Practical considerations in prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19

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Salient features:

This article focuses on:

  • General treatment considerations
  • Patient selection for tiered anticoagulation therapy
  • Agent selection for tiered anticoagulation therapy
  • Discharge considerations

Detailed summary:

General treatment considerations

  • Guidance from the International Society on Thrombosis and Haemostasis recommends prophylactic anticoagulation for all patients who require hospital admission for COVID-19 in the absence of any contraindications such as active bleeding and a platelet count less than 250 × 103 /µL.
  • For critically ill patients with COVID-19, barriers to obtaining diagnostic testing to confirm or rule out active bleeding, such as endoscopy or colonoscopy, may be present, further complicating treatment decisions.
  • Low-molecular-weight heparin (LMWH) has been suggested as the anticoagulant of choice for reducing healthcare staff contact with patients in the absence of a compelling reason not to use it.
  • Fondaparinux may be considered for patients with a history of heparin-induced thrombocytopenia or aversion to receipt of porcine derivatives.
  • Heparins have anti-inflammatory properties and have added benefit in COVID-19 cases where proinflammatory cytokines are markedly elevated.
  • Clinicians may wish to consider a 3-tiered approach to stratifying anticoagulation intensity.
  • The 3 tiers are low-intensity anticoagulation (tier I), intermediate-intensity anticoagulation (tier II), and therapeutic-dose anticoagulation (tier III).
  • An additional area of clinical controversy involves patients’ use of home oral anticoagulants while admitted to the inpatient setting.
  • Hospitalized patients, particularly critically ill patients, may require invasive procedures, which may require interruption of oral anticoagulation therapy.
  • For any patient who is already taking an oral anticoagulation at home, it may be prudent to transition to therapeutic-dose LMWH or parenteral UFH infusion for the duration of hospitalization unless contraindications exist.

Patient selection for tiered anticoagulation therapy

Tier I:

  • Candidates for tier I anticoagulation include those with indications for standard prophylaxis.
  • This tier should be considered for patients without known thrombi or known malignancy; these are generally lower-acuity patients, such as non–critically ill medical patients.
  • This approach may be considered for patients with D-dimer levels less than 3 times the ULN that are not trending upward.

Tier II:

  • Tier II, or intermediate-intensity, anticoagulation may be appropriate for a patient with COVID-19 who requires a higher-intensity standard prophylaxis regimen.
  • A patient may be categorized into tier II based on acuity and/or VTE risk factors.
  • Tier II therapy could be considered for patients whose D-dimer level is above 3 times the ULN.
  • To determine VTE risk factors that may place patients in this category, clinicians should consider risk stratification models such as the Caprini score, IMPROVE risk score, and Padua Prediction Score models, all of which have been used in acutely ill hospitalized patients.
  • All critically ill patients should be considered for tier II therapy, at a minimum, if they do not have risk factors for VTE and/or the clinician team is otherwise not concerned about VTE development.

Tier III

  • Tier III therapy may be chosen for those patients with COVID-19 who have known or strongly suspected VTE.
  • Patients presenting with acute coronary syndrome should be categorized into this tier.
  • This tier can strongly be considered for any patient with a D-dimer level greater than 6 times the ULN or in a continued upward trend.
  • Moreover, therapeutic anticoagulation should be strongly considered for any patient with clinical sequelae of possible VTE, including an otherwise unexplained increase in oxygen requirement, a need for mechanical ventilation, alveolar dead space and organ failure with concern for microvascular thrombi.

Agent selection for tiered anticoagulation therapy

Tier I:

  • For low-intensity anticoagulation, clinicians should consider LMWH at standard prophylactic doses.
  • For example, enoxaparin 40 subcutaneously once daily.
  • For obese patients with a body mass index (BMI) greater than 40, an increase in LMWH dose should be considered.
  • Enoxaparin 40 mg subcutaneously every 12 hours may be employed for standard VTE prophylaxis.
  • In the presence of renal insufficiency, LWMH can be renally dose-adjusted or subcutaneous UFH therapy can be used instead. Preference may be given to subcutaneous UFH when renal function is poor or labile.
  • Increased doses of UFH may be an option for obese patients with a BMI of >40 in the setting of renal insufficiency.
  • Monitoring of anti-Xa levels during use of LMWH is not generally recommended; however, assaying anti-Xa levels to target a goal anti-Xa value of 0.2 to 0.5 unit/mL may be considered for obese patients.
  • Blood sampling for determination of the anti-Xa level should occur approximately 4 hours after a subcutaneous dose is administered and after approximately 4 doses.
  • In the event the level falls outside the target range, it is recommended to exercise best clinical judgment in adjusting doses.
  • In cases where heparin may be contraindicated and renal function allows, fondaparinux administered at a dosage of 2.5 mg subcutaneously daily may be considered for VTE prophylaxis.

