Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1989 May;86(10):3793–3797. doi: 10.1073/pnas.86.10.3793

von Willebrand factor synthesized by endothelial cells from a patient with type IIB von Willebrand disease supports platelet adhesion normally but has an increased affinity for platelets.

P G de Groot 1, A B Federici 1, H C de Boer 1, P d'Alessio 1, P M Mannucci 1, J J Sixma 1
PMCID: PMC287227  PMID: 2657729

Abstract

Endothelial cells were isolated from the umbilical vein of a patient with subtype IIB von Willebrand disease, and the biosynthesis and function of von Willebrand factor (vWF) synthesized by these cells were compared with those of vWF synthesized by endothelial cells from normal individuals. The patient's endothelial cells synthesized, stored, and secreted vWF indistinguishably from normal endothelial cells: it was synthesized as a prepolypeptide of Mr 270,000 and had a mature form of Mr 220,000; the full spectrum of multimers was found both inside the cells and in the culture medium; it was stored normally, in the Weibel-Palade bodies; and similar amounts of vWF were secreted into the medium and deposited in the extracellular matrix. In a perfusion set-up, the extracellular matrix from IIB cells supported platelet adhesion similarly to the matrix from normal cells. vWF secreted constitutively by IIB cells into the culture medium bound to platelets at concentrations of ristocetin lower than those necessary for vWF from normal cells. vWF stored in the Weibel-Palade bodies of type IIB cells was released upon stimulation with phorbol ester and bound almost completely to platelets even in the absence of ristocetin. Moreover, spontaneous platelet aggregation was induced by vWF synthesized by type IIB cells. These data support the hypothesis that the absence of highly multimeric forms of vWF in plasma of type IIB von Willebrand disease patients is due to specific removal of these multimers by platelets.

