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Abstract

Separately, von Willebrand disease and menorrhagia are two relatively common conditions; in combination they occur at a prevalence of approximately 11–16%. Such patients exhibit a reduced quality of life and can incur a relatively high rate of gynecologic interventions; for example dilatation and curettage, endometrial ablation and hysterectomy. Initial evaluation involves a focused history for the following bleeding symptoms: menorrhagia since menarche, easy bruising of greater than 5 cm 1–2 times/month, frequent gum bleeding when flossing or brushing teeth or epistaxis 1–2 times/month. In addition, for those who have already undergone invasive interventions with the subsequent risk for hemorrhage, inquiry should be made regarding excessive bleeding with childbirth, dental tooth extraction and/or surgery. Step-wise testing includes a complete blood cell count and an assessment of the prothrombin time, activated partial thromboplastin time, iron profile, serum creatinine and thyroid-stimulating hormone level, followed by Factor VIII level, von Willebrand factor antigen and ristocetin cofactor, followed by consideration of platelet aggregation studies. Additional hemostatic studies may include obtaining a Factor XI level and euglobulin clot lysis time. Intuitively, failure to diagnose an underlying hemostatic disorder may lead to continued menorrhagia and diminished quality of life, as well as unnecessary surgical interventions that may in turn be fraught with an increased risk of bleeding. The management of von Willebrand disease-related menorrhagia involves consideration of the patient's age, childbearing status and preference. In the adolescent, surgical intervention is not an option, whereas an older patient beyond her childbearing years may choose a hysterectomy as a definitive treatment in lieu of continued medical therapy with intranasal/subcutaneous 1-deamino-8-D-arginine vasopressin (DDAVP), oral antifibrinolytic agents or oral contraceptive. The sexually active patient may initially choose a trial of oral contraceptive or the levonorgestrel intrauterine device, Mirena®. Pending ongoing comparative trials in von Willebrand disease-related menorrhagia of intranasal DDAVP, tranexamic acid and the levonorgestrel intrauterine device, specific recommendations cannot be made at present regarding the superiority of one intervention compared with another. It should also be noted that the dose and schedule of intranasal DDAVP, tranexamic acid and ε-amino caproic acid have not been well established and warrant further study in combination and at various doses and schedules.

Keywords

desmopressin levonorgestrel intrauterine device menorrhagia platelet function disorders tranexamic acid von Willebrand disease

The intersection of menorrhagia & underlying disorders of hemostasis

Menorrhagia is a very common clinical problem [1]. An accepted definition is blood loss greater than 80 ml/menstrual cycle [2]. A total of 8–10% of women of reproductive age report menorrhagia [1,3]. Menorrhagia is an important cause of iron-deficiency anemia and subsequent morbidity [4]. Morbid events include dysmenorrhea, hospitalization, red blood cell transfusion and quality of life impairment in terms of daily activities of living, chronic pain and time lost from work or school [3]. Up to 60% of women with uncontrolled menorrhagia may choose to undergo hysterectomy, with the potential for attendant complications [5]. Additional surgical procedures for the control of menorrhagia include endometrial ablation and dilatation and curettage (D&C).

Underlying causes of menorrhagia include gynecologic organic pathology, systemic disease such as hypothyroidism [6] and acquired or inherited bleeding disorders. The traditional focus of the investigation of menorrhagia has been on the organic pathology of the uterus itself [3]. Women with menorrhagia frequently undergo intensive investigation, yet a cause for menorrhagia is never identified in approximately 50% of cases [3]. Menorrhagia has historically been a disorder almost exclusively in the domain of gynecologists. However, in part, although at a basic level, menstruation is a hemostatic process taking place at the endometrial mucosa by the interplay of platelets, von Willebrand factor (VWF), coagulation factors and fibrinolytic and antifibrinolytic proteins (Figure 1). Unsurprisingly, over the years hematologists have noted obstetric and gynecologic complications in their female patients with disorders of VWF, platelets, coagulant proteins and fibrinolysis [7,8]. Recently, several studies have unambiguously documented obstetric and gynecologic morbidity in females with von Willebrand disease (VWD). The vast majority of these patients (approximately 80%) develop menorrhagia [9 –14]. Recent studies have also clearly demonstrated that women with VWD experience:

Figure 1.

Schematic depiction of primary and secondary hemostasis.

