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  1. Article ; Online: Novel antiplatelet strategies targeting VWF and GPIb.

    Prasannan, Nithya / Scully, Marie

    Platelets

    2020  Volume 32, Issue 1, Page(s) 42–46

    Abstract: Von Willebrand factor has a pivotal role in primary hemostasis. Its role in thrombotic microangiopathies (TMA), as well as cardiovascular disease, has been demonstrated. Thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy, is a life- ... ...

    Abstract Von Willebrand factor has a pivotal role in primary hemostasis. Its role in thrombotic microangiopathies (TMA), as well as cardiovascular disease, has been demonstrated. Thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy, is a life-threatening condition with a high mortality rate if untreated. Current management strategies comprise plasma exchange to remove autoantibodies and replenish ADAMTS13, along with immunosuppressive agents in immune TTP. This review focuses on novel antiplatelet strategies that target VWF and GPIb. The benefits of the nanobody caplacizumab in achieving faster normalization of platelet count, as well as reduced thromboembolic events were shown through TITAN and HERCULES trials, and these findings have been practice changing. The use of caplacizumab in patients with immune TTP (iTTP) has now become well established. Potential benefits of ARC1779 and N-acetylcysteine have also been shown on a small scale in iTTP, however these lack evidence through larger randomized controlled trials. Further therapies, some in early phase, others in clinical practice, target platelet aggregation within arteries and their utility is presented with cerebrovascular disorders.
    MeSH term(s) Humans ; Platelet Aggregation Inhibitors/pharmacology ; Platelet Aggregation Inhibitors/therapeutic use ; Platelet Glycoprotein GPIb-IX Complex/metabolism ; von Willebrand Factor/metabolism
    Chemical Substances Platelet Aggregation Inhibitors ; Platelet Glycoprotein GPIb-IX Complex ; glycoprotein receptor GPIb-IX ; von Willebrand Factor
    Language English
    Publishing date 2020-07-02
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1034283-7
    ISSN 1369-1635 ; 0953-7104
    ISSN (online) 1369-1635
    ISSN 0953-7104
    DOI 10.1080/09537104.2020.1786038
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2888: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Peak ADAMTS13 activity to assess ADAMTS13 conformation and risk of relapse in immune-mediated Thrombotic Thrombocytopenic Purpura.

    Prasannan, Nithya / Dragunaite, Bertina / Subhan, Maryam Owais / Thomas, Mari / de Groot, Rens / Singh, Deepak / Vanhoorelbeke, Karen / Scully, Marie

    Blood

    2024  

    Abstract: Previous studies have demonstrated that more than 38% of immune-mediated thrombotic thrombocytopenic purpura (TTP) patients in remission with activity >50% had an open ADAMTS13 conformation. We assessed ADAMTS13 conformation in remission (ADAMTS13 ... ...

    Abstract Previous studies have demonstrated that more than 38% of immune-mediated thrombotic thrombocytopenic purpura (TTP) patients in remission with activity >50% had an open ADAMTS13 conformation. We assessed ADAMTS13 conformation in remission (ADAMTS13 activity >60%), focussing on peak ADAMTS13 activity levels and longitudinal assessment in 420 samples across 157 patients. Fewer cases had open conformation at peak ADAMTS13 activity compared to unselected remission samples with ADAMTS13 activity>60% (23% vs 43%). Patients with a closed ADAMTS13 conformation at peak ADAMTS13 activity had an 8-fold lower relapse rate in the subsequent year (9% vs 46%; OR 8.4, p=0.007) and a 5-fold lower relapse rate within 2 years (23% vs 62%; OR 5.3, p=0.02) compared to cases with an open conformation. Patients with an open conformation at peak ADAMTS13 activity required pre-emptive anti-CD20 treatment earlier than patients with a closed conformation (median 10 vs 25 months, p=0.02). Longitudinally, an open conformation was evident at, and often preceded relapse. Where the conformation was already open prior to relapse, an increase in conformation index at relapse was seen despite undetectable anti-ADAMTS13 IgG antibody. In cases with detectable anti-ADAMTS13 IgG antibody, these became undetectable prior to achieving closed conformation, highlighting the relapse risk even with undetectable anti-ADAMTS13 IgG antibody and the clinical utility of open/closed during monitoring. This is the first study to show an association between relapse risk and ADAMTS13 conformation when activity levels are at a peak. Open conformation identifies antibody mediated subclinical disease which is not detectable through current ADAMTS13 testing.
    Language English
    Publishing date 2024-03-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2023023269
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Delayed normalization of ADAMTS13 activity in acute thrombotic thrombocytopenic purpura in the caplacizumab era.

    Prasannan, Nithya / Thomas, Mari / Stubbs, Matthew / Westwood, John-Paul / de Groot, Rens / Singh, Deepak / Scully, Marie

    Blood

    2023  Volume 141, Issue 18, Page(s) 2206–2213

    Abstract: The benefits of caplacizumab in acute immune-mediated thrombotic thrombocytopenic purpura (iTTP) are well established. We identified a delayed normalization of a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13 (ADAMTS13) ... ...

