Performance Related Factors Are the Main Determinants of the von Willebrand Factor Response to Exhaustive Physical Exercise

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Abstract

Background

Physical stress triggers the endothelium to release von Willebrand Factor (VWF) from the Weibel Palade bodies. Since VWF is a risk factor for arterial thrombosis, it is of great interest to discover determinants of VWF response to physical stress. We aimed to determine the main mediators of the VWF increase by exhaustive physical exercise.

Methods

105 healthy individuals (18–35 years) were included in this study. Each participant performed an incremental exhaustive exercise test on a cycle ergometer. Respiratory gas exchange measurements were obtained while cardiac function was continuously monitored. Blood was collected at baseline and directly after exhaustion. VWF antigen (VWF:Ag) levels, VWF collagen binding (VWF:CB) levels, ADAMTS13 activity and common variations in Syntaxin Binding Protein-5 ( STXBP5, rs1039084 and rs9399599), Syntaxin-2 ( STX2, rs7978987) and VWF (promoter, rs7965413) were determined.

Results

The median VWF:Ag level at baseline was 0.94 IU/mL [IQR 0.8–1.1] and increased with 47% [IQR 25–73] after exhaustive exercise to a median maximum VWF:Ag of 1.38 IU/mL [IQR 1.1–1.8] (p<0.0001). VWF:CB levels and ADAMTS13 activity both also increased after exhaustive exercise (median increase 43% and 12%, both p<0.0001). The strongest determinants of the VWF:Ag level increase are performance related (p<0.0001). We observed a gender difference in VWF:Ag response to exercise (females 1.2 IU/mL; males 1.7 IU/mL, p = 0.001), which was associated by a difference in performance. Genetic variations in STXBP5, STX2 and the VWF promoter were not associated with VWF:Ag levels at baseline nor with the VWF:Ag increase.

Conclusions

VWF:Ag levels strongly increase upon exhaustive exercise and this increase is strongly determined by physical fitness level and the intensity of the exercise, while there is no clear effect of genetic variation in STXBP5, STX2 and the VWF promoter.

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Most cited references 46

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Age-predicted maximal heart rate revisited.

H Tanaka, K. Monahan, D Seals (2001)

We sought to determine a generalized equation for predicting maximal heart rate (HRmax) in healthy adults. The age-predicted HRmax equation (i.e., 220 - age) is commonly used as a basis for prescribing exercise programs, as a criterion for achieving maximal exertion and as a clinical guide during diagnostic exercise testing. Despite its importance and widespread use, the validity of the HRmax equation has never been established in a sample that included a sufficient number of older adults. First, a meta-analytic approach was used to collect group mean HRmax values from 351 studies involving 492 groups and 18,712 subjects. Subsequently, the new equation was cross-validated in a well-controlled, laboratory-based study in which HRmax was measured in 514 healthy subjects. In the meta-analysis, HRmax was strongly related to age (r = -0.90), using the equation of 208 - 0.7 x age. The regression equation obtained in the laboratory-based study (209 - 0.7 x age) was virtually identical to that obtained from the meta-analysis. The regression line was not different between men and women, nor was it influenced by wide variations in habitual physical activity levels. 1) A regression equation to predict HRmax is 208 - 0.7 x age in healthy adults. 2) HRmax is predicted, to a large extent, by age alone and is independent of gender and habitual physical activity status. Our findings suggest that the currently used equation underestimates HRmax in older adults. This would have the effect of underestimating the true level of physical stress imposed during exercise testing and the appropriate intensity of prescribed exercise programs.

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Biochemistry and genetics of von Willebrand factor.

