Module 2: Anticoagulant, Antiplatelet, and Thrombolytic Drugs

Question 1

Pathophysiology of Coagulation

Answer 1

Hemostasis is the process through which bleeding is stopped after a blood vessel is injured

Stage 1 - Formation of Platelet Plug:
When a blood vessel is damaged, platelets (a type of blood cell) quickly adhere to the site of injury.
These activated platelets release chemicals that make nearby platelets sticky. These sticky platelets then aggregate (clump together) at the site of injury, forming a temporary “platelet plug” to seal small breaks in the injured vessel.

Stage 2 - Coagulation:
Coagulation involves a cascade of reactions that lead to the formation of a blood clot. This process can be divided into two pathways:
**Intrinsic Pathway: Triggered by damage inside the vascular system, and is activated by factors that are intrinsic (present within the blood).
**Extrinsic Pathway: Initiated by external trauma that causes blood to escape from the vascular system and is activated by tissue factor (TF) released by damaged tissues.
Both pathways lead to the activation of Factor X, which converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin, forming a mesh that traps blood cells and forms a stable clot.

Keeping Hemostasis Under Control:
The body regulates clot formation to ensure that clots form only at the site of injury and do not extend beyond what is necessary to stop bleeding.
Anticoagulants, like antithrombin and proteins C and S, help to control the clotting process and prevent excessive clotting.

Physiologic Removal of Clots:
After a vessel heals, the clot needs to be removed. The process of fibrinolysis dissolves the clot. Plasminogen in the clot is converted to plasmin, which breaks down the fibrin mesh.

Thrombosis:
Arterial Thrombosis: Occurs in arteries, often due to atherosclerosis. These clots can block the flow of oxygen-rich blood to organs and tissues, potentially causing heart attacks or strokes.

Venous Thrombosis: Occurs in veins, usually in the legs (deep vein thrombosis). Clots can travel to the lungs (pulmonary embolism), posing serious health risks.

Question 2

Overview of Drugs for
Thromboembolic Disorders

Answer 2

Three major groups
 Anticoagulants: Disrupt the coagulation cascade,
thereby suppressing the production of fibrin
 Antiplatelets: Inhibit platelet aggregation
 Thrombolytics: Promote lysis of fibrin, causing
dissolution of thrombi

Question 3

UH vs LMWH

Answer 3

Unfractionated heparin (UFH) and Low Molecular Weight Heparin (LMWH) are both anticoagulant medications used to prevent and treat blood clots, but they have some key differences in their structure, mechanism of action, dosing, and monitoring requirements.

Structure and Mechanism of Action:
Unfractionated Heparin (UFH):
UFH is a mixture of long chains of sugar molecules (glycosaminoglycans) of varying sizes.
It works by binding to the protein antithrombin, which then inactivates thrombin and Factor Xa, important components of the clotting cascade.
UFH impacts both thrombin (Factor IIa) and Factor Xa.

Low Molecular Weight Heparin (LMWH):
LMWH is made up of shorter chains of sugar molecules, making it more predictable in its effect.
Like UFH, LMWH enhances the activity of antithrombin, but it has a greater effect on Factor Xa than on thrombin.
Due to its more predictable effect, LMWH is often preferred for patients receiving treatment outside of the hospital.

Dosing and Monitoring:
Unfractionated Heparin:
Requires regular monitoring of blood coagulation levels, typically using the activated partial thromboplastin time (aPTT) test, to ensure the dosage is effective and safe.
Dosage adjustments are often needed based on these test results.
Can be given as an intravenous infusion or as an injection.

Low Molecular Weight Heparin:
Requires less monitoring compared to UFH because of its more predictable effect.
Dosing is usually based on the patient’s weight, and routine blood tests are generally not necessary.
Administered as a subcutaneous injection.

Use Cases:
Unfractionated Heparin is often used in situations where rapid anticoagulation is necessary, such as during surgery or in a hospital setting, where it can be closely monitored.
Low Molecular Weight Heparin is commonly used for the prevention and treatment of clots in outpatient settings, including treatment of deep vein thrombosis and prevention of clots in patients undergoing surgeries.

Side Effects:
Both UFH and LMWH can increase the risk of bleeding. However, LMWH generally has a lower risk of heparin-induced thrombocytopenia (HIT), a serious side effect where the platelet count drops, compared to UFH.

