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tfS\S\S
(\)L+
1f2*3
bacteriaah
:PHYSSIZE
Teaching and Learning Technology Programme
produced by the
Haemostasis stemtemmunoglobulins
h$B K
6.B K
bacteriaah2
*?B K
Andrew MacLennan & John M Basford
Biochemistry Department
University of Wales, Cardifffffffffffffffff
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THE PURPOSE OF HAEMOSTASIS
Haemostasis is the name given to systems that prevent blood loss. The mechanisms involved are important as without them the smallest injury could lead to death. There are two main mechanisms by which haemostasis occurs:
(a) Platelet aggregation
(b) Coagulation
In the following pages these two processes will be discussed in detail and shown using animation techniques. At the end there will be a quiz on the material covered. Your score and the answers to questions answered incorectly will be given at the end of the quiz.
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MOVE ON TO NEXT PAGE AT ANY TIME
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Factor Xa :::
Has clusters of negative charges
Binds directly to aggregated platelet surface
Converts fibrinogen into fibrin
Converts prothrombin into thrombin
Activates fibrinoligaseee
Which of the following are proteolytic enzymes :
Thrombin
Fibrinoligase
Factor Va
Factor Xa
Factor X
glutamate residues on the surface
g-carboxyglutamate residues on the surface
Glutamate & aspartate residues on the surface
Clusters of different negative residues on the
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Platelets normally have contact with :
Red blood cells
Other platelets
Luminal surface of endothelial cells
Collagen
Plasma
The conversion of prothrombin to thrombin on an aggregated platelet surface:
Takes place at a faster rate than in solution
Serves to localize blood coagulation to damage site
Takes place at a slower rate than in solution
Takes place at a similar rate to that in solution
Requires the presence of calcium ions t damage site site
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B"13a"
B"13b"
B"13c"
B"13d"
B"13e"
B"14a"
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B"14d"
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Phosphatidyl serine :
Is negatively charged
Is present on outer surface of platelet plasma membrane
Is present on outer surface of aggregated platelet plasma membrane
Is present on outer surface of platelet vesicle membrane
Is present on inner surface of platelet vesicle membrane
Some characteristics of the blood coagulation system are :
It includes a series of protein-proteinase activations
Is an example of a biochemical amplifier
Results in the formation of fibrin
Is localised to the damage site by platelet aggregation
Requires calcium ions to proceedons to proceedium ions to proceed
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B"15a"
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Individual fibrin monomers within hard clots are :
Cross-linked together by disulphide bonds
Cross-linked together by peptide bonds
Cross-linked together by isopeptide bonds
Cross-linked together by g-glutamyl,e-lysine links
Held together by links involving g-carboxylglutamate
The formation of a 3-D fibrin mesh occurs as a result of :
Release of fibrinopeptide B from protofibrils
Release of fibrinopeptide B from fibrinogen
Release of fibrinopeptide A from protofibrils
Release of fibrinopeptide A from fibrinogen
Action of fibrinoligase
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B"17a"
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B"18e"
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Percentage of fibrinogen mass lost on conversion to fibrin is approx :ox :
Fibrinogen is soluble because :::::::::::::::::::::::::::
It is trinodular
It has fibrinopeptide A and B regions
It has not been cross-linked
It no glutamate residues
It has lost fibrinopeptide A
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Score
Press the 'Score' button after finshing the questions to obtain your final score.
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"The covalent links formed between adjacent fibrin monomers create
extensive covalently-linked network structure."
"ligase"
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The covalent links formed between adjacent fibrin monomers create an extensive covalently-linked network structure.
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Basic
Answers to Haemostasis Questions
The answers to the problems that you got wrong can be seen below. Once you have read the correct answer click the mouse in the white box to move onto the next answer.
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answer20
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Question 20:
Both fibrinopeptides A and B carry significant charge which makes them hydrophilic and their presence mask binding sites that allow polymerization of fibrin monomersfibrinopeptide A.to the repressor site and CAP site respectively.to the DNA.
answer19
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Question 19:
The molecular mass of fibrinogen is 340,000. The mass of a single fibrinopeptide is approximately 2000. The four fibrinopeptides consitute approximately 2% of the total mass of fibrinogen.. is the mass of the four fibrinopeptides.
answer18
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Question 18:
The release of fibrinopeptide A only allows the formation of protofibrils. Release of fibrinopeptide B from the protofibrils allows them to aggregate side-to-side and form a 3-D network...
answer17
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Question 17:
The fibrin monomers within a hard clot are cross-linked together by isopeptide bonds. These covalent bonds are between the g-carbonyl group of the glutamine and the e-amino group of lysine.
answer16
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Question 16:
The blood coagulation system includes a series of protein-proteinase activations. This cascade is a biochemical amplifier which results in the formation of a fibrin mesh. Localization of the coagulation system to the damaged site is achieved by platelet aggregation and requires calcium ions.
answer15
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Question 15:
Phosphatidyl serine is a negatively charged phospholipid that is found on the inner surface of the platelet vesicle membranes. When the vesicles fuse with the platelet plasma membrane the phosphatidyl serine is incorporated into the outer surface of the plasma membrane.
answer14
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Question 14:
The conversion of prothrombin to thrombin on the aggregated platelet surface takes place at a faster rate than in solution due to the localization mechanism. High concentrations of both factor Xa and prothrombin are generated on the aggregated platelet plasma membrane leading to a rate hundreds of times faster than in solution.
answer13
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Question 13:
Platelets circulate in the blood stream and as such have contact with red blood cells, other platelets, the luminal surface of the endothelial cells and plasma. Platelets only come into contact with collagen when the blood vessel is damaged.
answer12
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Question 12:
Thrombin and factor Xa are proteolytic enzymes. Factor X is the zymogen of factor Xa and as such has no proteolytic activity. Factor Va is accessory factor which enhances the activity of factor Xa. Fibrinoligase is a transamidase - it breaks one amide bond to form another.
