Marie Scully

• University College London

The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS-CoV-2 virus ('Long COVID') is not fully understood. Cases were recruited from a Long COVID clinic (N=32; 44± 12y; 10(31%)men), and age/sex-matched healthy controls (HC) (N=19; 40± 13y; 6(32%)men) from University College London staff and stude...

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening inherited deficiency of the von Willebrand factor-cleaving metalloprotease, ADAMTS13, leading to consumptive thrombocytopenia due to microvascular thrombosis. Symptoms typically present either in early infancy, in adulthood during pregnancy, or in a...

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) results from autoantibody-mediated severe deficiency of ADAMTS13, the Von Willebrand factor (VWF)-cleaving protease. In this context, ultra-large VWF multimers accumulate in the circulation, leading to increased platelet clumping, with subsequent severe thrombocytopenia, microangiopathic he...

Background Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening thrombotic microangiopathy caused by an inherited deficiency of the enzyme ADAMTS13. An ongoing phase 3 study (NCT03393975) and phase 3b continuation study (NCT04683003) are investigating the safety and efficacy of recombinant ADAMTS13 (rADAMTS13; TA...

Introduction The use of rituximab to prevent clinical TTP relapse is widely accepted practice. However, the optimal dosing and regimen remains unclear with a variety used across treating centres. ‘Standard’ dosing is extrapolated from dosing for lymphoproliferative diseases: an equally efficacious lower dose would be time & cost-saving. We are inve...

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening genetic disorder. Severe deficiency of the von Willebrand factor-cleaving metalloprotease ADAMTS13 results in the formation of platelet-rich microthrombi, leading to platelet consumption and thrombocytopenia. Current treatment strategies primarily f...

The objective of this guideline is to provide healthcare professionals with clear, up‐to‐date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement‐mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopath...

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening hereditary disorder that causes patients to experience significant morbidity and decreased health-related quality of life (HRQoL). A cTTP disease-specific patient-reported outcome (PRO) instrument that is reflective of patients' experiences with th...

Background: ADAMTS13 activity is one of the key investigations needed to diagnose thrombotic thrombocytopenic purpura, and there are a number of different assays available to measure it. HemosIL AcuStar, a chemiluminescent immunoassay, was developed and used as a quicker, automated test. In clinical practice, discrepancies between AcuStar and the...

A State of the Art lecture titled "Etiology and Outcomes of Thrombotic Microangiopathies in Pregnancy" was presented at the International Society on Thrombosis and Haemostasis Congress in 2022. First, it is important to understand changes in laboratory parameters in normal pregnancy, including complement levels, specifically the increase in C3, C4,...

Background: Severe deficiency in ADAMTS13 (<10%) and the loss of von Willebrand factor-cleaving function can precipitate the microvascular thrombosis associated with thrombotic thrombocytopenic purpura (TTP). Immune-mediated TTP (iTTP) patients have anti-ADAMTS13 IgG antibodies that inhibit ADAMTS13 function and/or increase ADAMTS13 clearance. iTT...

The benefits of caplacizumab in acute immune mediated TTP (iTTP) are well established. We identified a delay in normalisation of ADAMTS13 activity (>30%) in a subgroup of caplacizumab treated patients which was not evident in the pre-caplacizumab era. Caplacizumab treated patients (n=64) achieved ADAMTS13 activity >30% at median 31 days post PEX, c...

The risk of a drug associated with thrombotic thrombocytopenic purpura (TTP) demonstrating causality is rare, but it is important to keep an open mind of possible associations. Use of criteria to ascertain causality of drugs that may be related to thrombotic microangiopathies and exclude TTP, may be a useful resource. Commentary on: Schofield et al...

Background: Post-COVID syndrome (PCS) affects millions of people worldwide, causing a multitude of symptoms and impairing quality of life months or even years after acute COVID-19. A prothrombotic state has been suggested; however, underlying mechanisms remain to be elucidated. Objectives: To investigate thrombogenicity in PCS using a microfluid...

Background: Post-COVID syndrome (PCS) affects millions of people worldwide, causing a multitude of symptoms and impairing quality of life months or even years after acute COVID-19. A prothrombotic state has been suggested; however, underlying mechanisms remain to be elucidated. / Objectives: To investigate thrombogenicity in PCS using a microfluidi...

Objective: The management of exacerbations and disease relapse is important for patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP). Severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency during clinical remission is associated with risk of relapse and may guide prophylact...

