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Dynamics of von Willebrand factor reactivity in sickle cell disease during vaso-occlusive crisis and steady state.

Abstract

Essentials The role of von Willebrand Factor (VWF) in the pathophysiology of sickle cell disease is unclear. We assessed markers of VWF during admission for vaso-occlusive crisis (VOC) and steady state. VWF reactivity was higher during VOC and was associated with inflammation and neutrophil activation. Hyper-adhesive VWF may promote VOC in sickle cell disease.

SUMMARY

Background Endothelial activation plays a central role in the pathophysiology of vaso-occlusion in sickle cell disease (SCD), facilitating adhesive interactions with circulating blood cells. Upon activation, various adhesive molecules are expressed, including von Willebrand factor (VWF). Increased VWF levels have been observed in patients with SCD during steady state. However, the role of VWF in the pathogenesis of SCD vaso-occlusion is unclear. Objectives To longitudinally assess the quantity and reactivity of VWF and its regulating protease ADAMTS-13 during vaso-occlusive crisis (VOC). Methods In this observational study, we obtained sequential blood samples in adult SCD patients during VOC. Results VWF reactivity was significantly higher during VOC (active VWF, VWF glycoprotein Ib-binding activity, and high molecular weight multimers), whereas platelet count and levels of ADAMTS-13 antigen and ADAMTS-13 activity were concomitantly lower than during steady state. Levels of VWF antigen, VWF propeptide (VWF:pp) and ADAMTS-13 specific activity did not change during VOC. VWF reactivity correlated strongly with markers of inflammation and neutrophil activation, and was inversely correlated with the platelet count. In patients who developed acute chest syndrome, levels of VWF, VWF:pp and active, hyperadhesive VWF were significantly higher, whereas ADAMTS-13 activity was lower, than in patients without this complication. Conclusions We provide the first evidence that VOC in SCD is associated with increased reactivity of VWF, without a pronounced ADAMTS-13 deficiency. This hyper-reactivity may be explained by resistance of VWF to proteolysis, secondary to processes such as inflammation and oxidative stress. Hyperadhesive VWF, scavenging blood cells in the microcirculation, may thereby amplify and sustain VOC in SCD.

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  • Authors+Show Affiliations

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    Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

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    Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

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    Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

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    Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

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    Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

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    Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

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    Department of Internal Medicine, Slotervaart Hospital, Amsterdam, the Netherlands.

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    Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

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    Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.

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    Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Department of Plasma Proteins, Sanquin Research, Amsterdam, the Netherlands.

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    Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

    Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Department of Plasma Proteins, Sanquin Research, Amsterdam, the Netherlands.

    Source

    MeSH

    ADAMTS13 Protein
    Acute Disease
    Adult
    Anemia, Sickle Cell
    Cell Adhesion
    Endothelial Cells
    Female
    Humans
    Inflammation
    Male
    Microcirculation
    Neutrophils
    Oxidative Stress
    Pain
    Prospective Studies
    Vascular Diseases
    Young Adult
    von Willebrand Factor

    Pub Type(s)

    Journal Article
    Observational Study
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    28457019

    Citation

    Sins, J W R., et al. "Dynamics of Von Willebrand Factor Reactivity in Sickle Cell Disease During Vaso-occlusive Crisis and Steady State." Journal of Thrombosis and Haemostasis : JTH, vol. 15, no. 7, 2017, pp. 1392-1402.
    Sins JWR, Schimmel M, Luken BM, et al. Dynamics of von Willebrand factor reactivity in sickle cell disease during vaso-occlusive crisis and steady state. J Thromb Haemost. 2017;15(7):1392-1402.
    Sins, J. W. R., Schimmel, M., Luken, B. M., Nur, E., Zeerleder, S. S., van Tuijn, C. F. J., ... Fijnvandraat, K. (2017). Dynamics of von Willebrand factor reactivity in sickle cell disease during vaso-occlusive crisis and steady state. Journal of Thrombosis and Haemostasis : JTH, 15(7), pp. 1392-1402. doi:10.1111/jth.13728.
    Sins JWR, et al. Dynamics of Von Willebrand Factor Reactivity in Sickle Cell Disease During Vaso-occlusive Crisis and Steady State. J Thromb Haemost. 2017;15(7):1392-1402. PubMed PMID: 28457019.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Dynamics of von Willebrand factor reactivity in sickle cell disease during vaso-occlusive crisis and steady state. AU - Sins,J W R, AU - Schimmel,M, AU - Luken,B M, AU - Nur,E, AU - Zeerleder,S S, AU - van Tuijn,C F J, AU - Brandjes,D P M, AU - Kopatz,W F, AU - Urbanus,R T, AU - Meijers,J C M, AU - Biemond,B J, AU - Fijnvandraat,K, Y1 - 2017/06/05/ PY - 2017/01/27/received PY - 2017/5/1/pubmed PY - 2018/5/19/medline PY - 2017/5/1/entrez KW - cell adhesion KW - inflammation KW - sickle cell disease KW - vascular endothelium KW - von Willebrand factor SP - 1392 EP - 1402 JF - Journal of thrombosis and haemostasis : JTH JO - J. Thromb. Haemost. VL - 15 IS - 7 N2 - : Essentials The role of von Willebrand Factor (VWF) in the pathophysiology of sickle cell disease is unclear. We assessed markers of VWF during admission for vaso-occlusive crisis (VOC) and steady state. VWF reactivity was higher during VOC and was associated with inflammation and neutrophil activation. Hyper-adhesive VWF may promote VOC in sickle cell disease. SUMMARY: Background Endothelial activation plays a central role in the pathophysiology of vaso-occlusion in sickle cell disease (SCD), facilitating adhesive interactions with circulating blood cells. Upon activation, various adhesive molecules are expressed, including von Willebrand factor (VWF). Increased VWF levels have been observed in patients with SCD during steady state. However, the role of VWF in the pathogenesis of SCD vaso-occlusion is unclear. Objectives To longitudinally assess the quantity and reactivity of VWF and its regulating protease ADAMTS-13 during vaso-occlusive crisis (VOC). Methods In this observational study, we obtained sequential blood samples in adult SCD patients during VOC. Results VWF reactivity was significantly higher during VOC (active VWF, VWF glycoprotein Ib-binding activity, and high molecular weight multimers), whereas platelet count and levels of ADAMTS-13 antigen and ADAMTS-13 activity were concomitantly lower than during steady state. Levels of VWF antigen, VWF propeptide (VWF:pp) and ADAMTS-13 specific activity did not change during VOC. VWF reactivity correlated strongly with markers of inflammation and neutrophil activation, and was inversely correlated with the platelet count. In patients who developed acute chest syndrome, levels of VWF, VWF:pp and active, hyperadhesive VWF were significantly higher, whereas ADAMTS-13 activity was lower, than in patients without this complication. Conclusions We provide the first evidence that VOC in SCD is associated with increased reactivity of VWF, without a pronounced ADAMTS-13 deficiency. This hyper-reactivity may be explained by resistance of VWF to proteolysis, secondary to processes such as inflammation and oxidative stress. Hyperadhesive VWF, scavenging blood cells in the microcirculation, may thereby amplify and sustain VOC in SCD. SN - 1538-7836 UR - https://www.unboundmedicine.com/medline/citation/28457019/Dynamics_of_von_Willebrand_factor_reactivity_in_sickle_cell_disease_during_vaso_occlusive_crisis_and_steady_state_ L2 - https://doi.org/10.1111/jth.13728 DB - PRIME DP - Unbound Medicine ER -