Publications by authors named "Coen Maas"

68 Publications

Caging the dragon: Research approach to COVID-19-related thrombosis.

Res Pract Thromb Haemost 2021 Feb 8;5(2):278-290. Epub 2021 Mar 8.

Dept of Pulmonary Medicine Amsterdam Cardiovascular Sciences Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands.

The incidence of venous thrombosis, mostly pulmonary embolism (PE), ranging from local immunothrombosis to central emboli, but also deep vein thrombosis (DVT) in people with coronavirus disease 2019 (COVID-19) is reported to be remarkably high. The relevance of better understanding, predicting, treating, and preventing COVID-19-associated venous thrombosis meets broad support, as can be concluded from the high number of research, review, and guideline papers that have been published on this topic. The Dutch COVID & Thrombosis Coalition (DCTC) is a multidisciplinary team involving a large number of Dutch experts in the broad area of venous thrombosis and hemostasis research, combined with experts on virology, critically ill patients, pulmonary diseases, and community medicine, across all university hospitals and many community hospitals in the Netherlands. Within the consortium, clinical data of at least 5000 admitted COVID-19-infected individuals are available, including substantial collections of biobanked materials in an estimated 3000 people. In addition to considerable experience in preclinical and clinical thrombosis research, the consortium embeds virology-hemostasis research models within unique biosafety facilities to address fundamental questions on the interaction of virus with epithelial and vascular cells, in relation to the coagulation and inflammatory system. The DCTC has initiated a comprehensive research program to answer many of the current questions on the pathophysiology and best anticoagulant treatment of COVID-19-associated thrombotic complications. The research program was funded by grants of the Netherlands Thrombosis Foundation and the Netherlands Organization for Health Research and Development. Here, we summarize the design and main aims of the research program.
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http://dx.doi.org/10.1002/rth2.12470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938618PMC
February 2021

Dysregulated innate and adaptive immune responses discriminate disease severity in COVID-19.

J Infect Dis 2021 Feb 1. Epub 2021 Feb 1.

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, The Netherlands.

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive pro-inflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis reveals no specific inflammatory endotypes in COVID-19 patients. Functional assays reveal abrogated adaptive cytokine production (interferon-gamma, interleukin-17 and interleukin-22) and prominent T cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlight potential biomarkers of disease severity.
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http://dx.doi.org/10.1093/infdis/jiab065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928798PMC
February 2021

Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate.

Blood 2021 Mar;137(10):1392-1405

Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Polyphosphate is a procoagulant inorganic polymer of linear-linked orthophosphate residues. Multiple investigations have established the importance of platelet polyphosphate in blood coagulation; however, the mechanistic details of polyphosphate homeostasis in mammalian species remain largely undefined. In this study, xenotropic and polytropic retrovirus receptor 1 (XPR1) regulated polyphosphate in platelets and was implicated in thrombosis in vivo. We used bioinformatic analyses of omics data to identify XPR1 as a major phosphate transporter in platelets. XPR1 messenger RNA and protein expression inversely correlated with intracellular polyphosphate content and release. Pharmacological interference with XPR1 activity increased polyphosphate stores, led to enhanced platelet-driven coagulation, and amplified thrombus formation under flow via the polyphosphate/factor XII pathway. Conditional gene deletion of Xpr1 in platelets resulted in polyphosphate accumulation, accelerated arterial thrombosis, and augmented activated platelet-driven pulmonary embolism without increasing bleeding in mice. These data identify platelet XPR1 as an integral regulator of platelet polyphosphate metabolism and reveal a fundamental role for phosphate homeostasis in thrombosis.
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http://dx.doi.org/10.1182/blood.2019004617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955403PMC
March 2021

A Pathophysiological Perspective on the SARS-CoV-2 Coagulopathy.

Hemasphere 2020 Aug 10;4(4):e457. Epub 2020 Aug 10.

Van Creveldkliniek, Benign Hematology Center, University Medical Center Utrecht, Utrecht, The Netherlands.

Recent evidence is focusing on the presence of a hypercoagulable state with development of both venous and arterial thromboembolic complications in patients infected with SARS-CoV-2. The ongoing activation of coagulation related to the severity of the illness is further characterized by thrombotic microangiopathy and endotheliitis. These microangiopathic changes cannot be classified as classical disseminated intravascular coagulation (DIC). In this short review we describe the interaction between coagulation and inflammation with focus on the possible mechanisms that might be involved in SARS-CoV-2 infection associated coagulopathy in the critically ill.
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http://dx.doi.org/10.1097/HS9.0000000000000457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430228PMC
August 2020

Neutrophil fluorescence in clozapine users is attributable to a 14kDa secretable protein.

