Lecture 8 Flashcards
What’s the difference between a thrombus and clot?
Thrombus - clot formed in vivo
Clot - formed in vitro
Name and characterize two different thrombus
1) Red = Venous end = RBC, platelets, fibrin -> due to stasis ->DVT->PE
2) White = Arterial end = WBC, platelets, fibrin -> due to turbulence (i.e. atherosclerosis) -> MI
What is thrombosis?
Formation of thrombus (clot) in the ABSENCE of BV injury (i.e. no bleeding occurred)
What is Hemostasis? and the Process?
Plugging of a blood vessel to prevent blood loss.
1) Vasoconstriction: collagen exposed -> platelets ->bind and release ADP and 5-HT (vasoconstrictor).
2) Platelet Activation/Adhesion: Upon activation of platelets - release 5-HT/ADP/Thromboxane, platelets adhere via GP2b/3a.
3) Fibrin Deposition: Fibrinogen is converted to Fibrin - blankets the platelets/cells/proteins (clot)
What is the function of 5-HT?
Powerful vasoconstrictor
What is the function of ADP?
Causes platelet activation and change in shape.
How is thromboxane formed in the platelet?
Phospholipase A2 cleaves the PM and liberates Arachadonic Acid. AA is converted to Thromboxane via COX.
What activates platelets?
Collagen, VWF, thrombin, thromboxane, ADP
What kind of pathway is the Coagulation Pathway?
Amplification…each step creates an active enzyme that amplifies the next product.
2 pathways - INTRINSIC and EXTRINSIC.
What is prothrombin? How is it activated?
Prothrombin is the precursor for thrombin. Activated via Factor 10a. Thrombin is also known as 2a.
What is the intrinsic pathway?
A part of the coagulation pathways that converges at the level of Factor 10. Initiated by the cleavage of Factor 12 - Factor 12a.
What is the extrinsic pathway?
Tissue factor is exposed upon injury -> TF = Thromboplastin -> Factor 7 is converted to 7a -> Factor 10 is converted to 10a -> Prothrombin - Thrombin 2a -> Fibrinogen converted to Fibrin
What are the Factor-a’s?
Proteolytic Enzymes
What pathway is faster and why?
The extrinsic pathway is faster because less steps.
How is the Coagulation Pathway SELF regulated?
1) The thrombin-thrombmodulin complex activate Pn C –> inactivates inhibitors of plasminogen -> plasminogen converted to plasmin. Plasmin promotes fibrolysis.
2) Activation of Anti-Thrombin 3.
What physiological/pathological factors promote thrombosis?
Virchow’s Triad
1) Endothelial Dysfunction
2) Blood flow - turbulence, stasis of the blood
3) (Hyper) Coagulability Factors - in the blood
Drugs may affect co-agulation by impacting…?
1) Coagulation
2) Platelet activation/adhesion
3) Fibrinolysis
The following are Pro/Anti coagulants…(characteristics)
1) Vitamin K
2) Heparin
3) Warfarin
1) Vitamin K - pro-coagulant
2) Heparin - injected (not orally available), short term - ANTI
3) Warfarin - orally available, long term - ANTI
What is the pathway for Heparin?
Heparin(-ve, heavy) promotes the activity of antithrombin 3 (AT3)
- Form a complex with AT3 being the AS
- AT3 disables the protease activity -> Factor 10a and Thrombin (2a)
LMW Heparin + AT3 -> Factor 10 inhibition
Heparin + AT3 -> Factor 10 and 2a inhibition
Functions in the Intrinsic Pathway
What is LMW Heparin?
low molecular heparin - self administered, longer half life
What pathway does Heparin function in?
Intrinsic
What happens if you get a clot in the following:
1) Coronary Vessel
2) Carotid Vessel
1) MI
2) Stroke
How do you monitor the activity of Heparin?
APTT - Activated Partial Thromboplastic time.
Time it takes to clot after the addition of the following:
Ca2+, contact activator, phospholipid (mimics platelet membrane)
Test of: Intrinsic Pathway
The APTT tests which coagulation pathway?
Intrisinic
What are the adverse effects (AE) of Heparin?
Haemorrhage, thrombocytopenia (decrease in thrombocytes aka platelets), osteoporosis
What is the importance of Vitamin K?
Necessary in the formation of functional factors 2, 7, 9, 10
Reduced Vit K is a cofactor in the carboxylation of glutamate in factors.
Factor 2: Thrombin, 7: TF activates this, 10: Converts Thrombinogen to thrombin.
What are the function of coumarin derivatives? (Mechanism)
Inhibit Reduction of Vitamin K -> thus inhibiting function of gamma carboxylation of the factors -> factors can’t be activated.
Competing for Vit K reductase.
Warfarin Mechanism? Where does it work?
Competes for Vit K reductase. Only functions against factors not yet performed - slow onset.
Works IN-VIVO only
What can cause changes in the activity of Warfarin?
Highly bound to plasma protein - therefore increase levels of protein/liver function can alter the function of warfarin.
Vitamin K levels - if low levels of vitamin K, Warfarin can illicit a stronger effect
p450 levels: if the pathway is busy metabolizing other drugs, Warfarin levels can increase
Impaired platelet functions: can’t initiate/produce clotting factors as effectively thus Warfarin doesn’t have to compete as much.
Warfarin AE
Haemorrhage
How can you reverse the effect of Warfarin?
Vit K, Frozen Plasma
How do you monitor Warfarin?
PT; Prothrombin time
Functions through the Extrinsic System
Time it takes to clot after the addition of calcium, TF
INR: standardized values: PT of Patient/PT of standardized value
What are the features of some new anti-coagulant agents?
Low MW, Orally available, Predictable Dose-Response
Direct Attack on Factor 10a, and Thrombin
What does Aspirin do?
Aspirin is an anti-platelet drug.
Inhibits COX = no thromboxane
The portal vein sees a lot of platelets without COX - aspirin localized effect (first pass effect).
Spare PGI2: promotes dilation and decreases clotting
What is thromboxane
A protein produced in the COX pathway.
Promotes vasoconstriction and clotting
What is PGI2
Promotes dilation and decreases clotting
What does Abciximab do?
Binds to Gp2b/GP3a - prevents platelet adhesion/aggregation
What does clopidigrel do?
ADP antagonist - therefore no platelet activation
What is the fibrinolysis pathway?
Thrombin/Thrombomodulin activates Protein C -> inactivates inhibitor of plasminogen -> plasminogen - plasmin->fibrinolysis
What does Streptokinase do?
Activates plasminogen ->plasma -> clot buster
1 x use
antigenic
FIBRINOLYTIC DRUG
What does Alteplase do?
rTPA (recombinant tissue plasminogen activator)
Use may times since its not antigenic
CLOT SELECTIVE
FIBRINOLYTIC DRUG
