Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID19



## | introduc ti on
The novel coronavirus disease of 2019 (COVID- [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] (SARS) and Middle East respiratory syndrome (MERS-CoV). [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] [bib_ref] Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill..., Obi [/bib_ref] [bib_ref] Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from..., Giannis [/bib_ref] COVID-19 is associated with marked abnormalities in markers of hypercoagulability, including elevated levels of D-dimer, fibrinogen, and factor VIII; a shortened activated partial thromboplastin time (aPTT); and an elevated sepsis induced coagulopathy (SIC) score. [bib_ref] Cardiovascular considerations for patients, health care workers, and health systems during the..., Driggin [/bib_ref] Investigational therapies for the management of severely ill COVID-19 patients may carry an increased risk for VTE or have implications for drug-drug interactions with established agents used for the acute and chronic management of VTE, such as the direct oral anticoagulants (DOACs) and vitamin K antagonists such as warfarin.

## | me thods
This guidance statement is a collaborative effort of the Perioperative and Critical Care Thrombosis and Haemostasis Subcommittee, along with members of the Control of

## Anticoagulation and disseminated intravascular coagulation
Subcommittee of the SCC. The guidance provided is anchored on a narrative review of pertinent literature, with a search occurring until April 18, 2020, coupled with responses to a standardized and independently administered survey of preferred practices related to the diagnosis, prevention, and treatment of VTE in COVID-19 patients (Appendix S1) and conducted by the McMaster Centre for Transfusion Medicine using an independent, multi-institutional, and multidisciplinary panel of experts in the field of thrombosis and hemostasis.
The survey of experts was done using a single cross-sectional assessment approach with an expectation that all (100%) panelists would select a pre-specified management option or to indicate, through the "other option" category, that alternative management was preferred. This one-time approach, rather than a multi-step, iterative approach (eg, Delphi method), was deemed appropriate in the context of the topic (COVID-19 and thrombosis) where requisite evidence, typically used in an iterative approach, is not available. Our aim was to identify where consensus existed and, of equal importance, to identify where there was a lack of consensus on clinical management.

## | the d iag nos is of v te in hos pitalized covid -19 patients
The diagnostic assessment of suspected VTE in hospitalized COVID-19 patients is challenging, especially for critically ill patients in whom, typically, it is important to reliably confirm or exclude VTE. Imaging studies for deep vein thrombosis (DVT) or pulmonary embolism (PE) may be avoided due to concerns of transmitting infection in non-COVID-19
hospital wards or to health-care workers. The frequent finding of an elevated D-dimer in very ill hospitalized COVID-19 patients may prompt an aggressive diagnostic approach for VTE, despite the controversy that a very elevated D-dimer (>4.0 mg/L) may not be a reliable predictor of VTE in this population but rather a marker of poor overall outcome. [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] [bib_ref] ISTH interim guidance on recognition and management of coagulopathy in COVID-19, Thachil [/bib_ref] One recent study found a sensitivity of 85.0% and specificity of 88.5% for diagnosing VTE in patients with D-dimer levels >1.5 mg/L, but the study was based on a small sample size. [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] Bedside imaging studies such as point-of-care compression ultrasonography to assess for lower and upper extremity DVT or bedside echocardiography to assess for right ventricular strain associated with PE may be difficult to obtain due to patient instability or the requirement of prone positioning in patients with acute respiratory distress syndrome (ARDS), and may lack sufficient specificity and sensitivity to diagnose VTE as patients with pneumonia may have right ventricular strain without PE. [bib_ref] Early use of echocardiography in patients with acute pulmonary embolism: findings from..., Bikdeli [/bib_ref] However, in the clinical context of unexplained sudden deterioration of pulmonary status or acute lower extremity erythema or swelling, these tests may be useful in aiding the clinical suspicion for VTE.
These concerns should be balanced by emerging data that the incidence of VTE in hospitalized COVID-19 patients with severe pneumonia or in ICU settings is higher than that reported by historical data in similar patients, with an incidence of VTE of 27% (95% confidence interval [CI]: 17-37) in one study using standard thromboprophylaxis and an incidence of 25% in another study without prophylaxis. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] 

