7.5 Anticoagulants
Anticoagulants prevent thrombus formation and propagation by interfering with the coagulation cascade. They are critical in preventing stroke (atrial fibrillation), treating/preventing VTE, and managing acute coronary syndromes.
Coagulation Cascade Review
Intrinsic & Extrinsic Pathways → Common Pathway
Extrinsic: Tissue factor (TF) + VIIa → Xa (measured by PT/INR)
Intrinsic: XII → XIa → IXa + VIIIa → Xa (measured by aPTT)
Common: Xa + Va → prothrombin (II) → thrombin (IIa) → fibrinogen → fibrin clot
Vitamin K-Dependent Factors
Factors II (prothrombin), VII, IX, X—require γ-carboxylation for activity
Protein C & S (anticoagulant proteins) also vitamin K-dependent
Warfarin (Coumadin)
Mechanism
Vitamin K epoxide reductase inhibitor
Prevents recycling of vitamin K → ↓ synthesis of factors II, VII, IX, X, protein C/S
Oral anticoagulant—only vitamin K antagonist available
Pharmacokinetics
Delayed onset (2-3 days)—existing factors must be depleted
Factor VII has shortest t½ (~6h) → PT/INR changes first
Factor II (prothrombin) longest t½ (~60h) → full effect takes 5-7 days
Long duration—takes days to reverse after stopping
Monitoring & Dosing
INR (International Normalized Ratio): standardized PT measurement
Target INR: 2-3 (most indications), 2.5-3.5 (mechanical valves)
Frequent monitoring required—narrow therapeutic window
Dose adjustments based on INR trends
Clinical Uses
Atrial fibrillation (stroke prevention), VTE treatment/prevention
Mechanical heart valves (only oral option for this indication)
Largely replaced by DOACs for AFib/VTE (but warfarin still used)
Drug Interactions
Extensive interactions—CYP2C9 substrate
↑ INR (↑ bleeding): Antibiotics (kill vitamin K-producing gut flora), amiodarone, azole antifungals, NSAIDs
↓ INR (↓ efficacy): Rifampin, carbamazepine, vitamin K-rich foods (leafy greens)
Genetic polymorphisms: CYP2C9, VKORC1 affect dosing
Adverse Effects & Reversal
Bleeding: major risk, especially if INR >4
Skin necrosis (rare): paradoxical thrombosis (protein C depletes faster than procoagulant factors)
Teratogenic: fetal warfarin syndrome—contraindicated in pregnancy
Reversal: Vitamin K (PO/IV, slow), FFP, or 4-factor PCC (rapid for emergencies)
Heparin
Unfractionated Heparin (UFH)
Large, heterogeneous polysaccharide—activates antithrombin (AT)
AT binds and inactivates factors IIa (thrombin), Xa, IXa, XIa, XIIa
Heparin ↑ AT activity ~1000-fold (acts as cofactor)
Pharmacokinetics & Monitoring
IV or SC—NOT oral (large, charged molecule)
Immediate onset—drug of choice for acute situations
Short half-life (~1-2h)—can be rapidly discontinued
Monitoring: aPTT (target 1.5-2.5× control) or anti-Xa levels
Clinical Uses
ACS (STEMI/NSTEMI), acute VTE, during PCI, bridging to warfarin
Cardiopulmonary bypass, ECMO (short t½ advantage)
Pregnancy (doesn't cross placenta—safe)
Heparin-Induced Thrombocytopenia (HIT)
Type II (immune-mediated): IgG antibodies against heparin-PF4 complex
Paradoxical thrombosis (arterial > venous), ↓ platelets (usually 50% drop)
Onset: 5-10 days (or sooner if previous exposure)
Management: STOP heparin immediately, switch to direct thrombin inhibitor (argatroban, bivalirudin)
Do NOT give platelets or start warfarin acutely (↑ thrombosis risk)
Reversal
Protamine sulfate: binds heparin (ionic interaction), neutralizes ~1mg protamine per 100 units heparin
Risk: hypotension, bradycardia, anaphylaxis (fish allergy, prior insulin NPH use)
Low Molecular Weight Heparins (LMWHs)
Enoxaparin, Dalteparin, Tinzaparin
Shorter heparin fragments—activate AT to inhibit factor Xa >> IIa
Anti-Xa : anti-IIa ratio ~3:1 (vs. 1:1 for UFH)
Advantages Over UFH
SC administration—outpatient VTE treatment
Predictable pharmacokinetics (dose by weight)—NO monitoring needed (except renal failure, obesity, pregnancy)
Longer half-life (~4h)—once or twice daily dosing
Lower risk of HIT (~0.1% vs. 1-3% for UFH)
Clinical Uses
VTE treatment (outpatient DVT) and prophylaxis (surgery, hospitalized patients)
ACS (NSTEMI/unstable angina with conservative management)
Bridging anticoagulation in perioperative setting
Limitations
Renally cleared—avoid in severe renal impairment (CrCl <30)
Protamine partially reverses (~60%)—no complete reversal agent
Spinal/epidural hematoma risk with neuraxial anesthesia
DOACs - Direct Oral Anticoagulants
Direct Factor Xa Inhibitors
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
Directly inhibit factor Xa (no AT required)
Oral bioavailability, rapid onset (2-4h)
"-xaban" suffix
Direct Thrombin (IIa) Inhibitor
Dabigatran (Pradaxa)
Directly inhibits free and clot-bound thrombin
Prodrug—requires conversion to active form
"-gatran" suffix
Advantages Over Warfarin
NO routine monitoring (fixed dosing)
Fewer drug-drug and drug-food interactions
Rapid onset/offset—no bridging needed
Lower intracranial hemorrhage risk
Non-inferior or superior efficacy for stroke prevention in AFib
Clinical Uses
AFib: stroke prevention (preferred over warfarin in most patients)
VTE: treatment and prevention
NOT for mechanical valves (dabigatran studied—worse outcomes)
Dosing Considerations
Rivaroxaban: Once daily, take with food (VTE: 15mg BID × 21d, then 20mg daily)
Apixaban: Twice daily, best safety profile (lowest bleeding)
Edoxaban: Once daily, after 5-10d parenteral anticoagulation for VTE
Dabigatran: Twice daily, high GI side effects (~10% dyspepsia)
Dose adjustments for renal impairment, age, weight
Reversal Agents
Idarucizumab (Praxbind): dabigatran-specific monoclonal antibody (immediate reversal)
Andexanet alfa (Andexxa): recombinant Factor Xa decoy—reverses Xa inhibitors
For life-threatening bleeding or urgent surgery
Otherwise: supportive care, hemodialysis (dabigatran only—not protein-bound)
Parenteral Direct Thrombin Inhibitors
Argatroban
IV direct thrombin inhibitor
Primary use: HIT (heparin-induced thrombocytopenia)
Hepatically metabolized—safe in renal failure
Monitor aPTT
Bivalirudin
IV direct thrombin inhibitor
PCI anticoagulation, HIT
Short half-life—preferred for procedures
Fondaparinux
Synthetic Pentasaccharide
Selective factor Xa inhibitor (via AT activation)
SC injection, once daily, predictable PK—no monitoring
Uses: VTE prophylaxis/treatment, ACS, HIT (no cross-reactivity)
Renally cleared—contraindicated if CrCl <30
NO reversal agent, NOT dialyzable