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Anticoagulation

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Anticoagulation, Anticoagulant

  • See Also
  1. Warfarin (Coumadin)
  2. Aspirin
  3. Unfractionated Heparin
  4. Low Molecular Weight Heparin
  5. Thrombolytic
  6. Factor Xa Inhibitor
  7. Anticoagulation in Thromboembolism
  8. Antiplatelet Therapy for Vascular Disease
  9. Clotting Cascade
  10. Emergent Reversal of Anticoagulation
  • Definitions
  1. Direct Oral Anticoagulants (DOACs) or Non-Vitamin K Antagonist Oral Anticoagulant (NOACs)
    1. Direct Thrombin Inhibitors (e.g. Dabigatran)
    2. Factor Xa Inhibitors (e.g. Rivaroxaban, Apixaban, Edoxaban)
  • Indications
  • Venous Condition Prevention and Treatment
  1. See Anticoagulation in Thromboembolism
  2. See Anticoagulation in Atrial Fibrillation
  3. See Anticoagulation in Surgical Patients
  4. See Valve Replacement and Anticoagulation
  5. Conditions
    1. Deep Vein Thrombosis
    2. Pulmonary Embolism
    3. VTE Prophylaxis
    4. Mechanical Heart Valve Replacement
    5. Left Ventricular Thrombus
    6. Left Ventricular Aneurysm
    7. Atrial Fibrillation
      1. See CHADS2-VASc Score
  6. Medications: Agents affecting Clotting Pathway (PTT or INR)
    1. Warfarin (Coumadin)
    2. Unfractionated Heparin
    3. Low Molecular Weight Heparin
    4. Direct Oral Anticoagulants (DOACs) or Non-Vitamin K Antagonist Oral Anticoagulant (NOACs)
      1. Direct Thrombin Inhibitors (e.g. Dabigatran)
        1. Bind to Thrombin active site, preventing Fibrinogen conversion to Fibrin
      2. Factor Xa Inhibitors (e.g. Rivaroxaban, Apixaban, Edoxaban)
        1. Bind Factor Xa, preventing Thrombin generation
  7. Medications: Acute event in an Unstable Patient or prevention of complications
    1. Thrombolytic (e.g. t-PA, Streptokinase)
  8. Medications: Preventing complications from Venous Thromboembolism
    1. Greenfield Filter
  • Indications
  • Arterial Condition Prevention and Treatment
  1. See Antiplatelet Therapy for Vascular Disease
  2. Conditions
    1. History of Myocardial Infarction, Angina or coronary stenting (PTCA)
    2. History of Cerebrovascular Accident or Transient Ischemic Attack
    3. Peripheral Arterial Disease (e.g. Claudication)
  3. Medications: Agents affecting Platelet aggregation
    1. Aspirin
    2. Dipyridamole (Persantine) alone or in combination with Aspirin (Aggrenox)
    3. Thienopyridines
      1. Clopidogrel (Plavix)
      2. Ticagrelor (Brilinta)
      3. Prasugrel (Effient)
  4. Medications: Acute, unstable arterial event
    1. Thrombolytic (e.g. t-PA, Streptokinase)
      1. See High Risk Acute Coronary Syndrome Management
      2. See CVA Thrombolysis
      3. See PE Thrombolysis
    2. Glycoprotein IIB/IIIA Inhibitor
      1. Abciximab (ReoPro)
      2. Tirofiban (Aggrastat)
      3. Eptifibatide (Integrilin)
  • Contraindications
  1. See Major Bleeding Risk With Anticoagulants
  2. Significant active bleeding or bleeding risk
    1. See Hemorrhage in Anticoagulated Patients
    2. See Anticoagulation in Surgical Patients
    3. See Antiplatelet Agents in the Perioperative Period
  3. Atrial Fibrillation Relative Contraindications to Anticoagulation
    1. See HAS-BLED Score
    2. See Orbit Bleeding Risk Score
    3. See Outpatient Bleeding Risk Index
  • Mechanism
  1. See Clotting Cascade
  2. Clotting Cascade
    1. pathClottingCascade.png
  3. Full Thrombosis Pathway
    1. ThrombosisPathway.png
  4. Warfarin and other Vitamin K Antagonists (VKA)
    1. Warfarin and VKAs prevent activation of Factors 2, 7, 9 and 10
  5. Heparin
    1. Heparin binds to, and potentiates Antithrombin III (AT III)
      1. Antithrombin III binds to and inhibits Serine proteases, Factor IIa (Thrombin) and Factor Xa
      2. Antithrombin III also binds to and inhibits Factors IXa, XIa and XIIa
      3. Results in decreased Fibrin formation
    2. Unfractionated Heparin
      1. Composed of Polysaccharides of various lengths, resulting in less predictable Pharmacokinetics, requiring close monitoring
      2. Heparin also transiently interacts with Thrombin, independent of its action via Antithrombin 3
    3. Low Molecular Weight Heparin (LMHW, Enoxaparin)
      1. LMHW is a small fragment of the larger Heparin molecule (mucopolysaccharide)
      2. Allows for more predictable Pharmacokinetics, and fewer complications (bleeding, HIT)
