COAGULATION

CASCADE
PRESENTER: MUHAMMAD NUR AMIN BIN ABD RAHMAN
SUPERVISOR: DR MUHAMMAD ZIHNI BIN ABDULLAH
• HAEMOSTASIS = MECHANISMS THAT STOP BLOOD LOSS.
• THE THREE MAIN COMPONENTS INVOLVED IN HAEMOSTASIS ARE:

1. PLATELETS
2. ENDOTHELIUM
3. COAGULATION PROTEINS
• THREE KEY STEPS IN CLOT FORMATION:
1. VASOCONSTRICTION
2. PLATELET AGGREGATION
3. COAGULATION
 INITIATION OF HAEMOSTASIS-WHEN VESSEL IS DAMAGED,
PLASMA EXPOSED TO:

1. VON WILLEBRAND FACTOR:

• MAINLY SYNTHESIZED & STORED IN ENDOTHELIAL CELLS

• NORMALLY LIMITED AMOUNT IS SECRETED INTO VESSEL LUMEN
WHERE IT BINDS TO FACTOR VIII PROTECTING CLOTTING
FACTOR FROM DEGRADATION
• A DAMAGED VESSEL RELEASES LARGE AMOUNT OF VWF WHICH
BINDS PLATELETS TO SUBENDOTHELIAL COLLAGEN FIBRES
2. COLLAGEN FIBRES:

• SUBENDOTHELIAL COLLAGEN FIBRES EXPOSED IN

DAMAGED VESSEL
• PLATELET WILL BIND TO COLLAGEN (THROUGH A
BRIDGING VWF MOLECULE) AND BECAME ACTIVATED
3. TISSUE FACTOR (TF):

• IS EXPRESS BY SUBENDOTHELIAL CELLS SUCH AS

SMOOTH MUSCLES CELLS BUT NOT NORMALLY BY
ENDOTHELIAL CELLS, UNLESS THEY BECOME DAMAGED
• ACTIVATES PLASMA COAGULATION PROTEINS
(THROUGH THE EXTRINSIC PATHWAY) CULMINATING IN
THE PRODUCTION OF THROMBIN
 PLATELET ACTIVATION & AGGREGATION

• PLATELET IS A DISC-SHAPED ANUCLEAR CELL FRAGMENTS.

• LIFESPAN TYPICALLY 7 DAYS.
• DAMAGED VESSEL EXPOSES VWF, COLLAGEN & TF. PASSING PLATELETS BEING
ACTIVATED BY COLLAGEN, VWF & THROMBIN.
• WHEN ACTIVATED, PLATELET CHANGE SHAPE FROM DISC-LIKE TO STELLATE AND
RELEASE A NUMBER OF MOLECULES FROM STORAGE GRANULES.
 THE KEY STEPS OF PLATELET AGGREGATION ARE:

• SEROTONIN AND THROMBOXANE A2 ARE POTENT VASOCONSTRICTORS THAT REDUCE BLOOD FLOW
AT THE SITE OF INJURY.
• PLATELETS ARE ATTRACTED TO THE SITE OF INJURY.
• INITIALLY, PLATELETS ARE ACTIVATED BY AND BIND TO SUBENDOTHELIAL COLLAGEN (VIA VWF);
THE EXPOSED COLLAGEN BECOMES COATED IN A LAYER OF PLATELETS.
• THE NEXT COHORT OF PLATELETS CANNOT MAKE CONTACT WITH COLLAGEN.
• THEY ARE ACTIVATED BY THE ADP MOLECULES RELEASED FROM THE FIRST COHORT OF PLATELETS.
• BINDING OF ADP CAUSES THE PLATELETS TO CHANGE SHAPE AND RELEASE MORE CHEMICALS
FROM STORAGE GRANULES.
• ACTIVATED PLATELETS EXHIBIT A GLYCOPROTEIN ILB/IIIA RECEPTOR ON THEIR SURFACE.
FIBRINOGEN AND VWF ‘GLUE’ PLATELETS TOGETHER THROUGH THIS RECEPTOR.
• MORE AND MORE PLATELETS BECOME ACTIVATED AND BIND TO THE SITE OF INJURY,
FORMING A SOFT PLATELET PLUG.
• THE SOFT PLATELET PLUG FORMED IS OFTEN NOT ENOUGH TO ACHIEVE HAEMOSTASIS–
THE PLUG MUST BE REINFORCED TO MAKE A STRONG CLOT.
• THE STRANDS OF FIBRINOGEN THAT ARE INTERWOVEN IN THE SOFT PLATELET PLUG ARE
CONVERTED TO FIBRIN (A STRONG INSOLUBLE PROTEIN) BY THROMBIN, THE END POINT
OF THE COAGULATION CASCADE.
 COAGULATION CASCADE

