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CME

COVID-19-associated Coagulopathy

Overview

  • coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by novel coronavirus SARS-CoV-2 (Centers for Disease Control and Prevention 2020 Mar 22)
  • abnormalities in coagulation markers
    • coagulopathy is one of the most significant prognostic factors in patients with COVID-19 and is associated with increased mortality and admission to critical care
    • most commonly observed coagulopathy in patients hospitalized with COVID-19 (COVID-19-associated coagulopathy) is characterized by increased D-dimer and fibrinogen levels
    • some patients with severe COVID-19 develop coagulopathy meeting International Society on Thrombosis and Haemostasis (ISTH) criteria for disseminated intravascular coagulation (DIC); 71% of patients who did not survive hospitalization reported to have developed DIC compared to 0.6% of survivors
  • risk of hospital-associated venous thromboembolism (VTE)
    • patients with COVID-19 are at high risk of VTE, especially those who are immobilized, those in critical care, and those who have additional risk factors that predispose them to VTE, such as acute inflammatory state and hypoxia
    • thrombotic complications are common among patients admitted to the intensive care unit (ICU) for COVID-19 (reported in 17%-47%), especially pulmonary embolism (PE)
  • evaluation
    • evaluation for coagulopathy in patients with COVID-19
      • PubMed32281926Blood transfusion = Trasfusione del sangueBlood Transfus20200408laboratory tests to perform in patients with COVID-19 should include tests for hemostasis function and platelet count; evaluation of coagulation markers at hospital admission may be useful in identifying patients who need close monitoring
      • abnormal coagulation parameters to look for include (in order of importance)
        • significantly elevated D-dimer level (for example, 3-4 fold increase in D-dimer levels over normal range)
        • prolonged prothrombin time (PT)
        • platelet count < 100 × 109/L
        • fibrinogen < 2 g/L (part of assessment to identify development of DIC)
      • consider evaluating patients for DIC using ISTH DIC score; if score of < 5, DIC is unlikely and score should be recalculated every 1-2 days as required
      • consider evaluation of patients using sepsis-induced coagulopathy criteria, which helps identify patients at earlier phase of DIC, because these patients may benefit from heparin therapy
    • evaluation considerations for VTE
      • consider ultrasound screening for deep vein thrombosis, if possible, if hemostatic markers are abnormal
      • consider possibility of PE in patients with sudden onset of oxygenation deterioration, respiratory distress, or reduced blood pressure
      • strategies to reduce need for aerosol-generating testing, such as ventilation/perfusion scintigraphy, for detection of PE should be adopted; this includes rigorous pretest probability evaluation to help limit patients who are referred for imaging and preferential use of other imaging modalities such as computed tomography pulmonary angiography (CTPA)
  • thromboprophylaxis in patients hospitalized for COVID-19
    • all hospitalized patients should be given low-molecular weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux at prophylactic doses; if anticoagulation is contraindicated (for example, platelet count < 25-30 × 109/L, fibrinogen < 0.5 g/L, active bleeding), patients should be treated by leg compression
    • prophylactic dose LMWH should be given to all hospitalized patients with COVID-19 even in the setting of abnormal coagulation tests in the absence of bleeding; abnormal PT or activated partial thromboplastin time is not a contraindication for pharmacological thromboprophylaxis
    • thromboprophylactic anticoagulation duration
      • anticoagulants should be given for the entire duration of hospitalization and continued for 7-14 days after hospital discharge
      • consider extended thromboprophylaxis (for up to 42 days) in patients with high risk for VTE (for example, patients with reduced mobility, history of VTE, with co-existing conditions such as cancer, D-dimer level > 2 times upper level of normal, and age ≥ 75 years) if bleeding risk is low; options include rivaroxaban and betrixaban
    • all completely immobilized patients may benefit from intermittent pneumatic compression in addition to pharmacologic prophylaxis
    • optimal thromboprophylaxis is unknown; because of drug-drug interactions between antiviral treatments and direct oral anticoagulants and difficulty of monitoring and maintaining stable INRs while on vitamin K antagonists, patients taking direct oral anticoagulants or vitamin K antagonist should consider switching/bridging to LMWH or UFH with or without mechanical prophylaxis while ill
    • therapeutic anticoagulation is not indicated unless patient has documented VTE or atrial fibrillation; however, use of intermediate or full therapeutic dose anticoagulation in critically ill patients with COVID-19 without confirmed VTE is under investigation
  • management of patients with COVID-19 who develop coagulopathy
    • consider prophylactic dose LMWH
    • abnormal coagulation results (prolonged PT or activated partial thromboplastin time) do not require correction in patients who are not bleeding
    • consider following blood transfusion therapy strategy for patients with septic coagulopathy
    • if coagulopathy worsens, blood products should be administered
      • in patients who are not bleeding, goal is to maintain platelet count > 25 × 109/L
      • in patients who are bleeding, goal is to maintain
        • platelet count > 50 × 109/L
        • fibrinogen > 1.5 g/L
        • PT ratio < 1.5 (not same as INR)
    • management of DIC
      • most important aspect of DIC management is treatment of the underlying condition, which makes management of DIC especially difficult in patients with COVID-19
      • management of bleeding
        • consider fresh frozen plasma at 12-15 mL/kg (pragmatically, 1 bag/20 kg body weight or 4 units in an adult)
        • consider 1 adult therapeutic dose (1 apheresis unit or 4 pooled units) if platelet count is < 50 × 109/L
        • if bleeding continues and fibrinogen level is < 1.5 g/L, consider cryoprecipitate (2 five-unit pools to raise fibrinogen by about 1 g/L in an adult) or fibrinogen concentrate (if approved for use) usually given at dose of 3-4 g
        • patients with DIC should not be given antifibrinolytics
      • for management of overt thromboembolism or organ failure due to clot, consider low-dose anticoagulation with UFH with activated partial thromboplastin time target of < 1.5 or anti-Xa levels at low rate to inhibit thrombin generation
  • management of patients who develop VTE
    • parenteral anticoagulants (UFH or LMWH) are generally preferred due to lack of known drug-drug interactions (for example, with COVID-19 therapies)
    • direct oral anticoagulants have the advantage of lack of need for monitoring and easier discharge planning and outpatient management; but risks include, clinical deterioration and difficulty with timely reversal of anticoagulation at some hospitals
    • in patients who are ready for discharge, direct oral anticoagulants or LMWH may be preferred due to more limited contact needed with patients compared to other anticoagulants
    • in patients with PE, current guideline recommendations for the general population should be followed for reperfusion strategies
  • additional considerations in specific patient populations
    • patients already receiving antithrombotic therapy for pre-existing conditions (for example, VTE or atrial fibrillation) should continue with these medications but may need to be held if platelet count is < 30-50 × 109/L or if fibrinogen level is < 1 g/L
    • patients with COVID-19 requiring extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy or who have thrombosis of catheters or extracorporeal filters should have antithrombolitic therapy per standard of care for patients without COVID-19
    • in pregnant women, administer VTE prophylaxis similarly to those who are not pregnant; continue with antithrombotic therapy if already prescribed for another indication

General Information

Description

  • coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by novel coronavirus SARS-CoV-2 (Centers for Disease Control and Prevention 2020 Mar 22)
  • abnormalities in coagulation markers have been reported in patients hospitalized with COVID-19; coagulopathy is one of the most significant prognostic factors in patients with COVID-19 and is associated with increased mortality and admission to critical care (J Thromb Haemost 2020 May;18(5):1023full-text)
  • patients with COVID-19 are at risk of hospital-associated venous thromboembolism (VTE) especially those who are immobilized, those in critical care, and those who have additional risk factors that predispose them to VTE such as acute inflammatory state and hypoxia (Thrombosis UK 2020 Mar 25PDF)

