Section 6 - Anti-thrombotic (Anti-coagulant) Therapy

Thrombosis

Thrombus formation under pathological conditions into otherwise normal vessels

Thrombus

A blood Clot that forms in a vessel

Thrombi

• Solid masses formed from blood components (platelets, fibrin, RBCs) within intact blood vessels or the heart.

• Often in response to abnormal hemostasis or endothelial injury.

• Can obstruct blood flow or embolize.

Embolus

• Detached intravascular mass (thrombus, fat, air, etc.) that travels through circulation and lodges in a distant vessel.

• potentially causing obstruction and ischemia.

Emboli

• Plural of embolus

• multiple intravascular particles (e.g., thrombi, fat, air, tumor) that travel through blood and obstruct distant vessels.

• often leading to tissue ischemia or infarction.

Mechanism of DIC

Trigger: endothelial damage or tissue thromboplastin release
• Initiates systemic activation of coagulation cascade
• Widespread microvascular thrombi form
• Platelets and clotting factors consumed
• ↓ Fibrinogen, thrombocytopenia
• Ischemia and infarction from blocked vessels
• Bleeding from lack of clotting components
• Organ failure from hypoxia and fibrin deposition

Causes of DIC (General)

• Bacterial infections → cytokines damage endothelium → expose tissue factor → initiate clotting
• Intravascular parasites → vessel wall trauma → activates intrinsic pathway
• Surgery → tissue disruption → massive thromboplastin release → triggers coagulation
• Major trauma → crush injuries release TF-rich material → widespread thrombin activation
• Casting of legs → prolonged stasis + pressure → endothelial injury → local clotting spreads
• Burns → widespread endothelial loss → exposes subendothelial collagen → triggers clotting
• Snake venom → direct procoagulant activity (thrombin-like enzymes) → uncontrolled fibrin deposition
• Acute Promyelocytic Leukemia (APL) → blasts release procoagulants (e.g., cancer procoagulant) → initiates systemic coagulation

Secondary Fibrinolysis: Complications of Pregnancy

• Dead fetus syndrome → retained fetal tissue releases thromboplastin → systemic clotting
• Amniotic fluid embolus → AF enters circulation → contains TF & procoagulants → activates clotting
• Abruption placentae → placental detachment releases large amounts of TF into maternal blood
• Preeclampsia → endothelial dysfunction and vasospasm → triggers clot formation
• Eclampsia → severe progression of preeclampsia → worsens endothelial injury
• HELLP syndrome → hemolysis + liver injury + low platelets → promotes DIC-like state
• ↑ Coagulation factors (VII, VIII, IX, XII, I) → hypercoagulable state → increases risk of widespread clotting
• ↓ Protein S → impairs anticoagulant control of thrombin → favors clot propagation

Signs of Secondary Fibrinolysis

• Oozing at IV sites, mucous membranes
• Bleeding from GI, urinary, and respiratory tracts
• Hematuria, hematemesis, epistaxis
• Diffuse bruising or petechiae
• Delayed clot formation or rebleeding
• ↑ Fibrin degradation products (e.g., D-dimer)

Anti-Thrombotics

• Used to limit or prevent clot formation
• Act by suppressing synthesis or function of hemostatic components
• Goal: prevent thrombosis while avoiding excessive bleeding (hemorrhage)
• Balance efficacy with bleeding risk management

Warfarin (Coumadin, Jantoven)

General

• Mechanism: Inhibits vitamin K epoxide reductase → prevents recycling of vitamin K → blocks γ-carboxylation of clotting factors II, VII, IX, X (and proteins C, S, Z) → produces nonfunctional factors
• Effect: Delays clot formation by reducing availability of functional vitamin K–dependent factors
• Monitoring: PT and INR (goal INR: 2–3); long half-life (~5 days)
• Caution: Interfered with by vitamin K–rich foods

Warfarin (Coumadin, Jantoven)

Uses

– Long-term anticoagulation (e.g., atrial fibrillation)
 – Mechanical heart valves
 – Treatment and prevention of DVT/PE
 – Hypercoagulable states (e.g., protein C/S deficiency)

