The coagulation pathway involves both intrinsic and extrinsic pathways that activate coagulation factors in a cascade. The intrinsic pathway is initiated inside blood vessels by factor XII contacting collagen. The extrinsic pathway is initiated outside by tissue factor. Both pathways activate factor X and lead to the common pathway where thrombin converts fibrinogen to fibrin to form a clot. Healthy endothelial cells prevent clotting through mechanisms like producing nitric oxide and prostacyclin to inhibit platelets. Vitamin K is required for carboxylation of coagulation factors VII, IX, X and prothrombin to allow binding to platelet membranes and activation of the coagulation cascade. Warfarin works as an anticoagulant by blocking vitamin K and

1. Coagulation pathway

2. Thromboresistance of vascular endothelial
• Endothelial cells of blood vessels provide a selectively permeable barrier between the circulating
blood and the tissues.
• The normal endothelial cell lining neither activates coagulation nor supports platelet adhesion
• Thus, normal endothelial cell is called a nonthrombogenic surface
• Endothelial cells are highly negatively charged, a feature that may repel the negatively charged
platelets.
• Endothelial cells synthesize prostacyclin (PGI2) and nitric oxide, vasodilators and powerful
inhibitors of platelet aggregation.

3. What cause blood not clot
Antiplatelet molecules/platelet inhibiting molecules
1. Healthy endothelial cell produce antiplatelet agents called
1. Nitric oxide(NO)
2. Prostacyclin(PG-I2) and
3. ADP-diphosphatase enzyme
• These antiplatelet bind to platelets receptors and inhibits platelets bind to
endothelial lines
• ADP-diphosphatase catalyze ADP which favor platelet aggregation

4. What keeps blood not clot
2.Healthy endothelial cell also produce heparin sulfate.
 Heparin sulfate bind anti-thrombin and inhibit thrombin(factor-II), factors IX and X).
3. Healthy endothelial also synthesize Thrombomodulin.
• Thrombomodulin bind thrombin and modulate its activity
Thrombin then bind protein-C and activate it. Activated protein-C inhibit factors like V
and VII
These all above factors keeps blood uncoagulated and liquid.

5. What make blood not clot
4.Healthy endothelium produce tissue plasminogen activator(T.P.A)
• Tissue plasminogen activator bind plasminogen released by liver and convert it to plasmin.
• Plasmin take the circulating fibrin and degrade it to inhibit coagulation

6. Coagulation initiation
• When there is a damage to endothelial cell the antiplatelet or anticoagulation
properties of endothelial cell will be inhibited
• Damaged endothelial cells start to produce von Willebrand factor(VWF) that stick with
underline collagen
• VWB bind with platelet through its receptors and form process called platelet adherence
• Once vwf bind to platelet, the platelet activated, and its PLC cleaves membrane
phospholipid to arachidonic then TXA2 by cyclooxygenase.
• TXA2 has two function (vasoconstrictor and platelet aggregator)

7. Coagulation initiation
• Ca2+ used to sticks coagulating factors to each others and into phospholipid
membrane.
• Because both coagulation factors and phospholipid membranes are negatively
charged that can repeal each other and can't form aggregation.
• Aspirin inhibit COX and prevent platelet aggregation.
• alpha granules of platelet release PDGF that stimulate collagen synthesis to seal
damage
• Platelet aggregation is loose, and it is primary platelet formation

8. Hemostasis
• Haemostasis is the body's normal physiological response for the prevention and
stopping of bleeding.
• It is a complex series of events involving both cellular and plasma components
• The actual mechanism of haemostasis can be divided into two main components.
• primary haemostasis
• secondary haemostasis

9. Components of Hemostasis
1.Primary haemostasis – platelet aggregation at the site of injury to form a
temporary platelet plug.
• There are four phases involved in primary haemostasis:
1. vasoconstriction,
2. platelet adhesion,
3. platelet activation,
4. platelet aggregation.
2. Secondary haemostasis – formation of stable fibrin clot

10. Coagulation
• Is a complex physiological process by which soluble fibrinogen convert to
insoluble fibrin
• Clotting can prevent us from bleeding to death and protect us from the entry of
bacteria and viruses.
• The coagulation factors are present in circulation as inactive zymogen forms.
• They are converted to their active forms only when the clotting process is
initiated.
• This would prevent unnecessary intravascular coagulation.