Abnormal Coagulation Markers in Patients With COVID-19

  • mechanisms and clinical consequences of coagulopathy
    • PubMed32294295Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200415in severe cases of COVID-19, SARS-CoV-2 induces a cytokine storm that ultimately results in impaired pulmonary gas exchange and activation of the coagulation cascade, causing thrombotic manifestations (J Thromb Haemost 2020 Apr 15 early online)
    • acute respiratory distress syndrome (ARDS) is one of the most common complications of COVID-19 and activation of coagulation system plays a role in pathogenesis of ARDS
      • PubMed32239799Journal of thrombosis and haemostasis : JTHJ Thromb Haemost202005011851020-10221020median plasma concentrations of tissue factor and plasminogen activator inhibitor-1 (PAI-1) reported to be significantly higher in patients with ARDS (at 7 days) compared to patients without ARDS (data not from COVID-19 patients) (J Thromb Haemost 2020 May;18(5):1020)
      • PubMed32239799Journal of thrombosis and haemostasis : JTHJ Thromb Haemost202005011851020-10221020lung coagulopathy thought to involve localized tissue factor-mediated thrombin generation and depression of bronchoalveolar plasminogen activator-mediated fibrinolysis, mediated by PAI-1 increase (J Thromb Haemost 2020 May;18(5):1020)
      • current concept of hypercoagulative states is supported by autopsies that have demonstrated small fibrinous thrombi in small pulmonary arterioles in areas of both damaged and more preserved lung parenchyma in 8 out of 10 cases (J Thromb Haemost 2020 Apr 15 early online)
    • thrombotic complications are common among patients admitted to the intensive care unit (ICU) for COVID-19 (reported in 17%-47%, depending on follow-up duration), especially pulmonary embolism (PE)
    • limited reports of bleeding in the setting of COVID-19 (J Thromb Haemost 2020 May;18(5):1023full-text)
  • common coagulation marker abnormalities in patients who require hospitalization
    • most commonly observed coagulopathy in patients hospitalized with COVID-19 (COVID-19-associated coagulopathy) is characterized by increased D-dimer and fibrinogen levels (American Society of Hematology [ASH] resource for COVID-19 and coagulopathy 2020 May 18)
    • elevated D-dimers level
    • prolonged prothrombin time (PT)
      • modest increase observed among hospitalized patients with COVID-19 and among those who die or require critical care
      • subtle increase may not be noticed if PT is reported as INR
      • Reference - J Thromb Haemost 2020 May;18(5):1023full-text
    • some patients with severe COVID-19 develop coagulopathy meeting International Society on Thrombosis and Haemostasis (ISTH) criteria for disseminated intravascular coagulation (DIC)
      Table 1. Summary of Findings Comparing COVID-19-associated Coagulopathy and Disseminated Intravascular Coagulation
      Coagulation MarkersCOVID-19-associated CoagulopathyDisseminated Intravascular CoagulationPrognosis Associated With Abnormal finding
      PTModestly increasedHigher than in CACHigher ICU admission and mortality
      aPTTNormalOften increasedNot mentioned
      D-dimerMarkedly increasedIncreasedHigher ICU admission and mortality
      FibrinogenIncreasedDecreasedHigher mortality when decreased
      PlateletsMild thrombocytopenia (around 100 × 109/L)Moderate-to-severeHigher mortality

      Abbreviations: aPTT, activated partial thromboplastin time; CAC, COVID-19-associated coagulopathy; ICU, intensive care unit; PT, prothrombin time.


      Reference - ASH resource for COVID-19 and coagulopathy 2020 May 18.

  • Evidence Synopsis


    Abnormalities in coagulation markers at hospital admission, such as elevated D-dimer level, prolonged PT, and elevated fibrin degradation product are associated with decreased survival and increased risk of ICU admission among patients with COVID-19.
    • Study Summary
      higher D-dimer levels associated with nonsurvival and/or ICU admission in adults hospitalized for COVID-19
      Details
      studySummary
      • Cohort Study based on cohort study
      • 83 adults (median age 64 years, 67% men) with confirmed COVID-19 presenting to St. James' Hospital in Dublin, Ireland between March 13, 2020 and April 10, 2020 were evaluated
      • upon hospital admission, all adults received supportive care
      • low-molecular-weight heparin (enoxaparin) thromboprophylaxis was administered as part of standard care according to weight and renal function
      • 4 adults were on therapeutic anticoagulation on admission (2 on apixaban, 1 on edoxaban, and 1 on warfarin)
      • at time of publication, 50 adults were discharged, 20 adults remained hospitalized, and 13 adults had died; 23 patients required ICU admission during the disease course
      • coagulation markers on admission
        • comparing nonsurvivors and/or ICU admission vs. survivors and no ICU admission
          • median D-dimer level 1 mg/L vs. 0.8 mg/L (p = 0.018)
          • median fibrinogen level 5.6 g/L vs. 4.5 g/L (p = 0.045)
        • no significant differences in PT or aPTT between groups
      • coagulation markers at day 4 of admission
        • comparing nonsurvivors and/or ICU admission vs. survivors and no ICU admission
          • median D-dimer level 1.2 mg/L vs. 0.8 mg/L (p = 0.003)
          • median fibrinogen level 5 g/L vs. 5 g/L (not significant)
          • median PT 13.1 seconds vs. 12.5 seconds (p = 0.007)
        • no significant difference in activated partial thromboplastin time (aPTT) between groups
      • no incidence of overt DIC defined according to ISTH DIC score reported
      • PubMed32330308British journal of haematologyBr J Haematol20200424Reference - Br J Haematol 2020 Apr 24 early online
    • Study Summary
      higher D-dimer level, fibrin degradation product, and prolonged PT on admission associated with decreased survival in patients hospitalized for COVID-19 pneumonia, with 71.4% of patients who died developing overt DIC
      Details
      Hematologic_Disordershigher D-dimer level, fibrin degradation product, and prolonged prothrombin time on admission associated with decreased survival in patients hospitalized for COVID-19 pneumonia, with 71.4% of patients who died developing overt DIC (J Thromb Haemost 2020 Apr)04/23/2020 10:16:59 AMstudySummary
      • Cohort Study based on retrospective cohort study
      • 183 patients (mean age at disease onset 54.1 years) with confirmed COVID-19 pneumonia presenting to Tongji hospital in Wuhan, China between January 1, 2020 and February 3, 2020 had their clinical and laboratory records evaluated
      • 41% had chronic diseases such as cardiovascular and cerebrovascular disease, respiratory system disease, malignancy, or chronic liver or kidney disease
      • all patients received antiviral and supportive therapies
      • by February 13, 2020, 11.5% had died, 42.6% were discharged, and 45.9% remained in hospital in stable condition; patients who died were significantly older (mean age 64 years vs. 52 years among survivors; p < 0.001)
      • comparing nonsurvivors vs. survivors
        • baseline patient characteristics (median)
          • D-dimer level 2.12 mg/L vs. 0.61 mg/L (p < 0.001)
          • fibrin degradation product 7.6 mg/L vs. 4 mg/L (p < 0.001)
          • PT 15.5 seconds vs. 13.6 seconds (p < 0.001)
          • aPTT 44.8 seconds vs. 41.2 seconds (p = 0.096)
          • fibrinogen level 5.16 g/L vs. 4.51 g/L (not significant)
          • antithrombin activity 84% vs. 91% (p = 0.096)
        • development of overt DIC as defined by ISTH diagnostic criteria (≥ 5 points) in 71.4% vs. 0.6%; median time to DIC 4 days
        • factors associated with nonsurvival at 10 days and 14 days after hospitalization
          • elevated D-dimer levels, prolonged PT, or elevated fibrinogen degradation products (p < 0.05)
          • reduced fibrinogen levels and antithrombin activity (p < 0.05)
      • PubMed32073213Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200401184844-847844Reference - J Thromb Haemost 2020 Apr;18(4):844, commentary can be found in J Thromb Haemost 2020 Apr;18(4):786
    • Study Summary
      D-dimer > 1 mg/L associated with increased in-hospital mortality in adults with COVID-19
      Details
      studySummary
      • Cohort Studybased on retrospective cohort study
      • 191 adults aged 18-87 years (median age 56 years, 62% men) with laboratory-confirmed COVID-19 admitted to 2 hospitals in Wuhan, China, who died (28%) or were discharged by January 31, 2020, were assessed
      • 95% received antibiotics, and 21% received antivirals (lopinavir/ritonavir)
      • D-dimer > 1 mg/L on admission associated with increased in-hospital mortality (adjusted odds ratio 18.42, 95% CI 2.64-128.55) compared to ≤ 0.5 mcg/mL in multivariate analysis
      • comparing nonsurvivors vs. survivors
        • D-dimer > 1 mg/L in 81% vs. 24% (p < 0.0001)
        • platelet count < 100 × 109/L in 20% vs. 1% (p < 0.0001)
        • median PT 12.1 seconds vs. 11.4 seconds (p = 0.0004)
        • coagulopathy (3 second extension of PT or 5 second extension of aPTT) developed in 50% vs. 7% (p < 0.0001)
      • PubMed32073213Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200401184844-847844Reference - Lancet 2020 Mar 28;395(10229):1054, editorial can be found in Lancet 2020 Mar 28;395(10229):1014
    • Study Summary
      higher D-dimer levels and longer PT at hospital presentation associated with increased risk of ICU admission in adults with COVID-19
      Details
      studySummary
      • Cohort Study based on prospective cohort study
      • 41 adults (median age 49 years) with laboratory-confirmed COVID-19 admitted to hospital by January 2, 2020 in Wuhan, China were evaluated
      • 32% of adults had underlying conditions including, diabetes, hypertension, and cardiovascular disease
      • 41% of adults admitted to ICU
      • patient characteristics on admission comparing ICU admission vs. no ICU admission
        • median D-dimer 2.4 mg/L vs. 0.5 mg/L (p = 0.0042)
        • median PT 12.2 seconds vs. 10.7 seconds (p = 0.012)
        • median aPTT 26.2 seconds vs. 27.7 seconds (not significant)
        • median platelet count 196 × 109/L vs. 149 × 109/L (not significant)
        • platelet count < 100 × 109/L in 8% vs. 4% (not significant)
      • PubMed31986264Lancet (London, England)Lancet2020021539510223497-506497Reference - Lancet 2020 Feb 15;395(10223):497
    • Study Summary
      D-dimer level ≥ 0.5 mg/L reported in 59.6% of patients with severe COVID-19 and 69.4% of patients with COVID-19 admitted to ICU who required mechanical ventilation, or who died
      Details
      studySummary
      • Cohort Study based on cohort study
      • 1,099 patients (median age 47 years; 0.9% of patients were < 15 years old) with laboratory-confirmed COVID-19 admitted to 550 hospitals across China between December 11, 2019 and January 29, 2020 had their records evaluated
      • on admission, 173 patients (16%) had severe COVID-19 and 926 patients (84%) had nonsevere COVID-19; severity of disease defined using the American Thoracic Society guidelines for community-acquired pneumonia
      • primary composite outcome, which included admission to ICU, use of mechanical ventilation, or death, in 67 patients (6%)
      • baseline patient characteristics
        • comparing severe disease vs. nonsevere disease (no p values reported)
          • D-dimer level ≥ 0.5 mg/L in 59.6% vs. 43.2%
          • median platelet count 138 × 109/L vs. 172 × 109/L
          • platelet count < 150 × 109/L in 57.7% vs. 31.6%
          • DIC in 0.6% vs. 0%
        • comparing development of primary composite outcome vs. no primary composite outcome (no p values reported)
          • D-dimer ≥ 0.5 mg/L in 69.4% vs. 44.2%
          • median platelet count 157 × 109/L vs. 169 × 109/L
          • platelet count < 150 × 109/L in 46.6% vs. 35.5%
          • DIC in 1.5% vs. 0 %
      • PubMed32109013The New England journal of medicineN Engl J Med20200228Reference - N Engl J Med 2020 Apr 30;382(18):1708full-text
    • Study Summary
      higher levels of D-dimer and fibrin degradation product in severe COVID-19 compared to less severe disease
      Details
      studySummary
      • Cohort Study based on prospective cohort study
      • 94 patients with confirmed COVID-19 admitted to Renmin Hospital in Wuhan, China between January 21, 2020 to February 10, 2020 were evaluated
      • patients were stratified as having ordinary severity (49 patients), severe disease (35 patients), or critical disease (critical disease) according to New Pneumonia Diagnosis and Treatment of COVID-19 fifth trial version (current version)
        Table 2. Mean Coagulation Parameters According to Severity of COVID-19
        ParametersOrdinary SeveritySevere DiseaseCritical Disease
        D-dimer2.14 mg/mL19.11 mg/mL*20.04 mg/mL
        Fibrin degradation products7.92 mg/mL60.01 mg/mL*69.15 mg/mL
        Prothrombin time12.2 seconds12.65 seconds12.8 seconds
        Activated partial thromboplastin time28.56 seconds29.53 seconds29.41 seconds
        Fibrinogen5.1 g/L4.76 g/L5.59 g/L

