Antiplatelet, Anticoagulant, and Fibrinolytic Drugs¶
Chapter 123 | Part 4: Oncology and Hematology · Part 4 – Hematologic Disorders & Hemostasis · Chapter 123
Key Clinical Points¶
- Arterial thrombi are platelet-rich (white); venous thrombi are fibrin-rich (red).
- Aspirin irreversibly acetylates COX-1, inhibiting thromboxane A2 synthesis.
- Thienopyridines (clopidogrel, prasugel) irreversibly block P2Y12 receptors; ticagrelor is a reversible P2Y12 inhibitor.
- GP IIb/IIIa antagonists (abciximab, eptifibatide, tirofiban) block the final common pathway of fibrinogen and von Willebrand factor (VWF) binding.
- Heparin binds antithrombin via a pentasaccharide sequence to inhibit factor Xa and thrombin; LMWH has a higher anti-factor Xa to anti-thrombin ratio than unfractionated heparin.
- Prasugrel is contraindicated in patients >75 years or with prior stroke/TIA.
- Ticagrelor is associated with dyspnea in up to 15% of patients.
- Vorapaxar inhibits thrombin-mediated activation by targeting the PAR-1 receptor.
- Warfarin's efficacy and dosage are influenced by CYP2C9 and VKORC1 polymorphisms.
- Fibrinolytic agents (alteplase, tenecteplase, reteplase) differ in half-life and resistance to PAI-1 inhibition.
1. DEFINITION & OVERVIEW¶
Thromboembolic disorders are major causes of morbidity and mortality. Thrombosis occurs in arteries or veins, with distinct mechanisms:
• Arterial thrombosis: Platelet-rich, triggered by vessel injury and high shear forces (e.g., MI, stroke). ◦ Appearance: White due to platelet dominance. • Venous thrombosis: Fibrin-rich, initiated by stasis and tissue factor exposure (e.g., DVT, PE). ◦ Appearance: Red due to trapped RBCs.
1.1 Distinction Between Arterial and Venous Thrombosis¶
Key differences in clot composition and pathogenesis:
• Arterial thrombosis: ◦ Platelet adhesion to collagen/VWF under high shear. ◦ Thromboxane A2 release amplifies platelet aggregation. ◦ GP IIb/IIIa receptor activation mediates fibrinogen bridging. • Venous thrombosis: ◦ Initiated by stasis and tissue factor exposure. ◦ Fibrin dominates due to low shear conditions. ◦ Antithrombin-heparin complex inhibits factor Xa and thrombin.
2. EPIDEMIOLOGY¶
Venous thrombosis (VTE) risk factors include:
• Genetic: Factor V Leiden, prothrombin G20210A mutation, antithrombin/protein C/S deficiencies. • Acquired: Obesity, pregnancy, cancer, immobility, hyperhomocysteinemia.
Incidence: 4.3-fold increased risk in pregnant/postpartum women (199.7 per 100,000 woman-years).
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Thrombosis involves interplay between coagulation, fibrinolysis, and platelet activation:
• Fibrinolytic defects: PAI-1 4G/5G polymorphism, TAFI elevation (linked to DVT/CVD). • Metabolic syndrome: Increased PAI-1, reduced fibrinolysis, procoagulant state. • Inflammation: Neutrophils/macrophages modulate thrombus formation/resolution.
3.1 Fibrinolysis and Thrombosis¶
• tPA/PAI-1 imbalance reduces fibrinolytic activity. • TAFI elevation stabilizes fibrin clots, increasing thrombotic risk.
4. CLINICAL FEATURES¶
Clinical manifestations depend on thrombus location:
• Arterial: Acute MI (chest pain), ischemic stroke (neurological deficits), limb gangrene. • Venous: DVT (calf swelling, Homan's sign), PE (pleuritic chest pain, hypoxia).
5. DIFFERENTIAL DIAGNOSIS¶
Distinguish based on thrombus composition and clinical context:
• Arterial vs venous: White vs red thrombi; acute vs chronic presentation. • Thrombophilia screening: Factor V Leiden, protein C/S levels, PAI-1 genotype.
6. DIAGNOSTIC APPROACH¶
- Initial Screening for DVT/PE:
- Perform D-dimer.
- Perform compression ultrasound.
- Perform CT pulmonary angiography.
- Genetic Testing (Indicated in recurrent VTE or family history):
- Factor V Leiden (PCR).
- Prothrombin G20210A mutation.
- Protein C/S activity assays.
- Fibrinolytic Assays:
- PAI-1 activity.
- TAFI plasma levels.
7. MANAGEMENT & TREATMENT¶
Therapeutic strategies depend on thrombus type:
• Arterial: Antiplatelet agents (aspirin, clopidogrel) + anticoagulants (rivaroxaban). • Venous: LMWH/DOACs (apixaban, rivaroxaban) for DVT/PE. • Fibrinolytics: Systemic alteplase for massive PE; catheter-directed therapy for extensive DVT.
