Anticoagulation Dosing Guideline for Adult COVID-19 Patients

Anticoagulation Dosing Guideline for Adult COVID-19 Patients

Enoxaparin is the preferred first line anticoagulant for patients diagnosed with COVID-19. The incidence of HIT with enoxaparin is less than 1%.

1. 2. 3.

VTE Prophylaxis:

 

VTE prophylaxis will be considered for COVID-19 patients who are low risk.

Low risk COVID-19 patient

Not receiving mechanical ventilation

D-Dimer < 6 mg/L

ESRD on iHD without clotting

Kidney Function

BMI (kg/m2)

Dosing of Enoxaparin

Concern for HIT or LMWH Failure

CrCL ≥ 30 mL/min

18.5-39.9

30mg SUBQ Q12H

Consult Hematology

40-49.9

40mg SUBQ Q12H

≥ 50

60mg SUBQ Q12H

CrCL < 30 mL/min OR

ESRD/AKI on RRT

18.5-39.9

30mg SUBQ Q24H

Consult Hematology

≥ 40

40mg SUBQ Q24H

Special Population:

 

< 18.5 (or weight < 50kg)

Heparin 2500 SUBQ Q8H

Consult Hematology

*Contraindications: Platelets < 25 K/uL or Fibrinogen < 50 mg/dL or active bleeding

Therapeutic anticoagulation

Therapeutic anticoagulation will be considered for COVID-19 patients who are considered high risk or diagnosed with an acute VTE.

High risk COVID-19 patient (for all hospitalized patients):

  Receiving mechanical ventilation AND D-dimer > 6 mg/L OR

  Acute kidney injury (Scr increase 0.3 mg/dL above baseline) +/- CVVHD/AVVHD/SLED or IHD with clotting
Anti-Xa level goals for enoxaparin therapy (when indicated):

1. Therapeutic peak LMWH level (Drawn 4 hours after 3rd dose): 0.6-1 anti-Xa units/mL

2. Therapeutic trough LMWH level (Drawn 1 hour prior to 3rd dose): < 0.5 anti-Xa units/mL

  

Kidney Function

 

BMI

(kg/m2)

Dosing of Enoxaparin

Concern for HIT or LMWH Failure

CrCL ≥ 30 mL/min

12-49.9

1 mg/kg SUBQ Q12H

Bivalirudin infusion (see Anticoagulation COVID- 19 guidelines for dosing)

≥ 50

0.8 mg/kg SUBQ Q12H
**monitor peak anti-Xa level with 3rd dose

 Consult pharmacist to assist with obtaining anti- Xa level and dose adjustment

CrCL < 30mL/min

12-49.9

1 mg/kg SUBQ 24H

Bivalirudin infusion (see Anticoagulation COVID- 19 guidelines for dosing)

≥ 50

0.8mg/kg SUBQ Q24H
**monitor peak anti-Xa level with 3rd dose

 Consult pharmacist to assist with obtaining anti- Xa level and dose adjustment

ESRD or AKI on RRT

 

0.8 mg/kg SUBQ Q24H (MAX dose 1mg/kg Q24H) **monitor peak and trough anti-Xa level with 3rd dose

 Consult pharmacist to assist with obtaining anti- Xa level and dose adjustment

Bivalirudin infusion (see Anticoagulation COVID- 19 guidelines for dosing)

If minor bleeding prior to obtaining steady state anti- Xa levels

  Decrease dose to 0.5 mg/kg and monitor anti-Xa peak and trough with 1st dose of new regimen

  Consult pharmacist to assist with obtaining anti- Xa levels and dose adjustment

*Contraindications: Platelets < 50 K/uL or fibrinogen < 100 mg/dL or active bleeding

Intra-dialytic anticoagulation for renal replacement therapy

Nephrology service will determine the need for a booster dose of IV enoxaparin when ordering renal replacement therapy  Renal replacement therapy (iHD/SLED/CRRT)

o Enoxaparin 30 mg IV x 1 preferably prior to or within an hour of starting dialysis o If HIT positive or enoxaparin failure, recommend switching to bivalirudin

 

This guideline/pathway is not intended to be a substitute for clinical judgement. The risk of bleeding must be weighed against the risk of thrombosis and its consequences.

