Theme 2: Lecture 2 - Platelets and Haemostasis Flashcards
What is the endothelium?
Layer of cells lining inner surface of all vessel walls and have a huge total surface area
What is the function of the endothelium?
- Controls blood fluidity and flow
- Controls size of blood vessel
- When intact: contributes to preventing clots
- When injured: promotes local clotting on exposed basement membrane
- Signals inflammatory cells to areas needing defence/repair
- Gate-keeper between blood and tissues
- Actively controls extravasation of fluid, cells & molecules
What is haemostasis
process which causes bleeding to stop
What does the endothelium secrete under normal conditions
Inhibitors of haemostasis
What does the endothelium secrete when injured
von Willebrand factor (and stops secreting haemostasis inhibitors)
von Willebrand factor
a blood protein that is an important trigger for many aspects of clotting
Haemorrhage
large amount of blood loss
How do platelets form the primary haemostatic plug due to vessel wall injury
- Platelet adhesion (to endothelium wall)
- Platelet activation (causes platelets to do a lot of different things)
- Platelet aggregation (platelets stick together to begin to form a plug)
Examples of vasoconstrictors
- Serotonin
- ADP
- Thromboxane A2
What do platelets release in order to aid blood clotting
vasoconstrictors and prothrombotic agents
How does vasoconstriction aid in blood vessel repair
it slows down blood flow
Virchow’s triad
the three types of increased risk for thrombosis:
- endothelial injury leading to plug formation
- hypercoagulability
- venous stasis
Megakaryocyte
- the precursor to platelets
- Made in the bone marrow
- 4000/megakaryocyte
- Polypoid
Polypoid
multi nuclueated
Thrombocyte
Platelet
Thrombocytopaenia
low platelet count in the blood
Normal platelet count (in relation to RBCs)
20X < RBCs
Normal platelet size
2-3 µm
What happens to platelets when they are activated
- exocytose dense granules
- change shape
- increase respiratory rate
Which part of haemostasis is platelet activation required for
- aggregation of platelets
- some coagulation steps
Resting platelet shape
smooth and disc shaped
Activated platelet shape
irregular shape with many protruding pseudopodia
Where do platelets adhere to
exposed collagen in the basement membrane
What dense granules do platelets exocytose when activated
- Serotonin
- ADP
- Calcium
What is platelet aggregation stimulated by
ADP
Which drug blocks platelet aggregation
Prasugrel
How does platelet aggregation occur
via fibrinogen
More details of platelet activation
- Extracellular ADP causes activation of the P2Y receptor on the surface of platelets
- This leads to cation flow inside the platelet
- Platelets release Thromboxane A2
- ADP leads to positive feedback on platelets as more ADP is released
Clotting factors
- All circulate as inactive precursors *E
- Most are enzymes, which cleave other factors to activate them
Which clotting factors aren’t enzymes
Factor V and Factor VIII
What are Factors V and VIII
- co factors allowing the enzymes to function
- work with factor X
Why is the initial activating factor segregated
So that the clotting cascade isn’t constantly activated
Where is tissue factor located
behind endothelial cells
Where are the clotting factor precursors (except tissue factor)
Circulating in the blood
Thrombosis
pathological clotting of the blood that can lead to clogging of a blood vessel
When can thrombosis occur spontaneously
where blood flow is slow
How do labs stop blood from clotting
with citrate or heparin
Plasma
fluid portion of the blood
Serum
fluid left after blood clotting
How do plasma and serum differ
they are almost identical except that serum is missing fibrinogen, clotting factors II, V, VIII
embolism
abnormal migration of clot (or other intravascular object
What are the 2 coagulation cascades
- extrinsic (tissue factor) pathway
- intrinsic (contact activation) pathway
Extrinsic pathway
- Requires secretion of tissue factor to occur
- Initiation of coagulation
- Tissue factor (under endothelium) + factor VIIa
Intrinsic pathway
- All factors/proenzymes are already in place
- Amplification of process through positive feedback
How is thrombin activated
- Activated by Factor Xa, but poorly
- Factor Va is a co-factor for Factor Xa
- Together they activate Thrombin well
What are the pathways to activate factor X
- Extrinsic pathway
- Intrinsic pathway
- Thrombin also activates it (positive feedback)
Where is there positive feedback in coagulation
Thrombin activates co-factors (inactive factor V and VIII) to activate itself
What are coagulation factors in the prothrombin group
Factors II VII IX X
describe the prothrombin coagulation factors
- So called because they act on prothrombin and turn it into thrombin
- They are Enzymes
- Vitamin K needed for synthesis
- Require Ca2+ for activation
- Stable
What are the coagulation factors in the thrombin group
Factors I V VIII
describe the thrombin coagulation factors