Pharmacol Res Perspect 2020 10;8(5):e00627

Department of Respiratory Medicine, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

Clozapine is the only antipsychotic agent with demonstrated efficacy in refractory schizophrenia. However, use of clozapine is hampered by its adverse effects, including potentially fatal agranulocytosis. Recently, we showed an association between neutrophil autofluorescence and clozapine use. In this study, we evaluated the subcellular localization of clozapine-associated fluorescence and tried to elucidate its source. Neutrophils of clozapine users were analyzed with fluorescence microscopy to determine the emission spectrum and localization of the fluorescence signal. Next, these neutrophils were stimulated with different degranulation agents to determine the localization of fluorescence. Lastly, isolated neutrophil lysates of clozapine users were separated by SDS-PAGE and evaluated. Clozapine-associated fluorescence ranged from 420 nm to 720 nm, peaking at 500-550 nm. Fluorescence was localized in a large number of small loci, suggesting granular localization of the signal. Neutrophil degranulation induced by Cytochalasin B/fMLF reduced fluorescence, whereas platelet-activating factor (PAF)/fMLF induced degranulation did not, indicating that the fluorescence originates from a secretable substance in azurophilic granules. SDS-PAGE of isolated neutrophil lysates revealed a fluorescent 14kDa band, suggesting that neutrophil fluorescence is likely to be originated from a 14kDa protein/peptide fragment. We conclude that clozapine-associated fluorescence in neutrophils is originating from a 14kDa soluble protein (fragment) present in azurophilic granules of neutrophils. This protein could be an autofluorescent protein already present in the cell and upregulated by clozapine, or a protein altered by clozapine to express fluorescence. Future studies should further explore the identity of this protein and its potential role in the pathophysiology of clozapine-induced agranulocytosis.
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http://dx.doi.org/10.1002/prp2.627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437349PMC
October 2020

Influenza-induced thrombocytopenia is dependent on the subtype and sialoglycan receptor and increases with virus pathogenicity.

Blood Adv 2020 07;4(13):2967-2978

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

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.
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http://dx.doi.org/10.1182/bloodadvances.2020001640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362372PMC
July 2020

Impaired Breakdown of Bradykinin and Its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection.

Semin Thromb Hemost 2020 10 11;46(7):835-837. Epub 2020 Jun 11.

CDL Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

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http://dx.doi.org/10.1055/s-0040-1712960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645818PMC
October 2020

Patterns of C1-Inhibitor/Plasma Serine Protease Complexes in Healthy Humans and in Hereditary Angioedema Patients.

Front Immunol 2020 5;11:794. Epub 2020 May 5.

Research Laboratory, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.

C1-inhibitor (C1-INH) is an important regulator of the complement, coagulation, fibrinolytic and contact systems. The quantity of protease/C1-INH complexes in the blood is proportional to the level of the activation of these four cascade-like plasma enzyme systems. Parallel determination of C1-INH-containing activation complexes could be important to understand the regulatory role of C1-INH in diseases such as hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE). We developed in-house ELISAs to measure the concentration of complexes of C1-INH formed with active proteases: C1r, C1s, MASP-1, MASP-2, plasma kallikrein, factor XIIa, factor XIa, and thrombin, as well as to determine total and functionally active C1-INH. We measured the concentration of the complexes in EDTA plasma from 6 healthy controls, from 5 with type I and 5 with type II C1-INH-HAE patients during symptom-free periods and from five patients during HAE attacks. We also assessed the concentration of these complexes in blood samples taken from one C1-INH-HAE patient during the kinetic follow-up of a HAE attack. The overall pattern of complexed C1-INH was similar in controls and C1-INH-HAE patients. C1-INH formed the highest concentration complexes with C1r and C1s. We observed higher plasma kallikrein/C1-INH complex concentration in both type I and type II C1-INH-HAE, and higher concentration of MASP-1/C1-INH, and MASP-2/C1-INH complexes in type II C1-INH-HAE patients compared to healthy controls and type I patients. Interestingly, none of the C1-INH complex concentrations changed significantly during HAE attacks. During the kinetic follow-up of an HAE attack, the concentration of plasma kallikrein/C1-INH complex was elevated at the onset of the attack. In parallel, C1r, FXIIa and FXIa complexes of C1-INH also tended to be elevated, and the changes in the concentrations of the complexes followed rather rapid kinetics. Our results suggest that the complement classical pathway plays a critical role in the metabolism of C1-INH, however, in C1-INH-HAE, contact system activation is the most significant in this respect. Due to the fast changes in the concentration of complexes, high resolution kinetic follow-up studies are needed to clarify the precise molecular background of C1-INH-HAE pathogenesis.
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http://dx.doi.org/10.3389/fimmu.2020.00794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214733PMC
March 2021

