key: cord-283267-72wrzw09
authors: Moores, Lisa K.; Tritschler, Tobias; Brosnahan, Shari; Carrier, Marc; Collen, Jacob F.; Doerschug, Kevin; Holley, Aaron B.; Jimenez, David; LeGal, Gregoire; Rali, Parth; Wells, Philip
title: Prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19: CHEST Guideline and Expert Panel Report
date: 2020-06-02
journal: Chest
DOI: 10.1016/j.chest.2020.05.559
sha: 
doc_id: 283267
cord_uid: 72wrzw09

Abstract: Background Emerging evidence shows that severe COVID-19 can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and venous thromboembolism (VTE). This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE. Methods A group of approved panelists developed key clinical questions by using the PICO (population, intervention, comparator, and outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19. MEDLINE (via PubMed or Ovid), Embase and Cochrane Controlled Register of Trials were systematically searched for relevant literature and references were screened for inclusion. Validated evaluation tools were used to grade the level of evidence to support each recommendation. When evidence did not exist, guidance was developed based on consensus using the modified Delphi process. Results The systematic review and critical analysis of the literature based on13 PICO questions resulted in 22 statements. Very little evidence exists in the COVID-19 population. The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements. Conclusions The evidence on the optimal strategies to prevent, diagnose, and treat venous thromboembolism in patients with COVID-19 is sparse, but rapidly evolving.

Remarks: The panel favors LMWH over UFH in order to limit staff exposure. The panel strongly cautions against the use of DOACs in critically ill patients secondary to their hemodynamic instability, the high likelihood of drug-drug interactions, and the high incidence of acute kidney injury in these patients. In addition, there is a lack of evidence for anticoagulant thromboprophylaxis even in non-COVID critically ill patients.

against the use of antiplatelet agents for venous thromboembolism (VTE) prevention.

weight-based dosing) or full treatment dosing, per existing guidelines.

Remarks: Although there has been some concern for increased risk of VTE in hospitalized COVID-19 patients, there is insufficient data to justify increased intensity anticoagulant thromboprophylaxis in the absence of randomized controlled trials.

weight-based dosing) or full treatment dosing, per existing guidelines.

COVID-19 patients occupy a different level of risk for VTE than other severely ill nonsurgical, medical ICU patients. There is also insufficient data regarding bleeding risk in this population, and given severity of illness, it may be just as likely that critically ill is not likely that adding mechanical prophylaxis in this population would cause major harm. We recommend that providers adhere to existing guidance regarding the use of mechanical thromboprophylaxis.

pharmacological thromboprophylaxis, we suggest the use of mechanical thromboprophylaxis. 11 . In critically ill COVID-19 patients, we suggest against routine ultrasound screening for the detection of asymptomatic deep vein thrombosis (DVT). 

adjusted LMWH or intravenous UFH. The use of LWMH will limit staff exposure and avoid the potential for heparin pseudo-resistance. In patients without any drug-todrug interactions, we suggest initial oral anticoagulation with apixaban or rivaroxaban. Dabigatran and edoxaban can be used after initial parenteral anticoagulation. Vitamin K antagonist therapy can be used after overlap with initial parenteral anticoagulation.

Remarks: The panel has downgraded the most recent ACCP recommendation regarding the use of oral anticoagulants in patients hospitalized with COVID-19 secondary to the high risk of rapid clinical deterioration in these patients. In addition, it is likely that many of these patients will be on concomitant therapy (antiviral agents or other investigational treatments) that can significantly affect the pharmacodynamics of and bleeding risk associated with the DOACs. Thus LMWH or UFH are favored over oral anticoagulants.

13. For outpatient COVID 19 patients with proximal DVT or PE and no drug-to-drug interactions, we recommend apixaban, dabigatran, rivaroxaban or edoxaban. Initial parenteral anticoagulation is needed before dabigatran and edoxaban. For patients who are not treated with a DOAC, we suggest vitamin K antagonists over LMWH (for patient convenience and comfort). Parenteral anticoagulation needs to be overlapped with vitamin K antagonists.

14. In critically ill COVID-19 patients with proximal DVT or PE, we suggest parenteral over oral anticoagulant therapy. In critically ill COVID-19 patients with proximal DVT or PE who are treated with parenteral anticoagulation, we suggest LMWH or fondaparinux over UFH. 