answer11
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Question 11:
Factor Xa has clusters of negatively charged g-carboxygutamate residues on its surface. It binds to the aggregated platelet surface via calcium ions. It is a proteolytic enzyme which converts prothrombin into thrombin....
answer10
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Question 10:
Platelets have vesicles containing 5-hydroxtryptamine, a vasoconstrictor. These vesicles have negatively charged phosopholipids on their inner surface so on fusing with the platelet plasma membrane the negative charges are transferred to the outer surface of the plasma membrane.
polymerase or by forming a bend in the DNA.by forming a bend in the DNA.
answer9
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Question 9:
Fibrin no longer has the fibrinopeptides A and B so it contains 2a chains, 2b chains and 2g chains. sor also increases the affinity of RNA polymerase for the promoter by 100 fold. The result of this is that when lactose enters the cell the RNA polymerase is ready to start transcription immediately, leading to very quick production of the proteins.
answer8
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Question 8:
Fibrinogen contains 2a(A) chains, 2b(B) chains and 2g chains.nsation rises. Glucose concentration has no effect on the lactose concentration or the allolactose concentration. on or the allolactose concentration. enters the cell the RNA polymerase is ready to start transcription immediately, leading to very quick production of the proteins.
answer7
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Question 7:
Haemostasis is the process that prevents blood loss. Minor damage may be rectified by the aggregation of platelets alone. Major damage is repaired by platelet aggregation and the triggering of the coagulation system......eading to low lactose uptake into the cell. is made so only a small amount of lactose enters the cell. uction of the proteins.
answer6
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Question 6:
Protofibrils are are polymers of fibrinogen from which fibrinopeptide A has been released. The cleavage of fibrinopeptide A unmasks sites that allow the polymerisation to occur. polymerisation to occur. amount of permease is made so only a small amount of lactose enters the cell. ion immediately, leading to very quick production of the proteins.
answer5
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Question 5:
Aggregated platelets bind calcium ions to which prothrombin and factor Xa bind. Factor Va, which enhances the activity of factor Xa, also associates with aggregated platelets. This system localises haemostasis to the site of injury. only a small amount of lactose enters the cell. ion immediately, leading to very quick production of the proteins.
answer4
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Question 4:
Fibrinoligase forms isopeptide bonds linking the e-amino group of the lysine to the g-carbonyl group of the glutamine. Ammonia is released in the process. galactose. f lactose because only a small amount of permease is made so only a small amount of lactose enters the cell. ion immediately, leading to very quick production of the proteins.
answer3
"answer3"
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Question 3:
Platelets will adhere to collagen, which is only exposed at a damaged site. It also adheres to aggregated platelets, forming a plug which can stop minor bleeding...... ry of lactose because only a small amount of permease is made so only a small amount of lactose enters the cell. ion immediately, leading to very quick production of the proteins.
answer2
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Question 2:
Thrombin cleaves both fibrinopeptide A and B. It also activates the enzyme Fibrinoligase.......AP-cAMP complex, increasing the efficiency with which the enzyme can bind to the promoter. nly a small amount of permease is made so only a small amount of lactose enters the cell. ion immediately, leading to very quick production of the proteins.
answer1
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Question 1:
A typical turnover number for a proteolytic enzyme is 10 molecules of substrate per second... transacetylase - i.e those that control the entry and metabolism of lactose.
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BIBLIOGRAPHY
D. Voet & J.G Voet - BIOCHEMISTRY (1990)
Pages 1087 - 109555555555555
J. Hywel Thomas & B. Gillham - WILL'S BIOCHEMICAL BASIS OF MEDICINE - 2nd Edition, Pages 303-320
L. Stryer - BIOCHEMISTRY - 3rd Edition
Pages 248-258
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EPEAT OR MOVE ON TO THE NEXT PAGEns to the second bundle at one end and the third bundle at the other end to form a mesh system.
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CONVERSION OF SOFT CLOT TO HARD CLOT:
The fibrin network formed is a 'soft clot', so called because the interactions between the fibrin molecules are non-covalent (hydrophobic, van derWaals, electrostatic and hydrogen bonding). Thus the network can be dispersed by increasing the temperature to 45 degrees centigrade or by addition of hydrogen bond breakers eg urea . A 'hard clot' is one where the adjacent fibrin monomers are covalently cross-linked. These cross-links are isopeptide bonds between specific glutamine and lysine residues on neighbouring fibrin molecules. Isopeptide bonds are formed by the enzyme Fibrinoligase (factor XIIIa) which is activated by thrombin.
rombin.
ID 31
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Thrombin
Fibrinogen
Fibrinogen
Fibrinopeptides A + B
Cross-linked Fibrin
XIIIa (Fibrinoligase)
"fib1"
"fib2"
"fib3"
"fib4"
"node1"
"node2"
"node3"
"node4"
"node5"
"inter1"
"inter2"
"inter3"
"inter4"
"inter5"
"inter6"
"arm1"
"arm2"
"site1"
"site2"
"site3"
"site4"
"site5"
"site6"
"site7"
"site8"
0, 50, 100
0, 50, 100
240, 50, 100
240, 50, 100
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 75.3125, 0
0, 50, 100
240, 50, 100
0, 75.125, 100
0, 75.125, 100
240, 75.125, 100
240, 75.125, 100
0, 50, 100
240, 50, 100
enterPage
enterPage
node1
node2
node3
node4
node5
inter1
inter2
inter3
inter4
inter5
inter6
site1
site2
site3
site4
site5
site6
site7
site8
node1
node2
node3
node4
node5
site1
site2
site3
site4
site5
site6
site7
site8
node1
node2
node3
node4
node5
inter1
inter2
inter3
inter4
inter5
inter6
site1
site2
site3
site4
site5
site6
site7
site8
CO - NH
(CH )
- NH - CH - CO -
- NH - CH - CO -
|
(CH )
|
NH
- NH - CH - CO -
(CH )
NH
CO
(CH )
- NH - CH - CO -
Lysine
Glutamine
FIBRINOLIGASE
ID 30
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-- p1b-p6b are platelets without vesicles.
