TY - JOUR
T1 - Plasma from patients with vaccine-induced immune thrombotic thrombocytopenia displays increased fibrinolytic potential and enhances tissue-type plasminogen activator but not urokinase-mediated plasminogen activation
AU - Keragala, Charithani B.
AU - McFadyen, James D.
AU - Ho, Heidi
AU - McCutcheon, Fiona M.
AU - Liu, Zikou
AU - Stevens, Hannah
AU - Monagle, Paul
AU - Chunilal, Sanjeev
AU - Medcalf, Robert L.
AU - Tran, Huyen
N1 - Funding Information:
Funding information This study was supported (in part) by research funding from the Medical Research Future Fund (Australia; grant 2015305 to H.T.).
Funding Information:
This study was supported (in part) by research funding from the Medical Research Future Fund (Australia) to H.T. (grant ID: 2015305). C.B.K was supported by a Research Training Program Scholarship from Monash University. J.M. is supported by a Heart Foundation Future Leader Fellowship The authors would also like to acknowledge the contribution of Joanne Haywood and team at the Special Coagulation Laboratory (Monash Health, Clayton) and Dr Emma Leitinger (hematologist, Monash Health, Clayton) for their role in the collection and processing of plasma samples used in this study. We also would like to acknowledge Associate Professor Vivien Chen and members of the flow cytometry laboratory (Concord Hospital, New South Wales, Australia) and Associate Professor Tim Brighton (Prince of Wales Hospital, New South Wales, Australia) for the provision of functional platelet activation results and their role in adjudicating the diagnosis of vaccine-induced immune thrombotic thrombocytopenia.
Funding Information:
This study was supported (in part) by research funding from the Medical Research Future Fund (Australia) to H.T. (grant ID: 2015305). C.B.K was supported by a Research Training Program Scholarship from Monash University. J.M. is supported by a Heart Foundation Future Leader Fellowship The authors would also like to acknowledge the contribution of Joanne Haywood and team at the Special Coagulation Laboratory (Monash Health, Clayton) and Dr Emma Leitinger (hematologist, Monash Health, Clayton) for their role in the collection and processing of plasma samples used in this study. We also would like to acknowledge Associate Professor Vivien Chen and members of the flow cytometry laboratory (Concord Hospital, New South Wales, Australia) and Associate Professor Tim Brighton (Prince of Wales Hospital, New South Wales, Australia) for the provision of functional platelet activation results and their role in adjudicating the diagnosis of vaccine-induced immune thrombotic thrombocytopenia. C.B.K. and R.L.M. performed literature search, conceptualization, preparation of figures, study design, data collection, data analysis, data interpretation, and writing and editing of the manuscript. J.D.M. performed the literature search, conceptualization, study design, data analysis, data interpretation, and writing and editing of the manuscript. H.H. performed data collection, data analysis, and data interpretation. F.M.M. H.S. P.M. and S.C. performed data collection, data analysis, data interpretation, and writing and editing of the manuscript. Z.L. prepared the figures and performed data collection, data analysis, and data interpretation. H.T. performed literature search, conceptualization, study design, data collection, data analysis, data interpretation, and writing and editing of the manuscript. C.B.K. H.H. F.M.M. Z.L. H.S. and R.L.M. have no conflict of interest to declare. J.D.M. P.M. S.C. and H.T. declare that they were coinvestigators on a Medical Research Future Fund (Australia; ID: 2015305) that provided the funds for this project. P.M. also declares being an associate investigator of a grant provided by AstraZeneca related to COVID-19 vaccines, being on the AstraZeneca Advisory Board (unpaid) for the Asia-Pacific Thrombosis with thrombocytopenia meeting, and being on the International Society for Thrombosis and Haemostasis Guidelines and Guidance Committee and was in receipt of the AstraZeneca vaccine exploring the differences in the response to vaccination with the AstraZeneca and Pfizer vaccines. Funding information This study was supported (in part) by research funding from the Medical Research Future Fund (Australia; grant 2015305 to H.T.).
Funding Information:
Venous blood was collected from 10 patients diagnosed with VITT according to national and international guidelines [ 3 , 6 , 7 ] ( Supplementary Table ) as part of the VITT case-control study, funded by Medical Research Future Fund grant 2015305 (ethics approval number 85392). The clinical and laboratory characteristics of these cases are summarized in Table 1 . Sixty percent of these patients were male (median age of 58.5 years), presenting approximately 10 days after the first dose of ChAdOx1 nCoV19 vaccine. A single case (patient 8) did not have radiological confirmation of thrombosis but fulfilled the criteria for “Pre-VITT” having presented with severe headaches [ 8 ] and after adjudication by the Thrombosis and Haemostasis Society of Australia and New Zealand VITT working group, was included as a positive case. The median D-dimer value in the VITT patient group was 40 × the upper limit of normal (ULN).
