Anticoagulants, Antiplatelets, and Thrombolytics Notes

Hemostasis Physiology Review

• Understanding hemostasis physiology and vocabulary is crucial for understanding anticoagulant and antiplatelet drugs.
• Hypercoagulation leads to excessive clot formation, causing obstructions, pulmonary embolism (PE), and stroke.
• The body has mechanisms to control clotting and remove clots to prevent hypercoagulation.

Types of Thrombi

• Arterial thrombi
• Venous thrombi

Hemostasis Stages

• Stage 1: Platelet Plug Formation
  • Platelet aggregation: Platelets clump together, forming a temporary fix.
  • Facilitated by collagen, thrombin, platelet activation factor (PAF), adenosine diphosphate (ADP), and thromboxane A (TXA_2).
• Stage 2: Coagulation
  • The coagulation cascade converts fibrinogen to fibrin, creating a stable clot.
  • Fibrinogen to fibrin.

Coagulation Pathways

• Intrinsic pathway: Activated by internal vessel damage.
• Extrinsic pathway: Activated by external damage.
• Pathways converge, providing targets for anticoagulant drugs.
• Conversion of plasminogen to plasmin.

Platelet Aggregation Details

• Inactive platelets float freely.
• Injury activates collagen, thrombin, PAF, ADP, and thromboxane A2 (TXA_2).
• Activation of platelets.
  • Glycoprotein IIb/IIIa receptors become activated.
  • Fibrinogen binds to receptors, linking platelets.
  • ADP and thromboxane A(TXA_2) stimulate platelet aggregation and coagulation.

Coagulation Cascade

• Intrinsic pathway: Contact activation.
• Extrinsic pathway: Tissue factor activation.
• Coagulation factors activate each other in a self-reinforcing cascade.
• Drugs like warfarin and heparin inhibit specific factors in the cascade.
• Factor Xa is a critical intersection point in the cascade.

Role of Thrombin

• Thrombin (Factor IIa) is essential for converting fibrinogen to fibrin.
• Heparin enhances antithrombin activity, inhibiting thrombin and preventing fibrin formation

Fibrinolysis

• Plasminogen is converted to plasmin, which breaks down fibrin clots.
• This process keeps hemostasis under control and removes clots.

Arterial vs. Venous Thrombosis

• Arterial Thrombosis
  • Occurs in arteries, often in the heart.
  • Caused by plaque rupture, leading to platelet aggregation.
• Venous Thrombosis
  • Occurs in veins, usually in the legs (deep vein thrombosis - DVT).
  • Caused by sluggish blood flow, not plaque rupture.
  • Venous thrombi can cause pulmonary embolism (PE) if the clot travels.

Pharmacology Overview

• Anticoagulants: Disrupt the coagulation cascade and suppress fibrin production.
• Antiplatelet drugs: Inhibit platelet aggregation.
• Thrombolytics: Promote lysis of fibrin via plasmin, dissolving thrombi.
• All three classes of drugs increase the risk of hemorrhage.

Anticoagulants

• Inhibit activity of clotting factors (Xa, thrombin).
• Inhibit synthesis of clotting factors.

Heparin and Derivatives

• Unfractionated Heparin: Enhances antithrombin activity, inhibiting thrombin (Factor IIa).
  • Derived from animal sources.
  • Rapid-acting anticoagulant for emergencies.
  • Administered IV (continuous or intermittent) or SubQ.
  • Does not cross mucous membranes.
• Low Molecular Weight Heparin (LMWH): E.g., Enoxaparin (Lovenox).
  • Shorter chain molecule, more predictable.
  • Less problematic than unfractionated heparin.
• Fondaparinux: Synthetic heparin.

Heparin Types Configuration

• Unfractionated Heparin: Long, highly polar polysaccharide chain.
• Low Molecular Weight Heparin: Shorter chain.
• Fondaparinux: Shortest, synthetic.

Unfractionated Heparin

• Inhibits Factors Xa and thrombin, preventing fibrin formation.
• Therapeutic Uses:
  • Rapid anticoagulation.
  • Preferred during pregnancy (does not cross the placenta).
  • Pulmonary embolism (PE), evolving stroke, DVT.
  • Open-heart surgery and renal dialysis.
  • Low-dose post-operative injections for DVT prevention.
• Administration: IV or SubQ.

