Coagulation Disorders and Disseminated Intravascular Coagulation (DIC)
Step‐by‐Step Evolution of Vertebrate Blood Coagulation
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Transcript of Step‐by‐Step Evolution of Vertebrate Blood Coagulation
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Russell F. Doolittle
The Step-by-Step Evolution of Vertebrate Blood Coagulation
UC San Diego
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Bernstein and Kairinen (1971)
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R. Williams, 1980
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Blood clotting in humans is very complex. It involves more than two dozen genetically encoded proteins.
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Fibrinogen FibrinMonomer
Fibrin Cross-linkedFibrin
LysedFibrin
Thrombin
Antithrombin
Thrombomodulin
Prothrombin
Xa
TAFIXIIIa
XIII
Plasmin
Plasminogen
u-PAt-PA
PAI-1
VIIIa
XIa
IXa
XI
X
-Antiplasmin2
Va
ProtC
VIII
V
TF/fVII
VII
tissue factorTFI
APC
ProtS IX
XIIaKallikrein
XII
Prekallikrein
(HMWK)
Pro-u-PA
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Fibrinogen FibrinMonomer
Fibrin
Thrombin
Mammalian blood clotting can be divided into sets of reactions.
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Fibrinogen FibrinMonomer
Fibrin Cross-linkedFibrin
ThrombinProthrombin
XIIIa
XIII
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Fibrinogen FibrinMonomer
Fibrin Cross-linkedFibrin
ThrombinProthrombin
Xa
XIIIa
XIII
VIIIaIXa
X
LysedFibrin
Va VIIIV
TF/fVII
VII
tissue factor
Plasmin
Plasminogen
u-PAt-PA
Pro-u-PA
IXXIIa
Kallikrein
XII
Prekallikrein(HMWK)
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The Delicate Balance
thrombinfibrinogen
factor VII
factor Xfactor IXfactor Vfactor VIIIfactor XIfactor XIIfactor XIII
prekallikreinPAI-1
tissue factorplasminogen
fibrinprotein Cantithrombin3
gelation fluidity
tissue factor inhibitor
t-PAu-PA
thrombomodulinprotein S
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Thrombin-clottable fibrinogen is found in all vertebrate
animals, but not in protochordates (amphioxus, tunicates,
etc.) or invertebrate animals.
The earliest diverging vertebrates (lampreys and hagfish) have
six-chained, fully differentiated fibrinogens that polymerize
and cross-link the same as mammalian ones.
It is well established that:
Vitamin-K dependent factors play a role in the clotting of
lower vertebrates like the lamprey and hagfish.
It was long ago predicted that some factors would not
play a role in the clotting of lower vertebrates.
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Doolittle R. F. (1993) Thromb Haemost. 70:24-28.
The evolution of vertebrate blood coagulation: a case of Yin and Yang
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How did blood clotting become so complex?
Why is it so complex?
How can we find out?
We can start to answer these questions by examining clotting in more primitive creatures.
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Protostomes Deuterostomes
Crustacea EchinodermataArachnidaInsecta (Protochordata) Vertebrata
Five Animal Groups with Different Types of Blood Clotting
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Hagfish
Lamprey E. shark
Pufferfish Zebrafish
Frog
Lizard Chicken
Mouse Human
(70 mya)
(310 mya)
(430 mya)(500 mya)
(550 mya)
Sea Squirt
Amphioxus
(380 mya)
Platypus
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Many of the clotting proteins are multi-domainedand involve various combinations of common domains.
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Prothrombin
K K SPG
Protein C, factor VII.Factor IX, Factor X
SPG
K
u-PA
SPF1
F1
t-PA
E KK SPF1
E
F2
KEE
Factor XII
SPF1F2
Plasminogen
P KKKKK SP
K
Kringle SP
Serine protease
P
G
GLA
PAN
EGFFN2
FN1
FN3
FRED
CP- A
Serpin Kunitz
Carboxypep
TGDiscoidin
Sushi cc
E
E
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TBHUTBBO
F9HUF9BO
F9FUAF9FUB
F10BOF10HUF10FUF7HU
F7BOF7FUB
F7FUAF7FUC
PCBOPCHU
PCFU
TBFU
Vitamin-K Dependent Factors (GLA-containing)
Thrombins
Factors IX
Factors X
Factors VII
Proteins C
*
**
*
* Gene duplication HU = human BO = bovine FU = puffer fish
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Today it is possible to find out what clotting factors a creature has by computer searching of whole genome databases.