In late December 2019, a novel beta coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease of 2019 (COVID-19) was identified. It was officially declared a pandemic by the World Health Organization (WHO) in March of 2020. 1 Emerging evidence shows that severe COVID-19 can be complicated by coagulopathy. In the most severe cases, this manifests as disseminated intravascular coagulation (DIC), which is a pro-thrombotic condition with a high risk of venous thromboembolism (VTE). 2 The presence of DIC in these patients has been found to be a strong predictor of mortality. In a retrospective review of 183 consecutive patients with COVID-19 at a single institution, Tang and colleagues noted that 71.4% of nonsurvivors and 0.6% of survivors showed evidence of overt DIC (as defined by the validated International Society on Thrombosis and Haemostasis DIC score). 3 The literature also demonstrates that many patients with COVID-19 have highly abnormal D-dimer levels which were also prognostic. The incidence of VTE in COVID-19 patients is not well defined, but early reports suggest it may be higher than in non-COVID hospitalized patients with similar degrees of illness, even in the presence of prophylactic anticoagulation. [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] The mechanism for this is likely multifactorial. In fact, it could be argued that the lungs of patients with COVID-19 exhibit all components of Virchow's triad-hypercoagulable state, endothelial injury, and stasis of blood flow. High plasma levels of several proinflammatory cytokines (IL-2, IL-7, granulocyte colony-stimulating factor, IP10, MCP1, MIP1A and tumor necrosis factor-α) have been observed in COVID-19 patients admitted to the intensive care unit (ICU). 2 As in other critical illnesses, this systemic cytokine storm triggers the coagulation system and a hypercoagulable sate. There is also evidence of significant endothelial injury, as evidenced by reports of significantly elevated von Willebrand Factor (VWF) and Factor VIII (FVIII) levels. 16 Finally, severe COVID-19 is manifested as severe acute respiratory distress syndrome (ARDS). Current evidence-based guidelines recommend positive pressure ventilation with high levels of positive end-expiratory pressure (PEEP) and fluid restriction, 17 both of which may lead to decreases in pulmonary blood flow, leading to stasis and microthrombosis.

The recognition of the coagulopathy with COVID-19, and the early evidence that suggests that thrombosis in these patients is higher than that seen in similarly ill hospitalized patients with other respiratory infections has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE. Current evidence in this specific population is lacking, but reports are emerging daily. The goal of this guidance statement is to review the current evidence that is available and, wherever possible, translate this into practical recommendations. Where this was not possible, the authors would like to remind readers that several well-done evidence-based guidelines regarding the management of patients with VTE and DIC in the non-COVID population exist and should direct patient care until robust trials can be completed in the COVID-19 population. [18] [19] [20] [21] [22] [23] Given the rapidity with which new evidence is evolving, the authors consider this to be a living document with plans to update the guidance statements as appropriate.

The primary aim of this CHEST panel was to provide practical guidance on the most urgent questions regarding the prevention, diagnosis, and treatment of VTE in patients diagnosed with COVID-19. CHEST appointed a Chair for the panel (LKM) who recruited panelists based upon their established expertise within the field of thromboembolism. The list of panelists was approved by CHEST leadership. All panel members were educated about the process and schedule. Formal conflict of interest review was not performed by the Professional Standards Committee given the timeline for the project, but all panelists were reminded that they would be required to disclose all relevant conflicts prior to voting and at the time of submission of the manuscript to the journal. The majority of panelists had no conflicts of interest to disclose.

Two panelists (MC, GL) do not receive any personal honoraria and/or consulting fees, but do receive funds that go directly to their institutional research fund. In order to reduce any perceived conflict, they abstained from voting on any statements that had overlap with their research or consulting relationships. Search strategies and inclusion criteria were broad given the anticipated low level of evidence at the time they were conducted.

Screening and full text selection were performed in duplicate by the pairs. No meta-analyses or randomized controlled trials were available. Most of the evidence included retrospective cohorts and case series. Thus, none of the available direct and indirect literature provided sufficient evidence for the development of evidence tables or recommendations. The panel agreed that patients with COVID-19 appear to be a unique population with evolving evidence that their risk of thrombosis is higher than other hospitalized acutely ill medical or ICU patients.

When this evidence was enough (albeit very low level) to adjust existing guideline statements, the panel made modifications to existing statements from CHEST guidelines. 19, 20 When this was not possible, the panel simply applied existing guidance and adjusted the wording to this population. All of the statements in this document are thus expert opinion. When the perceived benefits outweighed perceived risks, the panel chose to "recommend" an intervention. When the balance of risk and benefit was less certain, the panel chose only to "suggest" an intervention.

Search results and suggestions written by the panel pairs for each PICO question were shared with all panel members. During a conference call, suggestions were reviewed and subsequently re-written based on panel input. This was followed by another conference call with 100% participation, soliciting additional comments and input. All panel members participated in the development of suggestions to be incorporated in the initial round of the modified Delphi survey. The modified Delphi technique is a widely accepted method for the development of consensus among experts. 24 To achieve consensus, a priori decision was made to conduct up to three rounds of anonymous voting or until consensus was achieved (defined a priori as consensus agreement at ≥80% with a minimal response rate of 80%) for each draft 

We found 11 studies that reported on VTE rates in patients diagnosed with COVID-19 (Table   2 ). [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] 25 All 11 were observational reports at high risk for selection bias, and 8/11 were retrospective. These studies included a total of 1,373 patients, the majority (800 (58.0%)) of whom were treated in an ICU. One other study reported 40% (407/1099) of inpatients have a high risk for VTE by Padua risk score, but did not report VTE rates. 26 This study, however, had major limitations (e.g., 8% of patients had missing values for age and missing values for other variables were not reported). Prevalence and incidence rates of TE are reported in Tables 3 and   4 . Given the heterogeneity of the studies, we chose not to pursue a pooled analysis.