Surgical interventions for menorrhagia control

Diminished quality of life

Chronic iron-deficiency anemia

Peripartum hemorrhage

Surgical interventions for menorrhagia control

Approximately 25% of women with VWD have undergone a D&C as part of the evaluation of menorrhagia [9]. In a study of 99 women with type I VWD, 7% underwent a hysterectomy prior to the diagnosis of VWD for control of menorrhagia [12]. In a study by Woo and colleagues, four out of five women diagnosed with VWD (representing 13% of a cohort with menorrhagia documented spectrophotometrically) had undergone a hysterectomy for control of menorrhagia prior to VWD testing [15].

Diminished quality of life

Quality of life (QoL) scales have documented a diminished QoL along with increased dysmenorrhea and time lost from school and work [12,16,17]. Of a total of 180 women with VWD published in the literature, 39–46% reported losing time from work or school [12,16]. Dysmenorrhea was also reported in approximately half of the patients in both studies. Hemoperitoneum has also been reported mid-cycle from rupture of a hemorrhagic corpus luteum cyst [12,18,19]. The reader should be cautioned that it is not clear to what degree the QoL impairment in VWD-related menorrhagia is more pronounced than in women with menorrhagia who do not have VWD [20]. This is an area of ongoing study.

Chronic iron-deficiency anemia

A high baseline prevalence of anemia has been reported in 28–66% of VWD patients with menorrhagia [9,12]. Furthermore, preliminary data suggest that iron-deficiency anemia may be implicated as a cofactor in the cognitive impairment noted in women with VWD and menorrhagia [17].

Peripartum hemorrhage

A significant proportion of women with VWD require red blood cell transfusions at the time of childbirth (7[21]–17%[12]), particularly if they were previously undiagnosed [18].

Additional bleeding symptoms in VWD women from a case–control study are presented in Table 1 [12].

Table 1.

Inventory of nonmenstrual bleeding symptoms.

Frequency of bleeding symptom	VWD patients n = 81 (type 1)	Controls n = 150	p-value*
Bruising frequently	78.3%	24.3%	0.001
Dental work-related bleeding	68.7%	7.9%	0.001
Epistaxis	45.7%	38.8%	0.3
Gingival bleeding	59%	39.5%	0.004
Hematuria	8.4%	9.9%	0.7
Joint bleeding	4.8%	0%	0.006
Muscle bleeding	6%	0%	0.002
Rectal bleeding	14.5%	14.5%	0.9
Surgical-related bleeding	43.4%	4%	0.001

Adapted from [12]

chi-square analysis; VWD: von Willebrand disease

von Willebrand disease & menorrhagia

The observations outlined above served as a starting point for the hematology research community to focus their efforts in detecting VWD in women with menorrhagia so that they could be provided with hemostatic interventions such as 1-deamino-8-D-arginine vasopressin (DDAVP), which may reduce the morbidity of monthly menstruation, childbirth and future invasive procedures such as a dental extraction. In a recent systematic review of 11 prevalence studies of VWD in 988 women presenting with menorrhagia, Shankar and colleagues reported an overall prevalence of VWD of 13% (95% confidence interval [CI]: 11–15.6%) [22]. The prevalence was higher in the European studies, at 18% (95% CI: 15–23%) compared with the North American studies at 10% (95% CI: 7.5–13%). The authors speculate that the difference (p = 0.007) is likely to be the result of differences in the studies, which include method of recruitment of study population, method of assessing menstrual blood loss, ethnic composition of the study population and criteria for laboratory diagnosis regarding use of race- and ABO blood group-specific values for VWF. Despite the presence of a definite subset of women with menorrhagia having VWD, mass testing of women is not feasible. In general, the probability of VWD in a woman with menorrhagia would be greatest if she has had menorrhagia since menarche [23], menstrual bleeding that is ovulatory (regular periods) and multiple mucocutaneous bleeding symptoms.

