CVS 8 and 9 - Haemostasis and Thrombosis Flashcards
What are the 2 general functions of haemostasis?
- Prevent blood loss from intact vessels
2. Arrest bleeding from injured vessels
Define coagulation.
Process by which blood converted from liquid to solid state
Explain the 2 ways in which platelet adhesion can occur.
- When damage occurs to endothelial cells, sub endothelial layer is exposed (rich in collagen).
- > Method 1 - VWF (in small vessels with high shear stress)
1. Collagen can be recognised through Von Willebrand factor which binds to collagen and attracts platelets.
2. Platelets bind to Glycoprotein 1b receptor on VWF and become activated - > Method 2 - Occurs in larger vessels with lower shear stress.
1. Glycoprotein 1A on platelets directly bind to collagen and become activated.
What happens after platelet adhesion has occurred?
- Activated platelets release ADP and Prostaglandins (particularly thromboxane).
- Platelet aggregation now occurs. Glycoprotein 2B/3A receptors are activated on the platelet and fibrinogen can bind to them (fibrinogen acts as a glue clumping the platelets together).
- Thrombin (protease) generated which can directly activate platelets to aggregate.
Name 3 things that activated platelets do.
- Change shape
- Changes membrane composition (certain phospholipids inside the platelet come to the outside - they binds to the coagulation factors)
- They present new/activated proteins on their surface (e.g. GP 2B/3A to react with fibrinogen)
What is a platelets lifespan
8 days
Where are clotting factors, fibrinolytic factors and inhibitors synthesised? (3 SITES)
- Liver (majority)
- Endothelial cells (VWF particularly)
- Megakaryocytes (then packaged in the platelets)- Factor 5 is made in the megakaryocyte
Where is Tissue plasminogen activator (tPA) synthesised and what is its role?
Synthesised locally in endothelial cells, near to where the clot forms.
Role of tPA is to convert inactive plasminogen to plasmin.
How does dissolution of the clot occur?
1 Fibrin clot assembles plasminogen and tPA on its surface.
- tPA can now cleave plasminogen into plasmin.
- Plasmin is a proteolytic enzyme - can break down fibrin clot.
- Products of breakdown are Fibrin Degradation Products (FDPs).
How can tPA be used in therapy for treating MIs?
Combine with a bacterial activator (streptokinase).
What are the 2 Coagulation inhibitory mechanisms?
- Direct inhibition
2. Indirect inhibition
Explain direct inhibition.
- Antithrombin (3) - broad scale inhibitor which circulates in high concentrations. Inhibits most of the coagulation proteinases (not just thrombin)
- So antithrombin inhibits coagulation proteinases involved in the coagulation cascade (e.g. 11A, 9A, 10A, Thrombin (2A), etc.
- Antithrombin works by forming an inactive complex with coagulation factors and they are then cleared from circulation.
(HEPARIN ACCELERATES ANTITHROMBIN ACTION - hence used in anticoagulation in venous thrombosis/pulmonary embolism)
Explain indirect inhibition.
- Mechanism to slow down amount of thrombin that is generated. Involves protein C pathway and protein C anticoagulant pathway.
- Factors 5 and 8 are activated by trace amounts of thrombin - they make the coagulation cascade occur faster. Important acceleratory mechanism for thrombin formation.
- The formed thrombin then binds to Thrombomodulin (surface of endothelium) - changes the conformation of thrombin.
- Changed conformation of thrombin means Protein C is activated (and Protein C binds to thrombomodulin receptor). From here, Activated Protein C and Protein S (a cofactor) proteolytically inactivate Factors 5a and 8a.
What is factor 5 Leiden?
A common polymorphism (4% population) whereby their Factor 5a is not so easily inactivated.
Hence protein C inactivation pathway cannot inactivate Factor 5 Leiden so higher thrombosis risk.
What are 4 risk factors for thrombosis?
- Antithrombin deficiency
- Protein C deficiency
- Protein S deficiency
- Factor V Leiden
In normal haemostasis, what is the balancing act between?
(Fibrinolytic factors, anticoagulant proteins) vs coagulation factors, platelets
What is primary haemostasis?
Formation of unstable platelet plug.
(i.e. there could be something wrong with collagen, VWF, platelets).
Primary haemostasis is caused by defective/deficient:
- Collagen
- VWF
- Platelets
Give examples of how these deficiencies may arise
- Collagen - vessel wall
Steroid therapy makes collagen & vessel wall weak. Aging also weakens vessel wall. Scurvy.
- VWF - genetic deficiency
- Platelets - aspirin/other drugs. Thrombocytopenia = relative decrease in platelet count in blood
How can a failure in primary haemostasis occur
- If one has no VWF, platelets fly past the damaged endothelium and so cannot form a primary plug,
Name some defects/patterns of primary haemostasis.
NIGPEB
- (Prolonged) Nosebleeds.
