Upper extremity deep vein thrombosis in COVID-19: Incidence and correlated risk factors in a cohort of non-ICU patients

Background Venous thromboembolism is a frequent complication of COVID-19 infection. Less than 50% of pulmonary embolism (PE) is associated with the evidence of deep venous thrombosis (DVT) of the lower extremities. DVT may also occur in the venous system of the upper limbs especially if provoking conditions are present such as continuous positive airway pressure (CPAP). The aim of this study was to evaluate the incidence of UEDVT in patients affected by moderate-severe COVID-19 infection and to identify potential associated risk factors for its occurrence. Methods We performed a retrospective analysis of all patients affected by moderate-severe COVID-19 infection admitted to our unit. In accordance with the local protocol, all patients had undergone a systematic screening for the diagnosis of UEDVT, by vein compression ultrasonography (CUS). All the patients were receiving pharmacological thromboprophylaxis according to international guidelines recommendations. Univariate and multivariate analyses were used to identify risk factors associated with UEDVT. Results 257 patients were included in the study, 28 patients were affected by UEDVT with an incidence of 10.9% (95% CI, 7.1–14.7). At univariate analysis UEDVT appeared to be significantly associated (p< 0.05) with pneumonia, ARDS, PaO2/FiO2, D-dimer value higher than the age adjusted cut off value and need for CPAP ventilation. Multivariate analysis showed a significant association between UEDVT and the need for CPAP ventilation (OR 5.95; 95% IC 1.33–26.58). Increased mortality was found in patients affected by UEDVT compared to those who were not (OR 3.71; 95% CI, 1.41–9.78). Conclusions UEDVT can occur in COVID-19 patients despite adequate prophylaxis especially in patients undergoing helmet CPAP ventilation. Further studies are needed to identify the correct strategy to prevent DVT in these patients.

Thromboembolic Events in Critically Ill Children with Multiple Risk Factors for Venous Thrombosis

The risk for venous thromboembolism (VTE) is considered to be low in the general paediatric intensive care unit (PICU) population, and pharmacological thromboprophylaxis is not routinely used. PICU patients considered at high-risk of VTE could possibly benefit from pharmacological thromboprophylaxis, but the incidence of VTE in this group of patients is unclear. This was an observational, prospective study at a tertiary multi-disciplinary paediatric hospital. We used comprehensive ultrasonography screening for VTE in critically ill children with multiple risk factors for VTE. Patients admitted to PICU ≥72 hours and with ≥two risk factors for VTE were included. Patients receiving pharmacological thromboprophylaxis during their entire PICU stay were excluded. Since pharmacological thromboprophylaxis has not been proven effective for central venous catheter(CVC)-related VTE, the primary outcome was VTEs not related to the use of a CVC. Ultrasonography screening of the great veins was performed at PICU discharge. Seventy patients with median (interquartile range) 3 (2-4) risk factors for VTE were evaluated. Median age was 0.34 years (0.03-4.3) and median PICU length of stay 9 days (5-17). Regarding the primary outcome, no symptomatic VTEs occurred and no asymptomatic VTEs were found on ultrasonography screening. The observed proportion of VTE, 0 in 70 patients, corresponds to a VTE incidence of 0-5.1%. Conclusion: No VTEs where pharmacological thromboprophylaxis could potentially have been an effective prophylactic measure were found. This indicates that VTE is an uncommon event even in a selected group of severely ill small children considered to be at high risk of VTE.

Pharmacological Thromboprophylaxis in Patients With Cancer

Six evidence-based guidelines were identified regarding the long-term (6 months or longer) use of pharmacological thromboprophylaxis for the management of cancer-associated thrombosis. The guidelines used rigorous methodology, systematically searched for evidence, and were clearly reported. Anticoagulation therapy for 6 months or longer is recommended by 5 guidelines for patients with active cancer and venous thromboembolism to prevent recurrences of venous thromboembolism. However, the recommendations are weak and made based on low-quality evidence or expert consensus. Two guidelines recommend a low-molecular-weight heparin or direct oral anticoagulant for long-term use (6 months or longer) in patients with cancer. This recommendation is based on low- to high-certainty evidence. Two guidelines strongly recommend direct oral anticoagulants in patients with cancers in locations other than gastrointestinal or genitourinary cancers. This recommendation is based on high-quality evidence. No guidelines were identified regarding arterial thrombosis or chronic disseminated intravascular coagulation associated with cancer.

