Search

Background Patients with severe aortic stenosis (AS) are at risk of both bleeding and thrombotic events. The high shear and flow rates across the stenotic aortic valve (AV) degrade von Willebrand factor high molecular weight multimers increasing bleeding risk, but can also lead to platelet activation. The overall effect on thrombotic and endogenous fibrinolytic status remains unclear. We aimed to assess the relationship between AS severity and thrombotic and fibrinolytic profile. Materials and methods In a prospective, observational study, thrombotic and thrombolytic status was assessed in venous blood taken from patients with severe AS using the Global Thrombosis Test. This point-of-care technique measures the time for occlusive thrombus formation under high shear (OT), and the time for spontaneous lysis of the thrombus (LT). We related these parameters to indices of AS severity. Results and conclusions Our cohort comprised of 86 patients (age 79 ± 9 years, 58% male), of whom 25% were on single and 28% on dual antiplatelet medication, 47% on no antithrombotic therapy, and 1% on oral anticoagulation. Lysis time was inversely related to AV peak (r = −0.242, P = 0.04) and mean (r = −0.286, P = 0.012) gradients. The severity of AS, by gradient or valve area, was not related to OT, although OT was inversely related to platelet count (r = −0.248, P = 0.029). Heterogeneity in antithrombotic medications may have masked a relationship between AS severity and OT. We report that increasing severity of AS is related to more effective endogenous fibrinolysis, which may contribute to the increased propensity to bleeding.

Summary The impact of COVID‐19 infection on pregnant women remains relatively unknown but the physiological changes of pregnancy and hypercoagulability of COVID‐19 may further increase thrombotic risk. In this retrospective multicentre observational study, we report clinical characteristics and outcomes in 36 pregnant women requiring hospitalisation for COVID‐19 compared to a propensity‐matched cohort of non‐pregnant women. Pregnant women had a lower haemoglobin and higher lymphocyte counts but no differences in other haematological or biochemical parameters on admission compared to non‐pregnant women. There was no significant difference in the duration of hospitalisation; median two days (1–77) for pregnant versus eight days (1–49) for non‐pregnant women. A higher proportion of non‐pregnant women required mechanical ventilation [11/36 (31%) vs 3/36 (8%), P = 0·03] and received thromboprophylaxis with low‐molecular‐weight heparin (LMWH) within 24 h of admission [25/36 (69%) vs 15 /36(42%), P = 0·03] compared to pregnant women. One pregnant woman required extracorporeal membrane oxygenation. The rate of thrombosis was similar in both groups (one in each group). No women developed major bleeding or died. Data suggest that although non‐pregnant women had a severe clinical course, overall outcomes were not different between women with or without pregnancy. The use of thromboprophylaxis was inconsistent, demonstrating a need for establishing evidence‐based guidance for COVID‐19 during pregnancy.

Patients supported with extracorporeal membrane oxygenation (ECMO) experience a very high frequency of bleeding and ischaemic complications, including stroke and systemic embolism. These patients require systemic anticoagulation, mainly with unfractionated heparin (UFH) to prevent clotting of the circuit and reduce the risk of arterial or venous thrombosis. Monitoring of UFH can be very challenging. While most centres routinely monitor the activated clotting time and activated partial thromboplastin time (aPTT) to assess UFH, measurement of anti-factor Xa (anti-Xa) level best correlates with heparin dose, and appears to be predictive of circuit thrombosis, although aPTT may be a better predictor of bleeding. Although monitoring of prothrombin time, platelet count and fibrinogen is routinely undertaken to assess haemostasis, there is no clear guidance available regarding the optimal test.Additional tests, including antithrombin level and thromboelastography, can be used for risk stratification of patients to try and predict the risks of thrombosis and bleeding. Each has their specific role, strengths and limitations. Increased thrombin generation may have a role in predicting thrombosis. Acquired von Willebrand syndrome is frequent with ECMO, contributing to bleeding risk and can be detected by assessing the von Willebrand factor activity-to-antigen ratio, while the platelet function analyser can be used in urgent situations to detect this, with a high negative predictive value. Tests of platelet aggregation can aid in the prediction of bleeding.To personalise management, a selection of complementary tests to collectively assess heparin-effect, coagulation, platelet function and platelet aggregation is proposed, to optimise clinical outcomes in these high-risk patients. ispartof: THROMBOSIS AND HAEMOSTASIS vol:122 issue:04 pages:480-491 ispartof: location:Germany status: published

OBJECTIVES: Severe coronavirus disease 2019 is associated with an extensive pneumonitis and frequent coagulopathy. We sought the true prevalence of thrombotic complications in critically ill patients with severe coronavirus disease 2019 on the ICU, with or without extracorporeal membrane oxygenation. DESIGN: We undertook a single-center, retrospective analysis of 72 critically ill patients with coronavirus disease 2019-associated acute respiratory distress syndrome admitted to ICU. CT angiography of the thorax, abdomen, and pelvis were performed at admission as per routine institution protocols, with further imaging as clinically indicated. The prevalence of thrombotic complications and the relationship with coagulation parameters, other biomarkers, and survival were evaluated. SETTING: Coronavirus disease 2019 ICUs at a specialist cardiorespiratory center. PATIENTS: Seventy-two consecutive patients with coronavirus disease 2019 admitted to ICU during the study period (March 19, 2020, to June 23, 2020). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All but one patient received thromboprophylaxis or therapeutic anticoagulation. Among 72 patients (male:female = 74%; mean age: 52 ± 10; 35 on extracorporeal membrane oxygenation), there were 54 thrombotic complications in 42 patients (58%), comprising 34 pulmonary arterial (47%), 15 peripheral venous (21%), and five (7%) systemic arterial thromboses/end-organ embolic complications. In those with pulmonary arterial thromboses, 93% were identified incidentally on first screening CT with only 7% suspected clinically. Biomarkers of coagulation (e.g., D-dimer, fibrinogen level, and activated partial thromboplastin time) or inflammation (WBC count, C-reactive protein) did not discriminate between patients with or without thrombotic complications. Fifty-one patients (76%) survived to discharge; 17 (24%) patients died. Mortality was significantly greater in patients with detectable thrombus (33% vs 10%; p = 0.022). CONCLUSIONS: There is a high prevalence of thrombotic complications, mainly pulmonary, among coronavirus disease 2019 patients admitted to ICU, despite anticoagulation. Detection of thrombus was usually incidental, not predicted by coagulation or inflammatory biomarkers, and associated with increased risk of death. Systematic CT imaging at admission should be considered in all coronavirus disease 2019 patients requiring ICU.

