Week 1 Haemostasis and vascular pathology Flashcards
(43 cards)
Define haemostasis
Haemostasis is:
- a precisely orchestrated series of regulatory processes which
- culminates in the formation of a blood clot that
- prevents further blood loss from the injured vessel
List three things haemostasis allows
- Blood to be in a fluid state in normal vessels
- Formation of localised haemostatic clot at site of vascular injury
- Prevents haemorrhage
List three key components of haemostasis
1) vascular wall
2) platelets
3) coagulation cascade
Describe the basic blood vessel histology
1) Tunica intima- single layer squamous endothelium overlying basement membrane. BM overlies connective tissue and elastic layer
2) Tunica media- circularly arranged smooth muscle cells
3) Tunica adventitia- connective tissue, contains both vascular and neural supply.
Explain the role of endothelium both during normal physiology and during haemostasis.
Normally endothelium cells are:
- antiplatelet
- anticoagulant
- fibrinolytic
Key: endothelium acts as a barrier between thrombogenic subendothelium and coagulation factors in the blood.
Endothelium also expresses factors which prevent thrombosis in undamaged vessels.
Limits clot formation to the site of injury.
Describe the role of platelets in haemostasis
Describe the three stages by which platelets carry out their role.
Platelets:
- Form the primary haemostatic plug
- Provide a surface for the recruitment and concentration of coagulation factors. (activation exposes negatively charged phospholipid which binds coagulation factors and amplifies their activity).
Three stages of platelet activity:
1) Adhesion to the ECM at sites of vascular injury
2) Activation by the secretion of granules
3) Aggregation
List sequence of events initiated at the site of vascular injury to maintain normal haemostasis
Step 1: Vasoconstriction
Step 2: Primary haemostasis (formation of the primary platelet plug after interaction with the vessel wall)
Step 3: Secondary haemostasis (formation of insoluble, cross linked fibrin by activated coagulation factors- Thrombin- which stabilises the primary platelet plug )
Step 4: Clot stabilisation and resorption
Describe how vasoconstriction occurs
State what this achieves
- Neurogenic reflex
- Release of vasconstrictor endothelin by damaged endothelium
- Minimises blood loss
- Minimises interactions between platelets, clotting factors and the vessel wall
Describe the events in primary haemostasis
- Damage to the vessel wall leads to exposure of the subendothelium containing collagen and other prothombotic elements such as vWF.
- Platelets adhere to the exposed subendothelial matrix collagen and vWF and become activated
- Activated platelets transform from their normal discoid shape to elongated cells with spikey cytoplasmic projections (increase in SA to recruit other platelets)
- Activated platelets release their secretory granules (Degranulation). Secretory granules contain platelet agonists (e.g. thromboxane A2/ Serotonin and ADP) and coagulation factors and vWF.
- Activated platelets also flip negatively charged phospholipid to the externam membrane providing a binding site for coagulation factors, amplifies their activity and promotes fibrin formation.
- Cascade of adhesion, activation and aggregation to form the primary haemostatic plug.
Define seconday haemostasis
- Secondary haemostasis is the formation of insoluble, cross- linked fibrin by activated coagulation factors- specifically thrombin. Leads to stabilisation of the primary platelet plug.
Outline the events of secondary haemostasis
(Do not go into detail about the whole coagulation cascade, focus on key end events)
Secondary haemostasis:
- Exposure of Tissue factor (glycoprotein) on subendothlelial cells (SMC’s and fibroblasts) due to vessel wall damage
- Binding of Factor VII to tissue factor which activates it and initiates the coagulation cascade.
- Thrombin is generated which cleaves Fibrinogen into Fibrin
- Formation of insoluble, cross linked fibrin meshwork that stabilises primary haemostatic plug.
What is the coagulation cascade
By what process does this allow a small amount of initating factor to produce a clot?
- The coagulation cascade involves a series of proteolytic cleavages that convert inactive coagulation factors (proenzymes) to active coagulation factors (enzymes).
- By a process of amplification this allows a small amount of initating factor to produce a clot.
What does the coagulation cascade require? (List 5)
- Active coagulation factors (produced by proteolytic cleavage of inactive coagulation of factors).
* Factors XII, XI, X, IX, VII, and prothrombin - Cofactors:
* Acclerate the reaction, Factors V and VIII (5-8 ACCELERATE) - Negatively charged phospholipid
* Provided by the negatively charged phosphatidylserine on ACTIVATED platelets - Ca2+
- Vitamin K:
- Required for post translational modification and production of certain factors: (1972)
- factors X, IX, VII, II (prothrombin).