  6. Factor Xa Inhibitors (e.g. Rivoroxaban or Xarelto, Apixaban or Eliquis)
    1. Directly and reversibly bind the active site on Factor Xa
      1. Block Thrombin formation as a part of the Common Clotting Pathway
    2. Factor Xa Inhibitors are based on naturally occurring substances
      1. Antistasin
        1. Isolated in 1980s from Mexican leach extract
      2. Tick Anticoagulant Peptide (TAP)
        1. Isolated from the tick Ornithodoros moubata
  7. Indirect Xa Inhibitors (e.g. Fondaparinux)
    1. Binds Antithrombin III and modifies its form, substantially increasing its activity by 300 fold
    2. Super-charged Antithrombin III neutralizes Factor Xa at a markedly increased rate, resulting in Anticoagulation
  8. Direct Thrombin Inhibitors (e.g. Dabigatran)
    1. Selectively and reversibly inhibit free and clot-bound Thrombin
    2. Prevent conversion of Fibrinogen to Fibrin (which in turn prevents clot)
  9. ADP Inhibitors (Thienopyridine Class, e.g. Clopidogrel)
    1. Inhibits Platelet signal transduction
    2. Inhibits Platelet aggregation
    3. Reversibly binds Adenosine Diphosphate (ADP) P2Y12-Class Receptors (inhibits G-Protein, Adenyl cyclase)
  10. Aspirin
    1. Aspirin irreversibly inactivates cyclooxygenase (COX)
      1. Blocks Thromboxane and Prostaglandin synthesis
      2. Contrast with NSAIDS which reversibly block COX
    2. Platelet Effects (Thromboxane-related)
      1. Inhibits Platelet aggregation via cyclooxygenase blockade of Thromboxane A2 synthesis
      2. Aspirin Irreversibly poisons Platelets for their remaining life (8-10 days)
      3. New Platelets are generated at a rate of 10% per day (25,000/day for a patient with a 250,000 Platelet Count)
        1. By 2 days off Aspirin, a patient will have 50,000 normal Platelets (enough to counter bleeding)
  11. Thrombolytic (Tissue Plasminogen Activator or tPA, TNK-tPA or Tenecteplase)
    1. Serine protease binds Fibrin and activates Fibrin-bound plasminogen to plasmin
    2. Plasmin breaks down both Fibrin and Fibrinogen to Fibrin
      1. Fibrin Degradation Products result, which in turn also act to inhibit Fibrin formation
  • Drug Interactions
  1. Anticoagulants have significant Drug Interactions
  2. Greatest risk for Drug Interaction is with Warfarin
    1. See Warfarin Drug Interactions
  3. Direct Oral Anticoagulants (e.g. Dabigatran, Rivaroxaban) also have significant Drug Interactions
    1. Review specific agents for Drug Interactions (e.g. P-Glycoprotein, CYP3A4)
      1. Highest risk: Ketoconazole, Fluconazole, Ritonavir, Amiodarone
    2. Unknown safety and bleeding risk when combined with antiplatelet agents
    3. Reducing DOAC dose due to Drug Interaction risk may render it ineffective
  1. Direct Oral Anticoagulants (DOACs) may result in inaccurate results on clot and coagulation based assays
  2. Tests impacted by DOACs with alternative options
    1. Lupus Anticoagulant panel
      1. Consider ELISA Anticardiolipin Antibody and anti-beta2 GP1 Antibody as an alternative
    2. Activated Protein C resistance
      1. Consider Factor V Leiden as an alternative
  3. Tests impacted by DOACs (test when DOAC at trough level before next dose and interpret with caution)
    1. Protein C Activity
    2. Protein S Activity
    3. Antithrombin Activity
  4. References
    1. Choosing Wisely (American College of Clinical Pathology)
      1. https://www.choosingwisely.org/clinician-lists/ascp-hypercoagulable-workup/
    2. Adcock (2015) Thromb Res 136(1):7-12 +PMID:25981138 [PubMed]
    3. Murer (2016) Lab Med 47(4): 275-78 +PMID:27474775 [PubMed]
  • Management
  1. See Emergent Reversal of Anticoagulation
  2. Routine follow-up at least every 6 months
  3. Review compliance and adherence
    1. Review risk of thrombosis with non-compliance (e.g. Drug-eluting Stent thrombosis, VTE)
    2. Most Direct Oral Anticoagulants (e.g. Pradaxa, Eliquis) have short half-lives
    3. Review specific medication guidelines for when to take a forgotten dose
  4. Review bleeding risk
    1. Falls or other Trauma
    2. Gastrointestinal Bleeding, excessive Bruising
    3. Control Blood Pressure (manage Severe Hypertension aggressively)
    4. Exercise caution in age 75 years or older, and those who are significantly underweight
  5. Renal dysfunction (GFR <30 ml/min)
    1. Obtain Serum Creatinine before starting Anticoagulation