COVID-19 Is Associated with Endothelial Dysfunction and Enhanced Plasma Thrombin Generation Despite Pharmacological Thromboprophylaxis

Background Hospitalised patients with severe COVID-19 (requiring critical care level support) appear to be at increased risk of thrombosis despite standard pharmacological thromboprophylaxis. The magnitude of thrombotic risk in patients with COVID-19 of moderate severity (not requiring critical care) is less clear. The optimal approach to thromboprophylaxis (and the role of intensified thromboprophylaxis) remains to be determined. Evidence of endothelial dysfunction has been widely reported in COVID-19 (particularly in severe COVID) and this may contribute to hypercoagulability. Aim To assess differences in patterns of hypercoagulability and endothelial dysfunction between a group of patients with moderate COVID-19 and a group of age-matched hospitalized patients (SARS-CoV-2 PCR negative) receiving low molecular weight heparin (LMWH) thromboprophylaxis. Methods Blood was collected from individuals admitted to hospital with COVID-19 of moderate severity (not requiring critical care level support) and a group of age-matched patients admitted with infective/inflammatory illness (SARS-CoV-2 PCR negative). All subjects received standard-dose LMWH thromboprophylaxis, with blood drawn at 12 hours post-dose (and with measurement of anti-FXa activity levels). Circulating levels of endothelial & fibrinolytic markers including ICAM, PAI-1, VCAM, soluble thrombomodulin (sTM), and tissue plasminogen activator (tPA) were determined by ELISA. Thrombin generation (TG) in platelet-poor plasma was assessed by calibrated automated thrombography in the presence of tissue factor (Final concentration, 1pM & 5pM), thrombomodulin (TM) (Final concentration, 6.25nM), and an inhibitory anti-tissue factor pathway inhibitor antibody (anti-TFPI; Final concentration 100μg/mL). Results 14 COVID-19 positive subjects and 11 hospitalized controls were recruited. There were no differences in mean age (69.7±4.5 vs 61.6±4.7 years; p= 0.2) or mean Body mass index (25.7±1.1 vs 22.7±1.2 Kg/m2; p=0.1) between groups. No COVID-19 patient or control required critical care support. In the COVID group, radiological evidence of pneumonitis [diffuse (n=3) or peripheral infiltrates (n=7)] was present in the majority of cases. None of the COVID-19 cases were requiring supplemental oxygen at the time of recruitment. All controls were admitted with either respiratory or urinary infection [radiological evidence of pneumonia in 4/11; supplemental oxygen requirement in 2/11, (28-36% FiO2 via nasal cannula)]. Plasma levels of sTM, ICAM, PAI-1 & VCAM were similar in both groups. Levels of t-PA were significantly higher in the COVID group (8.31±4.35 vs 4.91±2.37 ng/mL; p= 0.005). Despite similar plasma anti-Xa activity in both groups (0.06 vs 0.04 IU/mL; p=0.2), mean endogenous thrombin potential (ETP) was significantly higher in the COVID group (1929±119.7 vs 1528±138.9 nM*min; p=0.02), although peak thrombin was similar (173.6±26 vs 161.5±31nM). ETP-TM ratio was similar between groups (0.3±0.1 vs 0.2±0.1; p=0.3). Despite increased ETP, the lag time to thrombin generation was significantly prolonged in the COVID group (8.3±0.6 vs 5.8±0.5 mins, p= 0.006). This pattern has previously been observed in vascular diseases associated with altered plasma tissue factor pathway inhibitor (TFPI) activity. In the presence of an anti-TFPI antibody, the difference in lagtime between groups was attenuated (4.7±0.2 vs 3.5±0.1 mins; p= 0.002) and the difference in overall thrombin generation (delta TG) between both groups became significantly increased (Fig.1). Conclusion Plasma thrombin generation is enhanced in patients with non-severe COVID-19 despite pharmacological thromboprophylaxis. Endothelial dysfunction is also observed in this group and appears to modulate parameters of plasma thrombin generation. The clinical implications of these observations are not known although clinical studies of intensified thromboprophylaxis in attenuating thrombotic risk and other complications are ongoing. Fig 1. Inhibition of TFPI activity enhances thrombin generation in COVID-19. In the presence of an inhibitory anti-TFPI antibody, peak plasma thrombin generation was enhanced in COVID-19 in contrast to that observed among SARS-CoV-2 PCR negative hospitalised patients (339.6+25.2 vs 247.4+10.1, p=0.01). Figure 1 Figure 1. Disclosures Maguire: Actelion: Research Funding; Bayer Pharma: Research Funding. Ni Ainle: Daiichi-Sankyo: Research Funding; Actelion: Research Funding; Leo Pharma: Research Funding; Bayer Pharma: Research Funding. Kevane: Leo Pharma: Research Funding.

