VTE Prophylaxis in Critical Care — Part 2: Pharmacologic Prophylaxis
Complete dosing tables for LMWH, UFH, and fondaparinux in ICU patients, renal and obesity dose adjustments, anti-Xa monitoring, key trial evidence (PROTECT, PREVENT, INSPIRATION), and duration of prophylaxis.
Pharmacologic Prophylaxis: Overview
Pharmacologic prophylaxis is the cornerstone of VTE prevention in critically ill patients. The choice of agent, dose, and monitoring strategy must be individualized based on renal function, weight, bleeding risk, platelet count, and clinical context.1 2 3
Agent Selection Summary
| Agent | Standard Prophylaxis Dose | Route | Key Advantages | Key Disadvantages |
|---|---|---|---|---|
| Enoxaparin | 40 mg once daily or 30 mg q12h | Subcutaneous | Predictable pharmacokinetics; once-daily dosing; lower HIT risk | Renal accumulation (CrCl <30); not easily reversible |
| Dalteparin | 5,000 units once daily | Subcutaneous | No dose adjustment needed for CrCl >20 mL/min; once-daily dosing; lower HIT risk | Cost; not fully reversible with protamine |
| UFH | 5,000 units q8h or q12h | Subcutaneous | Short half-life; fully reversible with protamine; no renal dose adjustment | Unpredictable pharmacokinetics; higher HIT risk; requires q8h dosing for optimal efficacy |
| Fondaparinux | 2.5 mg once daily | Subcutaneous | No HIT risk; once-daily dosing | Long half-life (17–21 h); no reversal agent; contraindicated if CrCl <30; not for body weight <50 kg |
Low-Molecular-Weight Heparin (LMWH)
Enoxaparin
Enoxaparin is the most extensively studied LMWH for VTE prophylaxis. Its predictable dose-response relationship and once- or twice-daily dosing make it well suited for ICU use.1 4
Standard Dosing
| Indication | Dose | Frequency | Route | Duration |
|---|---|---|---|---|
| Medical patient prophylaxis | 40 mg | Once daily | SC | Duration of acute illness / ICU stay |
| General surgical prophylaxis | 40 mg | Once daily | SC | Until fully ambulatory or discharge (minimum 7–10 days) |
| High-risk surgical (abdominal/pelvic cancer) | 40 mg | Once daily | SC | Extended: 28 days post-surgery |
| Hip/knee replacement | 30 mg | Every 12 hours | SC | 10–35 days |
| Hip fracture surgery | 40 mg | Once daily | SC | Extended: 28–35 days |
| Trauma | 30 mg | Every 12 hours | SC | Duration of immobility |
Timing of first dose:
- Medical prophylaxis: Initiate at admission or as soon as bleeding risk is acceptable
- Surgical prophylaxis: 40 mg given 2 hours preoperatively OR 30 mg given 12–24 hours postoperatively (depending on surgical bleeding risk)
Renal Dose Adjustments
| Creatinine Clearance (CrCl) | Dose Adjustment | Monitoring |
|---|---|---|
| >30 mL/min | No adjustment: 40 mg daily or 30 mg q12h | Routine anti-Xa monitoring not required |
| 20–30 mL/min | Reduce to 30 mg once daily | Consider anti-Xa monitoring (target 0.2–0.5 IU/mL at 4 h post-dose) |
| <20 mL/min | Avoid enoxaparin; use UFH instead | — |
| Hemodialysis (not on RRT during dosing) | Avoid enoxaparin; use UFH | — |
| CRRT | Limited data; if used, 30 mg daily with anti-Xa monitoring | Target anti-Xa 0.2–0.5 IU/mL |
Important: CrCl should be estimated using the Cockcroft-Gault equation. Serum creatinine may overestimate renal function in the critically ill (low muscle mass, fluid overload). In cases of rapidly changing renal function, anti-Xa monitoring is strongly recommended if LMWH is used.5
Obesity Dose Adjustments
| Body Weight / BMI | Recommended Dose | Evidence / Rationale |
|---|---|---|
| BMI 30–39.9 kg/m² | 40 mg once daily (standard dose acceptable) | Standard dose achieves adequate anti-Xa levels in most patients |
