1
Q
Define hemostasis
A
A process that maintains flowing blood in a fluid state and prevents loss of blood from sites of vascular injury.
2
Q
What are the factors that influences hemostasis?
A
- Integrity of vascular wall
- Platelets
3.Coagulation system - Fibrinolytic system
3
Q
What are the stages of hemostasis?
A
- Primary hemostasis - formation of platelet plug
- Secondary hemostasis - Fibrin & coagulation factors incoporate in plug to form a fibrin cloth / secondary hemostatic plug
3.Fibrinolysis - Break down and removal of clot formed
4
Q
When does the initiatialization of hemostasis occur?
A
- Vascular damage
- Exposed subendothelium
5
Q
What occurs during primary hemostasis?
A
- Platelet adhesion
- Platelet aggregation
- Platelet Plug formation
6
Q
What happens during secondary hemostasis?
A
Fibrin stabilization
7
Q
What are the two “players” of primary hemostasis?
A
- Vascular system
- Platelets
8
Q
What are the three types of blood vessels of the vascular system?
A
- Arteries & arterioles
- Veins & venules
- Capillaries
9
Q
What do arteries and arterioles do? Which one is smaller arteries or arterioles?
A
Arteries and arterioles carry blood away from heart to the capillaries.
10
Q
What do veins and venules do? Which of the two is smaller?
A
- Return blood from tissues back to the heart for oxygenation.
- Venules
11
Q
What do capillaries do in the cardiovascular system?
A
Microscopic vessels that connect the first two types of vessels (veins and arteries)
12
Q
What is the vascular intima made of?
A
monolayer of endothelial cells
13
Q
What is the function of the vascular intima?
A
Provides a smooth barrier between circulating blood and body tissues.
14
Q
Describe the structure of the capillaries.
A
Layer of endothelial cells on a basement membrane and surrounded by pericytes - no smooth muscle or fibroblasts
15
Q
What supports endothelial cells when they do their job?
A
Surrounding fibroblasts and smooth muscles cells
16
Q
Vascular intima functions are?
A
Promote coagulation and anticoagulation
17
Q
What do intact endothelial cells of the vascular intima produce?
A
Anticoagulant properties
18
Q
What do damaged endothelial cells of the vascular intima produce?
A
Procoagulant properties
19
Q
List anticoagulants of intact endothelial cells
A
Intact has negatively charged surface, heparan sulfate, thrombomodulin, Prostacyclin (PGI2), Tissue plasminogen activator (TPA), Tissue factor pathway inhibitor (TFPI), Nitric oxide
20
Q
List procoagulant functions of Damaged Endothelials cells
A
Vasoconstriction, collagen, von willebrand’s factor, and P - Selectin
21
Q
What does (occurs normally) negatively charged surface of endothelial cells do?
A
Repels platelets and hemostatic proteins
22
Q
Function of heparan sulfate
A
Enhances antithrombin activity
23
Q
Function of thrombomodulin
A
Activates protein C pathway
24
Q
Function of PGI2 (prostacyclin)
A
Triggers vasodilation and inhibits platelet aggregation
25
Function of tissue plasminogen activator (TPA)
Activates fibrinolytic system
26
Function of tissue factor pathway inhibitor (TFPI)
controls activation of extrinsic pathway
27
Function of nitric oxide
Inhibits platelet activation
28
Purpose of vasoconstriction
Minimizing escaped blood
29
function of collagen
Binds and activates platelets
30
Function of von willebrand's factor
Required for platelet adhesion
31
Function of P - selectin
Promotes platelet and WBC binding
32
Maturation time from blast stage to platelet formation is typically?
TBDL, to be done later
33
Normal marrow contains approximately ____ megakaryocytes
???
34
Normal circulation of life of a platelet is _____
8 - 10 days?
35
Platelets are removed or destroyed by ____ in liver and spleen or by active use
macrophages
36
Circulating platelets are distributed between spleen and blood. __Blank___ are always in the spleen
1/3
37
Average diameter of platelets in circulation is?
2.5 microns
38
Average number of platelets is?
140k - 450k / cmm (cubic millimeter or microliter)
39
What are the three zones of structures for a platelet?
1. Peripheral
2. Structural / Sol - gel
3. Organelle Zones
40
Peripheral zone includes... what?
1. Platelet plasma membrane (p.m.) - made of proteins and lipids
2. Glycocalyx - Rich in glycoproteins which serve as membrane receptors.
41
What is the predominant lipids of plasma membrane of a platelet?
phospholipids which form the basic structure of the cell.
