June 2026 QQ Review: VWF Gain of Function

Our June 2026 QQ, which drew 30 responses, asked, “What VWD subtype is caused by a VWF gain of function?” Here are your responses:

1. VWD type 1: 3 (10%)
2. VWD subtype 2A: 1 (3%)
3. VWD subtype 2B: 24 (80%)
4. VWD subtype 2M: 2 (7%)
5. VWD subtype 2N: 0
   

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VWD type 1 is the quantitative form of tVWD, in which the ratio of VWF:Ag to VWD:Ac is equal to or greater than 0.7. VWF:Ac, or VWF platelet-binding activity, traditionally measured using the VWF:RCo assay, is now measured using the VWF:GP1bM assay in most laboratories. At least 70% of VWD cases are type 1.

Type 2 VWD cases are qualitative disorders in which the ratio of VWF:Ag to VWF:Ac is less than 0.7. In subtype 2A, VWF multimer assembly may be faulty, or VWF may be abnormally sensitive to ADAMST13 degradation. In subtype 2M, VWF avidity for platelet membrane GP1 is diminished, and in 2N, VWF avidity for FVIII is diminished.

Here is a paraphrased description of VWD subtype 2B from Sarkar MK, Fritsma GA. Hemorrhagic Disorders and Laboratory Assessment, in Keohane EM, Butina MM, Mirza KM, Walenga JM. Rodak’s Hematology; Clinical Principles and Applications, 7th Edition, 2025:

In subtype 2B VWD, identified in less than 5% of all VWD patients, a mutation within the A1 domain, p.Pro1266Ile, raises the affinity of VWF for the GPIb subunit of platelet GPIb/IX/V, its customary binding site; a “gain-of-function” mutation. Abnormal HMW-VWF multimers spontaneously bind inactive platelets and are consequently unavailable for normal platelet adhesion as they are cleared with the bound platelet, causing mild to moderate thrombocytopenia.

The ristocetin-induced platelet agglutination (RIPA) assay identifies subtype 2B VWD. The assay resembles the (now obsolete) VWF: RCo activity assay except that the RIPA employs a reduced concentration of ristocetin reagent and uses the patient’s own platelets instead of reagent platelets as targets. Agglutination implies VWD Subtype 2B, which may be confirmed by molecular diagnosis.

There exists a platelet membrane mutation that raises GPIb affinity for normal HMW-VWF multimers, a condition called platelet-type VWD (PT–VWD) or pseudo-VWD. In this instance, the large VWF multimers are lost from the plasma, and platelets become adhesive as in subtype 2B VWD. Pseudo-VWD may be the more appropriate name, though seldom used, because this is not a true form of VWD. The prevalence of PT–VWD may be approximately 10% of patients misdiagnosed as subtype 2B VWD. Both clinically and by phenotypic laboratory assays, the two entities are indistinguishable; the diagnosis requires molecular testing. Further, platelet-type VWD is often mistaken for immune thrombocytopenia.

Click here for part one of a three-part “VWD Coag Conversation” featuring Robert Sidonio, MD.