11. Coagulation cascade
• The coagulation cascade is often classified into three pathways—
• the extrinsic pathway,
• the intrinsic pathway, and
• the common pathway

12. Intrinsic pathway
• It's "intrinsic" because it's initiated by a factor inside the blood vessel.
• It initiated when inactive factor XII contact with negatively charged collagen of exposed
endothelial cell
• Endothelial collagen is only exposed when endothelial damage occurs.
• Factor XIIA acts as a catalyst to activate factor XI to Factor XIA
• Factor XIA then goes on to activate factor IX to factor IXA.
• Factor IXA goes on to serve as a catalyst for turning factor X into factor Xa
• This process is known as a cascade.
• The intrinsic pathway is clinically measured as the partial thromboplastin time (PTT).

14. Extrinsic pathway
• The extrinsic pathway is triggered by a chemical called tissue factor that is
released by damaged cells.
• This pathway is "extrinsic" because it's initiated by a factor outside the blood
vessels.
• Tissue factor(TF) called factor III released from damaged endothelial .
• The source of TF is not circulating components that is why called extrinsic
• This TF activate factor VIIb to active form VIIa

15. Extrinsic pathway
• Activated factor VII activate factor X and form the rest of common pathway
• The extrinsic pathway is clinically measured as the prothrombin time (PT
• The activated factor XA, activate prothrombin (IIB) to thrombin(IIA)
• Activated factor II (thrombin) activate factor V, then activated factor V back
activate factor II
• Thrombin activate fibrinogen to fibrin(Ib-Ia)
• Common pathways: XI,II,V,I and XIII

16. Intrinsic vs extrinsic
• The intrinsic pathway consists of factors I, II, IX, X, XI, and XII. Respectively,
each one is named, fibrinogen, prothrombin, Christmas factor, Stuart-Prower
factor, plasma thromboplastin, and Hageman factor
• Extrinsic pathway consists of factors I, II, VII, and X.
• The common pathway consists of factors I, II, V, VIII, X
• The following are serine proteases: factors II, VII, IX, X, XI and XII.
• These are not serine proteases: factors V, VIII, XIII
• The factors circulate through the bloodstream as zymogens and are activated into
serine proteases.
• These serine proteases act as a catalyst to cleave the next zymogen into more
serine proteases and ultimately activate fibrinogen.

18. Negative Feedback
• To prevent over-coagulation, which causes thrombosis, there are certain processes to keep
the coagulation cascade in check.
• As thrombin acts as a procoagulant, it also acts as a negative feedback by activating
plasminogen to plasmin and stimulating the production of antithrombin (AT).
• Plasmin acts directly on the fibrin mesh and breaks it down. AT decreases the production
of thrombin from prothrombin and decreases the amount of activated factor X.
• Protein C and S also act to prevent coagulation, mainly by inactivating factors V and VIII

19. Factor Complexes
• Factors VII, IX, X, and prothrombin contain a domain in which one or more glutamate residues are
carboxylated to γ-carboxyglutamate in a reaction that requires vitamin K
• Prothrombin and factor X both contain 10 or more γ-carboxyglutamate residues that bind Ca2+.
• The Ca2+ forms a coordination complex with the negatively charged platelet membrane
phospholipids and the γ-carboxyglutamates.
• This reduce the repeal b/n carboxylated and membrane of platelet, then localize the complex
assembly and thrombin formation to the platelet surface

20. Vitamin K Requirement for Blood Coagulation
• The formation of the γ-carboxyglutamate residues on blood coagulation factors takes place in the
hepatocyte before release of the protein
• Within the hepatocyte, vitamin K is reduced to form vitamin KH2 by a microsomal quinone
reductase
• Vitamin KH2 is a cofactor for carboxylases that add a carboxyl group to the appropriate glutamate
residues in the proenzyme to form the carboxylated proenzyme
• In the same reaction, vitamin K is converted to vitamin K epoxide.
• To recover active vitamin KH2, vitamin K is first reduced to the quinone form by vitamin K
epoxide reductase, and then to the active hydroquinone form.

22. Warfarin as anticoagulant
• Warfarin (Coumadin) is a slow- and long-acting blood anticoagulant with a structure resembling
that of vitamin K.
• The structural similarity allows the compound to compete with vitamin K and prevent γ-
carboxylation of glutamate residues in factors II, VII, IX, and X and proteins C and S.
• The noncarboxylated blood clotting protein precursors increase in both the blood and plasma, but
they are unable to promote blood coagulation because they cannot bind calcium
• and thus cannot bind to their phospholipid membrane sites of activation.

24. • Cofactor Va contains a binding site for both factor Xa and prothrombin, the zymogen
substrate of factor Xa.
• Upon binding to the factor Va–platelet complex, prothrombin undergoes a conformational
change, rendering it more susceptible to enzymatic cleavage.
• Binding of factor Xa to the factor Va–prothrombin–platelet complex allows the
prothrombin-to-thrombin conversion
• Complex assembly accelerates the rate of this conversion 10,000- to 15,000-fold as
compared with non–complex formation