- So called because they are affected by thrombin
- Thrombin activates them
- V & VIII are co-factors
- Factor I is fibrinogen
- Increased in inflammation, pregnancy & with oral contraceptives
Which factor is prothrombin
Factor II
Which factor is fibrinogen
Factor I
Which factor is thrombin
Activated factor II
Which factor is fibrin
Activated factor I
Why can problems with the liver lead to clotting deficiency
Clotting factors are made by the liver
Vitamin K
-A class of related fat-soluble vitamins
-Is required to synthesize enzyme coagulation factors:
Prothrombin (II), VII, IX, X (calcium dependent proteases)
-Vit K essential for gamma carboxylation (an enzyme reaction) of clotting enzymes
Fibrinolysis
breaking apart a clot
Plasmin
- An enzyme
- Lyses fibrin – stops / destroys clots
- Starts as inactive Plasminogen, a protein made by liver
What does plasminogen require to mature
tissue factor activator (tPA)
Where is tissue factor activator located
on the surface of endothelial cells
Protein C
- Coagulation Inhibitor
- Starts as an inactive enzyme made by liver
- Activated on surface of endothelial cells
What does Protein C do
Inactivates Factor Va and VIIIa
Which protein does Protein C work with in inactivate Factor Va
Protein S
Antithrombin III (and heparin)
Peptide in blood made by liver
Why does Antithrombin III always work in association with heparin
because it’s very inactive itself
What does Antithrombin III (and heparin) do
Blocks activity of thrombin, Xa and IXa
What does heparin do in association with Antithrombin III
greatly increases Antithrombin III activity
What is heparin reversible by
protamine sulfate
What does Antithrombin III deficiency cause
risk of thrombotic disease
what is a recombinant form of Antithrombin III used for medically
thrombotic disorders
What does vitamin K deficiency result in
clotting insufficiency
Why is vitamin K deficiency rare
- vitamin K is made by bacteria of large intestine
- Also found in leafy green vegetables (e.g. broccoli)
What is vitamin K deficiency caused by
- GI disease
- no fat absorption
- Liver disease as this means no bile salts formed
What does warfarin do
- prevents recycling of vitamin K
- Depletes active vitamin K after a few days
Haemophilia A
- Clotting disorder
- Affects larger blood vessels
- Joints, muscles
- Wounds that bleed for days
- X linked
What causes Haemophilia A
congenital lack of factor VIII
How is haemophilia A treated
Treat with injected purified Factor VIII (expensive, rare)
Haemophilia B
- AKA Christmas disease
- defect of factor IX
- symptoms as per Haemophilia A
Describe how inflammation due do atherogenesis can cause haemostasis
-Monocytes enter lesion
-Become macrophages and consume cholesterol esters
-Can become foam cells
-Foam cells can die and release their contents
Which attract more monocytes, cytokines and chemo-attractants
-This leads to inflammation which can cause haemostasis
Describe the disease process of atherogenesis from lipid deposits
- LDL deposits lipids in lesion
- Cholesterol esters are non-aqueous which can make lesion solid / hard
- Cholesterol esters are oxidized, making oxygen radicals which makes them immunogenic
- Oxidized lipids are consumed by macrophages
- Which become Foam Cells which explode and attract more monocytes
Describe what happens to the endothelium in atherogenesis
-Endothelium expresses chemo attractants for monocytes to find and enter lesion
-When endothelium is lost, collagen stimulates coagulation
-Endothelium normally covers collagen and basement membrane
When endothelium is lost, vessel cannot control its dilation as endothelium normally provides nitric oxide
What do anti-platelet agents do
- block platelet activation
- Prevent clotting in arteries where anticoagulants have limited effects
- Used in acute coronary syndromes
Aspirin
- An anti-platelet agent
- Cyclo-oxygenase (COX) inhibitor
- Blocks formation of thromboxane A2 in platelets
- Lengthens bleeding time
- Does NOT increase coagulation time
- Prophylaxis for myocardial infarction
Prasugrel
- An anti-platelet agent
- ADP receptor inhibitor
Clopidogrel
- An anti-platelet agent
- ADP receptor inhibitor
Anti-coagulants
- Block production or activity of clotting factors
- Used to treat venous disease *E
- Prevent clotting in veins and in low pressure pulmonary circulation
What are anti-coagulants used as a prophylactic for
- DVT
- PE
What do heparins do
- An anti-coagulant
- Inhibit coagulation (with AT III) by inhibiting Factor Xa
NOACs
- Novel oral anticoagulants
- anti-coagulants
Dabigatran
- A NOAC (type of anti-coagulant)
- Thrombin inhibitor
Rivaroxaban
- A NOAC (type of anti-coagulant)
- Factor Xa inhibitor
Wararfin
- An anti-coagulant
- Vitamin K antagonist
- Slow onset (days)
- Requires monitoring
Fibrinolytics
- Drugs used primarily used to dissolve fibrin in arterial disease
- Used in acute coronary syndromes
Give 3 fibrinolytic drugs
- Tissue Plasminogen Activator (tPA)
- Streptokinase
- Urokinase
