Anticoagulation in Thromboembolism

Aka: Anticoagulation in Thromboembolism, Pulmonary Embolism Anticoagulation, Deep Vein Thrombosis Anticoagulation, PE Anticoagulation, DVT Anticoagulation, VTE Anticoagulation, Anticoagulation in Venous Thromboembolism, Breakthrough VTE, Breakthrough Venous Thromboembolism

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II. Indications

  1. Pulmonary Embolism
  2. Deep Vein Thrombosis (DVT)
    1. deepVeins.jpg
    2. Upper Extremity Deep Vein Thrombosis
      1. Brachiocephalic Vein
      2. Internal Jugular Vein
      3. Subclavian Vein
      4. Axillary Vein
      5. Basilic Vein (proximal aspect)
      6. Brachial Vein
      7. Ulnar Vein
      8. Radial Vein
    3. Lower Extremity Deep Vein Thrombosis
      1. Common Iliac Vein
      2. Internal Iliac Vein
      3. External Iliac Vein
      4. Deep Femoral Vein
      5. Femoral Vein ("Superficial" Femoral Vein)
      6. Popliteal Vein
      7. Gastrocnemius Vein (branch of popliteal vein)
      8. Anterior Tibial Vein
      9. Peroneal Vein
      10. Posterior Tibial Vein
      11. Soleus Vein (branch of Posterior Tibial Vein)
  3. Superficial Venous Thrombosis
    1. Proximal superficial clot (upper thigh) especially within 5 cm of deep system or
    2. Clot >7 cm long in leg (or 5 cm long in arm) or
    3. Known clotting disorder or
    4. Lack of improvement after 1 week

III. Management: CHEST Guidelines

  1. DVT (without PE) Guidelines 2021
    1. Distal lower extremity DVT (calf DVT below the popliteal vein)
      1. Perform serial Ultrasound without Anticoagulation
      2. Indications to start Anticoagulation
        1. DVT extension into proximal leg veins
        2. Distal DVT progression on serial Ultrasound
    2. Proximal DVT
      1. Initiate Anticoagulation
    3. Antiphospholipid Antibody Syndrome
      1. Treat with Vitamin K Antagonist (Warfarin) instead of DOAC
    4. Pregnancy
      1. Treat with Low Molecular Weight Heparin
    5. Active Cancer
      1. Treat with Low Molecular Weight Heparin
    6. References
      1. Stevens (2021) Chest 160(6): e545-608 [PubMed]

IV. Management: Disposition

  1. Pulmonary Embolism
    1. See Pulmonary Embolism
    2. Inpatient (typical) or if criteria met, outpatient Anticoagulation
    3. Consider Pulmonary Embolism Severity Index (PESI) to quantitate risk
  2. Deep Vein Thrombosis
    1. See Deep Vein Thrombosis
    2. Outpatient management in most cases

V. Labs

  1. Initial labs
    1. Complete Blood Count
      1. Polycythemia, Thrombocytosis,associated with Splenomegaly (myeloproliferative disorder)
    2. ProTime (INR)
    3. Partial Thromboplastin Time (PTT)
      1. Increased PTT without correction by 1:1 dilution with normal plasma
        1. Seen with Lupus Anticoagulant syndrome
    4. Comprehensive metabolic panel (Liver Function Tests and Renal Function tests)
      1. Anticoagulant doses may require adjustment
  2. Thrombophilia work-up in idiopathic or recurrent DVT
    1. See Thrombophilia
    2. Test only if results will direct therapy (especially duration of Anticoagulation)
    3. Reserve blood for tests prior to Anticoagulation
  3. Other testing to consider
    1. Urinalysis
      1. Proteinuria (e.g. Nephrotic Syndrome)
      2. Hematuria (e.g. cancer)
    2. Chest XRay
      1. Consider at time of initial diagnosis if chest CT was not done
      2. May indicate underlying malignancy

VI. Preparations: Initial Phase - Unstable Protocol with Unfractionated Heparin

  1. Unfractionated Heparin (weight based Heparin)
    1. Goal: PTT 1.5-2.5x normal
    2. Allows for invasive management in case of decompensation
    3. Preferred in submassive PE
    4. In high risk patients, consider initiating Heparin while awaiting definitive imaging