Acute respiratory distress syndrome in patients with Coronavirus disease 19 is associated with an unusually high incidence of pulmonary embolism and microthrombotic disease, with evidence for reduced fibrinolysis. We describe seven patients requiring invasive ventilation for COVID-19-associated acute respiratory distress syndrome with pulmonary thromboembolic disease, pulmonary hypertension ± severe right ventricular dysfunction on echocardiography, who were treated with alteplase as fibrinolytic therapy. All patients were non-smokers, six (86%) were male and median age was 56.7 (50–64) years. They had failed approaches including therapeutic anticoagulation, prone ventilation ( n = 4), inhaled nitric oxide ( n = 5) and nebulised epoprostenol ( n = 2). The median duration of mechanical ventilation prior to thrombolysis was seven (5–11) days. Systemic alteplase was administered to six patients (50 mg or 90 mg bolus over 120 min) at 16 (10–22) days after symptom onset. All received therapeutic heparin pre- and post-thrombolysis, without intracranial haemorrhage or other major bleeding. Alteplase improved PaO 2 /FiO 2 ratio (from 97.0 (86.3–118.6) to 135.6 (100.7–171.4), p = 0.03) and ventilatory ratio (from 2.76 (2.09–3.49) to 2.36 (1.82–3.05), p = 0.011) at 24 h. Echocardiographic parameters at two (1–3) days ( n = 6) showed right ventricular systolic pressure (RVSP) was 63 (50.3–75) then 57 (49–66) mmHg post-thrombolysis ( p = 0.26), tricuspid annular planar systolic excursion (TAPSE) was unchanged (from 18.3 (11.9–24.5) to 20.5 (15.4–24.2) mm, p = 0.56) and right ventricular fractional area change (from 15.4 (11.1–35.6) to 31.2 (16.4–33.1)%, p = 0.09). At seven (1–13) days after thrombolysis, using dual energy computed tomography imaging ( n = 3), average relative peripheral lung enhancement increased from 12.6 to 21.6% ( p = 0.06). In conclusion, thrombolysis improved PaO 2 /FiO 2 ratio and ventilatory ratio at 24 h as rescue therapy in patients with right ventricular dysfunction due to COVID-19-associated ARDS despite maximum therapy, as part of a multimodal approach, and warrants further study.

Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology. Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia. Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography. Measurements and Results: In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29–79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H2O; Murray lung injury score, 3.14 ± 0.53; mean ventilatory ratios, 2.6 ± 0.8) with evidence of hypercoagulability and fibrinolytic “shutdown”. The mean CT extent (±SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 ± 16.7%, 36.3 ± 24.7%, and 42.7 ± 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6). Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.

Objectives: The COVID-19 pandemic has generated a new type of acute respiratory distress syndrome (ARDS) arising as a complication of COVID-19 pneumonia. Extreme cases require the support of extracorporeal membrane oxygenation (ECMO). Here we present the outcomes of patients that underwent surgical tracheostomy or thoracic surgery at a single tertiary centre whilst on ECMO support for COVID-19 related ARDS. Methods: 18 patients requiring thoracic input whilst on ECMO support during the first wave of COVID-19 (March–June 2020) were included. Thoracic surgery was required both for performing surgical tracheostomies in the operating theatre and for treating emergencies arising under the ECMO treatment such as bleeding complications. Results: Thirteen patients underwent a surgical tracheostomy, whilst five patients had an invasive thoracic procedure. Anticoagulation was withheld for at least 12 h in the perioperative setting regardless of the indication. One patient was re-operated for haemothorax immediately after the end of the primary operation. 94.5% of the patients were successfully decannulated from ECMO support. Overall 30-day mortality in the cohort was 5.5% (1/18). Conclusions: Thoracic surgeons can play a valuable role in supporting an ECMO unit during the COVID pandemic, by treating ECMO related complications and by safely performing surgical tracheostomies. Withholding anticoagulation in the perioperative window was not associated with increased thromboembolic events and is desirable when interventions or surgery is indicated in this patient cohort to avoid excessive bleeding.

Summary Bleeding and thrombosis are major complications in patients supported with extracorporeal membrane oxygenation (ECMO). In this multicentre observational study of 152 consecutive patients (≥18 years) with severe COVID‐19 supported by veno‐venous (VV) ECMO in four UK commissioned centres during the first wave of the COVID‐19 pandemic (1 March to 31 May 2020), we assessed the incidence of major bleeding and thrombosis and their association with 180‐day mortality. Median age (range) was 47 years (23–65) and 75% were male. Overall, the 180‐day survival was 70·4% (107/152). The rate of major bleeding was 30·9% (47/152), of which intracranial bleeding (ICH) was 34% (16/47). There were 96 thrombotic events (63·1%) consisting of venous 44·7% [68/152 of which 66·2% were pulmonary embolism (PE)], arterial 18·6% (13/152) and ECMO circuit thrombosis 9·9% (15/152). In multivariate analysis, only raised lactate dehydrogenase (LDH) at the initiation of VV ECMO was associated with an increased risk of thrombosis [hazard ratio (HR) 1·92, 95% CI 1·21‐3·03]. Major bleeding and ICH were associated with 3·87‐fold (95% CI 2·10–7·23) and 5·97‐fold [95% confidence interval (CI) 2·36–15·04] increased risk of mortality and PE with a 2·00‐fold (95% CI1·09–3·56) risk of mortality. This highlights the difficult balancing act often encountered when managing coagulopathy in COVID‐19 patients supported with ECMO.