Question 4

Anticoagulants

Answer 4

Reduce the formation of fibrin
**Two mechanisms of action
 Inhibit the synthesis of clotting factors
 Inhibit the activity of clotting factors

Question 5

Heparin and Heparin Derivatives

Answer 5

Heparin (unfractionated)
 Enhances antithrombin
 Sources
* Lungs of cattle
* Intestines of pigs
 Rapid-acting anticoagulant
 Administered by injection only
* IV
 Continuous and intermittent
* Deep subcutaneous (subQ)

Question 6

Heparin (Unfractionated) Therapeutic Uses

Answer 6

Therapeutic uses
 Preferred anticoagulant during pregnancy and when rapid anticoagulation is required
 Pulmonary embolism (PE)
 Stroke evolving
 Massive deep vein thrombosis (DVT)
 Open heart surgery
 Renal dialysis
 Low-dose therapy postoperatively
 Disseminated intravascular coagulation (DIC)
 Adjunct to thrombolytic therapy

Adverse effects
 Hemorrhage
 Heparin-induced thrombocytopenia (HIT)
 Hypersensitivity reactions
 Contraindicated
 Thrombocytopenia
 Uncontrollable bleeding
 During and immediately after surgery of the eye, brain, or spinal cord
 Antidote for overdose (OD): Protamine sulfate
 Activated partial thromboplastin time (aPTT)

Question 7

Low-Molecular-Weight
(LMW) Heparins

Answer 7

Heparin preparations composed of molecules
that are shorter than those found in
unfractionated heparin
 Therapeutic uses
 Prevention of DVT after surgery
* Including replacement of hip, knee
 Treatment of established DVT
 Prevention of ischemic complications
* Patients with unstable angina, non–Q-wave myocardial
infarction (MI), and ST-elevation MI (STEMI)
Low-Molecular-Weight

Administered subQ
 Dosage based on body weight
 Antidote for toxicity: Protamine sulfate
 Costs more than unfractionated heparin
 Does not require monitoring; can be given at home
**Adverse effects and interactions
 Bleeding (but less than with unfractionated heparin)
 Immune-mediated thrombocytopenia
 Severe neurologic injury for patients undergoing spinal puncture
or spinal epidural anesthesia

Question 8

Other LMW Heparins

Answer 8

In the United States, two LMW heparins are
available:
 Enoxaparin
 Dalteparin

Question 9

Warfarin, an Oral Anticoagulant

Answer 9

Originally discovered when cattle were observed
ingesting spoiled clover silage
 Used as rat poison
 Failed suicide attempt with large dose brought
renewed clinical interest
 Clinical use
 Oral anticoagulant with delayed onset
 Vitamin K antagonist
 Blocks biosynthesis of factors VII, IX, and X and
prothrombin

Therapeutic uses
 Not useful in emergencies
 Long-term prophylaxis of thrombosis
* Prevention of venous thrombosis and associated pulmonary
embolism
* Prevention of thromboembolism (in patients with prosthetic
heart valves)
* Prevention of thrombosis during atrial fibrillation

Monitoring treatment
 Prothrombin time (PT)
 International normalized ratio (INR)
 Adverse effects
 Hemorrhage (vitamin K for toxicity)
 Fetal hemorrhage and teratogenesis from use during pregnancy
 Use during lactation
 Other adverse effects

Drug interactions
 Drugs that increase anticoagulant effects
 Drugs that promote bleeding
 Drugs that decrease anticoagulant effects
 Heparin
 Aspirin
 Acetaminophen

Warfarin overdose
 Vitamin K
 Dietary vitamin K: Mayonnaise, canola oil,
soybean oil, and green leafy vegetables
 Contrasts between warfarin and heparin

Question 10

Direct Thrombin Inhibitors

Answer 10

Direct inhibition of thrombin (unlike heparin,
which enhances the activity of antithrombin)

 Dabigatran etexilate: Oral prodrug that
undergoes conversion to dabigatran
 Advantages of dabigatran: Doesn’t require
monitoring of anticoagulation, little risk of
adverse interactions, same dose can be used for
all patients regardless of age or weigh

Dabigatran etexilate
 Therapeutic uses
-Atrial fibrillation

Dabigatran etexilate
 Adverse effects
-Bleeding
-No specific antidote to reverse dabigatran-
related bleeding
-Gastrointestinal (GI) disturbances

Question 11

Direct Thrombin Inhibitors Cont.

Answer 11

Hirudin analog: Bivalirudin [Angiomax]
 Prevents clot formation (combined with aspirin) in patients with unstable angina undergoing coronary angioplasty
 Mechanism of action
* Facilitates the actions of antithrombin
* Prevents conversion of fibrinogen to fibrin
* Prevents activation of factor XIII
 Adverse effects
* Bleeding
* Back pain
* Nausea, headache

Desirudin [Iprivask]
 Indicated for prevention of DVT in patients
undergoing elective hip replacement surgery
 Adverse effect
* Bleeding

Argatroban
 IV anticoagulant
 Direct inhibition of thrombin
 Indicated for prevention of DVT in patients
undergoing elective hip replacement surgery
 Prophylaxis and treatment of thrombosis in patients with HIT

Question 12

Direct Factor Xa Inhibitors

Answer 12

**Produce selective inhibition of factor Xa
**Rivaroxaban [Xarelto]
 Binds directly with factor Xa to cause inactivation
 Oral
 Prevention of DVT and PE after total hip or knee
replacement surgery
 Prevention of stroke in patients with atrial fibrillation
 Treatment of DVT and PE unrelated to orthopedic
surgery