    Abstract The benefits of caplacizumab in acute immune-mediated thrombotic thrombocytopenic purpura (iTTP) are well established. We identified a delayed normalization of a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13 (ADAMTS13) activity (>30%) in a subgroup treated with caplacizumab, not evident in the precaplacizumab era. Patients treated with caplacizumab (n = 64) achieved ADAMTS13 activity >30% at median 31 days after plasma exchange (PEX), compared with 11.5 days in the noncaplacizumab group (n = 50, P = .0004). Eighteen of 64 (28%) patients treated with caplacizumab had ADAMTS13 activity <10% at stopping caplacizumab with a longer time to ADAMTS13 activity >30% (median, 139 days after completing PEX). Eighteen of 64 (28%) patients receiving extended caplacizumab (31-58 days) failed to achieve ADAMTS13 activity >30% at the time of caplacizumab cessation, compared with 4 of 47 (8.5%) historical controls at a similar timepoint (30 + 28 days, P < .0001). Failure to achieve ADAMTS13 activity >30% within 30 + 28 days was 6 times more likely with caplacizumab (odds ratio, 6.3; P = .0006). ADAMTS13 antigen <30% at caplacizumab cessation was associated with increased iTTP recurrence (4/10 vs 0/9 in patients with ADAMTS13 antigen ≥30%). Admission anti-ADAMTS13 immunoglobulin G (IgG) antibody level did not predict recurrence. Anti-ADAMTS13 IgG antibody levels, immunosuppression, and ethnicity did not account for differences in ADAMTS13 activity response. ADAMTS13 antigen levels ≥30% may be useful to guide stopping caplacizumab therapy after extended use with ADAMTS13 activity <10%. The reason for delayed ADAMTS13 normalization is unclear and requires further investigation.
    MeSH term(s) Humans ; Purpura, Thrombotic Thrombocytopenic/drug therapy ; von Willebrand Factor ; Single-Domain Antibodies/therapeutic use ; Plasma Exchange ; ADAMTS13 Protein
    Chemical Substances caplacizumab (2R27AB6766) ; von Willebrand Factor ; Single-Domain Antibodies ; ADAMTS13 Protein (EC 3.4.24.87)
    Language English
    Publishing date 2023-01-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2022018847
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura.

    Doyle, Andrew J / Stubbs, Matthew J / Lester, Will / Thomas, Will / Westwood, John-Paul / Thomas, Mari / Percy, Charles / Prasannan, Nithya / Scully, Marie

    British journal of haematology

    2022  Volume 198, Issue 2, Page(s) 391–396

    Abstract: Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis ...

    Abstract Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13.
    MeSH term(s) ADAMTS13 Protein ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antigens, CD20 ; Humans ; Purpura, Thrombotic Thrombocytopenic/drug therapy ; Recurrence ; Rituximab/adverse effects ; Serum Sickness/chemically induced
    Chemical Substances Antibodies, Monoclonal, Humanized ; Antigens, CD20 ; Rituximab (4F4X42SYQ6) ; ADAMTS13 Protein (EC 3.4.24.87) ; ofatumumab (M95KG522R0) ; obinutuzumab (O43472U9X8)
    Language English
    Publishing date 2022-04-17
    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.18192
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh III Zs.182: Show issues Location:
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  5. Article ; Online: Impaired exercise capacity in post-COVID-19 syndrome: the role of VWF-ADAMTS13 axis.

    Prasannan, Nithya / Heightman, Melissa / Hillman, Toby / Wall, Emma / Bell, Robert / Kessler, Anna / Neave, Lucy / Doyle, Andrew / Devaraj, Akshitha / Singh, Deepak / Dehbi, Hakim-Moulay / Scully, Marie

    Blood advances

    2022  Volume 6, Issue 13, Page(s) 4041–4048

    Abstract: Post-COVID syndrome (PCS), or long COVID, is an increasingly recognized complication of acute SARS-CoV-2 infection, characterized by persistent fatigue, reduced exercise tolerance, chest pain, shortness of breath, and cognitive slowing. Acute COVID-19 is ...

    Abstract Post-COVID syndrome (PCS), or long COVID, is an increasingly recognized complication of acute SARS-CoV-2 infection, characterized by persistent fatigue, reduced exercise tolerance, chest pain, shortness of breath, and cognitive slowing. Acute COVID-19 is strongly linked with an increased risk of thrombosis, which is a prothrombotic state quantified by an elevated von Willebrand factor (VWF) antigen (Ag)/ADAMTS13 ratio that is associated with severity of acute COVID-19 infection. We investigated whether patients with PCS also had evidence of a prothrombotic state associated with symptom severity. In a large cohort of patients referred to a dedicated post-COVID-19 clinic, thrombotic risk, including VWF(Ag)/ADAMTS13 ratio, was investigated. An elevated VWF(Ag)/ADAMTS13 ratio (≥1.5) was present in nearly one-third of the cohort and was 4 times more likely to be present in patients with impaired exercise capacity, as evidenced by desaturation ≥3% and/or an increase in lactate level >1 from baseline on a 1-minute sit-to-stand test and/or a 6-minute walk test (P < .0001). Of 276 patients, 56 (20%) had impaired exercise capacity, of which 55% (31/56) had a VWF(Ag)/ADAMTS13 ratio ≥1.5 (P < .0001). Factor VIII and VWF(Ag) were elevated in 26% and 18%, respectively, and support a hypercoagulable state in some patients with PCS. These findings suggest possible ongoing microvascular/endothelial dysfunction in the pathogenesis of PCS and suggest a role for antithrombotic therapy in the treatment of these patients.
    MeSH term(s) ADAM Proteins ; ADAMTS13 Protein ; COVID-19/complications ; Exercise Tolerance ; Humans ; SARS-CoV-2 ; Thrombosis ; von Willebrand Factor
    Chemical Substances von Willebrand Factor ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
    Language English
    Publishing date 2022-06-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2021006944
    Database MEDical Literature Analysis and Retrieval System OnLINE

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