-- rp1, rp2, rp4
rbc's
-- rp3
made up
\(p1-p6) that will fill
-- There
3 layers
blood vessel - '
Kundamaged
--'hole'
einjured
'con'
zconstricted
"p1b"
"p2b"
"p3b"
"p4b"
"p5b"
"p6b"
"rp2"
2275, 300
"p1"
)5095, 1155
"p2"
)4315, 1140
"p3"
)3385, 1155
"p4"
)2890, 1065
"p5"
)2350, 1095
"p6"
)1885, 960
"rp3"
"rp1"
)3330, 2655
-1350, 2805
"rp4"
-3840, 2685
"rp5"
-285, 3090
"con"
Put ""
Normal
The integrity
endothelial cells
intact so
collagen surrounding
does
xcome
contact
contents
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
When
lining
ruptured exposing
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
"p1"
3800, 3870
"p2"
H250, 0
"p3"
H250, 0
"p4"
H250, 0
"p5"
H250, 0
"p6"
H250, 0
fa section
they adhere
release
5-HT."
H250, 0
H250, 0
H250, 0
"p1"
3850, 4170
"p2"
H250, 0
"p3"
H250, 0
"p4"
H250, 0
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p2"
H250, 0
"p3"
H250, 0
"p4"
H250, 0
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p2"
H250, 0
"p3"
H250, 0
"p4"
H250, 0
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p2"
4130, 3870
"p3"
H250, 0
"p4"
H250, 0
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p2"
4220, 4170
"p3"
H250, 0
"p4"
H250, 0
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p3"
H250, 0
"p4"
H250, 0
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p3"
H250, 0
"p4"
H250, 0
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p3"
4545, 4245
"p4"
H250, 0
"p5"
H250, 0
"p6"
H250, 0
"box"
"screen"
"ser1"
"ser2"
"ser3"
"ser4"
"ser5"
3330, 3180, 5115, 4350
2430, 2175, 5205, 4020
1545, 1350, 5310, 3675
-855, 315, 5445, 3465
3465, 1875
3420, 1830
)3525, 1935
"vac1"
"rel1"
)3270, 1125
4170, 1845
H0, -250
4185, 1845
H0, -250
H0, -250
4140, 1920
"vac2"
"rel2"
syLockScreen
4155, 1035
"drop1"
3210, 2160
3915, 795
3180, 2055
3555, 390
3165, 1995
4350, 1275
3240, 2310
"vac3"
"rel3"
H0, -250
4485, 2295
H0, -250
4545, 2175
H0, -250
4620, 2145
H0, -250
4470, 2325
"vac4"
"rel4"
2910, 1380
4560, 1365
3885, 2370
4380, 1125
3885, 2220
4095, 825
3885, 2040
4005, 585
3840, 1845
3975, 390
3810, 1800
4740, 1560
3885, 2475
"vac5"
"rel5"
H0, -250
H0, -250
H0, -100
3885, 960
1545, 1350, 5310, 3675
2430, 2175, 5205, 4020
3330, 3180, 5115, 4350
-855, 315, 5445, 3465
Platelets bind
other
already laid down so
can form a plug
stop minor bleeding"
H250, 0
H250, 0
H250, 0
"p4"
H200, 100
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p4"
3985, 3975
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p5"
H250, 0
"p6"
H250, 0
H250, 0
H250, 0
H250, 0
"p5"
H250, 0
"p6"
H250, 0
3870, 315
H250, 0
H250, 0
"p5"
4265, 3735
"p6"
H250, 0
H250, 0
H250, 0
"p5"
4385, 3960
"p6"
H250, 0
H250, 0
H250, 0
"p6"
4495, 3570
H250, 0
H250, 0
"p6"
4645, 3915
5-HT released causes
upstream
injury site
vasoconstrict so
flow
reduced."
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
H250, 0
REPEAT OR MOVE ON TO THE NEXT PAGE"
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group
vessel
script
Normal blood vessel - The integrity of the endothelial cells is intact so the collagen surrounding the blood vessel does not come into contact with the contents of the blood vessel.
script
When the endothelial cell lining is ruptured exposing the collagen to the contents of the blood vessel.
script
vessel
Wungroup
When platelets come into contact with a section of damaged blood vessel they adhere to the collagen and release the 5-HT.
script
screen
screen
screen
screen
screen
drop1
drop1
screen
screen
screen
screen
screen
Platelets bind to other platelets already laid down so they can form a plug that can stop minor bleeding
script
The 5-HT released causes the blood vessel upstream of the injury site to vasoconstrict so the blood flow at the injury site is reduced.
script
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script
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"bond1"
"bond2"
"bond3"
"bond4"
"bond5"
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bond1
bond2
bond3
bond4
bond5
ligase
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ID 30
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Animate6
Animate
words
EPEAT OR MOVE ON TO THE NEXT PAGEadjacent fibrin monomers create an extensive covalently-linked network structure.ork structure.ntly held together
ACTION OF FIBRINOLIGASE:
Press the 'Animate' button.
