key: cord-0773134-gu5huavn authors: Marshall, S. D.; Duggan, L. V. title: Risk stratification for SARS‐CoV‐2‐related venous thromboembolic events: time for a new paradigm? date: 2021-11-05 journal: Anaesthesia DOI: 10.1111/anae.15610 sha: debaef8fb27df0c5e15afc3b83b24a394ca127c3 doc_id: 773134 cord_uid: gu5huavn nan Twitter: @hypoxicchicken; @drlauraduggan SARS CoV-2 viral infection leading to COVID-19 has been identified as causing substantial peri-operative complications due to pulmonary and coagulation pathologies. Early studies suggested a postoperative mortality rate of 15-24% [1] [2] [3] , much higher than the global case fatality rate of 2.2% due to COVID-19 seen more generally [4, 5] . The risk factors and cause of death associated with this excess mortality have, until recently, not been clear; the recent study by the COVIDSurg and GlobalSurg collaboratives found an association between 30-day mortality with pulmonary complications and venous thromboembolism (VTE) [6] . The COVIDSurg and GlobalSurg collaboratives conducted a prospective observational study in October 2020 of patients > 18 y undergoing emergency or elective surgery. The degree of coordination and number of patients enrolled is impressive. In total, 128,013 patients in 1630 hospitals from 115 countries were enrolled. They observed a 50-90% increased risk of VTE in patients with a perioperative (7 days before to 30 days after surgery) or recent (1-6 weeks before surgery) SARS-CoV-2 infection after multivariable analysis. Concerningly, those patients who did develop VTE had a five-fold greater risk of mortality. Venous thromboembolism is a leading cause of preventable death in hospitals in high-income countries [7] . The use of decision-making prompts within electronic health records is now common in many countries and have helped standardise protocols for VTE prophylaxis. [8] . Although the authors state this was a planned sub-study and analysis from data collected in October 2020, no observational study of VTE is complete without the significant confounder of whether VTE prophylaxis was employed. Although VTE prophylactic regimes may vary, simply including a binary 'yes/no' variable for its use would Increased coagulation risk with SARS-CoV-2 infection is thought to be due to an inflammatory cytokine response, predominantly an over-expression of tissue factor stimulated by the pathogen. In contrast, emergency surgery is likely associated with a multitude of different mechanisms that may be unrelated to tissue factor expression [9] . Tissue factor expression is invariably a significant contributor to procoagulant risk particularly in traumatic injuries or where there is extensive damage to the vascular endothelium. The authors may be correct in assuming this mechanism has a 'ceiling effect' but it is not possible to tell without understanding the prophylactic regimes employed. Markers of the extent of the inflammatory reaction caused by COVID-19 are known to be associated with increased mortality. A meta-analysis of studies in ICUs in 2020 correlated rises in D-dimer, neutrophil count and ferritin levels and a reduction in platelet and lymphocyte counts with the risk of death [10] . While the specifics of the cause of death were not analysed, it is likely that these were also associated with VTE as organ damage from fatal SARS-CoV-2 infection observed post-mortem almost invariably includes evidence of pulmonary thrombosis. In a random sample of 10 post-mortem exams performed on patients who died from COVID-19, all had evidence of pulmonary thrombosis despite no clinical signs of VTE and all having had VTE prophylaxis [11] . Furthermore, another postmortem study found evidence of deep venous thrombosis in over half of the patients that were not evident clinically, with a third having pulmonary embolism as the direct cause of death [12] . The presence of apparently universal small to medium pulmonary vessel thrombosis in fatal COVID -19 infections has been suggested to be due to endothelial damage due to the diffuse alveolar damage [13] . Additionally, most patients also exhibit haemorrhage and infarction of the lung parenchyma. In short, the lung disease caused by SARS-CoV-2 infection is of both the alveoli and the pulmonary vasculature. The thrombotic disease occurs peripherally as thromboembolic insult, in addition to direct injury to the pulmonary vasculature [11] . While the COVIDSurg data observed clinically apparent VTE, the frequent subclinical peripheral venous thromboses and ubiquitous pulmonary vascular effects were not measured. It is not known to what degree these may be prevented and mitigated by prophylaxis. The COVIDSurg/GlobalSurg collaboration study raises valid questions about how we must now manage this increased VTE risk. Apart from following existing recommendations to delay surgery for 7 weeks post-infection (i.e. beyond the high-risk period) wherever possible [14] , the need to modify our existing VTE prophylaxis protocols for this at-increasedrisk population must also be examined. Changes will not be without risk; as with any anticoagulation regime, there is a balance between prevention of thrombotic complications and the potential for bleeding. Any changes to the current VTE prophylaxis guidelines will need to consider the risks of each of these events including the nature of the surgery and risks posed by additional procedures such a neuraxial blocks. This rigorous approach to assessment, risk stratification and escalation of thromboprophylaxis has already been successfully implemented in the ICU. In a cohort study of 188 patients, Atallah et al. demonstrated a