Polyphosphate nanoparticles on the platelet surface trigger contact system activation

Verhoef, J.; Barendrecht, Arjan D.; Nickel, Katrin F.; Dijkxhoorn, Kim; Kenne, Ellinor; Labberton, Linda; McCarty, Owen J. T.; Schiffelers, Raymond M.; Heijnen, Harry F. G.; Hendrickx, Antoni P. A.; Schellekens, Huub; Fens, Marcel H.A.M.; Maat, Steven de; Renné, Thomas; Maas, Coen

doi:10.1182/blood-2016-08-734988

Cited by 120 publications

(159 citation statements)

References 46 publications

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“…Although a recent study reported that platelet polyP can potently activate the contact pathway, that study used silica‐based methods for isolating polyP, which we have now shown can result in contamination with highly procoagulant silica particles . Furthermore, decades of studies have shown that activated platelets only very weakly activate the contact pathway of clotting …”

Section: Discussionmentioning

confidence: 90%

Polyphosphate, Zn2+ and high molecular weight kininogen modulate individual reactions of the contact pathway of blood clotting

Wang

Ivanov

Smith

et al. 2019

Journal of Thrombosis and Haemostasis

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Background: Inorganic polyphosphate modulates the contact pathway of blood clotting, which is implicated in thrombosis and inflammation. Polyphosphate polymer lengths are highly variable, with shorter polymers (approximately 60–100 phosphates) secreted from human platelets, and longer polymers (up to thousands of phosphates) in microbes. We previously reported that optimal triggering of clotting via the contact pathway requires very long polyphosphates, although the impact of shorter polyphosphate polymers on individual proteolytic reactions of the contact pathway was not interrogated. Objectives and methods: We conducted in vitro measurements of enzyme kinetics to investigate the ability of varying polyphosphate sizes, together with high molecular weight kininogen and Zn2+, to mediate four individual proteolytic reactions of the contact pathway: factor XII autoactivation, factor XII activation by kallikrein, prekallikrein activation by factor XIIa, and prekallikrein autoactivation. Results: The individual contact pathway reactions were differentially dependent on polyphosphate length. Very long-chain polyphosphate was required to support factor XII autoactivation, whereas platelet-size polyphosphate significantly accelerated the activation of factor XII by kallikrein, and the activation of prekallikrein by factor XIIa. Intriguingly, polyphosphate did not support prekallikrein autoactivation. We also report that high molecular weight kininogen was required only when kallikrein was the enzyme (ie, FXII activation by kallikrein), whereas Zn2+ was required only when FXII was the substrate (ie, FXII activation by either kallikrein or FXIIa). Activation of prekallikrein by FXIIa required neither Zn2+ nor high molecular weight kininogen. Conclusions: Platelet polyphosphate and Zn2+ can promote subsets of the reactions of the contact pathway, with implications for a variety of disease states.

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Section: Discussionmentioning

confidence: 90%

Polyphosphate, Zn2+ and high molecular weight kininogen modulate individual reactions of the contact pathway of blood clotting

Wang

Ivanov

Smith

et al. 2019

Journal of Thrombosis and Haemostasis

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“…Divalent metal ions such as calcium are abundant in platelet dense granules, suggesting that intracellular complexes might form. We recently confirmed that platelets contain and release particles of concentrated polyphosphate . Further investigation is needed to determine whether polyphosphate‐triggered contact activation contributes to physiological hemostasis.…”

Section: The Confusing Roles Of Contact Activation In Hemostasismentioning

confidence: 85%

“…Polyphosphate polymers are carried by and released by platelets and mast cells . These can trigger contact system activation through FXII.…”