: Fibrinoligase
: Isopeptide bond
* t$A
* *'A
bond1
bond3
bond5
bond2
@3 Q
bond4
--removes cross
the answer boxes
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A typical turnover number for a proteolytic enzyme is :
10 molecules of substrate sec
100 molecules of substrate sec
1000 molecules of substrate sec
10000 molecules of substrate sec
100000 molecules of substrate sec
Thrombin has the following action :
Releases fibrinopeptide B
Releases fibrinopeptide A from fibrinogen
Causes vasoconstriction of blood vessels
Activates fibrinoligase
Creates cross-links between fibrin moleculessssssssssssssss
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--same applies
questscores 2-20
--All forthcoming
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have
Jlayout except
4questscore2
B"1a"
B"1b"
B"1c"
B"1d"
B"1e"
B"2a"
B"2b"
B"2c"
B"2d"
B"2e"
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"quest3"
"quest4"
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Platelets adhere to :
Endothelial cells
Collagen
Fibrin
Red blood cells
Other aggregated plateletsssss
Fibrinoligase :
Creates isopeptide bonds
Links a-amino groups to a-COOH groups
Links g-amino groups to e-COOH groups
Links lysine and glutamine
Links e-amino groups to g-COOH groupss
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4questscore4
B"3a"
B"3b"
B"3c"
B"3d"
B"3e"
B"4a"
B"4b"
B"4c"
B"4d"
B"4e"
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"quest5"
"quest6"
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Which of the following associate with aggregated platelets :
Prothrombin
Thrombin
Protofibrils are polymers of :
Fibrinogen lacking fibrinopeptide A
Fibrinogen lacking fibrinopeptide B
Fibrinogen lacking fibrinopeptides A and B
Fibrinogen
Cross-linked fibrin
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B"5a"
B"5b"
B"5c"
B"5d"
B"5e"
B"6a"
B"6b"
B"6c"
B"6d"
B"6e"
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"quest7"
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Haemostasis comprises or may comprise ::::::::::::::
The process that prevents blood loss
Platelet aggregation alone
Coagulation alone
Platelet aggregation and coagulation
Aggregation of red blood cells
Fibrinogen contains :
2 a(A) chains
2 b(B) chains
2 a chains
2 b chains
2 g chainsins
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B"7a"
B"7b"
B"7c"
B"7d"
B"7e"
B"8a"
B"8b"
B"8c"
B"8d"
B"8e"
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"quest9"
"quest10"
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Fibrin contains :
2 a(A) chains
2 b(B) chains
2 a chains
2 b chains
2 g chains
Platelets contain :::::
Vesicles containing a vasodilalator
Vesicles with negative charge on inner surface
Vesicles containing 5-hydroxytryptamine
A nucleus
Vesicles with negative charge on outer surface
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4questscore9
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B"9a"
B"9b"
B"9c"
B"9d"
B"9e"
B"10a"
B"10b"
B"10c"
B"10d"
B"10e"
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"fibc"
"fib3"
"fib4"
"fib5"
"fib6"
"fib1"
280, 1815
"fib2"
4650, 1815
"Thrombin removes the fibrinopeptides
each fibrinogen molecule one
"throm"
)-930, 390
-720, 435
-405, 495
-135, 615
105, 735
420, 855
675, 975
990, 1125
1305, 1260
1515, 1290
"a1"
H-150, -150
"a1"
H-150, -150
"a1"
H-150, -150
1650, 1215
"a1"
H-200, -200
1815, 1125
"a1"
H-200, -200
1905, 1095
"a1"
H-200, -200
2085, 1035
"a1"
H-200, -200
2295, 990
"a1"
H-200, -200
2415, 930
"a1"
H-200, -200
"a1"
ZhorizPos
2415
4545
%, 930
4755, 900
4905, 960
5085, 1020
5235, 1095
5415, 1170
5535, 1170
5670, 1215
5910, 1275
"a3"
H-100, -100
"a3"
H-100, -100
"a3"
H-100, -100
6075, 1185
"a3"
H-200, -200
6345, 1125
"a3"
H-200, -200
6570, 1080
"a3"
H-200, -200
6780, 1050
"a3"
H-200, -200
6885, 1025
"a3"
H-200, -200
7335, 1005
"a3"
H-200, -200
7695, 930
"a3"
H-200, -200
7950, 900
"a3"
H-200, -200
8205, 870
"a3"
H-200, -200
8385, 870
"a3"
H-200, -200
"a1"
)1875, 1815
"a3"
)6270, 1815
"The release
A fragments expose sites that were previously masked."
)-930, 390
-720, 435
-405, 495
-135, 615
105, 735
420, 855
675, 975
990, 1125
1305, 1260
1515, 1290
"a2"
H-150, -150
"a2"
H-150, -150
"a2"
H-150, -150
1650, 1215
"a2"
H-200, -200
1815, 1125
"a2"
H-200, -200
1905, 1095
"a2"
H-200, -200
2085, 1035
"a2"
H-200, -200
2295, 990
"a2"
H-200, -200
2415, 930
"a2"
H-200, -200
"a2"
2415
4545
, 930
4755, 900
4905, 960
5085, 1020
5235, 1095
5415, 1170
5535, 1170
5670, 1215
5910, 1275
"a4"
H-100, -100
"a4"
H-100, -100
"a4"
H-100, -100
6075, 1185
"a4"
H-200, -200
6345, 1125
"a4"
H-200, -200
6570, 1080
"a4"
H-200, -200
6780, 1050
"a4"
H-200, -200
6885, 1025
"a4"
H-200, -200
7335, 1005
"a4"
H-200, -200
7695, 930
"a4"
H-200, -200
7950, 900
"a4"
H-200, -200
8205, 870
"a4"
H-200, -200
8385, 870
"a4"
H-200, -200
"a2"
)2205, 1815
"a4"
)6570, 1815
"These
are complementary
nodules
which they can bind non-covalently."
)2520, -510
ZvertPos
-510
1090
2520,
2520, 1150
360, 1815
2520, 1225
450, 1815
2520, 1300
600, 1815
2520, 1340
675, 1815
4590, 1815
4530, 1815
4425, 1815
4365, 1815
"This process
produce a
\, thin polymer - A PROTOFIBRIL."
