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Article ; Online: Mind and matter: The neurological complications of thrombotic thrombocytopenic purpura.

Shaw, Rebecca J / Dutt, Tina

2022 Volume 197, Issue 5, Page(s) 529–538

Abstract: Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal condition, with >90% mortality if untreated; deficiency of ADAMTS13 leads to widespread microvascular thromboses and organ injury particularly affecting organs with high shear ... ...

Abstract	Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal condition, with >90% mortality if untreated; deficiency of ADAMTS13 leads to widespread microvascular thromboses and organ injury particularly affecting organs with high shear stress, including the brain. The acute neurological complications have historically been those most feared by clinicians and synonymous with a poor prognosis. TTP, however, is no longer perceived as two extremes of acute presentation and remission, rather once diagnosed a chronic condition with the potential for a long-term symptom burden. Optimal neuroimaging timing and modality lacks consensus and as we learn more about the changes seen during the acute and chronic stages of TTP, there is scope for neuroimaging to play a greater role in guiding management and the secondary prevention of vascular disease. Reduced ADAMTS13 activity levels have been associated with increased thrombotic risk and novel therapies including caplacizumab and recombinant ADAMTS13 may offer a neuroprotective role. Given the increasing evidence of the neurocognitive and psychological disease in TTP, the importance of screening and timely intervention should not be underestimated. As more patients are surviving their initial TTP presentation, it is crucial for us to develop a greater understanding of the longer-term morbidity affecting these patients.
MeSH term(s)	ADAMTS13 Protein ; Humans ; Purpura, Thrombotic Thrombocytopenic/complications ; Purpura, Thrombotic Thrombocytopenic/diagnosis ; Purpura, Thrombotic Thrombocytopenic/therapy
Chemical Substances	ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2022-03-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.18127
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Article ; Online: Integrating psychology services for patients with thrombotic thrombocytopenic purpura: A specialist centre experience.

Shaw, Rebecca J / Bell, Joanne / Poole, Jason / Feely, Conor / Chetter, James / Dutt, Tina

EJHaem

2023 Volume 4, Issue 3, Page(s) 872–875

Language	English
Publishing date	2023-07-01
Publishing country	United States
Document type	Journal Article
ISSN	2688-6146
ISSN (online)	2688-6146
DOI	10.1002/jha2.726
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Article ; Online: Re-evaluation of the risk of venous thromboembolism after COVID-19 vaccination using haematological criteria

Shaw, Rebecca J. / Doyle, Andrew J. / Millen, Emily A. / Stowe, Julia / Tessier, Elise / Andrews, Nick / Miller, Elizabeth

Vaccine. 2023 Aug., v. 41, no. 36 p.5330-5337

2023

Abstract: An elevated risk of venous thromboembolism (VTE) following a first dose of the ChAdOx1 adenovirus-vectored vaccine was found in a national epidemiological study in England using routine discharge diagnosis codes. Separately, the syndrome of vaccine- ... ...

Institution	HaemSTAR collaborators
Abstract	An elevated risk of venous thromboembolism (VTE) following a first dose of the ChAdOx1 adenovirus-vectored vaccine was found in a national epidemiological study in England using routine discharge diagnosis codes. Separately, the syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) was identified using haematological criteria based on presence of thrombocytopenia, significantly elevated D-dimers and development of anti-PF4 antibodies. To re-evaluate risk estimates using haematological criteria, we obtained the haematology results for hospital admitted patients aged 18–64 years in 43 National Health Service trusts in England who were included in the national epidemiological study. Diagnoses were confirmed and haematological parameters obtained from local records without knowledge of vaccination status. The haematological parameters in patients admitted for a confirmed VTE following ChAdOx1 or BNT162b2 mRNA vaccination were then compared with those in a randomly selected 40% sample of unvaccinated patients with VTE. Overall, 12 (14%) of the 84 vaccinated cases had a diagnosis compatible with VITT, 11 after a first dose of ChAdOx1 and one after a first dose of BNT162b2. Thrombocytopenia (platelet count <150 × 10⁹/L) occurred in 17 vaccinated (20%) and 4 (4%) of 108 unvaccinated patients, with all 6 cases of severe thrombocytopenia (<50 × 10⁹/L) occurring within 42 days of a first dose of ChAdOx1. The attributable risk estimates for a cerebral venous thrombosis (CVT) or other VTE with thrombocytopenia after a first dose of ChAdOx1 vaccine were 2.82 and 9.62 per million doses respectively. However, elevated risks were also found after a first dose of ChAdOx1 for VTE without thrombocytopenia with relative incidences for CVT and other VTE of 2.67 (1.77–3.77) and 1.93 (1.57–2.35) respectively. While we identified a distinct population with features of VITT within 42 days of receiving ChAdOx1 vaccination, confirming current diagnostic criteria, we also found evidence of an increased risk of a VTE without thrombocytopenia after ChAdOx1 vaccine.
Keywords	COVID-19 infection ; blood platelet count ; epidemiological studies ; health services ; hematology ; hospitals ; risk ; thrombocytopenia ; thrombosis ; vaccination ; vaccines ; England ; COVID-19 ; Venous thromboembolism
Language	English
Dates of publication	2023-08
Size	p. 5330-5337.
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2023.06.006
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Article ; Online: Re-evaluation of the risk of venous thromboembolism after COVID-19 vaccination using haematological criteria.

