A mathematical framework for group analysis of von Willebrand factor multimeric composition following luminography

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Abstract

The objective of the present study was to establish a method for quantitative analysis of von Willebrand factor (vWF) multimeric composition using a mathematical framework based on curve fitting. Plasma vWF multimers from 15 healthy subjects and 13 patients with advanced pulmonary vascular disease were analyzed by Western immunoblotting followed by luminography. Quantitative analysis of luminographs was carried out by calculating the relative densities of low, intermediate and high molecular weight fractions using laser densitometry. For each densitometric peak (representing a given fraction of vWF multimers) a mean area value was obtained using data from all group subjects (patients and normal individuals) and plotted against the distance between the peak and IgM (950 kDa). Curves were constructed for each group using nonlinear fitting. Results indicated that highly accurate curves could be obtained for healthy controls and patients, with respective coefficients of determination (r²) of 0.9898 and 0.9778. Differences were observed between patients and normal subjects regarding curve shape, coefficients and the region of highest protein concentration. We conclude that the method provides accurate quantitative information on the composition of vWF multimers and may be useful for comparisons between groups and possibly treatments.

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Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis.

C Bressi, Z Ruggeri, M Zanobini … (2000)

Excessive bleeding may complicate congenital cardiac defects. To explain the pathogenesis of this abnormality, we evaluated selected parameters of primary hemostasis in patients with aortic valve stenosis before and after corrective surgery. We examined shear-induced platelet aggregation with the filter aggregometer test and von Willebrand factor (vWF) structure by evaluating the multimeric distribution and extent of subunit proteolysis. The platelet count was reduced before corrective surgery, and shear-induced platelet aggregation was impaired. Moreover, vWF multimers of higher molecular mass were decreased, and proteolytic subunit fragments were increased. After correction of the cardiac defect, all of these parameters returned to normal. Alterations of vWF and platelet function may contribute to the bleeding diathesis in patients with aortic valve stenosis. Improvement after corrective surgery suggests that the passage of blood through a stenosed aortic valve may result in shear forces that induce vWF interaction with platelets in the circulation and, in turn, trigger platelet clearance, vWF degradation, and the impairment of primary hemostasis.

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The complex multimeric composition of factor VIII/von Willebrand factor.

Z Ruggeri, T Zimmerman (1981)

We have analyzed the multimeric structure of factor VIII/von Willebrand factor in plasma by sodium dodecyl sulfate electrophoresis using gels of varying porosity and a discontinuous buffer system. Factor VIII/von Willebrand factor bands were identified by reaction with 125I-labeled affinity-purified antibody and subsequent autoradiography. In 1% agarose gels, normal plasma displayed a series of sharply defined oligomers. However, increasing the agarose concentration to 2.0% or utilizing mixtures of 0.8% agarose--1.75% acrylamide revealed two bands of lesser intensity interposed between the major bands. When the acrylamide concentration in the gels was increased to 2.5%, bands with a faster mobility than IgM and fibronectin were now evident. Type IIA von Willebrand's disease showed not only an absence of the larger multimers but also a relative increase in several of the newly identified bands as compared to type IIB, type I, and normal. These studies suggest that factor VII/von Willebrand factor in IIA von Willebrand's disease is structurally different from that in other forms of the disorder. They also indicate that the multimeric composition of factor VII/von Willebrand factor is more complex than can be explained by simple linear polymerization of a single protomer.

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Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma.

R Scharf, Andrew Dent, U Budde … (1993)

Twelve of 19 patients with myeloproliferative disorders showed a decrease of absence of the largest multimers of plasma von Willebrand factor (vWF) that correlated with elevated platelet counts but not with leukocyte counts. This suggested that platelets, rather than leukocytes, may be associated with the pathogenesis of the acquired vWF abnormality seen in these patients. To examine the hypothesis further, we studied 12 patients with reactive thrombocytosis after splenectomy. Increased platelet count (> 5 x 10(11)/L) after splenectomy was associated with vWF abnormalities indistinguishable from those detected in patients with myeloproliferative disorders. Accordingly, there was an inverse correlation between proportion of large vWF multimers and platelet, but not leukocyte, number: normalization of the platelet count was accompanied by restoration of a normal vWF multimeric pattern. These findings suggest that an increase in the number of platelets circulating in blood may favor the adsorption of larger vWF multimers onto the platelet membrane, resulting in their removal from the circulation and subsequent degradation.

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Journal

Journal ID (publisher-id): bjmbr

Title: Brazilian Journal of Medical and Biological Research

Abbreviated Title: Braz J Med Biol Res

Publisher: Associação Brasileira de Divulgação Científica (Ribeirão Preto, SP, Brazil )

ISSN (Print): 0100-879X

ISSN (Electronic): 1414-431X

Publication date (Print and electronic): November 2002

Volume: 35

Issue: 11

Pages: 1259-1263

Affiliations

[02] São Paulo SP orgnameFundação Pró-Sangue Brasil

[01] orgnameUniversidade de São Paulo orgdiv1Instituto do Coração orgdiv2Departamento de Cardiologia Pediátrica e Cardiopatias Congênitas

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Publisher ID: S0100-879X2002001100002 Publisher ID: S0100-879X(02)03501102

DOI: 10.1590/S0100-879X2002001100002

SO-VID: 7335e361-93f1-42ed-b7b6-7b0e33613aee

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This work is licensed under a Creative Commons Attribution 4.0 International License.

History

Date received : 23 April 2002

Date accepted : 06 August 2002

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Figures: 0, Tables: 0, Equations: 0, References: 20, Pages: 5

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A mathematical framework for group analysis of von Willebrand factor multimeric composition following luminography

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Most cited references 20

Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis.

The complex multimeric composition of factor VIII/von Willebrand factor.

Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma.

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