)-3540, 1185
-3540
-1275
, 1185
-1245, 1215
-1185, 1290
-1170, 1340
)8550, 1200
8550
7500
H-300
, 1200
6420, 1215
6345, 1275
6280, 1320
6210, 1340
)-3570, 1815
-3465, 1815
-3330, 1815
-3180, 1815
-3015, 1815
)8490, 1815
8400, 1815
8280, 1815
8175, 1815
8055, 1815
"REPEAT OR MOVE ON TO THE NEXT PAGE"
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Thrombin removes the fibrinopeptides of each fibrinogen molecule one at a time.
words
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
The release of the fibrinopeptide A fragments expose sites that were previously masked.
words
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
These sites are complementary to the sites on the end nodules to which they can bind non-covalently.
words
This process can continue to produce a long, thin polymer - A PROTOFIBRIL.
words
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HAEMOSTASIS VIA THE COAGULATION SYSTEM
Platelet aggregation may be enough to prevent blood loss when the damage to a blood vessel is slight and when the blood vessel is small, e.g a capillary. If the damage is extensive, as well as platelet aggregation, coagulation is triggered. Coagulation is initiated by the exposure of collagen and the release of the contents of the damaged endothelial cells. The end product of coagulation is a 3-dimensional mesh made out of fibrin covalently linked together. The size of the mesh is small enough to stop cells from escaping from the blood vessel. This fibrin mesh is commonly referred to as a blood clot.
Fibrin is made from the soluble plasma protein fibrinogen through the action of thrombin. This conversion is the last stage in a cascade of proteolytic reactions which involves nearly twenty different substances.The important features of the coagulation system is that:
(a) the response is rapid
(b) it is localised to the site of damage......
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&:&`&
'@'j'
(B(h(
,B-h-
.B/l/
/"0H0r0
0$1J1t1
1&2L2r2
6F7l7
<H=t>
Factor XII
Fibrinogen
XII a3
HMKKKKKKK
Factor XI
XI aaY
Factor IX
Fibrin (soft clot)
Thrombin
Prothrombinn
Factor X
Fibrin (hard clot)
VII aa
X aaa
IX aaaa
Factor VIII
V aaaa
Factor VIII
XIII aa
Factor XIII
VIII a
Factor IIII
Factor X
Factor VIII
Prekallikrien
N3&3K3
Kallikriennn
X505U5
Wound surface contact
Ca ,PLL
Ca ,PLL
j:B:g:
Ca ,PLL
Ca ,PLL
Ca ,PLL
Ca (?)
d><>a>
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No. of molecules produced sec
| T y
produced sec
MOVE ON TO NEXT PAGE AT ANY TIMEu
100000 fibrinnnnnn
10000 thrombinnmbin
1000 X aaaaaaaaaaa
100 IX aaaaaaaaaaaaa
10 XI aaaaaaaaaaaaaa
AMPLIFICATION
1 XII aaaaaaaaaaaaa
Localization of the blood clot to the site of injury is very important as more general coagulation is potentially hazardous. Localization is achieved by limiting the formation of thrombin to the negatively charged phospholipid membrane created on the surface of aggregated platelets.
When platelets aggregate, 5-HT-containing vesicles fuse with the platelet plasma membrane. The inner surface of the vesicle membranes contains phosphatidylserine, a negatively charged phospholipid, so on fusing with the vesicle membrane, the outer surface of the plasma membrane becomes negatively charged.
Calcium ions then bind to the negatively charged membrane. Both Xa and prothrombin have negatively charged areas and bind, through the positively charged calcium ions, to the platelet membrane. Thus high concentrations of enzyme and substrate generated on the membrane surface leading to reaction rates hundreds of times faster than in solution..... in solution.in solution.on.of times faster than in solution.es faster. a high concentration of enzyme and substrate the reaction proceeds hundreds of times faster.
"Negatively charged phospholipids e.g. phosphatidyl serine, are only found on the cytoplasmic side
cell membranes,
%such
xcome
contact
@blood plasma"
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Negatively charged phospholipids e.g. phosphatidyl serine, are only found on the cytoplasmic side of cell membranes, and as such do not come into contact with the blood plasma
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LOCALIZATION OF COAGULATION SYSTEM :
The negatively charged areas in factor Xa and prothrombin are clusters of g-carboxyglutamate residues. These residues contain 2 negatively charged carboxyl groups..
OOC COO
CH
CH
- NH CH CO -
"carb"
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, 2895
IJK`LD+o
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Animate2
Animate
neg10
neg11
neg12
neg13
neg14
neg15
negs1
negs2
neg17
negves2
neg17
negves1
prothrom
Prothrombin
HD DED
ZF2FWF
GXG}G
throm
Thrombin
Thrombin
"throm"
"va2"
"negs1"
"negs2"
"ca1"
"ca2"
"ca3"
"ca4"
"ca5"
"ves1"
"ves2"
leavePage
enterPage
leavePage
throm
negs1
negs2
enterPage
"throm"
"va2"
"negs1"
"negs2"
"ca1"
"ca2"
"ca3"
"ca4"
"ca5"
"ves1"
"ves2"
ZvertPos
3785
3185
2085,
2085, 3135
2085, 3785
"negves1"
"rel1"
H0, -100
H0, -100
H0, -100
-1560
H-100
1830, vertpos
1830, 990
3900
3150
4965,
4965, 3900
"negves2"
"rel2"
H0, -100
H0, -100
H0, -100
-1450
H-100
4890,
4890, 1250
)-405, 1485
)-420, 435
)6735, -330
-255, 1515
6630, -225
-180, 495
6540, -60
60, 1590
90, 615
)1740, -330
)8565, 765
345, 690
405, 1695
1860, -45
6315, 240
8115, 915
2010, 165
555, 795
645, 1800
6210, 420
7800, 1125
2145, 435
855, 930
885, 1860
6090, 705
2220, 660
7500, 1380
5955, 885
2295, 945
1065, 1065
1170, 2025
1395, 1365
2505, 1290
5805, 1140
7170, 1545
5670, 1365
1410, 2250
2790, 1530
1725, 1530
6885, 1800
5520, 1695
3015, 1770
1995, 1785
1575, 2400
5250, 1980
6465, 2055
2295, 2115
3255, 2010
4980, 2220
3570, 2175
2535, 2280
6195, 2265
1950, 2550
3735, 2415
2835, 2535
4785, 2430
5940, 2415
4635, 2580
3840, 2565
5745, 2580