• A COMPLEX BIOCHEMICAL PATHWAY INVOLVING A NUMBER OF PLASMA PROTEINS,

CULMINATING IN THE FORMATION OF THROMBIN.
• IT IS AN EXAMPLE OF A BIOLOGICAL AMPLIFICATION SYSTEM: STARTING FROM A
SMALL NUMBER OF ACTIVATED MOLECULES, THE SEQUENTIAL ACTIVATION OF
CIRCULATING COAGULATION PROTEINS RESULTS IN A MAGNIFIED RESPONSE.
 CLASSICAL PATHWAY

• CLASSICALLY, THE COAGULATION CASCADE IS INITIATED BY ONE OF TWO DISTINCT

PATHWAYS: INTRINSIC OR EXTRINSIC.
• THE TWO PATHWAYS CONVERGE ON A FINAL COMMON PATHWAY, RESULTING IN
THROMBIN FORMATION.
 EXTRINSIC PATHWAY

• IT IS ACTIVATED BY TF, WHICH IS NOT NORMALLY FOUND WITHIN THE LUMEN OF

INTACT BLOOD VESSELS.
• BLOOD VESSEL DISRUPTION EXPOSES CIRCULATING CLOTTING FACTORS TO
SUBENDOTHELIAL TF: ANY FACTOR VII PASSING THE SITE OF INJURY IS ACTIVATED TO
FACTOR VIIA.
• FACTOR VIIA ACTIVATES FACTOR X, THE CLOTTING FACTOR AT THE START OF THE
FINAL COMMON PATHWAY.
 INTRINSIC PATHWAY

• IN THIS PATHWAY, IT WAS RECOGNISED THAT INITIATION OF COAGULATION DID NOT

ALWAYS REQUIRE TF, ESPECIALLY IN VITRO; PLASMA CAN CLOT WITHOUT THE
ADDITION OF ANY EXTRINSIC MATERIAL.
• THE INTRINSIC PATHWAY IS ACTIVATED BY CONTACT WITH NEGATIVELY CHARGED
SUBSTANCES SUCH AS SUBENDOTHELIAL COLLAGEN IN VIVO OR GLASS IN VITRO.
• THE INTRINSIC PATHWAY INVOLVES A NUMBER OF CLOTTING FACTORS, CULMINATING
IN THE ACTIVATION OF FACTOR X AT THE START OF THE FINAL COMMON PATHWAY.
• WHILST THE INTRINSIC PATHWAY IS NOW THOUGHT TO HAVE ONLY A MINOR
HAEMOSTATIC ROLE IN VIVO, ITS UNDERSTANDING REMAINS IMPORTANT FOR THE
INTERPRETATION OF LABORATORY COAGULATION STUDIES AND THE DIAGNOSIS OF
SPECIFIC CLOTTING FACTOR DEFICIENCIES.
NORMAL VALUE OF:
• APTT = 21 – 35 SEC
• PT = 11 – 13.5 SEC
• THROMBIN TIME = 12 – 19 SEC
• INR (RATIO OF PATIENT’S PT OVER THE CONTROL FOR NORMAL POPULATION) = 0.8 – 1.5
 FINAL COMMON PATHWAY

