Protein S gene mutation c. 946C  > T (p. R316C ) contributed to ischemic stroke in a man with von Willebrand disease type 3 caused by two novel VWF gene mutations, c. 2328delT (p. A778Lfs 23) and c. 6521G  > T (p. C2174F )

• Published in: Clinical case reports Vol. 10; no. 8
• Main Authors: Hua, Baolai, Yan, Xiaobo, He, Bin, Shen, Lianjun, Poon, Man‐Chiu
• Format: Journal Article
• Language: English
• Published: 01-08-2022
• ISSN: 2050-0904; 2050-0904
• DOI: 10.1002/ccr3.6269

The risk factors for a family with VWD presenting with an ischemic stroke (IS) were explored. FVIII activity (FVIII:C), VWF antigen (VWF:Ag), and protein S activity were measured. Next generation sequencing (NGS) was performed targeting
F8
,
F9
,
VWF
,
PROC, and PROS1
. Sanger sequencing validation was performed on family members. The proband and his sister both had low FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) levels, confirming the diagnosis of type 3 VWD. His father had nearly normal levels of FVIII:C (58 IU/dL) and VWF:Ag (57 IU/dL). His daughter had type 1 VWD with decreased FVIII:C (46 IU/dL) and VWF:Ag (19 IU/dL). NGS identified a heterozygous VWF c.2328delT (p.A778Lfs*23) frame shift mutation only in the proband and his sister. Another VWF missense mutation, c.6521G > T (p.C2174F), was found heterozygous in all members studied. A
PROS1
mutation, c.946C > T (p.R316C), previously reported to relate to ischemic stroke, was found heterozygous in the patient, his father, and his daughter. Only the proband and daughter have a slightly decreased plasma protein S level. This may be the first case with type 3 VWD with severe VWF/FVIII deficiency presented with ischemic stroke contributed to by a protein S defect.