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Recent reports have highlighted rare, and sometimes fatal, cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia following the Vaxzevria vaccine. An underlying immunological mechanism similar to that of spontaneous heparin-induced thrombocytopenia (HIT) is suspected, with the identification of antibodies to platelet factor-4 (PF4), but without previous heparin exposure. This unusual mechanism has significant implications for the management approach used, which differs from usual treatment of CVST. We describe the cases of two young males, who developed severe thrombocytopenia and fatal CVST following the first dose of Vaxzevria. Both presented with a headache, with subsequent rapid neurological deterioration. One patient underwent PF4 antibody testing, which was positive. A rapid vaccination programme is essential in helping to control the COVID-19 pandemic. Hence, it is vital that such COVID-19 vaccine-associated events, which at this stage appear to be very rare, are viewed through this lens. However, some cases have proved fatal. It is critical that clinicians are alerted to the emergence of such events to facilitate appropriate management. Patients presenting with CVST features and thrombocytopenia post-vaccination should undergo PF4 antibody testing and be managed in a similar fashion to HIT, in particular avoiding heparin and platelet transfusions.

The novel coronavirus disease of 2019 (COVID‐19) pandemic, as declared by the World Health Organization, is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2). Cardiovascular disease and, in particular, venous thromboembolism (VTE) has emerged as an important consideration in the management of hospitalized patients with COVID‐19. The diagnosis of VTE using standardized objective testing is problematic in these patients, given the risk of infecting non‐COVID‐19 hospitalized patients and hospital personnel, coupled with the usual challenges of performing diagnostic testing in critically‐ill patients. Early reports suggest a high incidence of VTE in hospitalized COVID‐19 patients, particularly those with severe illness, that is similar to the high VTE rates observed in patients with other viral pneumonias, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS‐CoV).

Key Points The rate of symptomatic postdischarge VTE following hospitalization with COVID-19 is low., The association of severe coronavirus disease 2019 (COVID-19) with an increased risk of venous thromboembolism (VTE) has resulted in specific guidelines for its prevention and management. The VTE risk appears highest in those with critical care admission. The need for postdischarge thromboprophylaxis remains controversial, which is reflected in conflicting expert guideline recommendations. Our local protocol provides thromboprophylaxis to COVID-19 patients during admission only. We report postdischarge VTE data from an ongoing quality improvement program incorporating root-cause analysis of hospital-associated VTE (HA-VTE). Following 1877 hospital discharges associated with COVID-19, 9 episodes of HA-VTE were diagnosed within 42 days, giving a postdischarge rate of 4.8 per 1000 discharges. Over 2019, following 18 159 discharges associated with a medical admission; there were 56 episodes of HA-VTE within 42 days (3.1 per 1000 discharges). The odds ratio for postdischarge HA-VTE associated with COVID-19 compared with 2019 was 1.6 (95% confidence interval, 0.77-3.1). COVID-19 hospitalization does not appear to increase the risk of postdischarge HA-VTE compared with hospitalization with other acute medical illness. Given that the risk-benefit ratio of postdischarge thromboprophylaxis remains uncertain, randomized controlled trials to evaluate the role of continuing thromboprophylaxis in COVID-19 patients following hospital discharge are required., Visual Abstract

Travel appears to be a weak risk factor for venous thromboembolism (VTE) and is more relevant for passengers with additional VTE risk factors. The association is not limited to air travel and is related to duration of travel. Life-threatening pulmonary embolism (PE) is rare. There is limited evidence to support interventions, including 'sensible measures', graduated compression stockings (GCS) and low-molecular-weight heparin (LMWH). It is difficult to confidently define a population who would benefit from thromboprophylaxis and no validated risk assessment exists for this purpose. LMWH has traditionally been used for flight thromboprophylaxis but a direct oral anticoagulant (DOAC) would be a more appealing oral option.

Background: Emerging safety and efficacy data for rivaroxaban suggest traditional therapy and rivaroxaban are comparable in the morbidly obese. However, real-world data that indicate pharmacokinetic (PK) parameters are comparable at the extremes of body size are lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee (ISTH SSC) suggests avoiding the use of direct oral anticoagulants (DOACs) in patients weighing >120 kg or with a body mass index >40 kg/m 2 and gives no recommendation on the use of DOACs in those 120 kg, n = 74 BMI >40 kg/m 2, and n = 30

