Does a normal von Willebrand (vW) antigen level rule out type 2B von Willebrand disease?

Normal von Willebrand Antigen Does Not Rule Out Type 2B von Willebrand Disease

A normal von Willebrand factor (VWF) antigen level does not rule out type 2B von Willebrand disease, as this subtype is characterized by a qualitative defect rather than a quantitative deficiency. 1, 2

Laboratory Profile of Type 2B von Willebrand Disease

Type 2B von Willebrand disease is characterized by:

• Increased affinity of VWF for platelet glycoprotein Ib (GPIb) 1, 2
• VWF antigen (VWF:Ag) levels that can range from 30-200 IU/dL (normal to decreased) 1
• Decreased VWF ristocetin cofactor activity (VWF:RCo) typically <30 IU/dL 1
• VWF:RCo/VWF:Ag ratio usually <0.5-0.7 1, 3
• Loss of high molecular weight VWF multimers 3
• Enhanced ristocetin-induced platelet aggregation (RIPA) at low-dose ristocetin, though this can sometimes be normal 3, 2

Why Normal VWF:Ag Doesn't Rule Out Type 2B

The key diagnostic features of type 2B VWD are:

1. Qualitative defect: Type 2B is a qualitative defect in VWF function rather than a quantitative deficiency 1, 4
2. Gain-of-function mutations: These mutations enhance binding of VWF to platelet GPIb 2, 5
3. Variable VWF:Ag levels: According to the NHLBI guidelines, VWF:Ag can range from <30-200 IU/dL in type 2B VWD 1
4. Research evidence: A 2017 study specifically found that some patients with genetically confirmed type 2B VWD had normal VWF:Ag levels 2

Diagnostic Approach for Type 2B VWD

To diagnose type 2B VWD when VWF:Ag is normal:

• Calculate the VWF:RCo/VWF:Ag ratio (should be <0.5-0.7) 1, 3
• Perform RIPA testing (typically enhanced at low-dose ristocetin) 3
• Analyze VWF multimer pattern (loss of high molecular weight multimers) 3
• Consider genetic testing for mutations in the A1 domain of VWF 2, 5

Important Clinical Considerations

• Type 2B VWD can present with thrombocytopenia due to spontaneous binding of VWF to platelets 2, 5
• Bleeding risk in type 2B VWD is significant, with one study reporting major bleeding in 68.4% of affected individuals 2
• Common bleeding symptoms include menorrhagia, epistaxis, easy bruising, and oral cavity bleeding 2
• Some variants of type 2B VWD may have atypical laboratory findings, including normal RIPA at standard doses 2, 6

Pitfalls to Avoid

• Don't rely solely on VWF:Ag: A normal VWF:Ag level alone is insufficient to rule out type 2B VWD 1, 2
• Don't overlook ratio calculations: The VWF:RCo/VWF:Ag ratio is crucial for distinguishing type 2 from type 1 VWD 1, 3
• Be aware of atypical presentations: Some type 2B patients may have normal RIPA at 0.5 mg/mL 2
• Consider genetic testing: In cases with discordant laboratory findings, genetic analysis may be necessary for definitive diagnosis 2, 5

In conclusion, while type 2B VWD typically presents with decreased VWF:RCo, normal to decreased VWF:Ag, and a low VWF:RCo/VWF:Ag ratio, a normal VWF:Ag level alone does not exclude the diagnosis of type 2B VWD.