| BMI ≥40 kg/m² or weight >120 kg | 40 mg SC every 12 hours OR 0.5 mg/kg SC once daily | Standard once-daily dosing produces subtherapeutic anti-Xa levels in ~50% of morbidly obese patients |
| BMI ≥50 kg/m² or weight >150 kg | 60 mg SC every 12 hours (consider) | Very limited data; anti-Xa guided dosing strongly recommended |
Anti-Xa targets for prophylaxis in obesity: 0.2–0.5 IU/mL drawn 4 hours after the third or fourth dose.6 7
Dalteparin
Dalteparin is the LMWH studied in the largest ICU-specific randomized trial (PROTECT). Its pharmacokinetic profile makes it somewhat more favorable than enoxaparin in patients with renal impairment.8
Standard Dosing
| Indication | Dose | Frequency | Route |
|---|---|---|---|
| Medical/surgical ICU prophylaxis | 5,000 units | Once daily | SC |
| High-risk surgical (abdominal cancer) | 5,000 units | Once daily | SC (starting evening before surgery) |
| Orthopedic surgery | 5,000 units | Once daily | SC |
Renal Dose Adjustments
| Creatinine Clearance | Dose Adjustment | Notes |
|---|---|---|
| >20 mL/min | No adjustment: 5,000 units daily | Dalteparin accumulates less than enoxaparin in renal impairment |
| <20 mL/min | Consider anti-Xa monitoring if used; alternatively, use UFH | Target prophylactic anti-Xa: 0.2–0.5 IU/mL |
Obesity Considerations
- BMI ≥40 or weight >120 kg: Consider increased dose of 7,500 units SC once daily; anti-Xa monitoring recommended
- Very limited prospective data on weight-based dalteparin prophylaxis in obesity
Unfractionated Heparin (UFH)
UFH remains widely used in ICU settings, particularly in patients with renal impairment or those at high risk for urgent surgical intervention (given its short half-life and full reversibility).1 2
Standard Dosing
| Dosing Regimen | Indication | Notes |
|---|---|---|
| 5,000 units SC every 8 hours | Preferred for most ICU patients; medical and surgical prophylaxis | Q8h dosing provides superior VTE protection compared to q12h |
| 5,000 units SC every 12 hours | Lower-risk patients; those with higher bleeding risk | Less effective than q8h dosing; consider for transitional use |
Key evidence on q8h vs q12h UFH:
- A meta-analysis demonstrated that UFH 5,000 units SC every 8 hours reduces DVT incidence by ~20% compared to every 12 hours dosing, without a significant increase in major bleeding9
- For critically ill patients with multiple VTE risk factors, q8h dosing is strongly preferred
Renal Dose Adjustments
UFH is cleared by the reticuloendothelial system and does not require dose adjustment for renal impairment. This makes it the preferred agent when CrCl is <20 mL/min or when the patient is on intermittent hemodialysis.1
Obesity Considerations for UFH
| Body Weight / BMI | Recommended Dose | Notes |
|---|---|---|
| <100 kg | 5,000 units SC q8h (standard) | — |
| 100–150 kg | 7,500 units SC q8h | Limited prospective data; based on pharmacokinetic modeling |
| >150 kg | 10,000 units SC q8h (consider) | Anti-Xa monitoring recommended; target 0.1–0.4 IU/mL at 4 h post-dose |
Note: Fixed-dose UFH 5,000 units SC q8h produces subtherapeutic anti-Xa levels in a significant proportion of morbidly obese patients. Weight-adjusted dosing should be considered, with anti-Xa monitoring to verify adequate prophylactic levels.6
Fondaparinux
Fondaparinux, a synthetic factor Xa inhibitor, is primarily used as an alternative in patients with a history of or at high risk for heparin-induced thrombocytopenia (HIT), since it does not cross-react with HIT antibodies.10
Dosing
| Indication | Dose | Frequency | Route | Duration |
