Biochemistry of the blood coagulation system

Overview
Blood clotting has two components fibrin formation and platelet activation. When there is a blood vessel
injury, it activates the coagulation cascades and platelets. Coagulation cascades then convert prothrombin to
thrombin, which in turn converts fibrinogen to fibrin. The fibrin forms a polymer and stabilise the platelet
plug.
Regarding the structures of coagulation factors, they can be cleaved for activation and possess a serine
protease to activate the cascades.

Intrinsic & extrinsic pathways

The extrinsic pathway is triggered by tissue factor: VIIa complex. Tissue factor is located in the tissue
adventitia and expressed in most cells except endothelial cells. Once it is exposed to intravascular space after
vascular injury, it interacts with factor VIIa and forms a complex. The complex is strongly active and activate
factor X (as in extrinsic pathway) and factor IX (as in intrinsic pathway).

Positive feedback loops

Factor Xa
A positive feedback loop is involved in the initiation of coagulation cascade. The activation of factor X is a
self-strengthening process.
Factor X Xa (by TF:VIIa)

Factor IX IX-alpha (by factor Xa)

Factor IX-alpha IXa (by TF:VIIa)

Factor X Xa (by factor IXa)

Factor Xa is used to activate prothrombin or convert factor IX into factor IX-alpha

Thrombin
The activation of prothrombin also helps augment the effect of blood clotting. Thrombin converts:
Factor XI Xia
Factor VIII VIIIa
Factor V Va

Other co-factors
The following conversions are essential for the cascade, involveing factor IXa, Xa and thrombin.
Factor VIII is activated by factor IXa, Xa and thrombin.
Factor V is activated by factor Xa and thrombin.

Role of platelets
The inner surface of blood vessels is lined with a thin layer of endothelial cells that, in normal hemostasis, acts
to inhibit platelet activation by producing nitric oxide, endothelial-ADPase, and PGI2. Endothelial-ADPase
clears away the platelet activator, ADP.

Endothelial cells produce a protein called von Willebrand factor (vWF), a cell adhesion ligand, which helps
endothelial cells adhere to collagen in the basement membrane. Under physiological conditions, collagen is
not exposed to the bloodstream. vWF is secreted constitutively into the plasma by the endothelial cells, and is
stored in granules within the endothelial cell and in platelets.

Platelet activation and adhesion

When a platelet encounters a break in the endothelium, it encounters molecules that trigger its activation. One
such molecule is collagen, which is characteristically found almost everywhere except inside a blood vessel.
In addition, thromboxane A2, ADP and thrombin are other factors that trigger the same activation. Also, vWF
and tissue factor from the subendothelium are exposed to the bloodstream.
Platelet activation has the following events:
Exocytosis of the dense granules and alpha granules.
Activation of the membrane enzyme phospholipase A2. This leads to the formation of thromboxane A2
(TXA2)
Change in shape to a more amorphous form with projecting fingers.
Platelet adhesion is caused by the binding of fibrinogen by glycoprotein IIb/IIa.
Adhesion to collagen under the broken endothelium is caused by the binding to vWF receptor.
Coagulation reactions are promoted at the surface.

Von Willebrand factor

vWF binds to a number of cells and molecules:
Factor VIII is bound to vWF while inactive in circulation; factor VIII degrades rapidly when not bound to
vWF. Factor VIII is released from vWF by the action of thrombin.
vWF binds to collagen, e.g., when collagen is exposed in endothelial damage.
vWF binds to platelet GPIb, as GPIb-V-IX complex allows platelet adhesion

Phospholipid redistribution
Platelet activation further results in the floppase-mediated transport of negatively charged phospholipids to the
platelet surface. These phospholipids provide a catalytic surface (with the charge provided by
phosphatidylserine and phosphatidylethanolamine) for the tenase and prothrombinase complexes. Calcium
ions are essential for binding of these coagulation factors.
Tenase activate FX, i.e. (FIXa + FVIIIa) or (TF + FVII + Ca2+)
Prothrombinase activate prothrombin, i.e. (FXa + FVa)

Control of coagulation
Five mechanisms keep platelet activation and the coagulation cascade in check:

Protein C is activated by thrombin which binds to thrombomodulin on endothelial cell surface. Activated
Protein C, along with protein S, degrades FVa and FVIIIa. Also, activated Protein C cleaves FV to form
FVac (anticoagulant) to deactivate FVIII.

Antithrombin is a serpin that inhibits thrombin and FXa. With heparin on endothelial cells, it forms
complexes with thrombin or FXa to reduce thrombotic activity.

Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). It also inhibits excessive TFmediated activation of FVII and FX.

Prostacyclin (PGI2) is released by endothelium and inhibits platelet response (activation and release of
granules) via signal transduction.

Plasmin is activated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver.
This activation is done by tissue plasminogen activator (t-PA), which is synthesized and secreted by
endothelium. Plasmin degrades fibrin into soluble fibrin fragments.

Vitamin K
Vitamin K (in animals) is involved in the carboxylation of certain glutamate residues in proteins to form
gamma-carboxyglutamate (Gla) residues. Gla residues are usually involved in binding calcium. It plays a key
role in many biological processes, for example, blood coagulation (prothrombin, factors VII, IX, and X, and
proteins C, S, and Z).