Anticoagulation

David Ray Velez, MD

Definitions

Definitions

Antithrombotic Agents (“Blood Thinners”): Prevents Thrombosis/Blood Clots
- Includes Both Antiplatelet and Anticoagulant Drugs
Antiplatelet Medication: Prevents Platelet Aggregation
- Not Technically “Anticoagulation”
Anticoagulant Medication: Inhibits Clotting Factors

Agents

Unfractionated Heparin (UFH/Heparin)
Low Molecular Weight Heparin (LMWH)
- Enoxaparin (Lovenox)
- Dalteparin (Fragmin)
Fondaparinux (Arixtra)

Unfractionated Heparin (UFH/Heparin)

Mechanism: Activates Antithrombin (AT-III)
- Indirectly Inhibits Factors Xa and IIa
Monitor: PTT
Half-Life: 45-60 Minutes
Hold Timing Prior to Surgery: 6-12 Hours
Reversal: Protamine Sulfate
- Binds Heparin to Form an Ionic Compound that is Broken Down by the Reticuloendothelial System (RES)
- Give Slowly to Prevent Hypotension and Bradycardia
- Originally Made from Salmon Sperm
Complications:
- Bleeding
- Heparin-Induced Thrombocytopenia (HIT)
  - *See Heparin-Induced Thrombocytopenia (HIT)
  - Check Platelet Count Every 2-3 Days
- Osteoporosis
- Skin Necrosis

Low Molecular Weight Heparin (LMWH)

Agents:
- Enoxaparin (Lovenox) – Most Commonly Used
- Dalteparin (Fragmin)
Mechanism: Activates Antithrombin (AT-III)
- Indirectly Inhibits Factor Xa (Minimal Effect on Factor IIa)
Monitor: Factor-Xa Assay – Use is Evolving
Half-Life: 3-7 Hours (Over Double Heparin)
Hold Timing Prior to Surgery: 12-24 Hours
Reversal: Protamine Sulfate (Only Partial Neutralization – 60%)
Avoid in Severe Renal Disease (CrCl < 30 mL/min)
- Mild-Moderate Renal Disease is Not a Contraindication and Requires No Dose Adjustment
- Reduced Clearance Causes Increased Risk of Major Hemorrhage
Complications:
- Bleeding
- Heparin-Induced Thrombocytopenia (HIT)
  - *See Heparin-Induced Thrombocytopenia (HIT)
  - Lower Risk Than UFH But Still Present
- Skin Necrosis

Comparison of UFH to LMWH

UFH Benefits:
- Easier to Titrate and Discontinue – Rapid Onset and Short Half-Life
- Can Monitor Using PTT
- Safe to Use in Renal Failure
- Easier to Reverse
LMWH Benefits:
- Greater Bioavailability
- Better Correlation of Dose to Response
- Lower Risk of Bleeding and Heparin-Induced Thrombocytopenia (HIT)
- Lower Risk of Osteoporosis
- Longer Duration of Action Requires Less Frequent Administration

Fondaparinux (Arixtra)

Mechanism: Activates Antithrombin (AT-III)
- Indirectly Inhibits Factor Xa (No Effect on Factor IIa)
Monitor: Usually None
- Can Use a Factor-Xa Assay If Needed (Therapeutic Ranges Poorly Established)
Half-Life: 17-21 Hours
- *Very Long and Generally Not Used in the ICU
Hold Timing Prior to Surgery: 36-48 Hours
Reversal: None
Avoid in Severe Renal Disease – Reduced Clearance Causes Increased Risk of Major Hemorrhage
Complications:
- Bleeding
- *No Risk of Heparin-Induced Thrombocytopenia (HIT)

Agents

Warfarin (Coumadin)