Thrombotic thrombocytopenia purpura is characterised by microangiopathic haemolytic anaemia and red cell fragmentation on the peripheral smear, neurological involvement and thrombocytopenia. Diagnosis in the context of sickle cell disease can be challenging due to the inherent haemolytic state and the multitude of other associated complications of...

Disease relapse is recognised as a risk in immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP) after treatment of the acute presenting episode. Identification of patients at risk of relapse and its patterns are yet to be clearly established. We reviewed patients with iTTP having >3 years follow-up over 10-years in the United Kingdom to ident...

Objective The efficacy and safety of caplacizumab (CPLZ) for patients (pts) with immune-mediated thrombotic thrombocytopenic purpura (iTTP; also known as acquired TTP) were demonstrated in the Phase 3 HERCULES trial, with a 28-day follow-up period after end of treatment. Post-HERCULES (NCT02878603) evaluated the long-term outcomes of pts with iTTP...

Introduction: Caplacizumab demonstrated efficacy and safety in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in the Phase 3 HERCULES trial. However, data on long-term outcomes following caplacizumab treatment are limited. Objectives: The post-HERCULES trial (NCT02878603) evaluated long-term outcomes of patients with iT...

Chronic/refractory immune thrombocytopenia (ITP) is a rare and pathophysiologically heterogenous disorder with variable responsiveness to available treatments. Sutimlimab, a first-in-class humanized monoclonal anti-C1s IgG4 antibody, selectively inhibits the classical pathway. This Phase 1 study (NCT03275454) assessed safety, efficacy, pharmacokine...

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillb...

Modern therapy for acute TTP has resulted in a dramatic improvement in outcomes, with the combination of plasma exchange, immunosuppression, and caplacizumab being associated with >90% survival rates following an acute episode. TTP is no longer associated with just the acute episode, but requires long-term follow-up. There remains significant morbi...

This case series reports 40 patients (median age, 41 years [interquartile range (IQR) 32- 52, 22 men) with confirmed vaccine-induced immune thrombotic thrombocytopaenia after administration of their first ChAdOx1 nCov-19 (AstraZeneca) vaccine: 80% (n=32) developed symptoms within the first 14 days and 20% (n=8) within 14-28 days. The location and e...

Background: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) following the administration of the AstraZeneca (AZ) ChAdOx1 nCOV-19 vaccine is a well-recognised clinical phenomenon. The associated clinical and laboratory features have included thrombosis at unusual sites, thrombocytopenia, raised D-Dimer levels and positivity for immuno...

Post-COVID syndrome (PCS) or Long-COVID is an increasingly recognised complication of acute SARS-CoV-2 infection, characterised by persistent fatigue, reduced exercise tolerance chest pain, shortness of breath and cognitive slowing. Acute COVID-19 is strongly linked with increased risk of thrombosis; a prothrombotic state, quantified by elevated Vo...

T follicular helper (Tfh) cells regulate development of antigen-specific B-cell immunity. We prospectively investigated B-cell and cTfh subsets in 45 immune TTP patients at presentation and longitudinally after rituximab (RTX). B-cell phenotype was altered at acute iTTP presentation with decreased transitional cells and postgerminal centre (post-GC...

Infection with the SARS-CoV-2 virus, resulting in COVID-19 disease has presented a unique scenario associated with high thrombotic rates. The risk of venous thrombosis is some 3-6 fold higher than for patients admitted to hospital for other indications and for patients who have thrombosis, mortality appears increased. Thrombosis may be a presenting...

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....

Immune‐mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra‐rare, blood‐clotting disorder. Management historically relies on plasma exchange and immunosuppression; however, a 10%–20% mortality rate is still observed. Caplacizumab binds to von Willebrand factor and directly inhibits platelet aggregation; addition of caplacizumab to histor...

The COVID-19 pandemic has resulted in the rapid development of a range of vaccines against SARS-CoV-2. Vaccine induced immune thrombocytopenia and thrombosis (VITT) is a rare but life-threatening complication of primarily adenoviral based vaccines, associated with the presence of antibodies to a PF4/polyanion neoepitope, measured by ELISA assays. P...

Acquired immune thrombotic thrombocytopenic purpura (iTTP) is a rare disease with a poor prognosis if undiagnosed. It is caused by autoantibody production to the von Willebrand factor (VWF) cleaving protease, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Caplacizumab, an immunoglobulin directed to the...