Section: The Confusing Roles Of Contact Activation In Hemostasismentioning

confidence: 99%

Hereditary angioedema: the plasma contact system out of control

Maat

Hofman

Maas

2018

Journal of Thrombosis and Haemostasis

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The plasma contact system contributes to thrombosis in experimental models. Even though our standard blood coagulation tests are prolonged when plasma lacks contact factors, this enzyme system appears to have a minor (if any) role in hemostasis. In this review, we explore the clinical phenotype of C1 esterase inhibitor (C1-INH) deficiency. C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE). This inflammatory disorder is characterized by recurrent aggressive attacks of tissue swelling that occur at unpredictable locations throughout the body. Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE. Surprisingly, there is little evidence for thrombotic events in HAE patients, suggesting mechanistic uncoupling from the intrinsic pathway of coagulation. In addition, it is questionable whether a surface is responsible for contact system activation in HAE. In this review, we discuss the clinical phenotype, disease modifiers and diagnostic challenges of HAE. We subsequently describe the underlying biochemical mechanisms and contributing disease mediators. Furthermore, we review three types of HAE that are not caused by C1-INH inhibitor deficiency. Finally, we propose a central enzymatic axis that we hypothesize to be responsible for bradykinin production in health and disease.

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“…While histamine is primarily released from mast cells or basophils, the contact system is always present in circulation. Contact system activation is not only limited to excretion of mast cell‐released heparin but can also be triggered by, among others, platelet polyphosphate, activation of the endothelium and neutrophil extracellular traps …”

Section: Introductionmentioning

confidence: 99%

Evidence for bradykinin release in chronic spontaneous urticaria

Hofman

Elzen

Kuijpers

et al. 2020

Clin Experimental Allergy

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Background Chronic spontaneous urticaria (CSU) is characterized by recurrent itchy weals and/or angioedema and is believed to be driven by mast cell activation. It was shown that excessive mast cell activation during anaphylaxis initiates contact activation, resulting in bradykinin release. Evidence for bradykinin release was never demonstrated in CSU. Objective To study biomarkers of bradykinin release in CSU. Methods Plasma samples of CSU patients were collected during routine visits at the outpatient clinic. Cleaved high molecular weight kininogen (cHK) was used as a biomarker for bradykinin release. cHK, factor XIIa‐C1‐inhibitor (FXIIa‐C1‐INH), kallikrein‐C1‐INH, plasmin‐antiplasmin (PAP) complexes and soluble urokinase‐type plasminogen activator receptor (suPAR) levels were determined by ELISA. Clinical data and data on tryptase levels were collected from medical records. cHK levels were compared to previously determined levels in hereditary angioedema (HAE). Results One hundred seventeen samples from 88 CSU patients and 28 samples from healthy controls were analysed. Median cHK level in CSU was 9.1% (range: 1.4%‐21.5%), significantly increased compared to healthy controls (median 6.0% range: 0%‐19.9%; P = .0005) and comparable to HAE (n = 46, median 10.3%, range 0%‐44.3%, P > .9999). cHK levels normalized in patients during disease remission (median 6.5% range 1.5%‐20.8%) but were not dependent on the presence of angioedema, acute angioedema attacks or response to antihistamines. Surprisingly, cHK levels were inversely correlated to serum tryptase (r = −0.65 P = .0137). C1‐INH complexes and suPAR levels were not elevated in patients compared to healthy controls. PAP‐complex levels in patients were elevated compared to healthy controls but there was no correlation between PAP‐complex and cHK levels. Conclusions cHK levels are elevated in symptomatic CSU patients compared to healthy controls, indicating increased bradykinin production. Increased cHK levels are not limited to patients with angioedema. Clinical relevance If elevated bradykinin generation has clinical implications in the pathology of CSU is open to debate.

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Polyphosphate nanoparticles on the platelet surface trigger contact system activation

Cited by 120 publications

References 46 publications

Polyphosphate, Zn2+ and high molecular weight kininogen modulate individual reactions of the contact pathway of blood clotting

Polyphosphate, Zn2+ and high molecular weight kininogen modulate individual reactions of the contact pathway of blood clotting

Hereditary angioedema: the plasma contact system out of control

Evidence for bradykinin release in chronic spontaneous urticaria

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