semester 2: L6: Blood- Mechanisms of Homeostasis Flashcards
What is Haemostasis?
process of stopping bleeding
keep blood within the damaged vessel
What are the three steps of Haemostasis?
Vasoconstriction
Formation of platelet plug
Blood coagulation
What occurs in endothelium damage?
Collagen becoming exposed is the trigger for the platelets to come
The platelets activate and come to the site
The platelets aggregate and activation of Coagulation occurs
Thrombin is formed, which works with fibrinogen to form fibrin
Fibrin is a mesh which is constructed to form fibrin polymers
it is then retracted (ripped apart) forming fibrin fragments
What are platelets?
Produced in the bone marrow from megakaryocytes
Cytoplasmic extensions on the cell surface break off
anucleate
Smaller than red blood cells, colourless
Cytoplasm contains mitochondria, SER,
Granules (dense, alpha and lysosomal)
what role does serotonin and 5-HT receptors play in platelet aggregation?
vasoconstrictor
platelet activation and aggregation
What is platelet activating factor involved in?
platelet activation and aggregation converts memb phospholipids to thromboxane A2 thromboxane A2 vasoconstrictor increases capillary permeability inflammation also from monocytes and neutrophils
How is ADP involved in platelet activation?
from platelet mitochondria
platelet activation and aggregation
Vasoconstriction and platelet plug formation
How is the platelet plug formed?
all the factors involved in the activation of platelets lead to the production of loose platelet clumping, which causes vasoconstriction at the same time
This results in the temporary haemostatic plug
The temporary haemostatic plug is formed before the definitive haemostatic plug
What is the von Willebrand factor?
primary function is to bind to other proteins, mainly factor VIII (8)
What is Weibel palade?
These are bodies in endothelial cells that release von Willebrand Factor
Why don’t all platelets clump?
This is due to Nitric oxide
Nitric Oxide inhibits the platelet activation,
It also is a potent vasodilator
Which factors is Calcium involved in helping?
Factors; VII (7),
X (10),
IX (11),
II (prothrombin)
How does the Extrinsic Pathway of coagulation begin?
Set off by the tissue factor released in the endothelial cells, due to endothelial damage
How does the Intrinsic Pathway of coagulation begin?
Set off by the exposure of collagen due to endothelial damage, in which activates factor XII (12)
Where do the two pathways meet?
At Thrombin
What does Thrombin convert Fibrinogen into?
Fibrin Polymers
What do factors 2, 7, 9, 10 contain?
Contain vitamin K-dependent g-carboxyglutamate (Gla) residues
How do zymogens become active factors?
This is through the binding of calcium to the Gla residues
How do factors V, and VIII (8) become activated?
By thrombin
How does factor II change when activated?
Inactive factor II is Prothrombin, and when activated by Xa it becomes Thrombin
What things have to come together in order to activate factor 2?
Ca2+, factor Va, factor Xa and prothrombin
Prothrombinase complex
What does the prothrombinase complex combine with in order to drive Thrombin?
Complexes with Phosphatidylserine (PS) and Phosphatidylinositol (PI) on platelet surface
How does factor V play a part?
If body senses low concentrations of thrombin, factor V will activate
If the body senses there is enough thrombin concentration, Factor V will be cleaved
What exactly converts prothrombin to Thrombin?
Factor Xa and Factor Va and Ca2+ ions
What does Thrombin regulate?
Clot formation
How is a clot (thrombus) formed?
Platelet plug forms rapidly
Exposed collagen activates intrinsic pathway
Tissue factor in exposed sub-endothelial tissues activates extrinsic pathway
Thrombin activates platelets, factors XI, VIII and V
Fibrin forms clot, enmeshing platelets and erythrocytes
What is Tissue factor pathway inhibitor (TFPI)?
Plasma protein
Binds to TF/factor VIIa complex
What is Thrombomodulin?
Endothelial surface receptor protein
Binds thrombin
Complex activates protein C, which complexes with protein S and inactivates factor Va and factor VIIIa
What is Antithrombin III?
