Thrombosis Flashcards
Why does coagulation occur?
Immunological response
- Prevents blood loss
Describe arterial thrombosis.
- Mostly result from an atheroma rupture or damage to the endothelium (eg. MI, stroke)
- Platelet-rich thrombosis - mostly primary haemostasis
- May block downstream arteries - since they become narrower and more likely to be obstructed
Describe venous thrombosis
- Often results from stasis or a hyper-coagulant state (eg. DVT)
- Platelet-poor thrombus - mostly secondary haemostasis
- May move to the lungs
List some factors/substances that affect the coagulation-fibrinolysis balance. PART 1
- Tissue plasminogen activator: initiates fibrinolysis
- von Willebrand factor: activates platelets - in coagulation
- Tissue factor: initiates clotting - in coagulation
List some factors/substances that affect the coagulation-fibrinolysis balance. PART 2
- Antithrombin: inhibits clotting
- Prostaglandin I2: inhibits platelets
- Nitric oxide: inhibits platelets
INVOLVED IN FIBRINOLYSIS
What is Virchow’s Triad?
Describes the three categories that are thought to contribute to thrombosis
What are the components of Virchow’s Triad?
- STASIS: static blood lacks kinetic energy and tends to clot
- HYPER-COAGULANT STATE: eg. infection e.g sepsis, hereditary, drugs (eg. HRT)
- ENDOTHELIAL DAMAGE: eg. surgery or cannula
How are the valves involves in stasis?
Blood tends to eddy around the valves, increasing the risk of stasis.
What are the four possible fates of a thrombus?
- RESOLUTION
- EMBOLISM
- ORGANISED
- RECALANISED AND ORGANISED
What occurs during resolution?
Fibrinolytic system destroys the whole clot over time
What occurs during embolism?
- Thrombus dislodges and goes to the heart/lungs
- This is life threatening
What occurs during organisation?
- Endothelial cells grow over the clot
- Person more prone to having another clot due to the narrower vein
What occurs during recalanisation?
- Thrombus is so big that it can’t be grown over
- Can be grown through
What is the difference between a proximal DVT and a distal DVT?
With a proximal DVT, there is a higher risk of a pulmonary embolism and post-thrombotic syndrome.
- Rare in distal DVT
MINOR DIFFERENCE: Proximal affects upper leg. Distal affects lower leg.
What does a platelet release when it has been activated?
Releases thromboxane A2 and adenosine diphosphate (ADP)
- Both induce receptors for fibrinogen.
Describe the common pathway. PART 1
- Factor IXa activates Factor X by proteolysis to create Factor Xa.
- Factor Xa (FXa) cleaves prothrombin to form thrombin (FIIa).
- Thrombin (FIIa) is a protease that cleaves fibrinogen into fibrin.
Describe the common pathway. PART 2
- Thrombin cleaves Factors V and VIII to give FVa and FVIIIa. This is known as amplification. It can also activate platelets.
- FVa and FVIIIa together with Ca2+ form the tenase complex and prothrombinase complex
- These complexes assemble on the negatively charged phospholipid surfaces in the activated platelets.
What does fibrinogen promote?
- Blood clotting by activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor
Describe the prothrombinase complex.
- Negative surface of the activated platelet causes calcium, prothrombin and Factor Xa and Va to bind.
- Components all bind by a particular domain of glutamic acids (GLA); they stabilise the complex. Synthesis is Vitamin K dependent.
What can formation of the GLA domain be inhibited by?
Warfarin
What is fibrinolysis?
The breakdown of fibrin into fibrinogen
- Reverse of coagulation
How does coagulation occur?
- When endothelial cells become damaged/inflamed they favour coagulation
- Subendothelial cells release Von Willebrand factors
- Von Willebrand factors activate platelets and tissue factors initiate clotting
How is coagulation inhibited?
- Endothelial cells release nitric oxide which inhibit platelets
- Also produce prostaglandin 12 which inhibits platelet activation
- Endothelial cells express heparan and when bound to antithrombin, inhibits clotting
What can happen as a result of thrombosis in the leg?