But not the hagfish.
Whole genome databases are available for many vertebrates,including human, other mammals, opossum, platypus, chickenLizard, frog, and several fish. A draft genome is available for lamprey.
My students and I have been scouring the lamprey data base,as well as those other vertebrates listed above.
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Fibrinogen FibrinMonomer
Fibrin Cross-linkedFibrin
LysedFibrin
ThrombinProthrombin
Xa
XIIIa
XIII
Plasmin
Plasminogen
u-PAt-PA
VIIIaIXa
X
Va VIIIV
TF/fVII
VII
tissue factor
Pro-u-PA
IX
Human Blood Clotting
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Fibrinogen FibrinMonomer
Fibrin Cross-linkedFibrin
LysedFibrin
ThrombinProthrombin
Xa
XIIIa
XIII
Plasmin
Plasminogen
u-PAt-PA
VIIIaIXa
X
Va VIIIV
TF/fVII
VII
tissue factor
Pro-u-PA
IXmissing in lamprey
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Fibrinogen FibrinMonomer
Fibrin Cross-linkedFibrin
LysedFibrin
ThrombinProthrombin
Xa
XIIIa
XIII
Plasmin
Plasminogen
u-PAt-PA
X
Va V
TF/fVII
VII
tissue factor
Pro-u-PA
Lamprey System
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Lampreys have a simpler clotting system than other vertebrates.
(We’re anxious to find out what the hagfish has!)
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All fish have a simpler clotting system than tetrapods.
In particular, they lack the “contact phase” factors.
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factor XII factor XIIa
factor XI
factor XIafactor IX factor IXa
factor X
factor Xa
prekallikrein
-kallikrein
XIIa
prothrombin thrombin
The Contact System Proteases
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HGFASPE E KF1F2
factor XIISPE E KF1F2
K SP
SP
SPKKP plasminogen
SPP HGF
SPPP PP factor XI
PP PP SP PK
K K t-PAF1
u-PA
E
E
K KK
KK K K
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Without exception, all of the proteins involved in mammalian blood clottingare descended from other protein families that are not involved in clotting.
The backbone of clotting, like many other extracellular processes, islimited proteolysis, especially employing serine proteases. Hundreds ofserine proteases--all evolutionarily related--are found in animals.
There is also a full complement of serine protease inhibitors, membersof a widely spread family called “serpins.”
Factor V (or factor 5) and factor VIII (factor 8) are descended fromferroxidase enzymes that can be traced back to bacteria.
Fibrinogen is a multi-domain protein, the globular portions of whichhave numerous relatives throughout the animal kingdom.
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Occurrence of Genes for Contact Phase Proteases and Some Paralogs
Factor XI Prekallikrein Factor XII HGFA HGF Plasminogen t-PA
Human Yes Yes Yes Yes Yes Yes YesOpossum Yes Yes Yes Yes Yes Yes YesPlatypus No Yes Yes Yes Yes Yes YesChicken No Yes No Yes Yes Yes Yes Green Lizard No Yes Yes Yes Yes Yes Yes Frog No Yes Yes Yes Yes Yes YesZebra Fish No No No ? Yes Yes YesPuffer Fish No No No Yes Yes Yes YesLamprey No No No Yes Yes Yes Yes
Updated from Ponczek, Gailani & Doolittle, 2008
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Chromosomal locations of factor XII and HGFA
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3
Jawless Fish Fish Amphibians Reptiles Birds
monotremes marsupials eutherians
Mammals
1 2
4
Updated from Ponczek, Gailani & Doolittle, 2008
1,2,3 = gene duplications 4 = gene deletion
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Chromosomal locations of prekallikrein and factor XI
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Duplication leads to separatefactor XI and prekallikrein.
Sea Squirt
Hagfish
LampreyE. shark
Pufferfish Zebrafish
Frog
Lizard Chicken
Mouse Human
Period of invention.
Amphioxus
Block duplication leads to factors VIII and IX.First appearance of factor XII.
First appearance of prekallikrein.
Birds lose factor XII.
Did anything happen here?
Platypus
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In the amphioxus genome:
Lots of genes for fibrinogen-related domains (FREDs), but none for multi-domained fibrinogen.
