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Article ; Online: Toward gene therapy for congenital thrombotic thrombocytopenic purpura.

Dekimpe, Charlotte / Roose, Elien / Sakai, Kazuya / Tersteeg, Claudia / De Meyer, Simon F / Vanhoorelbeke, Karen

Journal of thrombosis and haemostasis : JTH

2022 Volume 21, Issue 5, Page(s) 1090–1099

Abstract: Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe deficiency in the plasma metalloprotease ADAMTS-13. The current management of cTTP is dependent on the prophylactic administration of ADAMTS-13 via plasma infusion. This is a ... ...

Abstract	Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe deficiency in the plasma metalloprotease ADAMTS-13. The current management of cTTP is dependent on the prophylactic administration of ADAMTS-13 via plasma infusion. This is a demanding therapy for patients because transfusions are lifelong and time-consuming and allergic reactions frequently occur. Although current management of cTTP controls acute episodes, it does not provide a long-lasting cure for this disease. The endogenous expression of ADAMTS-13 after gene transfer would provide a curative therapy and ongoing research explores various preclinical gene therapeutic approaches for cTTP. This review focuses on the current state of the literature regarding preclinical gene therapy studies for cTTP and on the challenges of developing a gene therapy medicinal product for cTTP.
MeSH term(s)	Humans ; Purpura, Thrombotic Thrombocytopenic/genetics ; Purpura, Thrombotic Thrombocytopenic/therapy ; ADAMTS13 Protein ; Plasma ; Blood Transfusion ; Genetic Therapy/adverse effects
Chemical Substances	ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2022-12-27
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2022.12.018
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Article ; Online: Diagnosis of thrombotic thrombocytopenic purpura: Easy-to-use fiber-optic surface plasmon resonance immunoassays for automated ADAMTS13 antigen and conformation evaluation.

Bonnez, Quintijn / Dekimpe, Charlotte / Bekaert, Tim / Tellier, Edwige / Kaplanski, Gilles / Joly, Bérangère S / Veyradier, Agnès / Coppo, Paul / Lammertyn, Jeroen / Tersteeg, Claudia / De Meyer, Simon F / Vanhoorelbeke, Karen

Journal of thrombosis and haemostasis : JTH

2024

Abstract: Background: Laboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS13 activity ranges between 10-20%. To prevent misdiagnosis, open ADAMTS13 conformation gained clinical attention as a novel ... ...

Abstract	Background: Laboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS13 activity ranges between 10-20%. To prevent misdiagnosis, open ADAMTS13 conformation gained clinical attention as a novel biomarker especially to diagnose acute iTTP in patient with diagnostic undecisive ADAMTS13 activity. Plasma ADAMTS13 conformation analysis corrects for ADAMTS13 antigen with both parameters being characterized in enzyme-linked immunosorbent assay (ELISA)-based reference assays requiring expert technicians. Objectives: To design ADAMTS13 antigen and conformation assays on automated, easy-to-use fiber-optic surface plasmon resonance (FO-SPR) technology to promote assay accessibility and diagnose challenging iTTP patients. Patients/methods: ADAMTS13 antigen and conformation assays were designed on FO-SPR technology. Plasma of twenty healthy donors and twenty acute iTTP patients were quantified and data from FO-SPR and ELISA reference assays were compared. Results: Following assay design, both antigen and conformation FO-SPR assays were optimized and characterized presenting strong analytical sensitivity (detection limit of 0.001 μg/mL) and repeatability (inter-assay variation of 14.4%). Comparative analysis suggests positive correlation (Spearman r of 0.92) and good agreement between FO-SPR and ELISA assays. As expected, FO-SPR assays showed a closed or open ADAMTS13 conformation in healthy donors and acute iTTP patients respectively. Conclusions: Both ADAMTS13 antigen and conformation assays were transferred onto automated, easy-to-use FO-SPR technology displaying potent analytical sensitivity and reproducibility. ADAMTS13 antigen and conformation were determined for healthy donors and acute iTTP patients showing strong correlation with ELISA reference. Introducing FO-SPR technology in clinical context could support routine diagnosis of acute iTTP patients, notably when ADAMTS13 activity fluctuates between 10-20%.
Language	English
Publishing date	2024-03-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2024.03.012
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Article ; Online: Improvement of recombinant ADAMTS13 production through a more optimal signal peptide or an N-terminal fusion protein.

