Anticoagulant Therapies and Heparin Monitoring

VTE Risk Factors

• Individuals at moderate or high risk of developing VTE:
  • Those who have recently undergone orthopedic & non-orthopedic surgery
  • Medically ill patients

VTE Prevention - Orthopedic & Non-Orthopedic Surgeries

• Drugs used:
  • Unfractionated Heparin (UFH):
    • Route: Intravenous (IV)
    • Dose: Based on individual needs, typically adjusted to achieve a specific activated partial thromboplastin time (aPTT)
    • Frequency: Continuous infusion
  • Low Molecular Weight Heparin (LMWH):
    • Route: Subcutaneous (SQ)
    • Dose: Varies depending on specific LMWH (Enoxaparin, Dalteparin, or Tinzaparin)
    • Frequency: Once or twice daily

VTE Prevention - Medically Ill Patients

• Drugs used:
  • Unfractionated Heparin (UFH):
    • Route: Intravenous (IV)
    • Dose: Based on individual needs, typically adjusted to achieve a specific aPTT
    • Frequency: Continuous infusion
  • Low Molecular Weight Heparin (LMWH):
    • Route: Subcutaneous (SQ)
    • Dose: Varies depending on specific LMWH (Enoxaparin, Dalteparin, or Tinzaparin)
    • Frequency: Once or twice daily
  • Fondaparinux (Arixtra):
    • Route: Subcutaneous (SQ)
    • Dose: Fixed-dose (2.5 mg once daily)
    • Frequency: Once daily
  • Warfarin (Coumadin):
    • Route: Oral
    • Dose: Starting dose is typically 5 mg daily, adjusted to achieve a desired international normalized ratio (INR)
    • Frequency: Once daily
  • Direct Oral Anticoagulants (DOACs):
    • Dabigatran (Pradaxa):
      • Route: Oral
      • Dose: Varies depending on indication
      • Frequency: Twice daily
    • Rivaroxaban (Xarelto):
      • Route: Oral
      • Dose: Varies depending on indication
      • Frequency: Once or twice daily
    • Apixaban (Eliquis):
      • Route: Oral
      • Dose: Varies depending on indication
      • Frequency: Once or twice daily
    • Edoxaban (Savaysa):
      • Route: Oral
      • Dose: Varies depending on indication
      • Frequency: Once daily

VTE Treatment

• Drugs Used:
  • Unfractionated Heparin (UFH):
    • Route: Intravenous (IV)
    • Dose: Based on individual needs, typically adjusted to achieve a specific aPTT
    • Frequency: Continuous infusion
    • Duration: Usually for initial treatment, then transitioned to other anticoagulation
  • Low Molecular Weight Heparin (LMWH):
    • Route: Subcutaneous (SQ)
    • Dose: Varies depending on specific LMWH (Enoxaparin, Dalteparin, or Tinzaparin)
    • Frequency: Once or twice daily
    • Duration: Can be used for initial treatment or as a bridge to oral anticoagulants
  • Fondaparinux (Arixtra):
    • Route: Subcutaneous (SQ)
    • Dose: Fixed-dose (2.5 mg once daily)
    • Frequency: Once daily
    • Duration: Can be used for initial treatment or as a bridge to oral anticoagulants
  • Warfarin (Coumadin):
    • Route: Oral
    • Dose: Starting dose is typically 5 mg daily, adjusted to achieve a desired international normalized ratio (INR)
    • Frequency: Once daily
    • Duration: Typically continued for several weeks or months
  • Direct Oral Anticoagulants (DOACs):
    • Dabigatran:
      • Route: Oral
      • Dose: Varies depending on indication
      • Frequency: Twice daily
    • Rivaroxaban:
      • Route: Oral
      • Dose: Varies depending on indication
      • Frequency: Once or twice daily
    • Apixaban:
      • Route: Oral
      • Dose: Varies depending on indication
      • Frequency: Once or twice daily
    • Edoxaban:
      • Route: Oral
      • Dose: Varies depending on indication
      • Frequency: Once daily
      • Duration: Typically for several weeks or months

Treatment of Massive Pulmonary Embolism (PE)

• Candidates for initial thrombolytic therapy:
  • Patients with hemodynamically unstable PE
  • Those at high risk for death or long-term disability

Unfractionated Heparin (UFH)

• Challenges:
  • Narrow therapeutic index
  • Requires frequent monitoring of anticoagulant effect

UFH Monitoring

• Anticoagulant effects can be monitored using two factors:
  • Antifactor Xa
  • aPTT
• Monitoring frequency:
  • Measure aPTT or antifactor Xa level before initiation to determine baseline
  • Then monitor every 6 hours after starting IV UFH
  • Monitor using either aPTT or antifactor Xa, not both.

UFH Adverse Effects

• Most concerning:
  • Bleeding
• Other common effects:
  • Thrombocytopenia (low platelet count)
  • Platelet monitoring is crucial for safety.