A qualitative review of the 11 studies reporting VTE prevalence and incidence is presented in Table 2 . Patient selection procedures varied across studies and were often unclear. A detailed description of testing procedures was also lacking in most studies. Some studies reported only deep vein thrombosis (DVT). 4, 12, 14 Only five studies specified whether pulmonary embolism (PE) was subsegmental or more proximal, 5, 6, 9, 10, 13 and only three studies provided detailed information on DVT location. 6, 9, 10 Universal screening for events also varied across studies, and in many, outcomes were reported on patients still hospitalized. Average duration of hospitalization and or the hospital day on which CTPA or lower extremity compression ultrasound (CUS) was performed was variably reported. Lastly, thromboprophylaxis rates in Chinese hospitals are reported to be as low as 20% in some studies, 26, 27 which affects interpretation of event rates in Chinese COVID-19 populations.

The panel first aimed to address the need for VTE prophylaxis in acutely ill hospitalized (general inpatient ward) and critically ill (ICU) patients with COVID-19. Our search identified 3 singlecenter studies reporting estimates for the incidence of VTE in acutely ill hospitalized patients ( Table 2 and 4) . 9, 10, 14 None of the studies allows for comparison between anticoagulant thromboprophylaxis and placebo, or comparison between different drugs or doses. The majority of patients included in those studies received anticoagulant thromboprophylaxis at prophylactic or higher dose. Lodigiani and colleagues reported a cumulative incidence of venous and arterial thromboembolic events of 6.6% during hospital admission. A total of 2.4% of the patients developed a PE, and 0.9% of the patients were diagnosed with a symptomatic isolated proximal DVT of the lower extremities. 9 As reported by Middeldorp et al, the cumulative incidence of symptomatic VTE was 9.2% at 14 days, comprising 1 patient with proximal PE, 1 patient with subsegmental PE, and 2 patients with distal DVT. 10 Xu and colleagues reported confirmation of DVT in 1 of 123 (0.8%) patients on the ward. 14 Noteworthy, most COVID-19 patients would have been eligible for at least 1 of the 3 landmark randomized controlled trials of anticoagulant thromboprophylaxis in acutely ill medical inpatients. [28] [29] [30] In these studies, the proportion of patients who developed symptomatic VTE or any VTE at 14-21 days was 0.3-1.0% and 2.8-5.6%, respectively. [28] [29] [30] Because the incidence of VTE in acutely ill medical inpatients is too low (below 1% without thromboprophylaxis) to justify anticoagulant thromboprophylaxis -and incurred risk of bleeding -in every patient, 19 several risk stratification scores have been developed to identify medical inpatients at higher risk of VTE. The Padua and IMPROVE risk scores are the most extensively validated scores, 31,32 but both showed heterogenous discriminatory performance in external validation studies 32-41 and they lack validation in an impact study. Considering that hospitalized patients with COVID-19 are confined to their room, immobilization, a major risk factor for VTE in medical inpatients, 42 affects many inpatients with COVID-19. Infectious disease is an additional risk factor for VTE, 42 which is present in all patients with COVID-19. Taking into account those risk factors and that the current estimates of the incidence of VTE in non-critically ill patients with COVID-19 is well above 1% even on anticoagulant thromboprophylaxis, the panel considers all hospitalized patients with COVID-19 at increased risk of VTE. We therefore suggest against individualized VTE risk assessment and suggest anticoagulant thromboprophylaxis in all hospitalized patient with COVID-19 in absence of contraindications.

Our search identified 11 studies providing estimates for the incidence or prevalence of VTE in critically ill patients with COVID-19 ( Table 2 and 3) . [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] 25 None of the studies allows for comparison between anticoagulant thromboprophylaxis and placebo, or comparison between different drugs. The proportion of critically ill patients with COVID-19 diagnosed with VTE on at least standard dose anticoagulant thromboprophylaxis ranged from 0 to 54%; 5-14,25 the reported cumulative incidence of VTE during hospital stay ranged from 20 to 59%. 7,10,11,13 One single-center retrospective cohort study of 449 patients hospitalized in the Tongji hospital in Wuhan suggests that heparin at prophylactic dose is associated with an absolute mortality reduction of 24% in patients with sepsis-induced coagulopathy (SIC) compared to no anticoagulant thromboprophylaxis. 27 No mortality difference was shown in patients that were less sick. Considering that low-molecular-weight heparin (LMWH) at prophylactic doses did not reduce mortality in a randomized placebo-controlled trial in critically ill patients with chronic obstructive pulmonary disease, 43 the mortality difference in sick patients with COVID-19 appears striking. However, the study has several major limitations. A total of only 22% of the patients received thromboprophylaxis; thromboprophylaxis was defined as the use of heparin ≥7 days which may have introduced immortal time bias; and the analysis was not adjusted for other potential confounders.