|---|---|---|---|---|
| VTE prophylaxis (medical) | 2.5 mg | Once daily | SC | Duration of acute illness |
| VTE prophylaxis (surgical) | 2.5 mg | Once daily | SC | First dose 6–8 h postoperatively; continue 5–9 days (up to 32 days for hip fracture) |
| HIT alternative (prophylactic dose) | 2.5 mg | Once daily | SC | Until HIT resolves and transition to warfarin or DOAC |
Contraindications and Precautions
| Contraindication | Rationale |
|---|---|
| CrCl <30 mL/min | Fondaparinux is 100% renally excreted; T½ prolonged to >40 h in severe renal failure |
| Body weight <50 kg | Increased bleeding risk; AUC significantly higher |
| Active major bleeding | — |
| Bacterial endocarditis | — |
| Thrombocytopenia (platelets <100,000/μL) | Increased bleeding risk |
Note: There is no established reversal agent for fondaparinux. Recombinant factor VIIa (rFVIIa) has been used in case reports of life-threatening bleeding, but this is off-label and efficacy is uncertain.10
Key Trial Evidence: LMWH vs UFH and Dose-Intensity
PROTECT Trial: Dalteparin vs UFH in the ICU
The Prophylaxis for Thromboembolism in Critical Care Trial was the largest randomized trial comparing LMWH to UFH specifically in critically ill patients.8
| Feature | Details |
|---|---|
| Design | Multicenter, double-blind, RCT |
| Population | 3,764 medical-surgical ICU patients at 67 centers |
| Intervention | Dalteparin 5,000 units SC daily vs UFH 5,000 units SC q12h |
| Primary outcome | Proximal leg DVT on twice-weekly compression ultrasonography |
| Results — Proximal DVT | Dalteparin 5.1% vs UFH 5.8% (HR 0.92; 95% CI 0.68–1.23; p = 0.57) — no significant difference |
| Results — PE | Dalteparin 1.3% vs UFH 2.3% (HR 0.51; 95% CI 0.30–0.88; p = 0.01) — significant reduction in PE with dalteparin |
| Results — HIT | Dalteparin 0.3% vs UFH 0.6% — trend favoring dalteparin |
| Major bleeding | No significant difference between groups |
| Mortality | No significant difference |
Clinical implications:
- LMWH (dalteparin) and UFH are comparable for DVT prevention in the ICU
- LMWH may offer a reduction in PE events
- LMWH is associated with a trend toward lower HIT incidence
- Major guideline panels recommend LMWH over UFH for most critically ill patients, with the caveat that UFH remains appropriate when LMWH is contraindicated (e.g., severe renal impairment)2 3
Important note regarding UFH dosing in PROTECT: The trial used UFH 5,000 units q12h, not the more efficacious q8h regimen. This has led some experts to argue that the comparison may not reflect the optimal UFH regimen.8
PREVENT Trial: Adjunctive IPC in the ICU
The PREVENT trial evaluated whether adding intermittent pneumatic compression (IPC) to pharmacologic prophylaxis would further reduce VTE in ICU patients.11
| Feature | Details |
|---|---|
| Design | Multicenter, open-label, RCT |
| Population | 2,003 medical-surgical ICU patients at 20 centers in Saudi Arabia |
| Intervention | Pharmacologic prophylaxis + IPC vs pharmacologic prophylaxis alone |
| Primary outcome | Proximal leg DVT on twice-weekly compression ultrasonography |
| Results — Proximal DVT | IPC + pharmacologic 3.9% vs pharmacologic alone 4.2% (HR 0.93; 95% CI 0.60–1.44; p = 0.74) — no significant difference |
| Results — PE | No significant difference |
| Results — Mortality | No significant difference |
Clinical implications:
- Adding IPC to pharmacologic prophylaxis did NOT significantly reduce proximal DVT, PE, or mortality in critically ill patients
- IPC remains recommended as standalone prophylaxis when pharmacologic prophylaxis is contraindicated