VII. Preparations: Initial Phase - Concomitant Protocol With Heparin

  1. Indications for concurrent Heparin Use (agents other than Rivaroxaban or Apixiban)
    1. Warfarin
    2. Dabigatran (Pradaxa)
    3. Edoxaban (Savaysa)
  2. Standard Heparin
    1. See Weight based Heparin nomogram for dosing
    2. Indications
      1. Severe Renal Insufficiency
      2. High risk of bleeding
      3. Hemodynamic instability
      4. Morbid Obesity
  3. Low Molecular Weight Heparin (LMWH)
    1. See Low Molecular Weight Heparin for dosing
    2. Efficacy
      1. Equivalent to standard Heparin in non-massive PE
        1. Quinlan (2004) Ann Intern Med 140:175-83 [PubMed]
        2. Mismetti (2005) Chest 128: 2203-10 [PubMed]
    3. Enoxaparin (Lovenox) 1 mg/kg twice daily
      1. Avoid single dose of 1.5 mg/kg daily (not recommended due to lower efficacy)
    4. Tinzaparin (Innohep) 175 anti-Xa IU per kg daily
      1. Dose (ml): (weight in kg) x 0.00875 ml/kg daily

VIII. Preparations: Initial Phase - Single agent DOACs that do not require concurrent Heparin

  1. See Warfarin alternatives in section below
  2. Rivaroxaban (Xarelto) was FDA approved for acute DVT management in Nov 2012
    1. As effective and safe as LMWH (see Xarelto for references)
    2. Initial: 15 mg orally twice daily for 21 days
    3. Maintenance: 20 mg orally daily
    4. Prevention of recurrence: 20 mg orally daily
  3. Apixaban (Eliquis)
    1. Initial: 10 mg orally twice daily for 7 days
    2. Maintenance: 5 mg orally twice daily
    3. Prevention of recurrence: 2.5 mg orally twice daily

IX. Management: Warfarin Initiation

  1. See Warfarin alternatives below (Rivaroxaban, Apixiban, Dabigatran)
  2. Start Warfarin (Coumadin) concurrent with LMWH
    1. May start concurrently with LMWH (as opposed to starting on day 1-2 as with older protocols)
    2. Delay in past has been due to initial prothrombotic effect of Warfarin
      1. However LMWH appears to counter this effect even early in course
  3. Warfarin and DOACs are contraindicated in pregnancy, severe liver disease, Breakthrough VTE, some cancers
    1. See DVT in Pregnancy
    2. Continue Low Molecular Weight Heparin in these cases
  4. Initial Warfarin Dosing
    1. See Warfarin for further dosing information
    2. Age <65 years: Start 10 mg daily
      1. Dose of 10 mg start was therapeutic 1.4 days earlier
      2. Kovacs (2003) Ann Intern Med 138:714-9 [PubMed]
    3. Age >65 years: Start 5 mg daily
    4. Age >75 years: Start 2.5 mg daily
  5. Check INR starting in 3 days
  6. Therapeutic INR: 2.0 to 3.0 IU
    1. Continue Heparin for a minimum of 5 days AND until INR is therapeutic

X. Management: Warfarin alternatives (Direct Oral Anticoagulants or DOACs)

  1. Precautions
    1. Avoid in pregnancy and Lactation (not studied, effects are unknown)
    2. See DVT in Pregnancy
    3. Avoid if poor adherence (DOAC levels fall subtheraputic even after a single missed dose)
    4. Avoid in those with Mechanical Heart Valves
    5. Rivaroxaban (Xarelto) and Apixiban (Eliquis) are being used for DVT in cancer as of 2020
      1. Avoid if GFR <30 (use Warfarin instead) or if high risk of bleeding (e.g. gastrointestinal cancer)
      2. Previously only Low Molecular Weight Heparin (LMWH) and Warfarin were used in cancer
      3. (2020) Presc Lett 27(6): 32-3
      4. Streiff (2018) J NatlCompr Canc Netw 16(11): 1289-303 [PubMed]
    6. Avoid in significant Renal Insufficiency (e.g. GFR <30 ml/min), esp. in underweight or over age 75 years old
      1. See specific agents for allowable GFR
  2. Indications (FDA approved as of 2012)
    1. VTE Prophylaxis
    2. DVT acute management (in place of LMWH) - see above
    3. DVT Anticoagulation
    4. PE Anticoagulation (not yet mainstream usage in PE)
      1. No adverse events when 106 low risk PE patients discharged on Rivaroxaban
        1. Hestia Criteria negative
        2. Beam (2015) Acad Emerg Med 22(7): 788-95 [PubMed]
  3. Preparations: No Heparin pretreatment needed (see above)
    1. Rivaroxaban (Xarelto)
      1. Oral Factor Xa Inhibitor that was FDA approved for acute DVT management in Nov 2012
      2. Rivaroxaban was found as effective and safe as LMWH (see Xarelto for references)
      3. See dosing above
    2. Apixiban (Eliquis)
      1. See dosing above
  4. Preparations: Requires concurrent Heparin for first 5-10 days
    1. Edoxaban (Savaysa)
      1. Dosing: 60 mg orally daily (adults >60 kg)
    2. Dabigatran (Pradaxa)
      1. Initial
        1. Dabigatran (Pradaxa) 150 mg orally twice daily AND
        2. Low Molecular Weight Heparin (LMWH) or standard Heparin for 5-10 days while starting Pradaxa
      2. Maintenance: 150 mg orally twice daily
      3. Prevention of Recurrence: 150 mg orally twice daily