## | v te prophyl a xis in non -i cu hos pitalized covid -19 patients
Hospitalized acutely ill medical patients, including those with infections such as viral pneumonia, are at increased risk for VTE, and antithrombotic practice guidelines recommend thromboprophylaxis with twice-or thrice-daily subcutaneous unfractionated heparin (UFH), once-daily subcutaneous low-molecular-weight heparin (LMWH), or fondaparinux to reduce this risk, although fondaparinux is infrequently used due to its long half-life and reversibility concerns. [bib_ref] Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, Kahn [/bib_ref] [bib_ref] American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis..., Schunemann [/bib_ref] Patients hospitalized with severe COVID-associated pneumonia may have a further heightened risk of VTE, but this issue remains unresolved. Preliminary reports in patients with severe pneumonia due to COVID-19 as well as previous reports of severe pneumonias/severe acute respiratory syndromes from other viruses such as influenza H1N1 or MERS-CoV suggest a multi-fold higher risk for VTE and, in particular, an increased risk for PE. [bib_ref] Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill..., Obi [/bib_ref] In addition, patient-specific VTE risk factors such as advanced age, a prior history of VTE, a history of or active cancer, immobility, and thrombophilia, had been incorporated prior to the COVID-19 era to assess overall VTE risk using standardized VTE risk assessment scores such as Padua VTE or IMPROVE VTE risk scores, [bib_ref] New paradigms in venous thromboprophylaxis of medically ill patients, Spyropoulos [/bib_ref] [bib_ref] A risk assessment model for the identification of hospitalized medical patients at..., Barbar [/bib_ref] [bib_ref] Predictive and associative models to identify hospitalized medical patients at risk for..., Spyropoulos [/bib_ref] which had been externally validated. [bib_ref] Validation of risk assessment models of venous thromboembolism in hospitalized medical patients, Greene [/bib_ref] [bib_ref] External validation of a risk assessment model for venous thromboembolism in the..., Mahan [/bib_ref] [bib_ref] External validation of the risk assessment model of the international medical prevention..., Rosenberg [/bib_ref] A recent study from China in hospitalized patients with COVID-19 reported that 40% of patients had a high risk of VTE using the Padua VTE model, although the use of thromboprophylaxis was not reported. [bib_ref] Attention should be paid to venous thromboembolism prophylaxis in the management of..., Wang [/bib_ref] The optimal VTE risk stratification scheme for hospitalized COVID-19 patients requires further study, including the use of very elevated D-dimer levels (>6 times the upper limit of normal that appear to be a consistent predictor of thrombotic events and poor overall prognosis in this population. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] However, given the relatively high rates of VTE found in early reports, the use of a "universal" thromboprophylactic strategy for all hospitalized patients with COVID-19 appears more appropriate than an individualized VTE risk assessment approach at present.

## | v te prophyl a xis in i cu hos pitalized covid -19 patients
Hospitalized COVID-19 patients who are managed in an ICU or CCU setting have an overall poor prognosis, with the proportion of severe cases approaching 26% (95% CI: 17.4-34.9) and reported case-fatality rates of 42%. [bib_ref] Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review..., Fu [/bib_ref] The presence of co-morbid conditions (eg, cardiovascular disease, obesity); a SIC score  4 and elevated levels of D-dimer (>6 times ULN), C-reactive protein, and troponins; and other markers of disseminated intravascular coagulopathy (DIC) as assessed by the ISTH scoring system are associated with a worse prognosis. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] It is uncertain whether changes in hemostasis parameters are a direct consequence of the SARS-CoV2 virus or a result of a systemic inflammatory response syndrome (SIRS) that is produced by a cytokine storm after viral infection. [bib_ref] COVID-19: consider cytokine storm syndromes and immunosuppression, Mehta [/bib_ref] In addition, the heightened prothrombotic tendency in the critically ill hospitalized patients with COVID-19 pneumonia, leading to VTE and especially, in situ pulmonary artery microthrombi, is evident in case series and pathologic studies as an endpoint of pulmonary inflammation. [bib_ref] Acute pulmonary embolism and COVID-19 pneumonia: a random association?, Danzi [/bib_ref] One study reported an incidence of VTE of 25% (20/81) and a mortality of 40% (8/20) among patients hospitalized with severe COVID-19 pneumonia who had VTE; another study found an incidence of VTE and arterial thromboembolism of 27% and 3.7%, respectively, in 184 COVID-19 patients who were in an ICU setting and were receiving standard-dose thromboprophylaxis. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] Last, the use of tissue plasminogen activator in the treatment of COVID-19-associated ARDS was associated with only transient improvement of pulmonary function. [bib_ref] Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome..., Wang [/bib_ref] The optimal thromboprophylaxis strategy in the critically ill hospitalized COVID-19 patient population is uncertain. Emerging clinical data suggest that the use of either prophylactic to intermediate doses of LMWH (eg, enoxaparin, 40-60 mg daily) in very sick COVID-19 patients (D-dimer > 6 times ULN; SIC score  4)
is associated with improved outcomes and a better prognosis. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] A previous report that assessed treatment-dose UFH in patients with ARDS who were afflicted with influenza H1N1, found that patients with H1N1-associated ARDS who received therapeutic anticoagulation had 33-fold fewer VTE events than those treated given prophylactic-dose UFH or LMWH. The use of empiric therapeutic-dose anticoagulation has been advocated by some for the critically ill hospitalized COVID-19 patients, especially in ICU settings; however, data on the efficacy and safety of this approach is limited. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] There are ongoing randomized trials that aim to assess the efficacy and safety of

