Anticoagulants and antiplatelet agents: mechanisms, drugs, and therapy monitoring

1. Hemostasis: Core Concepts

The hemostatic system is divided into primary (vascular-platelet) and secondary (plasma coagulation) hemostasis. Primary hemostasis involves platelet plug formation; secondary hemostasis involves fibrin reinforcement.

The plasma cascade includes two pathways: the extrinsic pathway (factor VII, assessed via PT/INR) and the intrinsic pathway (factors XII, XI, IX, VIII, assessed via aPTT), converging at factor X (common pathway) → thrombin → fibrin.

2. Classification of Anticoagulants

Direct

• Heparins: unfractionated heparin (UFH), low-molecular-weight heparins (LMWH — enoxaparin, nadroparin, dalteparin).
• Direct thrombin inhibitors: dabigatran (oral), bivalirudin, argatroban (parenteral).
• Direct factor Xa inhibitors: rivaroxaban, apixaban, edoxaban (oral); fondaparinux (parenteral).

Indirect (Vitamin K Antagonists)

• Warfarin, acenocoumarol.

3. Heparins

Unfractionated Heparin

• Mechanism: binds to antithrombin III → accelerates the inactivation of thrombin (IIa) and factor Xa (1:1).
• Route of administration: IV infusion, SC.
• Monitoring: aPTT (target 1.5–2.5 × control); anti-Xa in patients on ECMO.
• Indications: acute coronary syndrome, massive PE, emergency surgery, pregnancy.
• Adverse effects: bleeding, HIT (heparin-induced thrombocytopenia), osteoporosis with prolonged use.
• Antidote: protamine sulfate 1 mg neutralizes 100 IU of heparin.

Low-Molecular-Weight Heparins

• Predominant inhibition of factor Xa (anti-Xa/anti-IIa ratio 3–4:1).
• Subcutaneous administration, no routine laboratory monitoring required for most patients.
• Minimal risk of HIT and osteoporosis.
• Contraindicated in CKD with GFR < 30 (accumulation).
• Monitoring in pregnancy, obesity, CKD: anti-Xa activity.

4. Warfarin

• Mechanism: blockade of vitamin K epoxide reductase → impaired γ-carboxylation of factors II, VII, IX, X, as well as proteins C and S.
• Administration: oral, onset of action in 48–72 hours (due to long half-life of factor II depletion), peak at 3–5 days.
• Monitoring: INR (see target values in the table below).
• Metabolized via CYP2C9 and VKORC1 — numerous drug and dietary interactions (vitamin K-rich foods: green leafy vegetables, liver).
• Indications: non-valvular AF, prosthetic heart valves (especially mechanical), antiphospholipid syndrome, recurrent VTE failing DOAC therapy.
• Antidote: vitamin K₁, 4-factor prothrombin complex concentrate (KCentra) for major bleeding.

5. DOACs (Direct Oral Anticoagulants)

Advantages over warfarin: no laboratory monitoring, fixed dose, fewer drug interactions, lower risk of intracranial hemorrhage. Limitations: CKD (especially dabigatran — mandatory GFR > 30), mechanical heart valves (contraindicated), triple-positive APS.

6. Antiplatelet agents

Aspirin (ASA)

• Irreversible inhibition of platelet COX-1 → ↓ thromboxane A₂ synthesis.
• Effect lasts for the entire platelet lifespan (7–10 days).
• Doses: low (75–100 mg/day) — antiplatelet; high — anti-inflammatory.

P2Y₁₂ inhibitors

GPIIb/IIIa inhibitors

Abciximab, eptifibatide, tirofiban — IV, used in high-risk PCI and stent thrombosis. Effective, but increase bleeding risk.

7. Dual antiplatelet therapy (DAPT)

• Post-ACS — ASA + ticagrelor/prasugrel/clopidogrel for 12 months.
• Post-elective PCI — ASA + clopidogrel for 6 months (duration may be shortened in high bleeding risk).
• In high ischemic risk — extending DAPT beyond 12 months.

8. Complications and bleeding management

• Assessment of bleeding severity (BARC, TIMI, GUSTO scales).
• Discontinuation of antithrombotic therapy in life-threatening bleeding.
• Administration of specific antidotes (see tables above).
• Transfusion support (FFP, factor concentrates), antifibrinolytics (tranexamic acid) in surgical bleeding.
• HIT — complete discontinuation of heparin, switch to direct thrombin inhibitors (argatroban, fondaparinux).

9. Perioperative management

• Low-dose ASA — usually continued in most surgeries.
• Clopidogrel — discontinue 5 days before major surgery; individual approach if stented.
• Warfarin — discontinue 5 days prior, target INR < 1.5, LMWH "bridge" in high thrombotic risk (mechanical valves, recent VTE).
• DOACs — discontinue 24–48 hours prior for low bleeding risk, 48–72 hours for high risk (also depends on GFR).

10. FAQ

When to choose a DOAC vs. warfarin?
DOACs are the first-line standard for non-valvular AF and VTE. Warfarin is used for mechanical heart valves, triple-positive APS, and end-stage CKD where DOACs are contraindicated.

What is HIT and when to suspect it?
Heparin-induced thrombocytopenia is an immune-mediated condition where platelet count drops by 4–10 days by > 50% from baseline, paradoxically increasing thrombotic risk. Calculated using the 4Ts score.

What to do in massive bleeding on warfarin?
Discontinue warfarin, administer vitamin K 5–10 mg IV, 4-factor PCC (50 IU/kg). FFP if concentrates are unavailable.

Can an anticoagulant and an antiplatelet be combined?
Temporarily — yes (AF + ACS require triple therapy, followed by dual therapy). Individualized decision with bleeding risk assessment using HAS-BLED and CHA₂DS₂-VASc scores.

Why is the CHA₂DS₂-VASc score needed?
To assess stroke risk in AF. ≥ 2 points in men or ≥ 3 in women is an indication for lifelong anticoagulation. An online calculator is available.

See also: PE · Myocardial infarction · Stroke · Antihypertensives · CHA₂DS₂-VASc · HAS-BLED · Pharmacology catalog