"va"
1245, 1530, 1335, 1650
"va"
1275, 1485, 1500, 1695
"va"
1380, 1425, 1710, 1725
"va"
1515, 1335, 1980, 1770
"va"
1680, 1200, 2340, 1815
"va"
1890, 1080, 2760, 1875
"va"
2115, 975, 3180, 1920
"va"
2370, 810, 3645, 1980
"va"
2565, 660, 4110, 2070
"va"
2880, 495, 4590, 2175
3195, 330, 5190, 2190
H0, 100
H0, 100
H0, 100
H0, 100
"xa"
)-915, 1035
"xa"
-780, 1080
"xa"
-675, 1110
"xa"
-480, 1155
"xa"
-345, 1200
"xa"
-285, 1230
"xa"
-135, 1260
"xa"
75, 1320
"xa"
225, 1380
"xa"
375, 1425
"xa"
525, 1470
"xa"
720, 1545
"xa"
900, 1590
"xa"
1035, 1635
horizPos
1035
2535
"xa"
", 1635
"xa"
2835, 1665
"prothrom"
)8545, 1650
8545
3645
H-350
}, 1650
)3840, 1650
)3645, 1785
3960, 1620
3660, 1785
4110, 1620
3720, 1785
4320, 1620
"pro"
3930, 1785
4425, 1620
4080, 1695
4560, 1620
4110, 1485
4755, 1620
4170, 1380
4845, 1605
4335, 1185
4440, 795
4575, 525
4860, 315
5010, 135
5145, -105
5280, -255
5325, -375
5475, -495
5550, -585
5580, -690
default
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throm
negs1
negs2
negves1
negves1
negs1
vertpos
negves2
negves2
negs2
prothrom
prothrom
prothrom
throm
throm
throm
throm
throm
throm
throm
throm
default
horizPos:by
horizPos:to
horizPos
vertPos:by
vertPos:to
vertPos
The final stage of coagulation involves proteolysis but results in the formation of a fibrous clot rather than a further proteolytic enzyme.
Fibrinogen is a soluble plasma protein and is converted to an insoluble derivative, fibrin, by the final proteinase in the coagulation cascade, thrombin. Fibrin is insoluble and aggregates in an ordered way to form a 3-dimensional network with a mesh size similar in size to a red blood cell.
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CONVERSION OF FIBRINOGEN TO FIBRIN
Fibrinogen is a soluble plasma protein and is converted to an insoluble derivative, fibrin, by the final proteinase in the coagulation cascade, thrombin. Fibrin is insoluble and aggregates in an ordered way to form a 3-dimensional network with a mesh size similar in size to a red blood cell.
photorbc
"photo"
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photo
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photo
"photo"
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photo
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Trapped erythrocyte
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FIBRINOGEN STRUCTURE:
Fibrinogen has a molecular mass of 340,000 and consists of three pairs of polypeptide chains of similar size - a(A), b(B) and g, each containing approximately 500 amino acids. The arrangement of the chains is as follows:::
4 * 1
: Disulphide bondd
B : Fibrinopeptide BA
A : Fibrinopeptide AA
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FIBRINOGEN SHAPE:
Electron micrographs of fibrinogen shows it to have a trinodular structure. It can be represented diagramatically as follows:
fibgen photo
"photo2"
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Fibrinopeptide A
Fibrinopeptide B
Thrombin has a very limited action on fibrinogen - it cleaves only 4 peptide bonds out of approximately 3000 present. These bonds are broken in 2 stages. First thrombin cleaves a single Arg-Gly bond near the terminus of the a(A) chain releasing a small (15 amino acid) soluble fragment called FIBRINOPEPTIDE A. The fibrinopeptides mask sites that mediate intermolecular association.
ACTION OF THROMBIN:
photo2
"photo2"
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^ 6 [
Fibrinogen Molecules
"fibc"
"fib3"
"fib4"
"fib5"
"fib6"
"fib1"
280, 1815
"fib2"
4650, 1815
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" ,&6,@2J8r8
throm
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words
EPEAT OR MOVE ON TO THE NEXT PAGEce a long, thin polymer - A PROTOFIBRIL.y can bind non-covalently.
Animate3
Animate
"-` P
P1` P
,3` P
Z7` P
: Masked binding site
|9T9y9
: Complementery binding site
: Thrombinn
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RELEASE OF FIBRINOPEPTIDE B AND SIDE TO SIDE POLIMERIZATION OF PROTOFIBRILS:
Protofibril formation results in fibres two fibrinogen molecules thick. A fibrin clot, however, consists of fibres which may be tens of fibrin molecules thick. The formation of these thick fibres occurs after the release of fibrinopeptide B. The release of fibrinopeptide B allows side-to-side polymerization of protofibrils into bundles of varying thickness.
The molecule produced as a result of the release of both fibrinopeptides A and B is a fibrin monomer. This monomer polymerizes to produce a fibrin polymer.
bundles of varying thickness. Once fibrinopeptide B has been cleaved the parent molecule is known as fibrin.
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FORMATION OF FIBRIN NETWORK:
The two-stage release of the fibrinopeptides is important in allowing the formation of a 3-dimensional insoluble fibrin network. The production of protofibrils alone leads to the formation of a viscous solution but not to the formation of a gel. A gel, in which fibres form a 3-dimensional net, is required for coagulation. The 3-dimensional net is formed when protofibrils or bundles of protofibrils are incorporated into one protofibril bundle at one end and another bundle at its other end, forming cross-strands. This allows network formation. network formation.twork formation.t one end and incorporated into another bundle at its other end, forming cross-strands. This allows network formation.
"b10"
"proto1"
-2970, -995
-2970, 2060
"proto2"
-2970, 5835
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words
proto1
proto
proto2
throm
proto
z"o
6(` P
T-` P
&/` P
T3` P
&5` P
T9` P
proto1
^A~ 3
PF~ 3
proto2
^a~ 3
\l~ 3
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words
Animate4
Animate
"Bundle
protofibrils."
