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Thrombosis

Last reviewed: January 20, 2022 

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview

Although respiratory manifestations predominate in patients with COVID-19, other systems can also be affected. Early in the pandemic, international reports suggested a high rate of venous thromboembolism (Cui, April 2020; Klok, April 2020; Lodigiani, April 2020). These reports were confounded by a lack of uniform use of VTE prophylaxis, heterogeneous populations (ICU vs. non-ICU patients), and lack of prospective evaluation for VTE.  

As the pandemic has progressed, additional data suggests the incidence of VTE in hospitalized patients with COVID-19 is high, with reported incidences of up to 16% in the U.S. (Vaughn, July 2021; Bilaloglu, July 2020). Autopsy series have found evidence of small vessel thrombosis and microangiopathy in the lungs, as well as VTE; these studies were performed with patients who had severe disease (Lax, May 2020; Fox, July 2020; Wichmann, August 2020).   

Procoagulant responses likely result from specific interactions between host defense mechanisms and the coagulation system (Iba, September 2020). Multiple mechanisms may be implicated in COVID-19 patients who develop a procoagulative state in COVID-19 (Ortega-Paz, November 2020). D-dimer is often elevated (Berger, August 2020; Iba, September 2020), and several case series/reports have noted increased factor VIII and von Willebrand factor (Escher, April 2020), complement activation (Margo, April 2020), platelet activation (Manne, June 2020), increase in fibrinogen (Panigada, April 2020) and neutrophil extracellular traps (Middleton, September 2020). Some studies have also found antiphospholipid antibodies in patients with COVID-19 (Helms, June 2020; Zhang, April 2020) and heparin resistance (White, May 2020). 

Ambulatory patients  

For ambulatory patients with COVID-19 (without another indication for antithrombotic or antiplatelet therapy), antithrombotic and/or antiplatelet therapy solely for the prevention of thrombotic events is not recommended by the American College of Cardiology. The double-blind randomized ACTIV-4b trial enrolled ambulatory patients with mild COVID-19 and randomized them (1:1:1) to apixaban 5 mg twice daily, apixaban 2.5 mg twice daily or aspirin 81 mg once daily. The trial was terminated early as no thrombotic events were found after enrollment of 657 patients (Connors, November 2021). 

Postdischarge patients: The risk of VTE after hospitalization for COVID-19 is low (0.14%-1.55%) based on retrospective observational studies and is similar to patients hospitalized for other acute medical illnesses (Roberts, September 2020; Patell, September 2020; Giannis, May 2021). Hence, routine postdischarge thromboprophylaxis is not recommended after discharge. For certain high-VTE risk patients without COVID-19, postdischarge prophylaxis has been shown to be beneficial (Spyropoulos, August 2020). It is unclear how to prevent thrombotic events in ambulatory COVID-19 patients with a prior history of VTE at this time. 
 

Inpatients  

There is currently insufficient evidence to recommend either for or against the use of thrombolytic agents or higher than the prophylactic dose of anticoagulation for VTE prophylaxis for hospitalized patients with COVID-19 outside of a clinical trial. 

Inpatients not requiring ICU-level support: The ACTION trial, in which the majority of patients did not require ICU-level support, compared treatment-dose rivaroxaban (20 mg daily) to prophylactic-dose enoxaparin (40 mg daily) in hospitalized patients with COVID-19 and elevated D-dimer. This trial did not find a difference in the rate of death, duration of hospitalization or duration of supplemental oxygenation between the two treatment groups (Lopes, June 2021). In a multiplatform randomized controlled trial (ATTACC, ACTIV-4a, REMAP-CAP), COVID-19 inpatients not requiring ICU-level care or organ support were randomized to receive treatment-dose unfractionated heparin or low-molecular-weight heparin or standard prophylactic dose anticoagulation. The patients randomized to treatment-dose anticoagulation had more days without organ support than those randomized to prophylactic-dose anticoagulation (80.2% vs. 76.4%). However, there was no statistically significant difference in overall survival until discharge, while major bleeding was higher (1.9% vs. 0.9%) in the treatment-dose group (REMAP-CAP, ACTIV-4a, and ATTACC Investigators, August 2021; see detailed writeup below). 

