Venous Thromboembolism and Anticoagulation Flashcards
Primary Hemostasis
Involves vasoconstriction and platelet adhesion/aggregation
Secondary Hemostasis
Process where fibrin is formed
Fibrin = small insoluble proteins that form tight complexes
Classic clot production
General causes of clot formation:
Virchow’s Triad
- Hypercoagulable State
- Venous Stasis
- Vascular Wall Injury
Hypercoaguable State
Coagulation exceeds natural mechanisms
Genetic Causes
Malignancies
Venous Stasis
Immbility, Obstruction, impaired circulation
Vascular Wall Injury
Exposes tissues to:
- tissue-factor expressing cells
- collagen
-subendothelial tissues
- Strong initiators of primary and secondary hemostasis
Clotting process summary
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
Draw out the coagulation pathway.
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
Thrombin does…
Factor IIA
Activates fibrinogen to a fibrin clot
Amplifies its own production (+’ve feedback)
Activates platelets
Pro-inflammatory effects
Activates endogenous anticoagulation system
Vitamin K Antagonists Example
Warfarin
Which clotting factors are vitamin K dependent? Where and How are they produced?
- 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
Explain the pathway for activation of zymogens to coagulation factors? How does warfarin interfere with this process?
- 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.
How does warfarin exist?
- R and S enantiomer
- S-warfarin is the most potent
Warfin MOA and Onset of Action
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
How does genetics influence Warfarin?
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
Which pathway does Warfarin effect more?
Extrinsic Pathway
How is warfarin monitored?
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
Warfarin Drug Interactions
- Metabolism
Pharmacodynamic –. ANtiplatlets, other anticoagulats, herbals (garlic), VITAMIN K VITAMINS
Displacement –> Sulfonamides, ASA
Absorption –> Zinc, Mg, iron
How can coagulation be measured in laboratory tests to see if drug is working?
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
Direct Oral Anticoagulants Example
Dabigatran (IIA Inhibitor)
Apixiban (XA Inhibitor)
Why are DOACS advantage over warfarin?
Fixed dose for most adults – no need for monitoring of anticoag’n
Fast onset – work on existing/circulating factors
Monitoring of DOACS
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
Thrombomodulin
Converts Protein C to its active form aPC
Activated Protein C
Degrades vitamin K dependent clotting factors
Uses protein S as a cofactor
Heparin Sulfate
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
Plasminogen Activators
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)
Are fibrinolytic drugs the same as anticoagulant drugs?
NO
What are the two types of plasminogen activators?
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
Unfractionated Heparin
- Obtained from the gut mucosa of animals
- Mixture of proteins 1/3 active
Short half life of 60 minutes
IV or SQ
Unfractionated Heparin Mechanism of Action
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
Low Molecular Weight Heparin (LMWH)
Immediate onset of anticoagulation
Especially with IV administration (continuous infusion)
Intensity of anticoagulation easier to manipulate with continuous IV admin
LMWH Vs UFH VS Fondaparinux
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
Venous Thrombosis
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
Endogenous Anti-thrombotics
Prevents extension of clot to healthy cells
Thrombomodulin
Heparin Sulfate
Plasminogen Activators (fibronyltiic factors)
