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PHAR 121 > Venous Thromboembolism and Anticoagulation > Flashcards

Venous Thromboembolism and Anticoagulation Flashcards

1
Q

Primary Hemostasis

A

Involves vasoconstriction and platelet adhesion/aggregation

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2
Q

Secondary Hemostasis

A

Process where fibrin is formed
Fibrin = small insoluble proteins that form tight complexes
Classic clot production

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3
Q

General causes of clot formation:

A

Virchow’s Triad

  1. Hypercoagulable State
  2. Venous Stasis
  3. Vascular Wall Injury
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4
Q

Hypercoaguable State

A

Coagulation exceeds natural mechanisms
Genetic Causes
Malignancies

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5
Q

Venous Stasis

A

Immbility, Obstruction, impaired circulation

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6
Q

Vascular Wall Injury

A

Exposes tissues to:
- tissue-factor expressing cells
- collagen
-subendothelial tissues
- Strong initiators of primary and secondary hemostasis

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7
Q

Clotting process summary

A

Platelets adhere and aggregate on injured/exposed area

Clotting Cascade activated by platelets and injury itself

Generate fibrin clot –> reinforce the platelet “plug”

Damaged tissues covered

Triggering signals reduced dramatically

Anticoagulant and fibrinolytic pathways now predominate
Absence of strong clotting signals
Natural opposition to clotting stimulated with cascade

Eventually, clot disappears, tissue heals

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8
Q

Draw out the coagulation pathway.

A

Look at notes
Extrinsic and Intrinsic pathway

Intrinsic –> activated platlets, circulating molecules (TF, collagen), foreign bodies

Extrinsic –> Damage to tissues - exposure to subendothelial proteins Tissue factor

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9
Q

Thrombin does…

A

Factor IIA

Activates fibrinogen to a fibrin clot

Amplifies its own production (+’ve feedback)

Activates platelets

Pro-inflammatory effects

Activates endogenous anticoagulation system

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10
Q

Vitamin K Antagonists Example

A

Warfarin

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11
Q

Which clotting factors are vitamin K dependent? Where and How are they produced?

A
  • Factors –> II, VII, IX and X (and protein C and S)
  • Synthesized in liver but not activated until carboxylated
  • Carboxylation requires reduced vitamin K
  • Inactive enzymes (zymogens) in the blood but need to be activated
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12
Q

Explain the pathway for activation of zymogens to coagulation factors? How does warfarin interfere with this process?

A
  • Vitamin K dependent factors (zymogens) requires reduced vitamin K to be active
  • Reduced vitamin K will cause activation of the zymogens and produce oxidized vitamin K
  • For synthesis to continue, oxidized vitamin K needs to be reduced for a second time . This is carried out by vitamin K reductase.
  • ## Warfarin inhibits vitamin K reductase, interrupting the cycle. Less reduced vitamin K available to activate zymogens to active factors.
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13
Q

How does warfarin exist?

A
  • R and S enantiomer
  • S-warfarin is the most potent
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14
Q

Warfin MOA and Onset of Action

A

Inhibits synthesis of vit K-dependent factors
II, VII, IX, and X (+ Protein C & S)

NO effect on clotting factors already in circulation

Factor VII –> 6 hours 1/2 life elimination

Full anticoagulant effect requires reduction in all factors
Factor IIa –> t1/2 of 72 hours –> long time in blood stream
Probably takes at least 6 days

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15
Q

How does genetics influence Warfarin?

A

Dosing requirements highly variable

Due to polymorphisms in two genes coding for:
- CYP2C9 (metabolism)
- Vitamin K reductase (enzyme sensitivity to warfarin)

Individuals require close monitoring to individualize dosing

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16
Q

Which pathway does Warfarin effect more?

A

Extrinsic Pathway

17
Q

How is warfarin monitored?

A

Thus, effects can be monitored using a blood test = PT
PT = Prothrombin Time
measurement can depend on reagents used

Laboratories always convert PT to an international Normalized ratio (INR)
INR of 1 = NO anticoagulant effect –> Normal anticoagulation time
Usual target INR of 2-3 –> clotting time is delayed, the intensity of anticoagulation has been increased

18
Q

Warfarin Drug Interactions

A
  • Metabolism
    Pharmacodynamic –. ANtiplatlets, other anticoagulats, herbals (garlic), VITAMIN K VITAMINS
    Displacement –> Sulfonamides, ASA
    Absorption –> Zinc, Mg, iron
19
Q

How can coagulation be measured in laboratory tests to see if drug is working?