        * p < 0.05 vs. ordinary severity.

      • PubMed32172226Clinical chemistry and laboratory medicineClin Chem Lab Med20200316Reference - Clin Chem Lab Med 2020 Mar 16 early online
  • Study Summary
    thrombocytopenia associated with severe COVID-19
    Details
    studySummary
    • Systematic Review based on systematic review of observational studies
    • systematic review of 9 cohort studies evaluating association between severity of disease and platelet count in 1,779 patients with COVID-19
    • 22.4% of patient had severe disease; severe disease defined as
      • composite of ICU admission, need for mechanical ventilation, or death in 2 studies
      • ICU admission in 2 studies
      • need for mechanical ventilation in 5 studies
    • factors associated with severe disease compared to nonsevere disease
      • thrombocytopenia (odds ratio 5.13, 95% CI 1.81-14.58) in analysis of 4 studies with 1,427 patients
      • lower platelet count (weighted mean difference -31 × 109/L, 95% CI -35 to -29 × 109/L) in analysis of 9 studies with 1,779 patients, result limited by significant heterogeneity
    • compared to survivors, nonsurvivors associated with lower platelet count (weighted mean difference -48 × 109/L, 95% CI -57 to -39 × 109/L) in analysis of 3 studies
    • PubMed32178975Clinica chimica acta; international journal of clinical chemistryClin Chim Acta20200313506145-148145Reference - Clin Chim Acta 2020 Mar 13;506:145full-text
  • PubMed32268022The New England journal of medicineN Engl J Med2020042338217e38e38coagulopathy, antiphospholipid antibodies, and multiple cerebral infarctions detected in 2 men (69 and 70 years old) and 1 woman (65 years old) admitted to ICU for COVID-19 in case series (N Engl J Med 2020 Apr 23;382(17):e38)
  • PubMed32268022The New England journal of medicineN Engl J Med20200408petechiae reported in 1 patient out of 41 patients with confirmed COVID-19 (as of February 29, 2020) in Thailand (Clin Appl Thromb Hemost 2020 Jan;26:1076029620918308)PubMed32250159Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/HemostasisClin Appl Thromb Hemost202001012610760296209183081076029620918308

Risk of Venous Thromboembolism (VTE) in Patients With COVID-19

  • risk of VTE
    • 17%-47% of patients with severe COVID-19 reported to develop VTE in ICU
    • risk factors include
      • immobilized during critical care
      • acute inflammatory state that could potentiate hypercoagulable state
      • endothelial cell activation/damage due to binding of the virus to angiotensin-converting enzyme 2 (ACE2) receptor
      • Reference - Thrombosis UK Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19 (Thrombosis UK 2020 Mar 25PDF)
    • Study Summary
      Padua prediction score for VTE ≥ 4 at hospital admission associated with greater likelihood of being admitted to intensive care unit (ICU), requiring mechanical ventilation, being at high bleeding risk, and being ≥ 70 years old in patients with COVID-19
      Details
      studySummary
      • Cohort Study based on retrospective cohort study
      • 1,026 patients with laboratory-confirmed COVID-19 presenting to 31 provincial hospitals across China were evaluated for VTE risk using the Padua prediction score at admission
      • Padua prediction score ranges from 0 to 20, with score ≥ 4 considered to be at high-risk of VTE among hospitalized patients; 40% of cohort considered to be at high-risk based on Padua prediction score of ≥ 4
      • high-risk of bleeding defined as either
        • having ≥ 2 of
          • age > 40 years
          • hepatic failure (INR > 1.5)
          • severe renal failure (glomerular filtration rate < 30 mL/minute/m2)
          • admitted to ICU or coronary unit
          • central venous catheter insertion
          • diagnosed with rheumatic disease or active cancer
        • having 1 of
          • active gastroduodenal ulcer
          • bleeding in the past 3 months
          • platelet count < 50 × 109/L
      • compared to Padua score < 4, patients with Padua score ≥ 4 were more likely to
        • be admitted to ICU (odds ratio [OR] 12.82, 95% CI 5-32.91)
        • be at high bleeding risk (OR 8.51, 95% CI 3.74-19.35)
        • require mechanical ventilation (OR 13.17, 95% CI 5.56-31.19)
        • to be ≥ 70 years old (OR 4.85, 95% CI 2.83-8.31)
      • number of patients who developed VTE not reported
      • PubMed32278361The Lancet. HaematologyLancet Haematol20200409Reference - Lancet Haematol 2020 Apr 9 early onlinefull-text
      • see DynaMed calculator for Padua prediction score
  • Evidence Synopsis