BACKGROUND: Raised lipoprotein(a) [Lp(a)] is a cardiovascular risk factor common in patients with refractory angina. The apolipoprotein(a) component of Lp(a) exhibits structural homology with plasminogen and can enhance thrombosis and impair fibrinolysis. OBJECTIVES: The objective of the study was to assess the effect of lipoprotein apheresis on markers of thrombosis and fibrinolysis in patients with high Lp(a). METHODS: In a prospective, single-blind, crossover trial, 20 patients with refractory angina and raised Lp(a) > 50 mg/dL were randomized to three months of weekly lipoprotein apheresis or sham. Blood taken before and after apheresis/sham was assessed using the Global Thrombosis Test, to assess time taken for in vitro thrombus formation (occlusion time) and endogenous fibrinolysis (lysis time), as well as von Willebrand Factor, fibrinogen, D-dimer, thrombin/anti-thrombin III complex, prothrombin fragments 1 + 2, and thrombin generation assays. RESULTS: Lp(a) was significantly reduced by apheresis (100.2 [interquartile range {IQR}, 69.6143.0] vs 24.8 [17.2,34.0] mg/dL, P = .0001) but not by sham (P = .0001 between treatment arms). Apheresis prolonged occlusion time (576 ± 116 s vs 723 ± 142 s, P

Aims Approximately 20% of ischaemic stroke patients exhibit spontaneous arterial recanalization, attributable to endogenous fibrinolysis, which strongly relates to improved functional outcome. The impact of oral anticoagulants on endogenous fibrinolysis is unknown. Our aim was to test the hypothesis that apixaban enhances endogenous fibrinolysis in non-valvular atrial fibrillation (NVAF). Methods and results In a prospective cross-sectional analysis, we compared endogenous fibrinolysis in NVAF patients (n = 180) taking aspirin, warfarin, or apixaban. In a prospective longitudinal study, patients were tested before and after apixaban (n = 80). Endogenous fibrinolysis was assessed using the Global Thrombosis Test (GTT) and thromboelastography (TEG). Endogenous fibrinolysis [measured by GTT lysis time (LT)] was shorter on apixaban compared with warfarin or aspirin [median 1850 (IQR 1591–2300) vs. 2758 (2014–3502) vs. 2135 (1752–2463) s, P Conclusion Apixaban enhances endogenous fibrinolysis, with maximal effect in those with impaired fibrinolysis pre-treatment. Apixaban-treated patients exhibit more favourable fibrinolysis profiles than those taking warfarin or aspirin. Whether apixaban may confer additional thrombotic risk reduction in NVAF patients with impaired fibrinolysis, compared to warfarin, merits further study.

Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease 2019 (COVID-19). Patients on oral anticoagulants (OAC) prior to diagnosis of COVID-19 may therefore have better outcomes. In this multicentre observational study of 5 883 patients (≥18 years) admitted to 26 UK hospitals between 1 April 2020 and 31 July 2020, overall mortality was 29·2%. Incidences of thrombosis, major bleeding (MB) and multiorgan failure (MOF) were 5·4%, 1·7% and 3·3% respectively. The presence of thrombosis, MB, or MOF was associated with a 1·8, 4·5 or 5·9-fold increased risk of dying, respectively. Of the 5 883 patients studied, 83·6% (n = 4 920) were not on OAC and 16·4% (n = 963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis [hazard ratio (HR) 1·05, 95% confidence interval (CI) 0·93–1·19; P = 0·15] or in an adjusted propensity score analysis (HR 0·92 95% CI 0·58–1·450; P = 0·18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulation prior to diagnosis of COVID-19 was admission to the Intensive-Care Unit (ICU) (HR 1·98, 95% CI 1·37–2·85). Thrombosis, MB, and MOF were associated with higher mortality. Our results indicate that patients may have benefit from prior OAC use, especially reduced admission to ICU, without any increase in bleeding.

A significant proportion of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) with high risk of death. The efficacy of veno-venous extracorporeal membrane oxygenation (VV-ECMO) for COVID-19 on longer-term outcomes, unlike in other viral pneumonias, is unknown. In this study, we aimed to compare the 6 month mortality of patients receiving VV-ECMO support for COVID-19 with a historical viral ARDS cohort. Fifty-three consecutive patients with COVID-19 ARDS admitted for VV-ECMO to the Royal Brompton Hospital between March 17, 2020 and May 30, 2020 were identified. Mortality, patient characteristics, complications, and ECMO parameters were then compared to a historical cohort of patients with non-COVID-19 viral pneumonia. At 6 months survival was significantly higher in the COVID-19 than in the non-COVID-19 viral pneumonia cohort (84.9% vs. 66.0%, p = 0.040). Patients with COVID-19 had an increased Murray score (3.50 vs. 3.25, p = 0.005), a decreased burden of organ dysfunction (sequential organ failure score score [8.76 vs. 10.42, p = 0.004]), an increased incidence of pulmonary embolism (69.8% vs. 24.5%, p < 0.001) and in those who survived to decannulation longer ECMO runs (19 vs. 11 days, p = 0.001). Our results suggest that survival in patients supported with EMCO for COVID-19 are at least as good as those treated for non-COVID-19 viral ARDS.

