Coagulation cascade - Cell-based model





See Coagulation - Coagulation cascade - Cell-based model - Figure

Deficiency in classic model

The classic model cannot explain why severe deficiency in factors VIII and IX bleed spontaneously
... but deficiencies in XII, PK, HMWK do not.

NB:

  • PK = prekallikrein
  • HMWK = high molecular weight kininogen

Cell-based model

The cell-based model emphasise the roles of...

  • Factor VIIa and TF-bearing cells
    • Responsible for initiation
  • (Activated) platelets
  • The small amount of thrombin generated during the initiation phase

Contact activation (XIIa) has no role in initiating coagulation in vivo.


Coagulation is made up of 3 phases

  1. Initiation
    • Small amounts of thrombin created
  2. Amplification
    • Thrombin activates platelet, XI, VIII, V
    • TF/VIIa complex
  3. Propagation
    • Positive feedback loop by thrombin

Stage 1 - Initiation

TF-bearing cells are generally located outside the vasculature.

  • Other TF-bearing cells include:
    • Activated endothelial cells
    • Macrophages
    • Mononuclear cells

About 1% of factor VII circulates in the activated form (factor VIIa)

Step 1

When injury occurs, blood is exposed to tissue factors.

Factor VIIa rapidly binds to TF, forming TF / VIIa complex

NB:

TF / VIIa complex - aka extrinsic tenase complex

Step 2

The TF/VIIa complex then activates:

  • Factor VIIa (positive feedback)
  • Factor IXa (small amounts)
  • Factor X (small amounts)

Generation of factor IXa by TF / VIIa complex is...

  • A new step not present in the classical system.
  • i.e. earlier part of the intrinsic pathway is bypassed
  • The predominate action of TF / VIIa compex once factor V and VIII are activated.

At later stage, TF / VIIa complex will continue to provide some factor Xa, but factor Xa will mostly be provided by the intrinsic tenase complex (i.e. Xa / Va complex)

Step 3

Factor Xa activates factor V directly (but slowly).

These factor Va then binds to factor Xa to form prothrombinase complex (Xa/Va)

Step 4

Small amount of thrombin is generated by the Xa/Va complex

NB:

Amount of thrombin generated here is insufficient to convert fibrinogen to fibrin, but is sufficient to allow amplification to occur (if platelets can be found nearby).

Coagulation can NOT progress further beyond the initiation stage, unless platelets can leave vascular space and adhere to TF-bearing cells in the extravascular space

Stage 2 - Amplification

Thrombin diffuse away from TF-bearing cells

If there are platelets nearby, thrombin will bind to platelet surface receptors and cause platelet activation.

Otherwise thrombin will be inactivated quickly.


Activation of platelets results in:

  • Change in shape
  • Change in membrane phospholipid to procoagulant surface
  • Release of granules
    • Some contents will activate other platelets


In addition to platelet activation, thrombin will also activate:

  • Factor V
  • Breaks up the VIII / vWF complex
    • vWF is released
    • Factor VIII is then activated by thrombin
  • Factor XI

Stage 3 - Propagation

The propagation phase occurs on the surface of activated platelets.

Thrombin creates a positive feedback loop by activating

  • Factor XI
  • Factor VIII
  • Factor V

Factor IXa (generated by factor XIa and by TF / VIIa complex) binds to factor VIIIa to form tenase complex (which activates factor X)

Factor Xa binds to factor Va to form prothrombinase complex (which converts prothrombin into thrombin)

Thrombin leads to clot formation by:

  • Converting fibrinogen to fibrin
  • Activating factor XIII (which in turn leads to cross-linkage in the fibrin clot).

See Coagulation factors - Thrombin

Control of thrombin generation

Role of endothelial cells

Intact endothelial cells

  • Do NOT support coagulation reaction
  • Express proteins that are actively anticoagulant

These proteins include:

  • HSPG = heparin sulphated proteoglycans
  • TM = Thrombomodulin
  • TFPI = tissue factor pathway inhibitor

HSPGs

HSPGs are a binding site for antithrombin (AT)

HSPG-AT complex inactivates thrombin - similar to heparin-AT complex (which are not membrane-bound)

Thrombomodulin

Thrombin binds to thrombomodulin. The complex then rapidly activates protein C, which in turn inactivates factor Va and VIIIa

TFPI

Inhibits:

  • Factor Xa
  • Factor VIIa

When coagulation factors diffuse away from site of injury

When factor Xa moves away from TF bearing cell surface, it is rapidly inactivated by TFPI or AT.

Same occurs with thrombin.

However, factor IXa can move away. It is not inhibited by TFPI, and much more slowly inhibited by AT.

Reference:

A&A 2009