Inpatients requiring ICU-level support: The INSPIRATION trial enrolled 600 ICU patients with COVID-19 and showed that intermediate-dose prophylactic anticoagulation did not significantly impact the composite primary outcome of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation or 30-day mortality when compared with standard-dose prophylactic anticoagulation (INSPIRATION Investigators, March 2021). Results from the multiplatform randomized clinical trial (REMAP-CAP, ACTIV-4a, ATTACC) demonstrated that therapeutic anticoagulation did significantly impact the primary outcome of organ support-free days compared to prophylactic dose anticoagulation, and this trial ended early due to futility. On the contrary, there was an increase in the rate of major bleeding in patients randomized to treatment-dose anticoagulation (3.8% vs. 2.3%) (REMAP-CAP, ACTIV-4a, and ATTACC Investigators, August 2021; see detailed writeup below).

 

Guidelines

The American Thoracic Society recommends that all hospitalized patients with COVID-19 receive thromboprophylaxis therapy unless otherwise contraindicated. 

  • Low-molecular-weight heparin or fondaparinux should be used for thromboprophylaxis over unfractionated heparin and direct oral anticoagulants. 
  • There are insufficient data to justify routine increased intensity anticoagulant dosing in hospitalized or critically ill COVID-19 patients. 
  • Thromboprophylaxis for COVID-19 patients is not indicated in the outpatient setting. 
  • In critically ill COVID-19 patients, suggest against routine ultrasound screening for the detection of asymptomatic deep vein thrombosis. 
  • For critically ill COVID-19 patients with proximal DVT or pulmonary embolism, recommend parenteral anticoagulation therapy with therapeutic weight adjusted low-molecular-weight heparin or fondaparinux over unfractionated heparin. 

The American Society of Hematology recommends all hospitalized adults with COVID-19 receive pharmacologic thromboprophylaxis with low-molecular-weight heparin over unfractionated heparin (to reduce contact). 

  • Due to a lack of high-quality evidence, the use of empiric intermediate or high-dose anticoagulation is recommended only in the context of a clinical trial. 
  • American Society of Hematology guidelines on the use of anticoagulation for patients with COVID-19 are forthcoming. 

Interim guidance from the National Institutes of Health, American College of Cardiology and International Society on Thrombosis and Haemostasis are also available. For special populations (e.g., children, pregnant people), please refer to relevant society guidelines or our patient populations section. 

 

Key Literature 

In summary: Clinicians should have a high clinical suspicion for thrombotic events in COVID-19 patients, given the potential of a hypercoagulable state and the apparently high incidence of thrombosis in admitted patients, particularly in the ICU setting. Several randomized controlled trials are investigating the effects of anticoagulation dosing on COVID-19 patient outcomes.

Therapeutic Anticoagulation With Heparin in Critically Ill Patients With COVID-19 (REMAP-CAP, ACTIV-4a, and ATTACC Investigators, August 2021).

 Overall, in this multiplatform adaptive-design trial (REMAP-CAP, ACTIV-4a, ATTACC) comparing therapeutic versus prophylactic dose anticoagulation in critically ill hospitalized patients with COVID-19, there was no benefit for therapeutic anticoagulation in reducing need for organ support or death at 21 days. The trial was stopped early per prespecified criteria for futility.

Study population:

  • 1,103 patients hospitalized for COVID-19, majority of patients were enrolled through REMAP-CAP.
  • 534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis.
  • Median age was 60.4 (therapeutic dose) and 61.7 years (usual care).

Primary endpoint:

  • 21-day organ support–free days among patients who survived to hospital discharge.

Key findings:

  • The trial was stopped early as prespecified criteria for futility were met.
  • Therapeutic anticoagulation did not offer significant benefit for the primary outcome of organ support–free days compared to prophylactic dose anticoagulation.
  • On the contrary, there was an increase in the rate of major bleeding among patients who were randomized to treatment-dose anticoagulation (3.8% vs. 2.3%).

Limitations:

  • Open-label design with possible ascertainment bias.
  • Substantial proportion of patients were in the United Kingdom, where national practice guidelines changed during the trial to recommend that patients with COVID-19 who were admitted to an ICU receive intermediate-dose anticoagulation for thromboprophylaxis.

 

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients With COVID-19 (REMAP-CAP, ACTIV-4a, and ATTACC Investigators, August 2021).

Overall, in noncritically ill patients with COVID-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.

Study population:

  • 2,219 moderately ill patients with COVID-19 were included in the final analysis.

Primary outcome:

  • 21-day organ support–free days among patients who survived to hospital discharge.