Vaccines for COVID-19 were developed with unprecedented speed and since January 2021, the AstraZeneca/Oxford University ChAdOx1 nCoV-19 vaccine has been administered to over 400 million people globally.1 In April 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency reported a possible association between ChAdOx1 nCoV-19 and a rare syndrome of unusual site thrombosis combined with thrombocytopenia, termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Frequency of VITT varies across age groups. Overall, 411 cases of VITT have been reported to the MHRA by 21 July 2021 with fatality rate of 17.76% (73/411).2 We report our experience of four VITT cases from a single tertiary referral centre in London, UK, who suffered cerebral venous sinus thrombosis (CVST) with or without thrombosis elsewhere. Baseline clinical and laboratory features are shown in table 1. Informed written consent was obtained from all patients before publication. All patients fulfilled the proposed diagnostic criteria for VITT3 4. Each case was reportedvia the MHRA Yellow card scheme and other national VITT–CVST surveillance projects. View this table: Table 1 Baseline characteristics and laboratory markers of four patients presenting with cerebral venous sinus thrombosis following AstraZeneca/Oxford University ChAdOx1 nCoV-19 vaccine All four patients were women aged 41–46 years and diagnosed with VITT 7–28 days post ChAdOx1 nCov-19 vaccination. Each presented with headache and varying degrees of neurological deficit. Detailed case histories are provided in the online supplemental material. Neuroimaging for patient 1 demonstrated extensive thrombosis involving both the dural venous sinuses and superficial cortical veins as well as associated subarachnoid haemorrhage in the parietal sulci bilaterally (figure 1A–D) but no thrombosis detected in imaging of the abdomen. Patient 2 initially presented with superior sagittal sinus thrombosis associated with right-sided neurological deficit (figure 1E), branch intrahepatic portal venous thrombus and non-occlusive segmental pulmonary arteries filling defects consistent …

This study aimed to determine the impact of major hemorrhage (MH) protocol (MHP) activation on blood administration and patient outcome at a UK major cardiothoracic center. MH was defined in patients (> 16 years) as those who received > 5 units of red blood cells (RBCs) in 10 units in 24 hours. Data were collected retrospectively from patient electronic records and hospital transfusion databases recording issue of blood products from January 2016 to December 2018. Of 134 patients with MH, 24 had activated MHP and 110 did not have activated MHP. Groups were similar for age, sex, baseline hemoglobin, platelet count, coagulation screen, and renal function with no difference in the baseline clinical characteristics. The total number of red cell units (median and [IQR]) transfused was no different in the patients with activated (7.5 [5–11.75]) versus nonactivated (9 [6–12]) MHP (p = 0.35). Patients in the nonactivated MHP group received significantly higher number of platelet units (median: 3 vs. 2, p = 0.014), plasma (median: 4.5 vs. 1.5, p = 0.0007), and cryoprecipitate (median: 2 vs. 1, p = 0.008). However, activation of MHP was associated with higher mortality at 24 hours compared with patients with nonactivation of MHP (33.3 vs. 10.9%, p = 0.005) and 30 days (58.3 vs. 30.9%, p = 0.01). The total RBC and platelet (but not fresh frozen plasma [FFP]) units received were higher in deceased patients than in survivors. Increased mortality was associated with a higher RBC:FFP ratio. Only 26% of patients received tranexamic acid and these patients had higher mortality at 30 days but not at 24 hours. Deceased patients at 30 days had higher levels of fibrinogen than those who survived (median: 2.4 vs. 1.8, p = 0.01). Patients with activated MHP had significantly higher mortality at both 24 hours and 30 days despite lack of difference in the baseline characteristics of the patients with activated MHP versus nonactivated MHP groups. The increased mortality associated with a higher RBC:FFP ratio suggests dilutional coagulopathy may contribute to mortality, but higher fibrinogen at baseline was not protective.

Diseases such as myocardial infarction, ischaemic stroke, peripheral vascular disease and venous thromboembolism are major contributors to morbidity and mortality. Procoagulant, anticoagulant and fibrinolytic pathways are finely regulated in healthy individuals and dysregulated procoagulant, anticoagulant and fibrinolytic pathways lead to arterial and venous thrombosis. In this review article, we discuss the (patho)physiological role and laboratory assessment of fibrin, factor XIII and endogenous fibrinolysis, which are key players in the terminal phase of the coagulation cascade and fibrinolysis. Finally, we present the most up-to-date evidence for their involvement in various disease states and assessment of cardiovascular risk.

Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease-19 (COVID-19). Patients on oral anticoagulants prior to diagnosis of COVID-19 may therefore have better outcomes. We aimed: To first document the frequency of thrombosis, major bleeding and multiorgan failure (MOF) in patients admitted with COVID-19 and the contribution of these complications to 90-day mortality. To then determine the effects of oral anticoagulation, use prior to admission on the same outcomes as well as the requirement for Intensive Care Unit (ICU) admission, when compared to a propensity matched cohort of patients not taking oral anticoagulants prior to admission. Methods: This was a multicentre observational cohort including adult patients (≥18 years) admitted to 26 UK hospitals between 1st of April 2020 and 31 July 2020. Findings: A total of 5883 patients were included in the study. Overall mortality was 29.2%. Incidences of thrombosis, major bleeding and MOF were 5.4%,1.7% and 3.3% respectively. The presence of thrombosis, major bleeding, or MOF were associated with a 1.8, 4.5 or 5.9-fold increased risk of dying, respectively. Of the 5883 patients studied, 83.6% (n= 4920) were not on oral anticoagulants (OAC) and 16.4% (n=963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis (HR 1.05 (95%CI 0.93-1.19) P=0.15) or in an adjusted propensity score analysis (HR 0.92 (95%CI 0.58-1.450, P=0.18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulants prior to admission was treatment in ICU (HR 1.98 [95%CI 1.37-2.85]). Interpretation: Thrombosis, major bleeding, and MOF were associated with higher mortality. Our results indicate that patients may continue to benefit from OAC after admission, especially reduced admission to ICU, without any increase in bleeding. Funding: Bayer plc supported the study by providing the investigator-initiated funding (P87339) to setup the multicentre database of the study. Declaration of Interest: DJA received funding from Bayer plc to setup the multicentre database of the study as an investigator-initiated funding and received research grant from Leo Pharma. ML received consultation and speaker fees from Astra-Zeneca, Sobi, Leo-Pharma, Takeda and Pfizer. PN received research grants from Novartis, Principia and Rigel, unrestricted grants from Sanofi, Chugai and Octapharma and honoraria from Bayer. RA received fees from Alexion, Bayer, BMS, Pfizer and Portola. SS has received meeting sponsorship, speaker fees and/or consultancy from Bayer, Pfizer, NovoNordisk, Sobi, Chugai/Roche and Shire/Takeda. SS receives funding support from the Medical Research Council (MR/T024054/1). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). SL has received speaker fees from Bayer, BMS and Pfizer. Others have no conflict of interests to declare. Ethical Approval: The study was approved by the Health Research Authority (HRA), Health and Care Research Wales (HCRW) and received local Caldicott Guardian support in Scotland (reference number: 20/HRA/1785). Data was collected both retrospectively and prospectively from patient clinical records by the treating medical team with no breach of privacy or anonymity by allocating a unique study number with no direct patient identifiable data; therefore, consent was waived by the HRA.