• ALONG WITH A NUMBER OF COFACTORS (FACTOR V, CA2+ AND PLATELET FACTOR 3,

PF3), FACTOR XA (PRODUCED BY EITHER THE INTRINSIC OR EXTRINSIC PATHWAY)
CONVERTS PROTHROMBIN (FACTOR II) TO THROMBIN (FACTOR IIA).
• THROMBIN THEN ACTS ON THE FIBRINOGEN MESH WITHIN THE PLATELET PLUG,
HYDROLYSING THE SOLUBLE FIBRINOGEN TO PRODUCE INSOLUBLE FIBRIN STRANDS.
• IN ADDITION, THROMBIN HAS OTHER KEY ROLES:
• ACTIVATION OF FACTOR XIII. FACTOR XIIIA FORMS COVALENT CROSSBRIDGES
BETWEEN FIBRIN STRANDS IN THE PLATELET PLUG, FORMING A STABLE CLOT.
• GENERATION OF A POSITIVE-FEEDBACK LOOP. THROMBIN ACTIVATES FACTORS V AND
VIII, WHICH FEED INTO THE COAGULATION CASCADE TO PRODUCE MORE THROMBIN.
• ACTIVATION OF PROTEIN C. THROMBIN FORMS A COMPLEX WITH THROMBOMODULIN
(AN ENDOTHELIAL CELL MEMBRANE PROTEIN). THE PLASMA GLYCOPROTEIN PROTEIN C
IS ACTIVATED BY THE THROMBIN–THROMBOMODULIN COMPLEX, PRODUCING
ACTIVATED PROTEIN C. ACTIVATED PROTEIN C IS AN IMPORTANT INHIBITOR OF
COAGULATION, AS IT DEACTIVATES FACTORS VA AND VIIIA.
• THESE CLASSICAL PATHWAYS EXPLAIN THE MECHANISM OF COAGULATION IN VITRO
AND REFLECT THE LABORATORY CLOTTING SCREEN.
• HOWEVER, THERE ARE A NUMBER OF FLAWS WITH THE CLASSICAL MODEL THAT HAVE
MORE RECENTLY LED TO THE DEVELOPMENT OF A CELL-BASED COAGULATION
MODEL, WHICH IS THOUGHT TO BETTER REFLECT THE MECHANISM OF IN VIVO
COAGULATION.
 CELL – BASED MODEL

• INVOLVES 3 PHASES.
• IT HAS THROMBIN AT ITS CENTER.
• THROMBIN IS INVOLVED IN ITS OWN GENERATION AND REGULATION THROUGH
FEEDBACK LOOPS, AS WELL AS THE CONVERSION OF FIBRINOGEN TO A CROSS-LINKED
FIBRIN POLYMER.
• INITIATION PHASE:

• COAGULATION IS TRIGGERED BY VESSEL DAMAGE, WHICH EXPOSES PLASMA TO

TF.
• THIS PHASE TAKES PLACE ON A TF-BEARING ENDOTHELIAL CELL.
• ANY NEARBY FACTORS V AND VII BECOME ACTIVATED AND THE GO ON TO
ACTIVATE OTHER NEARBY CLOTTING FACTORS.
• THIS CULMINATES IN THE FORMATION OF A SMALL AMOUNT OF THROMBIN.
• IN ADDITION, PASSING PLATELETS ARE ACTIVATED BY TF AND VWF AND BY THE
SMALL AMOUNT OF THROMBIN THAT HAS BEEN FORMED.
• AMPLIFICATION PHASE:

• THIS PHASE INVOLVES FURTHER ACTIVATION OF CLOTTING

FACTORS AND PLATELETS IN PREPARATION FOR THE
LARGE-SCALE GENERATION OF THROMBIN.
• PROPAGATION PHASE:

• THIS PHASE OCCURS ON THE SURFACE OF AN ACTIVATED

PLATELET LOADED WITH ACTIVATED CLOTTING FACTORS.
• WITH ALL OF ITS COFACTORS IN PLACE, THE ACTIVATED
PLATELET CAN CATALYZE THE FORMATION OF LARGE
AMOUNTS OF THROMBIN.
 REFERENCES:

• BASIC PHYSIOLOGY FOR ANAESTHETISTS BY DAVID CHAMBERS, CRISTOPHER HUANG

AND GARETH MATTHEWS SECOND EDITION 2019