In critically ill medical patients without COVID-19, the failure rate of anticoagulant thromboprophylaxis in randomized controlled trials ranged from 6 to 16%. [43] [44] [45] The incidence of VTE in cohort studies of critically ill medical patients varies depending on patient population. 19 Pooled risk estimates for benefits and harms of anticoagulant thromboprophylaxis in critically ill medical patients without COVID-19 differ across meta-analyses, 19, 22, 46 but practice guidelines consistently recommend anticoagulant thromboprophylaxis with LMWH (or unfractionated heparin [UFH]) over no such therapy. 19, 22 We recommend anticoagulant thromboprophylaxis in all critically ill patients with COVID-19, because current evidence suggest that the failure rate of thromboprophylaxis in critically ill patients with COVID-19 seems higher than in randomized controlled trials assessing anticoagulant thromboprophylaxis in critically ill medical patients without COVID-19 and at least as high as the failure rate in prospective cohort studies of critically ill patients with severe sepsis or septic shock. 47 

recommend anticoagulant thromboprophylaxis over no anticoagulant thromboprophylaxis.

We did not identify any studies allowing for comparisons between different anticoagulants for thromboprophylaxis in acutely ill hospitalized patients with COVID-19. LMWH, UFH, fondaparinux, and DOACs have each been assessed in randomized trials of thromboprophylaxis in acutely ill hospitalized patients without COVID-19. 22 Compared to placebo, parenteral anticoagulant thromboprophylaxis with LMWH or fondaparinux reduces the risk of symptomatic PE and any DVT. 22 Pooled results indicate no statistically significant difference in symptomatic DVT, major bleeding or mortality. 22 No difference in critical outcomes have been shown in randomized trials comparing LMWH and UFH; no randomized study compared fondaparinux with LMWH/UFH. 22 Compared to LMWH, DOACs do not reduce the risk of PE or symptomatic DVT, but are associated with an increased risk of major bleeding (relative risk [RR], 1.70; 95% confidence interval [CI], 1.02-2.82). 48 Therefore, the panel recommends using LMWH, fondaparinux or UFH over the use of DOACs in acutely ill hospitalized patients with COVID-19.

Considering the reduced nursing staff exposure with LMWH or fondaparinux due to the oncedaily administration and the possibly lower risk of heparin-induced thrombocytopenia with LMWH or fondaparinux compared to UFH, we suggest LMWH or fondaparinux over UFH in acutely ill hospitalized patients with COVID-19. patients requiring hospitalization to be substantially greater than the benefits of aspirin thromboprophylaxis. Consequently, we do not consider antiplatelet agents a reasonable alternative to anticoagulant prophylaxis in these patients for VTE events.

against the use of antiplatelet agents for VTE prevention.

We found no studies that reported a comparison of one specific anticoagulant thromboprophylaxis regimen to another. One retrospective study reported a reduction in mortality with heparin at prophylactic doses (most were on 40-60 mg enoxaparin per day) compared to no prophylaxis in a highly select group of ICU patients. 27 This study suffers from confounding by indication for prophylaxis and lack of adjustment for co-factors in the specific analysis that found a mortality difference with heparin. For all comers in this study, there was no mortality difference related to heparin prophylaxis. In a single-center retrospective study of 2773 patients of whom 786 (28%) received therapeutic anticoagulation, in-hospital mortality was similar between anticoagulated and non-anticoagulated patients (22.5% vs. 22.8%). 50 Among mechanically ventilated patients, in-hospital mortality was lower in patients who received anticoagulation (29%, median survival of 21 days) than in those who did not receive anticoagulation (63%, median survival of 9 days). In a multivariable Cox proportional hazards model, longer duration of therapeutic anticoagulation was associated with a reduced risk of mortality. The risk of major bleeding was 3% and 1.9% in anticoagulated and nonanticoagulated patients, respectively. Of note, pulmonary hemorrhage was not part of the definition of major bleeding and the incidence of VTE was not reported. While this study is hypothesis-generating and supports the rationale for randomized controlled trials evaluating thromboprophylaxis at therapeutic doses, it should not inform patient management due to its limitations. First, the authors did not specify anticoagulant agents, the indication for anticoagulation and whether non-anticoagulated patients did receive anticoagulant thromboprophylaxis. Second, the results may be flawed by immortal time bias, confounding by indication and other residual confounding. Finally, the median duration of anticoagulation was 3 days which challenges the biological plausibility of the large mortality reduction observed among mechanically ventilated patients.

Several studies provide data that are indirectly relevant. A retrospective, observational report on 16 ICU patients (all mechanically ventilated and diagnosed with ARDS) reported no VTE events in patients who had VTE anticoagulant thromboprophylaxis titrated to serum coagulation studies and adjusted for body mass index (BMI). 25 They used LMWH, anti-thrombin concentrate, and clopidogrel, and there is no report on bleeding rates. Several other studies report high VTE rates despite standard prophylaxis in critically ill COVID-19 patients. 6, 12, 14 Because all identified studies of VTE rates and anticoagulant thromboprophylaxis regimens for hospitalized COVID-19 patients are observational with select populations, definitive interpretation is difficult. It seems critically ill, intubated patients with COVID-19 can develop a profound coagulopathy and form clot at a high rate despite prophylaxis. While adjusting prophylaxis by coagulation studies seems reasonable, specific protocols have not been systematically studied nor bleeding rates reported. Of note, several studies have reported critically ill COVID-19 patients are at high risk for bleeding based on the IMPROVE bleeding risk score. 14,26 Until we have more data, an accurate risk-benefit assessment of VTE versus bleeding, particularly with increasing anticoagulant thromboprophylaxis above standard dosing, is not possible.

