Anticoagulants and Antiplatelets

Anticoagulants

• Vitamin K antagonists (warfarin) inhibit γ-carboxylation of clotting factors II, VII, IX, and X in the liver; Factor VII is depleted first (shorter half-life), explaining the transient hypercoagulable state when initiating therapy
• Unfractionated heparin (UFH) binds to antithrombin III (ATIII), potentiating its inhibition of Factors IIa and Xa; requires continuous IV infusion and frequent monitoring
• Low-molecular-weight heparin (LMWH) has more selective Factor Xa inhibition and more predictable pharmacokinetics; allows subcutaneous dosing with less monitoring
• Direct thrombin inhibitors (dabigatran) directly bind and inactivate Factor IIa (thrombin) in a reversible manner; peak levels occur 1-3 hours after oral dosing
• Factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) directly and reversibly inhibit Factor Xa, preventing prothrombinase complex assembly and subsequent thrombin generation; these are part of the direct oral anticoagulants (DOACs) class

Antiplatelets

• Aspirin irreversibly acetylates cyclooxygenase (COX) in platelets, preventing thromboxane A2 (TXA2) synthesis; effect lasts the platelet lifespan (~7-10 days)
• P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor) block ADP receptors on platelets, preventing platelet activation and aggregation; clopidogrel requires hepatic metabolism by CYP3A4 to active metabolite
• Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) block the final common pathway of platelet aggregation by preventing fibrinogen and von Willebrand factor bridging
• Phosphodiesterase inhibitors (dipyridamole) increase intracellular cAMP in platelets, inhibiting aggregation

Indication-Based Presentations (Why anticoagulants/antiplatelets are prescribed)

• Acute coronary syndrome (ACS): Chest pain with ST-elevation or dynamic troponin elevation; dual antiplatelet therapy (aspirin + P2Y12 inhibitor) is foundational
• Atrial fibrillation with elevated stroke risk: Palpitations, irregular pulse, CHA₂DS₂-VASc score ≥2 (males) or ≥3 (females) indicating need for anticoagulation
• Venous thromboembolism (DVT/PE): Unilateral leg swelling/pain (DVT) or dyspnea/chest pain (PE); anticoagulation prevents recurrence and propagation
• Ischemic stroke/TIA: Acute focal neurologic deficits; antiplatelet therapy for non-cardioembolic stroke, anticoagulation for cardioembolic sources

Complications Presentations (Adverse effects)

• Bleeding: Spontaneous hemorrhage, ecchymosis, hemoptysis, GI bleeding, or intracranial hemorrhage (most feared complication)
• Heparin-induced thrombocytopenia (HIT): Thrombocytopenia developing 5-14 days after heparin initiation with paradoxical thrombosis
• Warfarin skin necrosis: Painful erythema and necrosis typically on fatty areas (breasts, buttocks) occurring 3-5 days after initiation due to temporary hypercoagulability

Monitoring and Baseline Assessments

• INR (International Normalized Ratio) for warfarin: Target range typically 2-3 for most indications (2.5-3.5 for mechanical heart valves); checked at baseline, 3-5 days after initiation, then weekly × 4 weeks, then monthly
• Activated partial thromboplastin time (aPTT) for UFH: Target therapeutic range is 1.5-2.5× control; checked at baseline, 6 hours after initiation, then daily during therapy; correlates with efficacy
• Anti-Xa level for LMWH: Therapeutic range 0.5-1.0 IU/mL (4 hours post-dose); primarily used in renal insufficiency, obesity, or pregnancy; most patients don't require monitoring
• No routine monitoring required for DOACs in standard patients; baseline renal function (eGFR) and CBC essential for dose selection and safety
• Platelet count for all anticoagulants: Baseline and day 3-5 to screen for HIT; if HIT suspected, check 4Ts score and HIT antibody (ELISA)
• Renal function (eGFR) critical for all agents: DOACs contraindicated if eGFR <15 (most); UFH preferred in severe renal disease
• Baseline coagulation studies (PT, aPTT, fibrinogen) and CBC before any anticoagulation initiation

Clinical Decision Tools

• CHA₂DS₂-VASc score: Stratifies stroke risk in atrial fibrillation; each point represents annual stroke risk (1 point = ~1% annual risk)
• HAS-BLED score: Predicts bleeding risk on anticoagulation; helps guide agent selection and intensity of monitoring

ANTICOAGULANT AGENTS

Vitamin K Antagonists (Warfarin)

• Mechanism: Inhibits γ-carboxylation of vitamin K–dependent factors (II, VII, IX, X)
• Dosing: Loading typically 5-10 mg daily × 2-3 days, then maintenance 2-10 mg daily (highly variable); titrate by INR
• Advantages: Oral route, long track record, reversal agent available (fresh frozen plasma, prothrombin complex concentrate [PCC], or vitamin K1)
• Disadvantages: Narrow therapeutic window, multiple drug/food interactions (especially vitamin K), slow onset/offset, requires frequent INR monitoring
• Special considerations: Transient hypercoagulability on initiation due to Factor VII depletion before factors II, IX, X deplete; bridge with heparin (UFH or LMWH) for acute thrombotic conditions
• Reversal: Vitamin K1 10 mg IV (slow infusion), FFP 10-15 mL/kg, or PCC (preferred for rapid reversal)

