PB0359 - Atypical type 2B von Willebrand disease (VWD2B): key role of ristocetin-induced platelet aggregation at lower doses (RIPA-LD) to guide diagnosis. A single-center experience.

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

SC

Santiago Castera, Sr.

Biochemist, Ms.
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina
CABA, Ciudad Autonoma de Buenos Aires, Argentina

Co-Author(s)

AM

Alberto Maria Fabiana

PhD
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
CABA, Ciudad Autonoma de Buenos Aires, Argentina
AW

Adriana I. Woods, PhD

Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
Ciudad Autonoma de Buenos Aires, Ciudad Autonoma de Buenos Aires, Argentina
MI

Marcelo Francisco Ingratti

Biochemist
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
CABA, Ciudad Autonoma de Buenos Aires, Argentina
MF

Monica Marianela Fochesato

Biochemist
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
CABA, Ciudad Autonoma de Buenos Aires, Argentina
SG

Silvia Grosso

Biochemist
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
CABA, Ciudad Autonoma de Buenos Aires, Argentina
EV

Evangelina Valda

MD
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
CABA, Ciudad Autonoma de Buenos Aires, Argentina
AB

Alicia N. Blanco

PhD
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
CABA, Ciudad Autonoma de Buenos Aires, Argentina

Presenting Author(s)

Analia Sánchez-Luceros, MD, PHD

MD, PhD
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
CABA, Ciudad Autonoma de Buenos Aires, Argentina

Background: VWD2B includes VWF variants with an increased affinity for the platelet receptor glycoprotein Ib (GPIb). Individuals with 2B-VWD present a deficiency of high molecular weight multimers (HMWM), thrombocytopenia, VWF GPIb binding/VWF:Ag ratio < 0.7, and RIPA-LD aggregation. Some atypical 2B-VWD variants show no phenotypic changes, except RIPA-LD aggregation in carriers. However, the guideline on the diagnosis of VWD (2021) suggests targeted genetic testing over RIPA-LD to diagnose VWD2B.

Aims: Our study aims to describe patients who initially presented with RIPA-LD aggregation, assessing the utility of RIPA-LD in guiding the VWD2B diagnosis.

Methods: Fifteen patients from eleven families (I-XI) affected by VWD2B, were studied. FVIII:C (one-Stage), VWF:RCo (aggregometry), VWF:GP1bM (immunoturbidimetry), VWF:Ag and VWF:CB3 (ELISA), RIPA-LD with different doses (0.4-0.7 mg/mL ristocetin), VWF-multimers (electrophoresis), exon-28-VWF sequencing (Sanger) were performed.

Results: All patients showed RIPA-LD aggregation at doses≤0.6 mg/mL as the initial finding (Table1). Only 2/15 patients had thrombocytopenia (Ia and IIa) and abnormal VWF:RCo/VWF:Ag ratios (IIa and IIIa). VWF:GPIbM/VWF:Ag vs VWF:CB3/VWF:Ag ratios correlated positively, while VWF:RCo/VWF:Ag did not (Figure1). Genomic analysis revealed 6 different disease-causing variants (DCVs). Carriers of p.V1316M, p.R1306W, p.P1337L, and p.M1304V presented a low VWF:CB3/VWF:Ag ratio, associated with absent/decreased HMWM. Carriers of p.P1266L and p.R1336Q presented normal laboratory values. No DCVs were identified in family XI.

Conclusion(s): Patient Va and her mother (Vb) presented different phenotypic patterns. Co-inheritance of other DCV from her father (not available) could potentially explain the low VWF:RCo and VWF:CB3. Performing a comprehensive VWF-gene sequencing is crucial to identify phenotype-driven variants in Family XI and Patient Va. RIPA-LD guided us in identifying the p.R1336Q variant (not published), likely associated with the disease due to its localization in the A1-domain. RIPA-LD aggregation played a key role in deepening the study, allowing the characterization of typical and atypical 2B-VWD patients. Therefore, we strongly recommend its application in the first line of diagnosis.