8.4 Anticoagulants, Antiplatelets, Thrombolytics & Reversal Agents

Parenteral Anticoagulation & Heparin-Induced Thrombocytopenia

Parenteral anticoagulants interrupt the coagulation cascade to prevent thrombus propagation in Acute Coronary Syndromes (ACS), Venous Thromboembolism (VTE), and percutaneous coronary interventions (PCI). Vigilant laboratory monitoring and rapid detection of adverse immune responses are mandatory nursing responsibilities.

1. Unfractionated Heparin (UFH)

• Mechanism of Action: High-molecular-weight mucopolysaccharide that binds to antithrombin III (ATIII). This binding produces a conformational change in ATIII, accelerating its inhibition of Factor IIa (thrombin) and Factor Xa by 1,000-fold.
• Laboratory Monitoring: Monitored using activated partial thromboplastin time (aPTT, target 1.5 to 2.5× control, typically 60–80 seconds) or anti-Factor Xa assay (target 0.3 to 0.7 units/mL). Titrated using standardized nurse-driven protocol tables.
• ACS Dosing Protocol: Initial IV bolus 60 units/kg (maximum 4,000 units), followed by continuous infusion at 12 units/kg/hr (maximum 1,000 units/hr).
• Heparin-Induced Thrombocytopenia (HIT): Immune-mediated Type II HIT occurs in up to 3% of patients exposed to UFH. Pathophysiology: Exposure to heparin induces formation of IgG autoantibodies against the Heparin-Platelet Factor 4 (PF4) complex. The immune complex binds platelet Fcgamma RIIa receptors, triggering intense systemic platelet activation, microvascular thrombosis, and rapid platelet consumption.
• Clinical Recognition & 4Ts Score: Suspect HIT if platelet count drops by >50% from baseline or absolute count falls <100,000/μ L, typically developing 5–14 days after heparin initiation (or <24 hours if exposed to heparin within the past 100 days). Calculate the 4Ts Score (Thrombocytopenia, Timing of platelet drop, Thrombosis presence, oTher causes of thrombocytopenia).
• Emergency HIT Nursing Protocol:
  1. IMMEDIATELY DISCONTINUE all heparin products (including UFH drips, subcutaneous heparin, LMWH, heparin flushes, and heparin-coated catheters).
  2. DO NOT administer platelet transfusions (transfused platelets act as fuel for the antibody-driven thrombotic fire).
  3. Initiate an alternative non-heparin parenteral Direct Thrombin Inhibitor (DTI):
     • Bivalirudin: Direct, reversible DTI. Short half-life (25 minutes), cleared via combination of intravascular proteolysis (80%) and renal elimination (20%). Preferred in PCI and in hepatic impairment; because roughly 20% is renally cleared it requires dose reduction in renal impairment, so argatroban is the better choice in severe AKI.
     • Argatroban: Synthetic direct DTI. Monitored via aPTT (1.5 to 2.5× baseline). Cleared exclusively by the liver; ideal for patients with severe acute kidney injury.

2. Low Molecular Weight Heparin (LMWH - Enoxaparin / Lovenox)

• Mechanism of Action: Depolymerized UFH fragments that selectively inhibit Factor Xa over Factor IIa (3:1 to 4:1 ratio of anti-Xa to anti-IIa activity).
• Pharmacokinetics & Dosing: High subcutaneous bioavailability (90%) with predictable pharmacokinetics. Dosing for ACS/VTE: 1 mg/kg subcutaneously Q12H. Renally cleared; if Creatinine Clearance (CrCl < 30 mL/min), adjust dosage to 1 mg/kg once daily.
• Monitoring: Routine aPTT monitoring is useless. Anti-Xa monitoring is reserved for severe obesity (BMI > 40 kg/m²), renal impairment, pregnancy, and recurrent thrombosis.