## | guidance statement 3
VTE prophylaxis in sick ICU hospitalized COVID-19 patients:
1. Routine thromboprophylaxis with prophylactic-dose UFH or LMWH should be used after careful assessment of bleed risk. Intermediate-dose LMWH (50% of respondents) can also be considered in high risk patients. Patients with obesity as defined by actual body weight or BMI should be considered for a 50% increase in the dose of thromboprophylaxis. Treatment-dose heparin should not be considered for primary prevention until the results of randomized controlled trials are available.

## Multi-modal thromboprophylaxis with mechanical methods (ie,
intermittent pneumonic compression devices) should be considered (60% of respondents).

## | dur ati on of thromboprophyl a xis in hos pitalized covid -19 patients
The risk of hospital-associated VTE extends for up to 6 weeks post-hospital discharge in high VTE risk medically ill patients, including those with pneumonia, sepsis, and any condition requiring management in an ICU setting. [bib_ref] New paradigms of extended thromboprophylaxis in medically ill patients, Macdougall [/bib_ref] At least 60% of all VTE events in medically ill patients occur in the post-hospital discharge period, with the first 3 weeks being associated with a >five-fold increased risk in fatal PE. 14 Earlier studies of extended thromboprophylaxis with DOACs revealed either limited efficacy or an increase in major bleed risk, and particularly due to these safety concerns, the most recent antithrombotic guidelines recommended against routine post-discharge thromboprophylaxis in medically ill patients, including those with pneumonia. [bib_ref] American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis..., Schunemann [/bib_ref] However, more recent data reveal that in selected populations at high VTE risk and low bleed risk, based on key risk factors or risk models for thrombosis and bleeding, extended-duration thromboprophylaxis for approximately 4 weeks with prophylactic-dose LMWH (eg, enoxaparin, dalteparin, tinzaparin) or a DOAC (eg rivaroxaban, betrixaban) provides a net clinic benefit by reducing VTE risk without incurring a significant increase in the risk of major bleeding. [bib_ref] Rivaroxaban for thromboprophylaxis in acutely ill medical patients, Cohen [/bib_ref] [bib_ref] Improved Benefit Risk Profile of Rivaroxaban in a Subpopulation of the MAGELLAN..., Spyropoulos [/bib_ref] [bib_ref] Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced..., Hull [/bib_ref] This benefit appears more pronounced in patients whose index hospitalization was due to infectious disease, particularly pneumonia. [bib_ref] Rivaroxaban for thromboprophylaxis among patients recently hospitalized for acute infectious diseases: a..., Cohoon [/bib_ref] Recent data also support that a modified IMPROVE VTE score using established cut-offs plus elevated D-dimer (>2 times ULN) identifies patients at an almost three-fold higher risk for VTE in whom there is a significant benefit for extended-duration thromboprophylaxis. [bib_ref] Modified IMPROVE VTE risk score and elevated d-dimer identify a high venous..., Spyropoulos [/bib_ref] This finding may be especially relevant for post-discharge VTE risk mitigation in COVID-19 patients. In the absence of COVID-19-specific data, it is reasonable to consider extended-duration thromboprophylaxis with LMWH or a DOAC for at least 2 weeks and up to 6 weeks post-hospital discharge in selected COVID-19 patients who are at low risk for bleeding and with key VTE risk factors such as advanced age, stay in the ICU, cancer, a prior history of VTE, thrombophilia, severe immobility, an elevated D-dimer (>2 times ULN), and an IMPROVE VTE score of 4 or more.

## | guidance statement 4
Duration of VTE prophylaxis for hospitalized COVID-19 patients:
1. Either LMWH (30%) or a DOAC (ie, rivaroxaban or betrixaban; 30% of respondents) can be used for extended-duration thromboprophylaxis.
2. Extended post-discharge thromboprophylaxis should be considered for all hospitalized patients with COVID-19 that meet high VTE risk criteria. The duration of post-discharge thromboprophylaxis can be approximately 14 days at least (50% of respondents), and up to 30 days (20% of respondents).

