Anticoagulants and Reversal Study Guide

Question 1

What component factors make up the intrinsic coagulation pathway?

Answer 1

Intrinsic Pathway: XII →XI → IX → VIII→X

Question 2

What component factors make up the extrinsic coagulation pathway?

Answer 2

Extrinsic Pathway: III →VII → X

Question 3

What component factors make up the common coagulation pathway?

Answer 3

Common Pathway: X→II→I →XIII→ stable clot

Question 4

What component factors make up the intrinsic, extrinsic, and common coagulation pathways?

Answer 4

Intrinsic Pathway: XII →XI → IX → VIII→X

Extrinsic Pathway: III →VII → X

Common Pathway: X→II→I →XIII→ stable clot

Question 5

Name three main categories of anticoagulant drugs.

Answer 5

1. Inhibitors of clotting factor synthesis (example: warfarin)
2. Inhibitors of thrombin (example: heparin)
3. Antiplatelet drugs (example: ASA, Plavix, Integrilin)

Question 6

Where do the inhibitors of clotting factor synthesis (ie. warfarin) exert their effect?

Answer 6

Warfarin elicits its effects by inhibiting vitamin K epoxide reductase, thus blocking the conversion of vitamin K epoxide to Vitamin K.

(Without Vitamin K, inactive clotting Factors II, VII, IX, and X are produced – meaning these factors lack the γ-carboxyglutamyl side chains needed to interact with platelet membranes)

Question 7

Where do the inhibitors of thrombin (ie. heparin) exert their effect?

Answer 7

Heparin demonstrates its effects by binding to and activating antithrombin III.

Activated antithrombin III subsequently inhibits serine proteases in the clotting cascade - specifically thrombin (Factor IIa) and Factor Xa (both are COMMON PATHWAY factors strongly inhibited by antithrombin III) and Factors IX, XIA, and XIIa (all INTRINSIC clotting factors only partially inhibited by antithrombin III).

Question 8

Where do antiplatelet drugs (ie. ASA, plavix, intergrillin) exert their effects?

Answer 8

Antiplatelet drugs work via 3 different pathways:

1. ASA/COX inhibitors work by blocking cyclooxygenase, which limits the production of arachidonic acid needed to synthesize thromboxane A2 in platelets.
2. Drugs like Plavix work by irreversibly modifying ADP receptors on platelet membranes so that ADP, released by aggregating platelets at the site of injury, cannot bind and activate the platelet.
3. Drugs like Integrilin work by blocking GpIIb-IIIa receptors on platelet membranes. These receptors are essential in binding to fibrinogen and creating a cross-link to a neighboring platelet to form a thrombus.

Question 9

Name 4 phases of hemostasis.

Answer 9

At the site of vessel injury, the following will happen:

contraction, adhesion, activation, aggregation.

1. Contraction (Phase) - The vessel wall contracts to attempt a tamponade effect to reduce blood flow due to expression of thromboxane A2 & ADP.
2. Adhesion (phase) - vWF is secreted from the endothelial lining & Glycoprotein Ib (GpIb) receptors emerge from the surface of platelets. These actions result in GpIb attaching to vWF & attracting platelets to the site of injury; vWF makes the platelets “sticky” thus allowing them to adhere to the site of injury
3. Activation (phase) - The platelet transforms its structure by swelling to become oval & irregular (stellate) in shape. As this occurs 2 more Glycoproteins emerge 2b(IIb) & 3a(IIIa) with the purpose to link other activated platelets (the goal here is to form a plug at the site of injury)
4. Aggregation (phase) - As all the above is happening, the platelets are releasing a flood of mediators (various granules & thrombin) which are responsible for platelets forming an unstable clot.

Question 10

What does INR stand for, what is it’s normal value, and what anticoagulant drug does it evaluate?

Answer 10

International Normalized Ratio

INR norm: 0.9 - 1.2

Warfarin

(INR checks for deficiency of factors I, II, V, VII or X; but is most sensitive to decreases in factor VII which is one of the vitamin K dependant factors)

Question 11

What does aPTT stand for, what is it’s normal value, and which anticoagulant drugs does it evaluate?

