Haemostasis Flashcards
Definition of haemostasis
Arrest of blood loss from damaged vessels
Vital to life
Definition of thrombosis
Local coagulation or clotting of blood
Definition of embolism
Lodging of a blockage causing material in a blood vessel
Definition of thrombocytopenia
Decreased no of platelets in the blood
Can lead to bruising and bleeding
Definition of thrombolytics
Used for rapid removal of thrombus in coronary and cerebral artery thrombosis
Definition of anticoagulants
Used for venous thrombosis and sometimes in arterial thrombosis
Definition of anti platelet drugs
Used to reduce thrombosis risk short and long term
Name the receptors on the platelets and what they attach to
- GPIb
- GPVI
- Integrin a2b1
GPIb = vWF binding
GPVI = collagen binding Integrin = collagen and vWF binding
Describe the steps in primary haemostasis
Platelets exposed to collagen and vWF in ECM
Endothelin release, NO and prostaglandin inhibition => VC
GPIb binds to vWF from endothelium, binds to collagen => activation, binds to other platelets
Activated COX => thromboxane formation => platelet activated VC
Seretonin => VC
ADP => fibrinogen receptor (GPIIbIIIa) exposure, activate
Fibrinogen cross links via GPIIbIIIa => platelet plug
What initiates the extrinsic pathway
Tissue factor (TF) present on the cell surface of tissues is normally not in contact with blood
If there is endothelial damage, F7 in blood comes into contact with TF
Describe the extrinsic pathway (initiation)
TF + F7 => F7aTF F10 => F10a F5 => F5a + Ca F2 (prothrombin) => F2a (thrombin) F1 (fibrinogen) => F1a (fibrin) => provides rigidity and strength to repair
F2a (thrombin) activates F13
F13 => F13a => provides rigidity and strength to repair
Some steps need Ca2+ and phospholipids
What initiates the intrinsic pathway
F12 is a plasma protein, activated when in contact with an injured blood vessel
Describe the intrinsic pathway
F12 => F12a F11 => F11a F9 => F9a F8 => F8a F10 => F10a F5 => F5a + Ca F2 (prothrombin) => F2a (thrombin) F1 (fibrinogen) => F1a (fibrin) => stable fibrin clot
F2a (thrombin) activates F13
F13 => F13a activates F1a to form a stable fibrin clot
What factors are activated by F2a (thrombin)
Importance of the cascade and thrombin
Thrombin initiates amplification and propagation by activating F8 F5 F13 F10 F11 F9
Cascade accelerates clotting to reduce excess blood loss
How do the 2 extrinsic and intrinsic pathways relate to each other
Conversion of 10 => 10a onwards
Differences in different types of thrombosis in arterial and venous
- when and where
- components
- prophalactic drug
- causes what conditions
- clot color
Arterial
- Atherosclerosis at vascular injury/disturbed flow
- platelets
- antiplatelets
- MI, strokes
- white
Venous -Stasis, vascular injury after trauma -RBC, fibrin, some platelets Anticoagulants -Cardiovascular associated death -red
Name the 3 components of Virchow’s triad
Vascular damage
Low flow/stasis
Hypercoagulability
What are the consequences when the fibrous cap of the plaque is disrupted
- 2 possible outcomes
- clot builds up
- clot breaks down
Fibrous cap disrupted
Coagulation cascade activated as lipid contents are released
Clot builds up => thrombosis
Clot breaks down => embolism downstream
When to use anti platelet drugs
What are the risks
Prevent secondary atherothrombotic/VC events
Increased hemorrhage risk
What is the mechanism of aspirin (anti platelet drugs)
What are the AEs
COX 1 inhibition
COX 2 unaffected => prostacyclin production, stops haemostasis
GI harmorrhage
What is the mechanism of P2Y12 antagonists (anti platelet drugs)
What are the AEs
Name the 2 irreversible drugs and the genetic effects on use
Name the 2 reversible drugs
Prevents ADP P2Y12 binding => decreased activation and aggregation
Irreversible
- clopidogrel (2 reactions, CYP450)
- prasugrel (1 reaction, unaffected by CYP)
Reversible
- ticagrelor
- cangrelor
Hemorrhage
What is the mechanism of GPIIbIIIa (anti platelet drugs)
What are the AEs
Name the 2 types of drugs used and some examples
Prevents fibrinogen binding
Haemorrhage, thrombocytopenia
Fab fragments
-Tirofiban, Abcimiximab
Small molecule inhibitors
-Eptifibatide
What are the problems with current anti platelet therapy
Incomplete efficacy due to multiple activation pathways
Variable responses
Bleed risk, but outweigh cardiac event risk
Genetics
Side effects
What is the mechanism of heparin (anticoagulant)
What are the 2 types
What are the pros and cons of both
Inhibits F2, 9, 10, 11, 12 directly/indirectly via antithrombin 3
Unfractionated
- cheap, short T1/2
- protamine antidote
- continuous infusion, monitoring needed
- variable bioavailability
- increased HIT risk
Low weight (Enoxaparin)
- increased bioavailability
- decreased HIT risk
- expensive
- partial protamine reversal
What is the mechanism behind warfarin (anticoagulant)
What are the pros and cons
Modifies liver synthesized factors (F2, 7, 9, 10)
- long term oral treatment
- vitamin K/factor replacement antidote
- frequent monitoring needed
- affected by diet, genes, drugs
What is the mechanism behind F10a inhibitors (anticoagulant)
What are the pros
What are the 3 examples of direct oral inhibitors
What are the 2 examples of indirect IV inhibitors
DIrect F10a inhibition
Indirect antithrombin 3
- predictable PK
- HIT rare
Direct
- Rivaroxaban
- Apixaban
- Edoxaban
IV
- Fondaparinux
- Idraparinux
What is the mechanism behind thrombin inhibitors
What are the 3 examples of IV thrombin inhibitors
What is an example of a direct thrombin inhibitor. What is this used to treat
Binds to factor binding site
IV
- hirudin
- desirudin
- lepirudin
Direct
-dagabitran for AF, DVT
How does the management of traditional anticoagulants vary from DOACs
Anticoagulants
- regular blood tests
- dietary consideration
DOACs
- less INP monotiroing
- decreased risk of uncontrolled bleeds
- faster acting
How do the antidotes differ between anticoagulants and DOACs
Anticoagulants
- warfarin => vit K
- heaprin => protamine
DOACs
-only dagabitran has an AD
Describe how HIT can arise
- 1st exposure
- 2nd exposure
1st exposure
-platelet F4 binds to heparin => AB prod
2nd exposure
-AB binds to Fc on platelet => thrombocytopenia, thrombus formation
When would you use anticoagulants
-2 situations
Inhibit coagulation cascade
Prophylaxis
Describe the fibrinolytic system
F2a + Thrombomodulin => APC
F5a, F8a => F5, 8
Plasminogen =(TPA)=> Plasmin
Fibrin =(Plasmin)=> Fibrinogen
What is the mechanism behind streptokinase (fibrinolytic)
What are the pros and cons
What is the AD
Binds, activates plasminogen
Lyse arterial thumb
Allergenic
High haemorrhage risk
Tranexaemic acid
What is the mechanism behind alteplase (fibrinolytic)
What are the pros and cons
Binds, activates plasminogen bound fibrin
Non allergenic
Lyse arterial thrombin
High hemorrhage risk