Mechanism: Inhibits Vitamin K-Dependent Decarboxylation of Glutamic Residues of Clotting Factors
- Inhibits: Factors II, VII, IX, X, and Protein C and S
Monitor: INR
Half-Life: 36-42 Hours
Hold Timing Prior to Surgery: 5 Days
- May Consider Bridging with Short-Acting Anticoagulation
Reversal:
- 4-Factor PCC – The Fastest Method of Reversal
- Fresh Frozen Plasma (FFP) – Rapid Effect but Must Be Thawed First
- Vitamin K – Takes 6-12 Hours to Effect
  - Permanent Effect, While FFP and PCC are Only Temporary
- *See Blood Products
Complications:
- Bleeding
- Skin Necrosis
  - Due to a Relatively Short Half-Life of Protein C and Protein S
    - Causes an Initial Hypercoagulable State
    - Higher Risk with Protein C Deficiency
  - Prevent by Co-Administration of Heparin While Initiating Therapy
  - Management: Stop Coumadin, Give Vitamin K, and Start Therapeutic Heparin
- Teratogenic
  - Crosses Placenta and Not Safe to Use in Pregnancy
  - OK to Use While Breastfeeding

Agents

Direct Thrombin Inhibitors (DTI)
- Argatroban
- Dabigatran (Pradaxa)
- Bivalirudin (Angiomax)
Direct Factor Xa Inhibitors
- Apixaban (Eliquis)
- Rivaroxaban (Xarelto)

Direct Thrombin Inhibitors (DTI)

Univalent Agents:
- Argatroban
- Dabigatran (Pradaxa)
Bivalent Agents:
- Bivalirudin (Angiomax) – Analog of Hirudin (Occur Naturally in Leeches)
- Lepirudin – Discontinued
Mechanism: Directly Inhibits Factor IIa (Thrombin)
Metabolism:
- Argatroban: Liver
- Others: Kidney
- Mnemonic: Excretion of Direct Thrombin Inhibitors
  - Argatroban: “Arg!” – Drunken Pirates Have Bad Livers – Excreted in Liver
  - -rudin: Its “Rude” to Pee on People – Excreted in Kidneys
Monitor: Usually None but Can Prolong PT/PTT (Unreliable)
Half-Life:
- Dabigatran (Pradaxa): 12-17 Hours
- Others: 30-60 Minutes
Hold Timing Prior to Surgery: 2-3 Days
Reversal:
- Dabigatran: Idarucizumab (Praxbind) or Dialysis
- Others: None Available

Direct Factor Xa Inhibitors

Agents:
- Apixaban (Eliquis)
- Rivaroxaban (Xarelto)
- Edoxaban (Savaysa)
- Mnemonic: Xa Inhibitors “Ban Xa” and Have “-xa-ban” in the Name
Mechanism: Directly Inhibits Factor Xa
Monitor: Usually None but Can Prolong PT/PTT (Unreliable)
Half-Life: 6-12 Hours
Hold Timing Prior to Surgery: 2-3 Days
Reversal: Andexanet Alfa (AndexXa) – Recombinant Factor Xa
- May Also Consider PCC

Antithrombotic Reversal

Heparin
- Protamine Sulfate – Binds Heparin to Form an Ionic Compound that is Broken Down by the Reticuloendothelial System (RES)
- Give Slowly to Prevent Hypotension and Bradycardia
Lovenox
- Protamine Sulfate (Only Partial Reversal)
Warfarin (Coumadin)
- 4-Factor PCC – The Fastest Method of Reversal
- Fresh Frozen Plasma (FFP) – Rapid Effect but Must Be Thawed First
- Vitamin K – Takes 6-12 Hours to Effect
  - Permanent Effect, While FFP and PCC are Only Temporary
- *See Blood Products
Direct Thrombin Inhibitors (Argatroban, Dabigatran, Bivalrudin)
- Dabigatran: Idarucizumab (Praxbind) or Dialysis
- Others: None
Direct Factor Xa Inhibitors (Apixaban/Eliquis, Rivaroxaban/Xarelto)
- Andexanet Alfa (AndexXa) – Recombinant Factor Xa
  - Dosing Varies Based Upon the Anticoagulant
  - Short Half-Life May Require Redosing
  - No Prothrombotic Effects Due to Structural Modifications
- May Also Consider PCC

Hold Timing Before Surgery

Bridging Therapy