Anticoagulation Guidance for Patients with COVID-19

Thrombosis Mitigation Strategy for ICU Patients with COVID Infection

Therapeutically anti-coagulate patients with known indications
Consider therapeutic anticoagulation when there is a high clinical suspicion for an acute VTE event
PE in patients with acute pulmonary decompensation
Obtain venous dopplers in the absence of the ability to R/O pulmonary emboli
Provide aggressive dosing for VTE prophylaxis based on BMI and renal function
LMWH (enoxaparin) is the primary agent except ESRD and very low BMI
Utilize a validated bleeding risk assessment tool to assess risk:benefit ratio
Utilize mechanical prophylaxis* in addition to LMWH/UFH or alone if active bleeding/extremely high risk
Post-ICU treatment strategy depends on individual patient thrombotic and bleeding risk

Background and Rationale

COVID-19 induced coagulopathy (CIC), the clinical and pathologic hypercoaguable state evident in patients with SARS-
CoV-2 infection, has led practitioners to consider institution of therapeutic anticoagulation as standard practice for the
most severely ill patients. Laboratory findings consistent with an immunothrombotic state has raised concerns that the
coagulopathy is a significant driver of COVID-19 pathophysiology, particularly since increased mortality is associated with
the presence of elevated pro-inflammatory markers, especially D-dimer. Contributory to the pro-thrombotic situation
include binding of the virus to the angiotensin 2 receptor as well as the elevated thrombotic risk associated with critical
illness. Emerging data report an increased incidence of clotting abnormalities, with one series demonstrating
thromboembolism in 58% of ICU patients after 21 days.
The optimal intensity of anticoagulation for management of CIC is unknown. In the absence of controlled trials
observational data informs our body of knowledge. An early report from a retrospective case series reported a mortality
benefit in patients with sepsis-induced coagulopathy receiving VTE prophylaxis (primarily LMWH) compared with no
prophylaxis. A subsequent retrospective study evaluating outcomes in therapeutically anticoagulated mechanically-
ventilated patients demonstrated reduced mortality compared to those who were not. Despite these encouraging results
the inherent risk of confounding with such data requires confirmation of any therapeutic strategy under the conduct of
a randomized controlled trial. Given the quality of the data together with the emerging nature of the coagulopathic state
there remains no definitive evidence to therapeutically anti-coagulate patients with COVID-19 outside of the usual
medical indications or under the conduct of a clinical trial. This conclusion is supported by published guidance from the
International Society of Thrombosis and Haemostasis (ISTH), American College of Cardiology (ACC) and Anticoagulation
Forum (AC Forum).
In the absence of therapeutic anticoagulation it is essential to optimize dosing of prophylactic agents. Critically Ill
patients in general and those with COVID-19 specifically are at the highest risk for the development of VTE. The presence
of coagulopathy, concomitant immobility, utilization of neuromuscular blockade and presence of indwelling intravenous
catheters significantly increase the risk of a venous thromboembolic event. Additionally many patients with COVID-19
possess comorbid conditions that contribute to baseline VTE risk such as obesity and vascular disease. Therefore, the
therapeutic strategy should reflect those utilized in the highest risk subgroups (i.e. spinal cord injury).
Low-molecular weight heparin is the guideline preferred agent for VTE prophylaxis in critically ill patients and is
recommended by the aforementioned groups for COVID-19 infected patients where appropriate for renal function. It is
important to note that in this population LMWH may have reduced subcutaneous absorption and as such proper dosing
is essential to ensure therapeutic efficacy. The highest doses titrated to therapeutic effect (anti-Xa) will provide the best
opportunity to administer the amount required to achieve therapeutic targets. To attain the optimal risk benefit ratio a
validated bleeding risk assessment tool should be utilized to objectify the risk as well as appreciate the potential drivers
of that risk.