- The role of IPC as adjunctive therapy to pharmacologic prophylaxis in the ICU is not supported by this trial11
INSPIRATION Trial: Intermediate-Dose vs Standard-Dose Prophylaxis
The INSPIRATION trial addressed whether intermediate-dose anticoagulation was superior to standard-dose prophylaxis in critically ill patients.12
| Feature | Details |
|---|---|
| Design | Multicenter, open-label, RCT |
| Population | 562 ICU patients with COVID-19 in Iran |
| Intervention | Intermediate-dose enoxaparin (1 mg/kg daily) vs standard-dose (40 mg daily) |
| Primary outcome | Composite of venous or arterial thrombosis, ECMO treatment, or 30-day mortality |
| Results | Intermediate-dose 45.7% vs standard-dose 44.1% (OR 1.07; 95% CI 0.76–1.52; p = 0.69) — no significant difference |
| Major bleeding | Intermediate-dose 2.5% vs standard-dose 1.4% — numerically higher but not statistically significant |
Clinical implications:
- Intermediate-dose prophylaxis did NOT improve outcomes compared to standard-dose prophylaxis in critically ill patients (studied in COVID-19)
- Intermediate-dose prophylaxis carried a numerically higher bleeding risk
- Standard-dose prophylaxis remains the recommended approach for critically ill patients12
Additional Dose-Intensity Evidence
| Trial | Population | Comparison | Primary Outcome | Result |
|---|---|---|---|---|
| REMAP-CAP / ACTIV-4a / ATTACC (ICU stratum) | Critically ill COVID-19 | Therapeutic-dose vs standard-dose prophylaxis | Organ support-free days | Therapeutic dose did NOT improve outcomes in critically ill; increased bleeding13 |
| REMAP-CAP / ACTIV-4a / ATTACC (non-ICU stratum) | Moderately ill COVID-19 (hospitalized, non-ICU) | Therapeutic-dose vs standard-dose | Organ support-free days | Therapeutic dose IMPROVED outcomes in moderately ill, non-ICU patients14 |
| HEP-COVID | Hospitalized COVID-19 with elevated D-dimer | Therapeutic enoxaparin vs standard prophylaxis | VTE, arterial TE, death | Therapeutic dose reduced composite outcome; most benefit in non-ICU patients15 |
Summary of dose-intensity evidence:
- Standard-dose prophylaxis is the recommended default for critically ill patients
- Therapeutic-dose anticoagulation does not improve outcomes in the ICU and increases bleeding risk
- Intermediate-dose prophylaxis has not demonstrated superiority over standard-dose
- In moderately ill (non-ICU) hospitalized patients, therapeutic-dose anticoagulation may be beneficial (studied in COVID-19 — generalizability to non-COVID populations uncertain)
Anti-Xa Monitoring
Anti-Xa (anti-factor Xa) levels can be used to monitor the anticoagulant effect of LMWH and UFH, particularly in clinical situations where standard dosing may result in subtherapeutic or supratherapeutic drug levels.5 16
When to Monitor Anti-Xa Levels
| Clinical Scenario | Rationale |
|---|---|
| Renal impairment (CrCl 20–30 mL/min) on LMWH | Risk of drug accumulation |
| Morbid obesity (BMI ≥40 or >120 kg) | Risk of subtherapeutic levels with standard dosing |
| Low body weight (<50 kg) | Risk of supratherapeutic levels |
| Pregnancy | Increased volume of distribution; increased renal clearance |
| CRRT or ECMO | Altered drug clearance |
| Unexpected VTE despite prophylaxis | To verify adequate drug levels |
| Unexpected bleeding on prophylaxis | To rule out supratherapeutic levels |
Target Ranges
| Agent | Purpose | Target Anti-Xa Level | Timing of Draw |
|---|---|---|---|
| Enoxaparin | Prophylaxis | 0.2–0.5 IU/mL | 4 hours after the 3rd or 4th dose |
| Dalteparin | Prophylaxis | 0.2–0.5 IU/mL | 4 hours after the 3rd or 4th dose |