PICO Questions and DELPHI Methodology for the Management of Venous Thromboembolism Associated with COVID-19

Patients with coronavirus disease 2019 (COVID-19) have a higher risk of venous thromboembolic disease (VTE) than patients with other infectious or inflammatory diseases, both as macrothrombosis (pulmonar embolism and deep vein thrombosis) or microthrombosis. However, the use of anticoagulation in this scenario remains controversial. This is a project that used DELPHI methodology to answer PICO questions related to anticoagulation in patients with COVID-19. The objective was to reach a consensus among multidisciplinary VTE experts providing answers to those PICO questions. Seven PICO questions regarding patients with COVID-19 responded with a broad consensus: 1. It is recommended to avoid pharmacological thromboprophylaxis in most COVID-19 patients not requiring hospital admission; 2. In most hospitalized patients for COVID-19 who are receiving oral anticoagulants before admission, it is recommended to replace them by low molecular weight heparin (LMWH) at therapeutic doses; 3. Thromboprophylaxis with LMWH at standard doses is suggested for COVID-19 patients admitted to a conventional hospital ward; 4. Standard-doses thromboprophylaxis with LMWH is recommended for COVID-19 patients requiring admission to Intensive Care Unit; 5. It is recommended not to determine D-Dimer levels routinely in COVID-19 hospitalized patients to select those in whom VTE should be suspected, or as a part of the diagnostic algorithm to rule out or confirm a VTE event; 6. It is recommended to discontinue pharmacological thromboprophylaxis at discharge in most patients hospitalized for COVID-19; 7. It is recommended to withdraw anticoagulant treatment after 3 months in most patients with a VTE event associated with COVID-19. The combination of PICO questions and DELPHI methodology provides a consensus on different recommendations for anticoagulation management in patients with COVID-19.

1087 Establishing Guidelines for VTE Prophylaxis for Acute ENT Admissions

Aim VTE prophylaxis is a vital aspect of patient safety. The decision whether to offer pharmacological thromboprophylaxis is a balance of risk versus benefit. There is a low incidence of VTE in ENT patients, admissions are often short and active bleeding on admission is not uncommon (epistaxis patients, already on anticoagulation are particularly difficult to manage}. There are no clear, specialty specific guidelines to assist in these frequently encountered endeavours. Method The number of emergency ENT admissions who had a documented VTE during admission or in the 28 days following was used to calculate the incidence of VTE in acute admissions. An audit of VTE prophylaxis and documentation was also conducted using 20 admissions over 24 hours. Results Incidence was 0.12%. 75% had a documented VTE risk assessment. Only 50% patients were prescribed chemical and mechanical thromboprophylaxis. 0% had appropriately documented that the patient did not require thromboprophylaxis on the drug chart (as per trust guidelines). Conclusions The results showed that both documentation and prescribing related to VTE prevention were poor. By highlighting the low incidence amongst this patient group, we were able to establish clearer guidance for VTE prophylaxis in acute ENT admissions and a protocol to standardise the management of anticoagulation in actively bleeding epistaxis patients.