Anticoagulation in Pregnant Patients: Antenatal and Postpartum

Management of anticoagulation therapy during labor and delivery requires specialized care and planning and should be managed similarly in pregnant patients with COVID-19 as other conditions that require anticoagulation in pregnancy.

  Prophylactic anticoagulation o

  Therapeutic anticoagulation

o For a high risk critically ill pregnant patient less than 22 weeks gestation or post-partum, enoxaparin should be considered

 

All low risk pregnant women with suspected or confirmed COVID-19 infection should receive prophylactic unfractionated

 

heparin upon admission to reduce risk of

venous thromboembolism

Trimester

Dosing of Heparin

Concern for HIT

1st

5000-7500 units SUBQ Q12H

Consult Hematology

  

2nd

7500-10000 units SUBQ Q12H

3rd

10000 units SUBQ Q12H

Gestational age

Kidney Function

BMI (kg/m2)

Dosing of Enoxaparin

Concern for HIT or LMWH Failure

Less than 22 weeks

CrCL ≥ 30 mL/min

12-49.9

1 mg/kg SUBQ Q12H
**monitor peak anti-Xa level with 3rd dose

 Consult pharmacist to assist with obtaining anti-Xa level and dose adjustment

Consult Hematology

≥ 50

0.8 mg/kg SUBQ Q12H
**monitor peak anti-Xa level with 3rd dose

 Consult pharmacist to assist with obtaining anti-Xa level and dose adjustment

CrCL < 30mL/min

12-49.9

1 mg/kg SUBQ 24H
**monitor peak anti-Xa level with 3rd dose

 Consult pharmacist to assist with obtaining anti-Xa level and dose adjustment

Consult Hematology

≥ 50

0.8mg/kg SUBQ Q24H
**monitor peak anti-Xa level with 3rd dose

 Consult pharmacist to assist with obtaining anti-Xa level and dose adjustment

ESRD or AKI on RRT

0.8 mg/kg SUBQ Q24H (MAX dose 1mg/kg Q24H)
**monitor peak and trough anti-Xa level with 3rd dose

 Consult pharmacist to assist with obtaining anti-Xa level and dose adjustment

Consult Hematology

If minor bleeding prior to obtaining steady state anti-Xa levels

  Decrease dose to 0.5 mg/kg and monitor anti-Xa peak and trough with 1st dose of new regimen

  Consult pharmacist to assist with obtaining anti-Xa levels and dose adjustment

*Contraindications: Platelets < 50 K/uL or fibrinogen < 100 mg/dL or active bleeding

o For a high risk critically ill pregnant patient greater than 22 weeks gestation, unfractionated heparin should be considered due to its short half-life and reversibility

 aPTTs should be monitored according to institutional protocol
 Unfractionated heparin, low molecular weight heparin, and warfarin do not accumulate in breast milk and do not induce an

anticoagulant effect in the newborn; therefore, they can be used in breastfeeding women with or without COVID-19 who require VTE prophylaxis or treatment

o Direct-acting oral anticoagulants are not routinely recommended due to lack of safety data
o Direct thrombin inhibitors should be used as a last line option with an assessment of benefit versus risk in patients who

require anticoagulation and are unable to receive heparin products (e.g., heparin-induced thrombocytopenia) due to limited data available

Thisguideline/pathwayisnotintendedtobeasubstituteforclinicaljudgement. Theriskofbleedingmustbeweighedagainsttheriskofthrombosisanditsconsequences.

Bivalirudin: therapeutic anticoagulation

Due to the liver injury that may be seen in patients with COVID-19, bivalirudin is the preferred direct thrombin inhibitor for the treatment of HIT, enoxaparin failure, or patients receiving extracorporeal membrane oxygenation (ECMO).

IHD – intermittent hemodialysis, CRRT – continuous renal replacement therapy Dose adjustments:

* If aPTT >3x baseline, consider holding infusion for 1 hour and re-starting at 50% lower rate

 Monitoring:
o aPTT q 4 hours following initiation of infusion and following dosing adjustment – target aPTT 50-80 o If 2 consecutive aPTTs are at goal, check aPTT q 24 hours
o CBC as appropriate based upon clinical status of patient

Bivalirudin for renal replacement therapy

 CVVH: no loading dose, bivalirudin 2 mg/hour one hour prior to RRT until completion o If doses of 2 mg/hour are ineffective, increase bivalirudin dose by 20%