Shaw, Rebecca J / Doyle, Andrew J / Millen, Emily A / Stowe, Julia / Tessier, Elise / Andrews, Nick / Miller, Elizabeth

Vaccine

2023 Volume 41, Issue 36, Page(s) 5330–5337

Abstract	An elevated risk of venous thromboembolism (VTE) following a first dose of the ChAdOx1 adenovirus-vectored vaccine was found in a national epidemiological study in England using routine discharge diagnosis codes. Separately, the syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) was identified using haematological criteria based on presence of thrombocytopenia, significantly elevated D-dimers and development of anti-PF4 antibodies. To re-evaluate risk estimates using haematological criteria, we obtained the haematology results for hospital admitted patients aged 18-64 years in 43 National Health Service trusts in England who were included in the national epidemiological study. Diagnoses were confirmed and haematological parameters obtained from local records without knowledge of vaccination status. The haematological parameters in patients admitted for a confirmed VTE following ChAdOx1 or BNT162b2 mRNA vaccination were then compared with those in a randomly selected 40% sample of unvaccinated patients with VTE. Overall, 12 (14%) of the 84 vaccinated cases had a diagnosis compatible with VITT, 11 after a first dose of ChAdOx1 and one after a first dose of BNT162b2. Thrombocytopenia (platelet count <150 × 10
MeSH term(s)	Humans ; Venous Thromboembolism/epidemiology ; Venous Thromboembolism/etiology ; BNT162 Vaccine ; COVID-19 Vaccines/adverse effects ; State Medicine ; COVID-19/epidemiology ; COVID-19/prevention & control ; Vaccination/adverse effects ; Thrombocytopenia/chemically induced ; Thrombocytopenia/epidemiology ; Purpura, Thrombocytopenic, Idiopathic ; Hematology
Chemical Substances	BNT162 Vaccine ; COVID-19 Vaccines
Language	English
Publishing date	2023-06-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2023.06.006
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Article ; Online: Intracranial hemorrhage in immune thrombotic thrombocytopenic purpura treated with caplacizumab.

Schofield, Jeremy / Shaw, Rebecca J / Lester, Will / Thomas, Will / Toh, Cheng-Hock / Dutt, Tina

Journal of thrombosis and haemostasis : JTH

2021 Volume 19, Issue 8, Page(s) 1922–1925

MeSH term(s)	ADAMTS13 Protein ; Humans ; Intracranial Hemorrhages/chemically induced ; Purpura, Thrombotic Thrombocytopenic/diagnosis ; Purpura, Thrombotic Thrombocytopenic/drug therapy ; Single-Domain Antibodies ; von Willebrand Factor
Chemical Substances	Single-Domain Antibodies ; von Willebrand Factor ; caplacizumab (2R27AB6766) ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2021-06-09
Publishing country	England
Document type	Case Reports
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.15363
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Article ; Online: COVID-19 and immunothrombosis: emerging understanding and clinical management.

Shaw, Rebecca J / Bradbury, Charlotte / Abrams, Simon T / Wang, Guozheng / Toh, Cheng-Hock

British journal of haematology

2021 Volume 194, Issue 3, Page(s) 518–529

Abstract: The COVID-19 pandemic has been the most significant health crisis in recent global history. Early studies from Wuhan highlighted COVID-19-associated coagulopathy and a significant association with mortality was soon recognised. As research continues ... ...

Abstract	The COVID-19 pandemic has been the most significant health crisis in recent global history. Early studies from Wuhan highlighted COVID-19-associated coagulopathy and a significant association with mortality was soon recognised. As research continues across the world, more evidence is emerging of the cross-talk between the innate immune system, coagulation activation and inflammation. Immunothrombosis has been demonstrated to play a key role in the pathophysiology of severe COVID-19, with extracellular histones and neutrophil extracellular traps detected in the plasma and cardiopulmonary tissues of critically ill patients. Targeting the components of immunothrombosis is becoming an important factor in the treatment of patients with COVID-19 infection. Recent studies report outcomes of intermediate and therapeutic anticoagulation in hospitalised patients with varying severities of COVID-19 disease, including optimal dosing and associated bleeding risks. Immunomodulatory therapies, including corticosteroids and IL-6 receptor antagonists, have been demonstrated to significantly reduce mortality in COVID-19 patients. As the pandemic continues, more studies are required to understand the driving factors and upstream mechanisms for coagulopathy and immunothrombosis in COVID-19, and thus potentially develop more targeted therapies for SARS-CoV-2 infection, both in the acute phase and in those who develop longer-term symptom burden.
MeSH term(s)	Animals ; Blood Coagulation ; COVID-19/blood ; COVID-19/complications ; COVID-19/immunology ; COVID-19/therapy ; Disease Management ; Humans ; Immunogenic Cell Death ; Inflammation/blood ; Inflammation/etiology ; Inflammation/immunology ; Inflammation/therapy ; SARS-CoV-2/immunology ; Thrombosis/blood ; Thrombosis/etiology ; Thrombosis/immunology ; Thrombosis/therapy
Language	English
Publishing date	2021-07-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.17664
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Article ; Online: Damage-associated cellular markers in the clinical and pathogenic profile of vaccine-induced immune thrombotic thrombocytopenia.