Patients with menorrhagia who do not meet laboratory criteria for VWD may have other or superimposed disorders of hemostasis, such as Factor VIIII, IX [9] or XI deficiency [24], or disorders of fibrinolysis [25,26] or platelet function [27,28]. In terms of platelet dysfunction, Philipp and colleagues studied 74 women with idiopathic menorrhagia [28]. Platelet aggregation abnormalities were noted in a high proportion of these women. Maximal percent platelet aggregation was decreased with one or more agonists in 35 (47.3%) women. Decreased ATP release was also noted in a substantial proportion of the patients compared with controls. The abnormalities were far more prevalent in the black population. In light of this data and other preliminary data [30] showing a relatively high prevalence of platelet function abnormalities in menorrhagia and that such a patient may respond to desmopressin [29], further study of the potential role of subtle platelet aggregation and release abnormalities is required. Concurrent study of platelet aggregation and release in normal menstruating women will be important in determining whether these abnormalities are a cause of heavy menstruation or an effect of normal and/or heavy menstruation. In summary, a sizeable proportion of patients with documented menorrhagia may have diagnostic tests or symptoms suggestive of an underlying bleeding disorder.

Hemostasis evaluation in menorrhagia

Laboratory investigation for an underlying disorder of hemostasis in a woman with menorrhagia cannot be carried out by the practitioner in a vacuum, oblivious to the clinical history. Consequently, the first step is not venipuncture but a focused history to establish the family history of bleeding and a personal history of bleeding symptoms as outlined in Figure 2 and Table 1, based on the author's clinical experience and retrospective data [9 –14]. These symptoms (using albeit arbitrary cut-offs) for all women include:

Figure 2.

Step-wise hemostasis evaluation in menorrhagia.

Easy bruising of greater than 5 cm 1–2 times/month

Frequent gum bleeding when flossing or brushing teeth

Epistaxis 1–2 times/month

In addition, for those having already undergone invasive interventions with subsequent risk for hemorrhage, inquiry should be made regarding excessive bleeding with childbirth, dental tooth extraction and/or surgery.

These discriminatory symptoms are derived from case-control studies of a total of approximately 200 women with previously diagnosed VWD compared with women without VWD. A limitation of such data is that the symptoms are self reported and consequently there can be a recall bias. All of the symptoms described above occurred significantly more frequently in women with VWD compared with normal, menstruating controls [12,13]. Furthermore, in the Royal Free London (London, UK) study, carried out by Kadir and colleagues on the prevalence of VWD in menorrhagia, compared with the non-bleeding disorder menorrhagia patients, those with VWD were more likely to report the following [23]:

Menorrhagia since menarche (65 vs 9%)

Bleeding after dental extraction (46 vs 7%)

Postoperative bleeding (62 vs 8%)

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 should have been less of a recall bias.

Both primary and secondary evaluations are summarized in Figure 2. 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 should be considered in those females considering major surgical intervention.

Since there will be instances where a history will not be helpful in cases of unprovoked, unreliable or forgetful patients, hemostasis testing in terms of VWF analysis should be considered in those scheduled for surgical management of extensive menstrual bleeding. In line with this, Kadir and colleagues reported that 8% of the VWD patients identified in their prevalence study had no additional bleeding symptoms [23].

The initial laboratory evaluation for an underlying disorder of hemostasis should be the complete blood cell count (CBC). This will rule out thrombocytopenic bleeding. Further evaluation of thrombocytopenia is outlined in Table 2. The CBC also assesses the degree, if any, of anemia. At least two-thirds of women in the general population with menorrhagia are iron deficient [4], as has also been noted in a study of women with VWD [12]. There also appears to be an inverse relationship between subnormal VWF levels and the prevalence of iron deficiency, as reported by Beck and Limoni [31].

Table 2.

Approach to the patient with thrombocytopenia based on four possible underlying mechanisms.

Mechanism	Relevant aspects to consider
	History	Physical	Laboratory
1. Bone marrow suppression
(a) Exogenous	Query for: Alcohol use Sulfa-containing medications	–	–
(b) Endogenous (bone marrow disease – aplastic anemia, leukemia, lymphoma, metastatic cancer)	–	–	Examine blood smear for abnormal cells Is rest of the full blood cell count normal? If not then bone marrow examination likely needed
2. Consumption
(a) Hypersplenism	Query for history for occult liver disease – alcohol use, hepatitis	Assess for splenomegaly	Consider abdominal ultrasound to assess for splenomegaly
(b) DIC	Query for acute symptoms for sepsis or chronic symptoms for malignancy	–	Check PT, aPTT and fibrinogen level Examine smear for red blood cell fragments
(c) HUS-TTP	Query for acute neurological symptoms	Check neurological exam	Check PT, aPTT and fibrinogen level Examine smear for red blood cell fragments
			Check serum chemistries for hemolysis and renal failure
(d) von Willebrand disease Type 2B	Query for family history of bleeding	–	von Willebrand factor levels
3. Pseudothrombocytopenia
	–	–	Examine blood smear for clumping; if present repeat the platelet count in non-EDTA-containing tube
4. Immune-mediated destruction
(a) ITP, primary	–	–	–
(b) ITP, secondary	Query for: History of HIV risks, History of hyperthyroidism, History of medication use (e.g., valproic acid, quinidine)	Assess for signs of thyroid disease	Consider HIV test TSH, T₃, T₄