Heparin (UFH) – Mechanism of Action

• Binds antithrombin (AT) → induces conformational change
• Enhances AT inhibition of IIa, Xa, IXa, XIa, XIIa, and plasmin
• Heparin is not consumed → acts as a cofactor repeatedly
• ↓ circulating AT with prolonged use (feedback inhibition)

Heparin (UFH) – Indications

• First-line anticoagulant for venous thrombosis, PE, acute coronary syndrome
• Used acutely, often followed by oral anticoagulants (e.g., warfarin)
• Administered IV or subQ; effects reversed with protamine sulfate

Heparin (UFH) – Monitoring & Risks

• Monitored using: APTT or Anti-Xa assay
• Expected therapeutic range:
 – APTT: 1.5–2.5× the normal reference interval
 – Anti-Xa: 0.3–0.7 IU/mL (if used)
• Monitor closely due to risk of Heparin-Induced Thrombocytopenia (HIT)
• Gradual tapering required to avoid rebound thrombosis due to ↓ antithrombin (AT)

LMWH – Mechanism of Action

Derived from UFH via depolymerization
• Binds AT and preferentially inhibits factor Xa
• Less activity against thrombin (IIa) due to shorter chain length
• Longer half-life and more predictable response than UFH

LMWH – Indications

• Treatment and prevention of DVT, PE, post-surgical thrombosis
• Often used instead of UFH due to ease of dosing
• Administered subcutaneously, does not require routine monitoring

LMWH – Monitoring & Risks

• Monitored using: Chromogenic Anti-Xa assay (only when needed)
• Expected therapeutic range:
 – Anti-Xa (twice-daily dosing): 0.6–1.0 IU/mL
 – Anti-Xa (once-daily dosing): 1.0–2.0 IU/mL
• APTT is not useful for LMWH
• Typically does not cause HIT, but may cross-react with HIT antibodies in affected patients

DTIs – Mechanism of Action

Bind directly to active site of thrombin (IIa)
• Block thrombin's ability to convert fibrinogen → fibrin
• Inhibit both free and fibrin-bound thrombin
• Effectively neutralize thrombin without antithrombin

DTIs – Indications

• Used as heparin alternatives, especially in HIT/HITTS

• Drugs include:
   – Argatroban (Novostan) – IV, half-life ~50 min
   – Bivalirudin (Angiomax) – IV, half-life ~25 min
   – Dabigatran (Pradaxa) – oral, half-life 10–18 hrs

DTIs – Monitoring & Dosing

• Monitored using: APTT
• Expected therapeutic range: 1.5–3× the mean baseline APTT
• No routine monitoring needed for dabigatran, but APTT or TT may be used if needed
• Reversal agent: Idarucizumab (for dabigatran only)
• Effective even when antithrombin (AT) levels are low or bypassed

Direct Factor Xa Inhibitors – Mechanism of Action

• Bind directly to and inhibit Factor Xa
• Prevent conversion of prothrombin (II) → thrombin (IIa)
• Block both free and clot-bound Xa
• Act independently of antithrombin

Direct Factor Xa Inhibitors – Indications

• Used in treatment and prevention of DVT, PE, stroke (AFib)
• Common agents: Rivaroxaban, Apixaban, Edoxaban
• Oral administration; do not require routine monitoring

Direct Factor Xa Inhibitors – Interference & Monitoring

• • Drugs: Rivaroxaban, Apixaban, Edoxaban
  • Monitoring test (if needed): Drug-specific chromogenic Anti-Xa assay
  • Expected therapeutic range (approximate, varies by drug/dose/timing):
   – Rivaroxaban: Peak Anti-Xa = 100–300 ng/mL
   – Apixaban: Peak Anti-Xa = 100–200 ng/mL
  • Routine monitoring not required
  • Interfere with PT and APTT → false prolongation
  • May cause false ↓ in factor assays and false ↑ in Protein C/S, AT, LA assays
  • Do not interfere with immunoassays

Anti-Platelets – Mechanism of Action (Aspirin & NSAIDs)

• Inhibit cyclooxygenase (COX) enzyme
  • ↓ synthesis of Thromboxane A₂ (TXA₂)
  • TXA₂ normally promotes platelet aggregation & vasoconstriction
  • Result: ↓ platelet aggregation, ↓ clot formation
  • Irreversible (aspirin), reversible (other NSAIDs)

