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Acute thrombotic thrombocytopenic purpura (TTP) is a life-threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality.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 understand the issues affecting prompt initiation of PEX.The trainee research network HaemSTAR conducted a retrospective nationwide review of adults presenting to UK hospitals with a first episode of acute TTP.Data on 148 patients treated at 80 UK hospitals between 2014 and 2019 demonstrated that 64.8% of patients received PEX within 24 h. Diagnostic uncertainty was the most commonly cited reason for delayed treatment. Conversely, a shorter time to PEX occurred in patients who had red cell fragments or severe thrombocytopenia identified on their first complete blood count. Availability of on-site PEX was associated with a greater proportion of patients receiving PEX within 8 h compared to patients transferred, but by 24 h there was no difference between the two groups and two-thirds of all patients had received their first PEX. The mortality rate for patients that received PEX was 9.2%, with 27.8% of deaths linked to delayed treatment initiation.This is the first multi-center evaluation of treatment delays in acute TTP and it will inform targeted pathways to improve prompt access to life-saving intervention.

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.

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal condition, with90% 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.

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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) having to co-ordinate transfer to a tertiary site. To understand issues affecting practice the trainee research network HaemSTAR conducted a retrospective nationwide review of patients presenting to UK hospitals with TTP against British Society of Haematology clinical guidelines (Scully et al, B J Haem 2012). Analysis was conducted on the time from hospital presentation to initiation of treatment and impact on patient outcomes. Method: Adults ≥18 years presenting to hospital between 1st June 2014 and 1st June 2019 with first episode acute TTP and ADAMTS13 level Results: Data on 148 patients treated at 80 UK hospitals was used for analysis (demographics table 1). 142 patients (96%) received PEX, 67 (47%) at site of presentation and 75 (53%) after hospital transfer. 6 patients died before receiving PEX. 37 patients (25%) received PEX within 8 hrs of hospital presentation, 91 patients (61%) within 24 hrs. 33 patients (22%) commenced PEX more than 48 hrs from presentation. The overall median time to PEX from initial presentation was 15 hours (95% CI 11.3-18.7). Availability of on-site PEX was associated with earlier treatment initiation with median time to PEX for those treated on site 10 hrs (95% CI 7.7-12.3) vs. 21 hrs (95% CI 16.8-25.2) for patients transferred. A blood film comment of red cell fragments significantly impacted time to treatment: in 24 cases with no fragments documented median time to PEX was 110 hrs (95% CI 39-181) vs. 10 hrs (95% CI 8.5-11.5) in cases where fragments were reported (fig 1). On univariate and multivariate analysis age 96 patients (62%) received steroids within 24 hrs of presentation, 98 of 128 patients with cardiac/CNS involvement (77%) received rituximab within 48 hrs and 12 patients (8%) received platelet transfusion in the absence of major bleeding. 19 patients (12%) died within 30 days of presentation (median time to death 10 days, range 0-23). In 7 of these cases (37%) a delay >24 hrs from presentation to diagnosis was reported despite presence of fragments in 4 cases. Mortality did not correlate with availability of on-site PEX. Discussion: This is the first multi-center record of time to treatment from initial presentation of acute TTP. Results comply with guidance for rapid initiation of PEX with 61% patients commencing within 24 hrs of presentation and, from June 2017, 34% of patients initiating PEX within 8 hrs. The recent increase in early PEX initiation correlates with initiatives to improve treatment pathway efficiency following diagnosis of TTP. Early use of steroids and rituximab correlated with earlier use of PEX indicating where timely diagnosis was made there was good compliance with guidelines. Inappropriate use of platelets appeared attributable to misdiagnosis. Older patients, those with higher platelet counts and Hb and absence of red cell fragments on film report were more likely to experience prolonged time to initiation of PEX. This does not appear related to PEX access, but most likely the difficulty of making TTP diagnosis in this cohort. That 22% of patients initiated PEX over 48 hrs from admission indicates the issue is relatively common and with several deaths occurring in this group we suggest initiatives to increase early diagnosis should be prioritised. Full contributor list: http://haemstar.org/flash-mob-audit-2019/ Disclosures McCulloch: Sanofi: Research Funding. Nicolson:Principia Biopharma: Research Funding; Novartis: Research Funding; Rigel pharmaceuticals: Research Funding; Bayer: Honoraria. Shaw:Octapharma: Research Funding. Scully:Alexion: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau.

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.

Background The COVID-19 pandemic has highlighted the potentially lethal consequences of cross-talk between coagulation, inflammation and innate immune processes. Hospitalised COVID-19 patients die of respiratory and multi-organ failure and these patients have evidence of extensive immune cell death, which would result in the release of nuclear material, such as histones. Extracellular histones have been associated with adverse clinical outcome and our work has shown that they are directly pro-coagulant [Blood. 2020, in press], pro-inflammatory [J Immunology. 2013;191(5):2495-2502] (induce C-reactive protein (CRP) release) and can cause pulmonary thrombosis [AJRCCM. 2013;187(2):160-9]. We therefore hypothesize that circulating histones play a central role in affecting poor outcomes in patients with COVID-19. Methods One hundred and three COVID-19 patients were recruited at the Royal Liverpool University Hospital, in accordance with the ISARIC/WHO Clinical Characterisation Protocol for Severe Emerging Infections in the UK (CCP-UK). Inclusion criteria: (1) proven confirmed swab positive or high likelihood of infection OR (2) one or more of the following symptoms: fever of ≥ 38⁰C, new cough, dyspnoea OR tachypnoea AND admitted to a healthcare facility. Exclusion criteria: confirmed diagnosis of a pathogen unrelated to COVID-19 and no indication or likelihood of co-infection with a relevant pathogen. Patients were categorised into three groups based on severity of infection: mild (minimal symptoms and/or incidental finding), severe (dyspnoea or hypoxia) and critical (respiratory failure, shock or multi-organ failure). Circulating histones were quantified in patient plasma and associated with severity of infection, coagulation parameters, inflammatory and organ injury markers. Results Admission histone levels were significantly (P Conclusions Admission histone levels are associated with disease severity, coagulation activation, inflammation and organ dysfunction in COVID-19 patients. This study indicates that elevated circulating histones might play a key role in the immuno-thrombotic pathogenesis of COVID-19. Disclosures No relevant conflicts of interest to declare.

