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Complement activation negatively affects the platelet response to thrombopoietin receptor agonists in patients with immune thrombocytopenia: : a prospective cohort study

Åkesson, Alexander LU ; Bussel, James B ; Martin, Myriam LU ; Blom, Anna M LU orcid ; Klintman, Jenny LU ; Ghanima, Waleed ; Zetterberg, Eva LU and Garabet, Lamya (2023) In Platelets 34(1). p.1-9
Abstract

Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected... (More)

Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected before and two, six and 12 weeks after the initiation of TPO-RA therapy. Plasma levels of complement degradation product C4d and soluble terminal complement complexes were assessed. Patients with significantly elevated baseline levels of terminal complement complexes exhibited more often an inadequate platelet response (p = .04), were exclusively subjected to rescue therapy with intravenous immunoglobulin (p = .02), and did not respond with a significant platelet count increase during the study period. C4d showed a significant (p = .01) ability to distinguish samples with significant terminal complement activation, implying engagement of the classical complement pathway. In conclusion, elevated levels of complement biomarkers were associated with a worse TPO-RA treatment response. Larger studies are needed to confirm these results. Biomarkers of complement activation may prove valuable as a prognostic tool to predict which patients that potentially could benefit from complement-inhibiting therapy in the future.

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Abstract (Swedish)
Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected before... (More)
Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected before and two, six and 12 weeks after the initiation of TPO-RA therapy. Plasma levels of complement degradation product C4d and soluble terminal complement complexes were assessed. Patients with significantly elevated baseline levels of terminal complement complexes exhibited more often an inadequate platelet response (p = .04), were exclusively subjected to rescue therapy with intravenous immunoglobulin (p = .02), and did not respond with a significant platelet count increase during the study period. C4d showed a significant (p = .01) ability to distinguish samples with significant terminal complement activation, implying engagement of the classical complement pathway. In conclusion, elevated levels of complement biomarkers were associated with a worse TPO-RA treatment response. Larger studies are needed to confirm these results. Biomarkers of complement activation may prove valuable as a prognostic tool to predict which patients that potentially could benefit from complement-inhibiting therapy in the future. (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Purpura, Thrombocytopenic, Idiopathic, Receptors, Thrombopoietin/agonists, Prospective Studies, Thrombocytopenia, Biomarkers, Complement Activation, Thrombopoietin/pharmacology, Recombinant Fusion Proteins
in
Platelets
volume
34
issue
1
article number
2159019
pages
1 - 9
publisher
Taylor & Francis
external identifiers
  • pmid:36636835
  • scopus:85146195345
ISSN
1369-1635
DOI
10.1080/09537104.2022.2159019
language
English
LU publication?
yes
id
578da745-e0b3-4cb5-a1e5-934f92d71688
date added to LUP
2023-01-16 20:20:17
date last changed
2024-06-29 02:28:34
@article{578da745-e0b3-4cb5-a1e5-934f92d71688,
  abstract     = {{<p>Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected before and two, six and 12 weeks after the initiation of TPO-RA therapy. Plasma levels of complement degradation product C4d and soluble terminal complement complexes were assessed. Patients with significantly elevated baseline levels of terminal complement complexes exhibited more often an inadequate platelet response (p = .04), were exclusively subjected to rescue therapy with intravenous immunoglobulin (p = .02), and did not respond with a significant platelet count increase during the study period. C4d showed a significant (p = .01) ability to distinguish samples with significant terminal complement activation, implying engagement of the classical complement pathway. In conclusion, elevated levels of complement biomarkers were associated with a worse TPO-RA treatment response. Larger studies are needed to confirm these results. Biomarkers of complement activation may prove valuable as a prognostic tool to predict which patients that potentially could benefit from complement-inhibiting therapy in the future.</p>}},
  author       = {{Åkesson, Alexander and Bussel, James B and Martin, Myriam and Blom, Anna M and Klintman, Jenny and Ghanima, Waleed and Zetterberg, Eva and Garabet, Lamya}},
  issn         = {{1369-1635}},
  keywords     = {{Humans; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin/agonists; Prospective Studies; Thrombocytopenia; Biomarkers; Complement Activation; Thrombopoietin/pharmacology; Recombinant Fusion Proteins}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{1--9}},
  publisher    = {{Taylor & Francis}},
  series       = {{Platelets}},
  title        = {{Complement activation negatively affects the platelet response to thrombopoietin receptor agonists in patients with immune thrombocytopenia: : a prospective cohort study}},
  url          = {{http://dx.doi.org/10.1080/09537104.2022.2159019}},
  doi          = {{10.1080/09537104.2022.2159019}},
  volume       = {{34}},
  year         = {{2023}},
}