Kangro, Kadri / Roose, Elien / Dekimpe, Charlotte / Vandenbulcke, Aline / Graça, Nuno A G / Voorberg, Jan / Ustav, Mart / Männik, Andres / Vanhoorelbeke, Karen

Journal of thrombosis and haemostasis : JTH

2022 Volume 20, Issue 10, Page(s) 2379–2385

Abstract: Background: Recombinant human ADAMTS13 (rADAMTS13) is a key protein in fundamental research for investigating its mode of action and the pathophysiology of thrombotic thrombocytopenic purpura (TTP). However, the expression of rADAMTS13 is quite low in ... ...

Abstract	Background: Recombinant human ADAMTS13 (rADAMTS13) is a key protein in fundamental research for investigating its mode of action and the pathophysiology of thrombotic thrombocytopenic purpura (TTP). However, the expression of rADAMTS13 is quite low in mammalian cells, which makes the production of the protein time-consuming and labor-intensive. Objectives: We aimed at increasing the yield of rADAMTS13 by (1) using a more optimal signal peptide (SP) and (2) constructing an N-terminal fusion protein of ADAMTS13 with human serum albumin domain 1 (AD1-ADAMTS13). Methods: Six SPs were investigated to select the most optimal SP. Expression plasmids containing the most optimal SP and ADAMTS13 cDNA or the fusion construct AD1-ADAMTS13 were generated and transiently transfected into CHOEBNALT85 cell-line. Expression levels of rADAMTS13 in expression medium were analyzed and compared with the expression level of rADAMTS13 with native SP (nat-SP). Results: Expression of rADAMTS13 with coagulation factor VII (FVII) SP was 3-fold higher (16.00 μg/ml) compared with the expression with nat-SP (5.03 μg/ml). The highest yields were obtained with AD1-ADAMTS13 protein with a 15-fold higher concentration (78.22 μg/ml) compared with the expression with nat-SP. The rADAMTS13 expressed with FVII-SP retained its activity (104.0%) to cleave von Willebrand factor, whereas AD1-ADAMTS13 demonstrated even higher activity (144.3%). Conclusion: We succeeded in generating expression vectors that yield (1) rADAMTS13 at higher levels because of more optimal FVII-SP and (2) high levels of AD1-ADAMTS13 N-terminal fusion protein. The highest expression levels were obtained with AD1-ADAMTS13 N-terminal fusion protein, which is paving the way for highly efficient protein production.
MeSH term(s)	ADAM Proteins/genetics ; ADAM Proteins/metabolism ; ADAMTS13 Protein/genetics ; ADAMTS13 Protein/metabolism ; Animals ; DNA, Complementary ; Factor VII/metabolism ; Humans ; Mammals/genetics ; Mammals/metabolism ; Protein Sorting Signals/genetics ; Purpura, Thrombotic Thrombocytopenic ; Recombinant Proteins/metabolism ; Serum Albumin, Human ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism
Chemical Substances	DNA, Complementary ; Protein Sorting Signals ; Recombinant Proteins ; von Willebrand Factor ; Factor VII (9001-25-6) ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87) ; Serum Albumin, Human (ZIF514RVZR)
Language	English
Publishing date	2022-07-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.15819
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Article ; Online: Measuring ADAMTS-13 activity to diagnose thrombotic thrombocytopenic purpura: a novel, fast fiber-optic surface plasmon resonance immunoassay.