Key findings:

  • The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met.
  • The patients randomized to treatment-dose anticoagulation had more days without organ support than those randomized to prophylactic-dose anticoagulation (80.2% vs. 76.4%).
  • However, there was no statistically significant difference in overall survival until discharge while major bleeding was higher (1.9% vs. 0.9%) in the treatment-dose group.

Limitations:

  • Open-label design with possible ascertainment bias.
  • Generalizability limited as detailed participant screening data were not available, so common reasons for exclusion from the trials are unknown.

 

Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial (Connors, November 2021).

Overall, the ACTIV-4B Outpatient Thrombosis Prevention Trial is the first study to provide reliable information about the effects of antithrombotic therapy in outpatients with COVID-19.

Study population:

  • Outpatients with symptomatic COVID-19 were randomly assigned to receive aspirin 81 mg per day, apixaban at prophylactic dose (2.5 mg twice daily), apixaban at therapeutic dose (5 mg twice daily) or placebo.

Outcome:

  • Composite outcome: mortality at 45 days, hospitalization for cardiovascular or pulmonary symptoms, symptomatic venous or arterial thromboembolism.

Key findings:

  • When compared with placebo, aspirin and apixaban at either dose did not improve the composite outcome.
  • Bleeding complications were highest with therapeutic dose apixaban, followed by prophylactic apixaban and aspirin (9.2% vs. 6.7 vs. 4.2%); the rate in the placebo group was 2.2 percent.
  • All bleeding events were minor or clinically relevant nonmajor bleeding, and there were no deaths in any group.

Limitations:

  • The number of events was very small.
  • The trial was stopped after only 657 individuals were enrolled rather than the planned 7,000.

 

Anticoagulation, Bleeding, Mortality and Pathology in Hospitalized Patients With COVID-19 (Nadkarni, October 2020).

Overall, in this retrospective study evaluating the association of anticoagulation on in-hospital outcomes in patients with COVID-19, there was an association of lower mortality and intubation in patients receiving therapeutic and prophylactic anticoagulation compared to no anticoagulation. There was a trend toward decreased mortality with therapeutic anticoagulation compared with prophylactic anticoagulation; this was not statistically significant. The study is limited by a lack of balance in baseline characteristics.

Study population:

  • 4,389 patients with laboratory-confirmed SARS-CoV-2 infection in five New York City hospitals.
    • 900 patients received therapeutic anticoagulation, 1,959 patients received prophylactic anticoagulation, and 1,530 patients did not receive anticoagulation.
    • Patients who received both therapeutic and prophylactic anticoagulation during the admission were excluded.
  • The median age was 65 years (interquartile range, 53-77 years), 44% were women, 26% self-identified as African American and 27% as Hispanic/Latinx.
  • 8% of the sample had hypertension, and 22.6% had diabetes.
  • Approximately one-tenth of the total cohort were on anticoagulation or antiplatelet medications prior to admission (1.8% and 8.5%, respectively).
  • The median initial D-dimer was 1.7 (IQR, 0.9-3.6).
  • D-dimer concentrations were highest in the patients who received therapeutic anticoagulation (median, 2.3 μg/ml; interquartile range, 1.2-5.8 μg/ml).
  • On hospital presentation, patients in the therapeutic anticoagulation group had higher blood pressures, faster heart and respiratory rates, and lower oxygen saturation.

Primary endpoint:

  • In-hospital mortality.

Key findings:

  • Therapeutic anticoagulation (N=900; 20.5%) and prophylactic anticoagulation (N=1,959; 44.6%) were associated with lower in-hospital mortality (aHR, 0.53; 95% CI, 0.45-0.62 and aHR, 0.50; 95% CI, 0.45-0.57, respectively) and intubation (aHR, 0.69; 95% CI, 0.51-0.94 and aHR, 0.72; 95% CI, 0.58-0.89, respectively), compared to no anticoagulation (N=1,530; 34.9%).
  • When initiated ≤48 hours from admission, there was no statistically significant difference in mortality between therapeutic (N=766) versus prophylactic anticoagulation (N=1,860) (aHR, 0.86; 95% CI, 0.73-1.02; p=0.08).
  • 89 patients (2%) had major bleeding adjudicated by clinician review, with 27 of 900 (3%) on therapeutic, 33 of 1,959 (1.7%) on prophylactic and 29 of 1,530 (1.9%) on no anticoagulation.
  • Of 26 autopsies, 11 (42%) had thromboembolic disease not clinically suspected, and three of those 11 (27%) were on therapeutic anticoagulation.