Detecting oral kallikrein-targeting therapy through triggered contact activation: A phase I study.

J Allergy Clin Immunol 2020 12 29;146(6):1446-1449.e5. Epub 2020 Apr 29.

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.03.038DOI Listing
December 2020

The Fibronectin Type II Domain of Factor XII Ensures Zymogen Quiescence.

Thromb Haemost 2020 Mar 15;120(3):400-411. Epub 2020 Jan 15.

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Factor XII (FXII) zymogen activation requires cleavage after arginine 353 located in the activation loop. This cleavage can be executed by activated FXII (autoactivation), plasma kallikrein (PKa), or plasmin. Previous studies proposed that the activation loop of FXII is shielded to regulate FXII activation and subsequent contact activation. In this study, we aimed to elucidate this mechanism by expressing and characterizing seven consecutive N-terminally truncated FXII variants as well as full-length wild-type (WT) FXII. As soon as the fibronectin type II domain is lacking (FXII Δ1-71), FXII cleavage products appear on Western blot. These fragments display spontaneous amidolytic activity, indicating that FXII without the fibronectin type II domain is susceptible to autoactivation. Additionally, truncated FXII Δ1-71 is more easily activated by PKa or plasmin than full-length WT FXII. To exclude a contribution of autoactivation, we expressed active-site incapacitated FXII truncation variants (S544A). FXII S544A Δ1-71 is highly susceptible to cleavage by PKa, indicating exposure of the activation loop. In surface binding experiments, we found that the fibronectin type II domain is non-essential for binding to kaolin or polyphosphate, whereas the following epidermal growth factor-like domain is indispensable. Binding of full-length FXII S544A to kaolin or polyphosphate increases its susceptibility to cleavage by PKa. Moreover, the activation of full-length WT FXII by PKa increases approximately threefold in the presence of kaolin. Deletion of the fibronectin type II domain eliminates this effect. Combined, these findings suggest that the fibronectin type II domain shields the activation loop of FXII, ensuring zymogen quiescence.
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http://dx.doi.org/10.1055/s-0039-3402760DOI Listing
March 2020

Cold-induced urticarial autoinflammatory syndrome related to factor XII activation.

Nat Commun 2020 01 10;11(1):179. Epub 2020 Jan 10.

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Hereditary autoinflammatory diseases are caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). Here, we report a four-generation family with cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identify a substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Functional analysis reveals enhanced autocatalytic cleavage of the mutated protein and spontaneous FXII activation in patient plasma and in supernatant of transfected HEK293 cells expressing recombinant W268R-mutated proteins. Furthermore, we observe reduced plasma prekallikrein, cleaved high molecular weight kininogen and elevated plasma bradykinin. Neutrophils are identified as a local source of FXII. Interleukin-1β (IL-1β) is upregulated in lesional skin and mononuclear donor cells exposed to recombinant mutant proteins. Treatment with icatibant (bradykinin-B2-antagonist) or anakinra (interleukin-1-antagonist) reduces disease activity in patients. In conclusion, our findings provide a link between contact system activation and cytokine-mediated inflammation.
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http://dx.doi.org/10.1038/s41467-019-13984-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954242PMC
January 2020

Evidence for bradykinin release in chronic spontaneous urticaria.

Clin Exp Allergy 2020 03 21;50(3):343-351. Epub 2020 Jan 21.

Laboratory of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

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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http://dx.doi.org/10.1111/cea.13558DOI Listing
March 2020

Heparin Forms Polymers with Cell-free DNA Which Elongate Under Shear in Flowing Blood.

