Theme 2: Lecture 2 - Platelets and Haemostasis Flashcards
1
Q
What is the endothelium?
A
Layer of cells lining inner surface of all vessel walls and have a huge total surface area
2
Q
What is the function of the endothelium?
A
- 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
3
Q
What is haemostasis
A
process which causes bleeding to stop
4
Q
What does the endothelium secrete under normal conditions
A
Inhibitors of haemostasis
5
Q
What does the endothelium secrete when injured
A
von Willebrand factor (and stops secreting haemostasis inhibitors)
6
Q
von Willebrand factor
A
a blood protein that is an important trigger for many aspects of clotting
7
Q
Haemorrhage
A
large amount of blood loss
8
Q
How do platelets form the primary haemostatic plug due to vessel wall injury
A
- 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)
9
Q
Examples of vasoconstrictors
A
- Serotonin
- ADP
- Thromboxane A2
10
Q
What do platelets release in order to aid blood clotting
A
vasoconstrictors and prothrombotic agents
11
Q
How does vasoconstriction aid in blood vessel repair
A
it slows down blood flow
12
Q
Virchow’s triad
A
the three types of increased risk for thrombosis:
- endothelial injury leading to plug formation
- hypercoagulability
- venous stasis
13
Q
Megakaryocyte
A
- the precursor to platelets
- Made in the bone marrow
- 4000/megakaryocyte
- Polypoid
14
Q
Polypoid
A
multi nuclueated
15
Q
Thrombocyte
A
Platelet
16
Q
Thrombocytopaenia
A
low platelet count in the blood
17
Q
Normal platelet count (in relation to RBCs)
A
20X < RBCs
18
Q
Normal platelet size
A
2-3 µm
19
Q
What happens to platelets when they are activated
A
- exocytose dense granules
- change shape
- increase respiratory rate
20
Q
Which part of haemostasis is platelet activation required for
A
- aggregation of platelets
- some coagulation steps
21
Q
Resting platelet shape
A
smooth and disc shaped
22
Q
Activated platelet shape
A
irregular shape with many protruding pseudopodia
23
Q
Where do platelets adhere to
A
exposed collagen in the basement membrane
24
Q
What dense granules do platelets exocytose when activated
A
- Serotonin
- ADP
- Calcium
25
What is platelet aggregation stimulated by
ADP
26
Which drug blocks platelet aggregation
Prasugrel
27
How does platelet aggregation occur
via fibrinogen
28
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
29
Clotting factors
- All circulate as inactive precursors *E
| - Most are enzymes, which cleave other factors to activate them
30
Which clotting factors aren't enzymes
Factor V and Factor VIII
31
What are Factors V and VIII
- co factors allowing the enzymes to function
| - work with factor X
32
Why is the initial activating factor segregated
So that the clotting cascade isn't constantly activated
33
Where is tissue factor located
behind endothelial cells
34
Where are the clotting factor precursors (except tissue factor)
Circulating in the blood
35
Thrombosis
pathological clotting of the blood that can lead to clogging of a blood vessel
36
When can thrombosis occur spontaneously
where blood flow is slow
37
How do labs stop blood from clotting
with citrate or heparin
38
Plasma
fluid portion of the blood
39
Serum
fluid left after blood clotting
40
How do plasma and serum differ
they are almost identical except that serum is missing fibrinogen, clotting factors II, V, VIII
41
embolism
abnormal migration of clot (or other intravascular object
42
What are the 2 coagulation cascades
- extrinsic (tissue factor) pathway
| - intrinsic (contact activation) pathway
43
Extrinsic pathway
- Requires secretion of tissue factor to occur
- Initiation of coagulation
- Tissue factor (under endothelium) + factor VIIa
44
Intrinsic pathway
- All factors/proenzymes are already in place
| - Amplification of process through positive feedback
45
How is thrombin activated
- Activated by Factor Xa, but poorly
- Factor Va is a co-factor for Factor Xa
- Together they activate Thrombin well
46
What are the pathways to activate factor X
- Extrinsic pathway
- Intrinsic pathway
