At some point or another, there is a strong probability that we have all seen that dreaded flow chart. You know, the one with all the roman numerals that looks like it was created with the sole intent of confusing us. The one that we try to memorise but secretly hope that no one ever asks us about it. Do you know the one I’m talking about? That’s right; the dreaded coagulation or clotting cascade! And this article is going to simplify it to a point that you not only get it, but remember it as well!
What is involved with the clotting cascade?
The body is a complex and beautiful thing with processes in place that are nothing short of amazing. The clotting cascade is no exception. It is no secret that the clotting cascade is complex and the extremely smart people that figured it out over time deserve a huge round of applause (amongst the numerous grants and awards they probably received)! The image below outlines all the processes involved in the coagulation pathway in order for the body to form a blood clot:
Why should I invest my time learning about the clotting cascade?
The processes of the clotting cascade can be mind numbingly confusing! Whenever I tell people that we are doing an education session on the clotting cascade, I get a unified groan. Well, hopefully it is the clotting cascade and not me personally that elicited those unhappy groans. But I understand their frustration with having to learn about something with no perceivable practical purpose. After all, isn’t it all just roman numerals scattered over a dedicated page in a text book that we haven’t read for a while? Why would anyone invest their time trying to understand such concepts if there is no clinical relevance for it? However, what if the clotting cascade was simplified to a point that made it practical and useful to you? What if it was tailored to be clinical relevant to you and helped you with the management of a patient with coagulation issues?
How can the complex processes involved within the clotting cascade be simplified?
- There are 13 clotting factors that are labelled with roman numerals
- We are now in 2016 and we are going to use simple numerics in our simple flow chart
- Each of the 13 clotting factors have an inactivated form (roman numeral) that is converted into an activated form (roman numeral with a little “a” at the end)
- We are going to assume that the whole point of the clotting cascade is to activate the clotting factors, thereby making the little “a” redundant
- We are going to remove any numbers with an “a” at the end from our simple flow chart and assume that the singular number we now see denotes that the relevant inactive clotting factor has been activated
- There are a lot more clotting proteins and factors involved in the clotting cascade in addition to the 13 main clotting factors denoted by roman numerals
- We are going to focus on the ones that are clinically relevant to us at the bedside in our simple flow chart
What activates the clotting cascade?
If there is damage directly to the blood vessel, the underlying collagen is exposed to the circulating platelets within the blood stream. Platelets bind directly to the collagen and create a “platelet plug”. This adhesion is strengthened further by von Willebrand factor (vWF) that helps form additional links between the platelets and collagen. All of this is a temporary measure that occurs while the clotting cascade is triggered in order to strengthen the platelet plug into a clot, as shown in the simple flow chart below:
There are two pathways involved with the clotting cascade that meet at a certain point to become a common pathway. The intrinsic pathway is activated by damage directly to the blood vessel and the exposure of collagen to the circulating platelets within the blood. The extrinsic pathway is activated by many things including damage directly to the blood vessel, tissue damage outside of the blood vessel, hypoxia, sepsis, malignancy and inflammation. I tend to remember the intrinsic pathway as the injury pathway, and the extrinsic pathway as the everything pathway.
In the past, it was believed that the intrinsic and extrinsic pathways were parallel to each other and played an equal role in the coagulation process. It is now believed that the extrinsic pathway is more dominant, acting as the “spark” that kick starts the coagulation process. When thrombin is activated via the extrinsic pathway, it is usually quickly deactivated by the opposing anticoagulation pathways within the body that aim to maintain a balance. Therefore, thrombin needs to call a few friends to boost the coagulation effect within the body. Thrombin activates the intrinsic pathway through the activation of factor 8 and 11. It also activates factor 5, 7 and 13 thereby increasing the coagulation effects of the extrinsic and common pathways. Despite the intrinsic pathway being activated as a result of the extrinsic pathway being activated, the intrinsic pathway still has the ability to be independently activated secondary to the exposure of collagen to the circulating platelets within the blood.
How do I easily remember which clotting factor goes where?
I have found that people tend to remember things better, especially numbers, when there is a pattern associated with it. It is important to note that the only clotting factor that I have utilised a roman numeral for in the simple flow chart above is factor X (10). I have done this on purpose to remind everyone that this is the cross road where the intrinsic and extrinsic pathways meet, thereby becoming the common pathway from that point onwards.