A recent guideline reviewed the data on SIC and DIC in non COVID-19 patients. 23 The authors noted that SIC/DIC can lead to a pro-thrombotic coagulopathy. They concluded adjustment to standard anticoagulant thromboprophylaxis in the presence of SIC/DIC remains controversial but could be considered. Whether COVID-19 induces a different or more profound type of SIC/DIC remains unknown, but even if one assumes it is similar to non-COVID-19 SIC/DIC, the optimal approach to anticoagulant thromboprophylaxis is uncertain.

Remarks: Although there has been some concern for increased risk of VTE in hospitalized COVID-19 patients, there is insufficient data to justify increased intensity anticoagulant thromboprophylaxis in the absence of randomized controlled trials.

Our search identified no study reporting incidence of VTE or major bleeding after hospital discharge in patients with COVID-19. In non-COVID patients, a significant proportion of VTE events associated with hospitalization occur after discharge. [28] [29] [30] 51 Anticoagulant thromboprophylaxis up to 45 days after discharge reduces the risk of VTE following hospital admission (RR, 0.61; 95% CI, 0.44-0.83) but increases the risk of major bleeding (RR, 2.04; 95% CI, 1.42-2.91). 52 A post-hoc analysis of the MAGELLAN trial suggests that extended thromboprophylaxis is associated with a net benefit in patients at high risk of VTE as per modified IMPROVE score and low risk of bleeding (i.e., absence of active cancer, dual antiplatelet therapy, history of bronchiectasis or pulmonary cavitation, active gastroduodenal ulcer, or any bleeding in the previous 3 months). 53 However, in the MARINER trial of 12,069 patients at risk of VTE as per modified IMPROVE score, rivaroxaban 10 mg daily for 45 days after hospital discharge did not reduce symptomatic VTE. 54 The recent American Society of Hematology practice guideline recommend against the use of extended thromboprophylaxis, because they determined a net harm associated with extended thromboprophylaxis. 22 Many hospitalized patients with COVID-19 would likely have been eligible for randomized controlled trials assessing extended thromboprophylaxis and it appears therefore justified to extrapolate relative treatment effects from those studies to hospitalized patients with COVID-19. Assuming that patients with COVID-19 incur the same risk of bleeding as patients without COVID-19 at high risk of VTE (i.e., 0.7% at 35 days after discharge without extended thromboprophylaxis in patients at low risk of bleeding) 53 and that symptomatic VTE is associated with a similar burden to patients as major bleeding, 22 

benefit.

We were unable to identify any studies that reported on mechanical methods for prophylaxis in COVID-19 patients. While it may seem reasonable to add mechanical to pharmacological prophylaxis in patients thought to be at high baseline risk for VTE, a recent randomized controlled trial found no benefit to this approach. 55 Therefore, it seems unlikely that mechanical, in addition to pharmacological prophylaxis will affect VTE rates in critically ill patients with COVID-19.

likely that adding mechanical prophylaxis in this population would cause major harm.

We recommend that providers adhere to existing guidance regarding the use of mechanical thromboprophylaxis.

pharmacological thromboprophylaxis, we suggest the use of mechanical thromboprophylaxis.

Screening ultrasound for asymptomatic DVT is not routinely performed in critically ill patients.

Lower extremity ultrasound is reserved for critically ill patients with a clinical suspicion for VTE.

General screening ultrasound carries an increased risk of personnel exposure and resource utilization during the COVID-19 pandemic. As we have noted, there is growing evidence to suggest that patients with COVID-19 are at an increased risk of VTE events. 6, 56 This risk is exacerbated in critically ill ICU patients compared those on a general medical ward. 9, 10 Middeldorp et al, reported an increased incidence of venous thrombosis in ICU (32%) vs non-ICU patients (1.6%). 10 Lodigiani et al, reported similar venous thrombosis rates in ICU (4.16%) vs non-ICU patients (1.27%). 9 Cui et al, suggested a 25% (20 out of 81 ICU patients) rate of DVTs in their critically ill cohort, but none of the patients in the study were on pharmacological thromboprophylaxis. 4 We found inconsistent methods of ultrasound screening in COVID-19 patients. In the study by Middeldorp et al, ultrasound was performed every 5 days in ICU patients, and 10 days prior to data analysis in cross-sectional fashion for general ward patients. 10 In a second study by Lljitos et al, screening ultrasound was performed at the time of ICU admission (between day 1 and 3) and then at day 7. 8 We, therefore suggest against routine screening, but suggest a low threshold for performing lower extremity ultrasound or full body ultrasound in COVID-19 patients who experience abrupt hypoxemia or clinical deterioration.