Oral Anticoagulants, Antiplatelets, Fibrinolytics & Specific Reversal Protocols

Oral Anticoagulants: Warfarin vs. DOACs

• Warfarin (Coumadin):
  • Mechanism of Action: Synthetic Vitamin K antagonist. Inhibits Vitamin K epoxide reductase complex subunit 1 (VKORC1), blocking hepatic gamma-carboxylation of Vitamin K-dependent clotting factors (Factors II, VII, IX, X) and anticoagulant Proteins C and S.
  • Monitoring & Target INRs: Monitored using International Normalized Ratio (INR).
    • Target INR 2.0 to 3.0: Non-valvular Atrial Fibrillation, VTE treatment/prevention, bioprosthetic valve replacement.
    • Target INR 2.5 to 3.5: Mechanical mitral valve prostheses, mechanical aortic valves with additional risk factors.
  • Bridging Therapy: Full anticoagulant onset requires 3–5 days due to long half-lives of Factor II (60–72 hours) and Factor X. Parenteral anticoagulation (UFH/LMWH) must overlap with Warfarin for at least 5 days AND until INR is therapeutic for ≥ 24 hours.
• Direct Oral Anticoagulants (DOACs):
  • Direct Factor Xa Inhibitors: Apixaban (Eliquis), Rivaroxaban (Xarelto), Edoxaban.
  • Direct Thrombin Inhibitor: Dabigatran (Pradaxa).
  • Clinical Indications & Contraindications: Indicated for stroke prevention in non-valvular AFib and VTE management. Absolute Contraindication: Mechanical prosthetic heart valves and moderate-to-severe mitral stenosis (RE-ALIGN trial demonstrated excess stroke and valve thrombosis with Dabigatran).

Antiplatelet Therapy Strategies

• Aspirin (ASA): Irreversibly acetylates platelet cyclooxygenase-1 (COX-1), blocking Thromboxane A2 (TXA₂) synthesis for the 7–10 day lifespan of the platelet. Loading dose: 162 to 325 mg non-enteric coated chewed; maintenance: 81 mg daily.
• P2Y₁₂ Receptor Antagonists:
  • Clopidogrel (Plavix): Irreversible prodrug requiring two-step hepatic CYP2C19 bioactivation. Reduced efficacy in CYP2C19 poor metabolizers or when co-administered with CYP2C19 inhibitors (omeprazole). Loading: 300–600 mg; maintenance: 75 mg daily.
  • Prasugrel (Effient): Irreversible prodrug; more rapid and potent platelet inhibition than clopidogrel. Contraindicated in patients with prior stroke or TIA (high intracranial bleeding risk).
  • Ticagrelor (Brilinta): Direct-acting, reversible P2Y₁₂ inhibitor (not a prodrug). Dosed 90 mg BID. Special AACN Mandate: Maintenance Aspirin dose co-administered with Ticagrelor MUST NOT exceed 100 mg daily (81 mg daily standard in US); higher aspirin doses reduce ticagrelor efficacy (PLATO trial). Side effects: dyspnea and ventricular pauses.
  • Cangrelor (Kengreal): Intravenous reversible P2Y₁₂ inhibitor with immediate onset (2 min) and short half-life (3--6 min) for PCI.
• Glycoprotein IIb/IIIa Inhibitors (Eptifibatide / Tirofiban): IV agents blocking final common pathway of platelet aggregation. Used in high-risk PCI. Monitor for acute severe thrombocytopenia within 2–4 hours.

Fibrinolytic (Thrombolytic) Therapy

• Agents & Mechanism: Alteplase (tPA) and Tenecteplase (TNK-tPA). Recombinant tissue plasminogen activators that convert plasminogen to plasmin, degrading fibrin clots.
• STEMI Indication: Indicated for acute STEMI within 12 hours of symptom onset when primary PCI cannot be performed within 120 minutes of first medical contact. Door-to-needle target time is <30 minutes. Tenecteplase is administered as a single weight-based IV bolus.
• Absolute Contraindications: Any prior intracranial hemorrhage, known structural cerebrovascular lesion, malignant intracranial neoplasm, ischemic stroke within 3 months, active internal bleeding (excluding menses), significant closed-head trauma within 3 months, suspected aortic dissection.

Specific Pharmacologic Reversal Protocols