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Routine thromboprophylaxis (TP) in newly-diagnosed multiple myeloma (NDMM) patients comprises either aspirin for standard risk patients or low molecular weight heparin for high risk patients. Studies using DOACs in cancer patients include few with myeloma. The aim of this feasibility clinical trial was to establish the foundations for creating a multicentre trial and identify any safety concerns with apixaban. Patient perspectives were sought. NDMM patients were stratified according to VTE risk and randomised to either standard TP or apixaban 2.5 mg BD and reviewed every 3 weeks throughout their chemotherapy. Two focus groups were carried out on 2 occasions at King’s College Hospital and Guy’s Hospital, London. Each lasted an hour, were recorded, transcribed and themes explored using NVivo 11. Ten patients were recruited, 2 considered high risk and received apixaban and 8 standard risk; 4 randomised to aspirin and 4 to apixaban. Five patients and 2 carers participated in the focus groups. There were no major bleeding or VTE events. Patients were not aware of the thrombotic risk associated with cancer. There is a lack of both written and verbal information on this topic. Myeloma patients were happy to be included in more than one trial simultaneously. Our study provides information on the difficulties facing physicians and patients on obtaining evidence of the safety of DOACs in the context of myeloma. Despite patients being happy to co-recruit into thromboprophylaxis trials along with chemotherapy trials this is not current practice. EudraCT Number: 2015-002668-18 Electronic supplementary material The online version of this article (10.1007/s11239-019-01891-0) contains supplementary material, which is available to authorized users.

Budd-Chiari syndrome (BCS) is a rare, potentially fatal disease characterized by hepatic venous outflow tract obstruction. Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin therapy, with mortality approaching 10%. The reported prevalence of HIT in adults is 0.2-5.2%. Expert consensus through case reports is the only existing evidence of HIT in BCS. To our knowledge, this is the first study to formalize this anecdotal evidence.A retrospective analysis was carried out of patients presenting at a tertiary liver centre with acute liver failure because of BCS or BCS as the primary indication for liver transplantation between 2000 and 2013. The prevalence of HIT in the study group was compared with the highest reported prevalence in adult medical patients receiving heparin (5.2%). Mortality, length of stay and liver transplantation rates were also studied.Of 32 BCS patients, 9 (28.1%) developed HIT, significantly higher than the previously reported prevalence of HIT in medical patients (5.2%) (P0.0001). There was no difference in mortality (P=0.66), length of stay (P=0.58) and liver transplantation rate (P=0.39) between HIT-positive and HIT-negative patients.The prevalence of HIT (28.1%) in our cohort of BCS patients is significantly higher than that in the general population (0.2-5.2%). Although this study was not powered to detect outcome differences, as heparin is the mainstay of acute BCS treatment, this represents a significant risk. We recommend a high index of suspicion for HIT in patients with BCS and thrombocytopenia, an appropriate HIT-testing strategy and consideration of direct thrombin inhibitors.

The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed-dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex 'real-world' patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting.