Sci Rep 2019 12 4;9(1):18316. Epub 2019 Dec 4.

Department of Clinical Chemistry & Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Heparin is a widely used anticoagulant which inhibits factor Xa and thrombin through potentiation of antithrombin. We recently identified that the nucleic acid stain SYTOX reacts with platelet polyphosphate due to molecular similarities, some of which are shared by heparin. We attempted to study heparin in flowing blood by live-cell fluorescence microscopy, using SYTOX for heparin visualisation. Immunostaining was performed with monoclonal antibodies directed against various heparin-binding proteins. In addition, we studied modulation of heparin activity in coagulation assays, as well its effects on fibrin formation under flow in recalcified whole blood. We found that SYTOX-positive polymers appear in heparinised blood under flow. These polymers typically associate with platelet aggregates and their length (reversibly) increases with shear rate. Immunostaining revealed that of the heparin-binding proteins assessed, they only contain histones. In coagulation assays and flow studies on fibrin formation, we found that addition of exogenous histones reverses the anticoagulant effects of heparin. Furthermore, the polymers do not appear in the presence of DNase I, heparinase I/III, or the heparin antidote protamine. These findings suggest that heparin forms polymeric complexes with cell-free DNA in whole blood through a currently unidentified mechanism.
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http://dx.doi.org/10.1038/s41598-019-54818-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892814PMC
December 2019

A mutation in the kringle domain of human factor XII that causes autoinflammation, disturbs zymogen quiescence, and accelerates activation.

J Biol Chem 2020 01 26;295(2):363-374. Epub 2019 Nov 26.

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands. Electronic address:

Coagulation factor XII (FXII) drives production of the inflammatory peptide bradykinin. Pathological mutations in the gene, which encodes FXII, provoke acute tissue swelling in hereditary angioedema (HAE). Interestingly, a recently identified mutation, causing a W268R substitution, is not associated with HAE. Instead, FXII-W268R carriers experience cold-inducible urticarial rash, arthralgia, fever, and fatigue. Here, we aimed to investigate the molecular characteristics of the FXII-W268R variant. We expressed wild type FXII (FXII-WT), FXII-W268R, and FXII-T309R (which causes HAE), as well as other FXII variants in HEK293 freestyle cells. Using chromogenic substrate assays, immunoblotting, and ELISA, we analyzed expression media, cell lysates, and purified proteins for FXII activation. Recombinant FXII-W268R forms increased amounts of intracellular cleavage products that are also present in expression medium and display enzymatic activity. The active site-incapacitated variant FXII-W268R/S544A reveals that intracellular fragmentation is largely dependent on autoactivation. Purified FXII-W268R is highly sensitive to activation by plasma kallikrein and plasmin, compared with FXII-WT or FXII-T309R. Furthermore, binding studies indicated that the FXII-W268R variant leads to the exposure of a plasminogen-binding site that is cryptic in FXII-WT. In plasma, recombinant FXII-W268R spontaneously triggers high-molecular-weight kininogen cleavage. Our findings suggest that the W268R substitution influences FXII protein conformation and exposure of the activation loop, which is concealed in FXII-WT. This results in intracellular autoactivation and constitutive low-grade secretion of activated FXII. These findings help to explain the chronically increased contact activation in carriers of the FXII-W268R variant.
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http://dx.doi.org/10.1074/jbc.RA119.009788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956518PMC
January 2020

A head-to-head comparison of conjugation methods for VHHs: Random maleimide-thiol coupling versus controlled click chemistry.

Int J Pharm X 2019 Dec 21;1:100020. Epub 2019 Jun 21.

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

Targeted delivery of therapeutics is an attractive strategy for vascular diseases. Recently, variable domains of heavy-chain-only antibodies (VHHs) have gained momentum as targeting ligands to achieve this. Targeting ligands need adequate conjugation to the preferred delivery platform. When choosing a conjugation method, two features are critical: a fixed and specified stoichiometry and an orientation of the conjugated targeting ligand that preserves its functional binding capacity. We here describe a comparison of popular maleimide-thiol conjugation with state-of-the-art "click chemistry" for conjugating VHHs. First, we demonstrate the modification of VHHs with azide via Sortase A mediated transpeptidation. Subsequently, optimal clicking conditions were found at a temperature of 50 °C, using a 3:1 M ratio of DBCO-PEG:VHH-azide and an incubation time of 18 h. Second, we show that stoichiometry was controllable with click chemistry and produced defined conjugates, whereas maleimide-thiol conjugation resulted in diverse reaction products. In addition, we show that all VHHs - independent of the conjugation method or conjugated residue - still specifically bind their cognate antigen. Yet, VHH's functional binding capacities after click chemistry were at least equal or better than maleimide thiol conjugates. Together these data underline that click chemistry is superior to maleimide-thiol conjugation for conjugating targeting ligands.
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http://dx.doi.org/10.1016/j.ijpx.2019.100020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733300PMC
December 2019

