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Substantial inter\u2010individual variation in VWF plasma levels exists among the healthy population. Prior to secretion, VWF polymers are assembled and condensed into helical tubules, which are packaged into Weibel\u2010Palade bodies (WPBs), a highly specialized post\u2010Golgi storage compartment in vascular endothelial cells. In the inherited bleeding disorder Von Willebrand disease (VWD), mutations in the VWF gene can cause qualitative or quantitative defects, limiting protein function, secretion, or plasma survival. However, pathogenic VWF mutations cannot be found in all VWD cases. Although an increasing number of genetic modifiers have been identified, even more rare genetic variants that impact VWF plasma levels likely remain to be discovered. Here, we summarize recent evidence that modulation of the early secretory pathway has great impact on the biogenesis and release of WPBs. Based on these findings, we propose that rare, as yet unidentified quantitative trait loci influencing intracellular VWF transport contribute to highly variable VWF levels in the population. These may underlie the thrombotic complications linked to high VWF levels, as well as the bleeding tendency in individuals with low VWF levels.<\/jats:p>","DOI":"10.1111\/febs.16421","type":"journal-article","created":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T09:48:04Z","timestamp":1646473684000},"page":"6863-6870","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Dispatch and delivery at the ER\u2013Golgi interface: how endothelial cells tune their hemostatic response"],"prefix":"10.1111","volume":"289","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4184-6171","authenticated-orcid":false,"given":"Marije","family":"Kat","sequence":"first","affiliation":[{"name":"Molecular Hematology Sanquin Research and Landsteiner Laboratory Amsterdam University Medical Center University of Amsterdam The 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