aPTT: activated partial thromboplastin time; DIC: Disseminated intravascular coagulation; EDTA: Ethylenediaminetetraacetate; HUS-TTP: Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura; ITP: Immune (idiopathic) thrombocytopenia purpura; PT: Prothrombin time; TSH: Thyroid-stimulating hormone.

Those women with a positive screen and normal platelet count should undergo a logical, step-wise sequence of testing for various disorders of hemostasis. Accurate hemostasis testing is crucial, as the specificity of bleeding symptoms is poor, with many normal patients without an identifiable disorder of hemostasis reporting bleeding symptoms [12]. Hemostasis testing should ideally be carried out on-site with immediate on-site processing, given the frequent misdiagnosis of VWF deficiency when samples are sent to a distant site due to the activation/degradation of the sample over time [32].

This phase of hemostasis testing (as outlined in Figure 2) typically includes assessing the prothrombin time (PT), activated partial thromboplastin time (APTT) (if not already performed), VWF antigen, ristocetin cofactor, Factor VIII, ABO type, Ivy bleeding time and/or in vitro closure time (PFA-100). The tests and the rationale for performing them in this phase of evaluation in women with extensive menstrual bleeding are described in further detail below.

Prothrombin time & activated partial thromboplastin time

These are standard, readily available tests of hemostasis carried out in the evaluation of the bleeding patient. However, in general, these tests carry a very low positive and negative predictive value for an underlying bleeding disorder [33]. In consideration of acquired disorders of hemostasis, the PT screens for bleeding are most commonly associated with 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 this out. However, the sensitivity of a prolonged APTT for VWD is less than 40% [34]. On the other hand, in consideration of the severe, albeit rare, non-X-linked hemophilia disorders (deficiencies of Factor 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 [35].

A prolonged APTT necessitates a mixing study with pooled normal plasma to further distinguish between a deficiency state, such as hemophilia, or an inhibitor. An inhibitor may be an incidental finding in terms of a lupus anticoagulant or a potentially life-threatening condition in terms of acquired hemophilia A due to an autoantibody.

VWF antigen, ristocetin cofactor & Factor VIII levels

The approximately 13% (95% CI: 11.1–15.6%) prevalence [15,22,23,36,37] of VWD in menorrhagia patients leads one to consider VWF and Factor VIII levels as part of the initial hemostasis evaluation. However, the lack of cost-effectiveness and long-term outcome data precludes one from strongly advising up-front VWF testing for all patients at this time [20]. Intuitively, those patients with additional mucocutaneous bleeding symptoms and/or a family history of mucocutaneous bleeding symptoms are appropriate candidates for up-front VWF testing. The Factor VIII level can be reduced in VWD, as VWF protects Factor VIII from proteolytic cleavage [38]. Factor VIII deficiency alone may cause menorrhagia, even in the presence of normal VWF levels (i.e., mild hemophilia A) [9].

In ordering VWF and Factor VIII testing, the clinician must be aware that VWF and Factor VIII levels can fluctuate [39]. Hormonal factors, both exogenous and endogenous, are a potential mechanism in part for such fluctuation [40]. Consequently, there are several subtleties (Box 1) in the laboratory diagnosis of VWD that warrant clarification.

Testing in relation to the menstrual cycle

Levels may decrease during menses [41,42].

Testing in relation to combination oral contraceptive use

There is currently a lack of evidence demonstrating a definite effect of combination oral contraceptives (OCs) on VWF levels [42]. A practical approach would be to continue to test women when on OCs, particularly if they are experiencing menorrhagia or other mucocutaneous bleeding symptoms, since if the subnormal VWF levels are contributing to the bleeding at that point in time, then the OC would appear not to be raising the VWF and Factor VIII levels.