- Blocks venous return causing the leg to become congested with fluid
- Increases capillary pressure so filtration increases. Causes oedema
- Hypoxia may occur as some cells are not supplied with oxygen
- Thrombosis might become dislodged and make its way to the heart
What happens during post-thrombotic syndrome? PART 1
- Occurs when a big vein is blocked by a clot
- Causes inflammation along with damage to valves from the thrombus
- Causes valvular incompetence which combines with persistent venous obstruction to cause small superficial veins to haemorrhage
What happens during post-thrombotic syndrome? PART 2
- Increase in tissue permeability leading to oedema (swelling) due to release of inflammation factors
- Pain, swelling and ulceration follows
What happens when a small venous thrombus reaches the heart? PART 1
- Highly unlikely to be lodged in the heart
- Will pass through the right atrium and ventricle into the pulmonary artery and reach the lungs
- Pass down the arterioles and may get lodged blocking these arterioles.
What happens when a small venous thrombus reaches the heart? PART 1
- Leads to the formation of a slight VQ mismatch - area of the lung that is not perfused but is well ventilated
- Cause hypoxia and in severe cases will eventually leads to necrosis or oedema
What happens when a large venous thrombus reaches the heart?
- Pass through the right atria and the right ventricle
- Enters the pulmonary artery and becomes lodged
- Causes embolism that can block both pulmonary arteries
How are blood clots formed? PART 1
- Von Willebrand factors bind to and activate platelets.
- Activated platelets release Thromboxane A2 and Adenosine Diphosphate (ADP)
- Bind to receptors on adjacent platelets and increases expression of the fibrinogen receptor (a glycoprotein complex)
How are blood clots formed? PART 2
- Fibrinogen binds to its receptor and hold the platelets together (called aggregation)
- Once a few platelets aggregate they form a negatively charged clump where the fibrinogen is converted to fibrin and the fibrin clot is crosslinked (called coagulation)
How can subendothelial cells be exposed?
- Tissue damage
- Release of inflammatory factors
What is the purpose of having different pathways leading to the common pathway in blood clotting?
- Allows for the amplification of proteases found
- One protease can cleave many molecules which can form many proteases
Which is more important, the extrinsic or intrinsic pathway?
The extrinsic pathway is more important
- It is shown that mutations in the extrinsic pathway have a much bigger effect than mutations of the intrinsic pathway
What is the role of tissue plasminogen activator?
- Serine protease found on endothelial cells which catalyses the activation of plasminogen (in circulation) to plasmin.
-Plasmin then catalyses the breakdown of the cross linked fibrin cloth into fragments called D-dimers
What is the role of antithrombin?
- A small protein molecule made by the liver which circulates in the plasma.
- Binds to heparan, found on endothelial cells, to form active antithrombin which inhibits clotting by inactivating thrombin and other components
How are stroke and myocardial infarctions treated?
Using thrombolytic agents such as tissue plasminogen activator
What is primary haemostasis?
Aggregation of platelets
What is secondary haemostasis?
Conversion of fibrinogen into fibrin
What are the three basic steps of fibrinolysis?
- Aggregation of platelets
- Conversion of fibrinogen to fibrin
- Thrombin converted from prothrombin
What do anticoagulants do?
Prevent thrombosis
What happens if the endothelial cells get damaged and the subendothelial cells get exposed?
von Willebrand factors will bind to platelets and start a clot
What do antithrombin and hepsrin do?
Inhibit clotting prostaglandins, platelets and nitric oxide
What is the extrinsic pathway?
- Tissue factor is a receptor for VIIa which is bound to negatively charged platelet phospholipid surface along with calcium.
- VIIa activates Xa and the common pathway starts
What is the extrinsic pathway triggered by?
Transcription factors which activates factor VII
RECAP: Why do the veins need valves?
Prevent backflow of blood
RECAP: What would happen if the veins were to contract?
Venous return occurs
Describe the process of platelet adherence.
- Von Willebrand factor on subendothelial cells activates platelets.
- Circulating Von Willebrand factor may bind to exposed subendothelial cells
- Activated endothelial cells can also express von Willebrand factor
Describe the intrinsic pathway.
- Begins in the blood stream. It is basically activated when blood is exposed to collagen (or other damaged surfaces).
- Activated when you put blood onto a charged surface such as glass.
Why are D-dimers measured clinically?
- Measured to see the level of thrombolysis
- Degradation products of thrombuses are D dimers