Factors Increasing Bleeding Risk with UFH

• Medications contributing to bleeding risk with UFH:
  • Antiplatelet drugs
  • NSAIDs
  • Other antithrombotic therapies

4 T's Used for Diagnosis of Heparin-Induced Thrombocytopenia (HIT)

• Four T's:
  • Thrombocytopenia
  • Timing of platelet count fall
  • Thrombosis
  • Other explanation for falling platelets

Monitoring Overall Blood Loss (Bleeding) With UFH

• Check hemoglobin and hematocrit levels
• A drop in these levels may indicate blood loss somewhere in the body

Monitoring UFH Patients

• Key monitoring parameters:
  • aPTT or antifactor Xa efficacy
  • Platelet count for safety
  • Hemoglobin and hematocrit levels

Low Molecular Weight Heparins (LMWHs)

• Difference from UFH:
  • LMWHs have a smaller side chain, preventing them from binding to thrombin as tightly as UFH.
  • They inhibit factor Xa more effectively than factor IIa (thrombin) due to their smaller side chain.

Available LMWHs

• Commonly used LMWHs include:
  • Enoxaparin (Lovenox)
  • Dalteparin (Fragmin)
  • Tinzaparin (Innohep)

Advantages of LMWH over UFH

• LMWHs offer several advantages:
  • More predictable anticoagulant dose response
  • Improved subcutaneous bioavailability
  • Dose independent clearance
  • Longer half-life
  • Better absorption

Dosing Differences Between LMWHs

• Dosing for Enoxaparin is expressed in milligrams.
• Dosing for Dalteparin and Tinzaparin is expressed in units of antifactor Xa activity.

Monitoring LMWH

• Monitoring with LMWH is not typically necessary due to its predictable anticoagulant response, especially with SQ administration.
• Baseline labs should be obtained, including:
  • CBC with platelets
  • Serum creatinine
• Monitor:
  • Anti-Xa activity
  • Serum creatinine

LMWH Contraindications

• LMWH use is contraindicated for patients with:
  • A history of heparin-induced thrombocytopenia (HIT)

Monitoring Parameters for LMWH

• Monitoring parameters for LMWH include:
  • Anti-Xa
  • aPTT does not inhibit factor IIa as effectively as UFH.

Timing of Monitoring for LMWH vs. UFH

• Monitoring timing is different for LMWH and UFH:
  • LMWH: Baseline, then 4 hours after
  • UFH: Baseline, then 6 hours after

aPTT and LMWH

• aPTT tells you nothing about the effectiveness of LMWH.
• You must evaluate anti-Xa levels to assess effectiveness.

LMWH Side Effects

• Common side effects of LMWH:
  • Bleeding (less frequent compared to UFH)
  • Epidural and spinal hematomas in patients with epidural catheters
  • Thrombocytopenia, but it is important to avoid LMWH in patients with a history of HIT.
  • LMWH is generally safe during pregnancy.

Fondaparinux

• Characteristics of Fondaparinux:
  • It's a pentasaccharide, not a heparin.
  • Unlike heparin, it does not have tails, so it does not interact with thrombin.
• Fondaparinux does not bind tightly to thrombin.
• Fondaparinux inhibits factor Xa.
• Unlike UFH and LMWH, Fondaparinux does not impact platelet function.

Main Indication for Fondaparinux

• Patients with HIT

Fondaparinux Brand Name

• Brand name: Arixtra

Fondaparinux Monitoring

• Monitor:
  • Hemoglobin, hematocrit, and kidney function (serum creatinine)
  • Platelet monitoring is not necessary as it does not impact platelet function.

Administration Routes for Anticoagulants (SQ & IV)

• SQ administration routes are commonly used with:
  • LMWH
  • Fondaparinux

Fondaparinux Dosing Frequency

• Fondaparinux is dosed:
  • Once daily

Summary of Anticoagulant Monitoring

• UFH: Monitor aPTT or anti-Xa
• LMWH: Monitor anti-Xa and serum creatinine
• Fondaparinux: Monitor kidney function only, as it has stable pharmacokinetics.

Fondaparinux Safety in Elderly & Pregnant Patients

• Fondaparinux is safe in elderly patients, but bleeding risk may increase with age.
• It is also safe during pregnancy.

Most Common Adverse Effect of Fondaparinux

• The most common adverse effect of Fondaparinux is:
  • Bleeding

When to Discontinue Fondaparinux

• Discontinuation of Fondaparinux use is recommended when:
  • Creatinine clearance (CrCl) is less than 30 ml/min.

Warfarin

• Warfarin requires:
  • Continuous monitoring
  • Patient education
  • It has a narrow therapeutic index.
  • It has many drug and food interactions.

Warfarin Mechanism of Action (MOA)

• Warfarin is a racemic mixture of the R and S isomers:
  • The S isomer is primarily metabolized by CYP2C9.
  • The R isomer is metabolized by other enzymes, including CYP1A2 and CYP3A4.

Warfarin's Effect on Vitamin K-Dependent Clotting Factors

• Warfarin inhibits the synthesis of vitamin K-dependent clotting factors:
  • Factor VII
  • Factor IX
  • Factor X
  • Factor II (prothrombin)
• These factors have varying half-lives:
  • Factor VII has the shortest half-life, measured in hours.
  • Other factors have half-lives measured in days.

