Hematology and Oncology Book


Anticoagulation in Thromboembolism

Aka: Anticoagulation in Thromboembolism, Pulmonary Embolism Anticoagulation, Deep Vein Thrombosis Anticoagulation, PE Anticoagulation, DVT Anticoagulation, VTE Anticoagulation, Anticoagulation in Venous Thromboembolism
  1. See Also
    1. Anticoagulation
    2. Deep Vein Thrombosis
    3. Pulmonary Embolism
    4. Superficial Thrombophlebitis
    5. Major Bleeding Risk With Anticoagulants
  2. Disposition
    1. Pulmonary Embolism
      1. Inpatient (typical) or if criteria met, outpatient Anticoagulation
      2. Consider Pulmonary Embolism Severity Index (PESI) to quantitate risk
    2. Deep Vein Thrombosis
      1. Inpatient or outpatient management depending on risk
      2. See Deep Vein Thrombosis
  3. 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
  4. 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
  5. 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
  6. Preparations: Initial Phase - Single agents 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
  7. 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
  8. 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
  9. 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 to 2.5 mg twice daily
          2. Xarelto (Rivaroxaban) 20 mg daily 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)
  10. Management: Recurrent VTE on Warfarin or DOAC
    1. Indications
      1. Recurrence despite therapeutic on Anticoagulation for at least 2 weeks
    2. Evaluate for compliance
      1. Has been consistently therapeutic
      2. Have agents been taken consistently and correctly (e.g. Rivaroxaban needs to be taken with food)
    3. Evaluate for underlying cause of strong Thrombophilia
      1. Cancer
      2. Antiphospholipid Antibody Syndrome
    4. Evaluate for Warfarin resistance
      1. Factor X activity and Factor II >40% of normal and
      2. Warfarin level
    5. 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) or
      3. Change to LMWH (e.g. Lovenox) for 3-6 months
        1. Consider re-trialing Warfarin after stable period on LMWH
        2. If VTE recurrs despite LMWH, then increase LMWH dose by 25-33%
      4. Avoid IVC Filter unless Anticoagulation is contraindicated in the face of a large PE or proximal DVT
    6. References
      1. Osinbowale (2009) Cleve Clin J Med 76(12): 724-30 [PubMed]
  11. Management: Risk Stratification in Idiopathic first DVT
    1. 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]
    2. 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]
    3. Consider Aspirin
      1. Indications: Unprovoked VTE (idiopathic) who are not continuing Anticoagulation after initial VTE management
      2. Dose: Aspirin 81 mg orally daily
      3. Brighton (2012) N Engl J Med 367:1979-87 [PubMed]
  12. Prevention
    1. See Deep Vein Thrombosis Prevention
    2. Unprovoked DVT or PE in patients who choose to discontinue Anticoagulation after initial therapy
      1. Consider Aspirin if patient does not wish to continue longterm Anticoagulation (see above)
  13. References
    1. (2014) Presc Lett 21(11): 61
    2. DeLoughery and Orman in Majoewsky (2012) EM:Rap 12(12): 4-5
    3. Hyers (2001) Chest 119:176S-93S [PubMed]
    4. Galioto (2011) Am Fam Physician 83(3): 293-300 [PubMed]
    5. Wigle (2019) Am Fam Physician 100(7): 426-34 [PubMed]
    6. Wilbur (2017) Am Fam Physician 95(5): 295-302 [PubMed]

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