Anticoagulants

Physiologic anticoagulants

• Inhibit intrinsic pathway:
  • Antithrombin (with heparin): inhibit factor 2(thrombin), 9, 10, 11, 12
  • Protein C: inhibit 5, 8; need VitK to synthesize
• Inhibit extrinsic pathway:
  • TFPI(Tissue factor pathway inhibitor): combine factor 10 to inhibit factor 7a

Tip

• Heparin: also affects VIII and IX → intrinsic pathway → PTT
• Warfarin: affects both intrinsic and extrinsic pathway, but VII has shorter half life → extrinsic pathway → PT
  • The half-lives of the procoagulants are ∼ 2–4 days (except for factor VII, which has a short half-life), while the anticoagulants only have half-lives of 6–10 hours.
  • Intrinsic pathway remains active another 2–3 days, while extrinsic pathway and protein C are already inactive.

• Direct thrombin inhibitors: prolonged thrombin time (TT), no change to PTT or PT (not routinely monitored)
• Direct factor Xa inhibitors: prolonged PT and PTT, unchanged thrombin time (not routinely monitored)

Tip

Anticoagulants cause thrombosis, this can also be seen in HIT.

Heparins (Unfractionated & LMWH)

• Unfractionated Heparin (UFH)
  • Mechanism: Binds Antithrombin III $\to$ irreversibly inactivates Thrombin (IIa) and Factor Xa. t
  • Clinical Use: Immediate anticoagulation (PE, ACS, DVT), safe in pregnancy.
  • Monitoring: Follow PTT.
  • Adverse Effects: Bleeding, Osteoporosis (long-term), Heparin-Induced Thrombocytopenia (HIT).
    • Pathophysiology: IgG antibodies form against Heparin-Platelet Factor 4 (PF4) complex. Immune complex activates platelets $\to$ thrombosis + thrombocytopenia.
  • Reversal: Antidote: protamine sulfate (a positively-charged protein that can neutralize negatively-charged heparin by forming inactive complexes)
    • Can’t give fresh frozen plasma (FFP), since it contains antithrombin III → enhances heparin effect
• Low Molecular Weight Heparin (LMWH)
  • Drugs: Enoxaparin, Dalteparin.
  • Mechanism: Acts more on Factor Xa than Thrombin. Better bioavailability and longer half-life than UFH.
  • Clinical Use: DVT prophylaxis/treatment, Acute Coronary Syndrome. Safe in pregnancy. t
  • Monitoring: None usually required (can monitor anti-Xa levels in renal failure or obesity).
  • Contraindications: Renal insufficiency (renally cleared).

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Vitamin K Antagonist (Warfarin)

• Mechanism
  • Inhibits Vitamin K epoxide reductase.
  • Interferes with $\gamma$-carboxylation of vitamin K-dependent clotting factors: II, VII, IX, X, and Proteins C & S.
  • Effect on Protein C/S (natural anticoagulants) occurs first $\to$ early transient hypercoagulable state.
• Clinical Use
  • Chronic anticoagulation (e.g., venous thromboembolism prophylaxis, prevention of stroke in atrial fibrillation).
  • “Bridge” therapy: to prevent transient hypercoagulable state and Warfarin Skin Necrosis
    • Start Heparin + Warfarin simultaneously. Discontinue Heparin once INR is therapeutic for >24 hrs (usually takes days due to long half-life of Factor II).
• Monitoring
  • PT/INR (Target INR usually 2.0–3.0; 2.5–3.5 for mechanical heart valves).
• Adverse Effects
  • Bleeding.
  • Teratogenic (bone/cartilage defects) $\to$ Avoid in pregnancy (Use LMWH).
  • Warfarin Skin Necrosis: Rare complication in pts with underlying Protein C deficiency. t

Warfarin reversal

	Warfarin overdose	Heparin overdose
Vitamin K	• Effective (takes days)	• Ineffective
FFP	• Effective (contains all blood clotting factors & proteins)	• Ineffective (contains antithrombin III → enhances heparin effect)
Protamine	• Ineffective	• Effective (heparin-specific antidote) t

• Stop warfarin.
• Administer IV vitamin K PLUS 4-factor prothrombin complex concentrate (PCC)
  • If PCC is unavailable, give fresh frozen plasma (FFP)
• Monitor INR every 6 hours until warfarin has been fully reversed (INR ≤ 1.1)

Warfarin interactions

Warfarin is metabolized by cytochrome P450 (CYP) enzymes.

• Decrease of anticoagulant effect
  • Rifampicin, carbamazepine, St. John’s wort, ginger, licorice: induce metabolic breakdown of warfarin via induction of cytochrome P450
  • Foods rich in vitamin K (e.g., kale, spinach): counter effect of warfarin
  • Gastric acid inhibition (PPI use), cholestyramine treatment: impaired uptake of warfarin
• Increase of anticoagulant effect
  • Several antidepressants and antibiotics, PPIs, amiodarone, grapefruit: impair metabolic breakdown via inhibition of cytochrome P450
  • Acetaminophen: metabolite of acetaminophen interrupts vitamin K cycle via inhibition of vitamin K-dependent carboxylase
  • Sulfonamides, sulfonylureas: competitively block or displace warfarin at plasma protein binding sites
  • Damage to gut flora (e.g., antibiotic therapy): impaired bacterial vitamin K synthesis

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Direct Factor Xa Inhibitors (“-xabans”)

• Drugs: Apixaban, Rivaroxaban, Edoxaban.
• Mechanism: Bind to and directly inhibit Factor Xa. t
  • Not blocking conversion from X to Xa
• Clinical Use: DVT/PE treatment and prophylaxis, Stroke prophylaxis in non-valvular atrial fibrillation.
• Advantages: Fixed oral dosing, no monitoring required.
• Adverse Effects: Bleeding.
• Reversal: Andexanet alfa.

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Direct Thrombin Inhibitors (DTIs)

• Act independently from antithrombin
  • The effect of most parenteral anticoagulants (except for direct thrombin inhibitors) works by enhancing native antithrombin III.
• Intravenous DTIs
  • Drugs: Bivalirudin, Argatroban.
  • Mechanism: Directly inhibit thrombin (Factor IIa).
  • Clinical Use: Anticoagulation in patients with HIT (Heparin-Induced Thrombocytopenia).
• Oral DTIs
  • Drugs: Dabigatran.
  • Mechanism: Directly inhibits thrombin.
  • Clinical Use: Venous thromboembolism, Atrial fibrillation.
  • Reversal: Idarucizumab (monoclonal antibody fragment).