Bonnez, Quintijn / Dekimpe, Charlotte / Tellier, Edwige / Kaplanski, Gilles / Verhamme, Peter / Tersteeg, Claudia / De Meyer, Simon F / Lammertyn, Jeroen / Joly, Bérangère / Coppo, Paul / Veyradier, Agnès / Vanhoorelbeke, Karen

Research and practice in thrombosis and haemostasis

2023 Volume 7, Issue 6, Page(s) 102171

Abstract: Background: Thrombotic thrombocytopenic purpura (TTP) is characterized by severe ADAMTS-13 activity deficiency (<10%). Diagnostic testing is challenging because of unavailability, high cost, and expert technician requirement of ADAMTS-13 enzyme assays. ... ...

Abstract	Background: Thrombotic thrombocytopenic purpura (TTP) is characterized by severe ADAMTS-13 activity deficiency (<10%). Diagnostic testing is challenging because of unavailability, high cost, and expert technician requirement of ADAMTS-13 enzyme assays. Cost-effective, automated fiber-optic surface plasmon resonance (FO-SPR) platforms show potential for developing diagnostic tests. Yet, FO-SPR has never been explored to measure enzymatic activities. Objectives: To develop an easy-to-use ADAMTS-13 activity assay utilizing optical fibers to rapidly diagnose TTP. Methods: The ADAMTS-13 activity assay was designed and optimized using FO-SPR technology based on a previously described enzyme-linked immunosorbent assay setup. A calibration curve was generated to quantify ADAMTS-13 activity in plasma of healthy donors and patients with acute immune-mediated TTP (iTTP), hemolytic uremic syndrome, or sepsis. ADAMTS-13 activity data from FO-SPR and fluorescence resonance energy transfer-based strategies (FRETS)-VWF73 reference assays were compared. Results: After initial assay development, optimization improved read-out magnitude and signal-to-noise ratio and reduced variation. Further characterization demonstrated a detection limit (6.8%) and inter-assay variation (Coefficient of variation, 7.2%) that showed good analytical sensitivity and repeatability. From diverse plasma samples, only plasma from patients with acute iTTP showed ADAMTS-13 activities below 10%. Strong Pearson correlation ( Conclusions: A fast ADAMTS-13 activity assay was designed onto automated FO-SPR technology. Optimization resulted in sensitive ADAMTS-13 activity measurements with a detection limit enabling clinical diagnosis of TTP within 3 hours. The FO-SPR assay proved strong correlation with the reference FRETS-VWF73 assay. For the first time, this assay demonstrated the capacity of FO-SPR technology to measure enzymatic activity in pre-clinical context.
Language	English
Publishing date	2023-08-19
Publishing country	United States
Document type	Journal Article
ISSN	2475-0379
ISSN (online)	2475-0379
DOI	10.1016/j.rpth.2023.102171
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Article ; Online: A novel von Willebrand factor multimer ratio as marker of disease activity in thrombotic thrombocytopenic purpura.

Falter, Tanja / Rossmann, Heidi / de Waele, Laure / Dekimpe, Charlotte / von Auer, Charis / Müller-Calleja, Nadine / Häuser, Friederike / Degreif, Adriana / Marandiuc, Dana / Messmer, Xavier / Sprinzl, Martin / Lackner, Karl J / Jurk, Kerstin / Vanhoorelbeke, Karen / Lämmle, Bernhard

Blood advances

2023 Volume 7, Issue 17, Page(s) 5091–5102

Abstract: Immune-mediated thrombotic thrombocytopenic purpura (iTTP), an autoantibody-mediated severe ADAMTS13 deficiency, is caused by insufficient proteolytic processing of von Willebrand factor (VWF) multimers (MMs) and microvascular thrombi. Recurrence of ... ...