Tables 3 and 4 summarize the reported DVT incidence in the published literature. was employed and if imaging was triggered by clinical parameters or as screening as only DVTs were found. The study suggested a 94% negative predictive value for D-dimer cut off of 1.0 ug/ml but did not compare to other biomarkers which correlated with VTE. 4 They also reported that other laboratory markers correlated with increased risk of VTE including the aPTT and lymphocyte count, but did not evaluate single cut points or trending values. Klok et al. 6 did not report on D-dimer levels but noted that prolongation of the PT >3 seconds or the aPTT >5 seconds were independently predictors of VTE. Again, the VTE surveillance was not well described.

Tang et al. 3 did not report on VTE incidence but noted derangement in coagulation and clotting markers -PT, aPTT, D-dimer, fibrin degradation products-were higher in non-survivors.

Dramatic increase of D-dimer also correlated with increase in all-cause mortality. It may follow that thrombosis is a major contributor to increase in all-cause mortality, as survival improved when patients received parenteral anticoagulation. 27 In conclusion, there is insufficient data to guide clinical practice for VTE diagnosis based on laboratory values. We suggest as in other inpatient populations biomarkers not be employed in the diagnostic evaluation for suspected DVT or PE.

Our literature search did not identify any randomized trials assessing the efficacy and safety of anticoagulants for the treatment of acute VTE in hospitalized or critically ill COVID-19 patients.

Although clinical practice guidelines recommend the use of DOACs for the vast majority of patients with acute symptomatic VTE 20, 21 , there are reasons to make different suggestions for the preferred anticoagulant in patients with COVID-19, particularly for the critically ill: 1) many of these patients require administration of inhibitors or inducers of P-glycoprotein (P-gp) or strong inhibitors or inducers of cytochrome P450 (CYP) enzymes. Treatment with potent P-gp inhibitors (e.g., antiretrovirals, azithromycin, others) was an exclusion criterion in most landmark randomized trials that assessed the efficacy and safety of DOACs in patients with acute VTE. 57-60 A recent study enrolled 12 consecutive patients on DOACs who were hospitalized with severe COVID-19. 61 For each patient, C-trough DOAC level was compared with the one measured before hospitalization. On average, C-trough levels were 6 times higher during hospitalization than in the pre-hospitalization period; 2) gastrointestinal dysfunction is a common problem in the critically ill patient, and can significantly affect the pharmacokinetics of oral drugs; and 3) acute renal failure is also common in the setting of critical illness, and DOACs are contraindicated in patients with severe (e.g., creatinine clearance <30 mL/min) renal failure.

For these reasons, the panel endorsed that in critically ill COVID-19 patients with proximal DVT or PE, parenteral anticoagulation might be preferred to oral anticoagulant therapy.

Unfractionated heparin has an unpredictable dose response and a narrow therapeutic window; therefore, monitoring is essential to ensure optimal efficacy and safety. Alternatively, LMWHs and fondaparinux have more predictable pharmacokinetics and a greater bioavailability than UFH. Due to these pharmacologic features, body weight-adjusted doses of LMWH or fondaparinux can be administered subcutaneously without laboratory monitoring in the majority of these patients. UFH, not LMWH, can be effected by the phenomenon of heparin resistance which can "pseudo", in which the aPTT does not reflect the anti Xa effect (best managed by avoiding the aPTT and monitoring by anti Xa levels), and true resistance in which case acute phase reactants common in inflammatory states increase UFH clearance and can greatly increase the doses required. The former situation is common with elevated FVIII levels, common in COVID-19 patients. The latter situation may delay attainment of therapeutic levels of anticoagulation, which is highly undesirable in an acute VTE situation. 62, 63 Based on this, and to avoid risk of exposure for staff, we suggest that LMWH or fondaparinux be used over UFH in critically ill COVID-19 patients with proximal DVT or PE. UFH might be preferred over LMWH or fondaparinux in patients at high bleeding risk (including those with severe renal failure [creatinine clearance <30 mL/min]), or in those with overt or imminent hemodynamic decompensation due to PE, in whom primary reperfusion treatment may be necessary).

Outpatients with COVID-19 and acute PE have not been described, but the approach to these patients can follow existing guidelines. Patients with VTE in the setting of COVID-19 are considered to have a provoking factor, and thus initial treatment should be for at least three months.

initial parenteral anticoagulation with therapeutic weight adjusted LMWH or intravenous UFH. The use of LWMH will limit staff exposure and avoid the potential for heparin pseudo-resistance. In patients without any drug-to-drug interactions, we suggest initial oral anticoagulation with apixaban or rivaroxaban. Dabigatran and edoxaban can be used after initial parenteral anticoagulation. Vitamin K antagonist therapy can be used after overlap with initial parenteral anticoagulation.