42
What is the purpose of cholesterol in the plasma membrane of the platelet?
stabilize the membrane, maintain fluidity, and helps control passage of materials (selective permeability)
43
What term describes "receptors needed for platelet adhesion & aggregation"
TBDL
44
Glycoprotein (GP) Ib, IX, and V binds to what?
thrombin, ristocetin, and to von willebrand's factor (vWF)
45
Glycoprotein Ib, IX, and V to thrombin, ristocetin, and to von willebrand's factor (vWF) activates what?
1. Activates platelets so they can adhere to subendothelial collagen
2. Expression of GP IIb, IIIa receptors
46
Glycoprotein (GP) VI binds to what? What happens when they bind together?
Collage; releases thromboxane A2 (TXA2) and ADP, and aids glycoprotein Ib / IX / V in adhering to site causing activation to occur. Thrombin is included based on slide 20.
47
GP IIb and GP IIIA binds to what?
Fibrinogen, which allows platelets to aggregate to each other.
48
GP IIb and GP IIIa binding to fibrinogen binds together, what happens?
Platelets aggregate to each other
49
What happens before platelets adhere to the subendothelial collagen?
Von Willebrande's Factor lays down over subendothelial collagen so platelets adhere to the von willebrande's factor "carpet". The bigger vWF the better.
50
What is the structural zone (Sol - gel zone) of a platelet?
System of membranes running throughout the cytoplasm; it includes the open canalicular system (OCS) and the dense tubular system (DTS)
51
What is the open canalicular system (OCS)?
Pore system that provides direct communication between intravellular and extracellular compartments. It allows granule contents to be moved to surface, and plasma & coag factors to enter into platelet. Note: Some coag. factors get concentrated.
52
What is the dense tubular system (DTS)?
Close internal membrane system (sER remnant) that pumps calcium ions to trigger microtubular - controlled changes in platelet shape that occurs once platelet is activated.
53
What is the dense tubular system (DTS) made of?
Made of phospholipids which support prostaglandin synthesis.
54
What is the microtubular / microfilamentous cytoskeleton of a platelet?
Gives the platelet the ability to contract to release contents of cytoplasmic granules.
55
What thing in the microtubules of the platelet provides support and ability to change a platelet's shape from a discoid to spiny once activated?
Actin; its also in muscles
56
What does the organelle zone of the platelet contain?
Organelles of the platelet. Its scattered through the cytoplasm. It includes to mitochondria, dense granules, alpha granules, glycogen granules, and lysosomes.
57
When are granules released in a platelet?
When the platelet is activated. It'll change from a discoid shape to a spiny shape.
58
Dense granules (dense bodies) do what?
Migrat to plasma membrane and release their contents directly into the plasma on activation. They are important in providing energy for the rest of platelet's activation process. Think "Dense boys with energy"
59
What do dense granules contain?
ADP, ATP, serotonin, and calcium
60
What is the purpose of alpha granules?
Fuse with OCS and participate in adhesion and platelet aggregation and support plasma coagulation.
61
What do alpha granules contain?
Fibrinogen, factor V, Factor XI, Protein S, Platelet derived growth factor (PDGF), and vWF.
62
What is the function of fibrinogen?
A plasma protein converted into fibrin by thrombin (discuss further later)
63
What is the function of platelet derived growth factor (PDGF)?
Stimulates smooth muscle cell growth after blood vessel cell wall injury.
64
Function of lysosomes in hemostasis?
Digestion of debris
65
What are the three major roles platelets have?
1. Form hemostatic plug immediately after an injury to blood vessel(s) aka primary hemostasis.
2. Provide cofactors & a reaction surface for coagulation cascade to happen on aka secondary hemostasis
3. Help maintain and repair vascular endothelium by producing several growths (Ex: PDGF)
66
What is the difference in primary and second hemostasis?
67
What are the general steps of primary hemostasis? Hint: theres four
1. adhesion = platelet activation
2. aggregation = platelet stick to each other (primary aggregation)
3. Degranulation = platelet granules release content (activated platelets become less dense)
4. Aggregate more! = attract more platelets to continue the process (secondary aggregation)
68
Out of all the steps in primary hemostasis which is an example of positive feedback?
