Rare form of von Willebrand disease may be misdiagnosed, new study finds
Case study links PT-VWD to a GP1BA mutation affecting platelet function
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A new case study describes a family with platelet-type von Willebrand disease (PT-VWD), a rare bleeding condition often mistaken for von Willebrand disease (VWD).
PT-VWD is referred to as a “nonidentical” twin of VWD type 2B because both conditions involve an abnormally increased interaction between platelets, the cell fragments that help blood clot, and the von Willebrand factor (VWF) protein, but they are caused by different genetic mutations.
“Distinguishing between PT-VWD and type 2B VWD remains critical for clinical management, as therapeutic strategies differ: patients with type 2B VWD may benefit from VWF replacement, whereas those with PT-VWD require platelet transfusion,” the researchers noted.
PT-VWD and type 2B VWD share features but differ genetically
The case study, “Second Report of A GPIbα LRR7 Variant (P.Leu194Phe) Supporting the Pathogenicity of Mutations Outside The C-Terminal Domain In Platelet-Type Von Willebrand Disease,” was published in Seminars in Thrombosis and Hemostasis.
VWF is a protein that acts like glue, helping platelets stick together to form a blood clot at the site of injury. In VWD, mutations in the VWF gene result in a missing or dysfunctional VWF protein, impairing clotting and causing abnormally heavy or prolonged bleeding.
Rather than a defect in the VWF gene, PT-VWD is caused by mutations in the GP1BA gene, which encodes a component of the GPIb protein on the surface of platelets that binds to VWF.
In PT-VWD, these mutations increase GPIb’s affinity for VWF, leading to excessive platelet-VWF interactions. This can cause the complex to be cleared too quickly from the bloodstream, resulting in mild-to-moderate mucocutaneous bleeding, such as nosebleeds, easy bruising, or heavy menstrual bleeding.
PT-VWD is often misdiagnosed as VWD type 2B, which is caused by mutations in the VWF gene that also increase the interaction between the VWF protein and GPIb.
Eight PT-VWD-causing GP1BA gene mutations have been reported so far. Of these, five are found in the beta-switch region, a part of the GPIb protein that directly interacts with VWF. Two other mutations have been identified in a separate GPIb region, the LRR domain, suggesting they may alter the protein’s shape to enhance its binding to VWF. One additional mutation has been reported in the macroglycopeptide region.
Case study describes family with rare PT-VWD mutation
Researchers in France described another family carrying a previously reported mutation in the GPIb LRR domain, outside of the beta-switch. In this case, PT-VWD was associated with a mild clinical presentation and normal platelet counts.
Doctors initially suspected VWD while evaluating a 1-year-old boy before corrective surgery for trigonocephaly, an abnormal triangle-shaped forehead.
Key clotting measurements were slightly lower than expected: VWF protein at 55% and VWF activity at 36%. In addition, testing showed increased platelet–VWF clumping at a low ristocetin concentration, based on a diagnostic blood test that measures how platelets clump in response to ristocetin.
The boy had no family history of bleeding problems, normal platelet counts, and had not shown unusual bruising or prolonged bleeding from routine events such as vaccinations or minor scratches. Although a platelet function test showed a moderately prolonged time to clot formation, other tests showed normal platelet receptor levels and a normal VWF pattern.
Genetic testing confirms GP1BA mutation in PT-VWD
Genetic testing provided an important clue, revealing a previously reported GP1BA gene mutation, c.580C>T. This mutation resulted in a change in GPIb (p.Leu194Phe) within the LRR domain. Based on this finding, the boy was diagnosed with PT-VWD.
A genetic assessment of his parents revealed that the mutation was inherited from the boy’s mother, who had normal platelet counts. Even so, she showed an elevated platelet-VWF response to ristocetin, like her son.
“This LRR variant … expands the typical PT-VWD phenotype by exhibiting a mild clinical presentation with a common feature, the increased [platelet-VWF clumping] at a low ristocetin concentration,” the researchers wrote.