Background: Immune thrombocytopenia (ITP) relapse following vaccination remains poorly reported in the adult population. Objectives: This report details real world data from the largest single-centre cohort of ITP relapse following SARS-CoV-2 vaccination. Methods: The vaccination status of 294 patients under active follow-up was reviewed. A to...

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is caused by severe ADAMTS-13 deficiency. Immune-mediated TTP develops due to autoantibodies against ADAMTS-13, whereas congenital TTP is caused by mutations in the ADAMTS13 gene. Diagnostic possibilities and treatment options in TTP have emerged in recent years, which pro...

Thrombotic thrombocytopenic purpura is an acute life-threatening disorder, associated with a mortality of 90% if unrecognised and untreated. The hallmark is thrombocytopenia and microangiopathic hemolytic anemia, with a blood film characterised by fragmented red cells and end organ damage. The mainstay of treatment is ADAMTS13 replacement, currentl...

Background: Acute thrombotic thrombocytopenic purpura (TTP) is a life-threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality. Objectives: To compare current practice in the United Kingdom (UK) against the standards set out in the 2012 British Society of Haematology guideline, and to better unders...

Thrombotic microangiopathy (TMA) is the broad definition for thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage. Two important categories are thrombotic thrombocytopenic purpura (TTP) and complement-mediated hemolytic-uremic syndrome (CM-HUS). Pregnancy and the immediate postpartum period are associated with TMAs specific to...

Background Thrombotic thrombocytopenic purpura (TTP), caused by a genetic or autoimmune-driven lack of ADAMTS-13 activity, leads to high levels of the ultra-large von Willebrand factor (VWF) multimers produced by endothelial cells, causing excess platelet recruitment into forming thrombi, often with mortal consequences. Treatments include plasma in...

Background: The post-HERCULES trial (NCT02878603) evaluated long-term safety and efficacy of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura (aTTP; also known as immune-mediated TTP), and efficacy of repeated use of caplacizumab for aTTP recurrence. Methods: Patients who completed the HERCULES trial were invited to partic...

Objective An integrated analysis based on the Phase 2 TITAN (NCT01151423) and Phase 3 HERCULES (NCT02553317) studies with caplacizumab (CPLZ) in acquired thrombotic thrombocytopenic purpura (aTTP) was performed to assess treatment differences on efficacy and safety outcomes that may have been undetected in the individual trials. Methodology In bot...

Background: Pregnancy outcomes in patients with atypical hemolytic uremic syndrome (aHUS) are not well-documented. Here, we present characteristics of and outcomes for patients with aHUS who became pregnant while enrolled in the Global aHUS Registry. Methods: The observational Global aHUS Registry (NCT01522183), initiated in April 2012, collects...

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a relatively novel term which describes patients who have developed a low platelet count and prothrombotic tendencies secondary to receiving a vaccine. The concept has been derived from the well-established phenomenon of heparin-induced thrombocytopenia, and several cases of VITT have now...

Background Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a new syndrome associated with the ChAdOx1 nCoV-19 adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2. Data are lacking on the clinical features of and the prognostic criteria for this disorder. Methods We conducted a prospective cohort study...

Background A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccinati...

Vaccine‐induced immune thrombocytopenia and thrombosis (VITT) following ChAdOx1 nCOV‐19 vaccine has been described, associated with unusual site thrombosis, thrombocytopenia, raised D‐dimer and high titre immunoglobulin‐G (IgG) class anti‐Platelet Factor 4 (PF4) antibodies. Enzyme linked immunosorbent assays (ELISA) have been shown to detect anti‐P...

The efficacy and safety of caplacizumab in individuals with acquired thrombotic thrombocytopenic purpura (aTTP) have been established in the phase 2 TITAN and phase 3 HERCULES trials. Integrated analysis of data from both trials was conducted to increase statistical power for assessing treatment differences in efficacy and safety outcomes. Caplaciz...

Background The mainstay of control of the coronavirus disease 2019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity. Methods We report findings...

Background Atypical hemolytic uremic syndrome (aHUS) is a rare disease in which uncontrolled terminal complement activation leads to systemic thrombotic microangiopathy (TMA). Pregnancy can trigger aHUS and, without complement inhibition, many women with pregnancy-triggered aHUS (p-aHUS) progress to end-stage renal disease (ESRD) with a high risk o...

The COVID‐19 pandemic has affected every part of the world causing major morbidity and mortality, as well as impacting heavily on the economy of every nation. As for other infectious diseases, vaccination is seen as the primary way to control the infection. A number of vaccines against COVID19 have now been approved internationally. The AstraZeneca...

