Anti-Coagulant, fibrinolytic, and anti-platelet agents

Question 0

Give the 4 groups of anticoagulants presented in lecture.

Answer 0

• Unfractionated heparin
• Low molecular weight heparin
• direct inhibitors of thrombin or Xa
• coumadin

Question 1

Define: anticoagulants, fibrinolytic agents, anti-platelet agents.

Answer 1

• Anticoagulant: drugs that work by either 1. inhibiting thrombin of F. Xa or 2. decreasing the level of competent clotting factors
• Fibrinolytic agents: accelerate degradation of existing fibrin clots
• Anti-platelet agents: inhibit platelet plug formation by inhibiting platelet activation of prevent them from aggregating

Question 2

Describe the mechanism and structure of heparin. What cells in the body naturally synthesize it?

Answer 2

• inactivates serine proteases (IIa, Xa, IXa, XIa, VIIa) by binding to antithrombin (AT-III)
• It is a proteoglycan with many (-) sulfates that bind (+) antithrombin
• Mast cells

Question 3

How is heparin administered? What its half-life?

Answer 3

• IV or SQ, NOT orally

- short half life of about 1 hour so need many administrations

Question 4

Indications of heparin use and toxicities.

Answer 4

• Indications: Rx of acute arterial and venous thromboembolism, prevention of thromboembolism in at-risk patients
• Toxicities: bleeding, osteoporosis when used for weeks-months, thrombocytopenia with potential thrombosis

Question 5

Describe Heparin-Induce Thrombocytopenia with Thrombosis (HIT)

Answer 5

• platelets’ alpha granules release PF4 (many + residues) that bind heparin and reside on platelets’ surfaces
• antibodies are generated against this complex and bind to platelet Fc receptors, triggering platelet activation and clumping
• Antibodies may also activate macrophages, yielding TF-bearing microparticles that fuel the fire
• Result: thrombocytopenia and microvascular thrombosis (arterial !!and venous)

Question 6

How should UFH be monitored?

Answer 6

• aPTT: 1.5- 2.0x baseline: helpful without being toxic

- PT is also prolonged, but less sensitive

Question 7

Compare and contrast the inhibitory action of UFH and LMWH

Answer 7

-UFH can inhibit thrombin and Xa due to its large enough size, but LMWH can only inhibit Xa and is too small to inhibit thrombin

Question 8

How is LMWH administered? What is its half-life?

Answer 8

• SQ
• longer than UFH, so required less injections a day
• dosed by patients weight

Question 9

T/F: Patients on LMWH are monitored by aPTT.

Answer 9

-false; at clinical doses, it does not prolong the aPTT

Question 10

T/F: LMWH is less immunogenic than UFH.

Answer 10

-True, it forms less complexes with PF4 and is less associated with thrombocytopenia

Question 11

When is LMWH used?

Answer 11

• pretty much the same as UFH
• Rx of acute arterial or venous thromboembolism
• Prevention of thromboembolism in patients with increased risk

Question 12

Name and compare and contrast the 3 examples of drugs that are direct thrombin inhibitors.

Answer 12

1. Lepirudin: approved for HIT use, renal excretion, IV
2. Argatroban: approved for HIT use, hepatic excretion, IV
3. Dabigatran: PO, long half life, renal excretion, fixed dose, monitoring not required, poorly reversible

Question 13

Give examples of Xa inhibitors and their properties.

Answer 13

1. Fondaparinux: IV and SQ

2. Apixaban, Rivaroxaban, Edoxaban, etc: PO, fixed dose, no monitoring, not easily reversed, replacements for coumadin

Question 14

How does coumadin (warfarin) work?

Answer 14

-inhibit recycling of vitamin K and therefore, depletes factors II, VII, IX, X, Protein C and protein S

Question 15

3 ways we get Vitamin K

Answer 15

1. eat it (green leafy vegetables)
2. gut flora
3. store it in liver for about 1 week

Question 16

How is coumadin administered and what are some of its uses?

Answer 16

• PO
• venous and (sometimes) arterial thrombosis to prevent recurrence
• atrial fibrillation to prevent thrombus formation and embolism
• prosthetic heart valves
• DVT prophylaxis
• rat poison

Question 17

How should patients on coumadin be monitored?

Answer 17

-PT test (increases) and INR

Question 18

Why is there a conundrum of coumadin dosing? What are its toxicities?

Answer 18

• very narrow therapeutic window: higher INR target is higher risk of bleeding, but lower INR is risk of clotting recurrence
• Bleeding (tx with Vitamin K and FFP), embryopathy in 1st trimester, coumadin-induced skin necrosis

Question 19

3 examples given of fibrinolytic factors.

Answer 19

• Streptokinase
• Urokinase
• Tissue-type Plasminogen Activator (t-PA)

Question 20

Fibrinolytic agents are not commonly used, but are sometimes. Describe scenarios they are indicated for use.

Answer 20

• acute MI
• PE
• Peripheral arterial occlusion
• DVT (proximal)
• Catheter occlusion (sometimes)

Question 21

2 contraindications of coumadin use and their risk

Answer 21

• Hemorrhagic CVA, intracranial neoplasm, recent cranial surgery/trauma, uncontrolled severe hypertension—Intracranial bleed risk
• Major surgery of thorax or abdomen (10 days), prolonged CPR, current severe bleeding— massive hemorrhage

Question 22

Current treatment of venous thrombosis

Answer 22

• Start on UFH (IV) or LMWH (SQ)
• Start coumadin (PO) within 1-2 days after heparin
• maintain on coumadin for 3-6 months (or forever)

Question 23

3 main categories of Anti-platelet agents and examples for each category.

Answer 23

1. Receptor antagonist: ADP2Y12 receptor antagonist; Clopidogrel (Plavex), Prasugrel, Ticlopidine (Ticlid)
2. Signal blockers: aspirin
3. Integrin (aIIbB3) blockers: ReoPro (Abiciximab), Integrilin (Epifibatide), Tirofiban (Aggrastat)

Question 24

Mechanism of aspirin.

Answer 24

-irreversibly inhibits COX-1 in TxA2 pathway so platelets do not recruit and aggregate with eachother

Question 25

Current uses of anti-platelet agents

Answer 25

1. Cardiac: maintaining stent and CABG patency, prevent recurrent MI’s, unstable angina
2. Cerebral: suppress transient ischemic attacks (TIA) and prevent recurrent non-hemorrhagic strokes
3. Others: myeloproliferative disorders with ARTERIAL thrombosis