    2. Previously Warfarin was recommended instead of Direct Oral Anticoagulants if GFR <30 ml/minute
      1. However, Warfarin associated bleeding risk also increases with decreased GFR
    3. Avoid Dabigatran (Pradaxa) if GFR <30 ml/min (80% renally excreted)
    4. Apixiban may be preferred when GFR <30 ml/min (lower overall bleeding risk, 25% renally excreted)
      1. See Apixiban for Renal Dosing (2.5 mg orally twice daily) indications
      2. Approved for use in Hemodialysis patients
    5. Rivaroxaban is also a good choice in Renal Insufficiency (if GFR >15 ml/min)
      1. See Rivaroxaban for Renal Dosing
      2. Approved for use in Hemodialysis patients
    6. References
      1. Swaminathan and Hayes in Herbert (2019) EM:Rap 19(8):10-11
      2. Weber (2019) Eur J Haematol 102(4): 312-8 +PMID:30592337 [PubMed]
  6. Consider Drug Interactions
    1. See Warfarin Drug Interactions
    2. Review specific medication P450 interactions
    3. Avoid NSAIDs
    4. If Aspirin is being used, confirm appropriate and at low dose (i.e. 81 mg daily)
    5. DOAC Drug Interactions that decrease Anticoagulation efficacy
      1. Rifampin
      2. Carbamazepine
  7. Restarting Anticoagulation after major Hemorrhage (e.g. Hemorrhagic CVA)
    1. Risk of embolic CVA in Atrial Fibrillation, Prosthetic Heart Valve versus risk of recurrent major bleeding
    2. Intracranial HemorrhageIncidence 1 in 250 on Anticoagulants yearly (and 15% recurrence rate)
    3. If Anticoagulation restarted, wait at least 4 weeks after Intracranial Hemorrhage (8-10 weeks if higher risk)
    4. Indications to restart Anticoagulation
      1. Prosthetic Heart Valve
      2. CHADS2-VASc Score 4 or higher (no studies to support a specific score for restarting Anticoagulation)
      3. Intracranial Hemorrhage predisposing risks have since been mitigated (e.g. Hypertension control)
  8. Anticoagulant selection and dosing adjustments - special circumstances
    1. Obesity (weight >120 kg or BMI >40)
      1. Warfarin (preferred)
      2. Apixaban (Eliquis)
      3. Rivaroxaban (Xarelto)
      4. Avoid Dabigatran (Pradaxa) and Edoxaban (Savaysa)
    2. Low body weight (<60 kg)
      1. Apixaban (Eliquis) 5 mg twice daily (2.5 mg twice daily if age >80, or Serum Creatinine >1.5 mg/dl)
      2. Edoxaban (Savaysa)
    3. Hemodialysis
      1. Apixaban (Eliquis) based on limited data
      2. Avoid other DOACs in Dialysis patients
    4. Conditions in which Warfarin is used instead of DOACs
      1. Mechanical Heart Valve
        1. Pradaxa and Apixaban have both shown higher thrombosis risk than Warfarin
      2. Moderate to severe Mitral Stenosis and Atrial Fibrillation
        1. Higher mortality and stroke risk with Rivaroxaban compared with Warfarin
      3. Left Ventricular Assist Device (LVAD)
      4. Antiphospholipid Antibody Syndrome and Thrombosis history
      5. Breakthough stroke on DOAC
      6. DOAC Drug Interactions that decrease Anticoagulation efficacy (e.g. Rifampin, Carbamazepine)
  9. References
    1. (2015) Presc Lett 22(10): 55-6
    2. (2017) Presc Lett 24(5): 28
    3. (2017) Presc Lett 24(7)
    4. (2022) Presc Lett 29(11): 62
  • Prevention
  • Bleeding Home Management
  1. Education
    1. Educate patients on prevention and control of minor bleeding
    2. Immediate evaluation for Head Injury, significant injury or bleeding that does not stop after 30 minutes
    3. Also seek medical care for Hematuria, Gastrointestinal Bleeding or Hemoptysis
    4. Bleeding may be a sign of excess Anticoagulation (e.g. supratherapeutic INR with Warfarin use)
    5. Avoid NSAIDS and Herbals that increase bleeding risk (e.g. Garlic, Ginkgo)
  2. Epistaxis
    1. Consider frequent Nasal Saline use to prevent Epistaxis
    2. If Epistaxis occurs, to pinch the nose in the soft region inferior to the nasal bridge for 10-15 min
    3. May use intranasal Oxymetazoline or Phenylephrine for up to 3 days if Nasal bleeding recurrs
  3. Skin Lacerations
    1. Employ strategies to avoid Skin Trauma (e.g. electric razor instead of razor blade)
    2. Elevate and apply pressure for 15 min to bleeding sites
    3. Consider Hemostatic Agents for recurrent bleeding (e.g. styptic pencil, woundSeal)
  4. References
    1. (2020) Presc Lett 27(9): 50-1
  • References
  1. Clemens and Oliver (2026) Crit Dec Emerg Med 40(10): 27-37