Unfractionated Heparin - Monitoring and Adverse Effects

• Adverse Effects: Hemorrhage (bleeding).
• Monitor for:
  • Hypotension, increased heart rate, bruising, mental status changes.
  • Black tarry stools (GI bleeding).
  • Pain out of proportion.
• Heparin-Induced Thrombocytopenia (HIT): Immune-mediated disorder.
  • Reduced platelet count, increased thrombotic events.
  • Monitor platelet counts in the first few days.
• Hypersensitivity reactions.

Unfractionated Heparin - Contraindications and Antidote

• Contraindications:
  • Existing risk of severe bleeding.
  • Surgery on the eye, brain, or spinal cord.
  • Thrombocytopenia.
• Antidote: Protamine sulfate.
  • Immediate effect, 2-hour duration.
  • Given by slow IV injection.

Unfractionated Heparin - Laboratory Monitoring

• Activated Partial Thromboplastin Time (aPTT)
  • Target: 60-80 seconds (1.5-2 times normal value of 40 seconds).
  • Monitor every 4-6 hours.
• Anti-Factor Xa Assay
  • Alternative to aPTT, more expensive.
• Titrate, do not abruptly stop

Low Molecular Weight Heparins (LMWH)

• Shorter chain molecules.
• Example: Enoxaparin (Lovenox).
• Therapeutic Uses:
  • Prevention of DVT after surgery.
  • Treatment of established DVT, prevention of ischemic complications.
• Administered SubQ.
• No aPTT monitoring required.
• Protamine sulfate is the antidote.

Oral Anticoagulants

Warfarin (Coumadin)

• Vitamin K antagonist; blocks synthesis of factors VII, IX, X, and prothrombin.
• Delayed onset, not for emergencies.
• Long-term prophylaxis against thrombosis.
• Drug of choice for mechanical heart valves.
• Long half-life (remains in system for 2-5 days).
• PT (Prothrombin Time) and INR (International Normalized Ratio), aim for INR of 2-3 in most clinical situations but 2.5-3.5 in patients with mechanical heart valves
• Hemorrhage is number one adverse effect; patients wear MedicAlert bracelets.
• Contraindicated in pregnancy (teratogenic).
• Vitamin K is the antidote.

Warfarin Monitoring Frequency

• Labs (PT/INR) must be completed:
  • Daily for the first 5 days.
  • Twice a week for 1-2 weeks.
  • Once a week for 1-2 months.
  • Every 2-4 weeks thereafter.

Direct Thrombin Inhibitors (Oral)

Dabigatran (Pradaxa)

• Directly inhibits thrombin.
• Advantages:
  • No monitoring of anticoagulation required.
  • Fewer interactions.
  • Fixed dose.
• Uses: Atrial fibrillation, hip/knee replacement, DVT/PE treatment.
• Adverse Effects: Bleeding, GI disturbances (abdominal pain, bloating, nausea).
• Idarucizumab (Praxbind) is the antidote.

Direct Factor Xa Inhibitors (Oral)

Rivaroxaban (Xarelto)

• Directly inhibits Factor Xa.
• Uses: Prevention of DVT/PE after surgery, stroke prevention in atrial fibrillation, treatment of DVT/PE.
• Advantages: Rapid onset, fixed dose, no monitoring.
• Adverse Effects: Bleeding.
• Andexanet alfa is the antidote.

Antiplatelet Drugs

Aspirin

• Inhibits cyclooxygenase, preventing platelet activation.
• Therapeutic Uses:
  • Ischemic stroke, TIAs, chronic stable angina, acute MI.
  • Primary prevention of MI in specific age groups.
• Adverse Effects: GI bleeding, hemorrhagic stroke.

Clopidogrel (Plavix)

• Reduces thrombotic events in acute coronary syndrome.
• Prevents stenosis in coronary stents.
• Reduces risk in MI, ischemic stroke and vascular events.
• Less risk for GI bleeding, less risk for intracranial hemorrhage.
• Potential fatal conditions characterized by thrombocytopenia, hemolytic anemia, and neurologic symptoms.
• Consult physician before stopping therapy.
• Interacts w/ proton pump inhibitors.

Glycoprotein IIb/IIIa Receptor Antagonists

Eptifibatide and Tirofiban

• Reversibly block glycoprotein IIb/IIIa receptors on platelets.
• Intravenous administration.
• Uses: Percutaneous coronary intervention (PCI), acute coronary syndrome.

Thrombolytics

Tissue Plasminogen Activator (TPA)

• Bind to plasminogen to from an active complex to prevent conversion to plasmin.
• Used for: Myocardial infarction, ischemic stroke, or massive pulmonary emboli.
• Dosage is weight based, continuous infusion milligrams per kilogram, always given IV.
• Greatest risk of intracranial bleeding.