Plasma levels of plasminogen activator inhibitor‐1 and bleeding phenotype in patients with von Willebrand disease

Abdul, Shiraazkhan; Boender, Johan; Eikenboom, Jeroen; Draat, Karin Fijn van; Mauser‐Bunschoten, Eveline P.; Meijer, Karina; Meris, Joke de; Gorkom, Britta A P Laros-van; Bom, Johanna G. van der; Leebeek, Frank W.G.; Rijken, D.C.; Willige, Shirley Uitte de

doi:10.1111/hae.13206

Cited by 6 publications

(4 citation statements)

References 22 publications

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“…In this substudy, we used different classification criteria than in previous projects in the WiN study. While using the most contemporary criteria makes for a better extrapolation of our data, caution should be used when comparing our results with previous reports from the WiN study, especially those on the association between fibrinolysis and bleeding 27,28 . We have previously shown that the requirement of VWF propeptide levels <5 U/dL in addition to low VWF antigen and activity levels improves the classification of type 3 VWD 11 …”

Section: Discussionmentioning

confidence: 62%

ADAMTS‐13 and bleeding phenotype in von Willebrand disease

Boender

Nederlof

Meijer

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Background The bleeding phenotype of von Willebrand disease (VWD) varies highly between patients and can only partly be explained by von Willebrand factor (VWF) parameters. By cleaving large VWF multimers into smaller, less active multimers, ADAMTS‐13 is an important regulator of VWF activity. However, it is unknown what the role of ADAMTS‐13 is in individuals with VWD. Objectives We therefore studied how ADAMTS‐13 activity is associated with the laboratory and bleeding phenotype in individuals with VWD. Methods We measured ADAMTS‐13 activity using the fluorescence resonance energy transfer substrate VWF 73 assay in 638 individuals with VWD in the nationwide cross‐sectional Willebrand in the Netherlands study and in 36 healthy controls. The bleeding phenotype was assessed using the Tosetto bleeding score. Results ADAMTS‐13 activity was similar in individuals with VWD (109% ± 20.6%) and controls (110% ± 19.7%). ADAMTS‐13 activity was higher in individuals with VWD with type 3 than those with type 1 (mean difference, 11.8%; 95% confidence interval [CI], 2.9%‐20.8%) or type 2 (mean difference, 16.1%; 95% CI, 7.1%‐25.1%). ADAMTS‐13 activity was not associated with the Tosetto bleeding score (0.1 Tosetto bleeding score increase per 10% ADAMTS‐13 increase, 95% CI, −0.2 to 0.3). Furthermore, ADAMTS‐13 activity did not differ between individuals with and without a bleeding event during the year preceding blood sampling (mean difference, 1.4%; 95% CI, −2.1% to 4.9%). Conclusion ADAMTS‐13 activity was highest in individuals with type 3 VWD, but it had only minor associations with VWF parameters. ADAMTS‐13 activity does not influence the bleeding phenotype in individuals with VWD.

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Section: Discussionmentioning

confidence: 62%

ADAMTS‐13 and bleeding phenotype in von Willebrand disease

Boender

Nederlof

Meijer

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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“…In addition, the potential role for variation in hemostatic pathways intertwined with thrombin generation, such as fibrinolysis, to nudge hemostasis either toward or away from balance, is increasingly apparent. Age to begin prophylactic factor replacement 22,24 Differences in severity between HA and HB 25,26 Null versus non-null mutation 11,32,34 Co-inheritance of a prothrombotic mutation 8,[39][40][41][42][43] Interindividual differences in fibrinolysis 67,73,76 Interindividual differences in cellular function 80,85 Heterogeneity in response to gene therapy 93,95 Abbreviations: HA, hemophilia A; HB, hemophilia B; PWH, people with hemophilia.…”

Section: Resultsmentioning

confidence: 99%

“…The balance between tPA and PAI-1 levels in PWH is not well characterized, but it is conceivable that the regulatory relationship between these two components may become destabilized during a bleeding event. The role of PAI-1 in PWH remains unclear, but it has been shown in VWD that low levels of PAI-1 are associated with an increase in severity of clinical bleeding phenotype 67 and it remains to be determined whether this is also the case in PWH. α 2 -AP deficiency results in accelerated fibrinolysis and excessive bleeding 68 ; however, whether α 2 -AP levels vary between individual PWH has yet to be fully investigated.…”