Apixaban [Eliquis]
 Selective inhibition of factor Xa
 Oral
 Inhibits free and clot-bound factor Xa, as well as
prothrombinase activity
 Prevention of stroke and systemic embolism in
patients with nonvalvular atrial fibrillation

Question 13

Antithrombin (AT)

Answer 13

**Endogenous compound that suppresses
coagulation, primarily by inhibiting thrombin and
factor Xa
 Used to prevent thrombosis in patients with
inherited AT deficiency
 Two preparations, marketed as ATryn and
Thrombate III

Question 14

Recombinant human AT
(rhAT), Sold as ATryn

Answer 14

Prevention of perioperative or peripartum
thromboembolic events in patients with inherited
AT deficiency
 Adverse effects
 Plasma-derived antithrombin

Question 15

Antiplatelet Drugs

Answer 15

spirin (ASA)
 Inhibition of cyclooxygenase
 Adverse effect
* Increases risk for GI bleeding
 Clopidogrel [Plavix]
-ADP receptor antagonist

Question 16

Aspirin (ASA)

Answer 16

Therapeutic uses
 Ischemic stroke
 Transient ischemic attack (TIA)
 Chronic stable angina
 Unstable angina
 Coronary stenting
 Acute MI
 Previous MI
 Primary prevention of MI

Adverse effects
 Bleeding
 GI bleeding and hemorrhagic stroke
 Enteric-coated tablets may not reduce the risk of GI bleeding

Question 17

Clopidogrel [Plavix]

Answer 17

Therapeutic uses
 Block P2Y12 ADP receptors on the platelet surface, preventing ADP-stimulated aggregation
 Prevents blockage of coronary artery stents
 Reduces thrombotic events in patients with acute
coronary syndromes
* Prevents stenosis of coronary stents; also for secondary prevention of MI, ischemic stroke, and other vascular events
 Adverse effects similar to those of aspirin
 Use with caution in combination with other drugs
that promote bleeding

Question 18

Antiplatelet Drugs

Answer 18

Other P2Y12 ADP receptor antagonists
 Prasugrel [Effient]
 Ticagrelor [Brilinta]
 Ticlopidine

Glycoprotein (GP) IIb/IIIa receptor antagonists
 Most effective antiplatelet drugs
 “Super aspirins”
 Reversible blockade of platelet GP IIb/IIIa receptors
 Therapeutic use
* Acute coronary syndromes
* Percutaneous coronary interventions

 Dipyridamole
 Dipyridamole + Aspirin
 Cilostazol [Pletal]

Question 19

Abciximab [ReoPro]

Answer 19

Binds to platelets in the vicinity of GP IIb/IIIa
receptors, thereby preventing the receptors from
binding fibrinogen
 Used in conjunction with aspirin and heparin
 Approved for IV therapy of ACS and for patients
undergoing PCI
 Can accelerate revascularization in patients
undergoing thrombolytic therapy for acute MI
 Antiplatelet effects persist for 24 to 48 hours after the infusion is stopped

Question 20

Eptifibatide [Integrilin]

Answer 20

Small peptide that causes reversible and highly
selective inhibition of GP IIb/IIIa receptors
 ACS
 Patients undergoing PCI
 Antiplatelet effects reverse within 4 hours of stopping the infusion

Question 21

Tirofiban [Aggrastat]

Answer 21

Selective and reversible inhibition of GP IIb/IIIa
receptors
 Used to reduce ischemic events associated with ACS and PCI
 Platelet function returns to baseline within 4 hours of stopping the infusion
 Bleeding is the primary adverse effect
 Risk of bleeding can be increased by other drugs that suppress hemostasis

Question 22

Thrombolytics: Alteplase (tPA)

Answer 22

Binds with plasminogen to form an active
complex
 Alteplase-plasminogen complex then catalyzes
the conversion of other plasminogen molecules
into plasmin, an enzyme that digests the fibrin
meshwork of clots

Therapeutic uses
 Myocardial infarction
 Ischemic stroke
 Massive pulmonary emboli

Adverse effects
 Bleeding
* Risk for intracranial bleeding higher than with streptokinase
* Whole blood or blood products (packed red blood cells, fresh
-frozen plasma)
* Aminocaproic acid [Amicar]
 Fever
 Advantages
 Does not cause allergic reactions
 Does not induce hypotension
Thrombolytics: Alteplase

Question 23

Tenecteplase [TNKase]

Answer 23

 Variant of human tissue plasminogen activator
(tPA, alteplase)
 Approved only for acute MI
 Easier to use

Question 24

Reteplase [Retavase]

Answer 24

Derivative of tPA produced by recombinant DNA
technology
 Short half-life (13 to 16 minutes)
 Approved only for acute MI