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The p.P1127S pathogenic variant lowers von Willebrand factor levels through higher affinity for the macrophagic scavenger receptor LRP1: Clinical phenotype and pathogenic mechanisms.
Sacco, Monica; Lancellotti, Stefano; Branchini, Alessio; Tardugno, Maira; Testa, Maria Francesca; Lunghi, Barbara; Bernardi, Francesco; Pinotti, Mirko; Giusti, Betti; Castaman, Giancarlo; De Cristofaro, Raimondo.
Afiliación
  • Sacco M; Dipartimento di Medicina e Chirurgia Traslazionale, Facoltà di Medicina e Chirurgia "Agostino Gemelli," Università Cattolica S. Cuore, Roma, Italy.
  • Lancellotti S; Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario "A. Gemell" IRCCS, Roma, Italy.
  • Branchini A; Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, Ferrara, Italy.
  • Tardugno M; Dipartimento di Medicina e Chirurgia Traslazionale, Facoltà di Medicina e Chirurgia "Agostino Gemelli," Università Cattolica S. Cuore, Roma, Italy.
  • Testa MF; Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, Ferrara, Italy.
  • Lunghi B; Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, Ferrara, Italy.
  • Bernardi F; Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, Ferrara, Italy.
  • Pinotti M; Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, Ferrara, Italy.
  • Giusti B; Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Firenze, Italy.
  • Castaman G; Laboratorio Genetico Molecolare Avanzato, SOD Malattie Aterotrombotiche, Azienda Ospedaliero- Universitaria "Careggi", Firenze, Italy.
  • De Cristofaro R; Dipartimento di Oncologia, Centro Malattie Emorragiche e della Coagulazione, Ospedale Universitario "Careggi", Firenze, Italy.
J Thromb Haemost ; 20(8): 1818-1829, 2022 08.
Article en En | MEDLINE | ID: mdl-35596664
ABSTRACT

BACKGROUND:

The index case is a 21-year-old Italian woman with a mild hemorrhagic syndrome and von Willebrand factor antigen (VWFAg) = 34.3 U/dl, VWF recombinant glycoprotein Ib (VWFGpIbR) = 32.8 U/dl, and factor VIII (FVIII) = 55.3 IU/dl.

AIMS:

The aim of this study is to characterize from a genetic and biochemical standpoint this low VWF phenotype.

METHODS:

Coagulation and biochemical methods were used to study the structural and functional pattern of VWF multimers in the index case's plasma. Recombinant wild-type and p.P1127S VWF variants were produced using human embryonic kidney (HEK)-293 cells. In addition, genetic screening was carried out to detect single nucleotide variants of some scavenger VWF/FVIII receptor genes such as CLEC4M, STAB2, and ASGR2.

RESULTS:

Genetic investigation revealed that the index case inherited from her mother the heterozygous missense mutation c.3379C > T (VWF exon 25), causing the p.P1127S substitution in the VWF D'D3 domain. The index case was also homozygous for the scavenger receptor ASGR2 c.-95 CC-genotype. Desmopressin normalized the VWF level of the patient, although its clearance was faster (t1/2  = 6.7 h) than in normal subjects (t1/2  = 12 ± 0.7 h). FVIII-VWF interaction, A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif-13 levels, ristocetin-induced-platelet-aggregation, and VWF multimeric pattern were normal. The p.P1127S variant was normally synthesized and secreted by HEK-293 cells, and molecular modeling predicts a conformational change showing higher affinity for the macrophagic scavenger receptor lipoprotein receptor-related protein 1 (LRP1), as also experimentally verified.

CONCLUSIONS:

The p.P1127S variant may cause a low VWF phenotype, stemming from an increased VWF affinity for the scavenger receptor LRP1 and, consequently, an accelerated clearance of VWF.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades de von Willebrand / Factor de von Willebrand Tipo de estudio: Prognostic_studies Límite: Adult / Female / Humans Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades de von Willebrand / Factor de von Willebrand Tipo de estudio: Prognostic_studies Límite: Adult / Female / Humans Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Italia