COVID-19 is a prothrombotic condition and a major focus of attention has been to reduce thrombosis in order to improve outcomes. Extracorporeal membrane oxygenation (ECMO) triggers contact activation of coagulation, platelet dysfunction and systemic anticoagulation which may contribute to both thrombosis and bleeding complications. Methods: Multicentre observational study of mortality, thrombosis, and bleeding complications in 152 consecutive patients (≥18 years) supported with VV ECMO during the first wave of the COVID-19 pandemic (1st of March 2020 to 31st of May 2020) from four nationally commissioned UK ECMO centres. Findings: Of 152 patients, mortality during ECMO up to 120 days was 21.1% (32/152) whilst overall all cause in- hospital mortality up to 143 days from ECMO initiation was 25.7% (39/152). Median duration on ECMO was 17 days (interquartile range [IQR] 11-29.7). On multivariate analysis, mortality increased with age (Hazard ratio [HR] 1.09 [95% CI 1.03 - 1.14]), P=0.002. Rates of major bleeding and thrombosis during ECMO were 25.0% (38/152) and 17.1% (26/152). Presence of major bleeding prior to or at initiation of ECMO and intracranial haemorrhage during ECMO conferred 3.65 ([95% CI 1.16 - 11.48], P=0.027) and 6.92 ([95% CI 2.66 - 18.02]

Background The role of dual energy computed tomographic pulmonary angiography (DECTPA) in revealing vasculopathy in coronavirus disease 2019 (COVID-19) has not been fully explored. Purpose To evaluate the relationship between DECTPA and disease duration, right ventricular dysfunction (RVD), lung compliance, D-dimer and obstruction index in COVID-19 pneumonia. Materials and Methods This institutional review board approved this retrospective study, and waived the informed consent requirement. Between March-May 2020, 27 consecutive ventilated patients with severe COVID-19 pneumonia underwent DECTPA to diagnose pulmonary thrombus (PT); 11 underwent surveillance DECTPA 14 ±11.6 days later. Qualitative and quantitative analysis of perfused blood volume (PBV) maps recorded: i) perfusion defect ‘pattern’ (wedge-shaped, mottled or amorphous), ii) presence of PT and CT obstruction index (CTOI) and iii) PBV relative to pulmonary artery enhancement (PBV/PAenh); PBV/PAenh was also compared with seven healthy volunteers and correlated with D-Dimer and CTOI. Results Amorphous (n=21), mottled (n=4), and wedge-shaped (n=2) perfusion defects were observed (M=20; mean age=56 ±8.7 years). Mean extent of perfusion defects=36.1%±17.2. Acute PT was present in 11/27(40.7%) patients. Only wedge-shaped defects corresponded with PT (2/27, 7.4%). Mean CTOI was 2.6±5.4 out of 40. PBV/PAenh (18.2 ±4.2%) was lower than in healthy volunteers (27 ±13.9%, p = 0.002). PBV/PAenh correlated with disease duration (β = 0.13, p = 0.04), and inversely correlated with RVD (β = -7.2, p = 0.001), persisting after controlling for confounders. There were no linkages between PBV/PAenh and D-dimer or CTOI. Conclusion Perfusion defects and decreased PBV/PAenh are prevalent in severe COVID-19 pneumonia. PBV/PAenh correlates with disease duration and inversely correlates with RVD. PBV/PAenh may be an important marker of vasculopathy in severe COVID-19 pneumonia even in the absence of arterial thrombus. Summary Significantly decreased (qualitative and quantitative) lung enhancement on dual-energy CT pulmonary angiography is an early feature of severe COVID-19 pneumonia and is associated with right ventricular dysfunction.

COVID‐19 is a highly prothrombotic disease, frequently requiring anticoagulation for prevention or treatment of thrombosis and to enable organ support (Bikdeli, Madhavan et al. 2020). The reported incidence of thrombosis in patients with COVID‐19 varies considerably depending on anticoagulant regimen, severity of disease and additional risk factors such as central lines. The most commonly used in‐hospital anticoagulants, unfractionated heparin (UFH) and low molecular weight heparin (LMWH), require antithrombin (AT) to exert their anticoagulant effect (Bussey and Francis 2004). Therefore, AT deficiency can result in failure achieve adequate anticoagulation with UFH or LMWH at usual doses.

Antiphospholipid antibodies are a heterogeneous group of autoantibodies that have clear associations with thrombosis and pregnancy morbidity, and which together constitute the 'antiphospholipid syndrome' (APS). However, the pathophysiology of these complications is not well understood and their heterogeneity suggests that more than one pathogenic process may be involved. Diagnosis remains a combination of laboratory analysis and clinical observation but there have been significant advances in identifying specific pathogenic features, such as domain I-specific anti-β2-glycoprotein-I antibodies. This in turn has pointed to endothelial and complement activation as important factors in the pathogenesis of APS. Consequently, although anticoagulation remains the standard treatment for thrombotic APS and during pregnancy, the realisation that these additional pathways are involved in the pathogenesis of APS has significant implications for treatment: agents acting outside the coagulation system, such as hydroxychloroquine for pregnancy complications and sirolimus as an inhibitor of the mammalian target of rapamycin (mTOR) pathway, are now under evaluation and represent a radical change in thinking for haematologists. Conventional anticoagulation is also under challenge from new, direct acting anticoagulants. This review will provide a comprehensive overview of the evolving understanding of APS pathogenesis and how this and novel therapeutics will alter diagnosis and management.

