A new study published in Blood Advances uses Innovative Research recombinant tissue-type plasminogen activator (tPA)
Absence of hyperfibrinolysis may explain lack of efficacy of tranexamic acid in hypoproliferative thrombocytopenia
Anton Ilich, Terry B Gernsheimer, Darrell J Triulzi, Heather Herren, Siobhan P Brown, Lori A. Holle, Andrew T. Lucas, Bas de Laat, Nahed El Kassar, Alisa S. Wolberg, Susanne May, Nigel S Key
Blood Advances
August 31, 2022
https://doi.org/10.1182/bloodadvances.2022008255
Key Points
- No evidence of fibrinolytic activation was observed in patients with hypoproliferative thrombocytopenia
- tPA-based fibrinolytic assays correlated well with TXA plasma concentrations and may be used as PD parameters in clinical trials of TXA
The American Trial Using Tranexamic Acid (TXA) in Thrombocytopenia (A-TREAT, NCT02578901) demonstrated no superiority of TXA over placebo in preventing WHO grade 2 or higher bleeding in severely thrombocytopenic patients requiring supportive platelet transfusion following myeloablative therapy for hematologic disorders. In this ancillary study, we sought to determine whether this clinical outcome could be explained on the basis of correlative assays of fibrinolysis. Plasma was collected from A-TREAT participants (n=115) prior to initiation of study drug (baseline) and when TXA was at steady-state trough concentration (follow-up). Global fibrinolysis was measured by 3 assays: euglobulin clot lysis time (ECLT), plasmin generation (PG), and tPA-challenged clot lysis time (tPA-CLT). TXA was quantified in follow up samples by tandem mass spectrometry. Baseline samples did not demonstrate fibrinolytic activation by ECLT or tPA-CLT. Furthermore, neither ECLT nor levels of PAI-1, tPA, plasminogen, alpha2-antiplasmin or plasmin-antiplasmin complexes were associated with a greater risk of WHO grade 2+ bleeding. TXA trough concentrations were highly variable (range: 0.7-10 ug/ml) and did not correlate with bleeding severity, despite the fact that plasma TXA levels correlated strongly with pharmacodynamic assessments by PG (Spearman r, -0.78) or tPA-CLT (r, 0.74). We conclude: 1] No evidence of fibrinolytic activation 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 correlated well with TXA drug levels.
Read the study in Blood Advances.
