Control of coagulation

1. CONTROL OF COAGULATION
BY
MED. LAB. SCT. GIOVANNA, JENNIFER.
NOVEMBER, 2018

2. OUTLINE
• INTRODUCTION
• PATHOPHYSIOLOGY
• THROMBOSIS AND HEMORRHAGE
• TISSUE FACTOR PATHWAY INHIBITOR
• PLASMIN AND PROSTACYCLIN
• PROTEIN C
• PROTEIN S
• ANTITHROMBIN III
• HEPARIN AND HEPARIN COFACTOR II
• PROTEIN Z DEPENDENT PROTEASE INHIBITOR (PZI)
• CONCLUSION
• RECOMMENDATION
• REFERENCES

3. INTRODUCTION
• Coagulation is the process by which blood forms clots.
• It is an important part of haemostasis where in a damaged
blood vessel wall is covered by a platelet and fibrin-
containing clot to stop bleeding and begin repair of the
damaged vessel.
• After the activation of the blood clothing cascade, the
enzymes must be localized to the area of injury and they
must be turned off accordingly. The regulation of the
coagulation cascade is a complex process that involves
several key players.

4. EPIDEMIOLOGY
• Because most bleeding disorders are X-linked and recessive it
occurs predominantly in males. Females usually are
asymptomatic carriers.
• The world wide incidence of coagulation control defects is
approximately 1 case per 5000 male individuals, with
approximately one third of affected individuals not having a
family history.
• The prevalence rate is 20.6 cases per 100,000 male individuals
with 60% of those having severe disease.

5. PATHOPHYSIOLOGY
• Factor deficiency,
• Factor dysfunction or
• Factor inhibitors
lead to disruption of the normal coagulation cascade, resulting in
spontaneous hemorrhage and /or excessive hemorrhage in response
to trauma.

6. Fig.1.1 Blood coagulation pathways. (Furie and Furie, 2005).

7. THROMBOSIS AND HEMORRHAGE
• The coordinated interplay of the molecules mentioned
above is crucial in preventing medical conditions such as
thrombosis and hemorrhage.
• Thrombosis is the excessive formation of blood clots that
ultimately blocks the normal flow of blood. The inability of
our body to inhibits the formation of blood clots will lead
to thrombosis.
• Hemorrhage is the process by which blood leaks out of the
blood vessels. The inability of our body to form clots lead
to hemorrhage.

8. FIBRINOLYSIS
• Fibrinolytic system is a parallel
system which is activated
along with activation of
coagulation cascade and
serves to limit the size of clot.
Fibrinolysis is an enzymatic
process that dissolves the
fibrin clot into fibrin
degradation products (FDPs)
by plasmin originating from
fibrin bound plasminogen in
liver.
• This reaction is catalysed by
tPA or urokinase plasminogen
activator (u-PA) released from
vascular endothelium.

9.  TISSUE FACTOR PATHWAY INHIBITOR (TFPI)
• Tissue factor pathway inhibitor (TFPI) limits the action of tissue
factor(TF).
• This polypeptide inhibits the activity of tissue factor-factor VII
complex .
• It also inhibits excessive TF-mediated activation of factor VII and
factor X.

10.  PROTEIN C
• Protein C is a major physiological anticoagulant.
• Protein C is a serine protease with potent anticoagulant, profibrinolytic
and anti-inflammatory properties
• A vitamin K-dependent serine protease enzyme that is activated by
thrombin to form activated protein C (APC).
• It is responsible for digesting activated factors V and VIII. It acts by
inhibiting activated factors V and VIII (with protein S and phospholipids
acting as cofactors).
• and Protein C is activated in a sequence that starts with Protein C and
thrombin binding to a cell surface protein thrombomodulin.
(Thrombomodulin is a transmembrane receptor on the endothelial
cells, it prevents the formation of the clot in the undamaged
endothelium by binding to the thrombin)Thrombomodulin binds these
proteins in such a way that it activates Protein C. The activated form,
along with protein S and a phospholipid as cofactors, degrades FVa and
FVIIIa.
 Endothelial protein C receptor (EPCR) is another transmembrane
receptor that helps in the activation of protein C.

11.  PROTEIN S
• Protein S is a vitamin K-dependent glycoprotein, synthesized by
endothelial cells and hepatocytes.
• It exists in plasma as both free (40%) and bound (60%) forms
(bound to C4b-binding protein)
• The anticoagulant activity is by virtue of free form while the
bound form acts as an inhibitor of the complete system and is up
regulated in the inflammatory states.
• It functions as a cofactor to APC in the inactivation of FVa and
FVIIIa.
• It also causes direct reversible inhibition of the prothrombinase
(Fva-FXa)
• Quantitative or qualitative deficiency of either (protein C or
protein S) may lead to thrombophilia (a tendency to develop
thrombosis).