7.1 Antiplatelet Drugs¶
Mechanism of action and clinical application:
• Aspirin: Irreversible COX-1 inhibition (75–325 mg/day). Inhibits TXA2 synthesis. • Thienopyridines: - Clopidogrel (75 mg/day): Requires CYP2C19 activation. - Prasugrel (10 mg/day): Requires CYP2C19 activation; contraindicated in patients >75 years or with prior stroke/TIA. • Ticagrelor: Reversible P2Y12 inhibitor (90 mg BID); associated with dyspnea in up to 15% of patients; discontinue 5 days before surgery. • Cangrelor: Reversible P2Y12 inhibitor. • GP IIb/IIIa Antagonists (Block final common pathway): - Abciximab (0.25 mg/kg IV). - Eptifibatide (180 mcg/kg IV). - Tirofiban.
7.2 Heparin and LMWH¶
• Unfractionated Heparin: Binds antithrombin via pentasaccharide sequence; inhibits factor Xa and thrombin (requires chain length ≥18 units). • LMWH: Higher anti-factor Xa to anti-thrombin ratio than unfractionated heparin; more predictable response; lower risk of heparin-induced thrombocytopenia (HIT). • Fondaparinux: Synthetic pentasaccharide; specifically accelerates factor Xa inhibition by antithrombin; no thrombin activity.
7.3 Direct Thrombin Inhibitors¶
Used as alternatives or specific agents:
• Desirudin (Half-life: 60 min IV). • Bivalirudin (Half-life: 25 min). • Argatroban (Half-life: 45 min).
7.4 DOACs¶
Direct Oral Anticoagulants:
• Rivaroxaban: Factor Xa inhibitor; 80% bioavailability. • Apixaban: Factor Xa inhibitor; 60% bioavailability. • Edoxaban: Factor Xa inhibitor; 50% bioavailability. • Dabigatran: Thrombin inhibitor; 6% bioavailability.
7.5 Fibrinolytic Agents¶
Mechanism of action for clot dissolution:
• Streptokinase: Binds to plasminogen → conformational change → activates additional plasminogen. • Alteplase (tPA): Standard tPA; contains F, EGF, K1, K2, and P domains. • Tenecteplase (TNK-tPA): Modified at P domain (substitution of "KHRR" with "AAAA" at positions 296–299); longer half-life; resistant to PAI-1 inhibition. • Reteplase (r-PA): Truncated variant; lacks F, EGF, and K1 domains.
8. PROGNOSIS & COMPLICATIONS¶
Major bleeding risks:
• Aspirin: 1–3% annual risk; increased with combination therapy. • GP IIb/IIIa inhibitors: Thrombocytopenia (5% for abciximab, 1% for others). • Vorapaxar: Increased intracranial bleeding risk. • Heparin-Induced Thrombocytopenia (HIT): - Criteria: Platelet count ≤100,000/μL or a decrease in platelet count of ≥50%. - Management: 1. Stop all heparins. 2. Give alternative anticoagulant (argatroban, bivalirudin, fondaparinux, or rivaroxaban). 3. Do not give platelet transfusions. 4. Do not give warfarin until the platelet count returns to its baseline level; if warfarin was administered, give vitamin K to restore the INR to normal. 5. Evaluate for thrombosis, particularly deep vein thrombosis.
9. SPECIAL CONSIDERATIONS¶
• Prasugrel: Contraindicated in patients >75 years or with prior stroke/TIA. • Ticagrelor: Discontinue 5 days before surgery; monitor for dyspnea (15%). • Warfarin: Dosage must be adjusted based on CYP2C9 and VKORC1 genotypes. • LMWH vs Heparin: LMWH preferred for predictable response and lower HIT risk.
10. KEY PEARLS & CLINICAL TRAPS¶
• Aspirin Resistance: Not routinely tested; no proven benefit of higher doses. • Combination Therapy: Clopidogrel + aspirin reduces MI/stroke risk by 20% but increases bleeding (2%/year). • Ticagrelor: Dyspnea is common (15%) but typically self-limiting. • Fibrinolysis Regulation: PAI-1 and α_2-antiplasmin are the primary regulators of the fibrinolytic system.