In this retrospective, single-centre, observational study, we assessed (i) use of anticoagulant and antiplatelet (AP) therapy, (ii) the duration of direct-acting oral anticoagulant (DOAC) discontinuation, (iii) renal function and (iv) PT and APTT as predictors of bleeding and blood product usage; in adults (>18 years) undergoing major cardiac surgery from 01.01.2015 to 31.12.2018. Comparisons were made between each treatment group (warfarin, DOAC and DOAC + AP) and untreated controls, and between warfarin and DOAC. A total of 2928 patients were included for analysis. Median (range) of DOAC discontinuation prior to surgery was five days (1-22) for DOAC and five days (2-7) for DOAC + AP. There were no differences in bleeding between anticoagulant groups versus control, or DOAC versus warfarin. There were no differences in blood product use between DOAC and warfarin patients. The duration of DOAC discontinuation but not the creatinine clearance influenced bleeding and blood products use. Thrombosis occurred in 0·7% and 3·1% in controls and patients on warfarin respectively (P = 0·099) with none among patients on DOAC or DOAC + AP. The PT/APTT had no predictive value. Median five-day discontinuation of DOAC +/- AP irrespective of renal function prevents an increase in bleeding compared to patients on warfarin or controls with no increase in thrombosis.

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder mediated by a heterogeneous group of autoantibodies collectively known as antiphospholipid antibodies (aPL). They include lupus anticoagulant (LA), IgG and IgM anticardiolipin antibodies (aCL) and anti-β2-glycoprotein I (anti-β2GPI) antibodies. It has been shown that those patients with all three aPL (triple positive) are at highest risk of both a first thrombotic event and of a recurrence, despite anticoagulation. In response to publication of a meta-analysis and a randomised controlled trial assessing the safety and efficacy of rivaroxaban versus warfarin in triple-positive APS with venous and/or arterial thrombosis, the Medicines and Healthcare Products Regulatory Agency (MHRA) and European Medicines Agency (EMA) issued recommendations that direct-acting oral anticoagulant (DOACs) should not be used for secondary prevention of thrombosis in all APS patients (although they did draw specific attention to the high risk of triple-positive patients). As there is less evidence for patients with single- or dual-positive patients with APS, this may be an over-interpretation of the data. In this review, we explore the available evidence on safety and efficacy of DOACs in thrombotic APS, the problem of detecting LA while on DOAC, and provide some practical guidance for managing this problem.

Background Patients presenting with INTERMACS-1 cardiogenic shock and necessitating VA-ECMO, often undergo coronary angiography and percutaneous coronary intervention (PCI). Therefore, a substantial subset of VA-ECMO patients will have an indication for dual antiplatelet therapy (DAPT) plus unfractionated heparin (UFH). According to atrial fibrillation registry data, bleeding incidence on DAPT combined with oral anticoagulation is significantly higher as compared to anticoagulation alone. Although it has been reported that the addition of low dose aspirin to UFH did not increase bleeding or transfusion in VenoVenous (VV)-ECMO patients, it remains to be elucidated whether the addition of DAPT to UFH on VA-ECMO-therapy enhances bleeding. Methods We report single center data for 100 VA-ECMO patients between 2011 and 2019. VA-ECMO-patients post-surgery were excluded. Patient demographics, blood product transfusions and reported/radiographically diagnosed bleeding or thrombotic complications were analysed. All VA-ECMO patients received UFH, aiming for an anti-Xa levels of at least 0,3 U/ml. Targets were hemoglobin 7 g/dl, fibrinogen 100 mg/dl (or 150 mg/dl when active bleeding) and platelet counts above 50/fL. DAPT-patients were on a low dose aspirin plus a P2Y12-inhibitor (clopidogrel or ticagrelor). Results 51% Of the VA-ECMO-group received DAPT (59% clopidogrel and 41% ticagrelor). UFH-levels were comparable between both groups. Patients on DAPT were significantly older (DAPT 52.8 vs. Control 41.3; p DAPT (plus UFH) vs control (plus UFH) Conclusions Haemorrhage is frequent during extracorporeal support. However, in our cohort, DAPT on top of UFH in the treatment of VA-ECMO-supported ischemic cardiogenic shock does not increase the risk of major bleeding. Therefore, DAPT should not necessarily be witheld in the setting of VA-ECMO. Interestingly, our data support a lower incidence of overt thromboses and a trend towards less FFP-transfusion. These findings suggest DAPT-induced platelet inhibition being protective against both thrombotic events and posibly consumptive coagulopathy without paying a price for major bleeding.

Background Selective groups of patients, presenting with INTERMACS-1 cardiogenic shock due to acute ischaemic heart failure, may benefit from mechanical circulatory support (MCS). Patients with biventricular failure, severe septic shock or oxygenation problems should be selected for VA-ECMO, although the left Impella-CP heart pump can be considered as a less invasive alternative in supporting predominantly left ventricular failure. Bleeding issues are a major concern in patients on MCS, especially in this group where triple anticoagulation therapy (unfractionated heparin (UFH) for prevention of pump thrombosis and dual antiplatelet therapy (DAPT) after coronary stenting) is necessitated. We aim to investigate the bleeding and transfusion rate in DAPT-patients on VA-ECMO versus Impella. Methods We report single center data for 51 VA-ECMO and 8 Impella patients between 2011 and 2019. Indication for MCS was acute ischaemic cardiogenic shock. Patient demographics, transfusions and reported/radiographically diagnosed bleeding (BARC-classification) complications were analyzed. All patients received UFH and low dose aspirin plus clopidogrel or ticagrelor. Impella flow was at least 2.5 L/min. Transfusion targets were Hb >7 g/dl, fibrinogen >100 mg/dl (or >150 mg/dl when active bleeding) and platelet count >50/fL. Results Impella patients were significantly older (VA-ECMO 52.8 vs. Impella 62.4; p=0.02) as compared to the VA-ECMO group. Anti-Xa-levels and length of the MCS-run (mean 7.9 VA-ECMO vs. 6.4 days Impella) were comparable in both groups. Occurrences of minor bleeds was comparable between both groups (mainly oozing from the insertion site in the ImpellaTM group 63% vs. VA-ECMO 72%; p>0.05) but major bleedings with BARC score of 3 or more were significantly lower in the Impella group (13% vs. VA-ECMO 65%; p=0.005). Platelet and red blood cell transfusions were significantly lower in the Impella group (0.1 units of platelets per day vs. 1.1 units of platelets per day on VA-ECMO; p=0.002 and 0.8 units of RBCs per day vs. 2.6 units of RBCs per day on VA-ECMO; p=0.02). Bleeding/transfusion VA-ECMO vs Impella Conclusions Bleeding is a frequent complication of MCS. However, in our cohort, triple anticoagulation in acute cardiogenic shock due to ischaemic left ventricle failure resulted in a lower major bleeding rate when support was given by the left Impella device as compared with VA-ECMO therapy group. As a result, platelet and red blood cell transfusions were lower in the Impella group. These findings are likely to be partly explained by the increased number and size of cannulas in VA-ECMO, as well as the increased risk of haemolysis and consumptive coagulopathy due to the complexity and extensive foreign body surface of the ECMO-circuit. We conclude that Impella support should be considered as a safer option than VA-ECMO with regards to bleeding in patients with ischaemic left ventricular failure who require DAPT and MCS as a bridge to recovery or other definitive therapy.