XI. Management: Duration of Anticoagulation

  1. Anticoagulation duration has undergone significant changes since 2010
    1. Prior 6-12 month Anticoagulation courses have dropped to 3 month recommendations in most cases
    2. Most difficult decision is determining who needs longterm therapy to prevent recurrence
      1. Those with transient causes (e.g. surgery, Trauma) are at low risk
      2. Thorough history and exam is paramount in determining if Thrombophilia risk exists
        1. Focus on idiopathic cases
        2. Test only those where history and exam indicates
      3. D-Dimer protocol below may assist in risk stratifying idiopathic VTE and risk of recurrence
  2. Very low risk: 6-12 weeks
    1. Symptomatic isolated calf vein thrombosis
  3. Low risk patient: 3 months
    1. Reversible Venous Thromboembolism Risk (transient risk such as post-operative event) or
    2. Upper extremity Deep Vein Thrombosis
  4. Low to Moderate risk patient: At least 3 months (and consider for life-long Anticoagulation)
    1. First idiopathic distal DVT
    2. First idiopathic Pulmonary Embolism
  5. Moderate to high risk patient: Longterm therapy
    1. See Recurrent Thromboembolism Risks
    2. Indications
      1. First idiopathic proximal DVT or PE
      2. Recurrent idiopathic DVT or PE
      3. Thrombophilia
    3. Protocol for reduced DOAC dosing in moderate risk patients on longterm Anticoagulation
      1. Consider switching to lower dose DOAC after 6 months of standard therapy
        1. Continue Warfarin at standard dose for Prosthetic Heart Valves or severe Renal Insufficiency
      2. Example doses:
        1. Eliquis (Apixaban) 5 mg twice daily decreased to 2.5 mg twice daily
        2. Xarelto (Rivaroxaban) 20 mg daily decreased to 10 mg daily
        3. Do not low dose of Dabigatran or Edoxaban (insufficient evidence)
      3. References
        1. (2017) Presc Lett 24(6): 31
  6. High risk patient: Low Molecular Weight Heparin or LMWH (e.g. Lovenox)
    1. Active cancer (continue therapy while cancer active or receiving cancer therapy)
      1. As of 2020, Apixaban and Rivaroxaban are being used for DVT in active cancer (see above)

XII. Management: Recurrent VTE on Warfarin or DOAC (Breakthrough VTE)

  1. Epidemiology
    1. Breakthrough VTE occurs in 2-3% of VTE cases over a 6 month period
  2. Definition of Breakthrough VTE
    1. Recurrence despite therapeutic on Anticoagulation for at least 2 weeks
    2. Pulmonary Embolism is an increased risk in the first 2 weeks after DVT diagnosis and Anticoagulation start
    3. DVT extension occurs in the first 2 weeks in up to 30% of patients despite Anticoagulation
  3. Evaluate for compliance
    1. Has patient been consistently therapeutic?
    2. Have agents been taken consistently and correctly (e.g. Rivaroxaban needs to be taken with food)?
  4. Consider other causes of symptoms
    1. Post-DVT swelling and pain
      1. Post-Thrombotic Syndrome
      2. Differentiate acute new or progressive Deep Vein Thrombosis (DVT) from chronic, residual DVT
    2. Post-PE Shortness of Breath, Chest Pain and reduced Exercise tolerance
      1. Post-Pulmonary Embolism Syndrome (50% of patients at 6 months)
      2. Evaluate for timing of symptoms (new or old)
      3. Negative D-Dimer makes new Pulmonary Embolism unlikely
  5. Evaluate for underlying cause of strong Thrombophilia
    1. Cancer
    2. Severe Antiphospholipid Antibody Syndrome (or other Vasculitis)
      1. Also consider in patients on DOAC with Breakthrough VTE
  6. Consider Drug Interactions
    1. See Warfarin Drug Interactions
    2. Consider Direct Acting Anticoagulant (DOAC) interactions (CYP3A4, P-Glycoprotein)
  7. Evaluate for Warfarin resistance
    1. Factor X activity and Factor II >40% of normal and
    2. Warfarin level
  8. Consider Heparin Induced Thrombocytopenia
    1. Consider in those on Heparin
  9. Management
    1. Consult hematology
    2. Change to LMWH (e.g. Lovenox) for 3-6 months (preferred strategy)
      1. Consider re-trialing Warfarin after stable period on LMWH
      2. If VTE recurrs despite LMWH, then increase LMWH dose by 25-33%
    3. Other options
      1. Consider switching from DOAC to Warfarin (allowing for monitoring of INR) or
      2. Increase Warfarin dose to target higher INR (e.g. 3 to 3.5)
      3. Avoid IVC Filter unless Anticoagulation is contraindicated in the face of a large PE or proximal DVT
  10. References
    1. DeLoughery in Swadron (2022) EM:Rap 22(5):19-20
    2. Osinbowale (2009) Cleve Clin J Med 76(12): 724-30 [PubMed]