Plasminflammation-An Emerging Pathway to Bradykinin Production.

Authors:
Coen Maas

Front Immunol 2019 27;10:2046. Epub 2019 Aug 27.

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

Plasminogen activation is essential for fibrinolysis-the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation participates in a wide variety of inflammatory conditions. One of these conditions is hereditary angioedema (HAE), a rare disease with characteristic attacks of aggressive tissue swelling due to unregulated production and activity of the inflammatory mediator bradykinin. Plasmin was already implicated in this disease decades ago, but a series of recent discoveries have made it clear that plasmin actively contributes to this pathology. Collective evidence points toward an axis in which the plasminogen activation system and the contact system (which produces bradykinin) are mechanistically coupled. This is amongst others supported by findings in subtypes of HAE that are caused by gain-of-function mutations in the genes that respectively encode factor XII or plasminogen, as well as clinical experience with the antifibrinolytic agents in HAE. The concept of a link between plasminogen activation and the contact system helps us to explain the inflammatory side effects of fibrinolytic therapy, presenting as angioedema or tissue edema. Furthermore, these observations motivate the development and characterization of therapeutic agents that disconnect plasminogen activation from bradykinin production.
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http://dx.doi.org/10.3389/fimmu.2019.02046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719523PMC
October 2020

Nomenclature of factor XI and the contact system.

J Thromb Haemost 2019 12 13;17(12):2216-2219. Epub 2019 Aug 13.

Department of Molecular and Cellular Hemostasis, Sanquin Research, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1111/jth.14595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893083PMC
December 2019

Design and characterization of α1-antitrypsin variants for treatment of contact system-driven thromboinflammation.

Blood 2019 11;134(19):1658-1669

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

The contact system produces the inflammatory peptide bradykinin and contributes to experimental thrombosis. C1 esterase-inhibitor (C1INH) deficiency or gain-of-function mutations in factor XII (FXII) cause hereditary angioedema, a life-threatening tissue swelling disease. C1INH is a relatively weak contact system enzyme inhibitor. Although α1-antitrypsin (α1AT) does not naturally inhibit contact system enzymes, a human mutation (M358R; α1AT-Pittsburgh) changes it into a powerful broad-spectrum enzyme inhibitor. It blocks the contact system, but also thrombin and activated protein C (APC), making it an unattractive candidate for therapeutic contact system blockade. We adapted the reactive center loop of α1AT-Pittsburgh (AIPR/S) to overcome these obstacles. Two α1AT variants (SMTR/S and SLLR/S) strongly inhibit plasma kallikrein, activated FXII, and plasmin. α1AT-SMTR/S no longer inhibits thrombin, but residually inhibits APC. In contrast, α1AT-SLLR/S residually inhibits thrombin, but no longer APC. Additional modification at the P1' position (S→V) eliminates residual inhibition of thrombin and APC for both variants, while retaining their properties as contact system inhibitors. Both α1AT-SMTR/V and -SLLR/V are superior to C1INH in reducing bradykinin production in plasma. Owing to their capacity to selectively block contact system-driven coagulation, both variants block vascular occlusion in an in vivo model for arterial thrombosis. Furthermore, both variants block acute carrageenan-induced tissue edema in mice. Finally, α1AT-SLLR/V, our most powerful candidate, suppresses epithelial leakage of the gut in a mouse model of colitis. Our findings confirm that redesign of α1AT strongly alters its inhibitory behavior and can be used for the treatment of contact system-mediated thrombosis and inflammation.
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http://dx.doi.org/10.1182/blood.2019000481DOI Listing
November 2019

High occurrence of antihistamine resistance in patients with recurrent idiopathic angioedema.

Clin Transl Allergy 2019 12;9:35. Epub 2019 Jul 12.

3Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Antihistamines are the most prescribed therapy in recurrent idiopathic angioedema, yet little is known about their efficacy. Herein, we report on clinical improvement with antihistamine therapy in 120 patients evaluating angioedema attack frequency. A high incidence (36%) of antihistamine refractory cases was observed. Forty percent of patients on antihistamine prophylaxis suffered from 1 or more angioedema attacks per month. Our findings stress the need for additional treatment options for recurrent idiopathic angioedema.
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http://dx.doi.org/10.1186/s13601-019-0274-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625121PMC
July 2019

Hereditary Angioedema: Insights into inflammation and allergy.

Mol Immunol 2019 08 4;112:378-386. Epub 2019 Jul 4.

Hospital Universitario La Paz, Unidad de Inmunología, IdiPAZ, Centro de Investigación Biomédica en Red (CIBERER U754), Paseo de la Castellana, 261, 28046, Madrid, Spain. Electronic address:

Hereditary Angioedema (HAE) is a rare autosomal recessive bradykinin (BK)-mediated disease characterized by local episodes of non-pitting swelling. Initially considered a complement-mediated disease, novel pathogenic mechanisms uncovered in the last decade have revealed new HAE-associated genes and tight physiological relationships among complement, contact, coagulation, fibrinolysis and inflammation. Uncontrolled production of BK due to inefficient regulation of the plasma contact system, increased activity of contact and coagulation factors or a deficient regulation of BK receptor-triggered intracellular signalling are on the basis of HAE pathology. In this new scenario, HAE can result from different mechanisms that may generate distinct clinical phenotypes of the disease. This review focuses in the recent advances and unsolved challenges in our comprehension of this ever increasingly complex pathology.
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http://dx.doi.org/10.1016/j.molimm.2019.06.017DOI Listing
August 2019

SERPINs-From Trap to Treatment.

Front Med (Lausanne) 2019 12;6:25. Epub 2019 Feb 12.

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

Excessive enzyme activity often has pathological consequences. This for example is the case in thrombosis and hereditary angioedema, where serine proteases of the coagulation system and kallikrein-kinin system are excessively active. Serine proteases are controlled by SERPINs (serine protease inhibitors). We here describe the basic biochemical mechanisms behind SERPIN activity and identify key determinants that influence their function. We explore the clinical phenotypes of several SERPIN deficiencies and review studies where SERPINs are being used beyond replacement therapy. Excitingly, rare human SERPIN mutations have led us and others to believe that it is possible to refine SERPINs toward desired behavior for the treatment of enzyme-driven pathology.
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http://dx.doi.org/10.3389/fmed.2019.00025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379291PMC
February 2019

Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo.

Arterioscler Thromb Vasc Biol 2018 08;38(8):1748-1760

From the Biomedical Engineering, School of Medicine (J.Z.-R., S.E.R., C.P., R.A.R., E.I.T., A.G., O.J.T.M.).

Objective- Terminal complications of bacterial sepsis include development of disseminated intravascular consumptive coagulopathy. Bacterial constituents, including long-chain polyphosphates (polyP), have been shown to activate the contact pathway of coagulation in plasma. Recent work shows that activation of the contact pathway in flowing whole blood promotes thrombin generation and platelet activation and consumption distal to thrombus formation ex vivo and in vivo. Here, we sought to determine whether presence of long-chain polyP or bacteria in the bloodstream promotes platelet activation and consumption in a coagulation factor (F)XII-dependent manner. Approach and Results- Long-chain polyP promoted platelet P-selectin expression, microaggregate formation, and platelet consumption in flowing whole blood in a contact activation pathway-dependent manner. Moreover, long-chain polyP promoted local fibrin formation on collagen under shear flow in a FXI-dependent manner. Distal to the site of thrombus formation, platelet consumption was dramatically enhanced in the presence of long-chain polyP in the blood flow in a FXI- and FXII-dependent manner. In a murine model, long-chain polyP promoted platelet deposition and fibrin generation in lungs in a FXII-dependent manner. In a nonhuman primate model of bacterial sepsis, pre-treatment of animals with an antibody blocking FXI activation by FXIIa reduced lethal dose Staphylococcus aureus-induced platelet and fibrinogen consumption. Conclusions- This study demonstrates that bacterial-type long-chain polyP promotes platelet activation in a FXII-dependent manner in flowing blood, which may contribute to sepsis-associated thrombotic processes, consumptive coagulopathy, and thrombocytopenia.
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http://dx.doi.org/10.1161/ATVBAHA.118.311193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205188PMC
August 2018

Advances in Clinical and Basic Science of Coagulation: Illustrated abstracts of the 9th Chapel Hill Symposium on Hemostasis.