    Thrombotic complications are common among patients admitted to the ICU for COVID-19 (reported in 17%-47%, depending on follow-up duration), especially pulmonary embolism (PE). Many of the thromboembolic events occurred despite thromboprophylaxis administration.
    • Study Summary
      objectively confirmed VTE in 20% of hospitalized adults with COVID-19, with ICU admission associated with higher incidence of VTE compared to regular ward admission
      Details
      Hematologic_Disordersobjectively confirmed VTE in 20% of hospitalized adults with COVID-19, with ICU admission associated with higher incidence of VTE compared to regular ward admission (J Thromb Haemost 2020 May 5 early online)05/20/2020 04:21:46 PMstudySummary
      • Cohort Study based on retrospective cohort study
      • 198 patients (mean age 61 years, 66% men) with COVID-19 admitted to ICU (75 patients) and regular ward (123 patients) from March 2 2020, until April 12, 2020 in Amsterdam, Netherlands were evaluated until death, hospital discharge, transferred to another hospital, or until April 30, 2020
      • thromboprophylaxis started in 84%, while 9.6% continued with therapeutic anticoagulation for a coexisting condition; thromboprophylaxis dosing
        • from March 3, 2020, patients in ICU received double dose nadroparin compared to patients with general ward; nadroparin 2,850 units twice daily if body weight < 100 kg and 5,700 units twice daily if body weight ≥ 100 kg
        • patients in regular ward were given nadroparin 2,850 units once daily if body weight < 100 kg and 5,700 units twice daily if body weight ≥ 100 kg
      • at baseline, median D-dimer level 2 mg/L in patients in ICU and 1 mg/L in patients in regular ward (P = 0.006)
      • as of April 30, 2020, 69% were discharged, 4% were transferred to another hospital, 19% died, and 8% were still hospitalized
      • objectively confirmed VTE included distal or proximal DVT, PE, or VTE at other sites, including catheter-related thrombosis
      • VTE outcomes
        • overall
          • objectively confirmed VTE in 20% (median follow-up 7 days)
            • PE with or without DVT in 6.6%
            • proximal DVT in 7.1%
            • distal DVT in 5.6%
            • upper extremity DVT in 0.5%
            • symptomatic VTE in 13%; diagnosed incidentally or by screening in 7.1%
          • cumulative incidence of VTE in 16% at day 7, 33% at day 14, and 42% at day 21; all VTEs were diagnosed in patients receiving thromboprophylaxis
        • comparing ICU vs. regular ward admission (no p values reported)
          • objectively confirmed VTE in 47% in ICU (at median 15 days) vs. 3.3% (at median 4 days)
          • cumulative incidence of VTE
            • 26% vs. 5.8% at 7 days
            • 47% vs. 9.2% at 14 days
            • 59% vs. 9.2% at 21 days
        • admission to ICU associated with higher risk of any VTE (hazard ratio 7.1, 95% CI 3.1-16) compared to regular ward admission, after adjusting for time varying variable
        • among patients in ICU who developed VTE, 58% were on double-dose prophylaxis and 41% were on regular dose prophylaxis
      • PubMed32369666Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200505Reference - J Thromb Haemost 2020 May 5 early online
    • Study Summary
      thromboembolic complications in 16.7% of adults admitted to the ICU and 6.4% of patients admitted to general ward for COVID-19
      Details
      Hematologic_Disordersthromboembolic complications in 16.7% of adults admitted to the ICU and 6.4% of patients admitted to general ward for COVID-19 (Thromb Res 2020 Apr 23)05/20/2020 04:20:53 PMstudySummary
      • Cohort Study based on retrospective cohort study
      • 388 adults (median age 66 years, 68% men) with laboratory confirmed COVID-19 admitted to ICU (61 adults) or general ward (327 adults) in Milan, Italy between February 13, 2020 and April 10, 2020 were evaluated
      • thromboprophylaxis in
        • all adults admitted to ICU received low-molecular-weight heparin (weight-adjusted in 17 adults) and therapeutic with direct anticoagulants in 2 adults
        • 75% of patients admitted to general ward received anticoagulation with prophylactic dose in 133 adults, intermediate-dose in 67 adults, and therapeutic dose in 74 adults, including those who continued ambulatory treatment for atrial fibrillation
      • primary outcome was thromboembolic complications, which included VTE, ischemic stroke, and acute coronary syndrome/myocardial infarction
      • imaging for VTE diagnosis performed in patients showing signs and symptoms of DVT or for those with unexplained clinical worsening of respiratory function or a rapid increase of D-dimer levels
      • analysis performed among closed cases defined as patients discharged, died, or diagnosed with thromboembolic event (48 closed cases in ICU and 314 closed cases in general ward)
      • in-hospital mortality 26% among closed cases
      • comparing ICU vs. general ward in closed cases (no p value reported)
        • ≥ 1 thromboembolic complication in 16.7% vs. 6.4%
        • VTE in 8.3% vs. 3.8%
        • PE with or without DVT in 4.2% vs. 2.5%
        • isolated proximal DVT in 2.1% vs. 1%
        • ischemic stroke in 6.3% vs. 1.9%
        • acute coronary syndrome/myocardial infarction in 2.1% vs. 1%
      • about 50% of thromboembolic complications developed within 24 hours of admission
      • PubMed32353746Thrombosis researchThromb Res202004231919-149Reference - Thromb Res 2020 Apr 23;191:9
    • Study Summary
      thrombotic complications in 18% of patients admitted to ICU for COVID-19-associated acute respiratory distress syndrome (ARDS) despite anticoagulation, with PE in 16.7%; COVID-19-associated ARDS associated with increased thrombotic complications, especially PE compared to non-COVID-19-associated ARDS
      Details
      studySummary
      • Cohort Study based on prospective cohort study
      • 150 patients (median age 63 years, 81% men) admitted to ICU for ARDS due to COVID-19 in France between March 3, 2020 and March 31, 2020 were followed until April 7, 2020 (mean ICU stay 9.6 days)
      • all patients received anticoagulant therapy (70% received prophylactic dosing and 30% received therapeutic dosing); 92.5% were treated with antiviral therapy
      • 95% of patients had elevated D-dimer and fibrinogen levels
      • mortality 8.7%; 67.3% were still intubated at time of analysis
      • thrombotic complications defined as any of deep vein thrombosis (DVT), PE, myocardial infarction, mesenteric ischemia, lower limb ischemia, or cerebral ischemic attack
      • 18% developed thrombotic complications (64 clinically significant events)
        • PE in 16.7% diagnosed at median 5.5 days after ICU admission
        • DVT in 2%
        • cerebral ischemic attack, limb ischemia, or mesenteric ischemia in 2.7% (no myocardial infarction reported)
      • in propensity matched analysis of 77 patients with COVID-19-associated ARDS matched to 145 patients with non-COVID-19 ARDS, COVID-19-associated ARDS associated with increased development of
        • thrombotic complications (adjusted odds ratio 2.7, 95% CI 1.1-6.6)
        • PE (adjusted odds ratio 9.3, 95% CI 2.2-40)
      • PubMed32367170Intensive care medicineIntensive Care Med20200504Reference - Intensive Care Med 2020 May 4 early onlinefull-text
    • Study Summary
      thrombotic complications in 31% of patients admitted to ICU for COVID-19 pneumonia despite thromboprophylaxis; presence of coagulopathy associated with increased risk of thrombotic complications
      Details
      Hematologic_Disordersthrombotic complications in 31% of patients admitted to ICU for COVID-19 pneumonia despite thromboprophylaxis; presence of coagulopathy associated with increased risk of thrombotic complications (Thromb Res 2020 Apr 10 early online)04/23/2020 10:16:04 AMstudySummary
      • Cohort Study based on cohort study
      • 184 patients (mean age 61 years) admitted to ICU in the Netherlands for confirmed COVID-19 pneumonia between March 7, 2020 and April 5th, 2020 were followed until death, discharge, or April 15, 2020 (median follow-up 7 days)
      • all patients had ≥ 1 dose of thromboprophylaxis (nadroparin; doses varied between hospitals)
      • as of April 5, 2020, 23 patients (13%) died, 22 patients (12%) were discharged, and 139 patients (76%) were still in ICU
      • primary outcome was composite of symptomatic acute PE, deep vein thrombosis, ischemic stroke, myocardial infarction, or systemic arterial embolism
      • cumulative incidence of primary outcome 31%
      • imaging confirmed VTE in 27% and arterial thrombotic events in 3.7%
      • PE was most frequent event (81% of events)
      • factors associated with increased risk of thrombotic complications
        • coagulopathy defined as spontaneous prolongation of prothrombin time > 3 seconds or activate partial thromboplastin time > 5 seconds (adjusted hazard ratio 4.1, 95% CI 1.9-9.1)
        • older age (adjusted hazard ratio 1.05/per year, 95% CI 1.004-1.01)
      • PubMed32291094Thrombosis researchThromb Res20200410Reference - Thromb Res 2020 Apr 10 early online
    • Study Summary
      lower-limb VTE in 25% of adults with COVID-19 pneumonia admitted to ICU, with higher D-dimer levels, prolonged activated partial thromboplastin time, older age, and lower lymphocyte count detected in adults who developed lower-limb VTE compared to adults who did not
      Details
      studySummary
      • Cohort Study based on retrospective cohort study
      • 81 adults (age range 32-91 years; mean age 59 years) with severe COVID-19 pneumonia admitted to ICU in Wuhan, China from January 30, 2020 to March 22, 2020 had their coagulation parameters and lower limb vein ultrasound evaluated
      • severity of COVID-19 pneumonia evaluated according to Fifth Revised Trial Version of the Novel Coronavirus Pneumonia Diagnosis and Treatment Guidance (current version)
      • 41% of adults had underlying chronic illness such as hypertension, diabetes, and coronary heart disease and 43% had history of smoking
      • prophylactic anticoagulation not administered
      • as of March 22, 79% were discharged, 10% had died, and 11% remained hospitalized
      • 20 adults (25%) developed lower-extremity VTE, of which 8 adults died
      • comparing lower-limb VTE vs. no lower-limb VTE, at baseline
        • mean D-dimer level 5.2 mg/L vs. 0.8 mg/L (p < 0.001)
        • mean activated partial prothrombin time 39.9 seconds vs. 35.6 seconds (p = 0.001)
        • mean age 68.4 years vs. 57.1 years (p < 0.001)
        • lymphocyte count 0.8 × 109/L vs. 1.3 × 109/L (p < 0.001)
      • no significant differences in prothrombin time, hemoglobin level, platelet count, or leukocyte count between groups
      • PubMed32271988Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200409Reference - J Thromb Haemost 2020 Apr 9 early online
  • PubMed32422076Annals of internal medicineAnn Intern Med20200514 thromboses in segmental and subsegmental pulmonary arterial vessels reported in postmortem examinations performed ≥ 48 hours after death in 10 deceased patients with COVID-19 who had prophylactic anticoagulant therapy (Ann Intern Med 2020 May 14 early online)