Testing in relation to the ABO type

It is well known that patients with blood type O have 25% lower VWF and Factor VIII levels [43]. Obviously, adjusting for the ABO blood type would require a lower VWF and Factor VIII 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, Nitu-Whalley and colleagues showed that type O patients with ristocetin cofactor levels between 35 and 50% had similar bleeding symptoms compared with non-O patients in that range [44]. It seems that whether the laboratory diagnosis of VWD should necessitate ABO adjustment is an academic issue. It is likely that a significant proportion of cases that have been diagnosed as mild VWD are nongenetic and related to blood type [45]. ABO typing is still advisable as 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, that it is not a ‘disease’ state and that they do not have a genetic mutation. This is particularly the case since patients who have mild depression of VWF levels should have a normal life expectancy.

Box 1.

Logistical issues to be considered in von Willebrand factor testing

Laboratory artifact and interpretation – von Willebrand factor (VWF) testing should be performed with:

– On-site laboratory processing and analysis

– Interpretation of results by clinical pathologist/hematologist

Potential effect of oral contraceptive (OC) and timing – ideally, the patient should be off OCs for 1 month and testing should be during menses

In cases of results in the normal range, repeat testing off OCs and during menses is advisable if:

– The first sample was obtained while the patient was still on OCs or was tested in the non-menses time frame

– The VWF levels were drawn in the appropriate time frame and off OCs but the VWF levels returned in the lower half of the normal range

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.

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 (RIPA) should be carried out for further classification of VWF [40]. However, prior to embarking on those relatively costly and time-consuming tests, the patient should be screened for hypothyroidism. This is due to the association of hypothyroidism with acquired VWD [6]. In such cases, thyroid replacement can result in resolution of the VWF deficiency [46].

In this phase of testing, in addition to a thyroid stimulating hormone (TSH), a serum creatinine test should be carried out, in part to rule out uremic bleeding, if this has not already been done. An iron profile should also be obtained as a baseline prior to any intervention. In the case of VWF deficiency, the multimer pattern and the pattern of RIPA allows for further subtyping [40]:

Type 1: normal multimers and normal RIPA

Type 2A: loss of intermediate and high molecular weight multimers and decreased RIPA

Type 2M: normal multimers but decreased RIPA

Type 2B: loss of high molecular weight multimers and increased RIPA

Type 3: virtual absence of all multimers; in addition VWF levels are usually undetectable and the Factor VIIII activity is 1–10%

Bleeding time & platelet function analyzer-100 closure time

Concurrent with VWF testing, a bleeding time (BT) and/or platelet function analyzer-100 closure time (CT) [47] could also be obtained as a baseline, since if such a test is prolonged in a VWF-deficient patient with extensive menstrual bleeding, it could be repeated postintervention to ensure adequate hemostasis. However, neither BT nor CT is advisable for up-front 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 [48] and platelet function disorders [48,49]. Both of these conditions could be cofactors that contribute to the bleeding risk and could be missed by screening with BT or CT.

Platelet aggregation & release studies

If both the initial hemostasis testing above and the gynecologic evaluation are completely normal, then further hemostasis testing can be considered in terms of platelet aggregation and release, as would normally be carried out in the investigation of a bleeding disorder in a patient with bleeding symptoms and a normal PT, APTT, CBC and VWF profile, since platelet function is a critical component of normal hemostasis [33]. As mentioned previously, a relatively high prevalence of platelet function abnormalities in patients with menorrhagia has been reported [28,30,50]. 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 [35], tests for fibrinolysis in terms of the screening euglobulin lysis test [51] and more specific fibrinolytic defects in terms of deficiencies of α2-anti-plasmin or plasminogen activator inhibitor. The latter two tests may specify a fibrinolytic state. In general, increased fibrinolysis has been reported in menorrhagia patients [25,26], but whether fibrinolysis is localized to the uterus or present systemically has not been fully studied.

Finally, there will be patients with multiple mucocutaneous bleeding symptoms in whom the above tests will be negative. Such patients may have a disorder of vascular fragility such as Osler Rendu Weber (hereditary hemorrhagic telangiectasia) or Ehler Danos. In the case of the former, the physical examination may reveal telangiectasisas, while in the case of the latter, their joints should be hypermobile.