Essentials Complement activation has a pathogenic role in thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Complement activation markers were elevated in anticoagulated thrombotic APS patients. Complement activation decreased in APS patients switching from warfarin to rivaroxaban. SummaryBackground Complement activation may play a major role in the pathogenesis of thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Aims To establish whether rivaroxaban, a direct factor Xa inhibitor, limits complement activation compared with warfarin in APS patients with previous venous thromboembolism (VTE). Methods A total of 111 APS patients with previous VTE, on warfarin target INR 2.5, had blood samples taken at baseline and at day 42 after randomization in the RAPS (Rivaroxaban in Antiphospholipid Syndrome) trial. Fifty-six patients remained on warfarin and 55 switched to rivaroxaban. Fifty-five normal controls (NC) were also studied. Markers of complement activation (C3a, C5a, terminal complement complex [SC5b-9] and Bb fragment) were assessed. Results APS patients had significantly higher complement activation markers compared with NC at both time-points irrespective of the anticoagulant. There were no differences between the two patient groups at baseline, or patients remaining on warfarin at day 42. In 55 patients randomized to rivaroxaban, C3a, C5a and SC5b-9 were lower at day 42 (median (ng mL−1) [confidence interval] 64 [29–125] vs. 83 [35–147], 9 [2–15] vs. 12 [4–18] and 171 [56–245] vs. 201 [66–350], respectively) but levels of Bb fragment were unchanged. There were no correlations between rivaroxaban levels and complement activation markers. Conclusions APS patients with previous VTE on warfarin exhibit increased complement activation, which is likely to occur via the classical pathway and is decreased by rivaroxaban administration. Rivaroxaban may therefore potentially provide an additional benefit to its anticoagulant effect in this patient group by limiting complement activation.

Introduction Bleeding is the major complication of anticoagulant therapy. Reversal of vitamin K antagonists (VKAs) in patients with major bleeding events (MBE) including intracranial haemorrhage (ICH) is achieved with prothrombin complex concentrate (PCC) and intravenous vitamin K. Administration of PCC or activated PCC is approved UK strategy for treating MBE associated with rivaroxaban or apixaban, pending approval of a specific reversal agent. In all cases there is concern regarding the incidence of thrombotic events. Methods In this respective review, the efficacy and safety of 4-factor PCCs for the management of MBE in 344 patients receiving rivaroxaban, apixaban or warfarin were compared from January 2016 to April 2018. All patients had full blood count, coagulation screen (INR for VKA) and biochemistry profile at presentation and prior to receiving PCC. Patients on rivaroxaban or apixaban had samples taken for drug level but did not wait for the results to administer PCC. Concomitant antiplatelet or nonsteroidal anti-inflammatory drugs, length of stay, thromboembolic events, re-bleeding at the same site and 30-day mortality were documented from medical records. Results Table 1: Baseline characteristics of the 344 patients Overall median (range) dose of PCC was 2000 units of Factor IX (500-5000). As expected, AF was more frequently the indication for apixaban and rivaroxaban (36/40, 90% and 29/40, 72.5%) than it was for warfarin (165/264, 62.5%). Patients with metallic heart valves or left ventricular thrombus received only warfarin. ICH was the most common indication for PCC in all three anticoagulant groups (137/344, 39.8%) followed by gastrointestinal bleeding (93/344, 27%). ICH was more frequently the indication for PCC in patients receiving rivaroxaban (25/40, 62.5%) and apixaban (21/40, 52.5%) compared to warfarin (91/264, 34.5%), p=0.003. Patients on warfarin more frequently received PCC for musculoskeletal bleeding (12.9%) compared to those on rivaroxaban (5%) and apixaban (5%), p=0.003. There were no differences in the other bleeding sites based on type of anticoagulant. No differences were observed in hemoglobin, platelet count and fibrinogen in patients based on type of anticoagulant or site of bleeding. Median (range) rivaroxaban and apixaban levels at time of receiving PCC were 230ng/ml (47-759) and 159ng/ml (45-255) respectively. Median INR pre- and post-PCC in patients on warfarin were 3.4 (1.9-15.4) and 1.2 (1.0-1.9) respectively. A significantly higher proportion of patients on apixaban (17/40, 42.5%) or rivaroxaban (14/40, 35%) received tranexamic acid compared to warfarin (51/264, 19.2%), p=0.001. Vitamin K was given to 227/264, 86% of patients on warfarin with median dose 5mg (range 1mg-10mg). There was no difference in number of red cell units, platelet or FFP used in the three anticoagulant groups. Overall 30-day mortality rate was 24.7% (85/344) and did not differ according to type of anticoagulant (p=0.17). Recurrent bleeding occurred in 18% overall, warfarin 15.8%, rivaroxaban 20% and apixaban 30.8%, p=0. 07. Recurrent thrombosis occurred in 4.1% (14/344) patients within 30 days of receiving PCC with no difference in three anticoagulant groups, p=0.83 (warfarin 4.2%, rivaroxaban 5.1% and apixaban 2.5%). Nearly half of the patients (48.1%), restarted anticoagulation in a median 13.5 days (6-44). Anticoagulation was restarted in a significantly higher proportion of patients on warfarin (138/264, 52.3%) compared to (10/40, 25%) on rivaroxaban and (13/40, 32.5%) on apixaban, p=0.001. In patients with ICH there were no differences in age or sex between groups. There were no differences in concomitant use of antiplatelet treatment, recurrent bleeding (overall 17.8%, warfarin 17.8%, rivaroxaban 20% and apixaban 15%, p=0.90) or 30-day mortality (overall 30-day mortality was 35%; warfarin 31.9%, rivaroxaban 44% and apixaban 38.1%, p=0.50). None of the patients with ICH on rivaroxaban or apixaban had thrombotic events and only 2/91 (2.2%) patients on warfarin had ischemic strokes within 30 days post PCC. Overall 30.6% of patients with ICH restarted anticoagulation with a median 15 days (10-42). In conclusion, there was no difference in the safety (thrombosis) and efficacy (30-day mortality and re-bleeding) in use of PCC to treat MBE in patients on warfarin, rivaroxaban and apixaban. Some differences may reflect indications for anticoagulation. Disclosures Jayakody Arachchillage: Octapharma: Other: Sponsored to attend an educational meeting; Mitsubishi Phama: Other: Sponsored to attend an educational meeting; Bayer: Other: Sponsored to attend educational meetings. Laffan:Roche: Consultancy, Speakers Bureau; Pfizer: Honoraria.