Transition from therapeutic enoxaparin to an oral anticoagulant

 Prior to discharge:
o All high-risk patients previously on therapeutic anticoagulation without a confirmed VTE may transition to a DOAC at

prophylactic doses
 Rivaroxaban 10 mg daily (for patients with a CrCl > 30 ml/min) OR apixaban 2.5 mg bid x 4 weeks

  In patients who do not have insurance coverage for a DOAC or in whom a DOAC may be contraindicated, prophylactic doses of enoxaparin may be used for the time frame listed above

  Warfarin may be considered in patients who have confirmed HIT

o All high-risk patients on therapeutic anticoagulation for a confirmed VTE may transition to a DOAC at treatment doses

 Rivaroxaban 15 mg bid x 21 days followed by 20 mg daily thereafter OR apixaban 10 mg bid x 7 days followed by 5 mg bid thereafter

  In patients who do not have insurance coverage for a DOAC or in whom a DOAC may be contraindicated, treatment doses of enoxaparin may be continued for the time frame listed above

  Warfarin may be considered in patients who have confirmed HIT

CrCl (ml/min)

Bivalirudin Initial dose (mg/kg/hour)

> 60

0.15 +/- 0.1

30-60

0.08 +/- 0.04

< 30

0.05 +/- 0.02

IHD (25% clearance by HD filters) or CRRT

0.07 +/- 0.03

aPTT (seconds)

Dose adjustment

Monitoring recommendations

<50

Increase infusion rate by 20%

Re-check aPTT 4 hours after rate change

50-80

No change

Re-check aPTT at 4 hours; if 2 consecutive aPTTs are at goal, check aPTT q 24 hours

>80*

Decrease infusion rate by 20%

Re-check aPTT 4 hours after rate change

  

All patients initiating enoxaparin should have a baseline and q48h fibrinogen, D-dimer, aPTT and PT/INR.

Determine COVID risk status

  

Low risk:*

  Not receiving mechanical ventilation

  D-dimer < 6 mg/L

  ESRD on iHD without clotting

High risk:○

  Receiving mechanical ventilation AND D-dimer > 6 mg/L

  Acute kidney injury (Scr increase 0.3 mg/dL above baseline) +/- CVVHD/AVVHD/SLED or IHD with clotting

     

Recommend Prophylactic Dose Enoxaparin□

Recommend Therapeutic Dose Enoxaparin■

  

 

BMI 18.5**– 39.9 kg/m2
CrCl > 30 ml/min: Enoxaparin 30 mg SUBQ q 12 hours

CrCl < 30 ml/min: Enoxaparin 30 mg SUBQ q 24 hours

BMI > 40 kg/m2

CrCl > 30 ml/min: Enoxaparin 40 mg SUBQ q 12 hours

CrCl < 30 ml/min: Enoxaparin 40 mg SUBQ q 24 hours

  

 

ESRD/AKI on RRT◊ Enoxaparin 0.8 mg/kg SUBQ q 24 hours

If minor bleeding, decrease enoxaparin dose to 0.5 mg/kg

If concern for HIT, switch to bivalirudin infusion^

Concern for HIT, LMWH failure, or patients receiving ECMO Recommend bivalirudin infusion^

      

  

Concern for HIT/ LMWH failure Consult hematology

BMI 12– 49.9 kg/m2

CrCl > 30 ml/min: Enoxaparin 1 mg/kg SUBQ q 12 hours

CrCl < 30 ml/min: Enoxaparin 1 mg/kg SUBQ 24 hours

BMI > 50 kg/m2◊

CrCl > 30 ml/min: Enoxaparin 0.8 mg/kg SUBQ q 12 hours

CrCl < 30 ml/min Enoxaparin 0.8 mg/kg SUBQ q 24 hours

   

BMI > 50 kg/m2

CrCl > 30 ml/min: Enoxaparin 60 mg SUBQ q 12 hours

CrCl < 30 ml/min or ESRD on iHD Enoxaparin 40 mg SUBQ q 24 hours

  

If receiving RRT and concern for circuit clot on prophylactic enoxaparin: Recommend additional Enoxaparin 30 mg IVP ONCE prior to or within one hour of initiating dialysis

 

If receiving RRT and concern for circuit clot on therapeutic enoxaparin: Recommend additional Enoxaparin 30 mg IVP ONCE prior to or within one hour of initiating dialysis

