41.1 Haemostasis Flashcards
What is a blood clot?
Semisolid mass composed of both platelets and fibrin entrapped in a mesh of fibrin and blood cells
Define haemostasis
Process that prevents excessive blood loss (haemorrhage)
How does a breach of the endothelium lead to platelet adhesion?
Exposes platelet receptors to ligands that are components of the subendothelial matrix: collagen (Ia), fibronectin and laminin (Ic)
How does AT III work?
Binds and inhibits factor Xa and thrombin
How does the endothelial lining of blood vessels prevent thrombosis?
-Physical barrier separating platelets and coagulation factors from stimulatory collagen
-Secretion of heparan sulphate to activate AT II
-Synthesis of inhibitors of platelet activation (prostacyclin, NO)
How does the extrinsic pathway occur if factor VII is inside the vascular system and tissue factor is on non vascular cells?
Injury to endothelium allows for Factor VII to come in contact with tissue factor which non proteolytically activates Factor VII to VIIa
How does thrombomodulin work?
Forms a complex with thrombin and removes it from circulation
How is haemostasis achieved (4)?
-Vasoconstriction
-Increased tissue pressure
-Platlet plug
-Coagulation (clot formation)
List the factors that inhibit clotting
-Blood flow
-TFPI (Tissue factor pathway inhibitor)
-Antithrombin III
-Thrombomdulin
-Activated protein C
-Clot degradation (fibrinolysis)
Other than adhesion, what does binding of platelet receptors to ligands cause?
Causes a conformational change in the receptor that initiates an intracellular signalling cascade leading to PLATELET ACTIVATION
State the intrinsic pathway
What activates the conversion of plasminogen to plasmin?
t-Pa (tissue plasminogen activator) (increased levels of t-Pa by caetcholamines)
What are platelets?
Thrombocytes: small colourless cell fragments of megakaryocytes made in bone marrow
Life spand of 8-10 days
Secrete vasoactive mediators (TXA2, 5-HT)
What are the ‘factors’?
Most are serine proteases- once activated it catalyses a specific proteolytic event in the subsequent factor
What are the three processes that occur when a platlet plug is formed?
-Adhesion
-Activation
-Aggregation
What are the two pathways in the coagulation cascade?
Intrinsic and extrinisic pathway that converge to a common pathway
What causes haemophilia?
Inability to synthesis clotting factors (VIII) (IX)
What causes the cleavage of X to Xa in the extrinsic pathway?
Tissue factor + Ca + Factor VIIa
What complex is required to convert X to Xa from the intrinsic pathway?
VIIIa and IXa (and Ca2+) complex
What does thrombin do?
Proteolysis of soluble fibrinogen to insoluble fibrin monomers that spontaneously polymerise to form a gel of fibrin polymers that traps blood cells
What does vWF bind to?
Platelet receptor glycoprotein Ib/Ia
What does Xa do?
With Va converts plasma protein prothromobin to thrombin (protease)
What follows platelet activation?
Aggregation
What form does plasmin circulate as?
Inactive plasminogen
What generates VIIa?
VII –> VIIa
-Thrombin: feedback activation (downstream product)
VIIa is a crucial modifier of X –> Xa
What helps to stabilise the platelet plug?
Conformational change in Gp IIb/IIIa exposes it and allows it to bind fibrinogen
-Fibrinogen in blood forms bridges between platelets
-stabilises platelet plug
What is the cause of platelet adhesion?
Increase in SHEARING force in response to injury causes platelets to adhere to themselves and other components (vascualr wall)
What is the purpose of a cascade?
Amplifies a signal = only a small amount of one factor generates large amounts of the downstream factors
What is tissue factor?
An integral membrane protein that is a receptor for Factor VII
What is vasospasm? When does it occur?
Narrowing of the arteries caused by persistent contraction of blood vessels (prevents haemorrhage)
What makes anti thrombin III?
Endothelial cells and the liver
What mediates platelet adhesion?
Platelet receptors - integrall membrane glycoproteins in the platelet membrane belonging to a class of receptors known as integrins
What reaction activates the common pathway?
X –> Xa
Xa is the first protease of the common pathway
What signal transduction cascade does platelet activation involve? What are the consequences of platelet activation?
-Activation of PLC
-Increase in intracellular Ca2+
-Exocytosis of dense storage granules (ADP, serotonin, vasoconstrictors: 5-HT, adrenaline)
-Exocytosis of alpha granules (vWF, Clotting factor V, PDGF (platelet activating factor) and fibrinogen deposition)
-Cyclooxyenease breaks down arachidonic aid to thromboxane A2 which is released
-Cytoskeletal morphological change: pseudopodia emerge (finger like projections) to increase surface area and adhesiveness of platelets
What stimulates the intrinsic coagulation cascade?
Abnormal surfaces:
-Negatively charged surfaces (activated platelet)
What triggers the extrinsic pathway?
Factors outside the vascular system: TISSUE FACTOR (factor III, thromboplastin) binding to factor VII
Initiates a cascade that occurs outside the vascular system
Responsible for initating clotting
What unites the extrinsic and intrinsic pathways?
The common pathway
Where is positive feedback in the clotting cascade?
Thrombin catalyses the formation of cofactors Va and VIIIa (and more)
Where is vWF found?
-secreted by endothelium in response to injury (hypoxia, high shear)
-found in alpha granules of platelets (released upon platelet activation)
Which cascade occurs alongside the platelet activation cascade?
Blood clotting/coagulation cascade
Which enzyme breaks down fibrin?
Plasmin (serine protease)
Which factor becomes activated at the beginning of the intrinsic cascade?
Factor XII (plasma protein) becomes factor XIIa
Which factors require vitamin K?
Factor X
Prothrombin
Factor VII
Factor IX
Protein C
Which platelet receptor ligand is found in plasma?
von Willebrand factor (vWF)
Why do platelets not normally adhere to endothelial cells?
Due to the negative charge on both surfaces:
-Endothelial cells have proteoglycans (heparan sulphate)
Why must the clotting cascade be regulated?
Too slow –> excessive bleeding
Too efficient –> excessive coagulation
