Thrombosis: Haemostasis in the Wrong Place Flashcards
What does coagulation prevent?
Coagulation prevents blood loss - immunological response
What does inflammation activate?
Inflammation activates coagulation which promotes inflammation
What is primary haemostasis?
Aggregation of platelets
What occurs during secondary haemostasis?
the conversion of fibrinogen -> fibrin
Summarise fibrinolysis
- Aggregation of Platelets
2a. Fibrinogen -> fibrin mesh via thrombin (protease)
2b. Prothrombrin -> thrombin via a culmination of a
cascade of similar activation steps
When do primary / secondary haemostasis occur?
These reactions are continuously occurring in the body
Describe the features of arterial thrombosis
Results from mostly atheroma rupture or damage to endothelium (e.g. MI / stroke)
Platelet rich ‘white’ thrombosis - mainly primary
May block arteries downstream
Outline the distinctive features of a venous thrombosis
Often results from stasis or a hyper-coagulant state (DVT)
Platelet poor ‘red’ thrombosis - mostly secondary
Can move to lungs
Which process is favoured by endothelial cells when damaged?
If damaged / inflamed, endothelial cells they may favour coagulation
What is released from the subendothelial cells during coagulation?
Subendothelial cells release Von Willebrand Factor or Tissue factor if disturbed
How does the blood ensure clotting doesn’t occur?
Many mechanisms are in place to prevent clotting
e.g.
- Binding of Heparan and antithrombin to their
receptors inhibits clotting
- Release of NO inhibits platelet activation
What is the role of tissue plasminogen activator?
Tissue plasminogen activator causes:
plasminogen -> plasmin
which lyses on clot forming D dimers
What is Virchow’s Triad?
Describes the 3 broad categories of factors that are thought to contribute to thrombosis:
- stasis
- hypercoagulant state
- endothelial damage
How does stasis cause thrombosis?
Static blood lacks kinetic energy and tends to clot
What causes a hypercoagulant state to occur?
Infection Hereditary drugs (HRT)
What can cause endothelial damage?
surgery or canula
What is the role of valves in veins?
One way valves prevent backflow of blood
How do veins transport blood back to the heart?
Contraction of nearby muscles squashes veins, acting as a pump to return blood to the heart
- low venous pressure aids this mechanism
How is risk of stasis increased around valves?
Blood tends to eddy around valves increasing the risk of stasis around the valves
What effect do varicose veins have on valves?
Varicose veins compromise valves, causing blood to pool leading to DVT
How does DVT occur?
Blocked venous return congests the affected organ with fluid - Pressure increases
More hydrostatic pressure pushes fluid out causing oedema and swelling
What is a major risk of DVT?
The thrombosis might become dislodged and make its way back to the heart
What is the fate of a thrombus?
- Resolution: resolves completely
- Embolism: usually lodges in smaller vessels blocking
blood flow - Organised: endothelium can grow over thrombus;
reducing stretchiness of vessel - Recanalised & Organised
Which vessels does a proximal DVT affect?
Common femoral v. Femoral V. Great saphenous V. External Iliac V. Deep femoral v. popliteal v.
- Higher risk of pulmonary embolism and post- thrombotic syndrome
Which vessels does a distal DVT potentially affect?
small saphenous v.
posterior & anterior tibial veins
What is post-thrombotic syndrome?
when a thrombus remains and continuously blocks blood flow for a longer duration
What are the consequences of post-thrombotic syndrome?
Inflammation along with damage to the venous valves from the thrombus itself
Valvular incompetence combined with persistence venous obstruction inducing:
- rupture of small superficial veins
- subcutaneous haemorrhage
- increased tissue permeability
What is a pulmonary embolism?
When an embolism returns to the lung via the right side of the heart
Describe the route taken by a pulmonary embolism
RA -> RV -> PA -> Lungs
Describe the pathology of a distal DVT
- rarely causes pulmonary embolism
- rarely causes post-thrombotic syndrome
- Not as serious as the thrombus is moving from area of
small vessels to larger vessel so has smaller effect
What is the fate of a venous thrombus in the lungs?
- Asymptomatic
- Can cause sudden death
Describe what occurs when a thrombolus may be asymptomatic
- small venous thrombolus
- slight V/Q mismatch
- or slight Infarct zone
What reasons could cause a venous thrombolus to cause sudden death ?
- large venous thrombolus
- saddle embolism blocks pulmonary arteries
What causes a saddle embolism?
Thrombus from femoral artery can cause saddle embolism
How are Platelets are activated ?