Tier II:

  • For patients in whom intermediate-intensity anticoagulation is appropriate, employing a higher-than-standard dose may be considered under the assumption that it may confer additional benefit in VTE prevention.
  • Enoxaparin 40 mg subcutaneously every 12 hours may be an option for patients with a BMI of <40.
  • A regimen of enoxaparin 0.5 mg/kg subcutaneously every 12 hours may be considered, especially if the patient is obese.
  • In the setting of renal insufficiency, heparin can be used at a higher dose (7,500 units subcutaneously every 8 hours).
  • A patient categorized into this tier have a change in clinical status, such as increased oxygen requirements, clinical evaluation for VTE with either point-of-care ultrasound or formal venous Doppler studies should be pursued if available.
  • Until VTE can be ruled out, VTE therapeutic-dose anticoagulation should be strongly considered.

Tier III:

  • Recommendations for high-intensity anticoagulation in critically ill patients with COVID-19 call for use of a therapeutic dosage of LMWH, such as enoxaparin 1 mg/kg subcutaneously every 12 hours (for patients with creatinine clearance [CLcr] above 30 mL/min) or 1 mg/kg subcutaneously once daily (for those with CLcr of less than 30 mL/min) or intravenous UFH titrated to maintain institution-specific therapeutic levels.
  • Enoxaparin 1.5 mg/kg subcutaneously daily may be considered for a non–critically ill patient in order to reduce the need for patient contact.
  • Monitoring of UFH therapy via anti-Xa assay should be used preferentially if available due to potentially elevated baseline aPTT levels in patients with COVID-19.
  • Use of LMWH is advantageous due to a need for less frequent laboratory monitoring and a lower workload burden on nursing staff.
  • In obese patients, clinicians may wish to consider use of enoxaparin at a dosage of 1 mg/kg subcutaneously every 12 hours (for patients with CLcr above 30 mL/min), with monitoring of anti-Xa levels to target a goal anti-Xa value of 0.6 to 1.0 unit/mL.
  • Blood samples for anti-Xa level determination should be drawn approximately 4 hours after a subcutaneous dose is administered and after approximately 4 doses.
  • If the anti-Xa level falls outside the target range, clinical judgement is necessary for dose adjustment.
  • UFH may be preferred when bleeding risk is elevated because it has a short half-life and its effects are easily reversible.
  • Intravenous UFH may also be an option for patients requiring invasive procedures.
  • For critically ill patients, intravenous UFH may be the preferred agent due to their risk of acute renal dysfunction.
  • Therapeutic heparin should also be considered for all critically ill patients receiving dialysis, including continuous renal replacement therapy (CRRT), and initiated according to institutional CRRT or VTE protocols.
  • It is important to ensure communication between pharmacy personnel and the nephrology service in order to balance risks of filter clotting and bleeding in the setting of uremia.
  • In cases involving contraindications to heparin use, clinicians may wish to consider use of therapeutic fondaparinux dosed according to patient weight.
  • Intravenous argatroban may be considered in the setting of renal impairment or labile renal function in cases where heparin is contraindicated and fondaparinux may not be ideal.
  • Direct thrombin inhibitors should be considered only if there are contraindications to heparin use due to a lack of data specific to the COVID-19 population.

Discharge considerations

  • Upon discharge all patients, regardless of tier, be assessed for ongoing need for continued prophylaxis.
  • Careful examination of additional risk factors for VTE, such as prolonged immobility while in quarantine, as well as trends in laboratory values, such as D-dimer, CRP, ferritin, and lactate dehydrogenase levels, should be reviewed.
  • Elevated inflammatory markers may indicate an increased risk of VTE upon a patient’s discharge to home, and continued prophylaxis may be warranted.
  • DOACs are an option if compliance concerns arise.
  • Duration of prophylactic therapy should be determined on a case-by-case basis, taking into account bleeding risk.
  • Consideration of extended prophylaxis of up to 45 days may be appropriate in patients at increased risk for VTE who are at low risk for bleeding.
  • For patients who had been using a DOAC at home and were transitioned to parenteral anticoagulation during an inpatient stay, a transition back to home DOAC therapy may be considered in the absence of evidence of treatment failure.
  • Upon discharge of patients with confirmed or suspected VTE, continuation of anticoagulation treatment for a minimum 3 months for provoked VTE can be chosen.
  • Treatment with therapeutic-dose LMWH or DOAC therapy can be considered in preference to warfarin, in accordance with current guidelines.
  • If VTE is not confirmed at time of discharge due to lack of test availability, the clinician may wish to treat according to conventional protocols for VTE.
  • Follow-up with primary care or specialty providers for ongoing reevaluation and extension of therapy must be ensured.

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