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Enoxaparin Dosing / VTE prophylaxis in ICU COVID patients

CrCL > 30 ml/min CrCL < 30 ml/min ESRD

BMI Dose BMI Dose Dose BMI
Below 20 UFH 5000 BID – TID Below 20
20 – 25.9 40 mg Daily 20 – 34.9 30 mg Daily UFH 5000 TID 20 – 34.9
26 – 39.9 30 mg BID
35 – 50 40 mg Daily UFH 7500 TID 35 – 50
40 – 50 40 mg BID
Above 50 60 mg BID Above 50 60 mg Daily UFH 10000 TID# Above 50

Monitoring
Monitor platelet count daily

Titrate prophylactic anticoagulant to a therapeutic response:

Enoxaparin (BMI > 40, CrCl < 30, Fluctuating renal function)
Obtain anti-Xa 4 – 5 hours after 3rd / 4th dose.
Goal 0.2 – 0.4 units/ml
Repeat based on clinical response and renal function.
UFH (BMI > 50)
Obtain mid-point aPTT or anti-Xa after 4th dose.
Goal aPTT 35 – 45 sec or anti-Xa 0.1 – 0.25 units/ml

Assess Bleeding Risk (IMPROVE bleeding risk; increased Risk with score > 7)
Review risk drivers such as actual bleeding / history vs. age/gender/moderate RF before considering less
aggressive prophylaxis strategies (UFH 5000 units BID or mechanical prophylaxis* alone)

Therapeutic Anticoagulation
Unfractionated heparin is the preferred agent for therapeutic anticoagulation in ICU patients due to it’s short
duration of action and the lack of accumulation in renal dysfunction. Therapeutic LMWH (enoxaparin) may
also be considered in patients with stable renal function who are unlikely to require invasive procedures and
who are not at high risk for bleeding.
Monitoring:
Standard heparin protocol or the low-intensity protocol use aPTT to adjust doses.
Anti-Xa# should be utilized to monitor heparin when the aPTT is elevated at baseline.
Goal Range: Full Intensity 0.3 – 0.7 units/ml
Low Intensity 0.3 – 0.5 units/ml (may adjust if significant bleeding risk)
Consult your ICU pharmacist for assistance in utilizing anti-Xas for UFH monitoring
#
In patients on LMWH, fondaparinux or DOACs within the previous 72 hours obtain a baseline
anti-Xa to evaluate for residual effect. If detectable, use of the anti-Xa to titrate the UFH must be
delayed.

*Mechanical Prophylaxis = Intermittent Pneumatic Compression Device

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Post ICU Considerations
Once a patient is transferred out of the ICU it is unclear if a high thrombotic risk persists. Each patient must
be considered individually with regard to risk of both thrombosis as well as bleeding.
Consult an anticoagulation management service pharmacist for assistance in selecting post-ICU and post
discharge treatment plans.
Continuation of VTE prophylaxis with maximum (ICU) doses:
 If ICU doses are tolerated from a bleeding standpoint and risk remains high (weakness or immobility,
elevated inflammatory markers, BMI > 40) it is reasonable to continue maximum doses.
o Assumes stable renal function as significant change will alter the dose and bleeding risk
 In the absence of above it is reasonable to de-escalate to standard dosing
Continuation of therapeutic anticoagulation
 In patients with a proven thrombus the standard treatment recommendations for a provoked VTE
would apply (3 months)
 In the absence of a proven thrombosis (i.e., initiated in the ICU because of high clinical suspicion
without objective evidence of a thrombus) continuation of therapeutic anticoagulation should be
carefully considered. Objective information utilized to initiate anticoagulation such as abrupt change
in respiratory status vs. lack of clinical improvement are relevant.
 Utilization of a risk assessment tools for bleeding may be useful to guide therapy. (see below)