- Von Willebrand factor on subendothelial cells (or
activated endothelial cells) activates platelets - Activated platelets release TxA2 - thromboxane & ADP
- inducing receptors for fibrinogen
- TxA2 & ADP bind to receptors on adjacent platelets
increasing GpIIb/IIIa expression - Collagen, thrombin & many other mediators activate
platelets
What causes platelet adherence?
Fibrinogen acts as a tether, holding platelets together
What is fibrinogen?
The soluble precursor to Fibrin present in circulation
What is required for successful coagulation?
A negatively charged platelets surface
What provides a negative platelet surface for coagulation to occur?
The clump of activated platelets provides the negative surface
What is coagulation?
Coagulation involves:
- conversion of fibrinogen -> fibrin
- cross-linking the clot
What are the pathways involved in coagulation?
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
Explain how the 3 coagulation pathways come together
Extrinsic pathway is the most significant in vivo
Intrinsic pathway forms the basis of lab tests of coagulation and has some interaction with the extrinsic pathway
- come together to common pathway (activating Fx)
Describe the features of the coagulation pathways
- Amplification of signals at each step
- Process can be inhibited at multiple steps
- Small amounts of activated factors cause big effects
- Factors constantly circulate blood
Outline the steps of Intrinsic & Extrinsic pathways leading to the Common Pathway
- Factor iXa activates Factor X by proteolysis -> FXa
- FXa cleaves prothrombin -> thrombin (FIIa)
- Thrombin (FIIa) cleaves fibrinogen -> fibrin
How does fibrinogen promote blood clotting?
Is converted to fibrin
Also forms bridges between and activating blood platelets by binding to their GPIIb/IIIa surface membrane fibrinogen receptor
Outline the stages of the final Common Pathway
- Thrombin cleaves Factors V and VIII -> FVa + FVIIIa
- FVa + FVIIa with plasma Ca2+ form:
Tenase Complex:
- FVIIIa + FIXa -> FXa
Prothrombinase Complex
- FVa + FXa -> thrombin
- Once enough thrombin produced, FXIIIa cross-links
fibrin fibres into solid clots - Once activated FVIIIa activates FXa => inhibiting
common pathway
What is tissue factor?
Receptor for FVIIIa also bound to a negatively charged surface of a platelet phospholipids, along with Ca2+
Where is tissue factor found?
TF is present on most subendothelial cells and is exposed if the endothelium is inhibited - ready for FVIIIa to bind
What is the role of Tissue factors?
Assemble on the charged phospholipid surfaces of the activated platelets. FVIIIa and FVa amplify existing reactions making them harder to overcome
What is the function of warfarin?
an anticoagulant that inhibits the production of carboxyglutamic residues
Describe the features of the prothrombinase complex
Factor Xa is bound to negatively charged platelet via GLA
What is GLA?
GLA domain is 10 - 12 glutamic acids in the N-terminus of the molecule converted to ɣ-carboxyglutamic acid
-> Vitamin K dependent process
What is the significance of coagulation pathways in the laboratory?
The common pathway is the bulk of the coagulation pathway - traditionally activated in the lab; still reflected in the way initiation pathways are described
Intrinsic & Extrinsic pathways represent laboratory tests still carried out today to assess coagulation
Describe what occurs in the extrinsic pathway
TF: receptor for VIIa, also bound to negatively charged platelet phospholipids surface along with calcium.
Once activated, VIIa activates Xa and the common pathway is initiated.
TF present in subendothelial cells;
exposed if endothelium is damaged, ready for VIIa to bind to & initiate coagulation.
Major one happening in vivo
triggered by tissue factor which activates factor VII and feeds into the common pathway.
Summarise the intrinsic Pathway
Activated when blood placed onto a charged surface such as glass.
Explain the consequence of defects in the pathways
Defects in the factors of the extrinsic pathway have far larger physiological effects than mutations in the enzymes of the intrinsic pathway.
How would we detect where a defect is present in the pathways?
Laboratory tests distinguish between activating the intrinsic or extrinsic pathways in order to assess where a defect may be.
Explain the use of thrombolytic agents
Some of these thrombolytic agents such as tissue plasminogen activator and related compounds are used to treat strokes and myocardial infarctions.
What is the role of tissue plasminogen activator?
Converts plasminogen -> Plasmin
What is the function of antithrombin?
Inhibits a lot of the enzymes in the coagulation cascade but thrombin and Factor VII in particular
Where is antithrombin found?
Expressed by endothelial cells
What is the role of Heparan?
Heparan binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation
What does activated AT do?
The activated AT then inactivates thrombin, factor Xa and other proteases