Management of menorrhagia in VWD

The relative efficacy of various treatments in terms of the level of evidence is shown in Table 3. The management of menorrhagia related to VWD involves consideration of several factors, notably the patient's age, childbearing status and preference. Treatment options are summarized in Table 4 based on the author's clinical approach to these patients. Obviously, surgical intervention is not an option in the adolescent, whereas an older patient beyond her childbearing years may personally choose a hysterectomy as a definitive treatment in place of continued medical therapy with intranasal/subcutaneous DDAVP, oral antifibrinolytic agents or OC therapy. Regardless of the patient's choice, it is reasonable to advise a laboratory trial for response to intranasal or subcutaneous DDAVP, since not all type 1 patients will respond (15% did not have doubling of their VWF levels in one study [11]) and since knowledge of the degree of response is helpful for future reference if the patient ever needs to undergo a procedure wherein DDAVP prophylaxis would be considered. It should be added that type 2 VWD patients typically do not respond to DDAVP, while type 3 patients never respond to DDAVP.

Table 3.

Summary of levels of evidence of menorrhagia treatments.

Intervention	Level of evidence in non-VWD menorrhagia	Level of evidence in VWD menorrhagia
Tranexamic acid	A in favor	B in favor
Intranasal DDAVP	Not studied	Conflicting data
Oral contraceptive	B in favor	C against but small
Levonorgestrel intrauterine device	B in favor	B in favor but small series
Mefenamic acid	B in favor	Not studied

DDAVP: 1-deamino-8-D-arginine vasopressin; VWD: von Willebrand disease

A: randomized control trial; B: observational; C: case series

Table 4.

Author's recommendations for age-related approach to management of bleeding disorder-related menorrhagia.

Menarche	Tranexamic acid 1 g orally every 6–8 h first 5 days of menses, if not available, EACA 4 g load then 2 g orally 4 times/day for approximately the first 5 days of menses Intranasal DDAVP one puff to each nostril first 1–3 days of menses Oral contraceptive
Childbearing	If contraception preferred: Levonorgestrel-intrauterine device Oral contraceptive Tranexamic acid or EACA as above Intranasal DDAVP as above
Post-childbearing	If medical therapy preferred: Tranexamic acid or EACA as above Intranasal DDAVP as above If surgery preferred: Endometrial ablation Hysterectomy

DDAVP: 1-deamino-8-D-arginine vasopressin; EACA; E-amino-caproic acid

1-deamino-8-D-arginine vasopressin

Intranasal or subcutaneous DDAVP can be considered to be one of the first options in the adolescent. Historically, only level C evidence (case series) has been obtained, with the subcutaneous form being rated very effective in 65% of 14 women using it through 43 periods; it was rated effective by 86% and rated to have no effect by 14% [52]. Another similar cohort study using the intranasal form with 721 daily uses in 90 women reported a rating of excellent in 64%, good in 28% and no effect in 8% [53]. In both studies, it should be emphasized that assessment was by patient report and not by the pictorial blood loss assessment chart (PBAC) or the spectrophotometric method. More recently, however, Kadir and colleagues have studied the efficacy of intranasal DDAVP with the PBAC that had a score greater than 100 [54]. Women were studied for two menstrual periods with one spray in each nostril (either placebo or 300 μg of DDAVP on day 2 and 3 of the period). A total of 39 women were recruited, of whom 30 had VWD and nine had other non-VWD bleeding disorders. A total of 29 received trial medication and completed the PBAC during at least one period. Regardless of whether the first treatment period involved the placebo or the intranasal DDAVP, there was a reduction in the PBAC score that was statistically significant (p = 0.01). There was a trend towards a lower score if it was intranasal DDAVP; however, this was not statistically significant at 0.37, with no significant difference in QoL in terms of absence from work or school, avoidance of social activities or use of other medications. Similar results were noted in a related study of 20 women with menorrhagia and an underlying platelet disorder comparing 300 μg of intranasal DDAVP with placebo. There was no statistically significant decrease in blood flow from 230 cc baseline (measured spectrophotometrically) to 192 cc with DDAVP, compared with 213 cc with the placebo. However, there was a statistically significant decrease to 155 cc if the DDAVP was combined with tranexamic acid [27]. Perhaps the concurrent use of tranexamic acid offsets the rise of tissue plasminogen activator after DDAVP infusion, although Edlund and colleagues did not report increased fibrinolytic activity in menstrual fluid post DDAVP [26].