Answer 11

Activated partial thromboplastin time

aPTT norm: 25 - 32 seconds

Heparin & Lovenox

(deals with intrinsic or common pathway disorders)

Question 12

What does PT stand for, what is it’s normal value, and what anticoagulant drug does it evaluate?

Answer 12

Prothrombin time

PT norm: 12 - 14 seconds

Warfarin

(related to extrinsic or common pathway disorders)

Question 13

What is the normal value for a “bleeding time” and which drugs does it evaluate?

Answer 13

bleeding time norm: 3 - 7 minutes

NSAIDs & ASA

measures platelet function, adhesion, aggregation (not a routine test)

Question 14

What is the normal range for antithrombin III?

Answer 14

norm: 80 - 120%

severely depressed in DIC; decreased levels may also explain subtherapeutic heparin dosing

Question 15

How is heparin is derived/created?

Answer 15

• Commercial preparations of heparin are most commonly prepared from bovine lung and bovine or porcine gastrointestinal mucosa.

Question 16

How is protamine derived/created?

Answer 16

• Protamine is an alkaline substance created from a low-molecular weight protein found in salmon sperm.
  sweet. …

Question 17

Name uses of heparin.

Answer 17

• prevention and treatment of venous thrombosis and pulmonary embolism
• prevention of mural thrombosis after MI
• treatment of unstable angina and rethrombosis after thrombolysis
• used to prevent thrombosis in extracorporeal devices used during cardiac surgery and dialysis
• to treat fetal growth retardation in pregnant women.

Question 18

How does heparin work?

Answer 18

• Heparin works by binding to antithrombin (formerly known as antithrombin III), which enhances this naturally occurring circulating anticoagulant by 1000 times!!!!!
• It enhances it’s ability to inactivate several coagulation enzymes including thrombin and factors 9-12.
• There is also evidence that it inhibits thrombin induced activation of factors 5 & 7.
• Additionally, it inhibits platelet function.

Question 19

How does protamine work to reverse heparin?

Answer 19

• Protamine works by binding to heparin to form a stable complex that is devoid of anticoagulant activity.
• These protamine-heparin complexes are then removed by the reticular endothelial system.
• The reason this binds with heparin is because it is essentially the opposite/complement of heparin. Heparin is a negatively charged acidic molecule and protamine is a positively charged alkaline molecule. (for knowledge)

Question 20

What are heparin doses for vascular procedures, DVT prophylaxis, cardio-pulmonary bypass (CPB), and protamine doses for reversal?

Answer 20

DVT prophylaxis: SQ 5000 units 2 hours prior to surgery then q 12 hours

Therapeutic dosages for DVT: start with 80 units per kg bolus then 18 units/kg/hr (several different variations to this)

CPB: 350-450 units/kg. Maintain ACT of 400-480 seconds. (note… certain hospitals have changed to monitor aPTT instead of ACT. Check policy)

Protamine: 1mg for every 100 units of heparin predicted to still be circulating (the guideline is typically 1.3 mg/kg).

(in the absence of heparin, protamine interacts with platelets and proteins, including fibrinogen, to manifest anticoagulation effects)

Question 21

What tests are used to measure protamine effective reversal of heparin?

Answer 21

Monitoring Parameters: Coagulation tests, aPTT or ACT.

Question 22

Side effects of heparin:

Answer 22

• hemorrhage
• allergic reaction
• CV changes
• altered protein binding
• altered cell morphology
• decreased antithrombin concentrations
• thrombocytopenia (two types)
  
  • • mild [3-15 days post therapy and with pts previously exposed to heparin]
  • • HITT [6-10 days post therapy and d/t formation of heparin-dependent anti-platelet antibodies that trigger platelet aggregation. D/C heparin immediately]

Question 23

What is the normal value for platelets?

Answer 23

200,000 - 400,000