Recurrent miscarriages and pregnancy-related complications cause significant stress to couples looking for successful pregnancy outcome as well as to health care professionals. There is conflicting evidence with respect to the presence and the strength of associations between inherited thrombophilia and these complications. A complete thrombophilia screen is expensive, and no proven effective treatment for women with recurrent miscarriage and inherited thrombophilia is currently available. Based on the concept of microvascular thrombosis of the placenta, women with recurrent miscarriage and placenta-related complications frequently get treated with antithrombotic therapy. In this narrative review, the authors explore the evolving understanding and evidence of inherited thrombophilia in recurrent miscarriages and other pregnancy complications, and whether antithrombotic treatment would modify pregnancy outcome in women with inherited thrombophilia. Finally, they provide some personal recommendations based on available evidence for clinical practice. In summary, inherited thrombophilia testing is not required outside a clinical trial for women with recurrent pregnancy losses or late pregnancy complications. The presence of thrombophilia markers does not generally indicate additional therapy during pregnancy, even if a heritable thrombophilic defect is found in women with recurrent miscarriages or late pregnancy complications.

Direct oral anticoagulants (DOACs) provide an effective, safe, and convenient therapeutic alternative to warfarin and other vitamin K antagonists (VKAs), and are now established for a wide range of indications. The use of DOACs in women merits special consideration due to two main situations: first, in relation to fertility, pregnancy, and lactation in women of reproductive age; second, because of their bleeding risk, leading to abnormal uterine and/or other genital tract bleeding. This review focuses on these two clinical situations, including approaches to management in the context of available information.

The management of pain and inflammation in haemophilic arthropathy is challenging due to the lack of anti-inflammatory analgesic agents perfectly suitable for this population. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of arthritis due to their analgesic and anti-inflammatory effects. Their use in persons with haemophilia (PWH), however, is limited due to increased risk of bleeding mainly from the upper gastrointestinal (UGI) tract. Cyclooxygenase-2 (COX-2) selective NSAIDs which have comparable analgesic effect to traditional NSAIDs (tNSAIDs) but with less UGI bleeding have been considered to be a suitable option for treatment of haemophilic arthropathy. COX-2 inhibitors, however, have an increased in the risk of cardiovascular (CV) disease. Although the atherosclerotic burden in PWH is similar to that in the general population, the risk of CV-related deaths is lower. PWH have a higher risk of GI bleeding and lower risk of thrombotic disease compared to general population. Therefore, when PWH require anti-inflammatory/analgesic agents, it seems reasonable to use lowest dose of COX-2 inhibitors for the shortest period together with a proton pump inhibitor. Helicobacter pylori infection should be tested for and eradicated prior to starting NSAID treatment in PWH. Furthermore, regular blood pressure and renal function test monitoring is required during COX-2 inhibitor treatment.

Intracranial hemorrhage (ICH) is a serious complication in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) and is associated with high mortality. It is unknown whether ICH may be a consequence of the ECMO or of an underlying disease. The authors first aimed to assess the incidence of ICH at initiation and during the course of VV-ECMO and its associated mortality. The second aim was to identify clinical and laboratory measures that could predict the development of ICH in severe respiratory failure. Data were collected from a total number of 165 patients receiving VV-ECMO from January, 2012 to December, 2016 in a single tertiary center and treated according to a single protocol. Only patients who had a brain computed tomography within 24 hours of initiation of ECMO (n = 149) were included for analysis. The prevalence and incidence of ICH at initiation and during the course of VV-ECMO (at median 9 days) were 10.7% (16/149) and 5.2% (7/133), respectively. Thrombocytopenia and reduced creatinine clearance (CrCL) were independently associated with increased risk of ICH on admission; odds ratio (95% confidence interval): 22.6 (2.6–99.5), and 10.8 (5.6–16.2). Only 30-day (not 180-day) mortality was significantly higher in patients with ICH on admission versus those without (37.5% [6/16] vs 16.4% [22/133]; p = 0.03 and 43.7% [7/16] vs 26.3% [35/133]; p = 0.15, respectively). Reduced CrCL and thrombocytopenia were associated with ICH at initiation of VV-ECMO. The higher incidence of ICH at initiation suggests it is more closely related to the severity of the underlying lung injury than to the VV-ECMO itself. ICH at VV-ECMO initiation was associated with early mortality.