Abstract	Immune-mediated thrombotic thrombocytopenic purpura (iTTP), an autoantibody-mediated severe ADAMTS13 deficiency, is caused by insufficient proteolytic processing of von Willebrand factor (VWF) multimers (MMs) and microvascular thrombi. Recurrence of acute iTTP is associated with persistence or reappearance of ADAMTS13 deficiency. Some patients remain in remission despite recurring or persisting severe ADAMTS13 deficiency. In a prospective 2-year observational study, we investigated VWF MM patterns and ADAMTS13 in patients with iTTP in remission and at acute episodes. Of the 83 patients with iTTP, 16 suffered 22 acute episodes whereas 67 remained in clinical remission during follow-up, including 13 with ADAMTS13 <10% and 54 with ADAMTS13 ≥10%. High -molecular weight to low-molecular weight VWF MM ratio based on sodium dodecyl sulfate-agarose gel electrophoresis was compared with ADAMTS13 activity. VWF MM ratio was significantly higher in patients in remission with <10% compared with ≥10% ADAMTS13 activity. Fourteen samples obtained from 13 to 50 days (interquartile range; median, 39) before acute iTTP onset (ADAMTS13 <10% in 9 patients and 10%-26% in 5) showed VWF MM ratios significantly higher than those from 13 patients remaining in remission with ADAMTS13 <10%. At acute iTTP onset, VWF MM ratio decreased significantly and was low in all patients despite <10% ADAMTS13. The VWF MM ratio does not depend exclusively on ADAMTS13 activity. The disappearance of high molecular weight VWF MMs resulting in low VWF MM ratio at iTTP onset may be explained by consumption of larger VWF MMs in the microcirculation. The very high VWF MM ratio preceding acute iTTP recurrence suggests that VWF processing is hampered more than in patients remaining in remission.
MeSH term(s)	Humans ; Purpura, Thrombotic Thrombocytopenic/diagnosis ; von Willebrand Factor/analysis ; Prospective Studies ; von Willebrand Diseases ; ADAMTS13 Protein
Chemical Substances	von Willebrand Factor ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2023-06-20
Publishing country	United States
Document type	Observational Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023010028
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Article ; Online: ADAMTS13 conformation and immunoprofiles in Japanese patients with immune-mediated thrombotic thrombocytopenic purpura.

Sakai, Kazuya / Matsumoto, Masanori / De Waele, Laure / Dekimpe, Charlotte / Hamada, Eriko / Kubo, Masayuki / Tersteeg, Claudia / De Meyer, Simon F / Vanhoorelbeke, Karen

Blood advances

2022 Volume 7, Issue 1, Page(s) 131–140

Abstract: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultrarare thrombotic disease caused by autoantibody-induced ADAMTS13 deficiency. Open ADAMST13 conformation, induced by autoantibodies, was identified as a novel biomarker for iTTP. ... ...

Abstract	Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultrarare thrombotic disease caused by autoantibody-induced ADAMTS13 deficiency. Open ADAMST13 conformation, induced by autoantibodies, was identified as a novel biomarker for iTTP. Determining immunoprofiles in patients with iTTP has been shown to guide the development of novel targeted therapies. However, these studies were done in mainly Caucasian iTTP cohorts. To validate those findings across other ethnic cohorts, we investigated 195 acute TTP plasma samples from the Japanese iTTP registry. Seventy-six of the 195 samples had detectable ADAMTS13 antigen levels, of which 94.7% were shown to have an open ADAMTS13 conformation. A positive correlation was observed between ADAMTS13 inhibitor titers (a diagnostic parameter in Japan) and anti-ADAMTS13 immunoglobulin G autoantibody titers. Studying anti-M, anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, anti-CUB1-2 autoantibodies and the corresponding immunoprofile showed that 73% of the patients had anti-CS autoantibodies and 25.8% had anti-M autoantibodies, with the latter being higher than in Caucasians. Stratifying patients according to their immunoprofiles revealed that the profile with only anti-CS autoantibodies was the most common immunoprofile similar to that in Caucasians (28.9%). Although this profile did not affect the 1-year TTP-related mortality rate, patients with autoantibodies against all 6 ADAMTS13 fragments had a higher risk for TTP-related death than other patients (P = .02). We here validated open ADAMTS13 as a novel biomarker for acute iTTP and determined the dominant immunoprofiling in the Japanese cohort, contributing to setting up the diagnosis and managing guidelines across different ethnic cohorts and developing ADAMTS13 variants that do not bind to the anti-CS autoantibodies.
MeSH term(s)	Humans ; Purpura, Thrombotic Thrombocytopenic/diagnosis ; Purpura, Thrombotic Thrombocytopenic/therapy ; East Asian People ; Autoantibodies ; Biomarkers ; Molecular Conformation ; ADAMTS13 Protein/metabolism
Chemical Substances	Autoantibodies ; Biomarkers ; ADAMTS13 protein, human (EC 3.4.24.87) ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2022-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022008885
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Article: Co(III)-NTA Mediated Antigen Immobilization on a Fiber Optic-SPR Biosensor for Detection of Autoantibodies in Autoimmune Diseases: Application in Immune-Mediated Thrombotic Thrombocytopenic Purpura