Publisher Copyright:
© 2023 International Society on Thrombosis and Haemostasis
PY - 2024/3
Y1 - 2024/3
N2 - Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus vector-based COVID-19 vaccines. VITT is associated with markedly raised levels of D-dimer; yet, how VITT modulates the fibrinolytic system is unknown. Objectives: We aimed to compare changes in fibrinolytic activity in plasma from patients with VITT, patients diagnosed with venous thromboembolism (VTE) after vaccination but without VITT (VTE–no VITT), and healthy vaccinated controls. Methods: Plasma levels of plasmin-antiplasmin (PAP) complexes, plasminogen, and alpha-2-antiplasmin (α2AP) from 10 patients with VITT, 10 patients with VTE–no VITT, and 14 healthy vaccinated controls were evaluated by enzyme-linked immunosorbent assay and/or Western blotting. Fibrinolytic capacity was evaluated by quantitating PAP levels at baseline and after ex vivo plasma stimulation with 50-nM tissue-type plasminogen activator (tPA) or urokinase for 5 minutes. Results: Baseline PAP complex levels in control and VTE–no VITT individuals were similar but were ∼7-fold higher in plasma from patients with VITT (P < .0001). VITT samples also revealed consumption of α2AP and fibrinogenolysis consistent with a hyperfibrinolytic state. Of interest, VITT plasma produced significantly higher PAP levels after ex vivo treatment with tPA, but not urokinase, compared to the other groups, indicative of increased fibrinolytic potential. This was not due to D-dimer as addition of D-dimer to VTE–no VITT plasma failed to potentiate tPA-induced PAP levels. Conclusion: A marked hyperfibrinolytic state occurs in patients with VITT, evidenced by marked elevations in PAP, α2AP consumption, and fibrinogenolysis. An unidentified plasma cofactor that selectively potentiates tPA-mediated plasminogen activation also appears to exist in the plasma of patients with VITT.
AB - Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus vector-based COVID-19 vaccines. VITT is associated with markedly raised levels of D-dimer; yet, how VITT modulates the fibrinolytic system is unknown. Objectives: We aimed to compare changes in fibrinolytic activity in plasma from patients with VITT, patients diagnosed with venous thromboembolism (VTE) after vaccination but without VITT (VTE–no VITT), and healthy vaccinated controls. Methods: Plasma levels of plasmin-antiplasmin (PAP) complexes, plasminogen, and alpha-2-antiplasmin (α2AP) from 10 patients with VITT, 10 patients with VTE–no VITT, and 14 healthy vaccinated controls were evaluated by enzyme-linked immunosorbent assay and/or Western blotting. Fibrinolytic capacity was evaluated by quantitating PAP levels at baseline and after ex vivo plasma stimulation with 50-nM tissue-type plasminogen activator (tPA) or urokinase for 5 minutes. Results: Baseline PAP complex levels in control and VTE–no VITT individuals were similar but were ∼7-fold higher in plasma from patients with VITT (P < .0001). VITT samples also revealed consumption of α2AP and fibrinogenolysis consistent with a hyperfibrinolytic state. Of interest, VITT plasma produced significantly higher PAP levels after ex vivo treatment with tPA, but not urokinase, compared to the other groups, indicative of increased fibrinolytic potential. This was not due to D-dimer as addition of D-dimer to VTE–no VITT plasma failed to potentiate tPA-induced PAP levels. Conclusion: A marked hyperfibrinolytic state occurs in patients with VITT, evidenced by marked elevations in PAP, α2AP consumption, and fibrinogenolysis. An unidentified plasma cofactor that selectively potentiates tPA-mediated plasminogen activation also appears to exist in the plasma of patients with VITT.
KW - fibrinogenolysis
KW - fibrinolysis
KW - plasmin-antiplasmin complexes
KW - plasminogen activation
KW - VITT
UR - https://www.scopus.com/pages/publications/85178634822
U2 - 10.1016/j.jtha.2023.10.027
DO - 10.1016/j.jtha.2023.10.027
M3 - Article
C2 - 37944898
AN - SCOPUS:85178634822
SN - 1538-7933
VL - 22
SP - 785
EP - 793
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 3
ER -
SDG 3 Good Health and Well-being