W3 14 Anticoagulants and haemostasis Flashcards
What does haemostasis mean?
The stopping of bleeding
What is coagulation?
The process by which blood turns to a solid
What is different in injury that triggers haemostasis?
In injury blood RBCs and platelets come into contact with the sub-endothelium, which is rich with thrombotic and pro-aggregating proteins.
Briefly, what are the stages in haemostasis?
Primary haemostasis - vasoconstriction to limit blood loss and platelet activation leading to platelet block
Secondary haemostasis - activation of coagulation cascade to stabilise the block. Thrombin cleaves fibrinogen to fibrin, which is deposited to stabilise the clot.
To restore homeostasis, plasmin is activated to degrade the fibrin clot = fibrinolysis
What is a thrombus made from?
Platelets - haemostatic plug (primary haemostasis)
Coagulation - fibrin clot (secondary haemostasis)
How do platelets usually circulate the blood?
In resting, non-activated form.
Platelet activation and inhibition is tightly regulated. Give some examples of platelet activators.
Collagen, thrombin, ADP, fibrinogen , VWF (leading to thrombosis)
Platelet activation and inhibition is tightly regulated. Give some examples of platelet inhibitors.
PGI2, NO (anti-thrombotic effect)
What are the stages of formation of a platelet plug?
Upon exposure of the sub-endothelium, platelets will interact with different receptors in the matrix, leading to rolling of platelets
This leads to their activation, and secretion of agonists from platelets, and their firm adhesion.
Will release molecules to recruit other platelets
Will aggregate through fibrinogen in the blood to form a platelet rich thrombus
What on platelets becomes activated allowing them to aggregate?
Active integrin is able to bridge a fibrinogen molecule to form a platelet aggregate, adhere, and spread to support the coagulation cascade to stabilise the thrombi.
What are characteristics of a resting platelet?
Discoid shape
Granular
Integrins inactive
What are the characteristics of activated platelets?
Shape change
Degranulation
Integrin activation
Aggregation, adhesion, spreading, procoagulant
What agonists do platelets release after they’re activated?
ADP and TXA2, working in an autocrine way by binding on platelet receptors, to further activate platelets
What substances are contained within the dense and a-granules of the platelet?
Dense granules - ADP, calcium, serotonin
a-granules - coagulation factors, anti-bacterial factors, chemo-attractants etc
What happens in secondary haemostasis?
Coagulation. At the site of damage, thrombin is generated. It cleaves plasma fibrinogen to form a fibrin clot.
What are the functions of thrombin?
Induces vasoconstriction to limit blood loss
Leads to a fibrin clot
Leads to coagulation amplification
Leads to platelet activation
What is the different between the intrinsic and extrinsic coagulation pathways?
Extrinsic pathway - occur during tissue damage, leading to the exposure of tissue factor which can interact with factor 7a, and activate Xa
Intrinsic pathway - not activated easily at site of injury, more pathogenic activity eg during bacterial infection or stent implementation. Polyanion charges can activate factor 12.
Both converge with the generation of factor Xa - the key driver of the coagulation cascade.
What does factor Xa allow?
Allows the generation of thrombin (IIa) from prothrombin (II)
There are 3 stages in thrombin formation for coagulation. What are they?
Initiation - due to exposure of tissue factor in the sub-endothelium, a small amount of thrombin is generated (not enough to form a fibrin clot)
Amplification - it activates other factors leading to more thrombin generation
Propagation - there is a burst of thrombin generation, crucial for fibrin formation and deposition
How is prothrombin turned to thrombin?
Prothrombinase complex is associated with the surface of platelets = Xa, calcium and Co-factor
It will traverse prothrombin (an inactive zymogen) into thrombin
Thrombin will cleave fibrinogen into fibrin to support clot generation
How does thrombin positively and negatively feedback?
Thrombin positively feedbacks to activate other coagulation factors to amplify the coagulation cascade
Also has negative feedback loop, and when thrombin is generated it can bind to its receptor, thrombomodulin on endothelial cells, to activate protein C to inhibit the coagulation factors
What 3 systems are there to limit/fight excess coagulation?
Tissue factor pathway inhibitor (TFPI) - limits tissue factor
Antithrombin - limits generation of thrombin
Activated protein C - activated by binding of thrombin to thrombomodulin, inhibits coagulation factors (Va and VIIIa)
What is fibrinolysis?
The degradation of a fibrin clot.
When is the fibrinolytic cascade activated?
Once coagulation is activated, and fibrin is deposited, to restore homeostasis, fibrinolytic cascade is activated.
What is the aim of the fibrinolytic cascade?
To transform plasminogen into plasmin.
What is the role of plasmin?
Plasmin will degrade the fibrin into fibrin-derived peptides, to inhibit the growth of the clot, to stabilise the vessel injury and prevent vascular occlusion.
How is plasminogen turned to plasmin?
tPA (tissue plasminogen activator) and uPA (urokinase-type plasminogen activator) will activate plasminogen into plasmin, to degrade the fibrin
What will thrombin do to fibrinolysis and how?
Thrombin will block fibrinolysis by activating TAFIa (thrombin-activatable fibrinolysis inhibitor). It can activate this by binding to thrombomodulin.