Horta, Sara / Qu, Jia-Huan / Dekimpe, Charlotte / Bonnez, Quintijn / Vandenbulcke, Aline / Tellier, Edwige / Kaplanski, Gilles / Delport, Filip / Geukens, Nick / Lammertyn, Jeroen / Vanhoorelbeke, Karen

Analytical chemistry. 2020 Sept. 15, v. 92, no. 20

2020

Abstract: Autoantibodies are key biomarkers in clinical diagnosis of autoimmune diseases routinely detected by enzyme-linked immunosorbent assays (ELISAs). However, the complexity of these assays is limiting their use in routine diagnostics. Fiber optic-surface ... ...

Abstract	Autoantibodies are key biomarkers in clinical diagnosis of autoimmune diseases routinely detected by enzyme-linked immunosorbent assays (ELISAs). However, the complexity of these assays is limiting their use in routine diagnostics. Fiber optic-surface plasmon resonance (FO-SPR) can overcome these limitations, but improved surface chemistries are still needed to guarantee detection of autoantibodies in complex matrices. In this paper, we describe the development of an FO-SPR immunoassay for the detection of autoantibodies in plasma samples from immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients. Hereto, hexahistidine-tagged recombinant ADAMTS13 (rADAMTS13-His₆) was immobilized on nitrilotriacetic acid (NTA)-coated FO probes chelated by cobalt (Co(III)) and exposed to anti-ADAMTS13 autoantibodies. Initial studies were performed to optimize rADAMTS13-His₆ immobilization and to confirm the specificity of the immunoassay for detection of anti-ADAMTS13 autoantibodies with FO-SPR. The performance of the immunoassay was then evaluated by comparing Co(III)- and nickel (Ni(II))-NTA stabilized surfaces, confirming the stable immobilization of the antigen in Co(III)-NTA-functionalized FO probes. A calibration curve was prepared with a dilution series of a cloned human anti-ADAMTS13 autoantibody in ADAMTS13-depleted plasma resulting in an average interassay coefficient of variation of 7.1% and a limit of detection of 0.24 ng/mL. Finally, the FO-SPR immunoassay was validated using seven iTTP patient plasma samples, resulting in an excellent correlation with an in-house-developed ELISA (r = 0.973). In summary, the specificity and high sensitivity in combination with a short time-to-result (2.5 h compared to 4–5 h for a regular ELISA) make the FO-SPR immunoassay a powerful assay for routine diagnosis of iTTP and with extension for any other autoimmune disease.
Keywords	analytical chemistry ; antigens ; autoantibodies ; autoimmune diseases ; biomarkers ; biosensors ; calibration ; cobalt ; detection limit ; diagnostic techniques ; humans ; nickel ; nitrilotriacetic acid ; patients ; thrombocytopenic purpura
Language	English
Dates of publication	2020-0915
Size	p. 13880-13887.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.0c02586
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Determination of anti-ADAMTS-13 autoantibody titers in ELISA: Influence of ADAMTS-13 presentation and autoantibody detection.