Remarks: The panel has downgraded the most recent ACCP recommendation regarding the use of oral anticoagulants in patients hospitalized with COVID-19 secondary to the high risk of rapid clinical deterioration in these patients. In addition, it is likely that many of these patients will be on concomitant therapy (antiviral agents or other investigational treatments) that can significantly affect the pharmacodynamics of and bleeding risk associated with the DOACs. Thus LMWH or UFH are favored over oral anticoagulants.

interactions, we recommend apixaban, dabigatran, rivaroxaban or edoxaban. Initial parenteral anticoagulation is needed before dabigatran and edoxaban. For patients who are not treated with a direct oral anticoagulant, we suggest vitamin K antagonists over LWMH (for patient convenience and comfort). Parenteral anticoagulation needs to be overlapped with vitamin K antagonists.

14. In critically ill COVID-19 patients with proximal DVT or PE, we suggest parenteral over oral anticoagulant therapy. In critically ill COVID-19 patients with proximal DVT or PE who are treated with parenteral anticoagulation, we suggest LMWH or fondaparinux over UFH.

Remarks: UFH might be preferred over LMWH or fondaparinux in patients at high bleeding risk (including those with severe renal failure), or in those with overt or imminent hemodynamic decompensation due to PE, in whom primary reperfusion treatment may be necessary. The decision to use UFH should be balanced with the risks associated with extra staff exposure and issues with heparin resistance as above.

Our literature search did not identify any randomized trials or prospective cohort studies assessing the efficacy or safety of any thrombolytic therapies for the management of critically ill patients with COVID-19 without objective evidence of VTE and VTE-associated hypotension.

This includes either systemic delivery or catheter-directed thrombolysis.

Due to the absence of direct evidence, the guideline panel decided to consider indirect evidence from another population of patients receiving thrombolysis. In a randomized trial of normotensive patients without COVID-19 but with objectively confirmed PE and right heart strain, systemic thrombolysis was associated with major bleeding in 11.5% of patients. 64 The risk of major bleeding has not been systematically assessed during COVID-19. Diffuse alveolar damage 15 and frank alveolar hemorrhage have been identified in autopsy specimens from COVID-19 patients 65 , suggesting bleeding risk could be high. Therefore, we recommend against thrombolytic therapy in COVID-19 patients without objectively confirmed PE and PE-induced hypotension (systolic blood pressure <90 mm Hg or blood pressure drop >= 40 mm Hg lasting for longer than 15 minutes). 20, 21 Patients with objectively confirmed PE who are normotensive represent a wide spectrum of disease. Some are very low risk of adverse outcome. Others are at the more severe end of the spectrum, and may present with signs, imaging, or laboratory markers that suggest the presence of right ventricular dysfunction. As we have stated in earlier CHEST Guidelines, 20 these patients should be monitored closely for signs of deterioration. Clearly patients who develop hypotension meet criteria for thrombolytic therapy. Deterioration that has not resulted in frank hypotension may also prompt the use of thrombolytic therapy (progressive increase in heart rate, progressive decrease in systolic blood pressure, an increase in jugular venous pressure, worsening gas exchange, signs of shock, progressive right heart dysfunction on echocardiography, or an increase in cardiac biomarkers). This recommendation was based on the trial by Meyer et al, in which almost 90% of patients with intermediate risk PE who received rescue thrombolysis survived. 64 None of the existing scores for assessing bleeding risk in patients with VTE have been studied or validated in patients with COVID-19. Until recently, we lacked any scores that were derived specifically from patients being treated with anticoagulants for VTE. Thus, we cannot recommend a specific risk score in patients with COVID-19. Several risk scores have been suggested, and many of the variables overlap between scores. We suggest that providers rely on institutional methods for assessing bleeding risk and would refer the reader to items noted to be associated with increased risk of bleeding as outlined in the most recent CHEST Guidelines 20 (age, previous bleeding, cancer, renal failure, liver failure, thrombocytopenia, previous stroke, diabetes, anemia, antiplatelet therapy. Poor anticoagulant control, comorbidities, recent surgery, frequent falls, alcohol abuse, non-steroidal anti-inflammatory use). Due to the absence of direct evidence, the guideline panel decided to consider indirect evidence (low-quality) available from other another population at high risk of recurrent VTE, patients with cancer-associated thrombosis. There are no studies assessing the treatment of recurrent VTE despite anticoagulation with DOACs. One retrospective study reported reasonable outcomes (recurrent VTE of 9% [95% CI: 2 to 25%]) when using therapeutic weightadjusted LMWH in patients with recurrent VTE despite oral anticoagulation with vitamin K antagonists. 66 Two small retrospective cohort studies have also reported reasonable outcome by increasing the dose of LMWH to 125% and 130% in patients with recurrent events despite therapeutic weight-adjusted LMWH. 67, 68 The rate of recurrent VTE and major bleeding was 8.6% (6/70, 95% CI 4.0-17.5%) and 4.3% (3/70; 95% CI 1.5-11.9%), respectively, among patients receiving increased dose (125 to 130%) of LMWH. 67 Finally, an International Society of Thrombosis and Haemostasis registry showed comparable findings to the aforementioned studies. 69 Based on indirect comparisons, we expect the net benefit of increasing the dose of LMWH by 25 to 30% in patients with COVID-19 and recurrent VTE despite therapeutic anticoagulation with LMWH and switching to LMWH in patients failing oral anticoagulation with a DOAC or vitamin K antagonist.

therapeutic weight adjusted LMWH (and documented compliance), we suggest increasing the dose of LMWH by 25 to 30%.

dabigatran, rivaroxaban or edoxaban (and documented compliance), or vitamin K antagonist therapy (in the therapeutic range) we suggest switching treatment to therapeutic weight-adjusted LMWH.