Direct Oral Anticoagulants (DOACs)

• Apixaban: 5 mg PO BID; reduce to 2.5 mg BID if age ≥60 AND weight ≤60 kg AND creatinine ≥1.5; renal clearance 27%; minimal food interaction
• Rivaroxaban: 20 mg PO daily with food (for non-VTE indications); must be taken with meals for optimal absorption; 66% renal clearance
• Edoxaban: 60 mg PO daily (reduce to 30 mg if weight ≤60 kg, eGFR 30-50, or concurrent strong P-gp inhibitors); 50% renal clearance

• Dabigatran: 150 mg PO BID; reduce to 110 mg B

Bleeding (class effect, dose-dependent)

• Intracranial hemorrhage: the most feared toxicity; risk is lower with DOACs than warfarin, while GI bleeding is somewhat higher with dabigatran and rivaroxaban. The ACC expert consensus pathway on bleeding in patients on oral anticoagulants frames management as: hold the drug, local hemostasis, transfusion support, then targeted reversal only for life-threatening or critical-site bleeding.
• Spinal/epidural hematoma: FDA boxed warning for all DOACs and LMWH with neuraxial anesthesia; the ASRA regional anesthesia guidelines dictate drug-specific hold intervals before catheter placement/removal.

Agent-specific toxicities

• Heparin-induced thrombocytopenia (HIT): IgG antibodies against platelet factor 4–heparin complexes crosslink FcγRIIa, causing platelet activation, thrombin generation, and paradoxical thrombosis despite a falling count. Per the ASH 2018 HIT guideline, stop all heparin, start a non-heparin agent (direct thrombin inhibitor such as argatroban, or fondaparinux/a DOAC), and confirm with immunoassay plus a functional serotonin-release assay.
• Heparin, other: hyperkalemia from aldosterone suppression, transaminitis, and osteoporosis with prolonged use (more with UFH than LMWH).
• Warfarin: skin necrosis from early depletion of protein C (shortest half-life of the vitamin K–dependent proteins), unmasking underlying protein C or S deficiency; purple toe syndrome from cholesterol microembolization; and teratogenicity (*fetal warfarin syndrome*—nasal hypoplasia, stippled epiphyses), so heparin/LMWH is used in pregnancy. Interactions run through CYP2C9 and dietary vitamin K.
• Aspirin: COX-1 inhibition strips gastric prostaglandin cytoprotection, causing ulcers/GI bleed; tinnitus and mixed respiratory alkalosis–anion gap acidosis in overdose; Reye syndrome in febrile children (AAP advises avoidance); aspirin-exacerbated respiratory disease (Samter triad).
• P2Y12 inhibitors: clopidogrel efficacy falls in CYP2C19 loss-of-function metabolizers; prasugrel is contraindicated after stroke/TIA; ticagrelor causes dyspnea and bradyarrhythmias and requires low-dose aspirin.
• GP IIb/IIIa inhibitors: acute profound thrombocytopenia within hours.

• Thrombocytopenia + new thrombosis on day 5–10 of heparin = HIT: the single best next step is to *stop all heparin (including flushes) and start a non-heparin anticoagulant*—not simply "stop heparin and observe." Never start warfarin alone in acute HIT; protein C depletion precipitates venous limb gangrene. Wait for platelet recovery, then overlap.
• Warfarin skin necrosis over fatty tissue on day 3–5 is the classic stem for underlying protein C deficiency; the mechanism is transient hypercoagulability, the same reason heparin bridging is required for acute thrombosis.
• Heparin resistance (aPTT won't rise despite escalating doses) points to *antithrombin III deficiency*—heparin has no intrinsic activity and works only as an ATIII catalyst.
• Lab pairing examiners love: warfarin prolongs PT/INR (extrinsic, factor VII shortest half-life); UFH prolongs aPTT (intrinsic). A common distractor is monitoring LMWH with aPTT—LMWH is followed with an anti-Xa level, and only in pregnancy, obesity, or renal impairment.
• Mechanical prosthetic valve = warfarin, full stop. DOACs are contraindicated there (higher thromboembolism and bleeding with dabigatran), as they are in moderate-to-severe rheumatic mitral stenosis, per the ACC/AHA valvular guideline. The same logic applies in pregnancy—warfarin is teratogenic, so LMWH/UFH is used, and DOACs are not recommended.
• Match the reversal agent: protamine for UFH (partial for LMWH, useless for fondaparinux), vitamin K plus 4-factor PCC for warfarin (PCC over FFP for life-threatening bleeding), idarucizumab for dabigatran, andexanet alfa for factor Xa inhibitors. Vitamin K alone is too slow for an actively bleeding patient.
• Aspirin's effect is irreversible for the platelet's ~7–10 day lifespan, so its "antidote" is transfused platelets; a normal platelet count with prolonged bleeding time is the classic profile.
• Clopidogrel is a prodrug: CYP2C19 loss-of-function alleles or omeprazole co-administration blunt activation—switch to pantoprazole or a different P2Y12 inhibitor. Per the ACC/AHA/ACCP/HRS atrial fibrillation guideline, DOACs are preferred over warfarin in most nonvalvular AF patients meeting CHA₂DS₂-VASc thresholds.