Evaluation

Evaluation for COVID-19-associated Coagulopathy

  • in outpatients with COVID-19, limited evidence to support evaluation of coagulation markers, including D-dimer levels, prothrombin time, platelet count, and fibrinogen (NIH Grade AIII) (NIH 2020 May 12)
  • hospitalized patients
    • PubMed32281926Blood transfusion = Trasfusione del sangueBlood Transfus20200408laboratory tests to perform in patients with COVID-19 should include tests for hemostasis function and platelet count (Blood Transfus 2020 Apr 8 early online)
    • abnormal coagulation parameters to look for include (in order of importance)
      • significantly elevated D-dimer level (for example, 3-to-4-fold increase in D-dimer levels over normal range)
      • prolonged prothrombin time
      • platelet count < 100 × 109/L
      • fibrinogen < 2 g/L (part of assessment to identify development of disseminated intravascular coagulation)
      • Reference - J Thromb Haemost 2020 May;18(5):1023full-text
    • PubMed32338827Journal of thrombosis and haemostasis : JTHJ Thromb Haemost202005011851023-10261023in addition to assessment of clinical characteristics of severe pneumonia and extent of lymphopenia to risk stratify patients, evaluation of coagulation markers at hospital admission may be useful in identifying patients who need close monitoring (J Thromb Haemost 2020 May;18(5):1023full-text)
    • however, there is limited evidence to recommend for or against using the data to guide management strategies (NIH Grade BIII) (NIH 2020 May 12)
    • results should be interpreted after accounting for underlying conditions that may influence tests results, such as presence of liver disease and intake of medications (for example, anticoagulants) (J Thromb Haemost 2020 May;18(5):1023full-text)

Evaluation for Disseminated Intravascular Coagulation (DIC) and Sepsis-Induced Coagulopathy (SIC)

  • consider diagnosis of DIC based on International Society on Thrombosis and Haemostasis (ISTH) DIC score; if score of < 5, DIC is unlikely and score should be recalculated every 1-2 days as required (Thrombosis UK 2020 Mar 25PDF)
  • PubMed32268022The New England journal of medicineN Engl J Med2020042338217e38e3821.6% of adults with COVID-19 reported to have met ISTH SIC criteria (total score ≥ 4) and these patients may have benefited from heparin therapy (N Engl J Med 2020 Apr 23;382(17):e38, Thrombosis UK 2020 Mar 25PDF)
  • ISTH guidance on DIC and SIC
    • DIC defined as "an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes that can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction"
    • SIC
      • DIC in sepsis is a coagulation disorder induced by infection that also represents an acute systemic inflammatory response that results in endothelial dysfunction
      • endothelial dysfunction and tissue injury caused by circulatory abnormalities can result in multiorgan failure and DIC as part of the thrombo-inflammatory response
      • evidence (from patients without COVID-19) suggests that early treatment of patients with sepsis and coagulopathy may reduce mortality; while assessing for overt DIC at admission followed by repeat evaluation 2 days later have reported improved outcomes, many patients with advanced coagulopathy, including those who meet the criteria for overt DIC, may have illness that is too advanced to experience large benefit from anticoagulant therapy
      • ISTH proposed SIC as a new category of DIC and developed a scoring system to identify an earlier phase of DIC in patients with sepsis
      • differences from scoring system for overt DIC
        • because hypofibrinogenemia is not usually observed in sepsis and fibrin-related markers typically do not correlate with sepsis severity, these markers were removed from the scoring system
        • Sequential Organ Failure Assessment (SOFA) score added to incorporate diagnosis of organ dysfunction and to confirm presence of sepsis (but not severity)
    • there is no gold standard for diagnosis for DIC but use of scoring systems can help determine which patients may benefit from therapy and to monitor treatment effect
    • Reference - J Thromb Haemost 2019 Nov;17(11):1989
  • see Disseminated Intravascular Coagulation (DIC) in Adults for additional information regarding evaluation of DIC in general population
  • DIC and SIC scoring systems
    Table 3. ISTH Scoring Systems for Overt Disseminated Intravascular Coagulation and Sepsis-induced Coagulopathy
    ParametersOvert DICSIC
    Platelet count
    • 2 points if < 50 × 109/L
    • 1 point if ≥ 50 × 109/L but < 100 × 109/L
    • 2 points if < 100 × 109/L
    • 1 point if 100 × 109/L but < 150 × 109/L
    FDP or D-dimer level
    • 3 points if marked increase
    • 2 points if moderate increase
    NA
    PT
    • 2 points if ≥ 6 seconds
    • 1 point if ≥ 3 seconds but < 6 seconds
    • 2 points if PT ratio > 1.4
    • 1 point if PT ratio > 1.2 but ≤ 1.4
    Fibrinogen1 point for < 1 g/L NA
    SOFA score*NA
    • 2 points if score ≥ 2
    • 1 point if score 1
    Positive scoreScore ≥ 5 suggests overt DICScore ≥ 4 suggests of SIC
    Abbreviations: DIC, disseminated intravascular coagulation; FDP, fibrin degradation product; ISTH, International Society on Thrombosis and Haemostasis; NA, not applicable; PT, prothrombin time; SIC, Sepsis-induced coagulopathy; SOFA, Sequential Organ Failure Assessment.


    * Sum of 4 items which includes, respiratory SOFA, cardiovascular SOFA, hepatic SOFA, and renal SOFA.


    Reference - J Thromb Haemost 2019 Nov;17(11):1989
                                    

Considerations for Evaluation for Venous Thromboembolism (VTE)

  • risk of VTE
    • patients with COVID-19 are at risk of hospital-associated VTE especially if immobilized or those in critical care
    • pulmonary vascular thrombosis may occur as a result of hypoxia, which stimulates coagulation
    • consider possibility of pulmonary embolism (PE) in patients with sudden onset of oxygenation deterioration, respiratory distress, or reduced blood pressure
    • Reference - Thrombosis UK Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19 (Thrombosis UK 2020 Mar 25PDF)
  • testing for VTE
    • in hospitalized patients, evaluate for presence of thromboembolic disease if any of (NIH Grade AIII)
      • worsening of pulmonary, cardiac, or neurological function
      • sudden, localized loss of peripheral perfusion
      • Reference - NIH COVID-19 Treatment Guideline (NIH 2020 May 12)
    • evaluation for deep vein thrombosis (DVT)
      • National Institutes of Health (NIH) states that there is limited evidence to recommend for or against routine testing for DVT without signs and symptoms, regardless of their coagulation markers status (NIH Grade BIII) (NIH 2020 May 12)
      • Italian Society on Thrombosis and Haemostasis (SISET) suggests ultrasound screening for deep vein thrombosis (DVT), if possible, if hemostatic markers are abnormal (Blood Transfus 2020 Apr 8 early online)
    • considerations when evaluating patient for PEPubMed32238427Journal of nuclear medicine : official publication, Society of Nuclear MedicineJ Nucl Med20200401
      • when performing aerosol-generating procedures such as ventilation/perfusion scintigraphy for detection of PE, personnel performing procedure should be protected by wearing a N95 mask or higher level respirator, eye protection, gloves, and gown
      • patients with PE have overlapping symptoms as those with COVID-19
      • ventilation/perfusion scintigraphy reported result in small leakage of aerosol from closed delivery system into the room with potential for expired air and aerosolized secretions transmitting infection to personnel within imaging suite
      • patients frequently cough after inhalation of radiopharmaceutical, which may further expose testing personnel to aerosolized secretions
      • after suspected aerosolization, equipment and imaging suite must undergo decontamination
      • suggested strategy to reduce need for ventilation scans and to minimize potential for aerosolization
        • patients should undergo rigorous pretest probability (for example, Wells criteria, Pulmonary Embolism Rule-out Criteria [PERC], or Geneva scoring system) and imaging limited only to appropriate patients
        • presence of lung parenchymal opacities should be evaluated on current chest x-ray or computed tomography (CT)
        • if lung opacification is present, patient should be evaluated by another imaging modality, usually with CT pulmonary angiography (CTPA)
        • if lungs are clear, consider perfusion scintigraphy using planar or tomographic imaging
          • if perfusion scan does not show segmental defects, result is considered negative for PE
          • if imaging demonstrates segmental defects, test is considered indeterminate and patient should be evaluated by alternate testing (such as CTPA) if greater certainty is needed
        • if leg symptoms are present or if CTPA is contraindicated (for example, due to contrast allergy), consider deep vein ultrasound to detect DVT or full ventilation/perfusion study with appropriate aerosol precautions (as clinically indicated)
      • Reference - J Nucl Med 2020 Apr 1 early online
  • for additional information on considerations for diagnosis of VTE during COVID-19 pandemic see J Vasc Surg Venous Lymphat Disord 2020 Apr 16 early online
  • see Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) for additional information regarding evaluation of patient with suspected VTE in general population

