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Case report of two siblings with type 2A von Willebrand disease involving a novel mutation within the calcium-binding site of the A2 domain of von Willebrand factor

Igid, Henry P.a; Thein, Kyaw Z.a; Castine, Michaelb; Quick, Donald P.a,c

Blood Coagulation & Fibrinolysis: June 2019 - Volume 30 - Issue 4 - p 161–167
doi: 10.1097/MBC.0000000000000798
CASE REPORTS
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Calcium-binding at the A2 domain protects von Willebrand factor (VWF) from cleavage by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS13) and is coordinated by five important residues (p.Asp1596, p.Arg1597, p.Ala1600, p.Asn1602, and p.Asp1498). Only variants of p.Arg1597 resulting in type 2A von Willebrand disease have been reported. We report a novel VWF variant, a heterozygous single nucleotide change, c.4493A>G, occurring at the p.Asp1498 residue of the calcium-binding site of the A2 domain in two sisters with type 2A von Willebrand disease. Modest increase in the VWF propeptide/VWF:Ag ratio (2.4 and 2.7) supports increased clearance of VWF. A literature review provided insight into the integral role of p.Asp1498 residue in calcium-binding and its role in the stabilization of other residues including p.Arg1597 and p.Asn1602. Studies done by other groups on engineered mutations involving p.Asp1498 reported increased susceptibility to ADAMTS13 proteolysis. Cellular studies are needed to confirm these mechanisms.

aDepartment of Hematology and Oncology, Texas Tech University Health Sciences Center, Lubbock, Texas

bHematology Oncology Clinic, Baton Rouge, Louisiana

cJoe Arrington Cancer Center, Covenant Health, Lubbock, Texas, USA

Correspondence to Kyaw Z. Thein, MD, Department of Hematology and Oncology, Texas Tech University Health Sciences Center, 3601 4th St Stop 9410, Lubbock, TX 79430-9410, USA. Tel: +1 347 828 3776; e-mail: kyaw.z.thein@ttuhsc.edu

Received 13 November, 2018

Revised 23 January, 2019

Accepted 24 January, 2019

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