Fibrinogenolysis and fibrinolysis in Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT)

Megan Simpson; Anuj Narwal; Eric West; Jill Martin; Catherine N Bagot; Andrew R Page; Henry G Watson; Claire S Whyte; Nicola J Mutch

doi:10.1016/j.jtha.2023.09.007

Fibrinogenolysis and fibrinolysis in Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT)

Megan Simpson, Anuj Narwal, Eric West, Jill Martin, Catherine N Bagot, Andrew R Page, Henry G Watson, Claire S Whyte, Nicola J Mutch^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

BACKGROUND: Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterised by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer and hypofibrinogenemia.

OBJECTIVE: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT.

METHODS: Plasma from 18 suspected VITT cases was tested for anti-PF4 by ELISA and characterised as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII, plasmin-α2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, factor XIII-A and plasminogen.

RESULTS: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation (DIC) while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1β, IL-6, IL-8, TNFα and C-reactive protein. In VITT patients, both fibrinogen and factor XIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors.

CONCLUSIONS: VITT patients show evidence of overt DIC and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.

Original language	English
Pages (from-to)	3589-3596
Number of pages	8
Journal	Journal of Thrombosis and Haemostasis
Volume	21
Issue number	12
Early online date	19 Sept 2023
DOIs	https://doi.org/10.1016/j.jtha.2023.09.007
Publication status	Published - Dec 2023

Bibliographical note

Acknowledgements
The authors would like to thank all the patients whose samples were used as part of this study, and all the NHS Scotland staff who collected patient samples and looked after these patients. We thank Aberdeen Royal Infirmary Haematology laboratory for conducting the anti-platelet factor 4 antibody testing and Dr Sue Pavord, Consultant Haematologist at Oxford Teaching Hospitals for help in gathering clinical data on the patients.
Funding
This research was supported by The University of Aberdeen Development Trust (RG16009). CSW and NJM are supported by the British Heart Foundation (PG/15/82/31721; PG/20/17/35050).

Keywords

Fibrinolysis
plasmin
thrombosis
vaccine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Simpson_etal_JTH_Fibrinogenolysis_and_Fibrinolysis_VOR
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Cite this

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title = "Fibrinogenolysis and fibrinolysis in Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT)",

abstract = "BACKGROUND: Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterised by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer and hypofibrinogenemia.OBJECTIVE: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT.METHODS: Plasma from 18 suspected VITT cases was tested for anti-PF4 by ELISA and characterised as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII, plasmin-α2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, factor XIII-A and plasminogen.RESULTS: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation (DIC) while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1β, IL-6, IL-8, TNFα and C-reactive protein. In VITT patients, both fibrinogen and factor XIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors.CONCLUSIONS: VITT patients show evidence of overt DIC and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.",

keywords = "Fibrinolysis, plasmin, thrombosis, vaccine",

author = "Megan Simpson and Anuj Narwal and Eric West and Jill Martin and Bagot, {Catherine N} and Page, {Andrew R} and Watson, {Henry G} and Whyte, {Claire S} and Mutch, {Nicola J}",

note = "Acknowledgements The authors would like to thank all the patients whose samples were used as part of this study, and all the NHS Scotland staff who collected patient samples and looked after these patients. We thank Aberdeen Royal Infirmary Haematology laboratory for conducting the anti-platelet factor 4 antibody testing and Dr Sue Pavord, Consultant Haematologist at Oxford Teaching Hospitals for help in gathering clinical data on the patients. Funding This research was supported by The University of Aberdeen Development Trust (RG16009). CSW and NJM are supported by the British Heart Foundation (PG/15/82/31721; PG/20/17/35050).",

year = "2023",

month = dec,

doi = "10.1016/j.jtha.2023.09.007",

language = "English",

volume = "21",

pages = "3589--3596",

journal = "Journal of Thrombosis and Haemostasis",

issn = "1538-7933",

publisher = "Wiley-Blackwell ",

number = "12",

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TY - JOUR

T1 - Fibrinogenolysis and fibrinolysis in Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT)

AU - Simpson, Megan

AU - Narwal, Anuj

AU - West, Eric

AU - Martin, Jill

AU - Bagot, Catherine N

AU - Page, Andrew R

AU - Watson, Henry G

AU - Whyte, Claire S

AU - Mutch, Nicola J

N1 - Acknowledgements The authors would like to thank all the patients whose samples were used as part of this study, and all the NHS Scotland staff who collected patient samples and looked after these patients. We thank Aberdeen Royal Infirmary Haematology laboratory for conducting the anti-platelet factor 4 antibody testing and Dr Sue Pavord, Consultant Haematologist at Oxford Teaching Hospitals for help in gathering clinical data on the patients. Funding This research was supported by The University of Aberdeen Development Trust (RG16009). CSW and NJM are supported by the British Heart Foundation (PG/15/82/31721; PG/20/17/35050).

PY - 2023/12

Y1 - 2023/12

N2 - BACKGROUND: Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterised by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer and hypofibrinogenemia.OBJECTIVE: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT.METHODS: Plasma from 18 suspected VITT cases was tested for anti-PF4 by ELISA and characterised as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII, plasmin-α2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, factor XIII-A and plasminogen.RESULTS: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation (DIC) while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1β, IL-6, IL-8, TNFα and C-reactive protein. In VITT patients, both fibrinogen and factor XIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors.CONCLUSIONS: VITT patients show evidence of overt DIC and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.

AB - BACKGROUND: Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterised by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer and hypofibrinogenemia.OBJECTIVE: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT.METHODS: Plasma from 18 suspected VITT cases was tested for anti-PF4 by ELISA and characterised as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII, plasmin-α2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, factor XIII-A and plasminogen.RESULTS: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation (DIC) while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1β, IL-6, IL-8, TNFα and C-reactive protein. In VITT patients, both fibrinogen and factor XIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors.CONCLUSIONS: VITT patients show evidence of overt DIC and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.

KW - Fibrinolysis

KW - plasmin

KW - thrombosis

KW - vaccine

U2 - 10.1016/j.jtha.2023.09.007

DO - 10.1016/j.jtha.2023.09.007

M3 - Article

C2 - 37734715

SN - 1538-7933

VL - 21

SP - 3589

EP - 3596

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

IS - 12

ER -

Fibrinogenolysis and fibrinolysis in Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT)

Abstract

Bibliographical note

Keywords

UN SDGs

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