Abrams, Simon T / Du, Min / Shaw, Rebecca J / Johnson, Carla / McGuinness, Dagmara / Schofield, Jeremy / Yong, Jun / Turtle, Lance / Nicolson, Phillip L R / Moxon, Christopher / Wang, Guozheng / Toh, Cheng-Hock

Journal of thrombosis and haemostasis : JTH

2023 Volume 22, Issue 4, Page(s) 1145–1153

Abstract: Background: Adenoviral vector-based COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) is rare but carries significant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully ... ...

Abstract	Background: Adenoviral vector-based COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) is rare but carries significant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully understood. The objectives were to explore the pathophysiological profile and examine for clinically informative biomarkers in patients with severe VITT. Methods: Twenty-two hospitalized patients with VITT, 9 pre- and 21 post-ChAdOx1 vaccine controls, were recruited across England, United Kingdom. Admission blood samples were analyzed for cytokine profiles, cell death markers (lactate dehydrogenase and circulating histones), neutrophil extracellular traps, and coagulation parameters. Tissue specimens from deceased patients were analyzed. Results: There were strong immune responses characterized by significant elevations in proinflammatory cytokines and T helper 1 and 2 cell activation in patients with VITT. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also significantly elevated. About 70% (n = 15/22) of patients met the International Society for Thrombosis and Haemostasis criteria for disseminated intravascular coagulation despite negligible changes in the prothrombin time. The increased neutrophil extracellular trap formation, in conjunction with marked lymphopenia, elevated lactate dehydrogenase, and circulating histone levels, indicates systemic immune cell injury or death. Both lymphopenia and circulating histone levels independently predicted 28-day mortality in patients with VITT. Conclusion: The coupling of systemic cell damage and death with strong immune-inflammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.
MeSH term(s)	Humans ; Histones ; COVID-19 Vaccines/adverse effects ; Purpura, Thrombocytopenic, Idiopathic ; Thrombocytopenia ; Thrombosis ; Vaccines ; Lymphopenia ; Lactate Dehydrogenases
Chemical Substances	Histones ; COVID-19 Vaccines ; Vaccines ; Lactate Dehydrogenases (EC 1.1.-)
Language	English
Publishing date	2023-12-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2023.12.008
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Article ; Online: Circulating histones play a central role in COVID-19-associated coagulopathy and mortality.

Shaw, Rebecca J / Abrams, Simon T / Austin, James / Taylor, Joseph M / Lane, Steven / Dutt, Tina / Downey, Colin / Du, Min / Turtle, Lance / Baillie, J Kenneth / Openshaw, Peter J M / Wang, Guozheng / Semple, Malcolm G / Toh, Cheng-Hock

Haematologica

2021 Volume 106, Issue 9, Page(s) 2493–2498

MeSH term(s)	Blood Coagulation ; Blood Coagulation Disorders/etiology ; COVID-19 ; Histones ; Humans ; SARS-CoV-2
Chemical Substances	Histones
Language	English
Publishing date	2021-09-01
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2021.278492
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Article ; Online: Real-world experience with caplacizumab in the management of acute TTP.

Dutt, Tina / Shaw, Rebecca J / Stubbs, Matthew / Yong, Jun / Bailiff, Benjamin / Cranfield, Tanya / Crowley, Maeve P / Desborough, Michael / Eyre, Toby A / Gooding, Richard / Grainger, John / Hanley, John / Haughton, Joanna / Hermans, Joannes / Hill, Quentin / Humphrey, Louise / Lowe, Gillian / Lyall, Hamish / Mohsin, Muhammad /

Nicolson, Phillip L R / Priddee, Nicole / Rampotas, Alexandros / Rayment, Rachel / Rhodes, Susan / Taylor, Alice / Thomas, William / Tomkins, Oliver / Van Veen, Joost J / Lane, Steven / Toh, Cheng-Hock / Scully, Marie

Blood

2020 Volume 137, Issue 13, Page(s) 1731–1740

Abstract: The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 ... ...

Abstract	The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Disease Management ; Female ; Fibrinolytic Agents/adverse effects ; Fibrinolytic Agents/therapeutic use ; Humans ; Male ; Middle Aged ; Purpura, Thrombotic Thrombocytopenic/drug therapy ; Purpura, Thrombotic Thrombocytopenic/epidemiology ; Single-Domain Antibodies/adverse effects ; Single-Domain Antibodies/therapeutic use ; Treatment Outcome ; United Kingdom/epidemiology ; Young Adult ; von Willebrand Factor/antagonists & inhibitors
Chemical Substances	Fibrinolytic Agents ; Single-Domain Antibodies ; von Willebrand Factor ; caplacizumab (2R27AB6766)
Language	English
Publishing date	2020-10-22
Publishing country	United States
Document type	Journal Article ; Multicenter Study
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2020007599
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