Full text

PDF
3793

Images in this article

3794Image
on p.3794
3795Image
on p.3795
3795Image
on p.3795
3795Image
on p.3795

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baumgartner H. R., Muggli R., Tschopp T. B., Turitto V. T. Platelet adhesion, release and aggregation in flowing blood: effects of surface properties and platelet function. Thromb Haemost. 1976 Feb 29;35(1):124–138. [PubMed] [Google Scholar]
  2. Baumgartner H. R. The role of blood flow in platelet adhesion, fibrin deposition, and formation of mural thrombi. Microvasc Res. 1973 Mar;5(2):167–179. doi: 10.1016/0026-2862(73)90069-1. [DOI] [PubMed] [Google Scholar]
  3. Cheresh D. A. Human endothelial cells synthesize and express an Arg-Gly-Asp-directed adhesion receptor involved in attachment to fibrinogen and von Willebrand factor. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6471–6475. doi: 10.1073/pnas.84.18.6471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ciavarella G., Ciavarella N., Antoncecchi S., De Mattia D., Ranieri P., Dent J., Zimmerman T. S., Ruggeri Z. M. High-resolution analysis of von Willebrand factor multimeric composition defines a new variant of type I von Willebrand disease with aberrant structure but presence of all size multimers (type IC). Blood. 1985 Dec;66(6):1423–1429. [PubMed] [Google Scholar]
  5. De Marco L., Girolami A., Zimmerman T. S., Ruggeri Z. M. Interaction of purified type IIB von Willebrand factor with the platelet membrane glycoprotein Ib induces fibrinogen binding to the glycoprotein IIb/IIIa complex and initiates aggregation. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7424–7428. doi: 10.1073/pnas.82.21.7424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. De Marco L., Mazzuccato M., Grazia Del Ben M., Budde U., Federici A. B., Girolami A., Ruggeri Z. M. Type IIB von Willebrand factor with normal sialic acid content induces platelet aggregation in the absence of ristocetin. Role of platelet activation, fibrinogen, and two distinct membrane receptors. J Clin Invest. 1987 Aug;80(2):475–482. doi: 10.1172/JCI113095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Federici A. B., Elder J. H., De Marco L., Ruggeri Z. M., Zimmerman T. S. Carbohydrate moiety of von Willebrand factor is not necessary for maintaining multimeric structure and ristocetin cofactor activity but protects from proteolytic degradation. J Clin Invest. 1984 Dec;74(6):2049–2055. doi: 10.1172/JCI111628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Grainick H. R., Williams S. B., McKeown L. P., Rick M. E., Maisonneuve P., Jenneau C., Sultan Y. Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor. J Clin Invest. 1985 Oct;76(4):1522–1529. doi: 10.1172/JCI112132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jaffe E. A., Hoyer L. W., Nachman R. L. Synthesis of antihemophilic factor antigen by cultured human endothelial cells. J Clin Invest. 1973 Nov;52(11):2757–2764. doi: 10.1172/JCI107471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lawrence J. B., Gralnick H. R. Asialo-von Willebrand factor inhibits platelet adherence to human arterial subendothelium: discrepancy between ristocetin cofactor activity and primary hemostatic function. Blood. 1987 Oct;70(4):1084–1089. [PubMed] [Google Scholar]
  11. Levene R. B., Booyse F. M., Chediak J., Zimmerman T. S., Livingston D. M., Lynch D. C. Expression of abnormal von Willebrand factor by endothelial cells from a patient with type IIA von Willebrand disease. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6550–6554. doi: 10.1073/pnas.84.18.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Loesberg C., Gonsalves M. D., Zandbergen J., Willems C., van Aken W. G., Stel H. V., Van Mourik J. A., De Groot P. G. The effect of calcium on the secretion of factor VIII-related antigen by cultured human endothelial cells. Biochim Biophys Acta. 1983 Sep 22;763(2):160–168. doi: 10.1016/0167-4889(83)90039-3. [DOI] [PubMed] [Google Scholar]
  13. Macfarlane D. E., Stibbe J., Kirby E. P., Zucker M. B., Grant R. A., McPherson J. Letter: A method for assaying von Willebrand factor (ristocetin cofactor). Thromb Diath Haemorrh. 1975 Sep 30;34(1):306–308. [PubMed] [Google Scholar]
  14. Maciag T., Hoover G. A., Stemerman M. B., Weinstein R. Serial propagation of human endothelial cells in vitro. J Cell Biol. 1981 Nov;91(2 Pt 1):420–426. doi: 10.1083/jcb.91.2.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nachman R., Levine R., Jaffe E. A. Synthesis of factor VIII antigen by cultured guinea pig megakaryocytes. J Clin Invest. 1977 Oct;60(4):914–921. doi: 10.1172/JCI108846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Rand J. H., Sussman I. I., Gordon R. E., Chu S. V., Solomon V. Localization of factor-VIII-related antigen in human vascular subendothelium. Blood. 1980 May;55(5):752–756. [PubMed] [Google Scholar]