Res Pract Thromb Haemost 2018 Jul 12;2(3):407-428. Epub 2018 Apr 12.

Blood Research Institute Blood Center of Wisconsin Milwaukee WI USA.

This 9th Symposium on Hemostasis is an international scientific meeting held biannually in Chapel Hill, North Carolina. The meeting is in large measure the result of the close friendship between the late Dr. Harold R. Roberts of UNC Chapel Hill and Dr. Ulla Hedner of Novo Nordisk. When Novo Nordisk was developing the hemophilia therapy that would become NovoSeven, they sponsored a series of meetings to understand the basic biology and clinical applications of factor VIIa. The first meeting in Chapel Hill was held April 4-6, 2002 with Dr. Roberts as the organizer. Over the years, the conference emphasis has expanded from discussions of factor VIIa and tissue factor to additional topics in hemostasis and thrombosis. This year's meeting includes presentations by internationally renowned speakers that discuss the state-of-the-art on an array of important topics, including von Willebrand factor, engineering advances, coagulation and disease, tissue factor biology, therapeutic advances, and basic clotting factor biology. Included in this review article are illustrated abstracts provided by our speakers, which highlight the main conclusions of each invited talk. This will be the first meeting without Dr. Roberts in attendance, yet his commitment to excellent science and his focus on turning science to patient care are pervasively reflected in the presentations by our speakers.
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http://dx.doi.org/10.1002/rth2.12095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046595PMC
July 2018

Virulence Associated Gene 8 of Enhances Contact System Activity by Inhibiting the Regulatory Function of Complement Regulator C1 Inhibitor.

Front Immunol 2018 4;9:1172. Epub 2018 Jun 4.

Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands.

is a Gram-negative bacterium and the causative agent of whooping cough. Whooping cough is currently re-emerging worldwide and, therefore, still poses a continuous global health threat. expresses several virulence factors that play a role in evading the human immune response. One of these virulence factors is virulence associated gene 8 (Vag8). Vag8 is a complement evasion molecule that mediates its effects by binding to the complement regulator C1 inhibitor (C1-INH). This regulatory protein is a fluid phase serine protease that controls proenzyme activation and enzyme activity of not only the complement system but also the contact system. Activation of the contact system results in the generation of bradykinin, a pro-inflammatory peptide. Here, the activation of the contact system by was explored. We demonstrate that recombinant as well as endogenous Vag8 enhanced contact system activity by binding C1-INH and attenuating its inhibitory function. Moreover, we show that itself is able to activate the contact system. This activation was dependent on Vag8 production as a Vag8 knockout strain was unable to activate the contact system. These findings show a previously overlooked interaction between the contact system and the respiratory pathogen . Activation of the contact system by may contribute to its pathogenicity and virulence.
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http://dx.doi.org/10.3389/fimmu.2018.01172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994690PMC
August 2019

Truncation of ADAMTS13 by Plasmin Enhances Its Activity in Plasma.

Thromb Haemost 2018 03 13;118(3):471-479. Epub 2018 Mar 13.

Department for Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) cleaves von Willebrand Factor (VWF) multimers to control their thrombogenicity. The fibrinolytic enzyme plasmin can cleave VWF in a similar manner. However, plasmin can also cleave ADAMTS13, which ultimately inactivates it. This leaves the overall role of plasmin in primary haemostasis uncertain.We investigated the combined molecular effects of plasmin on VWF and ADAMTS13. We first identified that plasmin destroys FRETS-VWF73 substrate by cleaving the ADAMTS13 binding region in a buffered system. We next investigated how plasmin affects both VWF and ADAMTS13 under static conditions in plasma by western blotting. We found that globular VWF is largely protected from plasmin cleavage. However, ADAMTS13 is rapidly cleaved under these conditions, suggesting inactivation. Surprisingly, we observed that plasmin enhances ADAMTS13 activity in a modified two-stage FRETS-VWF73 assay that protects FRETS-VWF73 substrate from degradation. In direct binding studies under the same conditions, we found that plasmin generates multiple C-terminally truncated forms of ADAMTS13 with VWF-binding capacity. In an effort to seek evidence for this mechanism in vivo, we analysed plasma from patients with systemic amyloidosis, which is hallmarked by a hyperfibrinolytic state. We found that their plasma contained increased levels of C-terminally truncated forms of ADAMTS13, which correlated with their hyperfibrinolytic state.We propose that truncation of ADAMTS13 by plasmin abolishes intramolecular self-association, which improves interaction with unfolded VWF.
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http://dx.doi.org/10.1055/s-0038-1627460DOI Listing
March 2018

