Haemostasis and Vascular Pathology Flashcards
Define haemostasis
A precisely orchestrated sequence of regulatory processes that culminate in the formation of a blood clot to limit bleeding from a site of vascular injury.
What are the roles of haemostasis?
Allows:
- Blood to be in a fluid state in a normal vessel
- Formtion of a localised haemostatic clot at sites of vascular injury
- Prevents haemorrhage
What are the 3 components of haemostasis?
Vascular Wall
Platelets
Coagulation cascade
Explain the structure of basic blood vessel histology
1: Tunica Intima (inner most layer)
- Endothelium (single layer of squamous cells)
- Basement membrane
- Connective tissue (subendothelium)
- Internal elastic lamina
2: Tunica Media
* Circumferentially arranged smooth muscle
3: Tunica Adventitia
* Connective tissue containing vascular and neural supply
What layers of the tunica intima are significant in haemostasis?
Endothlium
Connective tissue (subendothelium)
What is the role of the endothelium?
Endothelial cells are:
- Antiplatelet
- Anticoagulant
- Fibrinolytic
Act as a barrier between thrombogenic subendothelium and coagulation factors in the blood.
Express factors which prevent thrombosis in undamaged vessels and limit clot formation to sites of vascular injury.
What is the role of platelets in haemostasis?
How do they carry out this role?
Formation of initial platelet plug
Provide a surface for the recruitment and concentration of coagulation factors
Does this in 3 stages:
- Adhesion to extracellular matrix at sites of vascular injury
- Activation by secretion of granules
- Aggregation of platelets
What components does the clotting cascade require?
- Coagulation factors (pro-enzymes)
- Converted to activate coagulation factors:
- Factors XII, XI, IX, X, VII and prothrombin
- Converted to activate coagulation factors:
- Cofactors (reaction accelerators)
- Factors V and VIII
- Negatively charged phospholipid surface (platelet activation)
- Calcium Ions
- Vitamin K: factors VII, IX, X and prothrombin are dependent on vit K for correct production.
What are the 4 stages of haemostasis?
Vasoconstriction
Primary Haemostasis
Secondary Haemostasis
Clot Stabilisation and Resorption
What is the purpose of the vasoconstriction phase of haemostasis?
Minimise blood loss
Maximises interactions between platelets, clotting factors, and vessel wall
What is the vasoconstriction stage mediated by?
Reflex neurogenic mechanisms
Release of endothelin
Explain the process of primary haemostasis
- Damage to the vessel wall releases Von Willebrand Factors (vWF) and collagen from the exposed subendothelium.
- vWF binds to and activates platelets.
- Platelets grow spiky projections which allows platelet-platelet interaction.
- Platelets also release secretory granules which causes further platelet recruitment and aggregation.
- This process forms a primary platelet plug.
What occurs in secondary haemostasis?
Reinforcement of platelet plug
- Tissue Factor (expressed on smooth muscle cells and fibroblasts in subendothelium in response to damage) binds to and activates Factor VII and initiates the clotting cascade.
- Clotting cascade generates thrombin
- Thrombin claeves circulating fibrinogen into fibrin (insoluble)
- Fibrin meshwork is formed
- Fibrin binds more platelets
- Consolidates initial platelet plug
What is the purpose of the clotting cascade?
Production of thrombin which converts fibrinogen to fibrin, stabilising blood clot
What measures the extrinsic pathway?
Prothrombin time
Describe the process of the extrinsic pathway of the coagulation cascade
- Initiated by tissue factor (TF)
- TF activates FVII to FVIIa
- TF forms a complex with FVIIa and Ca2+ ions
- This complex activates FX and FIX
- This leads to the final common pathway
What measures the intrinsic pathway of the coagulation cascade?
Partial thromboplastin time (PTT)
Describe the process of the intrinsic pathway of the coagulation cascade
- Initiated when FXII comes into contact with a negatively charged surface (i.e. activated platelets) and is activated to FXIIa
- FXIIa activates FXI to FXIa
- FXIa activates FIX to FIXa
- FIXa activates FVIII to FVIIIa
- FIXa, FVIIIa and Ca2+ form a complex which activates FX
- This leads to the final common pathway
Describe the process of the final common pathway of the coagulation cascade
- FXa, cofactor Va and Ca2+ ions form prothrombinase complex.
- Prothrombnase activates prothrombin and converts it to thrombin
- Thrombin converts fibrinogen to fibrin
- Fibrin monomers spontaneously polymerise to form long fibres which form an insoluble network around the primary platelet plug.
- The clot is further stabilised by FXIIIa which is activated by thrombin which forms stronger cross links between e fibrin polymers.
What are the actions of thrombin?
- Conversion of fibrinogen to fibrin
- Amplifies coagulation process by activating:
- FXI
- FV
- FVIII
- Stabilises secondary haemostatic plug by activating FXIII
- Further platelet activation
- Pro-inflammatory effects: contributes to tissue repair and angiogenesis
- Anticoagulant effects: when interacting with normal endothelium, helps limit clots to site of injury
What occurs in the clot stabilisation and reabsorption stage of haemostasis?
Fibrin and platelet aggregates undergo contraction to form a permanent plug
Counter-regulatory mechanisms limit the clotting to the site of injury
Clot reabsorption and tissue repair
Involves the fibrinolytic system
Describe the process of the coagulation cascade in vivo
- TF forms complex with FVIIa
- TF-VIIa complex activates FIX and FX
- Activated platelet membrane catalyses prothrombin conversion to thrombin by FXa on its own.
- Thrombin activates V, VIII and XI
- IXa forms complex with VIIIa and Ca2+: much more potent activator of X than TF-VIIa complex
- Xa forms complex with Va and Ca2+: much more potent convertor of prothrombin to thrombin than Xa alone.
- Lots more thrombin is produced
Which factors limit coagulation?
- Dilution: blood flowing past the clot dilutes the clotting factors.
- Intact endothelium expresses anti-coagulation factors
- Circulating inhibitors:
- Antithrombin III- actively augmented by heparin-like molecules on intact endothelium: inhibits thrombin, FIXa, FXa, FXIa and FXIIa
- Fibrinolytic cascade
What drugs affect coagulation?
Heparin
- LMWH
- Unfractioned heparin
Warfarin