A

Average Clot - 6-8 mins –> prevent clotting by removal of Ca2+

Rechelated Blood –> Clots in 2-4 mins

Substances intrinsic to the plasma
Reduce clotting time to 26-33sec
Activated partial thromboplastin time (aPTT)

Substances extrinsic to the plasma
Reduce clotting time to 12-14 sec
Prothrombin time (PT) –> Sensitive to Warfarin –> Extrinsic pathway blood test

PT and aPTT are common blood tests to assess clotting ability based on patient’s blood samples
They are not sensitive to all drugs
Warfarin will prolong the PT, but the aPTT in somebody with Warfarin will look totally normal. aPTT is not sensitive to Warfarin

20
Q

Direct Oral Anticoagulants Example

A

Dabigatran (IIA Inhibitor)
Apixiban (XA Inhibitor)

21
Q

Why are DOACS advantage over warfarin?

A

Fixed dose for most adults – no need for monitoring of anticoag’n

Fast onset – work on existing/circulating factors

22
Q

Monitoring of DOACS

A

Routine monitoring not necessary (except prior to urgent surgery etc)

50% will have a normal PT while on DOAC therapy

aPTT may be used for dabigatran (IIa inhibitor) – not a perfect test.

Specialized tests will be used more frequently in the future

23
Q

Thrombomodulin

A

Converts Protein C to its active form aPC

Activated Protein C
Degrades vitamin K dependent clotting factors
Uses protein S as a cofactor

24
Q

Heparin Sulfate

A

Binds to a circulating protein “antithrombin” (synthzd in liver)

Antithrombin Inhibits factor IIa (thrombin), Xa and other activated clotting factors in the intrinsic pathway

Extremely slow reaction without heparan sulfate

25
Q

Plasminogen Activators

A

Synthesized and secreted by endothelial cells

Converts plasminogen to PLASMIN

Plasmin degrades fibrin into soluble products

Classified as a fibrinolytic (i.e., not an anticoagulant)

26
Q

Are fibrinolytic drugs the same as anticoagulant drugs?

A

NO

27
Q

What are the two types of plasminogen activators?

A

tissue type plasminogen activator (t-PA)
Predominant type secreted by endothelial cells
Promotes intravascular fibrinolysis

U-PA or urokinase
Primarily secreted in response to inflammatory stimuli
Promotes extravascular fibrinolysis

28
Q

Unfractionated Heparin

A
  • Obtained from the gut mucosa of animals
  • Mixture of proteins 1/3 active
    Short half life of 60 minutes
    IV or SQ
29
Q

Unfractionated Heparin Mechanism of Action

A

Binds to antithrombin (protein floating around doing almost nothing)

Heparin-AT complex:
Inactivates thrombin (factor IIa) and factor Xa

Inactivates several factors in intrinsic pathway

Effect can be monitored by aPTT

30
Q

Low Molecular Weight Heparin (LMWH)

A

Immediate onset of anticoagulation
Especially with IV administration (continuous infusion)

Intensity of anticoagulation easier to manipulate with continuous IV admin

31
Q

LMWH Vs UFH VS Fondaparinux

A

UFH –> Long protein chains –> 1:1 inhibition of Xa and IIA

LMWH –> Peptides generally shorter
3:1 Inhibition of Xa to IIa (Decreased IIa activity)
- Lower binding affinity for plasma proteins, cleared by kidneys, better bioavilability, longer plasma life
–> No monitoring

Fondaparinux –> Only factor XA activity
- Smaller pentasachharide sequence
-Renal clerance
- predictable does response
- No monitoring

32
Q

Venous Thrombosis

A

Pathologic clots in veins without obvious damage

Often occur in areas of disturbed flow (e.g., valve cusps)

Most often occurs in calf or thigh

Can result in poor tissue drainage
Causes edema and inflammation
Can lead to pulmonary embolism

Composed mainly of fibrin and RBC’s

Management/prevention involves anticoagulants

33
Q

Endogenous Anti-thrombotics

A

Prevents extension of clot to healthy cells

Thrombomodulin
Heparin Sulfate
Plasminogen Activators (fibronyltiic factors)

PHAR 121 (6 decks)

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