The guidance statements in this document were specifically created to address what were felt to be common, urgent clinical questions that frontline providers are likely to face regarding venous thromboembolism and hypercoagulability in patients with COVID-19.

There are important limitations with this guidance. First is the lack of direct evidence to inform the guidance. Clearly more is being shared on a daily basis, but this emphasizes the importance of enrolling patients in clinical trials wherever possible and the need for international collaboration in collecting and rapidly disseminating relevant clinical experience, gaps in knowledge, and the research agenda. Second, due to the urgency of the situation, the panel was unable to address all of the likely questions that have arisen. As we consider this a living document that will be updated, we will incorporate additional questions to these updates as needed. Finally, and perhaps most importantly, the current body of evidence does not allow us to delineate between macro (DVT/PE) and microthrombosis, and the approach to these may differ. It is possible that studies looking for the prevalence of DVT and PE fail to represent the microthrombosis which could drive at least a portion of mortality in these patients.

The strengths of this document are the multidisciplinary panel that was composed of experienced clinicians and researchers in the field, many with extensive experience in the development of evidence-based guidelines. In addition, despite the lack of a robust evidence base, the panel followed a robust methodologic approach to formulate specific questions, evaluate the literature, and seek consensus.

We must acknowledge that there are over 10 other international guidelines, guidance statements, or online references that address this topic (although most focus on prevention, not diagnosis or treatment). [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] While this can seem overwhelming, the authors would like to emphasize the relative consistency in these statements. Most of these guidelines recommend VTE prevention in all hospitalized patients with COVID-19, 70,71,73,75-77 while some do recommend risk assessment to guide the decision. 72, 74, 79 As we discussed earlier, given the underlying risk factors present in these patients and that the current estimates of the incidence of VTE in non-critically ill patients with COVID-19 is well above 1% even on anticoagulant thromboprophylaxis, the panel considers all hospitalized patients with COVID-19 at increased risk of VTE. We therefore suggest against individualized VTE risk assessment and suggest anticoagulant thromboprophylaxis in all hospitalized patient with COVID-19 in the absence of contraindications. Almost all of these documents recommend standard dosing for anticoagulant thromboprophylaxis. One mentions escalating the dose, stating that it can be considered in patients with a large increase in the D-dimer level or severe respiratory failure. 73 Another suggests increased dosing in the critically ill patient with COVID-19, but recognizes that this was based largely on expert opinion. 80 The statements are consistent in the recommendation for the use of LMWH or UFH in COVID-19 patients. Those that address the use of mechanical prophylaxis note that it should be used in patients with a contraindication, 70, 71, 75, 79, 80 or can be added to anticoagulant thromboprophylaxis in patients who are completely immobilized. 74, 80 Finally, only a few of these statement address the issue of extended duration prophylaxis. Bikdeli and colleagues note that there is no data in this population, although they state that it would be reasonable to take an individualized approach in each patient after risk stratifying for both thrombosis and bleeding risk. 72 The Italian Society on Thrombosis and Haemostasis recommends prophylaxis throughout the hospitalization and for an addition 7-10 days post discharge. 75 The American Society of Hematology recommends following current guidelines, which recommend against extended duration prophylaxis in hospitalized medical patients. 22, 71 As we noted earlier, we endorse this approach because the post-discharge VTE and major bleeding rates in COVID-19 patients are currently unknown.

It is our hope that clinicians caring for patients with COVID-19 will find this document helpful.

Clearly, we still need well designed randomized trials to answer many of our pressing questions.

These include optimal dosing of prophylactic anticoagulant therapy, patients who might benefit from full dose anticoagulant treatment, and the unique role of macro and microthombosis in COVID-19. We hope that this version of guidance will serve as a call to enroll patients in clinical trials wherever possible. We would also like to use this document as a call to reason. We are in a time of unprecedented economic, social, and medical uncertainty. We have been trained to accept uncertainty, and to be wary of undesirable consequences of acting too quickly on new observations that may not affect our usual care. As physicians, we are trained to practice evidence-based medicine. We need to always remember that any intervention can cause harm.

In a time when our decisions may be driven by emotion, we risk the tendency to rely on anecdotes and early, small case series or cohorts. As recently stated by Zagurly-Orly and Schwartzstein, "We must reason critically and reflect on the biases that may influence our thinking processes, critically appraise evidence in deciding how to treat patients, and use anecdotal observations only to generate hypotheses for trials that can be conducted with clinical equipoise. We must act swiftly but carefully, with caution and reason". 81 We look forward to updating this guidance when well-designed trials have been completed. 

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