Do the safety and efficacy outcomes reported in the clinical trials of direct oral anticoagulants (DOAC) translate to the 'real-world'? Background: A number of DOACs are now available for clinicians to prescribe in clinical practice. Whilst the results from large clinical trials demonstrate that these agents are as effective as vitamin K antagonists, there is some concern that the patients studied in the trials were not representative of patients, clinicians encounter in everyday practice. The aim of our study was to compare the real-world clinic population commenced on a DOAC to that from the clinical trials for these agents, in order to assess potential differences in safety and efficacy. Patients and methods: A retrospective observational cohort study was undertaken. Patients who were initiated on a DOAC (apixaban, dabigatran and rivaroxaban) at a large teaching hospital in South East London between 1st August 2012 and 31st July 2014 were identified through pharmacy issue data with those followed-up for a minimum of 6 months included. Baseline demographic data, rates of stroke/VTE and rates of major/non-major clinically relevant (NMCR) (ISTH definition) bleeding were assessed and compared to pooled data reported from the corresponding Phase III trials. Differences between groups were compared using t-tests or chi-squared tests. Results: During the review period, 748 patients were initiated on a DOAC, 365 for atrial fibrillation (AF) and 383 for venous thromboembolism (VTE). In terms of demographic differences, the real-world AF population comprised more females, were significantly older, had poorer renal function and a lower body weight. In contrast, the real-world VTE population typically had a higher body weight and poorer renal function, compared to the trial population, (table 1). Efficacy of DOACs was found to be similar across both the VTE and AF populations. With respect to safety, the real-world AF population experienced similar rates of major bleeding and a significantly lower rate of NMCR bleeding compared to the trial populations. In contrast, the real-world VTE population experienced a significantly higher rate of major bleeding, particularly gastrointestinal bleeding. Although the rate of NMCR bleeding was similar, there was a significantly higher rate of urogenital bleeding in the real-world VTE population, specifically heavy menstrual bleeding in women. Conclusions: The efficacy outcomes of DOAC use in a real-world AF and VTE population are consistent with the Phase III trials, despite some significant differences in baseline characteristics. However, a significantly increased rate of major bleeding was observed in the real-world VTE population, which requires further investigation. Table 1. Baseline demographic characteristics, efficacy and safety outcomes in the real-world population versus the trial population Atrial Fibrillation Venous Thromboembolism Trial population+N=28,342 Real-world population Trial population++ Real-world population N=365 N=8,716 N=383 Baseline Demographics, mean (SD) unless otherwise specified Age, years 72 (9.6) 76.8 * (12.1) 56.9 (14.2) 55.6 (18.7) Female (%) 10451 (36.9) 215 * (58.9) 3753 (43.1) 184 (48.0) Weight, kg 82.7 (19.5) 77.3 * (22.6) 84.9 (19.6) 88.2 * (23.0) Creatinine clearance, mL/min 69 (26.7) 58.1 * (26.9) 105.8 (40.7) 91.1 * (37.6) Concomitant aspirin therapy 10341 (36.5) 49 * (13.4) - 0 (0) Previous VKA use (%) 15711 (55.4) 193 (52.9) - 85 (22.2) Efficacy (%) All-cause mortality 1695 (6.0) 37 * (9.1) 160 (1.8) 10 (2.5) Stroke 676 (2.4) 8 (2.0) - 1 (0.3) VTE 39 (0.1) 1 (0.2) 192 (2.2) 7 (1.8) Safety (%) Major Bleeding 1419 (5.0) 17 (4.2) 79 (0.9) 15 * (3.8) Intracranial 170 (0.6) 1 (0.2) 6 (0.1) 2 * (0.5) Gastrointestinal 644 (2.3) 8 (2.0) 8 (0.1) 8 * (2.0) Non-major Clinically relevant (NMCR) bleeding 4824 (17.0) 30 * (7.4) 540 (6.2) 26 (6.6) Gastrointestinal - 9 (2.2) 53 (4.2) 10 (2.5) Urogenital 296 (4.2) 16 (3.9) 100 (2.5) 38 * (9.6) +Pooled data from ARISTOTLE, RE-LY and ROCKET-AF trials ++Pooled data from AMPLIFY, RE-COVER and EINSTEIN-PE/DVT trials *p Disclosures Patel: Bayer plc: Research Funding. Auyeung:Bayer PLC: Research Funding. Arya:Bayer plc: Research Funding.