Management

Thromboprophylaxis in Patients With COVID-19

  • International Society on Thrombosis and Haemostasis (ISTH) guidance for patients without coagulopathy (D-dimer not markedly raised, normal prothrombin time, normal platelet count, elevated fibrinogen)
    • if patient is admitted to the hospital for other clinical reasons, prophylactic dose low-molecular-weight heparin (LWMH) should be initiated
    • if patient is discharged, existing coagulation parameters should be used as baseline if symptoms reoccur
    • Reference - ISTH interim guidance on recognition and management of coagulopathy in COVID-19 (J Thromb Haemost 2020 May;18(5):1023)
  • Thrombosis United Kingdom guidance on prevention of hospital-associated venous thromboembolism (VTE) in COVID-19 patients (VTE occurring in hospital or up to 90 days post discharge)
    • risk of VTE should be assessed in all patients admitted to hospital and prophylaxis given to all patients at high-risk according to recommended guidance from various organizations on thromboprophylaxis in medical patients
      • example strategy
        • pharmacologic thromboprophylaxis given to all immobilized and severely ill patients with COVID-19, unless contraindicated
        • in patients with creatinine clearance > 30 mL/minute, LMWH or fondaparinux administered subcutaneously according to packet instructions
        • in patients with creatinine clearance < 30 mL/minute or those with acute kidney injury, unfractionated heparin (UFH) 5,000 units administered subcutaneously twice or three times daily or dose-adjusted LMWH may be given
        • all completely immobilized patients may benefit from intermittent pneumatic compression in addition to pharmacologic prophylaxis
        • in patients with platelet count < 30 × 109/L or bleeding, mechanical thromboprophylaxis should be used alone
    • optimal thromboprophylaxis is unknown; because of drug-drug interactions between antiviral treatments and direct oral anticoagulants (DOACs) and difficulty of monitoring and maintaining stable INRs while on vitamin K antagonists, patients taking DOACs or vitamin K antagonist should consider switching/bridging to LMWH or UFH with or without mechanical prophylaxis while ill
    • Reference - Thrombosis UK Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19 (Thrombosis UK 2020 Mar 25PDF)
  • Italian Society on Thrombosis and Haemostasis (SISET) guidance on thromboprophylaxis for patients hospitalized for COVID-19
    • all hospitalized patients should be given LMWH, UFH, or fondaparinux at prophylactic doses; if anticoagulation is contraindicated, patients should be treated by leg compression
    • anticoagulants should be given for entire duration of hospitalization and continued for 7-14 days after hospital discharge
    • consider thromboprophylaxis prior to hospitalization in cases of preexisting or persisting VTE risk factors such as reduced mobility, body mass index > 30 kg/m2, previous VTE, and active cancer
    • consider intermediate-dose LMWH (for example, enoxaparin 4,000 units subcutaneously every 12 hours) on case-by-case basis in patients with multiple risk factors for VTE
    • use of therapeutic doses of LMWH or UFH in setting of prophylaxis is a reasonable approach but currently not supported by evidence outside of VTE diagnosis or as bridging strategy for patients on vitamin K antagonists and is not suggested as standard approach for all patients with COVID-19
    • both vitamin K antagonists and DOACs have known drug-drug interactions with antiviral therapies; risks and benefits of each antithrombotic strategies and underlying hypercoagulable condition should be considered on case-by-case basis
    • close communication between all specialists is vital in the management of patients with COVID-19
    • Reference - SISET guidance on thromboprophylaxis for patients hospitalized for COVID-19 (Blood Transfus 2020 Apr 8 early online)
  • National Institutes of Health (NIH) guidance on thromboprophylaxis for patients hospitalized with COVID-19
    • for outpatients with COVID-19, initiating anticoagulant and antiplatelet therapy is not recommended for prevention of VTE or arterial thrombosis unless other indications are present (NIH Grade AIII)
    • administer VTE prophylaxis per standard of care for hospitalized adults (NIH Grade AIII)
    • diagnosis of COVID-19 should not alter management of VTE prophylaxis in children (NIH Grade BIII)
    • LMWH or UFH may be preferred in hospitalized critically ill patients due to their shorter half-lives, ability to be given IV or subcutaneously, and fewer known drug-drug interactions compared to oral anticoagulants (NIH Grade AIII); (see list of drug interactions accessed 2020 May 15)
    • insufficient data for or against use of thrombolytics or increasing anticoagulant doses for VTE prophylaxis in hospitalized adults with COVID-19 outside the setting of a clinical trial (NIH Grade BIII)
    • Reference - NIH COVID-19 Treatment Guideline (NIH 2020 May 12)
  • additional guidance
    • prophylactic dose LMWH should be given to all hospitalized patients with COVID-19 even in the setting of abnormal coagulation tests in the absence of bleeding; abnormal prothrombin time or activated partial thromboplastin time is not a contraindication for pharmacological thromboprophylaxis
    • thromboprophylaxis should be held only if platelet count is < 25 × 109/L or fibrinogen level is < 0.5 g/L
    • mechanical thromboprophylaxis should be used only if patient has contraindications to pharmacological thromboprophylaxis
    • therapeutic anticoagulation is not indicated unless patient has documented VTE or atrial fibrillation; however, use of intermediate or full therapeutic dose anticoagulation in critically ill patients with COVID-19 without confirmed VTE is under investigation
    • Reference - American Society of Hematology (ASH) resource for COVID-19 and coagulopathy 2020 May 18
  • extended postdischarge thromboprophylaxis
    • no data specific to patients with COVID-19 to help guide duration of thromboprophylaxis post discharge (J Am Coll Cardiol 2020 Apr 15 early online)
    • NIH recommendations on postdischarge thromboprophylaxis
      • routine discharge of patients on VTE prophylaxis is not generally recommended (NIH Grade AIII)
      • however, extended prophylaxis may be considered for patients at low-risk for bleeding and high-risk for VTE (NIH Grade BI); FDA-approved postdischarge anticoagulants for VTE prophylaxis include (based on data from patients without COVID-19)
        • rivaroxaban 10 mg/day for 31-39 days
        • betrixaban 160 mg on day 1, followed by 80 mg once daily for 35-42 days
      • Reference - NIH COVID-19 Treatment Guideline (NIH 2020 May 12)
    • aspirin has been investigated as prophylaxis for VTE in low-risk patients after orthopedic surgery and may be considered if criteria for postdischarge thromboprophylaxis has been met (ASH resource for COVID-19 and VTE/anticoagulation 2020 May 18)
    • patients at risk for postdischarge VTE include those with reduced mobility, with co-existing conditions such as cancer, previous VTE event, D-dimer level > 2 times upper level of normal, and older age (for example, ≥ 75 years) (NIH 2020 May 12, J Am Coll Cardiol 2020 Apr 15 early online)
  • additional information regarding prophylactic anticoagulation with heparin
    • heparin has anti-inflammatory properties; its use of heparin to block thrombin generation may reduce inflammatory response
    • dose adjustment may be needed in patients with high body mass index
    • PubMed32239799Journal of thrombosis and haemostasis : JTHJ Thromb Haemost202005011851020-10221020Reference - J Thromb Haemost 2020 May;18(5):1020
  • see Venous Thromboembolism (VTE) Prophylaxis for Medical Patients and Venous Thromboembolism (VTE) Prophylaxis in Critically Ill Patients for additional information regarding thromboprophylaxis in hospitalized patients (general population)
  • Study Summary
    treatment-dose anticoagulation associated with 29% in-hospital mortality and 63% in-hospital mortality among patients with COVID-19 who required mechanical ventilation; longer duration of anticoagulation may improve in-hospital survival
    Details
    Hematologic_Disorderstreatment-dose anticoagulation associated with 29% in-hospital mortality and 63% in-hospital mortality among patients with COVID-19 who required mechanical ventilation; longer duration of anticoagulation may improve in-hospital survival (J Am Coll Cardiol 2020 May 5 early online)05/20/2020 04:17:14 PMstudySummary
    • Cohort Study based on cohort study
    • 2,773 patients hospitalized with laboratory-confirmed COVID-19 in New York city, New York between March 14 and April 11, 2020 were treated with treatment-dose systemic anticoagulation (28% of patients) or no treatment-dose anticoagulation and then evaluated
    • systemic anticoagulation included oral, subcutaneous, or IV forms; median time to anticoagulation 2 days from admission for median 3 days of treatment
    • median duration of hospitalization 5 days
    • patients receiving treatment-dose had significantly higher prothrombin time, activated partial thromboplastin time, lactate dehydration, ferritin levels, C-reactive protein levels, and D-dimer values at baseline compared to those who did not receive treatment-dose anticoagulation
    • major bleeding defined as 1 of
      • hemoglobin 7 g/dL and any red blood cell transfusion
      • ≥ 2 units of red blood cell transfusion within 48 hours
      • diagnosis code for major bleeding
    • comparing treatment-dose anticoagulation vs. no treatment-dose anticoagulation
      • overall cohort
        • in-hospital mortality 22.5% vs. 22.8% (no p value reported)
        • median survival 21 days vs. 14 days (no p value reported)
        • mechanical ventilation 29.8% vs. 8.1% (p < 0.001)
        • major bleeding in 3% vs. 1.9% (not significant); among patients on treatment-dose anticoagulation, 63% had bleeding events after starting anticoagulation
      • among 395 patients who were mechanically ventilated
        • in-hospital mortality 29.1% vs. 62.7% (no p value reported)
        • median survival 21 days vs. 9 days
    • longer duration of anticoagulation associated with reduced risk of mortality (adjusted hazard ratio 0.86 per day, 95% CI 0.82-0.89)
    • PubMed32387623Journal of the American College of CardiologyJ Am Coll Cardiol20200505Reference - J Am Coll Cardiol 2020 May 5 early onlinefull-text
    • DynaMed Commentary

      It is unclear what the indications were to prompt treatment-dose anticoagulation, but it appears that the patients in the treatment-dose anticoagulation group may have had more severe COVID-19 upon presentation which could potentially partially explain the high incidence of mechanical ventilation among this cohort. In addition, it is unclear if patients in the control group (no treatment-dose anticoagulation) received no anticoagulation at all or a lower-dose anticoagulation during hospitalization.

