So remember the coagulation cascade has a domino effect. Once the first factor in the cascade is activated it will activate the next factor and so on. Let’s start at the end of the cascade with our final coagulation factor fibrinogen. What is fibrinogen and what does it do?

We know from primary hemostasis that fibrinogen participates in platelet aggregation by binding platelets together via the platelet receptor GP2b/3a. Fibrinogen is also the inactivated form of fibrin. When fibrinogen is activated it forms fibrin. Multiple cross-linked fibrin proteins combined with platelets create a clot! Where does fibrinogen come from?

Fibrinogen originates in the liver and is synthesized by hepatocytes, aka liver cells. hepato = of or relating to the liver, cytes = cells. Take good care of your liver! Fibrinogen floats around freely in the bloodstream. Think of it as one of those unmelted glue sticks from a glue gun waiting to be used. Ok, so how does fibrinogen become activated?

Before we get to how fibrinogen is activated, it’s important to understand the nomenclature of the coagulation cascade. Most factors go by their number for the inactivated form and by the number with an “a” for the activated form but a few factors like fibrinogen and prothrombin don’t usually go by their numbers so here’s a table below to use as a reference to avoid confusion.

Factor	Inactivated	Activated
1	Fibrinogen	Fibrin
2	Prothrombin	Thrombin
7	7	7a
9	9	9a
10	10	10a
11	11	11a
12	12	12a

(Most texts and references will also use roman numerals, for simplification I just use regular numbers.)

Now that we’re clearer on the nomenclature let’s get back to how fibrinogen becomes activated. If you look at the cascade above, fibrinogen is activated by factor 2, and since it must be the activated form, fibrinogen is activated by thrombin. (Remember inactive forms are just floating around in the blood stream ready to be activated if needed). So to quickly summarize, in the end stages of the coagulation cascade, thrombin activates fibrinogen which becomes fibrin which becomes a clot! Now that we understand how the cascade generally works and what the end product is, let’s start from the top of the cascade.

The cascade can be started by two pathways, the intrinsic pathway and the extrinsic pathway. As you can see above, both pathways flow to factor 10. Factor 10 on down is referred to as the common pathway because it’s common to both pathways! Let’s start with the extrinsic pathway.

The extrinsic pathway is activated when there is a break in a blood vessel wall allowing tissue factor (TF) which is present in subendothelial tissue to enter the blood stream. TF and calcium ions activate factor 7. TF can have multiple names and this is where some confusion can come in. TF can also be called factor 3 (rarely) or when combined with phospholipids can be referred to as thromboplastin.

So once factor 7 is activated, it forms a complex with TF which activates factor 10 of the common pathway which we will get to soon!

The intrinsic pathway is activated when factor 12 comes in contact with collagen, phospholipid, or subendothelium. This activates factor 12 which in combination with prekallikrein and high molecular weight kininogen (HMWK) activate factor 11. Prekalli-what?

Prekallikrein is a serine protease enzyme, and high molecular weight kininogen (HMWK) acts as a cofactor and both are referred to as contact factors (more on these later). Prekallikrein and HMWK both normally circulate in the blood stream. Basically, factor 12a, prekallikrein and HMWK activate factor 11. Factor 11a and calcium then activate factor 9. Factor 9a in the presence of factor 8 activates factor 10. Now we are back at the common pathway!

Quick note, factor 12a and HMWK convert prekallikrein to kallikrein, and via a positive feedback loop, kallikrein will catalyze the conversion of factor 12 to 12a. This strongly upregulates the pathway.

The common pathway, as we just learned, can be activated by the intrinsic or extrinsic pathway. Once activated, factor 10a, factor 5, and calcium convert prothrombin to thrombin. Thrombin, as we talked about earlier, converts fibrinogen to fibrin which will make a clot. Yes! However, thrombin has more responsibility than converting fibrinogen to fibrin and is one of the most important molecules in hemostasis. Here are its three main functions:

1. Thrombin converts fibrinogen to fibrin

2. Thrombin activates factors 8 and 5. (this upregulates the thrombosis/clotting process and really gets things going)

3. Thrombin helps stabilize fibrin monomers by activating factor 13. Factor 13a cross links fibrin monomers to form a stable fibrin clot.

Ok this is all great but where do all the factors come from and what are they?

Just like fibrinogen, all but one of the factors are made in the liver. The one factor that is not made in the liver is von Willebrand Factor which is made in endothelial cells. The factors can be further divided up into subgroups based on their function:

1. Substrate (substance upon which enzymes act) – fibrinogen

2. Cofactors (accelerate enzymatic reactions) – factors 3, 5, and 8

3. Enzymes

a. Serine proteases (cleave peptide bonds) – factors 2, 7, 9, 10, 11, 12, and prekallikrein

b. Transaminase (catalyzes reaction) – factor 13

Sometimes coagulation factors are grouped into the contact, prothrombin, and fibrinogen groups, what does that mean?

Factors can also be grouped by their physical properties. It’s important to put factors into different groups to recognize systemic patterns and help diagnose what is wrong with a patient.

1. Contact group – factors 11, 12, prekallikrein, and high molecular weight kininogen (HMWK). All of these factors are involved in the initial phase of the intrinsic system activation.

2. Prothrombin group – factors 2, 7, 9, and 10. These factors are also known as the vitamin K dependent factors (more on this later). It is called the prothrombin group because all of the factors have a similar biochemical resemblance to prothrombin, multiple glutamic acid units near the N-terminus.

3. Fibrinogen group – factors 1, 5, 8, and 13. This group is called the fibrinogen group because thrombin activates all of these factors including fibrinogen. Maybe it should have been called the thrombin group but unfortunately a lot of coagulation does not make logical sense at first glance. The clotting factor numbers are actually in order of their discovery and that’s why they are in such an odd order.

Why is it important to know if factors are vitamin K dependent? What role does vitamin K play in the coagulation process?

Vitamin K is necessary for the carboxylation of glutamic acid present on certain factors. Huh? What? This biochemical change of the factors makes them active factors. Without vitamin K they would remain inactive.

Ok, so now we have a basic understanding of how platelets form a plug, and how the cascade forms a clot. After the clot is formed and the bleeding has stopped, the coagulation cascade needs to stop and the clot needs to be removed.