Limitations:

  • This was a retrospective observational study; bias is possible.
  • Baseline characteristics in the patients who received therapeutic versus prophylactic anticoagulation were not well balanced. Notably, patients who received therapeutic anticoagulation were older and had more comorbid conditions.
  • There may be a higher proportion of patients on anticoagulation as compared to other institutions, as Mount Sinai initiated a system-wide protocol (wherein at least prophylactic anticoagulation was strongly encouraged with guidance provided for consideration of therapeutic anticoagulation based on various factors).
  • Patients who received less than 48 hours of therapeutic anticoagulation were categorized as not treated with anticoagulation.
  • It is not clear how the decision to use therapeutic anticoagulation (as opposed to prophylactic anticoagulation) was made. It was dependent on the treating physician.

 

Incidence of Thrombotic Complications in Critically Ill ICU Patients With COVID-19 (Klok, July 2020).

Study population:

  • Retrospective study of 184 COVID-19 patients in the ICU at three Dutch hospitals.

Primary endpoint:

  • The incidence of a composite outcome of symptomatic acute pulmonary embolism, deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism.

Key findings:

  • The cumulative incidence of the composite outcome was 31% (95% CI, 20%-41%), of which CT pulmonary angiogram and/or ultrasonography confirmed VTE in 27% (95% CI, 17%-37%) and arterial thrombotic events in 3.7% (95% CI, 0%-8.2%).
  • Pulmonary embolism was the most frequent thrombotic complication (N=25, 81%).

Limitations:

  • This was a retrospective study, with the potential for confounding.
  • VTE screening was not employed; therefore, incidence may have been higher.

 

Retrospective Cohort Study of Thrombosis in Hospitalized Patients With COVID-19 in a New York City Health System (Bilaloglu, July 2020).

Study population:

  • 3,334 hospitalized patients with COVID-19 at a single health system in New York City.

Primary endpoint:

  • Incidence of and risk factors for venous and arterial thrombotic events.

Key findings:

  • Thrombotic event(s) were documented in 533 patients (16%).
  • 207 of the events (6.2%) were VTE, and 365 (11.1%) were arterial (1.6% ischemic stroke, 8.9% MI and 1.0% systemic thromboembolism).
  • In 829 critically ill patients, 29.4% had a thrombotic event; among 2505 noncritically ill patients, 11.5% had a thrombotic event.
  • On multivariate analysis, factors associated with increased thrombosis risk were older age, male gender, Hispanic ethnicity, coronary artery disease, prior myocardial infarction and high D-dimer (> 500 ng/ml) on presentation.
  • All-cause mortality was 24.5%, and was higher in those with thrombotic events (43.2% vs 21.0%; p<0 .001).
  • A thrombotic event was independently associated with mortality (adjusted hazard ratio, 1.82; p<0 .001).

Limitations:

  • The retrospective nature of the study design may have introduced confounding into the results.
  • Patients were not prospectively assessed for thrombotic complications; subclinical thrombi may have been missed.
  • The study took place in a single health system, which may limit the generalizability of the results.

 

Incidence of Deep Vein Thrombosis Among Non‐ICU Patients Hospitalized for COVID‐19 Despite Pharmacological Thromboprophylaxis (Santoliquido, September 2020).

Study population:

  • 84 noncritically ill patients admitted consecutively to a hospital in Italy.
  • All patients received prophylactic doses of either enoxaparin or fondaparinux.

Primary endpoint:

  • Incidence of VTE (determined by screening of all patients with ultrasound, regardless of signs or symptoms of VTE) among non-ICU patients hospitalized for COVID-19 who received pharmacological thromboprophylaxis.

Key findings:

  • Seventy-two patients (85.7%) had respiratory insufficiency, required supplemental oxygen and had reduced mobility/were bedridden.
  • The incidence of DVT was 11.9% (10/84).

Limitations:

  • This was a small, single-center study; the results may not be generalizable.
  • 7% of patients had a history of cancer or current cancer, and 9.5% of patients had recent trauma and/or surgery; this may have confounded the results.
  • Ultrasound was not performed at admission but was performed early during hospitalization. It is possible DVT was present upon admission or that DTVs developed later in the hospitalization (and thus not captured).

 

COVID-19 and Coagulation: Retrospective Study of Bleeding and Thrombotic Manifestations of SARS-CoV-2 Infection (Al-Samkari, June 2020).

