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Pegasparaginase treatment alters thrombin generation by modulating the protein C and S system in acute lymphoblastic

Jack H Staddon1, Kristi J Smock, Joshua D Schiffman

  • 1aDepartment of Pediatrics, Division of Hematology and Oncology, University of Utah School of Medicine bDepartment of Pathology and ARUP Laboratories Institute for Clinical and Experimental Pathology, University of Utah School of Medicine cHuntsman Cancer Institute, University of Utah dHigh Risk Pediatric Cancer Clinic, University of Utah eDepartment of Medicine and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.

Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis
|July 22, 2015
PubMed

Insights

Pegasparaginase treatment in children with acute lymphoblastic leukaemia/lymphoma increases thrombosis risk by reducing protein C and S activity. This impairs the body's natural blood clot regulation, highlighting a key mechanism behind this dangerous side effect.

Area of Science:

  • Hematology
  • Pediatric Oncology
  • Pharmacology

Background:

  • Pegasparaginase is a crucial component in treating pediatric acute lymphoblastic leukemia (ALL) and lymphoma.
  • Patients undergoing this treatment exhibit a higher incidence of thrombotic events.
  • The underlying mechanisms contributing to this increased thrombosis risk require further elucidation.

Purpose of the Study:

  • To investigate the impact of pegasparaginase on thrombin generation pathways.
  • To assess the role of thrombomodulin in modulating thrombin generation in patients treated with pegasparaginase.
  • To evaluate changes in protein C and protein S activity and antigen levels post-treatment.

Main Methods:

  • Paired plasma samples were collected from pediatric patients before and after pegasparaginase treatment.
  • Thrombin generation assays were performed in the presence and absence of thrombomodulin.
  • Protein C and protein S antigen levels were quantified using immunoassays.

Main Results:

  • Plasma samples obtained post-pegasparaginase treatment showed diminished sensitivity to thrombomodulin-mediated reduction in thrombin generation compared to pre-treatment samples.
  • This observation suggests impaired protein C and S anticoagulant pathway function.
  • A statistically significant decrease in both protein C and protein S antigen levels was detected after pegasparaginase administration.

Conclusions:

  • Alterations in the protein C and S pathway are implicated in the increased thrombosis risk associated with pegasparaginase therapy in pediatric ALL/lymphoma patients.
  • Reduced protein C and S activity and antigen levels may be a key factor contributing to thrombotic complications.
  • These findings underscore the importance of monitoring and potentially managing the protein C and S pathway in these patients.

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