4th step, aggregating more platelet cells
69
Describe the first step of primary hemostasis in great detail. (get as many as you can)
1. Platelets bind directly to exposed in veins and venules
2. In Arteries and arterioles adhesion starts when vWF and collagen contact GP Ib / IX / V receptor on platelet surface.
3. GP VI binds to collagen
4. Binding of GP Ib / IX / V and GP VI promotes a shape change in platelet (activation)
5. Activation (shape change) causes granules and organelles move into platelet's center; and contraction of platelet squeezes cytoplasmic granules.
6. Calcium and ADP triggers cleaveage of specific platelet's plasma membrane phospholipids turning on phospholipase C (PLC)
7. PLC is a second messenger system that transfers signal to platelet interior. This causes rapid movement of both intracellular Ca from DTS storage, and of extracellular Ca into platelet through OCS.
8. GP IIb / IIIa receptor gets exposed on platelet surface so it's available for fibrinogen binding (which will be needed for aggregation)
9. Platelet's peripheral phospholipid orientations change, allowing coag. factors to bind.
10. Now platelet has adhered to blood vessel walls and is ready for 1st wave of aggregation.
Note: Increase calcium levels = platelet activation
70
Describe the second step of primary hemostasis in great detail
Platelets activated, a change in glycoprotein IIb and IIIa allows binding to fibrinogen.
71
Where does fibrinogen come from?
Comes from circulating plasma and platelet granules released due to activation
72
Complete this phrase from the powerpoint slide 33. " Blank is for fibrinogen"
2b3a is for Fbg
73
Describe step 3 of primary hemostasis in great detail
1. Platelets have undergone 1st wave now secrete even more of their granule contents (energy requiring exocytosis)
2. Step 3 occurs simultaenously with second wave of aggregation.
3. Granular release from dense granules cases local inflammation and vasodilation which increases blood flow
74
Describe step 4 of primary hemostasis
1. Takes longer
2. Platelets become more firmly attached to each other
3. Release of mediators are agonists for further stimulation of more incoming platelets
4. Binding of vWF and collagen to platelet receptors unmasks membrane phospholipid A2 (important for production of TxA2 and other prostaglandins)
5. TxA2 liberates sequestered calcium into cytoplasm. Calcium causes further cytoplasmic contractions, release of grnule contents, and platelet aggregation.
6. Thrombin cleaves fibrinogen to form fibrin, an essential component necessary to stabilize platelet plug.
75
Describe the primary platelet plug.
Relatively unstable; it must quickly become anchored to vessel wall by secondary hemostatic mechanisms (which begin with fibrin formation around the plug.)
76
What is formed when fibrinogen + thrombin combine?
Fibrin
77
Describe thromboxane action (TXA2).
TXA2 decelerates adenylate cyclase. Reduced cyclic AMP production by favoring ATP production because cyclic AMP is reduced. Ca2+ is released from dense tubular system (DTS) and activates platelet.
78
What are factors that limit growth of platelet aggregate?
1. Blood flow
2. Release of PGI2 (prostacyclin)
79
How does blood flow limit platelet aggregate?
Washes away coagulation - promoting factors
80
How does prostaglandin (PGI2) limit platelet aggregate?
The release of PGI2 from surrounding vascular tissues inhibit platelet aggregation inhibitor. PGI2 action is the opposite of TxA2
81
What is the reference value of platelets?
150k to 450k / mm^3
82
What is bleeding time?
An effective screening test of platelet function.
83
Reference time of bleeding time?
3 - 8 minutes
84
What can increase bleeding time?
1. Taking aspirin
2. patients with vWD (decrease in vWF)
3. Inherited congenital platelet abnormalities
4. Platelet count below 100k / mm^3
85
How is platelet aggregation measured?
With a platelet aggregometer!
Principle: Citrated, platelet rich plasma stirred in aggregometer while light beam passes through suspension.
- A chemical stimulus is added (collagen, ADP, ristocetin, etc.)
-Shape change from discoid to spiny occurs causing initial decrease in light transmittence
-Subsequent aggregation allows increase of light to pass t hrough suspension to photodetector and recorded as in light transmittence.
86
What is lumiaggregometry?
Uses firefly extract, luciferase to monitor both aggregation and granule release. Luciferase illuminates when in contact w/ energized ATP... platelet - dense granules contain both ATP and ADP. When platelets are activated, they release granules and aggregate with each other. ADP causes platelets to aggregate and ATP causes luciferase to glow.
87
Purpose of lumiaggregometry?
To detect faulty release of granules and storage pool diseases
Hematology 1 fall 2022
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