- Thrombin also activates it (positive feedback)
47
Where is there positive feedback in coagulation
Thrombin activates co-factors (inactive factor V and VIII) to activate itself
48
What are coagulation factors in the prothrombin group
Factors II VII IX X
49
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
50
What are the coagulation factors in the thrombin group
Factors I V VIII
51
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
52
Which factor is prothrombin
Factor II
53
Which factor is fibrinogen
Factor I
54
Which factor is thrombin
Activated factor II
55
Which factor is fibrin
Activated factor I
56
Why can problems with the liver lead to clotting deficiency
Clotting factors are made by the liver
57
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
58
Fibrinolysis
breaking apart a clot
59
Plasmin
- An enzyme
- Lyses fibrin – stops / destroys clots
- Starts as inactive Plasminogen, a protein made by liver
60
What does plasminogen require to mature
tissue factor activator (tPA)
61
Where is tissue factor activator located
on the surface of endothelial cells
62
Protein C
- Coagulation Inhibitor
- Starts as an inactive enzyme made by liver
- Activated on surface of endothelial cells
63
What does Protein C do
Inactivates Factor Va and VIIIa
64
Which protein does Protein C work with in inactivate Factor Va
Protein S
65
Antithrombin III (and heparin)
Peptide in blood made by liver
66
Why does Antithrombin III always work in association with heparin
because it's very inactive itself
67
What does Antithrombin III (and heparin) do
Blocks activity of thrombin, Xa and IXa
68
What does heparin do in association with Antithrombin III
greatly increases Antithrombin III activity
69
What is heparin reversible by
protamine sulfate
70
What does Antithrombin III deficiency cause
risk of thrombotic disease
71
what is a recombinant form of Antithrombin III used for medically
thrombotic disorders
72
What does vitamin K deficiency result in
clotting insufficiency
73
Why is vitamin K deficiency rare
- vitamin K is made by bacteria of large intestine
| - Also found in leafy green vegetables (e.g. broccoli)
74
What is vitamin K deficiency caused by
- GI disease
- no fat absorption
- Liver disease as this means no bile salts formed
75
What does warfarin do
- prevents recycling of vitamin K
| - Depletes active vitamin K after a few days
76
Haemophilia A
- Clotting disorder
- Affects larger blood vessels
- Joints, muscles
- Wounds that bleed for days
- X linked
77
What causes Haemophilia A
congenital lack of factor VIII
78
How is haemophilia A treated
Treat with injected purified Factor VIII (expensive, rare)
79
Haemophilia B
- AKA Christmas disease
- defect of factor IX
- symptoms as per Haemophilia A
80
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
81
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
82
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
83
What do anti-platelet agents do
- block platelet activation
- Prevent clotting in arteries where anticoagulants have limited effects
- Used in acute coronary syndromes
84
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
85
Prasugrel
- An anti-platelet agent
| - ADP receptor inhibitor
86
Clopidogrel
- An anti-platelet agent
| - ADP receptor inhibitor
87
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
88
What are anti-coagulants used as a prophylactic for
- DVT
| - PE
89
What do heparins do
- An anti-coagulant
| - Inhibit coagulation (with AT III) by inhibiting Factor Xa
90
NOACs
- Novel oral anticoagulants
| - anti-coagulants
91
Dabigatran
- A NOAC (type of anti-coagulant)
| - Thrombin inhibitor
92
Rivaroxaban
- A NOAC (type of anti-coagulant)
| - Factor Xa inhibitor
93
Wararfin
- An anti-coagulant
- Vitamin K antagonist
- Slow onset (days)
- Requires monitoring
94
Fibrinolytics
- Drugs used primarily used to dissolve fibrin in arterial disease
- Used in acute coronary syndromes
95
Give 3 fibrinolytic drugs
- Tissue Plasminogen Activator (tPA)
- Streptokinase
- Urokinase
