Layson L. Denney and Sarah H. Milton
History of present illness
A 14-year-old adolescent girl presented with a 3-day history of fatigue. She denied pain, fever, recent illness, sick contacts, difficulties sleeping, and symptoms of depression. She reported that her menstrual period ended two days ago and that she generally feels fatigued around the time of her menses, but her symptoms were worse this cycle.
Her medical history is significant for menarche at age 12.
Her menstrual cycles were initially irregular, but are now regular and 28 days. She generally soaks through a pad every two hours. She was seen by her pediatrician at ages five and eight for epistaxis. She reported frequent bruising, which she attributes to playing soccer. Her mother under- went a hysterectomy at age 37 for heavy bleeding, and her maternal grandmother had a history of “heavy periods.”
There are no known diagnoses of bleeding disorders in the family.
Physical examination
Vital signs:
Temperature: 36.5°C Pulse: 110 beats/min
Blood pressure: 123/76 mmHg Respiratory rate: 20 breaths/min Oxygen saturation: 100% on room air
HEENT:Normocephalic, atraumatic, conjunctival pallor Cardiovascular:Tachycardic, regular rhythm with no murmurs, rubs, or gallops
Lungs:Clear to auscultation bilaterally
Abdomen:Soft, nontender, nondistended, normal bowel sounds
Extremities:Multiple bruises on bilateral lower extremities in various stages of healing; no cyanosis, clubbing, or edema;
normal capillary refill Neurologic:Nonfocal Pelvic:Deferred Laboratory studies:
Hb: 8.8 g/dL (normal 12.0–15.0 g/dL) WBCs: 7000/μL (normal 3900–11 700/μL)
Platelet count: 250 000/μL (normal 172 000–440 000/μL) Pregnancy test: Negative
PPT (partial thromboplastin time): 67 s, corrected with 1 : 1 mixing with normal plasma (normal 25–36 s)
PT (prothrombin time) and INR (international normalized ratio): Both within normal limits
VVWF:Ag (von Willebrand factor antigen): 25 IU/dL (normal 50–160 IU/dL)
VWF:RCoA (ristocetin cofactor activity): 20 IU/dL (normal 50–160 IU/dL)
Factor VIII activity level: 50% of normal
How would you manage this patient?
The patient has von Willebrand disease (VWD), type I. This diagnosis should be suspected based on the history and was confirmed with laboratory results revealing anemia, a pro- longed partial thromboplastin time (PTT), normal prothrom- bin time (PT) and international normalized ratio (INR), and decreased von Willebrand factor antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCoA) and factor VII activity. Low levels of VWF:Ag, VWF:RCoA, and factor VIII suggest a quantitative defect that is consistent with type I VWD [1].
The patient was referred to a hematologist where the diagnosis was confirmed with repeat VWD laboratory testing. The patient was started on iron supplements and oral contraceptive pills, which resulted in return of her hemoglobin to normal levels, resolution of symptoms, and marked improvement in her heavy menstrual bleeding (HMB).
VWD is the most common inherited bleeding disorder. It is caused by mutations that lead to quantitative or qualitative impairment of von Willebrand factor (VWF). After endothe- lial injury, VWF is released from endothelial cells and activated platelets. It functions in primary hemostasis by forming adhesions between exposed collagen and platelets and between individual platelets, strengthening the platelet plug. In add- ition, VWF functions in the intrinsic pathway of secondary hemostasis as a carrier protein of factor VIII, aiding infibrin clot formation [1]. VWD is categorized into three types, which sequentially increase in severity. Type I is a quantitative defi- ciency and has an autosomal dominant inheritance pattern.
Type II is a qualitative deficiency and has autosomal dominant and recessive inheritance patterns. Type III is defined by severely decreased or absent VWF and has an autosomal recessive inheritance pattern [1].