Dekimpe, Charlotte / Roose, Elien / Kangro, Kadri / Bonnez, Quintijn / Vandenbulcke, Aline / Tellier, Edwige / Kaplanski, Gilles / Feys, Hendrik B / Tersteeg, Claudia / Männik, Andres / De Meyer, Simon F / Vanhoorelbeke, Karen

Journal of thrombosis and haemostasis : JTH

2021 Volume 19, Issue 9, Page(s) 2248–2255

Abstract: Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by inhibitory and/or clearing anti-ADAMTS-13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats, member 13) autoantibodies. To determine the presence and ...

Abstract	Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by inhibitory and/or clearing anti-ADAMTS-13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats, member 13) autoantibodies. To determine the presence and total level of anti-ADAMTS-13 autoantibodies, commercial and in-house developed ELISAs are performed. However, different ELISA methods vary in relation to the presentation of recombinant (r)ADAMTS-13 and the detection method of the anti-ADAMTS-13 autoantibodies. Currently, the influence of those different approaches on anti-ADAMTS-13 autoantibody titers is not known. Objectives: To assess the influence of different ADAMTS-13 presentation- and autoantibody detection methods on anti-ADAMTS-13 autoantibody titers in ELISA. Materials/methods: Anti-ADAMTS-13 autoantibody titers from 18 iTTP patients were determined using four different set-ups of anti-ADAMTS-13 autoantibody ELISAs. The ELISAs varied in the used presentation of rADAMTS-13 (directly coated full-length rADAMTS-13, directly coated rMDTCS and rT2C2, or antibody-captured full-length rADAMTS-13) and the detection antibodies (polyclonal anti-human IgG or monoclonal anti-human IgG Results: Strong correlations between the different anti-ADAMTS-13 autoantibody ELISA approaches were observed, when using polyclonal anti-human IgG detection antibodies recognizing all IgG subclasses similarly, independent of the method of rADAMTS-13 presentation. Anti-ADAMTS-13 autoantibody titers correlated less when using a mixture of monoclonal anti-human IgG Conclusion: Anti-ADAMTS-13 autoantibody levels using different methods of rADAMTS-13 presentation strongly correlate. However, the levels of anti-ADAMTS-13 autoantibodies are highly dependent on the detection antibody used, which should detect all IgG subclasses (IgG
MeSH term(s)	ADAMTS13 Protein ; Autoantibodies ; Enzyme-Linked Immunosorbent Assay ; Humans ; Purpura, Thrombotic Thrombocytopenic/diagnosis ; Thrombospondin 1
Chemical Substances	Autoantibodies ; Thrombospondin 1 ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2021-07-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.15297
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Article ; Online: Plasma and rhADAMTS13 reduce trauma-induced organ failure by restoring the ADAMTS13-VWF axis.

Kleinveld, Derek J B / Simons, Derek D G / Dekimpe, Charlotte / Deconinck, Shannen J / Sloos, Pieter H / Maas, M Adrie W / Kers, Jesper / Muia, Joshua / Brohi, Karim / Voorberg, Jan / Vanhoorelbeke, Karen / Hollmann, Markus W / Juffermans, Nicole P

Blood advances

2021 Volume 5, Issue 17, Page(s) 3478–3491

Abstract: Trauma-induced organ failure is characterized by endothelial dysfunction. The aim of this study was to investigate the role of von Willebrand factor (VWF) and its cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 ... ...

