Von Willebrand: An underdiagnosed disorder

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. Approximately 90% of women being treated at hemophilia centers in the United States carry the diagnosis of VWD.¹ Because women experience the hemostatic bleeding challenges of menstruation and childbirth, they are disproportionately affected by VWD.

Obstetricians and gynecologists may encounter women who have already been diagnosed or who have excessive reproductive tract bleeding and those patients should be evaluated for VWD. In his original 1926 paper, Finnish doctor Erik von Willebrand noted that women were twice as likely to be affected as men but while they are disproportionally affected by VWD, women are no more likely to inherit the condition than are men.² Indeed, with the exception of type 3 and type 2 N VWD, which are autosomal recessive (homozygous or compound heterozygous), transmission of VWD is autosomal dominant.³

VWF and types of VWD

VWD results from a deficiency of normal von Willebrand factor (VWF) due to insufficient or abnormal VWF. VWF is an elongated, multimeric protein (made up of multiple identical subunits) and has binding sites for platelets, collagen (in the subendothelium of blood vessels), and factor VIII (FVIII). Because VWF is required for normal adhesion of platelets to the site of a blood vessel injury and for protection of FVIII in the circulation, deficiency of normal VWF results in a bleeding disorder of varying severity depending on the VWF level, the FVIII level, and other modifying factors.

Not all VWD is caused by a defect in the von Willebrand gene, but the lower a patient’s VWF level, the more likely she is to have a genetic defect.³ The most common type of VWD, comprising 75% of symptomatic individuals, is type 1, which is characterized by a deficiency of normal VWF and is usually mild. Type 2 VWD is characterized by abnormal VWF. Type 3, which is rare, is characterized by the virtual absence of VWF and is severe.³

Prevalence

The reported prevalence of VWD depends on the population and the definition of disease. The prevalence based on the number of symptomatic patients seen at hemophilia treatment centers is 1 in 10,000.⁴ The prevalence based on the number of women with the diagnosis discharged after childbirth is 1 in 4000.⁵

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The prevalence based on identification of individuals with bleeding symptoms, low VWF, and a positive family history has been estimated to be as high as 1% to 2%.³

Diagnosis, classification

Several forms of VWD exist and current laboratory assays have limitations, so no single test reliably identifies the condition. The diagnosis is based on clinical features and laboratory tests. The initial laboratory work-up consists of a complete blood count to assess hemoglobin and exclude thrombocytopenia; as well as a prothrombin time (PT), an activated partial thromboplastin time (aPTT), and fibrinogen level (or thrombin clot time) to exclude a clotting factor deficiency.⁶

While these tests are useful for excluding clotting factor deficiencies, the aPTT may be normal in patients with VWD. The next series of tests includes specific tests for VWD including von Willebrand ristocetin cofactor activity (VWF:RCo), von Willebrand factor antigen (VWF:Ag) and FVIII.⁶ While a VWF:Co level of less than 40 IU/dL (international units per deciliter-the percent functional activity compared to an international reference) is highly likely to be associated with a genetic defect in the VWF gene,³ the National Institutes of Health/National Heart, Lung, and Blood Institute (NHLBI) criteria for the diagnosis of VWD requires a level <30 IU/dL. The range of 30–50 IU/dL is classified as “low VWF.”⁶ A VWF:RCo/VWF:Ag ratio ≤0.7 is indicative of type 2 VWD, a deficiency of normally functioning VWF.

Undetectable VWF is indicative of type 3 VWD. The inheritance, prevalence and phenotype of VWD by type are summarized in Table 1.

Results of testing may vary depending on multiple factors, including a patient’s age, stressors, inflammation, hormone levels, pregnancy, the quality of the laboratory, and the timeliness of sample processing. If the sample is not centrifuged promptly to separate the plasma, the plasma proteins may become degraded, yielding an artificially low VWF or FVIII level.⁶

Often, repeated analyses over several months are required. In many instances, only one of several tests in the panel may be abnormal. Further testing to determine the type and subtype of VWD includes analysis of von Willebrand multimers among other studies. Analysis for genetic mutations provides important information for research, but is not yet considered part of the diagnostic work-up for VWD.