12.  ANTITHROMBIN III
• A glycoprotein synthesized in the liver that resembles the structure of 𝛼1-antitrypsin
• Antithrombin is a typical member of the serine protease inhibitor (serpin) superfamily that
degrades the serine proteases: thrombin, FIXa, FXa, FXIa, and FXIIa.
• It binds with a high affinity to thrombin and inhibits its irreversibility
• It is constantly active, but its adhension to these factors is increased by the presence of
heparan sulfate (a glycosaminoglycan) or the administration of heparins (different
heparinoids increase affinity to Fxa, thrombin, or both).
• It also blocks the enzymes of the intrinsic pathway, such as factor IX, factor X, factor XI, and
factor XII.
• Antithrombin is Heparin and endogenous endothelial heparan sulfates, which are
heterogeneous but structurally similar to heparin, accelerate antithrombin’s inhibitory
actions.
• The neutralization of proteases by antithrombin is due to a stable enzyme: antithrombin
complex that is formed by a molecular mechanism characteristic of inhibitory serpins

13.  HEPARIN
• A negatively-charged glycosaminoglycan that is released by most
cells, which are immune cells found in the tissue surrounding
blood vessels.
• It acts as an anticoagulant(a substance that prevents
coagulation; that is it stops blood from clotting) by stimulating
the binding of antithrombin III to thrombin and other serine
proteases.
 HEPARIN COFACTOR II
• A plasma protein that works with heparin to inhibit the activity
of thrombin.

14.  PLASMIN
• Plasmin (a serine protease) is generated by proteolytic cleavage of plasminogen
(a zymogen that has a high affinity for fibrin), a plasma protein synthesized in
the liver. This cleavage is catalyzed (transformed into the active form) by
tissue-type plasminogen activator (t-PA), which is synthesized and secreted by
endothelium. Plasmin proteolytically cleaves fibrin into fibrin degradation
products that inhibit excessive fibrin formation.
• Plasmin activity is tightly regulated by its inhibitors ( 𝛼2-antiplasmin) thus
preventing widespread fibrinolysis
• Once t-PA is activated, plasmin can locate fibrin clots at injury sites and
hydrolyze the peptide bonds.
 PROSTACYCLIN
• Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-
linked receptors. This, in turn, activates adenylyl cyclase, which synthesizes
cAMP. cAMP inhibits platelet activation by decreasing cytosolic levels of calcium
and, by doing so, inhibits the release of granules that would lead to activation of
additional platelets and the coagulation cascade.

15.  Protein Z dependent protease inhibitor/ protein Z (PZI)
• It is a recently described component of the anticoagulant
system that is produced in the liver.
• It inhibits factor Xa in reaction requiring PZ and calcium.

16. CONCLUSION
• Coagulation system is kept in balance by activators
and inhibitors of the cascade which serve to bring
the system back into balance.

17. Coagulation system is kept in balance by activators and inhibitors of
clotting and fibrinolysis. Clotting occurs when blood vessels are
damaged and activators of coagulation factors are released. Clotting is
controlled by fibrinolysis. Inhibitors serve to bring the system back into
balance.

18. Fig. 1.3 Coagulation with arrows for negative and positive
feedback. (Pallister and Watson, 2010).

19. RECOMMENDATION
• Further studies are needed to explore major hereditary defects
involving molecules that control coagulation and new lines of
management especially for gene therapy which is the last hope for
millions of patients for complete eradication of these disorders.

20. REFERENCES
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12-369367-9. Retrieved 18 October 2012.
David Lillicrap; Nigel Key; Michael Makris; Denise O'Shaughnessy (2009). Practical
Hemostasis and Thrombosis. Wiley-Blackwell. pp. 7–16. ISBN 1-4051-8460-4.
Davie EW, Ratnoff OD (1964). "Waterfall sequence for intrinsic blood
clotting".Science. 145 (3638): 1310–2. Bibcode:1964Sci...145.1310D.
doi:10.1126/science.145.3638.1310. PMID 14173416.
Furie B, Furie BC (2005). "Thrombus formation in vivo". J. Clin. Invest. 115 (12):
3355–62. doi:10.1172/JCI26987. PMC 1297262 . PMID 16322780.
Hoffbrand, A. V. (2002). Essential haematology. Oxford: Blackwell Science. pp. 241–
243, 243-245, ISBN 0-632-05153-1.
Pallister CJ, Watson MS (2010). Haematology. Scion Publishing. pp. 336–347. ISBN 1-
904842-39-9.
Schmaier, Alvin H.; Lazarus, Hillard M. (2011). Concise guide to hematology. Chichester,
West Sussex, UK: Wiley-Blackwell. p. 91. ISBN 978-1-4051-9666-6.

21. THANK YOU