J Sadler (1998)

Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis, and deficiency of VWF, or von Willebrand disease (VWD), is the most common inherited bleeding disorder. VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. These activities appear to be regulated by allosteric mechanisms and possibly by hydrodynamic shear forces. VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. VWF is assembled from identical approximately 250 kDa subunits into disulfide-linked multimers that may be > 20,000 kDa. Mutations in VWD can disrupt this complex biosynthetic process at several steps to impair the assembly, intracellular targeting, or secretion of VWF multimers. Other VWD mutations impair the survival of VWF in plasma or the function of specific ligand binding sites. This growing body of information about VWF synthesis, structure, and function has allowed the reclassification of VWD based upon distinct pathophysiologic mechanisms that appear to correlate with clinical symptoms and the response to therapy.

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ABO(H) blood groups and vascular disease: a systematic review and meta-analysis.

Colin O. Wu, Selwyn Vickers, P. Clark … (2007)

Associations between vascular disease and ABO(H) blood groups have a long history, but no consensus exists regarding its magnitude and significance, or whether it relates to all disorders equally. An accurate calculation of risk would allow direct assessment of whether the effects of non-O status on thrombosis risk are of the magnitude predicted by its effect on von Willebrand factor/FVIII levels. We conducted a systematic review and meta-analysis of studies reporting associations with non-O blood groups. This gave pooled odds ratios of 1.25 [95% confidence interval (CI) 1.14-1.36] for myocardial infarction (MI), 1.03 (95% CI 0.89-1.19) for angina, 1.45 (95% CI 1.35-1.56) for peripheral vascular disease, 1.14 (95% CI 1.01-1.27) for cerebral ischemia of arterial origin, and 1.79 (95% CI 1.56 to 2.05) for venous thromboembolism (VTE). However, restriction to prospective MI studies only did not confirm the association (OR 1.01; 95% CI 0.84-1.23), although these studies may have failed to capture early-onset disease. For VTE, using a combined group of OO/A(2)A(2)/A(2)O as index, the combination of A(1)A(1)/A(1)B/BB gave an OR of 2.44 (95% CI 1.79-3.33) and A(1)O/ BO/A(2)B an OR of 2.11 (95% CI 1.66-2.68). This study confirms the historical impression of linkage between some vascular disorders and non-O blood group status. Although the odds ratios are similar to those predicted by the effect of ABO(H) on von Willebrand factor levels, further work is required to assess risk prospectively and to refine the effect of reducing O(H) antigen expression on thrombosis. However, as non-O and particularly A(1)A(1), A(1)B, BB constitute a significant proportion of the population attributable fraction of VTE, there may be a role for more widespread adoption of ABO(H) typing in testing strategies.

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Author and article information

Contributors

Toshiyuki Miyata: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 13 March 2014

Volume: 9

Issue: 3

Electronic Location Identifier: e91687

Affiliations

[1 ]Department of Haematology, Erasmus University Medical Center, Rotterdam, the Netherlands

[2 ]Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands

[3 ]Department of Rehabilitation Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands

National Cerebral and Cardiovascular Center, Japan

Author notes

* E-mail: f.leebeek@ 123456erasmusmc.nl

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: JEL SFEP MPMM FWGL. Performed the experiments: JEL MAHS. Analyzed the data: JEL MAHS SFEP MPMM FWGL. Contributed reagents/materials/analysis tools: JEL MAHS. Wrote the paper: JEL MAHS. Revising the manuscript: SFEP MPMM FWGL.

Article

Publisher ID: PONE-D-13-34965

DOI: 10.1371/journal.pone.0091687

PMC ID: 3953583

PubMed ID: 24626470

SO-VID: ef69d80e-c76c-46d0-b8f0-2fc879b6c57f

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 26 August 2013

Date accepted : 14 February 2014

Page count

Pages: 8

Funding

This work was supported by a grant of the Dutch Thrombosis Foundation (2010-3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Performance Related Factors Are the Main Determinants of the von Willebrand Factor Response to Exhaustive Physical Exercise

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Abstract

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PLOS Climate

Most cited references 46

Age-predicted maximal heart rate revisited.

Biochemistry and genetics of von Willebrand factor.

ABO(H) blood groups and vascular disease: a systematic review and meta-analysis.

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