| Enoxaparin | Treatment | 0.5–1.0 IU/mL (q12h dosing) or 1.0–2.0 IU/mL (daily dosing) | 4 hours post-dose |
| UFH (SC prophylaxis) | Prophylaxis | 0.1–0.4 IU/mL | 4 hours post-dose |
| Fondaparinux | Prophylaxis | 0.2–0.5 IU/mL (rarely monitored) | 3 hours post-dose |
Practical Considerations
- Anti-Xa assays must be calibrated to the specific drug being monitored (LMWH calibrators for LMWH; UFH calibrators for UFH)
- Trough levels (immediately before the next dose) can be used to assess accumulation: target <0.1 IU/mL for prophylaxis
- In critically ill patients with fluctuating renal function, anti-Xa monitoring should be repeated with each significant change in creatinine clearance
- Turnaround time for anti-Xa assays (typically 1–4 hours) should be considered when making clinical decisions
Duration of Prophylaxis
During ICU Stay
- Continue pharmacologic prophylaxis throughout the ICU admission as long as VTE risk remains elevated and bleeding risk is acceptable
- Reassess daily for changes in clinical status that affect the benefit-risk ratio
- Do not routinely discontinue prophylaxis during brief procedural interruptions if possible — coordinate with proceduralists to minimize prophylaxis gaps
Post-ICU / Inpatient
- Continue prophylaxis throughout the hospital stay until the patient is fully ambulatory
- Transfer orders should explicitly address VTE prophylaxis continuation
Extended Post-Discharge Prophylaxis
Extended-duration thromboprophylaxis after hospital discharge is recommended in specific high-risk populations:17 18
| Patient Population | Recommended Duration | Agent | Evidence Level |
|---|---|---|---|
| Major abdominal/pelvic cancer surgery | 4 weeks (28 days) post-surgery | Enoxaparin 40 mg SC daily or rivaroxaban 10 mg PO daily | Strong recommendation |
| Hip replacement surgery | 28–35 days post-surgery | Enoxaparin 40 mg SC daily or DOAC | Strong recommendation |
| Knee replacement surgery | 10–14 days post-surgery (up to 35 days) | LMWH or DOAC | Strong recommendation |
| Hip fracture surgery | 28–35 days post-surgery | LMWH or fondaparinux | Strong recommendation |
| Acutely ill medical patients (IMPROVE VTE score ≥4, low bleeding risk) | 31–39 days total (betrixaban or rivaroxaban studied) | Betrixaban 160 mg day 1 then 80 mg daily, or rivaroxaban 10 mg daily | Conditional recommendation |
| Trauma with prolonged immobility | Until ambulatory (minimum 14 days, often 4–6 weeks) | LMWH | Moderate recommendation |
| Spinal cord injury | Minimum 8–12 weeks | LMWH then transition to DOAC or warfarin | Moderate recommendation |
Key trials on extended prophylaxis:
- APEX trial (betrixaban): Demonstrated reduced VTE with extended prophylaxis (35–42 days) vs standard enoxaparin (6–14 days) in acutely ill medical patients with elevated D-dimer17
- MAGELLAN trial (rivaroxaban): Showed reduced VTE but increased bleeding with extended rivaroxaban in medical patients18
- MARINER trial (rivaroxaban): Extended prophylaxis with rivaroxaban 10 mg daily for 45 days post-discharge did not significantly reduce symptomatic VTE vs placebo in acutely ill medical patients, but did reduce VTE-related death19
Contraindications to Pharmacologic Prophylaxis
| Absolute Contraindications | Relative Contraindications (Individualize) |
|---|---|
| Active major hemorrhage | Platelet count 25,000–50,000/μL |
| Heparin-induced thrombocytopenia (for heparin products) | Recent minor bleeding (e.g., minor GI bleed now resolved) |
| Severe uncontrolled hypertension (SBP >230 or DBP >120) | INR >1.5 (without anticoagulant use) |