What is the goal of the coagulation cascade?
What pathways are there that can leads to this?
- To produce Thrombin which will convert Fibrinogen into Fibrin and stabilise the clot.
- There is the extrinsic pathway (initiated by tissue factor) and the intrinsic pathway (when factor XII contacts negatively charged phospholipid on platelet membrane)
- Extrinsic pathway and intrinsic pathway both converge on the common pathway (Activated factor Xa and cofactor V/ Ca2+ complex).
Describe the extrinsic pathway:
- initation
- propagation
- final products
What clinical test measures it? What conditions does this allow us to monitor?
Extrinsic pathway:
Initiation by Tissue factor (called extrinsic as the circualtion not usually exposed to TF).
Tissue factor activates factor VII (7) converting it to factor VIIa (7a).
Tissue factor, activated factor 7a and Ca2+ ions combine to form a complex that activates factor X and factor IX.
Conversion of factor X to factor Xa which initiates the common pathway. Results int the production of Thrombin and therefore fibrin.
Measure by prothrombin time which can be used to measure the effect of anticoagulant treatment (warfarin) and liver disease (liver produces prothrombin).
State the main actions of thrombin related to the coagulation cascade
Thrombin’s main action is the conversion of Fibrinogen to fibrin.
It also amplifies to coagulation cascade by activating more Factor XI, factor VIII and factor V.
(Activation of factor XI in intrinsic pathway, factor VIII which is required to convert factor X- Xa alongside factor IX, and factor V which combines with Xa and Ca2+ to convert prothrombin to thrombin).
It also stabilises the haemostatic plug by activating factor 13 (XIII). Factor XIIIa converts soluble fibrin to cross linked fibrin therefore stabilising plug.
State three additional actions of thrombin that are not directly related to the coagulation cascade
- Thrombin has proinflammatory effects
- Thrombin contributes to normal tissue repair and angiogenesis
- Throbin has anticoagulant effects when interacting with intact healthy endothelium, limits clots to site of injury.
What factors limit the coagulation cascade?
- Dilution by the flow of blood washing coagulation factors away
- Limited by the amount of negatively charged SA provided by activated platelets
- Anticoagulants expressed by intact adjacent endothelium
- Antithrombin III which inhibits Thrombin, Factors 9/10/11/12 (is augmented by heparin liked modules expressed on intact endothelium).
- Fibronolytic cascade
Name two drugs that can inhibit coagulation
1) Heparin
2) Warfarin
What is heparin? How is it administered?
What is its mechanism of action?
What two forms does it come in?
What are its uses?
Heparin is a negatively charged glycosaminoglycan administered by IV injection.
It binds to and activates antithrombin III (which inhibits thrombin, factor 9/10/11/12).
Comes in two forms:
1) Unfractionated Heparin which inhibits both Thrombin and Factor Xa
2) Low molecular weight Heparin which inhibits only factor Xa.
Uses: Inhibits clotting at low doses and prevents progression of established clots (higher doses).
Used in prevention/prophylaxis and in treatment of venous thromboembolism.
What is warfarin?
What is its mechanism of action?
What are its uses?
- Warfarin is a vitamin K antagonist.
- It binds to and inhibits the enzyme VKORC1 needed to reduce vitamin K.
- Vitamin K is required for the postranslational modification of factor 10, 9, 7 , 2 (Thrombin).
- Therefore Warfarin inhibits the synthesis of factor 10, 9, 7 and Thrombin.
- Uses: Prophylaxis and treatment of venous thromboembolism and ischaemic stroke in atrial fibrillation.
Name another class of drug that can be used in anticoagulation therapy that is not warfarin or heparin.
Name an example
Explain its mechanism of action.
NOAC= New oral anticoagulants
Example: Dabigatran
Mechanism of action: competitve reversible inhibitor of Thrombin
Haemostasis steps:
1) reflex vasoconstriction
2) Primary haemostasis
3) Secondary haemostasis
4) ??? Describe what this last step is and what system it involves.
- Step 4 of haemostasis: Clot stabilisation and fibrinolysis
- Fibrinolysis involves the activation of plasmin from plasminogen.
- Plasmin breaks down the fibrin clot.
- Conversion of plasminogen to plasmin is initiated by either: 1) Factor XII dependent pathway 2) Plasminogen activators released by intact adjacent endothelium. (E.g. t-PA= Tissue plasminogen activator).
Define haemorrhage
An extravasation of blood into the extravascular space.
