Pearls from the Cascade


David M. Miller


May 22, 2020

Overview & Learning Objectives

Overview of Hemostasis
The hemostatic process often is divided into three phases:

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 cascade 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:
  1. Activating Factor XI (XI -> XIa). XIa then contributes to more IXa & thus generation of Xa. Consequently, there is more conversion of Prothrombin to Thrombin
  2. Activating platelets via PAR receptors (protease-activated receptors). Activation of platelets leads to exposed anionic phospholipids, which support the assembly of the multi-component enzyme complexes. Activating platelets secrete Factor V from their alpha granules
  3. Activating Factor VIII
  4. Activating Factor V
    (see Figure Below)

Key elements of what is referred to as “Propagation” include:

  1. Further activation of Factor Xa via activated Factor VIII (VIIIa) along with activated Factor IX (IXa)
  2. Formation of the Prothrombinase Complex, which is activated factor V (Va), activated Xa, on the platelet phospholipid surface
  3. The Prothrombinase Complex converts one molecule of Prothrombin (II) to Thrombin (IIa)
  4. Thrombin then converts Fibrinogen to Fibrin, which then undergoes polymerization
  5. Activated Factor XIII (Factor XIIIa) functions to stabilize and crosslink overlapping fibrin stands (see Figure below)

Overview of Coagulation Tests

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

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