go to school 0.5 +1.4 3.1 +3.3 <0.0001 family activities 0.6 +1.4 3.5 +2.9 <0.0001 ability to enjoy life 0.9 +1.5 3.9 +3.3 <0.0001 sleep 1.3 +2.3 3.6 +3.1 <0.0001 mood 3.5 +2.8 5.6 +3.3 <0.0001 overall quality of life 1.7 +1.8 4.3 +3.1 <0.0001  with vWD, factor XI deficiency, and inwomen who are carriers of hemophiliaA and B (deficiencies of factors VIII andIX, respectively). APTT and PT assaysthat are normal, therefore, do not ex-clude a bleeding disorder. For this rea-son, it may be necessary to evaluatespecific factor levels in women withmenorrhagia.In women with normal screeningstudies (CBC, PT/PTT, vW panel andfactor XI activity) who complain of men-orrhagia, should be evaluated for factorVIII and factor IX levels especially if thereis a family history of bleeding. Of course,hereditary deficiencies of factors VII, V,and II may cause menorrhagia andshould be considered in certain fami-lies, although these deficiencies arerare. Some form of platelet functionanalysis should be considered such asbleeding time, platelet aggregation stud-ies, or the use of an automated plateletfunction analyzer (PFA) such as the PFA-100 (Dade Behring, Marburg, Germany).In those women in whom the cause ofbleeding still remains elusive, consid-eration should be given to performanceof euglobulin clot lysis time, fibrinogenactivity, PAI-1, and α 2-antiplasmin torule out hyperfibrinolysis or dysfibrino-genemia as a cause of bleeding. SeeTable 2.In women with menorrhagia, thy-roid function tests should be consid-ered, as hypothyroidism may lead toheavy menses. Hypothyroidism rep-resents an acquired form of vWD, asthese patients typically have low vWFlevels, which increase into the normalrange with appropriate thyroid supple-mentation therapy. MENORRHAGIA AND vWDMENORRHAGIA AND vWDMENORRHAGIA AND vWDMENORRHAGIA AND vWDMENORRHAGIA AND vWD Menorrhagia is the most commonmanifestation of bleeding in womenwith vWD and is reported in up to 80%.Most women with vWD report onset ofmenorrhagia with menarche.VWD is the most common heredi-tary bleeding disorder affecting 1%-3% of all people. This means thatabout 2.6 million persons in the UnitedStates have vWD. Bleeding in individu-als with vWD can be mild or life threat-ening, can occur with injury or traumaonly, or be spontaneous. The mostcommon symptoms of vWD includerecurrent nosebleeds, menorrhagia,easy bruising, unusual or excessivebleeding from the mouth or gums, andunusual or excessive bleeding aftersurgery, dental procedures, or injury.VWD is equally common in menand women because it is inherited inan autosomal dominant manner. Aparent with vWD has a 50% chance ofpassing the gene to each child. Somecases of vWD represent a spontane-ous mutation and there are rare casesof acquired vWD due to certain malig-nancies, autoimmune disorders, ordrug therapies. There are threecommon catego-ries of vWD. Type 1comprises 70%-80% of cases andis characterized bydecreased vWFactivity and anti-gen. As the vW pro-tein serves as acarrier of factor VIII,factor VIII levels aredecreased toabout the samelevel as the vWFantigen. Degreesof deficiency in type1 vWD can be mild,moderate, or se-vere. Type 2 vWDis characterized byan abnormal vWFprotein – a qualita-tive abnormality. Intype 2, the vWFantigen to activityratio is usually inthe range of 2:1.Type 3 vWD is char-acterized by es-sentially no circulating vWF. This se-vere form of deficiency is rare and bleed-ing manifestations can be life threaten-ing. In a 16-center study of women witheither type 2 or 3 vWD, 80% requiredtransfusion with blood products be-cause of excessive bleeding and in23%, menorrhagia necessitated hys-terectomy, primarily for control of men-strual bleeding.In patients with vWD, childbirth maypresent a unique challenge. Duringpregnancy, especially in the third tri-mester, levels of factor VIII and vWFincrease, in both normal women andthose with type 1 vWD. These levels,however, may not increase to the samedegree in normal women as those withvWD. Postpartum hemorrhage occursin 16%-30% with vWD, while rates of3%-5% are reported in the generalpopulation. Red cell transfusions areadministered to 7%-17% of