In both studies, intranasal DDAVP was relatively well tolerated and fluid intake was restricted to approximately 1.5 liters/day. Nonetheless, Kadir and colleagues reported weight gain in 12% of those taking DDAVP compared with none in those receiving placebo. Interestingly, the prevalence of headache (23%) was no different from the placebo group (24%).

In summary, more objective measurements of efficacy have not shown as great a benefit of intranasal DDAVP for VWD-related menorrhagia as prior studies using subjective assessment as the end point of efficacy. The question remains whether the efficacy of single agent DDAVP can be improved without an increase in the adverse event rate in terms of altering the schedule from the standard use of one puff to each nostril on days 2 and 3 of menses to twice daily dosing for the first 2 days or daily for 3 days. Also, further study of the efficacy and safety of combined therapy of intranasal DDAVP with antifibrinolytic therapy or OC is warranted, as are studies exploring alternative, novel hemostatic interventions.

Antifibrinolytic therapy

The rationale for antifibrinolytic therapy is well founded, as several studies have demonstrated increased fibrinolysis in uterine fluid in women with menorrhagia [26]. The seminal study by Bonnar and colleagues was a three arm randomized comparison of oral tranexamic acid (1 g after meals and at bedtime vs ethamsylate – a general hemostatic agent – and mefenamic acid – a prostaglandin synthetase inhibitor) [55]. There were approximately 25 patients per arm, each with prior documented heavy menstrual blood flow by the spectrophotometric method. There was a 54% decrease in menstrual flow compared with baseline in the tranexamic acid arm, compared with a 20% reduction in the mefenamic arm and no statistically significant decrease with ethamsylate. Further supportive evidence for tranexamic acid in menorrhagia has been through the evidence-based database of the Cochrane review, which concludes that it is an efficacious agent for menorrhagia in general [56]. The effective dose and frequency, however, remain unclear at this time, with only a total of seven women reported in the literature specifically regarding the effect of tranexamic on VWD- related menorrhagia [57 –59]. In four of the patients [58,59], treatment was by once daily dosing of 4 g for 3 consecutive days [58,59]. However, gastrointestinal distress would be of concern at this dose. A prodrug of tranexamic acid that has less gastrointestinal toxicity has been shown to be effective in reducing menstrual blood flow by 41% in non-VWD-related menorrhagia [60].

Hormonal therapy

In the Cochrane database of systemic reviews, OC therapy has not been proven to be superior to other medical treatments for the therapy of menorrhagia. In type 1 VWD patients, the effectiveness rated by patient assessment was approximately 25–44% [9,12]. However, counter-intuitively, in type 2 and 3 patients, the majority respond to OC [8,61] although the total number of patients treated with OC was only approximately 130. For the patient primarily choosing contraception, a trial of OCs is warranted, in that it may decrease menstrual flow and could reduce the risk of ovarian cyst hemorrhage and rupture, although this is a relatively infrequent occurrence [19]. An alternative hormonal option is therapy delivered through an intrauterine device. This may prove to be efficacious for VWD-related menorrhagia, given the robust body of literature in Europe showing its efficacy for menorrhagia in general. Several studies have shown 74–97% efficacy [62,63]. Recently, Kingman and colleagues studied the intrauterine device Mirena®, which releases the second-generation progesterone, levonorgestrel. In 16 women studied, primarily with VWD, a statistically significant reduction in menstrual blood flow was shown. Of the 16, nine developed amenorrhea and the remaining seven had a follow-up median PBAC of 47 compared with a median pre-insertion PBAC of 213 [64]. Additional study of nonhysterectomy gynecologic interventions, particularly in terms of the levonorgestrel intrauterine device, is in order given encouraging preliminary results of its efficacy, although whether the underlying bleeding disorder promotes prolonged spotting, as recently reported in one case [65], deserves further study, as persistent spotting is an indication for removal.

Lastly, hysterectomy remains an option for patients who are diagnosed with VWD at an age beyond their childbearing years, when definitive treatment is desired. A less invasive alternative would be endometrial ablation, but its long-term efficacy in VWD-related menorrhagia is not established at this time. In a small series of patients with VWD-related menorrhagia, only two had long-term control beyond 4 years of follow up after endometrial ablation, and three of seven required hysterectomy 10-, 11- and 26-months postablation, respectively [66].

