Normal Hemostasis

Maintenance of fluidity of blood while in vessel and formation of hemostatic plug on vascular injury

Steps in hemostasis:

1.Vasoconstriction due to local neural response, and release of endothelin from the endothelium

2.Primary hemostatic plug: due to platelet adhesion, activation, degranulation(ADP, TXA2) and recruitment of other platelets

3.Secondary hemostasis due to activation of coagulation cascade by tissue factor and phospholipid via extrinsic pathway- the end result being fibrin which traps the cells in the blood forming a clot

4.Counter regulation:

a.t-PA which activates plasmin( fibrinolytic cascade)
b.PAI: plasminogen activator inhibitor
c.Antithrombin III, protein c, protein S, thrombomodulin, PGI2, nitric oxide and ADPase

As a result of neurogenic reflex mechanism, there is a brief period of vasoconstriction added by local release of endothelin from the injured endothelium of blood vessel
Steps in primary hemostatic plug formation

Tissue factor synthesized by endothelium is released at the site of vascular injury
Activates co-agulation cascade
Activation of thrombin


cleaves fribinogen to fibrin and the fibrin is deposited at the site of injury
Further plaelet recruitment occurs
Other blood cells like RBCs and WBCs are also recruited leading to formation of thrombotic plug

t-PA which activates plasmin( fibrinolytic cascade)
PAI: plasminogen activator inhibitor
Antithrombin III, protein c, protein S, thrombomodulin, PGI2, nitric oxide and ADPase

Hemostatic Balance

Maintained by balance between anti-coagulant and pro coagulant factors dependent upon three general components
Blood vessel endothelium
Co-agulation cascade


Endothelial cells modulate both Antithrombotic and Prothrombotic activities.

ANTI-Thrombotic Properties

Anti-platelet effects – Intact epithelium, NO, PGI2, ADPase

Anti-coagulant effects
HEPARIN-like molecules expressed on endothelial membrane – cofactors for antithrombin III to inactivate thrombin and other factors like IXa and Xa
Thrombomodulin expressed on endothelial surface binds thromin and the complex
Activates protein C which in presence of protein S breaks Va and VIIIa
Tissue factor pathway inhibitor

Fibrinolytic effects - t-PA synthesized by endothelial cells promote fibrinolytic activity to clear fibrin deposits from endothelial surfaces


Exhibited when there is endothelial injury (Endothelial denudation is not essential)
Factors favoring it are-
Platelet effect - vWF
Pro-coagulant effect – bact. Endotoxin or cytokines synthesize Tissue factor
Anti-fibrinolytic effect - PAIs


two specific types of granules


express the adhesion molecule P-selectin on their membranes and contain

factors V and VIII,
platelet factor 4 (a heparin-binding chemokine),
platelet-derived growth factor (PDGF),
transforming growth factor α (TGF-α)

Dense bodies, or δ granules :
ionized calcium,

On contact with ECM constituents, platelets undergo 3 reactions:

1) ADHESION and shape change
2) SECRETION (release reaction)


To sub-endothelial ECM constituents
Bridged by vWF, a product of endothelial cells
Platelet attaches to it via GpIb receptor


Occurs soon after adhesion
initiated by the binding of agonists to platelet surface receptors followed by an intracellular phosphorylation cascade
Release of delta granules is more important particularly of ADP and calcium
ADP activation of platelets is essential for platelet aggregation, further release of ADP and phospholipid complex expression


Apart from ADP, TXA2, a product of platelet set up an autocatalytic reaction leading to build-up of an enlarging platelet aggregate, the primary hemostatic plug
Thrombin from coagulation cascade binds to a platelet surface receptor (PAR) and with ADP and TXA2 causes further aggregation.

Followed by platelet contraction, creating an irreversibly fused mass of platelets ("viscous metamorphosis") constituting the definitive secondary hemostatic plug.

At the same time, thrombin converts fibrinogen to fibrin within and about the platelet plug, essentially cementing the platelets in place

ADP activation of platelets induces a conformational change of the platelet surface exposing GpIIb-IIIa receptors so that they can bind fibrinogen. Fibrinogen then acts to connect multiple platelets together to form large aggregates.

Coagulation Pathway

The coagulation cascade is essentially a series of enzymatic conversions, turning inactive proenzymes into activated enzymes and culminating in the formation of thrombin.
Thrombin then converts the soluble plasma protein fibrinogen into the insoluble fibrous protein fibrin.

Each reaction in the pathway results from the assembly of a complex composed of :
enzyme (activated coagulation factor),
a substrate (proenzyme form of coagulationfactor),
a cofactor (reaction accelerator).

These components are assembled on a phospholipid complex and held together by calcium ions.

Once activated the coagulation cascade must be restricted to the local site of vascular injury to prevent clotting of the entire vascular tree.
Regulated by three types of natural anticoagulants

Anti thrombin III
Protein C and Protein S

With onset of coagulation cascade, fibrinolytic cascade is also activated to limit the the size of final clot
Primarily accomplished by plasmin


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