Study population:

  • 400 patients with COVID-19 admitted to hospitals in a Massachusetts health system.

Study endpoint:

  • Incidence of radiographically confirmed VTE, probable VTE (defined as a consistent clinical syndrome prompting the initiation of anticoagulation in patients unable to have imaging) and clinically significant non-vessel thrombotic events.

Key findings: 

  • The overall thrombotic complication rate was 9.5%.
  • The thrombotic complication rate in noncritically ill patients was 4.7%, and 18.1% in critically ill patients.
  • The overall rate of radiographically-confirmed VTE was 4.8% (3.1% in noncritically ill patients and 7.6% in critically ill patients).
  • All patients but one with VTE were receiving either prophylactic or full-dose anticoagulation.
  • The incidence of arterial thrombotic events was 2.8%; all these patients were receiving prophylactic or full-dose anticoagulation.
  • In multivariate analysis, thrombosis was primarily associated with inflammatory markers rather than coagulation parameters.

Limitations:

  • The retrospective nature of the study design may have introduced confounding.
  • Patients were not prospectively assessed for thrombotic complications; subclinical thrombi may have been missed.
  • The study took place in a single health system, which may limit the generalizability of the results.

 

Venous Thromboembolism (VTE) in COVID-19: Systematic Review of Reported Risks and Current Guidelines (Fontana, June 2020).

Study population:

  • 1,369 hospitalized patients with COVID-19 derived from 11 studies (one clinical trial, seven retrospective cohorts and three prospective cohorts).

Primary endpoint:

  • Systematic review; N/A.

Key findings: 

  • Risk of VTE ranged from 4.4%-8.2% in all hospitalized COVID-19 inpatients.
  • In critically ill patients, incidence ranged from 0%-35.5%.
  • Two studies at least partially screened for VTE in ICU inpatients with COVID-19 and found incidences of 24.7%-53.8%.

Limitations:

  • The study populations in the included papers were heterogeneous in terms of critically ill versus noncritically ill patients.
  • The quality of the studies included was variable.
  • Most but not all studies reported universal VTE prophylaxis.

 

Prevalence of Venous Thromboembolism (VTE) in Patients with Severe Novel Coronavirus Pneumonia (Cui, May 2020).

Study population:

  • Retrospective study of 81 hospitalized ICU patients with severe COVID-19 in China.
  • Thirty‐three patients (41%) had chronic medical conditions, including hypertension, diabetes and coronary heart disease.

Primary endpoint:

  • To determine the incidence of VTE in patients with severe COVID-19.

Key findings:

  • The incidence of VTE was 25% (20/81), and eight patients with VTE events died.
  • Patients who developed VTE vs. non-VTE were older, had lower lymphocyte counts, longer activated partial thromboplastin time (39.9 ± 6.4 vs. 35.6 ± 4.5 seconds, p=0.001), and higher D‐dimer (5.2 ± 3.0 versus 0.8 ± 1.2 µg/mL, p<0.001).
  • If 1.5 µg/mL was used as the D‐dimer cutoff value to predicting VTE, the sensitivity was 85.0%, the specificity was 88.5% and the negative predictive value was 94.7%.

Limitations:

  • This was a retrospective, single‐center study with a small sample size and the potential for confounding, limiting generalizability.

Additional Literature

Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients With COVID-19 (Paranjpe, July 2020): In this retrospective single health-system study in New York City, the association between administration of in-hospital anticoagulation was assessed in 2,773 hospitalized patients. Of these, 786 (28%) received therapeutic anticoagulation. In-hospital mortality for patients treated with anticoagulation was 22.5% with a median survival of 21 days, compared to 22.8% and median survival of 14 days in patients who did not receive therapeutic anticoagulation. Patients who received therapeutic anticoagulation were more likely to require invasive mechanical ventilation (29.8% vs. 8.1%; p<0.001) as compared to those who received prophylactic dose anticoagulation or did not receive anticoagulation. In patients who required mechanical ventilation (N=395), in-hospital mortality was 29.1% with a median survival of 21 days for those treated with therapeutic anticoagulation as compared to 62.7% with a median survival of 9 days in patients who did not receive treatment-dose anticoagulation. In a multivariate proportional hazards model, longer duration of anticoagulation treatment was associated with a reduced risk of mortality (aHR 0.86 per day; p<0.001). 

 

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