Overview & Learning Objectives
• The vascular phase
• The platelet phase
• The plasma phase
In this lesson, we will focus on the plasma phase, in which the coagulation factors are activated
Although the Clotting Cascade is very helpful in evaluating patients with coagulopathies, it is very important to realize that In Vivo coagulation follows a very different set of pathways
We will provide a brief overview of this pathway in the section below
Conceptually, the clotting cascde has been broken down into 3 stages:
1) Initiation
2) Amplification
3) Propagation
Let’s highlight key components of those stages in the following sections
In the body, coagulation is initiated with Tissue Factor
is exposed following damage to blood vessels. Following this, TF
binds to Factor VIIa
. These are the two key entities that make up what is referred to as the Extrinsic Pathway
in the clotting cascade.
Following initiation of the Extrinsic Pathway, coagulation progresses down what is often referred to as the “Common Pathway”, in which a small amount of Factor Xa
is generated, followed by a small amount of Thrombin
(see Figure below)
As seen above,
Tissue Factor
serves as a cofactor for the production of activated factor VII (Factor VIIa
). Tissue Factor
then binds Factor VIIA
. Thus, initiation is driven by the “extrinsic” pathway, as stated above.
The Factor VIIA
/Tissue Factor
complex that was created then activates Factor IX
to IXa
This complex of Factor VIIa
as the protease and Tissue Factor
as the cofactor and Factor X
as the substrate is referred to as the Extrinsic X-ase (see Figure below)
Of note, Factor X
is also activated by activated Factor IXa
Activated X (Factor Xa
) subsequently produces small amounts of Thrombin
by activating Prothrombin
In total, Initiation only produces about 5% of the overall thrombin
The remaining 95% is generated by the `Intrinsic Pathway
There is a mechanism by which after the initial generation of thrombin, negative feedback pathways are activated via TFPI
Xa interacts with tissue factor pathway inhibitor (TFPI) and turns off the extrinsic arm (see figure below)
Thrombin
plays a pivotal role in propagating the coagulation cascade via several mechanisms:
Factor XI
(XI -> XIa). XIa
then contributes to more IXa
& thus generation of Xa
. Consequently, there is more conversion of Prothrombin
to Thrombin
Factor V
from their alpha granulesFactor VIII
Factor V
Key elements of what is referred to as “Propagation” include:
Factor Xa
via activated Factor VIII (VIIIa
) along with activated Factor IX (IXa
)Prothrombinase Complex
, which is activated factor V (Va
), activated Xa
, on the platelet phospholipid surfaceProthrombinase Complex
converts one molecule of Prothrombin
(II) to Thrombin
(IIa)Thrombin
then converts Fibrinogen
to Fibrin
, which then undergoes polymerizationFactor XIIIa
) functions to stabilize and crosslink overlapping fibrin stands (see Figure below)The whole point of these two tests is to measure how long it takes for the blood to form fibrin
The PT (or INR) measures how long it takes to form fibrin using the extrinsic system, and the partial thromboplastin time (PTT) measures how long it takes to make fibrin using the intrinsic system
To do a PT, you add something that acts like tissue factor to the blood in the test tube, and you measure how long it takes to make fibrin. This mimics what happens in the body: the blood gets “exposed” to tissue factor, and it progresses along the extrinsic pathway to make fibrin
Although challenging to memorize in the abstract, understanding the factors in
Extrinsic Pathway
, Intrinsic Pathway
and Common Pathway
is incredibly useful when trying to understand coagulopathies in clinical medicine
Understanding the different levels needed for both normal hemostasis and “normal” lab tests is also incredibly helpful
The Table below is a nice reference table to help think through problems in clinical medicine (of note, the Vitamin K Dependent Factors are in Maroon color)
Differential Diagnosis for Abnormal Coags