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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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TRAINING and EDUCATION How I Treat In Brief 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 diagnos- ing, 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 diag- nosis 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. ASHClinicalNews.org • 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 platele B6VG2( &7F6WF֖GV6VBFVWBvw&VvFࢅ$2F7F7Bg&etc$6@V7W&W2FR&ƗGb6etbFvw&VvFRFRFVN( 2vFVWG2FR&W6V6Rb&7F6WFFR$766F7FwV6GR$g&У$"etBFR6'&V7BFv626&PW7F&Ɨ6VB'7V6ƗVB$֗pFW7G2FBFWFW&֖RbFRvbgV7F&&ƗG26fW'&VB'FRFVN( 0etb"'FVWG2( vVWF2FW7Fr6&RW6VBFFv6RGP$"etBBF7FwV6g&FVWBGPetBG&VFVBbGR$"et@2vFFW"7V'GW2betBFR7FbFW&f"GR$"etB2etb&W6RЦVBFW&FRf&b&V6&Bet`%etb"etbed66VG&FW2FRFV7BFW&W2W6VgVetB6ǒF2f&BFW6R6VFS( Ff'&ǗF72֖6&26BG&W֖26B( F6V7FF2vVG0( FW'fVF2f"WFW&R&VVFpG&WFW&RFWf6W2&FW&W2F֖2V7W&W2( FW6&W766WFFRDDe7FWF0wVRbFRFFW&WF2&Pf6&W76FVvG2W6RGR$"et@26G&fW'6FRfvr66R66V&2WFƖRFR6ЦVvW2B6G&fW'6W267W&FVǒFv2ЦrBVffV7FfVǒG&VFrFVG2vFGP$"etB66R3vrFVBvFF&&7FVgFW"DDeזV"Bvv2Fv6VBvFetBBbV'2BBVRF&Ц&7FVEB"V'2B'WBW etBGRv2Vv6RB7F'bVgV7G'V&VVFr'WBFB@FW&FR&6G&6WFfR2"Ff'&ЦǗF726v27G'V7FVBFFRDDeFRf'7BB6V6BFbW"V6W2FRDDe7FF6ǒVVBvFV7G'Vfr'WB6RFWfVVBEF@v'6VVBgFW"FrFRF6RF27F'bF&&7FVgFW DDe&6VB7W76f"GR$"etBv6v26f&VBf&&F'FW7G266RFRDDev2vVFW&FVB@&fVBW"V7G'VfrvRFB@vFBDDe2G&VFVBFf W"V6W2b6RB&R6vf6BVЧ7FF26VvW2vRvVB&V6VBet`&W6VVBFW&46Ɩ6Ww03