Physiology of Coagulation

Introduction

Coagulation is a complex process by which blood forms clots.

An important part of hemostasis.

The process is described in 2 steps:

PRIMARY

SECONDARY

Primary Hemostasis

Initiated within seconds.

Short lived.

Results in a soft platelet plug to seal the breach

in the vessel wall.

Primary Hemostasis

Step 1: Local Vasoconstriction

Step 2: Platelet adhesion and formation of soft platelet plug

Primary Hemostasis

Secondary Hemostasis

Platelet Membrane

Coagulation Factors

Co-factors

Role of Vitamin K

Vitamin K Oxido- Reductase

γ-Carboxylation

Evolution of Coagulation Theories

Both pathways are initiated independently and

Unite only at Factor X (FX) and Factor V (FV) level

CL

AS

SIC

AL

CO

AG

UL

AT

ION

CA

SC

AD

E

Pitfalls in cascade model

Cell Based Model of Coagulation

D. Monroe M. Hoffman

Proposal

The cascade is a biochemical model.

NOT a true reflection of what happens in the body.

Differences in these models

Cell Based Model of Coagulation

Initiation

[TF Cell]

Amplification

[Platelet]

Propagation [Active Platelet]

Stabilization

of Clot

Inhibition of Further

Coagulation

Five Steps Two Cells

What is Tissue Factor?

Initiation

TF-VIIa Complex

Activation of FX & FIX: FXa & FVa convert small amount of Prothrombin to Thrombi

Amplification

1

2

3

Propagation

THROMBIN

Clot formation

XIII aXIII

Fibrinogen Fibrin monomer Cross-linked mesh

Inactive Platelet Activated Platelet

Result !!

Inhibitors of Coagulation

• Inhibition of the TF-VIIa complex.

• Binds to directly inactivate thrombin as well as the factors (IXa, Xa, and XIa).

• Catalyses:Plasminogen Plasmin

Inhibitors of Coagulation

• Protein C is activated when thrombin binds to thrombomudulin.

• Protein S boosts the activity of Protein C.

• Jointly, they inactivate Factor Va & VIIIa.

• Plasmin degrades fibrin strands. Prevents build-up of excess clot.

Fibrinolytic System

Fibrinolysis R

ED

: S

UP

RE

SS

ES

BL

UE

: A

CC

EL

ER

AT

ES

Tissue Plasminogen

Activator [tPA]

α2 Antiplasmin Α2 Macroglobulin

Plasminogen Activator Inhibitor 1&2

Thrombin Activatable Fibrinolysis Inhibitor

Factor XIa, XIIa, Kallikrein

Urokinase

THROMBIN

Injury to vessel

Platelet activation by contact to endothelium & subendothelium, →formation of Platelet Plug

Coagulation pathway Activation → generation of thrombin & fibrin clot → Platelet Plug Stabilization

Fibrinolysis & Clot Removal

Control of clot extension by antithrombotic mechanisms

Healing & Repair of injury