Some genes for proteases with sequences that resemble thrombin or factor X,but no domainal arrangements that correspond to these factors..
There is a gene for a tranglutaminase that is 39% identical with factor XIII,but it lacks a thrombin-activation site.
A similar situation exists in sea squirt.
There are no bona fide clotting factor genes in the protochordate genomes .
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E E
K K
KK
K
Protein C, factor VII.Factor IX, Factor X
4-Kringle Protease
KKKK SP
Prothrombin
K K SPG
G
SPG K
u-PA
SP
t-PA
E KK SPF1
EF1
EF2
KEE
Factor XII
SPF1F2
KK
KF1 E
Plasminogen
P KKKKK SP
P K
E
E
E E
or HGFA
P
HGF
P KKKK SP
Updated from Jiang & Doolittle, 2003
Prekallikrein, Factor XI
P P SPPP
P
K
+4
-5
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Summary
Genomic sequence data are making it possible to reconstruct the individual events that have led to the complex system of blood clotting observed in mammals.
The raw material for all the many proteins involved in blood clottingwas available in the form of domains in the common ancestor ofvertebrates and protochordates.
The number of components increases as one moves up the evolutionary scale from the jawless fish to mammals. Even among mammals somerecently evolved features are apparent.
Reasonable scenarios can be presented that show a step-by-stepdevelopment of the process. Whole genome duplications may have played a role in expanding the inventory of similar proteins.
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Acknowledgements
Yong Jiang
Michel Ponczek
Justin Nand
Sung Hong
Da-Fei Feng
David Gailani (Vanderbilt)
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My friend, the lamprey (Petromyzon marinus)
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MA FA
Gene
Time Duplication
MB FB
Species diverge
Gene Duplication
MB LB
MA LA
divergeSpecies
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Newmarket, New Hampshire, May, 1962
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K
u-PA
SPF1KEE
Factor XII
SPF1F2
Prothrombin
K K SPG
Plasminogen
P KKKKK SP
K
KringleSP
Serine protease
G
GLA
P
PAN
F2
FN2
F1
FN1
Protein C, factor VII.Factor IX, Factor X
SPG
t-PA
E KK SPF1
EE
EGF
E
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fibrinogen -------------> fibrin + fibrinopeptidesthrombin
fibrin ----------------> cross-linked fibrinfactor XIIIa
plasmin
lysed fibrin (fragments D and E, etc.)
plasminogen ------------> plasmint-PA
prothrombin
fibrininactive t-PA -----------------> active t-PA
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“thrombocytes”
cell clot
(pro)thrombin
tissue factor
A Simple System (n = 2 plus cells)
(tissue factor, prothrombin, thrombocytes)
thrombin
(pro)thrombin
K K SPG
This can’t be! Prothrombin has kringles;Tissue factor interacts with EGF domains.
Unless prothrombin originally hadEGF domains!
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fibrinogen
fibrin
(pro)thrombin
tissue factor
Another Simple System (n = 3)
(tissue factor, prothrombin, fibrinogen)
thrombin
(pro)thrombin
K K SPG
This can’t be! Prothrombin has kringles.Tissue factor interacts with EGF domains.
Unless prothrombin originally hadEGF domains!
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Hagfish
LampreyDogfish
Pufferfish Zebrafish
Frog
Lizard Chicken
Mouse Human
(70 mya)
(310 mya)
(400 mya)(500 mya)
(540 mya)
Sea Squirt
Amphioxus
(380 mya)
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invertebrates
jawless fishes
jawed fishes
primates
myoglobin
Fir
st A
ppea
ranc
e
Mill
ion
Yea
rs
Hemoglobins
-200
-400
-600
-800
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X
VII
P
V
Xa
VIIa
TF
T T
Va
fibrinogen fibrin
Lamprey
IX
VII
X
IXa
VIIa
TF
T
VIIIa
fibrinogen
fibrin
P T
Xa
Va
V
T
Other Vertebrates
VIII
The simultaneous doubling of two interacting gene products is consistent with the 2R hypothesis.
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Other VertebratesLamprey
X
VII
PVIIa
TF
Va
Tfibrinogen fibrin
T
V
Xa
IX
IXa
T
VIIIa
X
VII
PVIIa
TF
Va
Tfibrinogen fibrin
T
V
Xa
VIII*