This month, Rebecca Kruse-Jarres, MD, MPH, and Jill M. Johnsen, MD, discuss the diagnosis and treatment of patients with type 2B von Willebrand disease (vWD).
This material was repurposed from "How I Treat Type 2B von Willebrand Disease," published in the January 4, 2018, edition of Blood.
- The diagnosis and management of type 2B vWD requires an understanding of the underlying physiology of vWF-platelet interaction.
- Treatment is similar to other types of vWD, but special consideration should be given to situations that can worsen thrombocytopenia, such as pregnancy.
- The mainstays of type 2B vWD treatment remain vWF replacement and vWD adjunct therapies (including antifibrinolytics and topical hemostatic agents).
- Treatment with DDAVP is controversial but may be a convenient option for some patients with minor bleeding.
- For patients with type 2B vWD who are pregnant or considering pregnancy, treatment planning requires close monitoring with a multidisciplinary team consisting of representatives from high-risk obstetrics, anesthesia, hematology, neonatology, pharmacy, blood bank, and the coagulation laboratory.
Introduction to vWD
This is a common and complex inherited bleeding disorder, with more than 20 distinct subtypes. Type 2 vWD is the second-most common type of vWD (after type 1 vWD), representing about 15 to 30 percent of all cases.
This subtype is distinguished from other vWD variants by a gain-of-function defect in von Willebrand factor (vWF) that causes enhanced binding to platelets, rather than binding to the site of the injury to the blood vessel.
Although type 2B vWD is defined by this single molecular defect, it is a clinically heterogeneous disorder that can be difficult to identify and manage.
In this article, the intricacies of diagnosing, treating, and managing type 2B vWD are discussed through two clinical cases.
Diagnosis of Type 2B vWD
The diagnosis of vWD is based on:
- history of mucocutaneous bleeding
- abnormal vWF-specific laboratory studies and/or a 2B vWD genetic variant
- family history consistent with autosomal dominant inheritance
Mucocutaneous bleeding indicates a defect in primary hemostasis, typical of vWD.
When vWD is suspected, it is critical to distinguish between type 2B vWD and other types of vWD because platelet-type vWD is not responsive to vWF replacement therapy. Initial testing to establish an accurate diagnosis of type 2 vWD requires the following laboratory tests:
- vWF antigen (vWF:Ag) is used to measure vWF protein in circulation, which is usually low in type 2B vWD.
- Platelet-dependent vWF activity is typically measured by the vWF ristocetin cofactor (vWF:RCo) assay, which quantifies plasma vWF's ability to aggregate normal platelets in the presence of the antibiotic ristocetin. In type 2B vWD, vWF:RCo can be disproportionately decreased relative to vWF:Ag. A ratio of vWF:RCo/vWF:Ag <0.7 is often observed in type 2 vWD.
- Factor VIII activity (FVIII:C) can be decreased to normal levels in patients with type 2B vWD.
- Consideration of vWF-collagen binding (vWF:CB), which can be decreased to normal.
- vWF multimer analysis is critical for the accurate classification of vWD subtype. Loss of large vWF multimers is often observed in type 2B vWD.
- Platelet count establishes a diagnosis of thrombocytopenia, which is common but not always present in type 2B vWD. However, thrombocytopenia is not seen in any other form of vWD, so clinicians must rule out pseudo-thrombocytopenia and other causes of abnormally low platelet counts.
- Ristocetin-induced platelet aggregation (RIPA) is distinct from vWF:RCo and measures the ability of plasma vWF to aggregate the patient's own platelets in the presence of ristocetin. The RIPA assay can distinguish type 2A from 2B vWD. The correct diagnosis can be established by specialized RIPA mixing tests that determine if the gain-of-function abnormality is conferred by the patient's vWF or by platelets.
- Genetic testing can be used to diagnose type 2B vWD and distinguish from platelet-type vWD.
Treatment of Type 2B vWD
As with other subtypes of vWD, the mainstay of therapy for type 2B vWD is vWF replacement therapy, in the form of recombinant vWF (rVWF) or vWF/FVIII concentrates.
The adjunct therapies useful in vWD also apply in this variant. These include:
- antifibrinolytics (aminocaproic acid, tranexamic acid)
- topical hemostatic agents
- interventions for uterine bleeding (intrauterine devices, hormonal therapies, anatomic measures)
- desmopressin acetate (DDAVP), a synthetic analogue of the antidiuretic hormone vasopressin (though its use in type 2B vWD is controversial)
The following case scenarios outline the challenges and controversies in accurately diagnosing and effectively treating patients with type 2B vWD.
Case #1: Managing a Patient With Thrombocytopenia After DDAVP
An 18-year-old woman was diagnosed with vWD at 6 years old and immune thrombocytopenia (ITP) at 12 years old, but her vWD type was unknown. She had a history of heavy menstrual bleeding, but did not tolerate oral contraceptive pills or antifibrinolytics, so was instructed to take DDAVP on the first and second day of her menses. The DDAVP symptomatically helped with menstrual flow, but she developed ITP that worsened after taking the dose.
This history of thrombocytopenia after DDAVP raised suspicion for type 2B vWD, which was confirmed via laboratory tests. Since the DDAVP was well-tolerated and improved her menstrual flow, we did not withhold DDAVP as a treatment option for her menses. If she had more significant hemostatic challenges, we would recommend vWF replacement therapy.
