Anticoagulants and Fibrinolytics

Question 1

Platelets

Answer 1

• Immediate responders
• Adhere to site of tissue damage
• Activated platelets initiate the coagulation cascade

Question 2

Coagulation Cascade

Answer 2

• Needs to be inactive under normal conditions: factors circulate in inactive form (Factor X => Xa)
• Needs to activate quickly when bleeding occurs: one pathway is short and fast (extrinsic)
• Cascade needs to amplify when bleeding occurs (fast pathway leads to “feed-forward” response that is longer and sustained (intrinsic)

Pathways converge at factor X

Question 3

Extrinsic Pathway

Answer 3

• Forms fibrin quickly
• One step to activate Factor X and three to make a clot
• Tissue factor is a potent initiator of clotting cascade which binds to factor VII and activates factor X

Question 4

Intrinsic Pathway

Answer 4

• Long and amplified response
• Four steps to activate Factor X and seven steps to make a clot
• Activated by thrombin and activated platelets

Question 5

Vitamin K

Answer 5

-Required for the activation of factor VII, X, and thrombin (II)

Question 6

PT

Answer 6

• Prothrombin Time
• Monitoring Test
• Used to assess the activity of pathway 1
• Detects/diagnoses bleeding or clotting disorders

Question 7

Anti-Thrombin

Answer 7

• Inactivates two factors in intrinsic pathway

- Inactivates thrombin IIa and Factor Xa

Question 8

aPTT

Answer 8

• Activated partial thromboplastin time

- Montiroing test to assess the activity of pathway 2

Question 9

Process for Monitoring Tests

Answer 9

• Draw venous blood sample
• Blue cap = citrate bind calcium and prevent clotting
• Add “Kaolin” (activates factor XII or add “thromboplastin” (tissue factor + phospholipids) depending on test
• Add calcium and measure the time it takes to clot

Question 10

Anticoagulation Drug Classes

Answer 10

• Indirect Factor Xa and Thrombin Inhibitions (UF Heparin)
• Factor Xa Inhibitors
• Direct Thrombin Inhibitors (Argatroban, bivalirudin)
• Vitamin K Inhibitors (Warfarin)

Question 11

Unfractionated Heparin (UFH)

Answer 11

• Indirect Factor Xa and Thormbin Inhibitor
• Activates anti-thrombin
• Subsequently inactivates two factors in intrinsic pathway: thrombin IIa and Factor Xa

Question 12

LMWH

Answer 12

• Indirect Factor Xa and Thormbin Inhibitor
• Low molecular weight heparin
• Activates anti-thrombin
• Inactivates Factor Xa and inactivating thrombin

Question 13

Fondaparinux

Answer 13

• Indirect Factor Xa Inhibitor
• Activates anti-thrombin
• But only inactivates Factor Xa

Question 14

Direct Factor Xa Inhibitors

Answer 14

• Oral anti-coagulants with predictable anti-coagulant effects, eliminating the need for monitoring
• Site of action: blood stream
• Andexanet - antidote for life-threatening bleeding, inactive/truncated form of Factor Xa that competes for drug binding

Question 15

Direct Factor Xa Inhibitor Examples

Answer 15

• Rivaroxaban (antidote approved)
• Apixaban (antidote approved)
• Edoxaban (off-label)
• Betrixaban (off-label)

Question 16

Hirudin Analogs

Answer 16

• Direct thrombin inhibitors (DTI)
• Site of action: blood stream
• Examples: Dabigatram (oral), argatroban (IV/SC), bivalirudin (IV/SC)
• Only antidote is Idarucizumab, only works for oral
• Requires monitoring via aPTT

Question 17

Vitamin K Antagonist

Answer 17

• Warfarin
• Inhibits vitamin K epoxide reductase
• Required to generate active vitamin K which then activates Factor VII, X, and thrombin (II)

Question 18

INR

Answer 18

• International Normalized Ratio

- Calculation based on PT test used to monitor the efficacy of warfarin

Question 19

Warfarin

Answer 19

• Narrow therapeutic range and large interindividual variability in dosing
• Pharmacogenetic information may improve time to stable dose (not usually used/recommended)
• Doses need to achieve INR form 2-3 and can vary 1-20 mg/d
• Genetic variants contribute to some of the warfarin dose variability (CYP2C92/3 and VKORC1 polymorphisms can increase bleeding risk)

Question 20

Warfarin Antidotes

Answer 20

• Life-threatening bleeding or elevated INRs can be reversed two ways
• Antidotes: vitamin K, Vitamin K + Four Factor Prothrombin Complex concentrate

Question 21

Fibrinolytics

Answer 21

• Activate plasminogen bound to fibrin and are used to degrade clots
• Fibrin-specific and non-fibrin specific plasminogen activators exist
• More common in those with STEMI, stroke, pulmonary embolism

Question 22

Fibrin-Specific Plasminogen Activators

Answer 22

• Alteplase (tPA)
• Tenecteplase
• Reteplase

Question 23

Non-Fibrin-Specific Plasminogen Activators

Answer 23

• Streptokinase

- Urokinase