thesewomen carrying the risk of transfusionreaction, sensitization, and diseasetransmission to the mother.Diagnosis of vWD is dependenton assimilation of clinical features andlaboratory results. The clinical andlaboratory diagnosis of vWD, however,can be difficult. This is, in part, due tonatural variations in vWF levels as theseproteins are acute phase reactants andlevels also vary with hormone status. Inaddition, vWF and factor VIII levels aredependent on ABO blood type, age,and race. Higher vWF levels occur innon-0 blood types and in African Ameri-cans, and levels tend to increase withage. There is no consensus as to theeffect of menstrual cycle and exog-enous hormone effect of vWF antigenand activity levels. It has been sug-gested, although inconclusively, thatvWF antigen and activity levels are low-est during menstruation. In the earlyfollicular phase of the menstrual cycle(less than day 7) most sex hormonesare at their baseline and vW levelsshow little variation between days 5-7.When vW testing is performed inwomen, day of the menstrual cycleshould be noted. In women that haveborderline results suggestive of vWD,repeat vW testing during days 5-7 of thecycle should be considered. The ma- jority of studies evaluating the effect onfemale sex hormones on vWF levelssuggest that estrogens increase vWFlevels in a dose dependent manner.For this reason, there is concern that adiagnosis of vWD may be missed ifwomen are tested while on hormonetherapy, including oral contraceptivetherapy, or during pregnancy. Untilfurther data are published, it is best to OCTOBER 2003 / CLINICAL HEMOSTASIS REVIEW 33333  TABLE 2. TABLE 2. TABLE 2. TABLE 2. TABLE 2. Recommended Screening Tests for Menorrhagia 1 st  Tier Tests for Menorrhagia Prothrombin TimeActivated Partial ThromboplastinTimeComplete Blood Countvon Willebrand PanelFactor VIII Activityvon Willebrand Factor Antigenvon Willebrand Factor ActivityFactor XI Activity 2 nd  Tier Tests for Menorrhagia Factor IX ActivityEvaluation of Platelet FunctionPlatelet AggregationPFA-100 3 rd  Tier Tests for Menorrhagia Fibrinogen Activity α 2-AntiplasminFactor XIII  test women at least two months off ofhormone therapy and at times otherthan during pregnancy or the postpar-tum period, when possible. MENORRHAGIA ANDMENORRHAGIA ANDMENORRHAGIA ANDMENORRHAGIA ANDMENORRHAGIA ANDBLEEDING DISORDERS OTHERBLEEDING DISORDERS OTHERBLEEDING DISORDERS OTHERBLEEDING DISORDERS OTHERBLEEDING DISORDERS OTHER THAN vWD THAN vWD THAN vWD THAN vWD THAN vWD Menorrhagia is reported in 57% ofwomen who are carriers of hemophiliaA and B, and in 60% of women withfactor XI deficiency. Menorrhagia alsooccurs in women deficient in factors VII,V, or II, although these deficiencies arerare. Most women with these inheritedbleeding disorders also report onset ofmenorrhagia with menarche.Carriers of hemophilia A and B candemonstrate a wide range of factor VIIIand IX levels respectively. Women withfactor VIII or IX levels below 50% mayhave an increased bleeding tendency.Menorrhagia, prolonged hemorrhagewith trauma, childbirth, or surgery andeasy bruising has been reported infemale carriers of hemophilia A and B.Factor XI deficiency is inherited inan autosomal manner in which ho-mozygotes have factor levels below15% while heterozygous deficients mayhave levels in the low normal range.Bleeding in factor XI deficiency is vari-able and does not always correlate wellwith factor XI levels. Factor XI deficiencyis rare.Platelet abnormalities due to ei-ther decreased number (thrombocy-topenia) or dysfunction are an impor-tant cause of menorrhagia. Idiopathicthrombocytopenic purpura is a frequentcause of thrombocytopenia in womenof reproductive age. Abnormalities ofplatelet function can be inherited oracquired. Medications such as aspirinand non-steroidal anti-inflammatoryagents are common causes of plateletdysfunction. It is important to considerdrug effect as women with menorrhagiacommonly suffer dysmenorrhea forwhich they may take non-steroidal anti-inflammatory agents. Hereditarycauses of platelet dysfunction includesurface glycoprotein receptor abnor-malities (Glanzmann’s thrombasthe-nia and Bernard Soulier Syndrome)and storage pool defects.  