- Immediate
- Gum bleeding
- Petechiae
- Easy bruising
- Menorrhagia (anaemia)
Explain briefly petechiae (JOE WELLER)
Small blood spots appearing in thrombocytopenic patients.
Appear spontaneously. Platelets constantly repairing damaged endothelium, and a lack of platelet manifests as petechiae.
What is secondary haemostasis?
Generation of thrombin from prothrombin.
Thrombin then converts fibrinogen into fibrin.
Fibrin forms the insoluble mesh around the platelets
How come haemophiliacs do not get clot stabilisation?
Haemophilia is a failure in secondary haemostasis.
Especially prominent in larger blood vessels.
They lack Factor 8/9.
This means that there is a failure of the thrombin burst (produced in normal individuals).
A much slower increase in thrombin means that fibrinogen is not converted to fibrin as much, meaning that not enough fibrin mesh is formed. Therefore clot not stabilised.
Give common examples of defects of secondary haemostasis.
Anything causing a defect/deficiency in Factors 1-13.
- Haemophilia - F8/9
- Liver disease
- Drugs
- Dilution
- Consumption
Briefly describe Dessminated Intravascular Coagulation.
- Generalised activation of coagulation (Tissue Factor is everywhere). TF should NOT usually be in circulation, only exposed when endothelial wall breaks down.
- All Coagulation factors used up, fibrinogen etc used up due to fibrinolysis.
- Associated with inflammation/sepsis/tissue damage
- May cause widespread bleeding, bruising, etc.
- Depositing fibrin in vessels can cause organ failure.
What is the pattern of bleeding for those with secondary haemostasis?
- Delayed (unlike primary)
- Prolonged
- Deeper - joints and muscles
- Small cuts usually do not cause excessive bleeding (As primary haemostasis is safe)
- Nosebleeds rare
- Bleeding after trauma/injury.
- Bleeding after intramuscular injections
What is a hallmark of haemophilia (A and B)?
Haemarthrosis.
Bleeding into joints - causes pressure buildup and is painful.
What are some occasions that may cause excess fibrinolysis?
- Excess fibrinolytic things (plasmin, tPA). Caused by therapeutic administration, tumours
- Deficient antifibrinolytic things (antiplasmin deficiency)
- Excess anticoagulant. Usually due to heparin, thrombin inhibitors or F10 inhibitors (i.e. therapy)
What is fibrinolysis?
Vessel repair and dissolution of clot.
What are the 2 effects of thrombosis?
- Obstructed flow of blood
2. Embolism
What is the prevalence of venous thromboembolism?
1 in 1000 - 10,000 per year.
Incidence doubles every decade
PE is the cause of 10% of hospital deaths
What are some consequences of thrombo-embolism?
- Valve damage - meaning more stasis
- Thrombophlebitic syndrome - swelling/ulcers in the leg due to damage
- Pulmonary hypertension
What factors contribute to getting a thrombosis?
- Genetic constitution
- Effect of age/illnesses/medication, etc
- Acute stimulus (e.g. long haul flight).
If above thrombotic threshold, you will get a thrombosis
Virchows Triad ?
- Blood (coagulativity) - dominant in venous thrombosis
- Vessel wall - dominant in arterial thrombosis
- Flow (stasis) - complex, involved in both
(faster blood flow = more activated coagulation factors get swept away - less chance of thrombus forming)
How can blood (coagulativity) increase risk of thrombosis?
- Deficiency in anticoagulant proteins (e.g. antithrombin, protein C, protein S)
- Increase in coagulative proteins (F8, F2/others, F5 Leiden, Thrombocytosis) which increases hypercoagulability
How can vessel wall impact risk of thrombosis?
(we know less about this)
- Many important coagulative proteins found on surface of endothelial cells.
- Thrombomodulin
- TF
(-TF pathway inhibitor)
Usually, vessel wall exhibits anticoagulative role
- Inflammation downregulates the anticoagulant properties (e.g. thrombomodulin) and upregulates procoagulant properties of vessel wall.
How can flow impact risk of thrombosis?
Reduced flow = increased risk of venous thrombosis
Can be caused by surgery, fracture, long haul flights, bed rest, etc
Give some examples of conditions that can alter blood coagulation and increase risk of thrombosis.
- Pregnancy
- Malignancy
- Surgery
- Inflammatory response
What therapy can we give for venous thrombosis?
- Help lyse clot by giving tPA (increased risk of bleeding)
- Limit recurrence/extension emboli - increase anticoagulant activity (e.g. heparin), decrease procoagulant factors, use anticoagulants that are direct inhibitors.
When is the only circumstance whereby thrombolytic therapy is given after a thrombosis?
If a stroke occurs.
Not done more often due to increased risk of bleeding
To prevent clotting - increase anticoagulant activity (heparin) and decrease procoagulant activity