Clinical characteristics of VWD include easy bruising, excessive bleeding from minor wounds, prolonged mucosal bleeding (such as epistaxis or bleeding after a dental procedure) and, in severe cases, soft tissue bleeding and hemarthrosis [2].
Although VWD can affect both sexes, special considerations in Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
women with VWD include HMB, postpartum hemorrhage, and other gynecologic conditions involving blood loss.
Identification of patients with a bleeding disorder begins with a thorough history. Emphasis should be placed on any history of excessive bleeding. Because of the inheritance patterns of VWD, a detailed family history of any bleeding abnormalities should be obtained. A careful medication history is important as any antiplatelet medications can exacerbate or instigate bleeding [1]. In women, careful attention to the menstrual history is important as HMB is the most common presenting symptom of VWD, experienced by 32–100% of women with VWD [3]. While the prevalence of VWD in the general population is 1%, the prevalence is 11–16% among women with HMB [4]. Careful attention to the menstrual history is particularly relevant in the adolescent population as HMB at menarche is often thefirst sign of VWD. The Ameri- can College of Obstetricians and Gynecologists emphasizes obtaining a thorough menstrual history at thefirst reproduct- ive health visit between the ages of 13 and 15. This visit should serve as an opportunity to evaluate patients for HMB indicative of a bleeding disorder [5]. A quantitative
approach to obtaining a menstrual history is preferred in which the clinician should inquire about the number of pads used, the frequency with which they are changed, and should consider the use of a menstrual calendar or pictorial bleeding assessments [2]. This patient’s combination of HMB as an adolescent and history of epistaxis should raise concern.
If the diagnosis of VWD is suspected based on history and physical examination, an initial laboratory evaluation should be performed including a complete blood count with periph- eral smear and coagulation studies [1,2]. An isolated PPT time that corrects on 1 : 1 mixing study with otherwise normal labs merits testing for VWD [6]. To test for VWD specifically, the provider should obtain a VWF ristocetin cofactor activity, VWF antigen, and clotting factor VIII activity assay (Fig. 78.1 [7]). Generally, a VWF ristocetin cofactor activity level of less than 30 IU/dL is characteristic of VWD. However, these levels may be influenced by diverse characteristics including age, race, timing in the menstrual cycle, pregnancy, or inflamma- tion. Referral to a hematologist for complete workup and definitive diagnosis is warranted. Additionally, classification of VWD into subtypes is complicated and is based on the
History and/or physical examination concerning for bleeding disorder
Consider Hematology Referral
No abnormalities Isolated prolonged Partial Thromboplastin
Time that corrects on a 1:1 mixing study OR
Hematology Referral
Hematology Referral
Alternative cause identified (isolated abnormal prothrombin time, thrombocytopenia, low fibrinogen, or
abnormal thrombin time)
VWD confirmatory testing - VWF Antigen
- VWF ristocetin cofactor activity
- Factor VIII Initial VWD testing
Initial Laboratory Assessment:
- CBC - Platelet Count - Prothrombin Time
- Partial Thromboplastin Time - thrombin time (optional) - fibrinogen (optional)
Fig. 78.1 Laboratory workup for patients with a history concerning for a bleeding disorder. (Adapted from [7].)
degree of quantitative and qualitative deficiencies in VWF and is best performed by a trained hematologist [1]. This patient had abnormalities on all of these tests.
It is important to identify women with VWD early due to the impact the disease can have on long-term health [8].
Women with bleeding disorders are more likely to develop any condition involving bleeding, such as hemorrhagic ovarian cysts and“Mittelschmerz”or midcycle pain [3]. Women with VWD are more likely than women without a bleeding disorder to experience exacerbated symptoms of common gynecologic conditions including endometriosis (30% vs. 13%), leiomyo- mas (32% vs. 17%), endometrial hyperplasia (10% vs. 1%), and polyps (8% vs. 1%), and ultimately are more likely to undergo hysterectomy (26% vs. 9%) [9]. Kirtava and colleagues found an increased incidence of miscarriage among women with VWD (15% vs. 9% of controls), as well as an increased risk of postpartum hemorrhage in women with VWD (59% vs.