TREATMENT TREATMENT TREATMENT TREATMENT TREATMENT Intranasally administered desmo-pressin (DDAVP) for the treatment ofmenorrhagia in women with vWD issuccessful 92% of the time. IntranasalDDAVP is typically given as a 2-8 daycourse with each menstrual cycle. Thistherapy is also beneficial in womenwho are carriers of hemophilia A and insome forms of platelet function defectssuch as storage pool disease. Sideeffects of DDAVP therapy include nau-sea, headache, and hyponatremia maydevelop if water intake is not restricted.The use of exogenous hormonesin the form of combined oral contracep-tives has been reported to decreasemenstrual flow and decrease the inci-dence of iron deficiency anemia inwomen with vWD. This mechanism ofmenorrhagia control is most likely duein part to inhibition of endometrialgrowth. Diminished menstrual bleed-ing may also be secondary to eleva-tions of factor VIII and vWF levels asso-ciated with the administration of estro-gen.The use of antifibrinolytic therapyhas also been effective in the treatmentof menorrhagia in women with vWD.Epsilon-amino caproic acid given orallyfor four days during the menstrual cycleis associated with decreased men-strual blood loss. Tranexamic acid,another form of antifibrinolytic therapy,has also been used effectively to con-trol blood loss with menstruation inEurope regardless of the type of under-lying hemostatic disorder. This drug isnot available as an oral compound inthe U.S.Women with factor XI deficiencyand menorrhagia may respond totranexamic acid therapy. Oral contrac-tive agents may also be used and likelyreduce bleeding due to their atrophiceffects on the endometrium. Thera-peutic interventions for women withfactor VII or V deficiency or carriers ofhemophilia B require further study. CONCLUSIONCONCLUSIONCONCLUSIONCONCLUSIONCONCLUSION Menorrhagia occurs in up to 10%of women. An underlying bleeding dis-order, most commonly vWD, should beconsidered and investigated in womenwith a normal pelvic examination. Ap-propriate diagnosis and therapy of anunderlying bleeding disorder in thispopulation can improve QOL and de-crease morbidity. REFERENCESREFERENCESREFERENCESREFERENCESREFERENCES Dilley A, Drews C, Miller C, et al. von Willebrand Disease and other inher- ited bleeding disorders in women with diagnosed menorrhagia.  ObstetGynecol. 2001;97(4):630.Kadir RA, Economides DL, Sabin CA, etal. Assessment of menstrual blood loss and gynaecological problems in pa- tients with inherited bleeding disorders. Haemophilia. 1999;5(1):40.Kadir RA, Economides DL, Sabin CA, etal. Frequency of inherited bleeding dis- orders in women with menorrhagia. Lancet. 1998;351(9101):485.Kadir RA, Economides DL, Sabin CA, etal. Variations in coagulation factors in women: Effects of age, ethnicity, men- strual cycle and combined oral contra- ceptive.  Thromb Haemost. 1999;82(5):1456.Kadir RA, Sabin CA, Pollard C, et al. Quality of life during menstruation in patients with inherited bleeding disor- ders.  Haemophilia. 1998;4(6):836.Kouides PA, Phatak PD, Burkart P, et al. Gynaecological and obstetrical mor- bidity in women with type I von Willebrand disease: Results of a patient survey.  Haemophilia. 2000;6(6):643.Kouides PA. Menorrhagia from a haematolgist’s point of view. Part I: Ini- tial evaluation.  Haemophilia. 2002;8(3):330.Kouides PA. Obstetric and gynaecological aspects of von Willebrand disease.  Best Pract Res ClinHaematol. 2001;14(2):381.Önundarson PT, Gudmundsdottir BR,Arnfinnsdottir AV, et al. von Willebrand factor does not vary during normal menstrual cycle.  Thromb Haemost.2001;85(1):183.Ragni MV, Bontempo FA, Hassett AC. Von Willebrand disease and bleeding in women.  Haemophilia. 1999;5(5):313.Siegel JE, Kouides PA. Menorrhagia from a haematologist’s point of view,part II: Management.  Haemophilia.2002;8(3):339.Woo YL, White B, Corbally R, et al. von Willebrand’s disease: An important cause of dysfunctional uterine bleed- ing.  Blood Coag Fibrinol. 2002;13(2):89. 4 4 4 4 4 CLINICAL HEMOSTASIS REVIEW / OCTOBER 2003

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