  17. Reinders J. H., De Groot P. G., Gonsalves M. D., Zandbergen J., Loesberg C., Van Mourik J. A. Isolation of a storage and secretory organelle containing Von Willebrand protein from cultured human endothelial cells. Biochim Biophys Acta. 1984 Jul 20;804(3):361–369. doi: 10.1016/0167-4889(84)90140-x. [DOI] [PubMed] [Google Scholar]
  18. Reinders J. H., Vervoorn R. C., Verweij C. L., van Mourik J. A., de Groot P. G. Perturbation of cultured human vascular endothelial cells by phorbol ester or thrombin alters the cellular von Willebrand factor distribution. J Cell Physiol. 1987 Oct;133(1):79–87. doi: 10.1002/jcp.1041330110. [DOI] [PubMed] [Google Scholar]
  19. Ruggeri Z. M., Pareti F. I., Mannucci P. M., Ciavarella N., Zimmerman T. S. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease. N Engl J Med. 1980 May 8;302(19):1047–1051. doi: 10.1056/NEJM198005083021902. [DOI] [PubMed] [Google Scholar]
  20. Ruggeri Z. M., Zimmerman T. S. Variant von Willebrand's disease: characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets. J Clin Invest. 1980 Jun;65(6):1318–1325. doi: 10.1172/JCI109795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ruggeri Z. M., Zimmerman T. S. von Willebrand factor and von Willebrand disease. Blood. 1987 Oct;70(4):895–904. [PubMed] [Google Scholar]
  22. Sadler J. E., Shelton-Inloes B. B., Sorace J. M., Harlan J. M., Titani K., Davie E. W. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6394–6398. doi: 10.1073/pnas.82.19.6394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sakariassen K. S., Aarts P. A., de Groot P. G., Houdijk W. P., Sixma J. J. A perfusion chamber developed to investigate platelet interaction in flowing blood with human vessel wall cells, their extracellular matrix, and purified components. J Lab Clin Med. 1983 Oct;102(4):522–535. [PubMed] [Google Scholar]
  24. Sakariassen K. S., Bolhuis P. A., Sixma J. J. Human blood platelet adhesion to artery subendothelium is mediated by factor VIII-Von Willebrand factor bound to the subendothelium. Nature. 1979 Jun 14;279(5714):636–638. doi: 10.1038/279636a0. [DOI] [PubMed] [Google Scholar]
  25. Slot J. W., Geuze H. J. Sizing of protein A-colloidal gold probes for immunoelectron microscopy. J Cell Biol. 1981 Aug;90(2):533–536. doi: 10.1083/jcb.90.2.533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sporn L. A., Marder V. J., Wagner D. D. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell. 1986 Jul 18;46(2):185–190. doi: 10.1016/0092-8674(86)90735-x. [DOI] [PubMed] [Google Scholar]
  27. Verweij C. L., Hart M., Pannekoek H. Expression of variant von Willebrand factor (vWF) cDNA in heterologous cells: requirement of the pro-polypeptide in vWF multimer formation. EMBO J. 1987 Oct;6(10):2885–2890. doi: 10.1002/j.1460-2075.1987.tb02591.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wagner D. D., Marder V. J. Biosynthesis of von Willebrand protein by human endothelial cells. Identification of a large precursor polypeptide chain. J Biol Chem. 1983 Feb 25;258(4):2065–2067. [PubMed] [Google Scholar]
  29. Wagner D. D., Marder V. J. Biosynthesis of von Willebrand protein by human endothelial cells: processing steps and their intracellular localization. J Cell Biol. 1984 Dec;99(6):2123–2130. doi: 10.1083/jcb.99.6.2123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wagner D. D., Mayadas T., Marder V. J. Initial glycosylation and acidic pH in the Golgi apparatus are required for multimerization of von Willebrand factor. J Cell Biol. 1986 Apr;102(4):1320–1324. doi: 10.1083/jcb.102.4.1320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wagner D. D., Olmsted J. B., Marder V. J. Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells. J Cell Biol. 1982 Oct;95(1):355–360. doi: 10.1083/jcb.95.1.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Willems C., Astaldi G. C., De Groot P. G., Janssen M. C., Gonsalvez M. D., Zeijlemaker W. P., Van Mourik J. A., Van Aken W. G. Media conditioned by cultured human vascular endothelial cells inhibit the growth of vascular smooth muscle cells. Exp Cell Res. 1982 May;139(1):191–197. doi: 10.1016/0014-4827(82)90332-9. [DOI] [PubMed] [Google Scholar]
  33. Zimmerman T. S., Dent J. A., Ruggeri Z. M., Nannini L. H. Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID, and IIE). J Clin Invest. 1986 Mar;77(3):947–951. doi: 10.1172/JCI112394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. de Groot P. G., Reinders J. H., Sixma J. J. Perturbation of human endothelial cells by thrombin or PMA changes the reactivity of their extracellular matrix towards platelets. J Cell Biol. 1987 Mar;104(3):697–704. doi: 10.1083/jcb.104.3.697. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES