Secondary Hemostasis Steps: Coagulation Cascade Pathway
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SAVE TIME studying with your own copy of the lecture below! QUICKLY learn the coagulation cascade! Step-by-step diagrams and memory tricks included!
Example Case
A female patient presents with altered mental status after a fall that occurred approximately 30 minutes ago. Her husband is with her and states she fell going down the stairs at home and has not been acting herself since.
He also informs you that she is on rivaroxaban, and she recently took her last dose 1 hour ago. You recall where in the coagulation cascade this medication acts and begin to think through your next steps if she is found to have a life threatening bleed.
Secondary Hemostasis: The Coagulation Cascade
Hemostasis is the process in which the body takes to stop bleeding from a damaged blood vessel.
There are 2 main phases to hemostasis:
Primary Hemostasis
Secondary Hemostasis
Primary hemostasis involves the formation of a platelet plug.
Secondary hemostasis involves the coagulation cascade.
We discussed primary hemostasis and the formation of a platelet plug in the previous lecture.
We will now focus on secondary hemostasis and the coagulation cascade in this lecture!
**I highly recommend checking out the primary hemostasis lecture because that will serve as a good prelude and segue into this lecture.
If you are trying to learn or refresh your memory on the coagulation cascade, then you have come to the right spot!
Yes, the coagulation cascade look overwhelming at first.
But fortunately……it doesn’t have to be!
You will learn some memory tricks that will help you memorize and understand the entire coagulation cascade in minutes!
So let’s get right into it!
Primary Hemostasis Recap
The body will take immediate action whenever there is damage to the endothelial lining of a blood vessel.
First, the injured blood vessel will constrict in order to reduce blood flow and hemorrhaging from the damaged site, a process known as vasospasm.
Decreased levels of nitric oxide and prostacyclin at the injured site, along with endothelin released by damaged endothelial cells, will lead to vascular smooth muscle contraction and vasoconstriction/vasospasm (see primary hemostasis lecture).
In addition to vasospasm, the damaged blood vessel will undergo primary hemostasis to form a platelet plug.
Primary hemostasis and the formation of a platelet plug is the body’s method to form a quick clot after there is injury to a blood vessel.
Secondary hemostasis and the coagulation cascade will then solidify and strengthen the primary platelet plug, which will be the focus of this lecture.
Secondary Hemostasis = The Coagulation Cascade
Secondary hemostasis involves the coagulation cascade.
Once the platelet plug is formed during primary hemostasis, the coagulation cascade further strengthens the blood clot (platelet plug) by creating a mesh-like structure called fibrin.
The coagulation cascade and the formation of a platelet plug occur simultaneously, however the coagulation cascade typically takes longer.
The goal of the coagulation cascade is to form fibrin, and it does so using several different steps that can be divided into 3 pathways:
The Common Pathway
The Extrinsic Pathway
The Intrinsic Pathway
Let’s walk through each pathway below!
Coagulation Cascade Pathways
Common Pathway
Extrinsic Pathway
Intrinsic Pathway
Common Pathway
Let’s begin by reviewing the common pathway of the coagulation cascade.
The important number to remember for the common pathway is the number 10.
The number 10 will help you remember factor X, which is the factor that initiates the common pathway.
Both the intrinsic and extrinsic pathways converge onto factor X, but more on this later!
For now, simply remember factor X is the start of the common pathway.
Activated factor X, along with the help of activated factor V, will then activate factor II.
Activated factor II will then activate factor I.
**Of note, you will see activated factors denoted using the letter “a”.
For example, inactive factor X = X; activated factor X = Xa
Factor II also goes by a different name.
The inactive form of factor II is called prothrombin, and the active form of factor II is called thrombin.
MEMORY TRICK: Factor II and thrombin can be remembered because “two” and “thrombin” both start with the letter “T”.
Factor I also goes by a different name.
The inactive form of factor I is called fibrinogen, and the active form of factor I is called fibrin.
