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2094 Absence of Hyperactivation of Fibrinolysis Explains the Lack of Hemostatic Efficacy of Prophylactic Tranexamic Acid (TXA) in Hypoproliferative Thrombocytopenia

Program: Oral and Poster Abstracts
Session: 321. Coagulation and Fibrinolysis: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical Practice (Health Services and Quality), Non-Biological therapies, Therapies, Biological Processes, Technology and Procedures, pathogenesis
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Anton Ilich, MD1*, Terry B. Gernsheimer, MD2, Darrell J Triulzi, MD3, Heather Herren, RN, MPH4*, Siobhan P Brown, PhD4*, Lori A Holle5*, Andrew T Lucas, Pharm D6*, Nahed El Kassar, MD, PhD7*, Alisa S. Wolberg, PhD8, Susanne May, PhD4* and Nigel S Key5

1Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
2Department of Medicine, Division of Hematology, University of Washington School of Medicine, Seattle, WA
3Division of Transfusion Medicine, Institute for Transfusion Medicine, Pittsburgh, PA
4Department of Biostatistics, University of Washington, Seattle, WA
5UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
6Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina At Chapel Hill, Chapel Hill, NC
7National Heart Lung and Blood Institute (NHLBI), National Institute of Health, Bethesda, MD
8UNC Blood Research Center, University of North Carolina At Chapel Hill, Chapel Hill, NC

Background: We previously reported the results of the A-TREAT study (American Trial Using Tranexamic Acid in Thrombocytopenia: NCT02578901). This randomized double-blind placebo-controlled trial demonstrated that TXA administration is not superior to placebo in preventing WHO grade 2 or higher bleeding in severely thrombocytopenic patients requiring supportive platelet transfusion following myeloablative therapy for hematologic disorders (Gernsheimer T., ASH 2020 Plenary Session).

Here, we present results of the A-TREAT ancillary study – Fibrinolysis Evaluation in A-TREAT (FEAT). Blood samples were collected from a subset (n=115) of A-TREAT participants just prior to initiation of study drug (when the platelet count was <30,000/µl) and at a later time point when TXA was at a steady state trough level (5 ±2 days following study drug initiation). Using global assays of fibrinolysis in plasma, our a priori hypotheses were that: 1] a baseline ‘hyperfibrinolytic’ profile would be associated with a higher proportion of grade 2+ bleeding; and 2] trough TXA levels would be associated with a ‘hypofibrinolytic’ profile and a lower proportion of grade 2+ bleeding.

Methods: Fibrinolysis in platelet-free citrated plasma was assessed by 3 global assays: euglobulin clot lysis time (ECLT), plasmin generation (PG), and tPA resistance clot lysis time (tPA-CLT) using previously described methods (Ilich A. RPTH 2020, Miszta A. JTH 2021). Trough plasma TXA concentration was measured using a validated tandem mass spectrometry assay. Individual fibrinolytic analytes (PAI-1, tPA, plasminogen, alpha2-antiplasmin and plasmin-antiplasmin complexes) were quantified by ELISA.

Results: Baseline samples did not demonstrate a hyperfibrinolytic profile by ECLT. To the contrary, ECLT values were significantly increased compared to healthy controls (figure 1). Furthermore, none of the measured fibrinolytic parameters (ECLT, tPA-CLT, total PAI-1, tPA, plasminogen, alpha2-antiplasmin or plasmin-antiplasmin complexes) at baseline were associated with a greater risk of grade 2+ bleeding during follow up, regardless of treatment arm. On the follow-up samples, neither pharmacokinetic (trough TXA concentration) nor pharmacodynamic parameters (PG or tPA-CLT) were associated with bleeding severity. A high inter-patient variability of TXA trough concentrations was noted in the treatment arm (min-max: 0.7-10 ug/ml), and drug levels correlated strongly with global fibrinolysis assessment by PG (Spearman r, -0.78, 95% CI -0.88 – -0.62) and tPA-CLT (r, 0.74, 0.56 – 0.85) (figure 2).

Conclusions:

1] No evidence of fibrinolytic hyperactivation was observed in these thrombocytopenic patients;

2] trough TXA concentrations varied significantly between patients receiving the same dosing schedule; and

3] tPA-CLT and PG parameters correlated well with TXA plasma concentrations and thus may be used to estimate the extent of fibrinolytic inhibition in patients treated with TXA.

Discussion: The absence of hyperactivation of endogenous fibrinolysis in this study is in contrast to our recent findings in trauma. Specifically, we reported that almost half of trauma patients demonstrated evidence of fibrinolytic hyperactivation (by ECLT) on admission (Ilich A. Thromb Res, 2021). Since TXA has been shown to reduce mortality due to bleeding in trauma (CRASH II, Lancet, 2010) and given that baseline hyperfibrinolysis is common in trauma, we hypothesize that the absence of fibrinolytic hyperactivation observed in the A-TREAT study patients likely explains the clinical lack of efficacy of TXA.

Disclosures: Gernsheimer: Amgen: Honoraria; Novartis: Honoraria; Principia: Research Funding; Rigel: Research Funding; Cellphire: Consultancy; Dova: Consultancy; Sanofi: Consultancy. Triulzi: Fresenius Kabi: Membership on an entity's Board of Directors or advisory committees; Realta: Membership on an entity's Board of Directors or advisory committees. Wolberg: Takeda: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; CSL Behring: Consultancy. Key: BioMarin: Consultancy, Honoraria, Other: Participation as a clinical trial investigator; Takeda: Research Funding; Grifols: Research Funding; Sanofi: Consultancy; Uniqure: Consultancy, Other: Participation as a clinical trial investigator, HOPE-B Steering Committee, Research Funding.

*signifies non-member of ASH