OC 39.5 - Enhanced thrombin and plasmin generation profiles in alpha-2-antiplasmin deficient patients: Data from the RBiN study

Monday, June 24, 2024

10:30 – 10:45 ICT

Room: 208 A-D

Presenting Author(s)

Bauke Haisma, MD

PhD student
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands
Nijmegen, Gelderland, Netherlands

Co-Author(s)

NB

Nicole M.A. Blijlevens

Internist-hematologist
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands
Nijmegen, Gelderland, Netherlands
MC

Marjon H. Cnossen

MD, PhD, professor
Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
Rotterdam, Zuid-Holland, Netherlands
Pd

Paul L. den Exter

Hematologist
Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
Leiden, Zuid-Holland, Netherlands
IK

Ilmar C. Kruis

Healthcare and research working group member
Netherlands Hemophilia Society, Nijkerk, the Netherlands
Nijkerk, Gelderland, Netherlands
Karina Meijer

MD, PhD, professor
Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Groningen, Groningen, Netherlands
LN

Laurens Nieuwenhuizen

MD
Department of Hematology, Maxima Medisch Centrum, Eindhoven, The Netherlands
Eindhoven, Noord-Brabant, Netherlands
Nick van Es, MD PhD

Internist-vascular medicine
Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands
Amsterdam, Noord-Holland, Netherlands
Roger E.G. Schutgens

Internist-hematologist
Department of Benign Hematology, van Creveldkliniek, University Medical Center Utrecht and University Utrecht, Utrecht, the Netherlands
Utrecht, Utrecht, Netherlands
Sanna R. Rijpma, PhD

Clinical chemist
Laboratory of Hematology, Department of Laboratory Medicine, Radboud university medical center, Nijmegen, the Netherlands
Nijmegen, Gelderland, Netherlands
Wv

Waander L. van Heerde

CSO
Enzyre
Nijmegen, Gelderland, Netherlands
SS

Saskia E.M. Schols

Internist-hematologist
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands
Nijmegen, Gelderland, Netherlands

Background: Fibrinolysis regulation involves the plasmin-inhibiting protein alpha-2-antiplasmin (A2AP). A2AP deficiency is a rare and relatively unidentified bleeding disorder characterized by increased fibrinolysis and subsequent bleeding. Global hemostatic assays may provide more insight into the malfunctioning of coagulation and fibrinolysis in these patients.

Aims: To unravel the underlying thrombin and plasmin generation disbalance in A2AP deficient patients leading to their bleeding phenotype.

Methods: The Nijmegen Hemostasis Assay (NHA) was used to assess thrombin and plasmin generation in 23 A2AP deficient patients (median age 50 years, 70% women) from the RBiN study. Analyzed parameters included lag time, thrombin peak time, thrombin peak height, thrombin potential, fibrin lysis time, plasmin peak height, plasmin velocity index and plasmin potential. These parameters were expressed as percentages of a reference obtained from 37 healthy controls (median age 46 years, 57% women). The NHA data were correlated with A2AP activity levels and ISTH-BAT scores of the A2AP deficient patients using Pearson correlation coefficients.

Results: A2AP deficient patients displayed significantly shorter fibrin lysis times (73%) and higher plasmin peak heights (203%), plasmin velocity indices (302%) and plasmin potentials (154%) compared to healthy controls. Moreover, significantly higher thrombin potentials (146%) and thrombin peak heights (132%) were observed. Patients’ A2AP activity levels ranged from 23% to 83%. Lower A2AP activity levels correlated with shorter fibrin lysis times (R=0.81) and higher plasmin peak heights (R=-0.70), plasmin velocity indices (R=-0.86), thrombin potentials (R=-0.50) and thrombin peak heights (R=-0.49). Higher ISTH-BAT scores correlated with lower A2AP activity levels (R=-0.66), shorter fibrin lysis times (R=-0.67), higher plasmin peak heights (R=0.60) and higher plasmin velocity indices (R=0.68).

Conclusion(s): A2AP deficient patients exhibit enhanced plasmin generation profiles that correlated strongly with both A2AP activity level and bleeding phenotype. Interestingly, significantly increased thrombin generation profiles were also found, probably due to a physiological compensation mechanism to restore the hemostatic balance.