"b1"
)-389, -509
ZvertPos
-509
"b1"
-389,
"Second bundle
{ joins
)one
"b2"
)8400, 3045
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
"b2"
H-580, -130
the other
"b3"
)150, 5800
5800
3600
H-200
"b3"
150,
protfibrils
form a mesh
"b4"
)-1670, 1440
horizPos
-1670
-270
"b4"
#, 1440
"REPEAT OR MOVE ON TO THE NEXT PAGE"
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words
Bundle of protofibrils.
words
Second bundle of protofibrils joins to first at one end.
words
A third bundle joins to the other end of the second bundle.
words
A fourth bundle of protfibrils joins to the second bundle at one end and the third bundle at the other end to form a mesh system.
words
REPEAT OR MOVE ON TO THE NEXT PAGE
words
default
horizPos:by
horizPos:to
horizPos
vertPos:by
vertPos:to
vertPos
"b10"
"proto1"
-2970, -995
-2970, 2060
"proto2"
-2970, 5835
"Thrombin cleaves the fibrinopeptide B fragments
gen, exposing sites that were previously masked."
"throm"
)-960, 915
-600, 1100
-240, 1285
120, 1470
300, 1365
"b1"
H-150, -150
360, 1290
"b1"
H-150, -150
495, 1245
"b1"
H-150, -150
"b1"
435, 1995
ZhorizPos
2640
$, 1245
2640, 1245
3020, 1320
3400, 1395
3780, 1470
3780, 1485
"b3"
H0, -250
"b3"
H0, -250
3915, 1395
"b3"
H0, -250
"b3"
H0, -250
3990, 1290
"b3"
H0, -250
"b3"
H0, -250
4155, 1245
"b3"
H0, -250
"b3"
H0, -250
"b3"
4140, 1995
4155
6540
, 1245
6540, 1245
7005, 1350
7470, 1455
7575, 1410
"b5"
H150, -150
7725, 1320
"b5"
H150, -150
7920, 1260
"b5"
H150, -150
8160, 1200
"b5"
H150, -150
8325, 1095
"b5"
7830, 1995
8325, 1095
8475, 1005
)8475, 3345
7926, 3255
7377, 3165
6828, 3075
6279, 2985
5730, 2895
5655, 2925
H250, 250
H250, 250
5550, 2985
H250, 250
H250, 250
5475, 3030
H250, 250
H250, 250
5355, 3090
H250, 250
H250, 250
5280, 3120
H250, 250
H250, 250
6375, 2877
5280
3435
H-250
, 3120
3435, 3120
3086, 3067
2737, 3015
2388, 2962
2040, 2910
1875, 2940
"b8"
H-150, 250
"b8"
H-150, 250
1695, 2985
"b8"
H-150, 250
"b8"
H-150, 250
1455, 3060
"b8"
H-150, 250
"b8"
H-150, 250
1245, 3135
"b8"
H-150, 250
"b8"
H-150, 250
1020, 3180
"b8"
H-150, 250
"b8"
H-150, 250
705, 3225
"b8"
H-150, 250
"b8"
H-150, 250
435, 3240
"b8"
H-150, 250
"b8"
H-150, 250
210, 3255
"b8"
H-150, 250
"b8"
H-150, 250
-120, 3255
"b8"
2670, 2892
-270, 3240
-540, 3225
-810, 3225
-1020, 3240
)-960, 915
-600, 1100
-240, 1285
120, 1470
300, 1365
"b2"
H-200, -200
360, 1290
"b2"
H-200, -200
495, 1245
"b2"
H-200, -200
"b2"
810, 1995
2640
, 1245
2640, 1245
3020, 1320
3400, 1395
3780, 1470
3780, 1485
"b4"
H0, -250
"b4"
H0, -250
3915, 1395
"b4"
H0, -250
"b4"
H0, -250
3990, 1290
"b4"
H0, -250
"b4"
H0, -250
4155, 1245
"b4"
H0, -250
"b4"
H0, -250
"b4"
4515, 1995
4155
6540
, 1245
6540, 1245
7005, 1350
7470, 1455
7575, 1410
"b6"
H200, -200
7725, 1320
"b6"
H200, -200
7920, 1260
"b6"
H200, -200
8160, 1200
"b6"
H200, -200
8325, 1095
"b6"
8205, 1995
8325, 1095
8475, 1005
)8475, 3345
7926, 3255
7377, 3165
6828, 3075
6279, 2985
5730, 2895
5655, 2925
"b9"
H250, 250
"b9"
H250, 250
5550, 2985
"b9"
H250, 250
"b9"
H250, 250
5475, 3030
"b9"
H250, 250
"b9"
H250, 250
5355, 3090
"b9"
H250, 250
"b9"
H250, 250
5280, 3120
"b9"
H250, 250
"b9"
H250, 250
"b9"
6015, 2892
5280
3435
H-250
, 3120
3435, 3120
3086, 3067
2737, 3015
2388, 2962
2040, 2910
1875, 2940
"b7"
H-150, 250
"b7"
H-150, 250
1695, 2985
"b7"
H-150, 250
"b7"
H-150, 250
1455, 3060
"b7"
H-150, 250
"b7"
H-150, 250
1245, 3135
"b7"
H-150, 250
"b7"
H-150, 250
1020, 3180
"b7"
H-150, 250
"b7"
H-150, 250
705, 3225
"b7"
H-150, 250
"b7"
H-150, 250
435, 3240
"b7"
H-150, 250
"b7"
H-150, 250
210, 3255
"b7"
H-150, 250
"b7"
H-150, 250
-120, 3255
"b7"
2325, 2892
-270, 3240
-540, 3225
-810, 3225
-1020, 3240
"The exposed
bind
complementary
outer nodules
molecules
other protofibrils."