There are clearly demonstrated links between unprovoked venous thromboembolism (VTE) and underlying malignancy. Previous studies have shown an incidence between 3 and 13% of subsequent cancer diagnoses in patients with unprovoked VTE. National guidance issued in the United Kingdom, 2012 recommend that all patients with a first unprovoked VTE are investigated for occult malignancy with a thorough history and examination, full blood count, liver function tests, calcium, chest X-ray and urinalysis with directed investigation of any positive findings. Additionally, abdomino-pelvic CT scans (and mammography in women) should be considered for all patients over 40 years with first unprovoked VTE without positive findings on basic investigations. We retrospectively reviewed all patients diagnosed with unprovoked VTE at King's College Hospital between April 2014 and March 2015, and results were followed up to July 2015. We excluded as provoked VTEs all cases associated with trauma, known malignancy, recent surgery or hospitalisation, prolonged immobilisation, long-haul travel, hormonal therapy, intravenous drug use, pregnancy or the puerperium. We examined extent of investigations performed and reviewed the incidence of occult malignancy in those with a first unprovoked VTE. Over the period of study, 544 patients were objectively diagnosed with pulmonary embolism (PE) or deep vein thrombosis (DVT). Of these, 140 cases were unprovoked in nature. 75/140 (53.6%) were male, with a median age of 56 years (range 22-97). All 140 patients had initial clinical assessment and bloods tests. 113 (80.7%) patients also had chest X-ray screening performed. Of the remaining 27 patients, 4 were not followed up in our centre. 75 (53.6%) patients had tumour markers taken, 74 (52.9%) patients had abdominal imaging (of which 61, 82.4% had CT abdomen and pelvis, remainder ultrasound) and 3 women had mammography. Tumour markers were abnormal in 26/75 (34.7%). Abdominal imaging was abnormal in 33/66 (50.0%) patients without a subsequent diagnosis of malignancy, with 18/66 (27.3%) requiring additional investigation to definitively exclude malignancy. 8/136 (5.9%) cases of occult malignancy were identified (see Table for characteristics). The majority of patients found to have occult malignancy were diagnosed at an advanced stage, with high subsequent mortality rates and minimal opportunity for intervention. Our findings compare favourably with the findings of the SOME trial with a low incidence of occult malignancy and questionable value of routine abdomino-pelvic imaging for otherwise asymptomatic patients with first unprovoked VTE. Such screening is likely to incur anxiety for patients, incidental findings and higher costs without demonstrable patient benefit. Abnormal tumour markers were common and non-specific and should not be performed routinely following unprovoked VTE. Targeted investigation for individuals with suggestive clinical features or abnormalities on baseline bloods, chest X-ray or urinalysis should be considered. | Cancer | Age/ Gender | VTE | Abnormal basic screen# | Tumour markers | Time to cancer diagnosis (days) | Stage/treatment | Time to death* (days) | | --------------- | ------------------ | ------------ | ---------------------- | -------------------------- | ------------------------------- | ----------------------------------------------------- | --------------------- | | Endometrial | 52F | Distal DVT | No | Not done | 131 | T1aM0N0 ¨C surgery (TAH + BSO) | N/A | | Endometrial | 57F | Distal DVT | Yes | CA125 3383 | | No formal staging, metastatic disease, no treatment | 45 | | Pancreatic | 52M | Proximal DVT | Yes | CA125 2832 | 17 | No formal staging, metastatic disease, no treatment | 19 | | Pancreatic | 57M | PE | Yes | CA125 583, CEA 96 | 20 | No formal staging, metastatic disease, no treatment | 65 | | Lung | 85F | PE | Yes | Not done | 85 | T3N1M1a ¨C chemotherapy | N/A | | Lung | 81M | PE | Yes | Not done | | T4N3M1b ¨C for palliation only | 49 | | Ovarian | 69F | PE | Yes | CA125 1224, CEA 6 | | No formal staging, metastatic disease, no treatment | 16 | | Unknown primary | 97F | Proximal DVT | Yes | AFP 29, CEA 626, CA125 316 | 1 | No formal staging, metastatic disease, for palliation | 6 | * #basic screen includes clinical assessment, renal/liver function, calcium, chest X-ray and urinalysis; *from time of VTE diagnosis Table 1. Characteristics of patients identified with occult malignancy, time to cancer diagnosis, staging of cancer, treatment received, and mortality Disclosures Arya: Bayer plc: Research Funding.

The direct oral anticoagulants (DOACs) are revolutionising the management of acute venous thromboembolism (VTE). Although favourable short term outcomes have been demonstrated with these agents, there is a growing need to improve our understanding of biological and clinical predictors of longer-term outcomes with all DOACs. In addition to reducing the need for dual anticoagulant coverage, the use of oral rivaroxaban, has accelerated the implementation of outpatient and early discharge treatment protocols for VTE, in particular for pulmonary embolism (PE). Although clinical trials provide evidence of efficacy and safety, there is a need for ongoing assessment of outcomes in unselected populations treated in routine 'real-world' clinical practice. As for most drugs, conditions requiring special attention include advanced age, impaired renal or liver function, extremes of body weight, presence of multiple co-morbidities, and the need for concomitant therapies. Such conditions commonly co-exist, particularly in elderly patients. In clinical practice patients aged 80 years or older and requiring anticoagulation are becoming increasingly common. In addition, trials do not report long-term adverse outcomes after VTE; aside from bleeding, currently there are no long-term data that assess the impact of the DOACs as part of a single-drug treatment algorithm on long-term recurrence. The FIRST registry will assess long-term outcomes of patients with acute VTE treated with rivaroxaban from diagnosis - our hypothesis is that the long-term outcomes for such patients will be favourable due to consistent anticoagulation intensity, particularly during the acute phase of thrombosis. There are currently no data describing post-thrombotic syndrome (PTS) or chronic thromboembolic pulmonary hypertension (CTEPH) incidence rates in patients treated with DOACs. Patients enrolled onto the FIRST registry will be followed up for five years with primary end-points defined as incidence of long-term sequelae (PTS and CTEPH, defined clinically) and secondary endpoints including recurrence, bleeding and anticoagulation related satisfaction and adherence scores. Analysis of these data may also contribute to improved risk stratification strategies to identify patients who have the greatest risk of adverse bleeding events, recurrence and long-term VTE-related morbidity. Recruitment is currently underway at 20 UK hospitals, with a target of 1500 patients, to be achieved by summer 2017. Disclosures No relevant conflicts of interest to declare.