Reference Tables¶
TABLE 123-1 Features of Gp IIb/IIIa Antagonists FEATURE Description¶
Harrison's 22e, p.945
| FEATURE | ABCIXIMAB | EPTIFIBATIDE | TIROFIBAN |
|---|---|---|---|
| Description | Fab fragment of humanized mouse monoclonal antibody |
Cyclical KGD- containing heptapeptide |
Nonpeptidic RGD mimetic |
| No | Yes | ||
| Plasma half-life | Short (min) | Long (2.5 h) | Long (2.0 h) |
| Long (days) | Short (s) | ||
| Renal clearance | No | Yes | Yes |
TABLE 123-2 Pharmacokinetic and Biophysical Limitations of Heparin LIMITATIONS Poor bioavailability at low doses…¶
Harrison's 22e, p.947
| LIMITATIONS | MECHANISM |
|---|---|
| Poor bioavailability at low doses | Binds to endothelial cells and macrophages |
| Variable anticoagulant response | Binds to plasma proteins whose levels vary from patient to patient |
| Limited activity against factor Xa incorporated in the prothrombinase complex and thrombin bound to fibrin |
Reduced capacity of heparin- antithrombin complex to inhibit factor Xa bound to activated platelets and thrombin bound to fibrin |
TABLE 123-3 Features of Heparin-Induced Thrombocytopenia FEATURES Thrombocytopenia Timing Type of heparin Type of…¶
Harrison's 22e, p.948
| FEATURES | DETAILS |
|---|---|
| Thrombocytopenia | Platelet count of ≤100,000/μL or a decrease in platelet count of ≥50% |
| Type of heparin | More common with unfractionated heparin than low- molecular-weight heparin |
| Thrombosis | Venous thrombosis more common than arterial thrombosis |
TABLE 123-5 Advantages of LMWH Over Heparin ADVANTAGE Better bioavailability and longer half- life after subcutaneous…¶
Harrison's 22e, p.948
| ADVANTAGE | CONSEQUENCE |
|---|---|
| Better bioavailability and longer half- life after subcutaneous injection |
Can be given subcutaneously once or twice daily for both prophylaxis and treatment |
TABLE 123-4 Management of Heparin-Induced Thrombocytopenia Stop all heparins. Give an alternative anticoagulant, such…¶
Harrison's 22e, p.948
| Stop all heparins. | |
|---|---|
| Give an alternative anticoagulant, such as argatroban, bivalirudin, fondaparinux, or rivaroxaban. |
|
| Do not give platelet transfusions. | |
| Do not give warfarin until the platelet count returns to its baseline level. If warfarin was administered, give vitamin K to restore the INR to normal. |
|
| Evaluate for thrombosis, particularly deep vein thrombosis. | |
| Predictable anticoagulant response | Coagulation monitoring is unnecessary in most patients |
| Lower risk of osteoporosis | Safer than heparin for extended administration |
TABLE 123-6 Comparison of LMWH and Fondaparinux FEATURES Number of saccharide units Catalysis of factor Xa inhibition…¶
Harrison's 22e, p.949
| FEATURES | LMWH | FONDAPARINUX |
|---|---|---|
| Number of saccharide units | 15–17 | 5 |
| Yes | ||
| Catalysis of thrombin inhibition | Yes | No |
| 90 | ||
| Plasma half-life (h) | 4 | 17 |
| Yes | ||
| Induces release of tissue factor pathway inhibitor | Yes | No |
| Partially |
TABLE 123-7 Comparison of the Properties of Desirudin, Bivalirudin, and Argatroban Molecular mass Site(s) of…¶
Harrison's 22e, p.950
| DESIRUDIN | BIVALIRUDIN | ARGATROBAN | |
|---|---|---|---|
| Molecular mass | 7000 | 1980 | 527 |
| Active site and exosite 1 |
Active site and exosite 1 |
||
| Renal clearance | Yes | No | No |
| No | No | ||
| Plasma half-life (min) | 60 (IV) 120–180 (SC) |
25 | 45 |
TABLE 123-8 Frequencies of CYP2C9 Genotypes and VKORC1 Haplotypes in Different Populations and their Effect on Warfarin…¶
Harrison's 22e, p.951
| GENOTYPE/ HAPLOTYPE |
FREQUENCY, % | PERCENTAGE DOSE REDUCTION COMPARED WITH WILD-TYPE |
||
|---|---|---|---|---|
| CAUCASIANS | AFRICAN AMERICANS (A/A) |
ASIANS (A) | ||
| CYP2C9 | ||||
| 1/1 | 70 | 90 | 95 | — |
| 1/2 | 17 | 2 | 0 | 22 |
| 1/3 | 9 | 3 | 4 | 34 |
| 2/2 | 2 | 0 | 0 | 43 |
| 2/3 | 1 | 0 | 0 | 53 |
| 3/3 | 0 | 0 | 1 | 76 |
| VKORC1 | ||||
| 37 | 82 | 7 | ||
| 45 | 12 | 30 | ||
| 18 | 6 | 63 |
TABLE 123-9 Comparison of the Pharmacologic Properties of the Direct Oral Anticoagulants CHARACTERISTIC Target Prodrug…¶
Harrison's 22e, p.953
| CHARACTERISTIC | RIVAROXABAN | APIXABAN | EDOXABAN | DABIGATRAN |
|---|---|---|---|---|
| Target | Factor Xa | Factor Xa | Factor Xa | Thrombin |
| No | No | No | ||
| Bioavailability | 80% | 60% | 50% | 6% |
| qd (bid) | bid | qd | ||
| Half-life | 7–11 h | 12 h | 9–11 h | 12–17 h |
| 33% (66%) | 25% | 35% | ||
| Interactions | 3A4/P-gp | 3A4/P-gp | P-gp | P-gp |