NEXT: Heavy menstrual bleeing in women with VWD

Heavy menstrual bleeding in women with VWD

While other symptoms include bruising; nosebleeds; bleeding after injury, surgery or tooth extraction; and postpartum bleeding, the most common bleeding symptom women with VWD experience is heavy menstrual bleeding (HMB).⁷ Among women with VWD, a high prevalence of HMB has been reported, ranging from 32% to 100%.⁶ Not only is there a high prevalence of HMB among women with VWD, but also there is a high prevalence of VWD among women with HMB. Among women with HMB, the prevalence of VWD has been reported to be between 5% and 20%⁶ and the prevalence among adolescents, who are less likely to have a structural explanation for their HMB, has been reported to be between 5% and 36%.⁸

Hemorrhagic ovarian cysts and other reproductive tract bleeding

Women with VWD experience other forms of abnormal reproductive tract bleeding besides HMB. Bleeding at the time of ovulation may result in a hemorrhagic ovarian cyst or bleeding into the peritoneal cavity. A survey conducted by the Centers for Disease Control and Prevention (CDC) found that 52% of women with VWD reported a history of ovarian cysts, compared to 22% of controls.⁹ This difference is likely explained by an increased incidence of hemorrhagic ovarian cysts. In the same CDC survey, 30% of women with VWD reported a history of endometriosis, compared to 13% of controls.⁹

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Because of their HMB, women with VWD may be more likely to experience retrograde menstruation and, consequently, endometriosis. There is no evidence that women with bleeding disorders are more likely to develop fibroids, but in the same CDC survey, 32% of women with VWD reported a history of fibroids compared to 17% of controls.⁹ Fibroids contribute to the development of HMB. Since women with VWD are more likely to develop HMB, they may be more likely to become symptomatic with fibroids. In the same CDC survey of women with VWD, 10% reported a history of endometrial hyperplasia compared to 1% of controls, and 8% reported a history of polyps compared to 1% of controls.⁹

It is doubtful that women with VWD are more likely to develop endometrial hyperplasia or polyps, but it is possible that these women become symptomatic sooner.

Risk of bleeding complications during pregnancy

Even in women with an inherited bleeding disorder such as VWD, most bleeding at the time of childbirth is obstetrical (due to failure of the uterus to contract or to retained placenta), surgical (due to incisions or lacerations) or (rarely) an acute acquired coagulopathy, but any bleeding at the time of childbirth may be aggravated by VWD. While VWF and FVIII levels rise during pregnancy, median levels in women with VWD remain below the levels of women without VWD and fall rapidly thereafter. They approach baseline by 1 week postpartum, and reach baseline by 3 weeks postpartum.¹⁰ Antepartum bleeding, postpartum hemorrhage, severe postpartum hemorrhage, and perineal hematoma are all increased by 2- to 10-fold in women with VWD.^5,11

Which women with HMB should be screened for VWD?

A multicenter study sponsored by the CDC has provided some guidance for screening women with HMB for VWD or other underlying bleeding disorders. In the study, 146 women with a physician diagnosis of HMB were administered a 12-page questionnaire and were tested for a wide range of bleeding disorders. A positive response to any 1 of 8 questions that clustered in 4 categories resulted in the highest sensitivity for a bleeding disorder.

The categories were: 1) duration of menses greater than or equal to 7 days and either “flooding” or impairment of daily activities with most periods; 2) a history of treatment of anemia; 3) a family history of a diagnosed bleeding disorder; and 4) a history of excessive bleeding after tooth extraction, delivery, miscarriage, or surgery. In a woman with HMB, a positive response to any 1 of the 8 questions in any of these 4 categories would justify further evaluation and/or referral to a hemostasis expert.

NEXT: Management of heavy menstrual bleeding

Management of heavy menstrual bleeding

Hormonal, hemostatic, and surgical therapies have been used to control HMB in women diagnosed with VWD. Figure 1 gives a suggested algorithm. For a woman who wishes to preserve her fertility but does not wish to become pregnant, the first choice of treatment for HMB should be hormonal therapy. Endometrial ablation or hysterectomy is an option for women who do not wish to preserve their fertility. Those who wish to become pregnant or fail hormonal therapy should be referred to a hemophilia treatment center or hemostasis expert for hemostatic therapy. Tranexamic acid (an anti-fibrinolytic medication) is an option and, for responders, desmopressin nasal spray is also a consideration.