Anti-Platelet Agents – Drug Classes & Names

• ADP receptor (P2Y₁₂) inhibitors
 – Clopidogrel (Plavix)
 – Ticagrelor (Brilinta)
 – Prasugrel (Effient)

• Glycoprotein IIb/IIIa inhibitors
 – Tirofiban (Aggrastat)
 – Abciximab (ReoPro)
 – Eptifibatide (Integrilin)

• PAR-1 antagonist (thrombin-related aggregation)
 – Vorapaxar (Zontivity)

• Phosphodiesterase inhibitor (↑ vasodilation, ↓ aggregation)
 – Cilostazol (Pletal)

Anti-Platelets – Monitoring & Clinical Notes

• Effect measured with Platelet Function Analyzer (PFA-100)
• Expected result: Prolonged closure time indicates platelet inhibition
• Most agents target platelet aggregation phase
• Aspirin/NSAID effect: ↑ PFA-100 closure time, especially with collagen/epinephrine cartridges
• COX inhibition is unique to aspirin and NSAIDs
• PAR-1 inhibitors not emphasized for exam purposes

Thrombolytics – Mechanism of Action

• Serine proteases that convert plasminogen → plasmin
• Plasmin degrades fibrin and fibrinogen in thrombi
• Breaks down clots to restore blood flow (e.g., in stroke, PE)
• Examples:
 – Fibrin non-specific: Streptokinase, Urokinase, Anistreplase
 – Fibrin-specific: tPA, Alteplase, Reteplase, Lanoteplase, Tenecteplase

Thrombolytics – Indications

• Acute ischemic stroke (within 3–4.5 hrs)
• STEMI when PCI unavailable
• Massive PE with hemodynamic compromise
• Severe DVT or arterial thrombosis in select cases
• Catheter occlusions (e.g., central lines)

Thrombolytics – Monitoring & Therapeutic Effects

• Monitored using:
 – Euglobulin clot lysis test (rarely used clinically)
 – Fibrinogen levels (↓ indicates activity)
 – PT, APTT, TT (↑ if fibrinolysis is systemic)
 – FDPs, D-dimer (↑ from fibrin degradation)
• Expected results:
 – ↓ fibrinogen
 – ↑ D-dimer, FDPs
 – ↑ PT/APTT/TT
• Common effect: hypofibrinogenemia
• Interferes with: most clotting assays due to fibrin degradation products

tPA (Tissue Plasminogen Activator)

• Fibrin-specific thrombolytic – activates plasminogen → plasmin at the clot site
• Dissolves fibrin-rich clots (e.g., embolic stroke, STEMI, PE)
• Includes drugs: Alteplase, Reteplase, Tenecteplase
• Most effective when given within 3–4.5 hours of stroke onset
• Monitored clinically; expect ↑ D-dimer, ↓ fibrinogen
• Major risk: intracranial hemorrhage

Mechanical Thrombectomy – Mechanism of Action

• Catheter-based procedure to physically remove a blood clot
• Stent retriever is inserted through a blood vessel (e.g., femoral artery)
• Device expands to trap and extract the clot

Mechanical Thrombectomy – Indications

• Acute ischemic stroke due to large vessel occlusion
• Typically used when:
 – tPA is contraindicated
 – tPA fails
 – Patient presents within 6–24 hours of symptom onset (based on perfusion imaging)
• Sometimes used in peripheral artery disease or DVT (less common)

Watchman – Mechanism of Action

• A small implantable device placed in the left atrial appendage (LAA)
• Physically seals off the LAA, a common site of clot formation in atrial fibrillation
• Prevents clots from escaping into circulation and causing stroke
• Device endothelializes over time, eliminating need for lifelong anticoagulation

Watchman – Indications

• Patients with non-valvular atrial fibrillation at increased stroke risk
• Especially considered for patients who:
 – Have contraindications to long-term anticoagulation
 – Are at high risk of bleeding on oral anticoagulants
• FDA-approved alternative to lifelong anticoagulant therapy
• 96% of patients in trials stopped anticoagulants within 45 days post-implant