Abstract	Trauma-induced organ failure is characterized by endothelial dysfunction. The aim of this study was to investigate the role of von Willebrand factor (VWF) and its cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) in the occurrence of endothelial permeability and organ failure in trauma. In an observational study in a level-1 trauma center, 169 adult trauma patients with clinical signs of shock and/or severe injuries were included. Trauma was associated with low ADAMTS13 and high VWF antigen levels, thus generating an imbalance of ADAMTS13 to VWF. Patients who developed organ failure (23%) had greater ADAMTS13-to-VWF imbalances, persistently lower platelet counts, and elevated levels of high-molecular-weight VWF multimers compared with those without organ failure, suggesting microthrombi formation. To investigate the effect of replenishing low ADAMTS13 levels on endothelial permeability and organ failure using either recombinant human ADAMTS13 (rhADAMTS13) or plasma transfusion, a rat model of trauma-induced shock and transfusion was used. Rats in traumatic hemorrhagic shock were randomized to receive crystalloids, crystalloids supplemented with rhADAMTS13, or plasma transfusion. A 70-kDa fluorescein isothiocyanate-labeled dextran was injected to determine endothelial leakage. Additionally, organs were histologically assessed. Both plasma transfusion and rhADAMTS13 were associated with a reduction in pulmonary endothelial permeability and organ injury when compared with resuscitation with crystalloids, but only rhADAMTS13 resulted in significant improvement of a trauma-induced decline in ADAMTS13 levels. We conclude that rhADAMTS13 and plasma transfusion can reduce organ failure following trauma. These findings implicate the ADAMTS13-VWF axis in the pathogenesis of organ failure.
MeSH term(s)	ADAMTS13 Protein ; Animals ; Blood Component Transfusion ; Humans ; Plasma ; Rats ; Thrombosis ; von Willebrand Factor
Chemical Substances	von Willebrand Factor ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
Language	English
Publishing date	2021-08-24
Publishing country	United States
Document type	Journal Article ; Observational Study
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2021004404
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Article ; Online: Effect of red blood cell transfusion on inflammation, endothelial cell activation and coagulation in the critically ill.

van Manen, Lisa / van Hezel, Maike E / Boshuizen, Margit / Straat, Marleen / de Man, Angelique M E / Dekimpe, Charlotte / Vanhoorelbeke, Karen / van Bruggen, Robin / Juffermans, Nicole P

Vox sanguinis

2021 Volume 117, Issue 1, Page(s) 64–70

Abstract: Background and objectives: Red blood cell (RBC) transfusion is a frequently applied intervention in an intensive care unit. However, transfusion is associated with adverse outcomes including organ failure and thrombo-embolic events. Mechanisms of these ... ...

Abstract	Background and objectives: Red blood cell (RBC) transfusion is a frequently applied intervention in an intensive care unit. However, transfusion is associated with adverse outcomes including organ failure and thrombo-embolic events. Mechanisms of these effects are not known but may be related to activation of the endothelium or of the coagulation or inflammatory system. We hypothesized that a RBC transfusion in the critically ill would result in further activation of these systems. Materials and methods: In 74 non-bleeding critically ill patients receiving one RBC unit, markers of inflammation, endothelial cell activation and coagulation were measured before transfusion, at 1 h after transfusion and 24 h after transfusion. The impact of disease severity of the recipient on these changes was assessed by comparing septic and non-septic patients (according to sepsis-3 definition) and by correlation of biomarkers with the sequential organ failure assessment (SOFA) score. Results: Levels of von Willebrand Factor (vWF), soluble ICAM-1, soluble thrombomodulin, fibrinogen and d-dimer were already high at baseline, whereas ADAMTS13 levels were low. VWF levels increased significantly 24 h after RBC transfusion (median 478% (338-597) vs. 526% (395-623), p = 0.009). The other biomarkers did not change significantly. Post transfusion change was not dependent on the presence of sepsis and was not correlated with SOFA score. Conclusion: RBC transfusion in critically ill patients was associated with an increase in circulating vWF levels, suggesting a further increase in activation of the endothelium, a finding that was independent of the presence of sepsis or organ injury level.
MeSH term(s)	Critical Illness ; Endothelial Cells ; Erythrocyte Transfusion ; Humans ; Inflammation ; Intensive Care Units
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article
ZDB-ID	80313-3
ISSN	1423-0410 ; 0042-9007
ISSN (online)	1423-0410
ISSN	0042-9007
DOI	10.1111/vox.13125
Database	MEDical Literature Analysis and Retrieval System OnLINE

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