بسم ا الرحمـــــــــن الرحيــــــــم Coagulation Course: Lecture-1
COAGULATION A dynamic look at the physiology
Akram Al-Hilali 2009
08/06/14
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TISSUE INJURY
Ac
m he c e tiv
l la o C
g
lr a ic
en
e
ed s a ele
Vasoconstriction and chemotaxis Platelet adhesion and aggregation
se o xp
d
Platelet activation and secretion
Fibrogenesis and healing
HEMOSTASIS Contact
Intrinsic Pathway of Coagulation activated
Tissue Thromboplastin
Extrinsic Pathway of Coagulation activated
FROM INJURY TO HEMOSTASIS AND HEALING 08/06/14
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PKa
PK
Tissue Factor
HMWK
TFPI Tissue Factor Pathway Inhibitor
FXIIa
FXII
C1 Inhibitor
FVII FXIa
FXI
FIX
FVIII
FVIIIa
TF-FVIIa FIXa
FXa
FX
ANTITHROMBIN III
FV
FVa PROTHROMBIN PROTEIN C
THROMBIN
THROBOMODULIN FIBRINOGEN
PROTEIN S
FIBRIN MONOMER
TPA, Urokinase PAI
FIBRIN POLYMER FXIII
FXIIIa FIBRIN CLOT
PLASMINOGEN CLOT LYSIS
08/06/14
PLASMIN Alpha-2 Antiplasmin
TAFI Thrombin-activatable Fibrinoolysis Inhibitor
4 DR.AKRAM ALHILALI-2000
THROMBOSIS vs. THROMBOLYSIS
In physiology, thrombosis only occurs at injured sites. In physiology, thrombolysis (fibrinolysis) occurs only within intact vessels. At injury site the aim of the clot is to close severed vessels and fill the tissue gap formed by the injury At injury site the aim of fibrinolysis is to resume blood flow within injured vessels. 08/06/14
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Thrombus in the Injury gap
Fibrinolytic agents Come from intact Endothelium to break Clot closing vessel
Injured tissue
Injured blood vessel
Immediate Hemostatic action
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LATER ON
Blood Flow restored- Healing of tissue starts
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HOW DO COAGULATION FACTORS FUNCTION?
Most are pro-enzymes or zymogens Each will act as a substrate for preceding activated factor. For example: FVIII will be cleaved at domains A and B by aFIX. Proteinase (or protease) action. Different from intestinal secretion enzymes by being specific proteases. Most potent enzyme is Thrombin. It not only allows fibrinogen to make fibrin polymers, but it also activates FXI, FV, FVIII and FXIII. Fibrinogen is not an enzyme. It is a substrate 08/06/14
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COAGULATION PROCESS IS A SERIES OF CASCADE REACTIONS
Few molecules need to be activated at the beginning. Number of activated molecules will multiply as the process goes on. Also steps will take shorter time as the process goes on. If there is no endothelial injury natural anticoagulants will be efficient enough to stop it, unless there is thromboplastin released into the circulation. One of the virtues of intact endothelium is the presence of thrombomodulin (fixed anticoagulant) that inhibits thrombin and activates Protein C. 08/06/14
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FIBRINOGEN
The single-stranded fibrinogen molecule cannot make a clot. It is weak and soluble. Multiple strands have to be joined together to make an insoluble fibrin thread. Only fibrin threads will be strong enough to hold the contents of the clot (mainly red cells). Single strands (monomers) will only join together if small pieces (fibrinopeptides A & B) are chopped off the ends of the threads. This chopping is done by enzyme action of thrombin at specific sites. 08/06/14
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FIBRINOGEN TO FIBRIN THROMBIN P NO I R FIB
N E G O IN R B FI
EP
ES D I T
A&
B
FI
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IN R B
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ROLE OF FACTOR XIII
To start with, fibrin monomers join by weak hydrogen bonds. They need FXIII (fibrin stabilizing factor) to join the monomers by strong peptide bonds. It is a transglutaminase. It joins glutamine in one monomer to lysine in another monomer by covalent bonds In absence of FXIII fibrin will be formed and hemostasis takes place, but clot will break easily and lead to recurrence of
bleeding. 08/06/14
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EXTRINSIC, INTRINSIC & COMMON PATHWAYS
The 2 pathways are needed for hemostasis. They meet at FX level. Factor X, with the assistance of FV begin the common pathway. Extrinsic pathway functions just after tissue injury and is not expected to keep acting for long. It is the immediate response (10”) following platelet aggregation to achieve hemostasis 08/06/14
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ROLE OF PLATELETS IN HEMOSTASIS
In addition to the role of aggregation, which helps hemostasis from minor injuries (as in bleeding time) platelets have a function within blood coagulation. Its surface, especially after activation, makes the platform on which the coagulation factors meet easily and react with each other. Without the phospholipid surface of platelets, coagulation factors in liquid phase do not meet easily. Fibrin threads are anchored to platelet surfaces by its receptor GPIIb/IIIa. 08/06/14
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FIBRIN-PLATELET WEB
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DOES THROMBUS FORM IN VIVO WITHOUT TISSUE INJURY?
It can happen if vascular endothelium is eroded by atheroma, cancer metastasis and vasculitis. It can happen with marked circulation stasis in a part of the body because of restriction of movement of the part. This may lead to some thromboplastin release. It can happen with thromboplastin release from bacteria (G-negative), in presence of IL-1 and monocytes, producing DIC. Amniotic fluid in blood leads to similar situation. It can happen with severe intravascular hemolysis, as in PNH. 08/06/14
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MINOR ACTIVATION PROCESS OF COGULATION
This is an ongoing process and considered physiologic. There are natural anticoagulants in blood that will deal with such minor events and prevent them from causing thrombosis or expanding. The process is stopped by anticoagulants at various stages, but if it does reach fibrin stage then fibrinolytic factors will lyse it. This is why D-dimers are normally above 0. 08/06/14
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PKa
PK
Tissue Factor
HMWK FXII
TFPI Tissue Factor Pathway Inhibitor
FXIIa
C1 Inhibitor
FVII FXIa
FXI
FIX
FVIII
FVIIIa
TF-FVIIa FIXa
FXa
FX
ANTITHROMBIN III
FV
FVa PROTHROMBIN PROTEIN C
THROMBIN
THROBOMODULIN FIBRINOGEN
PROTEIN S
FIBRIN MONOMER
TPA, Urokinase PAI
FIBRIN POLYMER FXIII
FXIIIa FIBRIN CLOT
PLASMINOGEN CLOT LYSIS
PLASMIN Alpha-2 Antiplasmin
TAFI
08/06/14 Procoagulant
Thrombin-activatable Fibrinoolysis Inhibitor Profibrinolytic
DR.AKRAM ALHILALI-2000
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THROMBOMODULIN the fixed anticoagulant th
e er
is
re e h m w t liu n e th e s e o pr nd y e nl ct O ta in
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