H0, 200
H0, 200
H0, 200
H0, 200
H0, 200
H0, 200
H0, 100
H0, -100
H0, 100
H0, -100
H0, 100
H0, -100
H0, 100
H0, -100
H0, 100
H0, -100
way bundles
are formed
varying thickness depending on
collisions
take place."
H0, -400
H0, -400
H0, -400
H0, -400
H0, -400
H0, -400
H0, -400
H0, -400
H0, -200
" This animation shows
building up
a ribbon. In reality they
$ up
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proto1
proto
proto2
Thrombin cleaves the fibrinopeptide B fragments from the fibrinogen, exposing sites that were previously masked.
words
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
throm
The exposed sites bind to complementary sites on the outer nodules of fibrin molecules of other protofibrils.
words
proto1
proto1
proto1
proto1
proto1
proto1
proto1
proto
proto1
proto
proto1
proto
proto1
proto
proto1
proto
In this way bundles of protofibrils are formed of varying thickness depending on the number of collisions that take place.
words
proto2
proto2
proto2
proto2
proto2
proto2
proto2
proto2
proto2
This animation shows the protofibrils building up to a ribbon. In reality they build up into thick bundles.
words
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words
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System
Times New Roman
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Haemostasis
Arial
j xsuJ
UDUgmJ
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Dialog
Collagen - in blood vessel wall if artery/vein : in connective tissue if capillary. Has no contact with circulating blood
CROSS SECTION OF A BLOOD VESSELLLLLLLLL
Collagen
Endothelial cell lining
cells
Put "Endothelial cell lining - continuous monolayer
cells completely surrounding
F lumen."
"Dialog"
mouseEnter
mouseEnter
Endothelial cell lining - continuous monolayer of cells completely surrounding the lumen.
Dialog
collagen
Put "Collagen -
blood vessel wall
artery/vein :
connective tissue
capillary. Has no contact
fcirculating
"Dialog"
mouseEnter
mouseEnter
Collagen - in blood vessel wall if artery/vein : in connective tissue if capillary. Has no contact with circulating blood
Dialog
plasma
"Plasma - fluid containing most coagulation factors
which cells
platelets circulate."
"dialog"
mouseEnter
mouseEnter
Plasma - fluid containing most coagulation factors and in which cells and platelets circulate.
dialog
Put "Erythrocyte /
blood cell."
"Dialog"
mouseEnter
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Erythrocyte / red blood cell.
Dialog
platelets
Put "Platelet - has a fundamental role
haemostasis."
"Dialog"
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Platelet - has a fundamental role in haemostasis.
Dialog
$ V 4
Move the mouse onto each part of the blood vessel.
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Basic
Basic
Z \ \
AIMS AND OBJECTIVES
2. g animations the significant features of haemostasis
2. tudents in their first or second years.
1. To illustrate using animations the significant features of haemostasis
2. 1. To illustrate using animations the significant features of haemostasis
2.
This program is intended for use by students in their first or second year taking Biochemistry as part of their course. The program makes use of animations to illustrate the dynamic and surface-mediated aspects of haemostasis. The aims and objectives are as follows:
1. To illustrate the events leading to platelet aggregation when blood
vessels are damaged.
2. To illustrate the importance of amplification and surface-mediated
events in coagulation.
3. To illustrate the important aspects of the fibrinogen-fibrin transition.
4. To test your understanding of the tutorial by means of a multiple-choice
quiz...
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You can distribute the unmodified material freely and modify it to your own requirements. However, we ask the following:
1. By all means give yourself credit for your work in your books but please leave this page unaltered in this book.
2. It is important that teaching material of this kind is disseminated as widely as possible, so please ensure that your material is also freely available.
3. Please send a copy of any modified or expanded versions of this program to Dr J.M Basford, Department of Biochemistry, University of Wales, Cardiff, CF1 1ST , Tel 44 222-874119 Fax 44 222-874116.
Internet Basford @Cardiff.ac.uk
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PLATELET STRUCTURE
Cytosol - Platelets do not have a nucleus as they are fragments from cells known as megakarocytes.
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Intracellular vesicles - they contain
5-hydroxytrypamine (a vasoconstrictor).
Membrane. There are sites on the membrane that have affinity for collagen.
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Glycogen granule
Mitochondrion
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Platelets
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Photo
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"con"
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vessel
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/(0X0
CfL2M
P.Q^Q
PLATELET AGGREGATIONN
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vessel
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67. G
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RAPID RESPONSE OF COAGULATION SYSTEM :
The coagulation pathway leading to the formation of the fibrin mesh has many steps which enables it to act as a biochemical amplifier. This amplifier is sometimes referred to as a cascade. Seven of the substances involved in the pathway are inactive forms of enzymes that are activated by the preceding enzymes in the cascade. An average turnover number for a proteolytic enzyme is ten substrate molecules per second. This means that the first enzyme will convert ten substrate molecules per second; the 10 enzyme molecules produced will then each be capable of generating the third enzyme at the rate of 10 molecules per second i.e. 100 molecules per second overall. The amplification factor is thus approx 10 for each stage. This causes a large response in a very short time. large response in a very short time. hort time.
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HAEMOSTASIS VIA PLATELET AGGREGATION
Platelets are unpigmented, enucleated blood cells that have fragmented from larger cells called megakarocytes. They have many vesicles containing a physiologically active substance called 5-hydroxytryptamine (5-HT) -see diagram on following page.
In a damaged section of blood vessel the platelets will adhere to the exposed collagen surrounding the vessel wall and then to other platelets. In this way a plug is formed that can stop minor bleeding. The association between platelets and collagen is mediated by the large multimeric plasma protein - von Willebrandt factor.
As the platelets aggregate they release the 5-HT causing vasoconstriction of the blood vessel, and in doing so reduce the blood flow at the site of injury.
If the damage is extensive then the coagulation system is triggered. ed.
"The von Willebrandt factor binds
a specific receptor on the platelet membrane
also
exposed collagen."
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The von Willebrandt factor binds to a specific receptor on the platelet membrane and also to the exposed collagen.