reduction of VTE events using a high-intensity, tailored approach to prophylaxis based on D-dimer levels and imaging studies [15] . This approach to longitudinal, daily observation of D-dimer levels triggering imaging and escalation of anticoagulant doses as required is unlikely to be successful outside the ICU due to the resources and acceptability of testing for those patients having relatively minor procedures. Nevertheless, an approach to tailoring therapy to risk is likely to be successful [16] . Guidance might be found in other settings such as for cancer surgery where a risk stratification score has been successfully applied in reducing the incidence of VTE in this cohort without increasing the risk of bleeding [17] . We believe that tailoring The current study did not include those aged <18 y. This Data in this study were collected in October 2020, before widespread vaccine availability. Currently, 65% of the UK population is fully vaccinated, with an additional 7% being partially vaccinated [19] (data updated 13 September 2021). Of note, SARS-CoV-2 vaccination is rarely associated with prothrombotic events via a very different mechanism to that induced by the viral infection itself [20] . Vaccineinduced thrombotic thrombocytopenia is not relevant to the peri-operative period or the need for additional prophylaxis. Nevertheless, the widespread uptake of immunisation since the COVIDSurg/GlobalSurg study would make a repeat of the study extremely difficult and add yet another complicating factor to an already impossible Gordian knot. The risk of peri-operative VTE caused by breakthrough infections of immunised patients is also unknown. Presumably, breakthrough infections produce a lesser inflammatory response and therefore lower-risk of thrombotic tendency. It would be very useful to repeat this study protocol given the fundamental change in the immunisation status of both general and peri-operative populations in many countries. In addition to questions arising from potential VTE risk profile changes due to vaccination, further research needs to identify which markers, in addition to viral testing, will be useful in predicting morbidity and mortality from VTE and pulmonary vascular thrombosis. Implementing these tailored approaches will likely be challenging. A process of shared decision-making will be needed between the surgeon, anaesthesia provider and patient, similar to negotiation of timing of surgery as outlined in the consensus guidelines [21] . Introduction of these tailored approaches would also need to be assessed to ensure they are successful in reducing the risk of VTE while not increasing the risk of postoperative bleeding. It is known that other viral illnesses cause a similar prothrombotic effect but it is not obvious to what degree this is problematic. SARS-CoV-2 may be typical or atypical in elevating the risks of VTE. In the future, there may be targeted therapies for the prevention of VTE related to tissue factor over-expression. These medications would hopefully minimise the risk of VTE without overly increasing the risk of haemorrhage. Until then, a risk stratification approach and tailoring of prophylactic measures depending on evidence or risk of SARS-CoV-2 infection has the potential to avoid preventable postoperative deaths. Postoperative outcomes in surgical COVID-19 patients: a multicenter cohort study Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study Factors associated with surgical mortality and complications among patients with and without Coronavirus disease 2019 (COVID-19) in Italy The global case-fatality rate of COVID-19 has been declining since Outcomes from intensive care in patients with COVID-19: a systematic review and meta-analysis of observational studies SARS-CoV-2 infection and venous thromboembolism after surgery: an international prospective cohort study Prevention of venous thromboembolism Use of computerized clinical decision support systems to prevent venous thromboembolism in surgical patients: a systematic review and meta-analysis Association of the risk of a venous thromboembolic event in emergency vs elective general surgery Factors associated with mortality in patients with COVID-19 admitted to intensive care: a systematic review and meta-analysis Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results From a prospective, single-center, clinicopathologic case series Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study Endothelial cell infection and endotheliitis in COVID-19 Timing of surgery following SARS-CoV-2 infection: an international prospective cohort study The impact of protocolbased high-intensity pharmacological thromboprophylaxis on thrombotic events in critically ill COVID-19 patients Individualized venous thromboembolism risk stratification using the 2005 Caprini score to identify the benefits and harms of chemoprophylaxis in surgical patients: a meta-analysis Impact of a risk-stratified thromboprophylaxis protocol on the incidence of postoperative venous thromboembolism and bleeding Incidence and risk factors associated with 30-day post-operative venous thromboembolism: a NSQIP-pediatric analysis Data. Coronavirus (COVID-19) vaccinations. 2021 SARS-CoV-2 Vaccine-induced immune thrombotic thrombocytopenia SARS-CoV-2 infection, COVID-19 and timing of elective surgery: a multidisciplinary consensus statement on behalf of the Association of Anaesthetists, the Centre for Peri-operative Care, the Federation of Surgical Specialty Associations, the Royal College of Anaesthetists and the LD is an Editor and SM an Associate Editor of Anaesthesia.No other competing interests declared.