Lecture 21: Thrombosis and embolism Flashcards
What is heamostasis?
The physiological response of a blood vessel to injury
- It serves to prevent blood loss by plugging leaks in injured vessels.
- In healthy vessels heamostasis is actively switched off to maintain the blood in a fluid state.
What do healthy vessels do?
Endothelial cells inhibit haemostasis
How do endothelial cells inhibit haemostasis?
- Physically insulating tissues from blood
- Producing enzymatic and chemical inhibitors of platelet activation i.e NO and Prostacyclins
- Producing antithrombin on their surface which binds and inactivates the coagulation enzyme thrombin
When vessels are injured, heamostasis is accomplished by co-operation between;
- Endothelial cells
- Platelets
- The ‘clotting cascade’ = coagulation cascade
How do endothelial cells promote haemostasis?
Injured endothelial cells;
Produce:
- Endothelin -> vasoconstriction
- von Willebrand factor (super glue) -> promoting platelet adhesion to the ECM proteins exposed by vessel injury.
- Tissue factor = thromboplastin -> activates the coagulation cascade.
Write some notes on platelets;
- Derived from megakaryocytes
- 7 day life span in circulation
- Chocolate chip like structures are alpha and dense granules that contain chemical mediators of haemostasis (spit these granules out and drive things)
How are platelets activated and what do they secrete?
- They become activated by ECM proteins (esp. collagen) that are exposed when the endothelial monolayer is damaged.
- Secrete chemical signals including Thromoxane A2, Vasoactive amines, and ADP
= Promote vasoconstriction and platelet aggregation
How is the importance of platelets demonstrated?
The importance of platelets is demonstrated by the effects on haemostasis of reduced platelet number or function
- Purpura (bleeding from skin capillaries)
- Major spontaneous haemorrhage
Describe the coagulation system:
- The coagulation system is a cascade of proteolytic reactions
- Inert circulating zymogens (precursors) are sequentially activated
- The cascade is initiated by several stimuli, esp tissue factor
- The penultimate step in the cascade is the activation of thrombin
Describe the coagulation cascade from thrombin:
- Thrombin catalyses fibronogen -> fibrin monomers
- Fibrin monomers then polymerise into fibrin strands
- Thrombin also activates platelets, and catalyses several earlier steps in the coagulation cascade
- Fibrin strands form a meshwork with fused platelets to form a stable haemostatic plug
What is thrombosis;
- Thrombosis occurs when the physiological mechanisms of haemostasis are activated inappropriately
- The formal definition of a thrombus is ‘a mass formed from blood constituents within the circulation during life’
Can break off as embolus and cause obstruction
What are thrombi composed of?
Thrombi are composed of:
- Fibrin and platelets
- Entrapped red and white blood cells
Is a thrombus a blood clot?
Thrombus does not equal blood clot
What is a blood clot?
Blood clot is formed in static blood:
- Involves primarily the coagulation system
- W/o interaction of platelets with the vessel wall
- i.e in vitro when blood is placed in a tube test tube or p.m
Describe a clot:
- Soft, jelly-like, and unstructured
- Clot is composed of a random mixture of blood cells suspended in serum proteins.
Describe Virchows triad:
Endothelial injury \+ Hypercoagulation (The blood constituents) \+ Abnormal blood flow (The blood flow)
= Thrombosis
What can damage the endothelium? (5 things)
- Atherosclerosis
- Hypoxia i.e heart endothelium
- Infection/inflammation
- Physical damage i.e crushing of veins, haemodynamic stress of hypertension
- Chemical damage
What can happen with artificial surfaces?
Artificial surfaces can;
- Activate the intrinsic coagulation cascade
- Bind pro-inflammatory compliment cascade proteins
- Bind other proteins that may activate platelets.
I.e can form thrombi, so, anti-coagulants, thus challenge is to create non-thrombogenic
What can change blood flow in arteries or the heart
In arteries or cardiac chambers, turbulence is a key cause
- Narrowing (atheroscelrosis)
- Aneurysms
- Infarcted MI
- Abnormal cardiac rhythm or valvular disease
What can change blood flow in veins?
In veins, stasis is an important cause
- Failure of the right side of the heart
- Immobilisation
- Compressed veins
- Varicose veins
- Blood viscosity (i.e sickle cell anemia, dehydration)
What do changes in blood flow cause?
- Platelets to come into contact with endothelium
- Impaired removal of pro-coagulant factors
- impaired delivery of anti-coagulant factors
- Directly cause injury or activation of endothelium
- Atherosclerotic plaques which are pro-coagulant
What do changes in blood constituents lead to?
Increased tendency to coagulate
What can cause changes in blood constituents?
Genetic causes
- Deficiency of anti-thrombin 3
- Deficiency protein C
Acquired causes
What are the acquired causes that lead to changes in blood constituents?
Tissue damage i.e trauma, MI
- Acute phase response from liver
- Pro-inflam / pro-coagulant / compliment factors
- Cytokines cause platelet release from bone marrow
Post-operative Malignancy Smoking (increased platelet activ) Elevated blood lipids Oral contraceptives (increase clotting)
What are the physiological mechanisms that limit coagulation?
- Restricted to local site of vascular injury
- 3 types of natural anti-coagulants
+ Antithrombins
+ Proteins C&S - Vit K dependant
+ Tissue factor pathway inhibitor - Fibrin cascade limits the size of final clot through action of plasmin which breaks down fibrin.
What is an emboli?
- An embolus is an intravascular mass (Solid, liquid or gas) carried by blood flow from its point or origin to a distant site
What are the effects of emboli?
- Stenosis -> Occlusion
- Pulmonary embolus can lead to;
- > Pulmonary infarction
- > Reduced CO
- > Right heart failure
- > Death if severe
- Mural thrombosis from LV or aorta -> enters systemic arterial system and can pass to brain, kidney, spleen etc
How does the loss of endothelial cells lead to thrombosis?
Loss of endothelial barrier exposes underlying cells which activate;
- Platelets
- The coagulation cascade