## | v te tre atment in hos pitalized covid -19 patients
There are multiple validated and approved strategies to treat hospitalized patients with a new VTE including the use of UFH/ LMWH bridging therapy to dose-adjusted warfarin, the use of UFH/LMWH lead-in therapy with a switch to dabigatran/edoxaban, or a monotherapy approach with rivaroxaban/apixaban. [bib_ref] Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report, Kearon [/bib_ref] In hospitalized COVID-19 patients, parenteral anticoagulation with UFH or LMWH may have advantages over other strategies due to the absence of known drug-drug interactions with antiviral agents or investigational therapies used to treat COVID-19. Moreover, the use of LMWH may have further advantages in this setting due to lack of routine monitoring and decrease of health-care worker exposure to infection due to frequent blood draws necessary with intravenous UFH, which may require higher-than-usual doses from possible heparin resistance due to acute phase reactants. DOACs may also have further disadvantages in this setting due to potential drug-drug interactions via CYP3A4 mechanisms with certain antivirals (ie, lopinavir/ritonavir) and immunomodulatory investigational COVID-19 therapies, as well as potential for lack of reversal agents or specific antidotes in some hospitals. [bib_ref] Cardiovascular considerations for patients, health care workers, and health systems during the..., Driggin [/bib_ref] However, in the post-hospital discharge setting, DOACs provide advantages over vitamin K antagonists such as warfarin due to the lack of need for routine monitoring and subsequent minimization of patient contact with the health-care environment.

## | guidance statement 5
VTE treatment in hospitalized COVID-19 patients: 3. The duration of treatment should be at least 3 months (50% of respondents).

## | d iscuss i on
COVID-19 is emerging as a highly contagious disease with coagulopathic manifestations that appear to have unique characteristics.
Initial data support a high incidence of thromboembolic disease, and especially VTE, in hospitalized COVID-19 patients, as well as poorer outcomes for COVID-19 patients with pre-existing cardiovascular disease. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] [bib_ref] Cardiovascular considerations for patients, health care workers, and health systems during the..., Driggin [/bib_ref] Due to the risk of infectivity with a need to minimize contact with health-care workers and the health system; the diagnosis of VTE in critically ill, unstable hospitalized COVID-19 patients (especially in the ICU) that may need prone positioning and may not be able to undergo standard objective testing; the potential for new VTE risk stratification strategies using novel dosing intensities of established thromboprophylaxis regimens; new paradigms of post-hospital discharge and extended thromboprophylaxis; and careful considerations of antithrombotic management due to the potential for drug-drug interactions with investigational or immunomodulatory therapies, health-care workers will need to understand special considerations for the management of VTE in hospitalized COVID-19 patients.
There is an urgent need for high quality data, especially from randomized controlled trials, using a coordinated effort by health-care What is the optimal agent/duration of extended thromboprophylaxis?

## Treatment of vte
What is the optimal agent and duration for VTE treatment? Inhospital? In the outpatient setting?
[fig] 5: Expert clinical guidance statements and clinical pathways from large academic health-care systems favor the use of standard-dose regimens with LMWH or UFH (especially for patients with a creatinine clearance < 30 mL/min); mechanical thromboprophylaxis (intermittent pneumatic compression) when anticoagulants were contraindicated; use of multimodal (anticoagulant and mechanical) prophylaxis strategies in the critically ill and completely immobile COVID-19 population; 7,28 and the use of VTE risk stratification using either clinical criteria (body mass index [BMI] >30 kg/m 2 ), VTE risk scores, and/or biomarkers (eg, very elevated D-dimer levels) to suggest intermediate-or higher-dose LMWH or UFH regimens (eg enoxaparin 0. mg/kg twice-daily; enoxaparin 40 mg twice-daily, intravenous UFH targeted to an anti-factor Xa level of 0.30-0.70 IU/mL). Many institutional protocols of hospitalized COVID-19 patients now incorporate obesity (BMI > 30 kg/m 2 ) or morbid obesity (BMI > 40 kg/m 2 ) to administer intermediate-dose LMWH for thromboprophylaxis. 29 [/fig]
[fig] 1: Established guidelines should be used to treat patients with confirmed VTE, with advantages of LMWH in the inpatient setting and DOACs in the post-hospital discharge setting. A change from treatment-dose DOAC or vitamin K antagonists (VKA) to in-hospital LMWH should be considered especially for patients in critical care settings or with relevant concomitant medications, and dependent on renal function and platelet counts. Anticoagulant regimens should not change based solely on D-dimer levels. 2. A change of anticoagulant regimen (ie, from prophylactic or intermediate-dose to treatment-dose regimen) can be considered in patients without established VTE but deteriorating pulmonary status or ARDS (50% of respondents). [/fig]