Management of Patients With COVID-19 Who Develop Coagulopathy

  • management of COVID-19-associated coagulopathy
    • International Society on Thrombosis and Haemostasis (ISTH) management algorithm
      • current ISTH-guided strategy is based on
        • reported association of D-dimer with high mortality in patients with COVID-19
        • evidence in patients with sepsis (not COVID-19-related) demonstrating multiorgan failure is more likely if coagulopathy develops and inhibition of thrombin generation may be of benefit in reducing mortality
        • management of coagulopathy (anticoagulation) as prevention for venous thromboembolism in patients who are critically ill
      • patients with coagulopathy
        • includes patients with
          • significantly elevated D-dimer level (for example, 3-4 fold increase in D-dimer levels over normal range)
          • prolonged prothrombin time (PT)
          • platelet count < 100 × 109/L
          • fibrinogen < 2 g/L
        • consider admitting patient (even in the absence of other concerns) and monitor once or twice daily
        • anticoagulation
          • consider prophylactic dose of low-molecular-weight heparin (LMWH) in all patients (including those who are not critically ill) who require hospitalization due to COVID-19, if not contraindicated (for example, active bleeding, platelet count < 25 × 109/L)
          • abnormal PT or activated partial thromboplastin time (aPTT) is not a contraindication
          • patients with renal impairment should be closely monitored
        • bleeding
          • reported to be rare in the setting of COVID-19
          • consider following blood transfusion therapy strategy for patients with septic coagulopathy
        • if coagulopathy worsens, blood products should be administered
          • in patients who are not bleeding, goal is to maintain platelet count > 25 × 109/L
          • in patients who are bleeding, goal is to maintain
            • platelet count > 50 × 109/L
            • fibrinogen > 1.5 g/L
            • PT ratio < 1.5 (not same as INR)
        • consider experimental therapies for COVID-19
      • Reference - ISTH interim guidance on recognition and management of coagulopathy in COVID-19 (J Thromb Haemost 2020 May;18(5):1023full-text)
    • guidance from Thrombosis UK
      • management of COVID-19-associated coagulopathy (prolonged PT or aPTT) - abnormal coagulation results do not require correction in patients who are not bleeding; no evidence for benefit
      • management of bleeding in patients with COVID-19
        • in patients with minor bleeding, complete blood count and coagulation testing should be performed; thromboelastography (TEG)/rotational thromboelastometry (ROTEM) may be used only if risk assessment demonstrates that aerosolization of blood is not a risk or if they can be used in a safety hood
        • in patients with major bleeding (for example, bleeding that leads to systolic blood pressure < 90 mmHg and/or heart rate > 110 beats/minute)
          • fresh frozen plasma (FFP) and red blood cells should be administered early
            • for FFP, initially at 12-15 mL/kg (pragmatically - 1 bag/20 kg body weight or 4 units in an adult) while waiting for baseline coagulation test results
            • further doses of FFP (at 12-15 mL/kg per dose) may be given based on laboratory test results, with transfusion trigger of PT or aPTT > 1.5 or if still awaiting coagulation test results
          • consider 1 adult therapeutic dose (1 apheresis unit or 4 pooled units) if platelet count is < 50 × 109/L in complex trauma, especially with head injury; limited evidence to suggest platelet count target > 75 × 109/L
          • if bleeding continues and fibrinogen level is < 1.5 g/L
            • consider cryoprecipitate (2 five-unit pools to raise fibrinogen by about 1 g/L in adult) or fibrinogen concentrate (if approved for use) usually given at dose of 3-4 g
            • FFP transfusion alone may not result in sufficient increase in fibrinogen; 4 units of FFP usually increases fibrinogen level by about 1g/L in adult
          • do not use tranexamic acid in COVID-19-associated disseminated intravascular coagulation (DIC); if the patient does not have DIC, tranexamic acid 1 g can be given over 10 minutes, followed by another 1 g if bleeding persists or restarts within 24 hours
        • other treatments
          • recombinant factor VIIa is not recommended
          • prothrombin complex concentrate is not recommended
      • Reference - Thrombosis UK Practical guidance for the prevention of thrombosis and management of coagulopathy and DIC of patients infected with COVID-19 (Thrombosis UK 2020 Mar 25PDF)
  • management of DIC
    • Thrombosis UK guidance on management of DIC
      • consider diagnosis of DIC based on ISTH overt DIC score; if score of < 5, DIC is unlikely and score should be recalculated every 1-2 days as required
      • most important aspect of DIC management is the treatment of the underlying condition, which makes management of DIC especially difficult in patients with COVID-19
      • management of bleeding
        • consider FFP at 12-15 mL/kg (pragmatically, 1 bag/20 kg body weight or 4 units in an adult)
        • consider 1 adult therapeutic dose (1 apheresis unit or 4 pooled units) if platelet count is < 50 × 109/L
        • if bleeding continues and fibrinogen level is < 1.5 g/L
          • consider cryoprecipitate (2 five-unit pools to raise fibrinogen by about 1 g/L in adult) or fibrinogen concentrate (if approved for use) usually given at dose of 3-4 g
          • FFP transfusion alone may not result in sufficient increase in fibrinogen; 4 units of FFP usually increases fibrinogen level by about 1 g/L in an adult
        • patients with DIC should not be given antifibrinolytics because recovery depends on endogenous fibrinolysis breaking down the disseminate thrombi
      • management of overt thromboembolism or organ failure due to clot
        • consider low-dose anticoagulation with UFH with aPTT target of <1.5 or anti-Xa levels at low rate to inhibit thrombin generation
        • limited evidence for therapeutic dose for reduction in mortality
    • see Disseminated Intravascular Coagulation (DIC) in Adults for additional information regarding management of DIC in general population
  • Study Summary
    prophylactic dose heparin may reduce mortality in adults with COVID-19 and sepsis-induced coagulopathy or D-dimer levels > 3 mg/L
    DynaMed Level2
    Details
    studySummary
    • Cohort Study based on retrospective cohort study
    • 449 adults (mean age 65 years) hospitalized for severe COVID-19 in Wuhan, China from January 1, 2020 to February 13, 2020 who were administered heparin for ≥ 7 days or no heparin were evaluated
      • heparin group (99 patients) received either enoxaparin 40-60 mg/day (94 patients) or UFH 10,000-15,000 units/day (5 patients)
      • all adults received antiviral and supportive treatments after admission
    • severe COVID-19 defined as respiratory rate ≥ 30 breaths/minute, arterial oxygen saturation ≤ 93% at rest, and PaO2/FiO2 ≤ 300 mm Hg
    • 60.6% of adults had ≥ 1 chronic underlying disease such as hypertension, diabetes, and heart disease
    • 21.6% of adults met sepsis-induced coagulopathy criteria (SIC) (total score ≥ 4)
    • by March 13, 2020, 70.2% of adults survived and 29.8% of adults had died
    • comparing heparin vs. no heparin
      • mortality among adults with SIC score ≥ 4, 40% vs. 64.2% (p = 0.029)
      • mortality among adults with D-dimer > 3 mg/L, 32.8% vs. 52.4% (p = 0.017)
    • no significant difference in 28-day mortality between groups overall or among adults with SIC score < 4
    • PubMed32220112Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200327Reference - J Thromb Haemost 2020 May;18(5):1094

Management of Patients With COVID-19 Who Develop Venous Thromboembolism (VTE)

  • for information regarding patients with COVID-19 who develop other large vessel thrombosis, see COVID-19 and Cardiovascular Disease Patients and COVID-19 and Special Populations
  • management of VTE in patients with COVID-19
    • patients with COVID-19 who experience a thromboembolic event or suspected to have thromboembolic event when imaging is not available should be managed with therapeutic anticoagulant therapy per standard of care for patients without COVID-19 (NIH Grade AIII) (NIH 2020 May 12)
    • anticoagulants choices
      • when choosing an anticoagulant, consider co-existence of renal or hepatic dysfunction, thrombocytopenia, and gastrointestinal function
      • while ill with COVID-19, parenteral anticoagulant, such as unfractionated heparin, may be preferred because of lack of known drug-drug interactions (for example, with COVID-19 therapies) and can be withheld temporarily as needed
      • however, unfractionated heparin requires frequent blood draws due to time required to achieve therapeutic activated partial thromboplastin time (aPTT), frequently exposing healthcare workers to patients with COVID-19
      • in patients who are unlikely to require procedures that necessitate temporary withholding of anticoagulation, low-molecular-weight heparin may be preferred
      • direct oral anticoagulants have the advantage of lack of need for monitoring and easier discharge planning and outpatient management; but risks include clinical deterioration and difficulty with timely reversal of anticoagulation at some hospitals
      • in patients who are ready for discharge, direct oral anticoagulants or low-molecular-weight heparin may be preferred due to more limited contact needed with patients (for example, INR monitoring if warfarin is administered)
      • PubMed32311448Journal of the American College of CardiologyJ Am Coll Cardiol20200415Reference - J Am Coll Cardiol 2020 Apr 15 early onlinefull-text
    • additional considerations for patients with pulmonary embolism (PE)
      • use of catheter-directed therapies should be limited to most critical patients
      • routine use of inferior vena cava filters should be avoided, except in cases of recurrent PE despite adequate anticoagulation or absolute contraindications to anticoagulation
      • current guideline recommendations for the general population should be followed for reperfusion strategies for acute PE
        • intermediate-risk, hemodynamically stable patients should be given anticoagulation; if the condition worsens, management includes rescue systemic fibrinolysis with catheter-directed options as an alternative
        • patients with overt hemodynamic instability should be managed with systemic fibrinolysis with catheter-directed options as an alternative, if not suited for systemic fibrinolysis
      • consider extracorporeal membrane oxygenation (ECMO) at bedside, rather than use of catheterization laboratory or operating room
      • Reference - J Am Coll Cardiol 2020 Apr 15 early onlinefull-text
    • additional considerations for patients with deep vein thromboembolism
      • most patients can be managed with anticoagulation, at home if possible
      • only patients who require endovascular techniques (local fibrinolysis or embolectomy) are those with phlegmasia or with truly refractory symptoms
      • Reference - J Am Coll Cardiol 2020 Apr 15 early onlinefull-text
  • see Management of Deep Vein Thrombosis (DVT) and Pulmonary Embolism Treatment for additional information regarding management of patient with VTE in general population

