Platelet degranulation and bleeding phenotype in a large cohort of Von Willebrand disease patients

Swinkels, Maurice; Atiq, Ferdows; Bürgisser, Petra E.; Moort, Iris van; Meijer, Karina; Eikenboom, Jeroen; Fijnvandraat, Karin; Galen, Karin P M van; Schols, Saskia E. M.; Bom, Johanna G. van der; Cnossen, Marjon H.; Voorberg, Jan; Leebeek, Frank W.G.; Bierings, Ruben; Jansen, A.J. Gerard; Coppens, Michiel; Meris, Joke de; Nieuwenhuizen, Laurens; Tamminga, R. Y. J.; Ypma, Paula F.; Eikenboom, H. C. J.; Smiers, Frans J.; Granzen, Bernd; Moenen, Floor C.J.I.; Brons, Paul; Kwawegen, Calvin B. van

doi:10.1111/bjh.18145

Cited by 3 publications

(2 citation statements)

References 15 publications

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“…However, circulating VWF levels do not always fully explain bleeding phenotypes, suggesting a role for alternative factors, like platelets. A positive correlation between PF4 and VWF : Ag levels in type 2A VWD patients (r = 0.229, p = 0.010) was found, which might indicate a similar interaction in vivo (53). Low plasma ADAMTS13 activity or reduced ratio of ADAMTS13 activity to VWF antigen or activity was found prevalent in patients with suspected HIT (54), which suggests that PF4 may reduce VWF cleavage by inhibiting ADAMTS13 activity.…”

Section: Potential Role Of the Pf4-vwf Complex In Immune-associated T...mentioning

confidence: 77%

New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF

et al. 2023

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Platelet factor 4 (PF4), also known as chemokine (C-X-C motif) ligand 4 (CXCL4), is a specific protein synthesized from platelet α particles. The combination of PF4 and heparin to form antigenic complexes is an important mechanism in the pathogenesis of heparin-induced thrombocytopenia (HIT), but vaccine-induced immune thrombotic thrombocytopenia (VITT) related to the COVID-19 vaccine makes PF4 a research hotspot again. Similar to HIT, vaccines, bacteria, and other non-heparin exposure, PF4 can interact with negatively charged polyanions to form immune complexes and participate in thrombosis. These anions include cell surface mucopolysaccharides, platelet polyphosphates, DNA from endothelial cells, or von Willebrand factor (VWF). Among them, PF4–VWF, as a new immune complex, may induce and promote the formation of immune-associated thrombosis and is expected to become a new target and therapeutic direction. For both HIT and VITT, there is no effective and targeted treatment except discontinuation of suspected drugs. The research and development of targeted drugs based on the mechanism of action have become an unmet clinical need. Here, this study systematically reviewed the characteristics and pathophysiological mechanisms of PF4 and VWF, elaborated the potential mechanism of action of PF4–VWF complex in immune-associated thrombosis, summarized the current status of new drug research and development for PF4 and VWF, and discussed the possibility of this complex as a potential biomarker for early immune-associated thrombosis events. Moreover, the key points of basic research and clinical evaluation are put forward in the study.

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Section: Potential Role Of the Pf4-vwf Complex In Immune-associated T...mentioning

confidence: 77%

New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF

et al. 2023

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“…We have recently shown that PF4 levels in plasma are positively correlated with current severity of bleeding phenotype in VWD type 1 patients [52]. PF4 is a chemokine that is mainly produced by megakaryocytes and stored in platelet alpha-granules, which means that systemic PF4 levels are reflective of platelet degranulation.…”

Section: Discussionmentioning

confidence: 99%

Quantitative super-resolution imaging of platelet degranulation reveals differential release of VWF and VWF propeptide from alpha-granules

Swinkels

Hordijk

Bürgisser

et al. 2022

Preprint

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Background:Platelet alpha-granules contain Von Willebrand factor (VWF), which is stored in eccentric alpha-granule nanodomains, and VWF propeptide (VWFpp). Differential release of VWF and VWFpp has been reported from endothelial cells. It is unclear if this also occurs during platelet alpha-granule exocytosis. We have recently developed a 3D super-resolution imaging workflow for quantification of platelet alpha-granule content based on Structured Illumination Microscopy (SIM). With this we can study alpha-granule cargo release following platelet activation in hundreds of platelets simultaneously.Aims:To study release of VWF and VWFpp from alpha-granules using quantitative super-resolution microscopy.Methods:Platelets were activated with PAR-1 activating peptide (PAR-1 ap) or collagen-related peptide (CRP-XL). Alpha-tubulin, VWF, VWFpp, SPARC and fibrinogen were imaged using 3D-SIM, followed by semi-automated analysis in FIJI. Uptake of anti-VWF nanobody during degranulation was used to identify alpha-granules that partially released content.Results:VWF+ and VWFpp+ structures overlapped nearly completely (~90%) in resting platelets, implying they are stored in similar eccentric alpha-granule nanodomains. A subset of VWF+/VWFpp+-structures was released completely at 0.6 μM PAR-1-ap, but at higher concentration (20 μM) significantly more VWFpp (85.3±1.6%) was released than VWF (37.6±1.4%). Release of other cargo was intermediate at 20 μM (SPARC: 62.2±1.4% ; fibrinogen: 51.9±2.9%), providing further evidence for differential cargo release. Similar results were obtained using CRP-XL. Anti-VWF nanobody was taken up by VWF+/VWFpp- structures and increased with stimulus strength, demonstrating these were post-exocytotic structures.Conclusions:VWF and VWFpp are differentially released from alpha-granules. This may affect how platelet-derived VWF and VWFpp contribute to formation and stabilization of hemostatic clots.

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Quantitative super-resolution imaging of platelet degranulation reveals differential release of von Willebrand factor and von Willebrand factor propeptide from alpha-granules

Swinkels¹,

Hordijk²,

Bürgisser³

et al. 2023

Journal of Thrombosis and Haemostasis

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Platelet degranulation and bleeding phenotype in a large cohort of Von Willebrand disease patients

Cited by 3 publications

References 15 publications

New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF

New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF

Quantitative super-resolution imaging of platelet degranulation reveals differential release of VWF and VWF propeptide from alpha-granules

Quantitative super-resolution imaging of platelet degranulation reveals differential release of von Willebrand factor and von Willebrand factor propeptide from alpha-granules

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