Desmopressin, a synthetic analog of vasopressin, stimulates release of endogenous stores of VWF from the Weibel-Palade bodies of endothelial cells. It is usually effective in type 1 VWD, sometimes effective in type 2 VWD, and ineffective in type 3 VWD (due to absent VWF). To assess effectiveness, a desmopressin challenge test may be performed. In type 2B, a form of type 2 VWD that is characterized by VWF with increased binding to platelets, desmopressin may cause a drop in platelets. Some hemostasis experts recommend against desmopressin in type 2B VWD for this reason. VWF concentrate is reserved for women with severe VWD who wish to preserve their fertility but have not responded to other therapies, including combinations of other therapies. Cryoprecipitate, which does not undergo viral inactivation, should not be used.

While hysterectomy among women with VWD carries a 3-fold increased risk of bleeding complications and 6-fold increased risk of transfusion,¹² women who require the operation should not be deprived of its benefits. Because HMB is often the primary bleeding symptom that women with VWD experience, hysterectomy can eliminate the symptom and significantly improve quality of life. Hysterectomy, like other major surgical procedures, should be performed in a hemophilia treatment center or other center with requisite support from hematology, anesthesiology, pharmacy, and the laboratory.

Management of pregnancy and childbirth

Ideally, planning for pregnancy begins before conception. Women with VWD contemplating pregnancy should be aware that they may be at increased risk of bleeding complications during pregnancy and are definitely at increased risk of postpartum hemorrhage. Prior to conception or during pregnancy, women should be offered the opportunity to speak with a genetic counselor regarding the inheritance of VWD and with a pediatric hematologist regarding evaluation of the infant after delivery. Women can be reassured that their infants will not be severely affected.

With the exception of type 3 (the severe form of the disease) and type 2 N VWD, which are autosomal recessive (homozygous or compound heterozygous), transmission of VWD is autosomal dominant.³ Therefore, unless the father of the infant has VWD, the infant’s phenotype will be mild or moderate. If the father of the infant has VWD and both parents have known genetic mutations, prenatal diagnosis of type 3 VWD is theoretically possible. Because of the increased risk of transfusion, women who have not already been vaccinated should be immunized against hepatitis A and hepatitis B.⁶

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Women with type 1 VWD with VWF:RCo and FVIII levels ≥50 IU/ dL and no history of severe bleeding do not require treatment at time of delivery. A recent study found that these women have the same estimated blood loss (EBL) at the time of delivery, same postpartum hematocrit, and same amount of lochial bleeding as women without VWD.10 Anesthesiologists should know that women whose VWF levels are >50 IU/dL (in the normal range⁶) in the last month of pregnancy will have levels >50 IU/dL intrapartum,¹⁰ allowing for the option of regional anesthesia. Because nonsteroidal anti-inflammatory drugs may affect platelet function and systemic hemostasis,¹³ they should be avoided and acetaminophen or opioid analgesia prescribed instead.

Because the fetus/neonate has a 50% chance of having VWD, invasive procedures such as use of scalp electrode and operative vaginal delivery should be avoided whenever possible. At time of delivery, cord blood can be collected and sent for von Willebrand studies. Circumcision of a male infant should be postponed until his VWD status is known.

NEXT: Algorithm for management of VWD-related menorrhagia

Women with type 3 VWD, type 2 VWD or type 1 VWD with FVIII or VWF levels lower than 50 IU/dL or a history of severe bleeding should be referred for prenatal care and delivery to a center where, in addition to specialists in high-risk obstetrics, there is a hemophilia treatment center and/or a hematologist with expertise in hemostasis. Laboratory, pharmacy, and blood bank support is essential. Prior to delivery or invasive procedures, these women should have the opportunity to meet with an anesthesiologist.

Prior to chorionic villus sampling, amniocentesis, or cervical cerclage, these women should receive prophylaxis with desmopressin or VWF concentrate. Candidates for treatment with desmopressin have usually received it at some time in their past and ideally would have been tested with a desmopressin challenge test to see how well they respond to the medication. If a desmopressin challenge test has not been performed prior to pregnancy, it should not be performed during pregnancy. In anticipation of delivery, FVIII and VWF:RCo levels should be obtained around 36 weeks’ gestation.⁶

Patients who require prophylaxis at the time of delivery for VWF:RCo levels lower than 50 IU/dL should be treated with VWF concentrate, which is safe for mothers and fetuses. Four VWF factor concentrates are currently licensed in the United States. Three are virally inactivated, purified plasma products with varying ratios of FVIII. The fourth is a recombinant VWF product and contains no FVIII. The product used will likely depend on the formulary at the institution where the patient delivers and the experience of the attending hematologist, who will make a product-specific calculation based on the patient’s weight, existing VWF level, and target VWF level. The target level should be ≥100 IU/dL intrapartum and during hospitalization.