Management in Specific Patient Populations

  • patients receiving anticoagulant or antiplatelet therapy for preexisting conditions
    • continue these medications (NIH Grade AIII) (NIH 2020 May 12)
    • in patients already receiving anticoagulant therapy for previous venous thromboembolism (VTE) or atrial fibrillation, therapeutic dosing should be continued, but may need to be held if platelet count is < 30-50 × 109/L or if fibrinogen level is < 1 g/L (ASH resource for COVID-19 and coagulopathy 2020 May 18)
    • continue with warfarin (NIH Grade AIII)
      • if unable to have INR monitored due to isolation, consider direct oral anticoagulants
      • in patients with mechanical heart valves, ventricular assist devices, valvular atrial fibrillation, or antiphospholipid antibody syndrome, or women who are lactating
      • Reference - NIH COVID-19 Treatment Guideline (NIH 2020 May 12)
    • consider balance between risk of thrombosis and risk of bleeding on case-by-case basis (ASH resource for COVID-19 and coagulopathy 2020 May 18)
    • for any anticoagulant or antiplatelet agent used, consider drug-drug interactions with other medications (see list of drug interactions accessed 2020 May 15) (NIH 2020 May 12)
  • patients on access devices
    • patients with COVID-19 requiring extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy or who have thrombosis of catheters or extracorporeal filters should have antithrombolytic therapy per standard of care for patients without COVID-19 (NIH Grade AIII)
    • in cases of recurrent clotting of access devices, intensity of anticoagulation may be increased after considering patient bleeding risk (for example, from standard prophylactic dose to intermediate dose or from intermediate dose to therapeutic dose) or type of anticoagulant administered may be switched (ASH resource for COVID-19 and VTE/anticoagulation 2020 May 18)
  • pregnant or lactating women hospitalized with COVID-19
    • in pregnant women
      • administer VTE prophylaxis similarly to those who are not pregnant (NIH Grade AIII)
      • heparin compounds are generally recommended in women who are pregnant; low-molecular-weight heparin (LMWH) is preferred over unfractionated heparin (UFH)
      • continue with antithrombotic therapy already prescribed for another indication (NIH Grade AIII)
      • manage anticoagulant therapy during labor and delivery similarly to those who are not pregnant (NIH Grade AIII)
    • in women who are lactating, consider UFH, LMWH, or warfarin, which do not accumulate in breast milk; however, do not administer direct oral anticoagulants (NIH Grade AIII)
    • Reference - National Institutes of Health (NIH) COVID-19 Treatment Guideline (NIH 2020 May 12)

Guidelines and Resources

Guidelines and Resources

Guidelines

International Guidelines

  • World Health Organization (WHO) technical guidance for coronavirus disease (COVID-19) can be found at WHO Coronavirus Disease (COVID-19)
  • PubMed32459046Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200527 International Society on Thrombosis and Haemostasis Scientific and Standardization Committee (ISTH/SSC) clinical guidance on diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19 can be found in J Thromb Haemost 2020 May 27 early online
  • International Society on Thrombosis and Haemostasis (ISTH) interim guidance on recognition and management of coagulopathy in COVID-19 can be found in J Thromb Haemost 2020 May;18(5):1023full-text
  • PubMed31410983Journal of thrombosis and haemostasis : JTHJ Thromb Haemost2019110117111989-19941989International Society on Thrombosis and Haemostasis (ISTH) guidance on diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation can be found in J Thromb Haemost 2019 Nov;17(11):1989

United States Guidelines

United Kingdom Guidelines

  • Thrombosis UK practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19 can be found at Thrombosis UK 2020 Mar 25PDF

European Guidelines

  • Italian Society on Thrombosis and Haemostasis (SISET) position paper on COVID-19 and Haemostasis can be found in Blood Transfus 2020 Apr 8 early online
  • Swiss Consensus Statement by the Working Party Hemostasis on PubMed32277760Swiss medical weeklySwiss Med Wkly20200411150w20247w20247thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19 can be found in Swiss Med Wkly 2020 Apr 6;150:w20247full-text
  • PubMed32327870Revista espanola de cardiologiaRev Esp Cardiol20200422Spanish Society of Cardiology position statement by the working group on cardiovascular thrombosis on antithrombotic treatment during COVID-19 pandemic can be found in Rev Esp Cardiol 2020 Apr 22 early online

Asian Guidelines

  • PubMed32307014Military Medical ResearchMil Med Res20200420711919Chinese Expert Consensus on diagnosis and treatment of coagulation dysfunction in COVID-19 can be found in Mil Med Res 2020 Apr 20;7(1):19full-text

Australian and New Zealand Guidelines

  • Thrombosis and Haemostasis Society of Australia and New Zealand (THANZ) guidelines on

Review Articles

  • PubMed32305883Journal of clinical virology : the official publication of the Pan American Society for Clinical VirologyJ Clin Virol20200409127104362104362review of coagulation abnormalities and thrombosis in patients with COVID-19 can be found in Lancet Haematol 2020 May 11 early onlinefull-text
  • review of coagulation disorders in corona virus infected patients can be found in J Clin Virol 2020 Apr 9 early online
  • PubMed32339221BloodBlood20200427review of COVID-19 and its implications for thrombosis and anticoagulation can be found in Blood 2020 Apr 27 early online
  • PubMed32302453Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200417review of thromboinflammation and hypercoagulability of COVID-19 can be found in J Thromb Haemost 2020 Apr 17 early online
  • review of disseminated intravascular coagulation in patients with COVID-19 pneumonia can be found in J Thromb Haemost 2020 Apr;18(4):786
  • PubMed32278338Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200411review of possible mechanisms for COVID-19-induced thrombocytopenia can be found in J Thromb Haemost 2020 Apr 11 early online
  • PubMed32311448Journal of the American College of CardiologyJ Am Coll Cardiol20200415review of COVID-19 and thrombotic or thromboembolic disease prevention, antithrombotic therapy, and follow-up can be found in J Am Coll Cardiol 2020 Apr 15 early online
  • PubMed32212240Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200401184786-787786review of minimal laboratory testing panels in patients with COVID-19 can be found in Semin Thromb Hemost 2020 Apr;46(3):379
  • PubMed32238427Journal of nuclear medicine : official publication, Society of Nuclear MedicineJ Nucl Med20200401review of diagnostic evaluation of pulmonary embolism during the COVID-19 pandemic can be found in J Nucl Med 2020 Apr 1 early online
  • PubMed32305585Journal of vascular surgery. Venous and lymphatic disordersJ Vasc Surg Venous Lymphat Disord20200416review of diagnosis and treatment of suspected venous thromboembolism during COVID-19 pandemic can be found in J Vasc Surg Venous Lymphat Disord 2020 Apr 16 early online
  • PubMed32396903Acta haematologicaActa Haematol202005121-81 review of venous thromboembolism in patients with COVID-19 can be found in Acta Haematol 2020 May 12 early onlinefull-text
  • PubMed32239799Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200402review of heparin use in COVID-19 can be found in J Thromb Haemost 2020 May;18(5):1020
  • PubMed32294321Journal of thrombosis and haemostasis : JTHJ Thromb Haemost20200415review of impact of COVID-19 pandemic on therapeutic choices in thrombosis-hemostasis can be found in J Thromb Haemost 2020 Apr 15 early online

References

Recommendation Grading Systems Used

  • National Institutes of Health (NIH) recommendation rating scheme
    • strength of recommendation
      • A - strong recommendation for the statement
      • B - moderate recommendation for the statement
      • C - optional recommendation for the statement
    • quality of evidence for recommendation
      • I - ≥ 1 randomized trials with clinical outcomes and/or validated laboratory endpoints
      • II - ≥ 1 more well-designed, nonrandomized trials or observational cohort studies
      • III - expert opinion
    • Reference - NIH COVID-19 treatment guideline (NIH 2020 Apr 21)

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