Post Discharge VTE Prophylaxis

Previous trials conducted in the acute medically ill hospitalized population have showed varying degrees of
VTE risk reduction, with benefits in part offset by an increased risk of bleeding. Assessment of individual
bleeding and thrombotic risk is warranted in order to limit prophylaxis to patients with optimized risk-benefit
profiles. To maintain equipoise, the decision to continue thromboprophylaxis post-discharge should be
considered on a case-by-case basis.
COVID + patients who may be reasonable for evaluation include:
 High risk patients identified by the ICU team due to a prolonged stay or significant deconditioning
o Transfer summary / ICU pharmacist communicates risk assessment
 Those with ongoing risk factors at time of discharge
o Significantly reduced mobility, weakness, or history of VTE
 Those with risk factors and persistent significant elevation in d-dimer near time of discharge
o Could consider obtaining repeat d-dimer to assess trend in a high risk patient
 Application of the Modified IMPROVE VTE / IMPROVEDD RAM (see below)
All patients considered must have low bleeding risk. May take into consideration risk factors such as those
outlined in the IMPROVE Bleeding RAM as well as the criteria below.
Exclusionary criteria may include those at high risk of bleeding features derived from previous RCTs:
 Dual antiplatelet therapy use  History of bronchiectasis, pulmonary
 Active gastroduodenal ulcer cavitation, or pulmonary hemorrhage
 Bleeding in the past 3 months  ESRD with CrCl < 15ml/min or on dialysis
 Active cancer  Drug Interactions: Concomitant CYP3A4
and/or P-gp inhibitors (rivaroxaban)
Based on available literature and ease of accessibility, either enoxaparin 40mg SQ daily or rivaroxaban 10mg
PO daily are reasonable agents for extended duration prophylaxis
 Assess patient accessibility prior to discharge, in conjunction with the outpatient pharmacy.
 If prescribed, length of therapy will depend on individual assessment such as perceived duration of
reduced mobility. These agents have been studied up to ~35-45 days post-discharge.

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 VTE Risk Assessment Models

Thrombosis Risk Assessment Model (RAM)

Modified IMPROVE VTE or Score Modified IMPROVE risk score:

IMPROVEDD(w/D-dimer) 4 or higher risk
Previous VTE 3 2 or 3 plus a plasma D-dimer 2x ULN
a
Known thrombophilia 2 Congenital or acquired condition leading to excess risk of thrombosisa
(e.g., factor V Leiden, lupus anticoagulant, factor C or factor S deficiency).
Current lower limb paralysis 2
or paresisb Leg falls to bed by 5 seconds, but has some effort against gravityb
(taken from NIH stroke scale).
History of cancerc 2
d Cancer (excluding nonmelanoma skin cancer) present at any time in the
Complete immobilization >1day 1 past 5 years (cancer must be in remission to meet eligibility criteria).c
ICU/CCU stay 1 Immobilization: confined to bed or chair with or without bathroom
Age >60 1 privileges.d

D-dimer >2x ULN 2

Bleeding Risk Assessment Tools

IMPROVE Bleeding Risk Score Riete Bleeding Score

Use for VTE prophylaxis bleeding risk Use for VTE treatment bleeding risk

Factor Points Factor Points

GFR 30-59 mL/min/m2 1 Recent Major Bleeding 2
Male vs female 1 Creatinine > 1.2 mg/dl 1.5
Age 40-84 y 1.5 Anemia 1.5
Current cancer 2 Cancer 1
Rheumatic disease 2
Clinically Overt PE 1
Central venous catheter 2
Age > 75 yrs 1
ICU/CCU 2.5
GFR < 30 mL/min/m2 2.5
Interpretation: (major bleeding events)
Hepatic failure (INR > 1.5) 2.5
Points Risk
Age > 85 y 3.5
0 Low (0.1%)
Platelet count < 50K 4
Bleeding in 3 months PTA 4 1-4 Intermediate (2.8%)
Active gastroduodenal ulcer 4.5 >4 High (6.2%)

Interpretation:
Bleeding Risk Increased with score > 7

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