Monitoring Warfarin

• Monitoring parameters for Warfarin:
  • Prothrombin time (PT): NOT aPTT
  • INR

Target INR for Most Warfarin Indications

• The target INR for most indications:
  • 2.5 (range: 2-3.0)

INR Interpretation

• A high INR level indicates:
  • Greater anticoagulation effect
  • Higher bleeding risk.
• A low INR level means:
  • Insufficient anticoagulation
  • Higher risk of clotting.

INR in Normal Individuals

• The normal INR range:
  • 1

Warfarin Monitoring Frequency

• INR monitoring frequency:
  • Hospitalized patients:
    • On the second day of initiation, then daily until INR is in the therapeutic range (2-3.0)
  • Outpatients:
    • Twice during the first week of therapy

Warfarin Dose Adjustment

• When the INR target range is achieved, adjust the dose as needed:
  • Check INR weekly until stable, then every 4 to 6 weeks.
  • After a dosage change, recheck in 1 week followed by weekly checks until INR stabilizes and then every 4-6 weeks.

Normal Warfarin Dose

• A starting dose of 5 mg/day is common.
• Lower doses are recommended for patients who are more prone to bleeding, including those with:
  • Elderly age
  • Poor nutrition
  • Liver disease
  • Genetic polymorphisms
  • Concurrent medication interactions
  • Elevated baseline INR

Loading Dose of Warfarin

• There is no significant benefit of giving a loading dose of Warfarin, as it does not rapidly achieve anticoagulation.
• While loading doses are FDA-approved, they don't make a significant difference for most people and are not recommended.

Warfarin Pharmacogenetics

• Guidelines generally discourage routine pharmacogenetics testing for guiding warfarin doses.

Warfarin Drug Interactions

• Drug-drug interactions can alter warfarin’s metabolism, impacting INR and bleeding risk:
  • Drugs that inhibit or induce CYP2C9, CYP1A2, and CYP3A4 have the greatest potential for impacting INR and bleeding.
  • Drugs affecting hemostasis or platelet function can increase bleeding risk without affecting INR.

Dietary Considerations with Warfarin

• Pay attention to green leafy vegetables, which are high in vitamin K:
  • Vitamin K counteracts warfarin's effect, reducing INR and increasing clot risk.

CYP Enzymes and INR

• CYPs that increase INR (leading to greater anticoagulation):
  • CYP inhibitors: 1A2, 2C9, 3A4
  • This can result in more bleeding.
• CYPs that decrease INR (leading to less anticoagulation):
  • CYP inducers: Medications for seizures, such as phenytoin
  • This can increase clot risk.

Impact of Green Leafy Vegetables on INR

• High intake of green leafy vegetables (high in vitamin K) will likely lead to a decrease in INR.
• This means the patient is at a higher risk for clotting.

Warfarin Adverse Effects

• Warfarin does not directly cause bleeding; it exacerbates bleeding from pre-existing lesions.
• Important to monitor for bleeding, which should not occur spontaneously in:
  • Nose
  • Gums
  • Skin
  • Urine
  • Stool
  • Teeth while brushing
  • Vagina
  • Gastrointestinal tract
• Signs of blood in stool: pink, red, black, or tarry
• Seek medical attention if bleeding occurs.

Warfarin Adverse Effects (cont.)

• Other adverse effects of Warfarin:
  • Purple-toe syndrome
  • Warfarin-induced skin necrosis

Direct Oral Anticoagulants (DOACs)

• DOACs directly inhibit thrombin or factor Xa without requiring any cofactors:
  • Dabigatran (Pradaxa): Direct thrombin inhibitor
  • Rivaroxaban (Xarelto), Apixaban (Eliquis), and Edoxaban (Savaysa): Factor Xa inhibitors

DOAC Drug Interactions

• Drug-drug interactions with DOACs:
  • Dabigatran is primarily eliminated through the kidneys and is most susceptible to changes in kidney function, making kidney function monitoring crucial.
  • Apixaban is the least renally eliminated and is often used in people with kidney problems.
  • Rivaroxaban has the most interactions with CYP3A4 enzymes, followed by Apixaban.
  • All DOACs are substrates of P-glycoprotein, and some interactions with P-glycoprotein inducers and inhibitors can impact their efficacy.

DOAC Monitoring

• Monitoring for DOACs:
  • Monitor for bleeding as the primary concern
  • Renal function and hemoglobin/hematocrit can also be monitored.

DOAC Selection for Patients with Kidney Disease

• For patients with poor kidney function, consider:
  • Apixaban

DOACs and CYP3A4/P-gp Metabolism

• DOACs that are substrates of CYP3A4 and P-glycoprotein:
  • Rivaroxaban
  • Apixaban
• DOACs that are NOT significantly metabolized by CYP3A4 but are P-glycoprotein substrates:
  • Edoxaban
  • Dabigatran
• Important P-glycoprotein inhibitors:
  • Amiodarone
  • Propafenone
  • Quinidine
  • Verapamil
• Important P-glycoprotein inducers:
  • Carbamazepine
  • Rifampin