21% of controls) [9]. They were also more prone to vulvar or vaginal hematomas, as well as delayed postpartum hemorrhage with a mean time to presentation of 15.7 days [9]. Addition- ally, women with VWD reported an increased negative effect of menstruation on their lives as compared to their peers [9].
Management of VWD is aimed at preventing bleeding and treating bleeding complications when they arise by increasing the levels of VWF and factor VIII [1]. Bleeding prophylaxis in women primarily focuses on the prevention of HMB. Com- bined hormonal contraception (oral contraceptive pill, patch, or vaginal ring) isfirst line for prevention of HMB associated with VWD. Combined hormonal contraception is highly effi- cacious with 88% of women with VWD reporting improve- ment in their HMB after initiation of treatment with oral contraceptive pills [1,2]. VWF levels are increased by oral contraceptive pills, and, so laboratory assessment should be obtained prior to initiating them, as was done in this patient.
The levonorgestrel intrauterine device is also effective in the treatment of HMB and is a suitable alternative therapy for all age groups [2,10,11]. Transexamic acid and ε-aminocaproic acid, both antifibrinolytics, are other treatment options and are often used in conjunction with oral contraceptive pills to control HMB [5].
Patients with VWD are at significant risk of bleeding with invasive procedures. Preoperative consultation with a hema- tologist is important so that laboratory studies can be ordered and a pre- and postoperative treatment plan can be developed.
For hemostatic control where blood loss occurs, 1-desamino- 8-D-arginine vasopressin (DDAVP) can be administered to
stimulate release of VWF from endothelial cells. DDAVP is intended for use over short intervals of 48–72 hours [6]. If a longer period of treatment is necessary, recombinant factor VIII and VWF concentrate can be administered to replace inherent deficiencies with exogenous factors [6].
Obstetric complications are common in women with VWD, which further underscores the importance of early diag- nosis as these complications are more readily managed if the diagnosis of VWD is known prior to conception [9]. During pregnancy, patients should have VWD laboratory testing prior to any invasive procedure. All patients should have testing in the third trimester with the goal of achieving factor VIII and ristocetin cofactor levels greater than 50 IU/dL prior to delivery through 3–5 days afterward [1]. A patient with type I disease with a factor VIII or ristocetin cofactor levels less than 50 IU/
dL, or any patient with type II or type III disease is a candidate for prophylaxis and delivery should be in a facility skilled in hemostasis with specialist help available [1]. For acute replace- ment at the time of delivery, VWF concentrate should be used instead of desmopressin as desmopressin can cause hyponatre- mia when administered with oxytocin [1,6]. Given the inherit- ance patterns of VWD, all women with it should be referred to a genetic counselor to discuss the genetic implications of the disease [6]. Further, their fetuses are at risk and invasive fetal procedures and operative vaginal delivery should be avoided given the potential for fetal hemorrhage.
Key teaching points
Providers should obtain a menstrual, past medical and family history as part of the initial reproductive health visit to aid in the identification of patients with von Willebrand disease (VWD).
The most common symptom in women with VWD is heavy menstrual bleeding (HMB). VWD should be high on the differential diagnosis in an adolescent with HMB and anemia.
Early diagnosis of von Willebrand disease can prevent unnecessary bleeding complications.
No single test reliably identifies VWD, and laboratory results are affected by various factors; patients should be referred to a hematologist for specific diagnosis, continued monitoring, and any necessary prophylaxis for invasive procedures or management of the peripartum period.
First-line treatment for HMB in VWD is combined hormonal contraceptives.
References
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Evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute
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1439–43.
3. James, AH. More than menorrhagia: a review of the obstetric and
gynecological manifestations of bleeding disorders.Haemophilia 2005;11:295–307.
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Some answers, more questions.
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www.nhlbi.nih.gov/guidelines/vwd/
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