Future perspective

The development of a cost-effective screening tool for an underlying bleeding disorder in women with menorrhagia is needed based on relevant bleeding symptoms.

The prevalence of VWD in certain menorrhagia subsets needs to be determined in the hope of developing specific screening guidelines – for example; the adolescent, the patient with fibroids and the patient with anovulatory bleeding. Further confirmation is required that platelet function abnormalities are associated with menorrhagia.

Further study of the role of combined hemostatic, hormonal and anatomic factors is in order as part of a multifactorial model of menorrhagia analogous to the present understanding of thrombosis as a multifactorial process.

Randomized and comparative studies with more objective measurements, and comparative studies of the presently available hemostatic measures singly and in combination (DDAVP, antifibrinolytics) using more objective measurements of efficacy are needed for all subtypes (VWD, platelet function defect or coagulation factor deficiencies) of bleeding disorder-related menorrhagia.

Pilot studies that aim to improve hemostatic therapy by altering the dose and/or schedule are required. Examples include intranasal DDAVP for 3 days or 12 h on day 1 of menses, or tranexamic acid at single daily high doses.

Additional studies of nonhysterectomy gynecologic interventions, particularly in terms of the levonorgestrel intauterine device, are in order given preliminary encouraging results of its efficacy.

Executive summary

Intersection of menorrhagia and underlying disorders of hemostasis

Menorrhagia is a common clinical condition noted in approximately 5% of women of reproductive age.

Approximately 50% of cases are idiopathic; an eighth or more of those cases may have an associated underlying disorder of hemostasis involving, either singly or in combination, von Willebrand factor (VWF) deficiency, coagulant protein factor deficiency, disorder of fibrinolysis or platelet dysfunction.

The identification of such patients may prove helpful in terms of offering hemostatic measures in the therapy of menorrhagia and reducing the hemorrhagic risk of invasive procedures ranging from dental extraction to major surgery.

Hemostasis evaluation in menorrhagia

The initial phase of hemostasis testing typically includes a prothrombin time (PT) and an activated partial thromboplastin time (APTT) (if not already performed), VWF antigen, ristocetin cofactor, Factor VIII, ABO type, Ivy bleeding time and/or in vitro closure time (PFA-100).

If initial hemostasis testing and gynecologic evaluation are completely normal, then further hemostasis testing can be considered in terms of platelet aggregation and release.

Management of menorrhagia in von Willebrand disease (VWD)

The management of menorrhagia related to VWD involves consideration of the patient's age, childbearing status and preference.

In the adolescent, surgical intervention is not an option, whereas an older patient beyond her childbearing years may personally choose a hysterectomy as definitive treatment in lieu of continued medical therapy with intranasal/subcutaneous 1-deamino-8-D-arginine vasopressin (DDAVP), oral antifibrinolytic agents or oral contraceptive (OC).

The sexually active patient may initially choose a trial of OC or the levonorgestrel-intrauterine device. Pending ongoing comparative trials in VWD-related menorrhagia of intranasal DDAVP, tranexamic acid and studies of the levonorgestrel intrauterine device; specific recommendations cannot be made at present regarding the superiority of any one intervention.

Regardless of the patient's choice, it is reasonable to advise a laboratory trial to measure the response to intranasal or subcutaneous DDAVP, since not all type 1 patients will respond and knowledge of the degree of response is helpful for future reference if the patient ever needs to undergo a procedure in which DDAVP prophylaxis would be considered.

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Von Willebrand Disease and other Disorders of Hemostasis in the Patient with Menorrhagia

Abstract

Keywords

The intersection of menorrhagia & underlying disorders of hemostasis

Surgical interventions for menorrhagia control

Diminished quality of life

Chronic iron-deficiency anemia

Peripartum hemorrhage

von Willebrand disease & menorrhagia

Hemostasis evaluation in menorrhagia

Prothrombin time & activated partial thromboplastin time

VWF antigen, ristocetin cofactor & Factor VIII levels

Testing in relation to the menstrual cycle

Testing in relation to combination oral contraceptive use

Testing in relation to the ABO type

Bleeding time & platelet function analyzer-100 closure time

Platelet aggregation & release studies

Management of menorrhagia in VWD

1-deamino-8-D-arginine vasopressin

Antifibrinolytic therapy

Hormonal therapy

Future perspective

References