Plasma protein
Binds to heparin on endothelial surface
Blocks factors IX (9), X (10), X1 (11), XII (12), Thrombin, Kallikrein
What is fibrinolysis?
Clot dissolution
What is a fibrin clot removed by?
fibrinolytic system
What is Plasminogen?
Plasma protein
Cleaved by tissue plasminogen activator (tPA) to form plasmin
What is tPA (tissue plasminogen activator)?
Secreted by endothelium
Activated by fibrin
How does Thrombosis develop?
Blood clotting occurs within intact vessels
Activated by atheroma
Can result from hypercoagulability or bacterial infection
What diseases can thrombosis lead to?
Coronary thrombosis=myocardial infarction
Stroke
Pulmonary embolism
Deep vein thrombosis (DVT)
What is the treatment for thrombosis?
Aspirin (inhibits TxA^2 formation)
Anti-platelet drugs (prevent aggregation/activation)
Anticoagulants (heparin; vitamin K antagonists, e.g. warfarin)
Thrombolytic agents (recombinant tPA, streptokinase)
What is von Willebrand’s disease?
Abnormal bruising and mucosal bleeding
Due to genetic deficiency of von Willebrand factor
What is Haemophilia?
Soft tissue bleeding and bleeding into joints
Due to genetic deficiency of factor VIII (haemophilia A) or factor IX (haemophilia B)
What is severe liver disease?
Deficiency of coagulation factors, reduced absorption of vitamin K
What treatments are there for Severe liver disease, Haemophilia, and von Willebrand’s disease?
Treat with procoagulants;
Vitamin K, desmopressin
What is Inflammation?
Response to injury or infection
Eliminate pathogen
Repair tissue
What are cell derived mediators of inflammation?
Prostaglandins Leukotrienes Histamine Platelet-activating factor ATP 5-HT (serotonin)
What is plasma derived mediators of inflammation?
Bradykinin
Complement fragments
What are neurotransmitter mediators of inflammation?
Substance P
Calcitonin gene-related peptide (CGRP)
What is arachidonic acid important in?
The formation Prostoglandin, and Thromboxane A^2, and Leukotriene
How is bradykinin formed?
Prekalikrein is activated by factor 12 to form kalikrein.
Kalikrein is involved in formation Bradykinin
Bradykinin is a Vasodilator and allows the WBC in to help the inflammatory process
Bradykinin is inactivated by angiotensin-converting enzyme
What are Substance P and CGRP?
they are localised in sensory nerves innervating blood vessels
vasoactive neuropeptides
roles in inflammatory and cardiovascular disease
effects on microvascular tone and permeability
recovery of microcirculation during wound healing phases
What is Tissue injury?
Injury due to trauma or immune hypersensitivity reactions
Damage to blood vessels
therefore, contact of blood with sub-endothelial and
extravascular tissues
Damaged endothelium and activated platelets
ATP, 5-HT (serotonin) and TxA2
Damaged cells produce prostaglandins
Bradykinin formed
What do sensory neuropeptides release?
Substance P
Calcitonin gene-related peptide (CGRP)
Give examples of tissue mast cells in which neuropeptides stimulate degranulation of?
Histamine (vasodilator)
PGD2, LTD4 (leukocyte chemoattractants)
What is complement system activated by?
contact of blood with tissues
The blood contains C3a and C5a (leukocyte chemoattractants)
What issues can arise from bradykinin and postglandins sensitising sensory nerves?
Hyperalgesia
Pain response
Itch response
What happens in Rubor?
Vasodilation leads to increased local blood flow
histamine, PGE2
What happens with a disorder like Calor?
Vasodilation
Stimulation of sensory nerves (ATP, PGs, 5-HT, bradykinin)
What happens within a Tumor?
Increased vascular permeability (histamine, LTD4, bradykinin, CGRP)
What happens within a Dolor?
Stimulation of sensory nerves (ATP, PGs, 5-HT, bradykinin)
What is the end result of inflammation?
Increased blood flow, vascular permeability and chemoattractants bring in leukocytes
Stimulate proliferation of fibroblasts and production of extracellular matrix (=scar)
Stimulate proliferation of muscle and epithelial cells