Anti-Xa goals (when indicated)◊

Therapeutic peak LMWH level (drawn 4 hours after the 3rd dose): 0.6-1 anti-Xa units/mL

Treatment trough LMWH level (drawn one hour prior to 3rd dose): < 0.5 anti-Xa units/mL

□Patients should not receive prophylactic dose enoxaparin if fibrinogen < 50 mg/dL, platelets < 25,000 K/uL, or active bleeding.
■ Patients should not receive therapeutic dose enoxaparin if fibrinogen < 100 mg/dL, platelets < 50,000 K/uL, or active bleeding.
*If patients transition from low-risk to high risk based upon criteria or develop a VTE on prophylaxis, full-dose anticoagulation is warranted

**If BMI < 18.5 kg/m2 or weight < 50 kg, recommend Heparin SQ 2500 units q 8 hours
◊If BMI > 50 kg/m2 or AKI/ESRD, recommend anti-Xa monitoring (consult pharmacy for assistance)
^Bivalirudin is preferred to argatroban given likelihood of elevated transaminases (e.g., secondary to medications, ischemia, among other causes) in the COVID patient
○Upon discharge, apixaban 2.5 mg bid x 4-6 weeks should be continued in patients without a confirmed VTE and normal renal function and 2 weeks for patients with AKI/ESRD. Warfarin may be considered in cases

of confirmed HIT. Patients with a confirmed VTE should be discharged on therapeutic anticoagulation.

References

1. Rush Anticoagulation Guidelines. Rush University Medical Center. May 2019

2. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low molecular weight heparin
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3. Tang N, Bai H, Chen X, Gong, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019
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4. Chen J, Wang X, Zhang S, Liu B, et al. Findings of acute pulmonary embolism in COVID-19 patients. Lancet Infect Dis 2020;
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5. Chan KE, Thadhani RI, Maddux FW. No difference in bleeding risk between subcutaneous enoxaparin and heparin for thromboprophylaxis
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6. Pon TK, Dager WE, Roberts AJ, White RH. Subcutaneous enoxaparin for therapeutic anticoagulation in hemodialysis patients. Thrombosis
Research 2014; 133: 1023-1028.

7. Davenport A. Review article: Low-molecular weight heparin as an alternative anticoagulant to unfractionated heparin for routine
haemodialysis treatments. Nephrology 2009; 14: 455-461.

8. Lim W, Cook DJ, Crowther MA. Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal
failure: A meta-analysis of randomized trials. J Am Soc Nephrology 2004; 15: 3192-3206.

9. Satissi D, Morgan C, Westhuyzen J, Healy H. Comparison of low molecular weight heparin (enoxaparin sodium) and standard
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10. Joannidis M, Kountchev J, Rauchenzauner M, Scheusterschitz N, et al. Enoxaparin vs. unfractionated heparin for anticoagulation during
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11. Batt TJ, Lincz LF, Prasad R, Patel RP, et al. Plasma levels of enoxaparin oligosaccharides, antifactor Xa and thrombin generation in
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12. Kiser TH, Fish DN. Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or
renal dysfunction. Pharmacotherapy 2006; 26:452·60.

13. KiserTH, Burchl C, Klem PM, Hassell KL. Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced
thrombocytopenia. Pharmacotherapy 2008; 28: 1115-24.

14. Kiser TH, MacLaren R, Fish DN, et al. Bivalirudin versus Unfractionated Heparin for Prevention of Hemofilter Occlusion During
Continuous Renal Replacement Therapy. Pharmacotherapy 2010; 30(11):1117–1126.

15. Mueller SW, MacLaren R, Fish DN. Prefilter Bivalirudin for Preventing Hemofilter Occlusion in Continuous Renal Replacement Therapy.

Ann Pharmacother 2009; 43:1360-5. 16.

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Royal College of Obstetricians and Gynaecologists (RCOG) and The Royal College of Midwives. Coronavirus (COVID-19)

Infection in Pregnancy. RCOG 2020 May 13

COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.

Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed May 19, 2020.

18. Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2018; 2(22):3317-3359. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30482767.

19. ACOG Practice Bulletin No. 196 summary: thromboembolism in pregnancy. Obstet Gynecol. 2018; 132(1): 243-248. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29939933.

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