| Platelet count <25,000/μL | Coagulopathy (aPTT >2× normal) |
| Hypersensitivity to the agent | Planned invasive procedure within 12–24 h |
| Active intracranial hemorrhage | Epidural/spinal catheter in situ (timing restrictions apply) |
| — | Severe hepatic impairment (Child-Pugh C) |
Neuraxial Anesthesia Timing
Safe intervals for LMWH and neuraxial procedures (to minimize epidural hematoma risk):20
| Agent | Hold BEFORE Needle/Catheter Placement | Hold BEFORE Catheter Removal | Resume AFTER Needle/Catheter Placement or Removal |
|---|---|---|---|
| Enoxaparin 40 mg daily | ≥12 hours | ≥12 hours | ≥4 hours after placement/removal |
| Enoxaparin 30 mg q12h | ≥12 hours | ≥12 hours | ≥4 hours after placement/removal |
| UFH 5,000 SC q8-12h | ≥4–6 hours; verify normal aPTT | ≥4–6 hours | ≥1 hour after placement/removal |
| Fondaparinux 2.5 mg daily | ≥36–42 hours | ≥36–42 hours | ≥6–12 hours after placement/removal |
Kahn SR, Lim W, Dunn AS, et al. “Prevention of VTE in Nonsurgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines.” Chest. 2012;141(2 Suppl):e195S-e226S. DOI: 10.1378/chest.11-2296 ↩︎ ↩︎ ↩︎ ↩︎
Gould MK, Garcia DA, Wren SM, et al. “Prevention of VTE in Nonorthopedic Surgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines.” Chest. 2012;141(2 Suppl):e227S-e277S. DOI: 10.1378/chest.11-2297 ↩︎ ↩︎ ↩︎
Schünemann HJ, Cushman M, Burnett AE, et al. “American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.” Blood Adv. 2018;2(22):3198-3225. DOI: 10.1182/bloodadvances.2018022954 ↩︎ ↩︎
Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. “Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings.” Ann Pharmacother. 2009;43(6):1064-1083. DOI: 10.1345/aph.1L194 ↩︎
Garcia DA, Baglin TP, Weitz JI, Samama MM. “Parenteral Anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines.” Chest. 2012;141(2 Suppl):e24S-e43S. DOI: 10.1378/chest.11-2291 ↩︎ ↩︎
Borkgren-Okonek MJ, Hart RW, Pantano JE, et al. “Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and antifactor Xa activity.” Surg Obes Relat Dis. 2008;4(5):625-631. DOI: 10.1016/j.soard.2007.11.010 ↩︎ ↩︎
Freeman AL, Pendleton RC, Rondina MT. “Prevention of venous thromboembolism in obesity.” Expert Rev Cardiovasc Ther. 2010;8(12):1711-1721. DOI: 10.1586/erc.10.160 ↩︎
Cook DJ, Meade MO, Guyatt G, et al. “Dalteparin versus Unfractionated Heparin in Critically Ill Patients (PROTECT).” N Engl J Med. 2011;364(14):1305-1314. DOI: 10.1056/NEJMoa1014475 ↩︎ ↩︎ ↩︎
King CS, Holley AB, Jackson JL, et al. “Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a metaanalysis.” Chest. 2007;131(2):507-516. DOI: 10.1378/chest.06-1861 ↩︎
Warkentin TE, Pai M, Linkins LA. “Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review.” Blood. 2017;130(9):1104-1113. DOI: 10.1182/blood-2017-04-778993 ↩︎ ↩︎
Arabi YM, Al-Hameed F, Burns KEA, et al. “Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis (PREVENT).” N Engl J Med. 2019;380(14):1305-1315. DOI: 10.1056/NEJMoa1816150 ↩︎ ↩︎
Sadeghipour P, Talasaz AH, Rashidi F, et al. “Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.” JAMA. 2021;325(16):1620-1630. DOI: 10.1001/jama.2021.4152 ↩︎ ↩︎
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ATTACC, ACTIV-4a, and REMAP-CAP Investigators. “Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.” N Engl J Med. 2021;385(9):790-802. DOI: 10.1056/NEJMoa2105911 ↩︎
Spyropoulos AC, Goldin M, Giannis D, et al. “Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial.” JAMA Intern Med. 2021;181(12):1612-1620. DOI: 10.1001/jamainternmed.2021.6203 ↩︎
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