BLOOD COAGULATION

Intrinsic pathway/Contact activation pathway

ACTIVATION OF CONTACT SYSTEM

Formation of the primary complex on collagen by high-molecular-weight

kininogen (HMWK), prekallikrein, and FXII (Hageman factor)
FXII becomes FXIIa
Prekallikrein is converted to kallikrein

CASCADE

FXIIa converts FXI into FXIa.

Factor XIa activates FIX,
FIXa with its co-factor FVIIIa form the tenase complex on platelet
Activates FX to FXa

The intrinsic pathway (also called the contact activation pathway) is much less
significant to haemostasis under normal physiological conditions than is the extrinsic
pathway. The minor role that the contact activation pathway has in initiating clot
formation can be illustrated by the fact that patients with severe deficiencies of FXII,
HMWK, and prekallikrein do not have a bleeding disorder. However, ICC seems to
be more involved in abnormal physiology states as in hyperlipidemic condition or
bacterial infiltration which lead to activation of thrombosis.
The intrinsic pathway requires the clotting factors VIII, IX, X, XI, and XII, proteins
prekallikrein (PK) and high-molecular-weight kininogen (HK or HMWK), as well as
calcium ions and platelet phospholipids.

Contact phase
Initiation of the intrinsic pathway occurs when prekallikrein, high-molecular-weight
kininogen, factor XI and factor XII are exposed to a negatively charged surface. This
is termed the contact phase and can occur as a result of interaction with
(negatively charged surfaces like) the phospholipids of circulating lipoprotein
particles such as chylomicrons, VLDLs, and oxidized LDLs (this is the basis of the role
of hyperlipidemia in the promotion of a pro-thrombotic state and the development
of atherosclerosis) or even due to the surface of bacteria, and through the
interaction with urate crystals, fatty acids, protoporphyrin, amyloid , and
homocysteine.

The plasma kinin forming system is called the contact system of plasma and is
composed of factor XII, factor XI, prekallikrein and HMWK. Factor XII, prekallikrein,
and HMWK saturably and reversibly bind to endothelial cells, platelets, and
granulocytes in a zinc-dependent reaction. Factor XII and HMWK are attracted to
negatively charged surfaces. HMWK has domains with binding sites for negativelycharged surfaces, prekallikrein and factor XI. When plasma makes contact with a
negatively charged surface, factor XII binds and is autoactivated to factor XIIa.
Factor XIIa then activates prekallikrein to kallikrein and kallikrein cleaves HMWK
releasing bradykinin. There is also reciprocal activation of factor XII by kallikrein
resulting in amplification of the system. Once the contact system is activated the
intrinsic pathway (described below) is initiated.
Cascade activation
The assemblage of contact phase components results in:
Conversion of prekallikrein to kallikrein activation of factor XII to factor
XIIaactivation of factor XI to factor XIa; Factor XIIa will also hydrolyze more
prekallikrein to kallikrein, establishing a reciprocal activation cascade. Kallikrein acts
upon HMWK leading to the release of bradykinin, a potent vasodilator. (In the
presence of Ca2+), factor XIa activates factor IX to factor IXa. Factor IX is a
proenzyme that contains vitamin K-dependent -carboxyglutamate (gla) residues,
whose serine protease activity is activated following Ca2+ binding to these gla
residues. Several of the serine proteases of the cascade (II, VII, IX, and X) are glacontaining proenzymes. Active factor IXa cleaves factor X, leading to its activation
to factor Xa. The activation of factor Xa requires assemblage of the tenase complex
(Ca2+ and factors VIIIa, IXa and X) on the surface of activated platelets. One of the
responses of platelets to activation is the presentation of phosphatidylserine (PS) and
phosphatidylinositol (PI) on their surfaces. The exposure of these phospholipids allows
the tenase complex to form. The role of factor VIII in this process is to act as a
receptor, in the form of factor VIIIa, for factors IXa and X. Factor VIIIa is termed a
cofactor in the clotting cascade.
FXa in turn binds FVa, a membrane- associated cofactor, to form the prothrombin
activator complex (composed of FVa, FXa, FVIIIa and platelet cell surface
phopsholipids)
Homeostatic mechanism within intrinsic pathway
The activation of factor VIII to factor VIIIa (the actual receptor) occurs in the
presence of minute quantities of thrombin. As the concentration of thrombin
increases, factor VIIIa is ultimately cleaved by thrombin and inactivated. This dual
action of thrombin, upon factor VIII, acts to limit the extent of tenase complex
formation and thus the extent of the coagulation cascade.
The Intrinsic mechanism of Prothrombin activator formation begins with trauma to the
blood - PF3 (Platelet Factor-3) secreted from platelets. ???

Haemostasis

Vasoconstriction (direct response of vascular smooth muscle injury and plateletreleased vasoconstrictors like serotonin)
Platelet plug formation (platelet adhesion, activation and aggregation)
Consolidation of platelet plug (clot formation by fibrin cross-linking)
Clot retraction (contraction of platelets due to integrins (that attach) and the
actin/myosin filaments (contractile proteins) which pull wound edge together)
Fibrinolysis (dissolution of clot following tissue healing)

Platelet adhesion
The von Willebrand factor (vWF), is a glycoprotein present in the plasma as well as
secreted by the vascular endothelial cells and the platelets. On exposure to
subendothelial collagen fibres, following vessel disruption, the circulating vWF binds
to it. The binding produces a conformational change in the glycoprotein such that it
can bind to platelet integrin GP Ib. Thus vWF binds platelets and anchors them to the
injured vessel wall.
Platelet activation
The binding of Vwf onto the GP Ib integrins on the platelets, initiates a G proteincoupled intracellular signalling pathway, that ultimately leads to the release of Ca2+
ions from the dense tubular system into the cytosol. The rising cytosolic concentration
of Ca2+ ions result in the following responses:

Actin/myosin contraction
Reorganisation of microtubules
Ca-mediated exocytosis/discharge of granules
Reorganisation of membrane proteins (new integrin GPIIb-IIa exposed)
Formation of thromboxane A2

Platelet aggregation
The newly exposed integrins GPIIb-IIa, on the activated platelet membrane binds to
thrombospondin (an adhesive protein secreted by the platelets) and fibrinogen
molecules. The fibrinogen and the thrombospondin molecules on the different
platelet surfaces, cross-link and result in platelet aggregation.