“Although type 2B von Willebrand disease is defined by [a gain-of-function defect in von Willebrand factor], it is a clinically heterogeneous disorder that can be difficult to identify and manage.”
â€”Rebecca Kruse-Jarres, MD, MPH, and Jill M. Johnsen, MD
In type 2B vWD, DDAVP is thought to cause release of higher-molecular-weight, hyperfunctional vWF that provokes transient platelet aggregation and thrombocytopenia. The potential to exacerbate bleeding or thrombocytopenia (which only appears with type 2B vWD) resulted in the longstanding practice of avoiding the use of DDAVP in type 2B vWD.
Side effects with DDAVP are common, but most are mild and generally subside after 24 hours. To minimize the risks of serious adverse events such as iatrogenic hyponatremia, fluids should be restricted.
DDAVP offers two advantages over other vWD treatments: It is more economical than factor concentrates and can be self-administered intranasally. And, despite the controversies, DDAVP is occasionally used to treat minor bleeding.
Before considering DDAVP for type 2B vWD, we recommend a monitored study demonstrating the platelet nadir and kinetics of platelet recovery, in addition to vWF responsiveness. A pharmacokinetic study is recommended for all types of vWD.
Case #2: Management of Type 2B vWD During Pregnancy
A 23-year-old with type 2B vWD was monitored throughout her pregnancy, labor, and delivery, as well as postpartum. During her pregnancy, vWF:Ag, vWF:RCo, and FVIII:C levels increased, but not to normal pregnancy levels. Thrombocytopenia became apparent and progressively worsened, with platelet counts decreasing from 350,000/µL before her pregnancy to 31,000/µL at 35 weeks.
Because of changes during pregnancy, laboratory testing at 34 to 36 weeks gestation is recommended to assess vWF levels close to delivery, and platelet counts (and vWF, when possible) should be monitored weekly thereafter.
At 38 weeks, the patient went into labor. She received vWF replacement at 60 IU/kg, but no platelet transfusion. She had an uncomplicated vaginal delivery without neuraxial anesthesia and without abnormal bleeding. She was maintained on vWF replacement at 30 IU/kg every 12 hours and started on tranexamic acid 1,300 mg orally three times daily.
During the final stages of labor for a vaginal delivery (or for bleeding at any time), we recommend an initial vWF replacement dose of 60 IU/kg to a target vWF:RCo greater than 50 percent.
For thrombocytopenic episodes, if platelet count is less than 50,000/µL, we request platelet transfusion within 30 minutes of a procedure, then aim for a platelet count greater than 50,000/µL and repeat transfusions as needed. For more severe thrombocytopenia (platelet counts less than 20,000/µL), we recommend platelet transfusion, frequent platelet-count monitoring, and repeat transfusions as needed.
For the duration of labor and delivery, maintenance vWF dosing starts at half the initial bolus dose every eight to 24 hours, adjusting for vWF:RCo peak and trough levels and monitoring FVIII:C levels.
For caesarean section (C-section), we aim for a vWF:RCo close to 80-100 percent and continue maintenance therapy as described for vaginal delivery. Goals for maintenance treatment after delivery by C-section are a vWF:RCo greater than 50 percent and platelet count greater than 20,000/µL for at least five days.
Neuraxial anesthesia is not recommended in patients with type 2 (and specifically 2B) vWD because of safety concerns and lack of evidence. We recommend that if neuraxial anesthesia is performed, it be done within one hour of vWF replacement therapy. If an epidural is placed, we request removal as soon as possible after delivery while drug levels are high.
Post-Partum Prophylaxis: Four days postpartum, the patient had experienced no excessive bleeding and vWF replacement dosing was reduced to 30 IU/kg every 24 hours for another three days. She completed two weeks of antifibrinolytic treatment. Four weeks after her last dose of vWF, she complained of heavy vaginal bleeding. She was treated with vWF replacement 60 IU/kg, followed by 30 IU/kg daily for two days. Tranexamic acid was restarted and she achieved good control of her bleeding.
Delayed postpartum hemorrhage (bleeding between 24 hours and 6 weeks postpartum) is common in women with vWD. For type 2B vWD, we recommend monitoring with vWF replacement for five to seven days, platelet transfusion as needed, and antifibrinolytic therapy for at least two weeks postpartum. If bleeding continues or recurs, additional treatment and other causes of bleeding should be considered.
Diagnosis of Type 2B vWD in the Newborn: Laboratory diagnosis in newborns is challenging, but screening may be done on cord-blood sampling. Cord blood vWF:Ag and FVIII:C may be normal, but the vWF:RCo can be decreased. Infants with type 2B vWD can have thrombocytopenia and platelet-clumping on peripheral smear. Genetic testing for a familial 2B vWD variant also can confirm or exclude the diagnosis.
Infants' bleeding risk is not known, but potential causes of hemorrhage should be avoided when possible. In cases of thrombocytopenia with bleeding or for invasive procedures, platelet transfusions should be given. In bleeding patients, both vWF replacement therapy and platelet transfusions should be considered.
Recently, development and use of bleeding-assessment tools have allowed for improved stratification of which patients require further testing and which are most likely to require treatment for their bleeding disorders.
New options for laboratory assessments of vWF activity under investigation include new platelet-binding assays that may offer more stable results than the vWF:RCo assay and provide insight into different functions of vWF.