XIII. Management: Risk Stratification in Idiopathic Unprovoked first VTE

  1. Precautions
    1. American Society of Hematology recommends longterm Anticoagulation for unprovoked VTE
      1. Ortel (2020) Blood Adv 4(19): 4693-738 +PMID:33007077 [PubMed]
      2. Mai (2019) Chest 155(6): 1199-216 +PMID:31174635 [PubMed]
    2. Consider HERDOO2 Model for Risk Stratification in women after first unprovoked VTE
      1. https://www.mdcalc.com/herdoo2-rule-discontinuing-anticoagulation-unprovoked-vte
      2. Male gender alone is a risk for recurrent VTE (RR 1.8 in unprovoked VTE)
    3. Balance the risk of recurrent VTE with the risk of serious bleeding on chronic Anticoagulation
      1. See HAS-BLED Score
      2. See Orbit Bleeding Risk Score
  2. D-Dimer after 3 months of Anticoagulation
    1. D-Dimer checked 4 weeks after stopping Anticoagulation
      1. Recurrent DVT is lower risk if D-Dimer is negative (3%/year contrasted with 9-10%/year if positive)
      2. (2006) NEJM 355:1780-9 [PubMed]
      3. Verhovsek (2008) Ann Intern Med 149(7): 481-90 [PubMed]
    2. D-Dimer protocol not recommended by ACCP
      1. Kearon (2016) Chest 149(2): 315-52 [PubMed]
  3. Ultrasound affected extremity at 3 months of Anticoagulation
    1. Recurrent DVT is low risk if residual thrombus <40%
    2. However, other studies suggest that residual venous Occlusion is not a risk for recurrent VTE
    3. (2008) Blood 112:511-5 [PubMed]
    4. Cosmi (2010) Eur J Vasc Endovasc Surg 39(3): 356-65 [PubMed]
  4. Consider Aspirin
    1. Indications: Unprovoked VTE (idiopathic) who are not continuing Anticoagulation after initial VTE management
    2. Efficacy: Number Needed to Treat (NNT) 33 to prevent one event per year
    3. Dose: Aspirin 81 mg orally daily
    4. Brighton (2012) N Engl J Med 367:1979-87 [PubMed]

XIV. Prevention

  1. See Deep Vein Thrombosis Prevention
  2. See DVT Prevention in Travelers
  3. See VTE Prophylaxis in Pregnancy
  4. Aspirin or other Antiplatelet Therapy
    1. Consider in unprovoked DVT or PE in patients who choose to discontinue Anticoagulation after initial therapy (see above)
    2. Suspend Aspirin or other Antiplatelet Therapy in stable cardiovascular disease while on VTE Anticoagulation
      1. Continue Aspirin and other antiplatelet agents only if clear indications (e.g. recent coronary stenting, Claudication)
      2. Otherwise, antiplatelet agents with Anticoagulation add significant bleeding risk without significant benefit
      3. Flumignan (2022) Cochrane Database Syst Rev (7): CD012369 [PubMed]

XV. References

  1. (2014) Presc Lett 21(11): 61
  2. DeLoughery and Orman in Majoewsky (2012) EM:Rap 12(12): 4-5
  3. Jean-Louis and Sethuraman (2023) Crit Dec Emerg Med 37(7): 4-11
  4. Hyers (2001) Chest 119:176S-93S [PubMed]
  5. Galioto (2011) Am Fam Physician 83(3): 293-300 [PubMed]
  6. Wigle (2019) Am Fam Physician 100(7): 426-34 [PubMed]
  7. Wilbur (2017) Am Fam Physician 95(5): 295-302 [PubMed]

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