Thromboprophylaxis in Patients with COVID-19: Systematic Review of National and International Clinical Guidance Reports

Background: Venous thromboembolism (VTE) is common among patients with severe coronavirus disease 2019 (COVID-19). Anticoagulation in hospitalized COVID-19 patients has been associated with survival benefit; however, the optimal thromboprophylaxis strategy has not yet been defined. Objective: To identify published guidance reports by national and international societies regarding thromboprophylaxis strategies in COVID-19 patients in different settings (outpatients, hospitalized, post-discharge). Methods: A systematic review of the literature (Pubmed/EMBASE) was conducted independently by two investigators. Results: Among 1942 initially identified articles, 33 guidance documents were included: 20 published by national and 13 by international societies. These documents provide recommendations mainly for hospitalized (97% of reports) and post-discharge (75%) COVID-19 patients, and less so for outpatients (34%). Thrombotic and bleeding risk stratification prior to any treatment decision is the cornerstone of all suggested thromboprophylaxis strategies; 81% of the documents recommend thromboprophylaxis for all hospitalized patients with a prophylactic dosage of low molecular weight heparin irrespective of VTE risk. Intermediate or therapeutic dose intensity is recommended in high VTE risk patients by 56% and 28% of documents, respectively. Mechanical thromboprophylaxis is suggested in case of high bleeding risk or contraindication to pharmacological thromboprophylaxis (59% of documents). Extended pharmacological thromboprophylaxis is recommended for patients with high VTE risk after hospital discharge (63% of documents). For non-hospitalized outpatients, 28% of documents recommend pharmacological thromboprophylaxis for high VTE risk. Conclusion: The current guidance identifies thromboprophylaxis in COVID-19 patients, especially during hospitalization, as of major importance for the prevention of VTE. Recommendations are derived from limited evidence from observational studies.

P133 Types and timing Of venous thromboembolism Prophylaxis for Traumatic Brain Injury (TOP TBI) Study

Background Patients with traumatic brain injury are at significant risk for both developing venous thromboembolisms and haemorrhagic progression. Pharmacological thromboprophylaxis and mechanical thromboprophylaxis may be able to minimise the incidence of venous thromboembolisms. Problematically, pharmacological thromboprophylaxis also has the potential to augment clinically significant intracranial haemorrhage expansion. Compounding this issue is that the evidence for mechanical thromboprophylaxis is not based on neurotrauma populations, and there is insufficient evidence to guide clinicians on the optimum agent, dose, and timing of pharmacological thromboprophylaxis. Based on the need for high quality evidence, we propose the Types and timing Of venous thromboembolism Prophylaxis for Traumatic Brain Injury (TOP TBI) Study. Aim To collect high quality and relevant data regarding thromboprophylaxis practice and associated outcomes - including rates of venous thromboembolisms, intracranial haemorrhage expansion and mortality – for TBI patients in the UK and Ireland in order to optimise management for these patients. Methods We will adopt a multicentre, prospective, observational cohort design. All neurosurgical units: in the UK and Ireland will be eligible to participate. Patient eligibility will be determined according to pre-specified criteria. Eligible cases will be prospectively recruited over two months and followed-up in 6 months. Based on epidemiological investigations and data from the Trauma Audit and Research Network, we expect to recruit between 1000 to 2000 patients. Anonymised data will be collected locally and submitted to a secure web-based central database. Outcome measures These include all-cause mortality, venous thromboembolism events, haemorrhagic progression, re-admission, surgical intervention, length of stay in admitting unit, neurological status, and Extended Glasgow Outcome Scale during follow-up. Conclusion TOP TBI is an important step in the ongoing efforts to optimise the outcomes of patients who have suffered a traumatic brain injury. It is hoped that the results will give insight into contemporary practice in the UK and Ireland and inform future studies.