How I Treat In Brief
TRAINING and EDUCATION
In “ How I Treat In Brief ,” we summarize recent “ How I Treat ” review articles , offering condensed versions of the diagnostic and therapeutic advice presented by experts in the field published in Blood . Here , 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 .
Type 2B von Willebrand Disease
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 .
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