Background Historically a diagnosis of thrombotic thrombocytopenic purpura (TTP) was made on autopsy. Following the identification of ADAMTS13 deficiency as central to the pathophysiology of TTP, measurement of the enzyme became a vital diagnostic tool. ADAMTS13 activity can be measured using fluorescence resonance energy transfer (FRET), immunoblotting (IB) or enzyme-linked immunosorbent assay (ELISA). However, such assays have traditionally been performed in only a few selective laboratories nationally. ADAMTS13 testing serves as both a diagnostic investigation for those with suspected TTP, as well as a method of monitoring those at risk of relapse. Due to the diversity in local practice, availability, and reporting of both acute and serial ADAMTS13 measurements, it remains unclear as to what constitutes best practice with regards to frequency of testing and how the test can result best support clinical decision making. Aim To review changing trends and patterns in ADAMTS13 testing before and after the set-up of a regional TTP Specialist Centre. To evaluate how this might inform future practice with regards to regional testing provision, patient monitoring and elective Rituximab. Methods This was a retrospective study of ADAMTS13 testing from 2011-18. Data was collected using the Trust electronic laboratory software system, instituted in 2011. The data was reviewed to identify serial trends in testing and in relation to the set-up of a regional TTP Specialist Service provision in 2013. Results A total of 2140 ADAMTS13 activity requests for 464 individual patients were performed between January 2011 and January 2018 using the Technoclone ELISA ADAMTS13 activity assay. A review of the number of ADAMTS13 activity tests performed demonstrated a serial annual rise with total tests per year- 2011: 39, 2012: 88, 2013: 137, 2014: 301, 2015: 401, 2016: 494, 2017: 679. This equated to a 17-fold increase in testing from 2011 compared to 2017, and 5-fold increase from 2013 to 2018 since the set-up of the regional Specialist Service. External referrals for testing constituted 14% of all ADAMTS13 activity requests with a significant 600% rise in all external requests between 2013 and 2018. These included external requests for analysis from 23 different hospital trusts, with the furthest requesting trust being 54 miles from the regional centre. 65% of external requests represented acute referrals with 35% representing monitoring requests for patients receiving shared care between their local hospital and Specialist Centre. Of all internal requests, 82% were from haematology followed by critical care and nephrology. In contrast to external requesting, of the internal requests only 5% were for acute diagnosis compared with 95% of requests made for monitoring purposes. ADAMTS13 activity for monitoring in this patient cohort represented a combination of assessing response to treatment following an acute diagnosis, as well as long term monitoring in remission to identify potential relapse. Internal requests for both acute and monitoring purposes rose annually, with a 20-fold increase in monitoring requests from 2011 to 2017, and a 3-fold increase in acute requests over the same time period. Conclusions ADAMTS13 testing has continued to significantly increase annually suggesting a combination of improved diagnostic awareness and increased disease monitoring. The setup of a regional clinical service including laboratory diagnostics results in a significant increase in acute testing requests serving a wide geographic area. In an era where agents are available to potentially avoid acute relapse, more patients are being monitored using serial ADAMTS13 measurements during follow-up. Although avoiding acute clinical relapse has significant implications for the health service and patient mortality, the economics of serial testing in a condition where the enzyme activity is so unpredictable, remains unclear. There is wide variation globally in ADAMTS13 testing and hence a wider evaluation of current practice and outcomes would not only be valuable in establishing greater consensus on best practice, but also inform us more of the natural history of this condition. Disclosures No relevant conflicts of interest to declare.

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterised by antibody mediated activity against ADAMTS13. Prompt diagnosis and treatment is critical in this rare condition which has an untreated mortality of around 90%. An ADAMTS13 activity level of 12 U/ml using the Technoclone ADAMTS13 inhibitor ELISA assay. Data collected included patient demographics, presenting symptoms, laboratory markers at first presentation, ADAMTS13 activity and antibody and number of relapses. Clinical relapse was defined as reappearance of clinical manifestations or laboratory parameters consistent with acute TTP and serological relapse was defined as ADAMTS13 activity of Disclosures No relevant conflicts of interest to declare.

The purpose of this study was to investigate the role of perceived control in the selection and effectiveness of coping strategies used by nursing home residents. A path analysis of a model of coping effectiveness was conducted using a cluster sample of 100 nursing home residents. Respondents were assisted in completing the Importance, Locus, and Range of Activities Checklist, the Jalowiec Coping Scale, two self-anchoring ladders measuring coping effectiveness, and an item measuring perceived health. Mental status was measured with the Pfeiffer Short Portable Mental Status Questionnaire. Results demonstrated that mental status and functional ability were positively related to perceived control (p < .01). Perceived health and the use of secondary control (e.g., prayer, getting help from family, and depending on others) were the only two variables positively influencing coping effectiveness (p < .01 and p < .05, respectively). Longitudinal studies are recommended to investigate these relationships as they evolve.