Coagulation factor XII in thrombosis and inflammation.

Blood 2018 04 26;131(17):1903-1909. Epub 2018 Feb 26.

Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor XII-driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. This suggests that the polyphosphate/factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes. In contrast to deficiency in factor XII providing safe thromboprotection, excessive FXII activity is associated with the life-threatening inflammatory disorder hereditary angioedema. The current review summarizes recent findings of the polyphosphate/factor XII-driven contact system at the intersection of procoagulant and proinflammatory disease states. Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders.
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http://dx.doi.org/10.1182/blood-2017-04-569111DOI Listing
April 2018

The Search for Biomarkers in Hereditary Angioedema.

Front Med (Lausanne) 2017 22;4:206. Epub 2017 Nov 22.

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

The unpredictable nature of attacks of tissue swelling in hereditary angioedema requires the identification of reliable biomarkers to monitor disease activity as well as response to therapy. At present, one can assess a C4 level (by ELISA) to assist in diagnosis but neither C4 nor C1 inhibitor levels reflect clinical course or prognosis. We will here review a collection of plasma proteins involved in blood coagulation, fibrinolysis, and innate immunity (Figure 1). A main focus is those proteins that are key to the formation of bradykinin (BK); namely, factor XII, plasma prekallikrein/kallikrein, high-molecular weight kininogen, and BK itself since overproduction of BK is key to the disease. Considerations include new approaches to measurement of active enzymes, ELISA methods that may supersede SDS gel analysis of bond cleavages, and examples of changes outside the BK cascade that may reflect when, where, and how an attack of swelling is initiated. We will discuss their usefulness as biomarker candidates, with pros and cons, and compare the analytical methods that are being developed to measure their levels or activity.
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http://dx.doi.org/10.3389/fmed.2017.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702621PMC
November 2017

Coagulation factor XII regulates inflammatory responses in human lungs.

Thromb Haemost 2017 10 17;117(10):1896-1907. Epub 2017 Aug 17.

Malgorzata Wygrecka, PhD, Department of Biochemistry, Faculty of Medicine,, Universities of Giessen and Marburg Lung Center, Friedrichstrasse 24, 35392 Giessen, Germany, Tel.: +49 641 99 47482, Fax: +49 641 99 47509, E-mail:

Increased procoagulant activity in the alveolar compartment and uncontrolled inflammation are hallmarks of the acute respiratory distress syndrome (ARDS). Here, we investigated whether the contact phase system of coagulation is activated and may regulate inflammatory responses in human lungs. Components of the contact phase system were characterized in bronchoalveolar lavage fluids (BALF) from 54 ARDS patients and 43 controls, and their impact on cytokine/chemokine expression in human precision cut lung slices (PCLS) was assessed by a PCR array. Activation of the contact system, associated with high levels of coagulation factor XIIa (Hageman factor, FXIIa), plasma kallikrein and bradykinin, occurred rapidly in ARDS lungs after the onset of the disease and virtually normalized within one week from time of diagnosis. FXII levels in BALF were higher in ARDS non-survivors than survivors and were positively correlated with tumor necrosis factor (TNF)-α concentration. FXII induced the production and release of interleukin (IL)-8, IL-1β, IL-6, leukemia inhibitory factor (LIF), CXCL5 and TNF-α in human PCLS in a kallikrein-kinin-independent manner. In conclusion, accumulation of FXII in ARDS lungs may contribute to the release of pro-inflammatory mediators and is associated with clinical outcome. FXII inhibition may thus offer a novel and promising therapeutic approach to antagonize overwhelming inflammatory responses in ARDS lungs without interfering with vital haemostasis.
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http://dx.doi.org/10.1160/TH16-12-0904DOI Listing
October 2017