Proteasome inhibitors have been associated with thrombotic microangiopathy (TMA) — a group of disorders characterised by occlusive microvascular thrombosis causing microangiopathic haemolytic anaemia, thrombocytopenia and end‐organ damage. To date, carfilzomib‐associated TMA has predominantly been described in relapsed/refractory myeloma patients....

Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare, complex, multisystem disease of dysregulated complement activity, characterized by progressive thrombotic microangiopathy (TMA), acute kidney injury, and multiorgan dysfunction which often progresses to chronic kidney disease. Results from the prospective clinical trial of ravulizuma...

Despite clinical remission and normal platelet counts, congenital TTP (cTTP) is associated with non‐overt symptoms. Prophylactic ADAMTS13 replacement therapy such as plasma infusion (PI) prevents acute episodes and improves symptomatology. There is no current method to investigate disease severity or monitor the impact of treatment. We utilize a dy...

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare, life-threatening disorder, mediated through severe ADAMTS13 deficiency causing multi-system micro-thrombi formation, and has specific human leukocyte antigen associations. We undertook a large genome-wide association study to investigate additional genetically distinct associations...

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission and relapse were initially proposed in 2003 and modified by the International Working Group (IWG) for TTP in 2017. T...

Microangiopathic hemolytic anemia (MAHA) in patients with cancer requires urgent diagnosis and treatment. MAHA associated with thrombocytopenia, suggests a thrombotic microangiopathy (TMA), where there is thrombus formation affecting small or larger vessels. It may be directly related to the underlying malignancy (either the initial presentation or...

Venous malformations (VMs) are ectatic channels which arise as a result of vascular dysmorphogenesis, commonly caused by activating mutations in the endothelial tyrosine kinase receptor (TIE2)/phosphatidylinositol 3-kinase (PI3Kinase) pathway. With a prevalence of 1% in the general population, and a diverse clinical presentation depending on site,...

The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting symptoms to cytokine storms, acute respiratory distress syndrome (ARDS), multi-organ failure and death. Identification of high-risk cases will enable appropriate intervention and escalation. This study investigates the routine laboratory tests and cytokin...

Severe COVID‐19 disease is a hyperinflammatory, pro‐thrombotic state. We undertook plasma exchange (PEX) to determine its effects on organ function and thrombo‐inflammatory markers. Seven critically ill adults with severe COVID‐19 respiratory failure (PaO2:FiO2 ratio < 200 mm Hg) requiring invasive or noninvasive ventilatory support and elevated th...

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, trialled in two multicentre, randomised-placebo-controlled trials leading to EU and FDA approval, has been available...

Introduction Severe COVID-19 disease is associated with a hyperinflammatory, pro-thrombotic state and a high mortality. A thrombotic phenotype rather than a coagulopathy is suggested and we undertook plasma exchange to determine its effects on organ function and thrombo-inflammatory markers. Methods Plasma exchange was carried out in seven critical...

Introduction Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by platelet (plt) destruction and/or impaired production. Some patients with ITP are refractory or have inadequate responses to existing therapy. In vitro data have demonstrated that the sera of ~50% of patients with ITP can activate the classical complement pathway...

Background: T follicular helper cells (Tfh), characterised by surface expression of CXCR5, PD1 and ICOS, regulate development of antigen-specific B cell immunity through germinal centre (GC) formation, generation of long-lived memory B cells and high-affinity plasma cells. Methods: In this prospective study of peripheral blood B and circulating Tfh...

Background: Acute Thrombotic Thrombocytopenic Purpura (TTP) is a life-threatening medical emergency and plasma exchange (PEX) is the only treatment shown to significantly impact acute mortality (Rock et al, N Engl J Med 1991). Diagnosis can be challenging and therein arrangements for PEX must be made, with most centers in the United Kingdom (UK) ha...

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombomicroangiopathy caused by deficiency of ADAMTS13. Acute neurological involvement is well described, but its long‐term impact requires evaluation. One‐hundred thirty‐one patients, following an acute TTP event, with severe headache or neurological symptoms had a cerebral MRI. Fifty‐six percen...

The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting symptoms to cytokine storms, acute respiratory distress syndrome (ARDS), multi-organ failure and death. Identification of high-risk cases will enable appropriate intervention and escalation. This study investigates the routine laboratory tests and cytokin...