Section: Interindividual Differences In Fibrinolytic Activity As a Pomentioning

confidence: 99%

Heterogeneity in Bleeding Tendency and Arthropathy Development in Individuals with Hemophilia

Rehill

McCluskey

O’Donnell

et al. 2021

Semin Thromb Hemost

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People with hemophilia (PWH) have an increased tendency to bleed, often into their joints, causing debilitating joint disease if left untreated. To reduce the incidence of bleeding events, PWH receive prophylactic replacement therapy with recombinant factor VIII (FVIII) or FIX. Bleeding events in PWH are typically proportional to their plasma FVIII or IX levels; however, in many PWH, bleeding tendency and the likelihood of developing arthropathy often varies independently of endogenous factor levels. Consequently, many PWH suffer repeated bleeding events before correct dosing of replacement factor can be established. Diagnostic approaches to define an individual's bleeding tendency remain limited. Multiple modulators of bleeding phenotype in PWH have been proposed, including the type of disease-causing variant, age of onset of bleeding episodes, plasma modifiers of blood coagulation or clot fibrinolysis pathway activity, interindividual differences in platelet reactivity, and endothelial anticoagulant activity. In this review, we summarize current knowledge of established factors modulating bleeding tendency and discuss emerging concepts of additional biological elements that may contribute to variable bleeding tendency in PWH. Finally, we consider how variance in responses to new gene therapies may also necessitate consideration of patient-specific tailoring of treatment. Cumulatively, these studies highlight the need to reconsider the current “one size fits all” approach to treatment regimens for PWH and consider therapies guided by the bleeding phenotype of each individual PWH at the onset of therapy. Further characterization of the biological bases of bleeding heterogeneity in PWH, combined with the development of novel diagnostic assays to identify those factors that modulate bleeding risk in PWH, will be required to meet these aspirations.

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“…This suggests that the severe bleeding problems of FXIII-deficient patients are not primarily caused by enhanced clot lysis, but by impaired (physical) stability of the clots due to insufficient formation of γ chain dimers and possibly α chain polymers. Enhanced fibrinolysis could contribute, however, to the severity of the bleeding tendency, as recently observed in a subpopulation of patients with von Willebrand disease [54]. …”

Section: (Patho)physiologic Aspectsmentioning

confidence: 99%

Inhibition of Fibrinolysis by Coagulation Factor XIII

Rijken

Willige

2017

BioMed Research International

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The inhibitory effect of coagulation factor XIII (FXIII) on fibrinolysis has been studied for at least 50 years. Our insight into the underlying mechanisms has improved considerably, aided in particular by the discovery that activated FXIII cross-links α2-antiplasmin (α2AP) to fibrin. In this review, the most important effects of different cross-linking reactions on fibrinolysis are summarized. A distinction is made between fibrin-fibrin cross-links studied in purified systems and fibrin-α2AP cross-links studied in plasma or whole blood systems. While the formation of γ chain dimers in fibrin does not affect clot lysis, the formation of α chain polymers has a weak inhibitory effect. Only strong cross-linking of fibrin, associated with high molecular weight α chain polymers and/or γ chain multimers, results in a moderate inhibition fibrinolysis. The formation of fibrin-α2AP cross-links has only a weak effect on clot lysis, but this effect becomes strong when clot retraction occurs. Under these conditions, FXIII prevents α2AP being expelled from the clot and makes the clot relatively resistant to degradation by plasmin.

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Plasma levels of plasminogen activator inhibitor‐1 and bleeding phenotype in patients with von Willebrand disease

Abstract: In young female VWD patients, we observed that low PAI-1 levels were associated with a higher bleeding score, which may partly explain the observed variability in bleeding phenotype in VWD patients.

Cited by 6 publications

References 22 publications

ADAMTS‐13 and bleeding phenotype in von Willebrand disease

ADAMTS‐13 and bleeding phenotype in von Willebrand disease

Heterogeneity in Bleeding Tendency and Arthropathy Development in Individuals with Hemophilia

Inhibition of Fibrinolysis by Coagulation Factor XIII

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