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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

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