Prescribing information and dosing calculators can be found on product websites. One product website gives the list price per unit of the manufacturer’s product ($0.60 per VWF:RCo unit) compared to the list price per unit of a competitor’s product ($0.75 per VWF:RCo unit). Neither includes the cost of administration, but the cost for a single dose of the medication for a typical patient weighing 70 kg and receiving 50 units per kg would be between $2000 and $3000.

During hospitalization, the dose may be administered periodically as a bolus, or, alternatively, as a continuous infusion.

Our practice is to administer a bolus on admission, followed by a continuous infusion of 2 IU/dL per hour. After discharge, the target VWF level should be ≥50 IU/dL. If ongoing therapy is necessary, we prescribe a daily bolus.

In a recent prospective, observational study of 35 pregnancies in 32 women, conducted at 5 prominent hemostasis centers, treatment was required for 17 pregnancies in 15 women. No consistent protocol was followed and treatment varied in intensity and duration.¹⁰ Patients were treated from the time of admission for childbirth until 1 day to 3 weeks postpartum. Despite treatment, these women had EBLs that were 50% greater, hematocrits that nadired 20% lower, and lochia that was significantly greater than women without VWD or than women who did not require treatment. This would suggest that women who require treatment are currently undertreated.

Desmopressin has been used to raise VWF and FVIII at the time of delivery in responders, but fluid retention, hyponatremia, and grand mal seizures have been reported with its use at the time of childbirth.¹⁴ Because fluids should be limited to 1000 mL per day during its administration, while women commonly receive 1–2 L or more of fluid at the time of a vaginal delivery and 2–3 L or more at the time of cesarean delivery, and given that oxytocin may further exacerbate hyponatremia, the use of desmopressin is best reserved until a patient is no longer receiving intravenous fluids.

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If required during pregnancy for prophylaxis at the time of procedures during pregnancy (as opposed to delivery), desmopressin is generally thought to be safe for mother and fetus.⁶

Tranexamic acid crosses the placenta and is transferred into breast milk. While there are no reported adverse fetal or neonatal effects, there is very little information. tranexamic acid is generally not used prior to delivery, but is an option for the prevention and management of bleeding after delivery.

Additional information

More information for providers is available on the websites of NHLBI, CDC and the Foundation for Women and Girls with Blood Disorders. Resources for patients are available on the websites of the CDC and the National Hemophilia Foundation.

REFERENCES

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2. von Willebrand E, Jurgens R. Dtsch Arch Klin Med. 1933;175:453-83.

3. James PD, Lillicrap D. von Willebrand disease: clinical and laboratory lessons learned from the large von Willebrand disease studies. Am J Hematol. 2012;87 Suppl 1:S4-11.

4. Sadler JE, Mannucci PM, Berntorp E, et al. Impact, diagnosis and treatment of von Willebrand disease. Thrombosis and haemostasis. 2000;84:160-74.

5. James AH, Jamison MG. Bleeding events and other complications during pregnancy and childbirth in women with von Willebrand disease. JTH. 2007;5:1165-9.

6. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14:171-232.

7. Kirtava A, Crudder S, Dilley A, Lally C, Evatt B. Trends in clinical management of women with von Willebrand disease: a survey of 75 women enrolled in haemophilia treatment centres in the United States. Haemophilia. 2004;10:158-61.

8. James AH. Obstetric management of adolescents with bleeding disorders. Journal of pediatric and adolescent gynecology 2010;23:S31-7.

9. 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.

10. James AH, Konkle BA, Kouides P, et al. Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis. Haemophilia. 2015;21:81-7.

11. Al-Zirqi I, Vangen S, Forsen L, Stray-Pedersen B. Prevalence and risk factors of severe obstetric haemorrhage. BJOG. 2008;115:1265-72.

12. James AH, Myers ER, Cook C, Pietrobon R. Complications of hysterectomy in women with von Willebrand disease. Haemophilia. 2009;15:926-31.

13. Schafer AI. Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol 1995;35:209-19.

14. Chediak JR, Alban GM, Maxey B. von Willebrand’s disease and pregnancy: management during delivery and outcome of offspring. AJOG. 1986;155:618-24.