Let’s do the intrinsic pathway first: 12 → 11 → 9 → 10. The pattern?
- Split 12 into two numbers; 1 and 2
- First, minus 1 to get from 12 to 11
- Then, minus 2 to get from 11 to 9
In order for factor 9 to activate factor 10, there needs to be factor 8 present. The pattern?
- Count 8, 9, 10
- You need 8 to get 9 to activate 10
Let’s do the extrinsic pathway second: 3 → 7 → 10. The pattern?
- Split the 12 from the intrinsic pathway again into two numbers; 1 and 2
- Add them together so that 1 + 2 = 3
- In order to get to 10, you need 7 more
In order for these patterns to work, the only clotting factor that you need to commit to memory is factor 12. The easiest way to remember this is that intrinsic starts with “I”, which points straight up like the hands of a clock at 12 o’clock.
Both the intrinsic and extrinsic pathways lead to factor 10, which is the start of the common pathway. The two key players in the common pathway are thrombin and fibrin. Fibrin is the most important part of the clotting cascade because fibrin is what traps the platelets, and is therefore clotting factor number 1. Thrombin is the second most important part of the clotting cascade because it activates just about everything, and is therefore clotting factor number 2. Both these activated factors have inactivated factors that come just before them. These inactivated forms sound very similar to their activated counterparts. Fibrin (activated factor 1) has fibrinogen (inactivated factor 1), and thrombin (activated factor 2) has prothrombin (inactivated factor 2). Just think of these inactivated forms carrying around additionally baggage, and once you cut off the additional baggage they are able to do what they are suppose to do. Thrombin comes before fibrin, so cut off “pro” as it comes before. Fibrin comes after thrombin, so cut of “ogen” as it comes after. Can’t remember whether it is thrombin or fibrin that comes first? Back at the start when we talked about how factor 3 is generally the “spark” that starts it all? Well, factor 3 is more commonly known as tissue factor 3 or simply as tissue factor (TF). What ends it all also goes in order of TF: thrombin –> fibrin! Once fibrin is activated, the fibrin fibres needs to stick to each other to form a fibrin net that is able to catch the platelets that are circulating within the blood stream. In order for fibrin to stick to each other, there needs to be factor 13 present. Think of factor 13 being the final clotting number and therefore, the final step to solidifying the clotting process!
In terms of the clotting factors activated by thrombin, it is pretty much all of the uneven numbers starting upwards from 5. This applies to everything but 9, because it just cannot be THAT simple! So just replace 9 with 8 instead and that gives you clotting factors 5, 7, 8, 11, 13. The other important component within the clotting cascade is calcium, also known as factor 4. If you’re living in Australia, there is a really easy way to remember which 4 factors require calcium to become activated. Remember the old television stations? Channel 2, 7, 9 and 10? Any arrows found between the factors 2, 7, 9 and 10 require calcium to continue the clotting cascade. These are also known as your vitamin K dependent clotting factors; your Australian old television channels. From the simple flow chart above, it is easy to see that the clotting process can be severely stunted without calcium present. It is for this reason that citrate is added to stored blood bags; it binds to calcium halting the clotting process within the blood in the bag. It is also why we should consider administering calcium to a patient requiring a massive blood transfusion, because we are effectively giving a bleeding patient blood that won’t clot…
How is this clinically relevant to me?
Now that you have a clearer understanding of the clotting cascade, tune in next time to gain answers to the following questions:
- Read Understanding How Anticoagulants Work to answer the following questions:
- Why are there different anticoagulants, how do they work and why are they chosen?
- What is APTT and INR actually measuring?
- Read Massive Blood Transfusions and Making the Blood Clot to answer the following questions:
- Why am I giving my bleeding patient:
- Pooled platelets?
- Fresh frozen plasma (FFP)?
- Desmopressin (DDAVP)?
- Tranexamic acid (TXA)?
- Calcium chloride or calcium gluconate?
- Why am I giving my bleeding patient:
And there we have it! The clotting cascade explained hopefully in a manner that is easy to understand and remember! If you want to commit it to memory, I suggest printing the simple flow chart and keeping it in an area that you visualise often. And practice makes perfect; do quick sketches of the clotting cascade or try explaining it to someone else!
- Leung, L. K. (2015). Overview of hemostasis. Retrieved from: https://www.uptodate.com/contents/overview-of-hemostasis
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