MEMORY TRICK: Factor I and fibrin can be remembered because “first” (factor I) and “fibrin” both start with the letter “F”.
Factors X and V will work together to activate and convert prothrombin (factor II) into its active thrombin form (factor IIa).
Thrombin will then cleave fibrinogen (factor I) into its active form fibrin ( factor Ia).
If you remember from above, we said the goal of the coagulation cascade is to form fibrin!
It is fibrin that helps form the strong mesh that holds the initial primary platelet plug together.
Memory Trick
Here’s the quick and easy way to remember the factors that make up the common pathway!
First, we said factor X is the magic number to remember for the common pathway.
Factor X is the start of the common pathway and is the factor in which both the intrinsic and extrinsic pathways converge.
To remember factor X just think “X marks the spot!”
Then the remainder factors in the common pathway are simply factors of 10!
In mathematics, the factor of a number is a number that divides the given number completely without any remainder.
The factors of 10 include: 10, 5, 2, and 1.
Coincidentally these are all the factors that make up the common pathway!
You’ll simply count backwards starting with factor X (remember X marks the spot) followed by factor V, then factor II, and then factor I.
Pretty cool eh?!
The common pathway involves all numbers that are factors of 10: X, V, II, and I
Activated factor X (Xa) and activated factor V (Va) convert prothrombin (factor II) into its active form thrombin (factor IIa). Thrombin then cleaves fibrinogen (factor I) into its active form fibrin (factor Ia). Fibrin creates the strong mesh in a blood clot.
Extrinsic Pathway
Now let’s move on to the extrinsic pathway.
The extrinsic pathway is easy!
The only major factor to remember for the extrinsic pathway is factor VII.
The extrinsic pathway is also known as the tissue factor pathway.
Damaged tissue and blood vessels will expose a protein called tissue factor (TF).
Tissue factor is also known as coagulation factor III.
TF (factor III) will activate factor VII.
Activated factor VII will then activate factor X (the common pathway), as it converges with the intrinsic pathway (explained next).
Activated factor X will then go down the common pathway explained above.
And that’s it for the extrinsic pathway!
Memory Trick
Here’s the quick and easy way to remember the extrinsic pathway!
Extrinsic starts with the letter “E” and the word “seven” contains 2 E’s (sEvEn).
This will help you remember factor VII makes up the extrinsic pathway!
Here’s the even cooler part….
If you also need to remember tissue factor (factor III) as being the initiator of the extrinsic pathway, well guess what?
The word “three” also contains 2 E’s! (thrEE)
This will help you remember factor III (TF) initiates the extrinsic pathway and activates factor VII.
Damaged blood vessels expose tissue factor (factor III), which activates factor VII. Activated factor VII (VIIa) activates factor X, which initiates the common pathway.
Intrinsic Pathway
The final pathway is the intrinsic pathway.
The intrinsic pathway is also referred to as the contact activated pathway.
This is because the intrinsic pathway is activated when factor XII comes into contact with the damaged blood vessel and platelet plug.
So the intrinsic pathway starts with factor XII.
Activated factor XII (XIIa) will then activate factor XI, which then activates factor IX.
Together activated factors IX and VIII will activate factor X, thereby converging with the extrinsic pathway onto the common pathway explained above.
Memory Trick
Here is the quick and easy way to remember the factors that make up the intrinsic pathway!
You will simply use all of the numbers above 7 that we have not used!
We know the intrinsic pathway starts with factor XII.
So you will simply count backwards from XII, but we will skip X because we already used it in the common pathway.
So we will start with factor XII and work our way down: XII, XI, skip X, IX, and VIII.
We will stop at VIII because we already used VII in the extrinsic pathway!
Factor XII is activated when it comes into contact with the damaged blood vessel and primary platelet plug. Activated factor XII (XIIa) will activate factor XI, which will activate factor IX. Activated factor IX (IXa) and activated factor VIII (VIIIa) work together and converge with the extrinsic pathway onto the common pathway to activate factor X.
Tricks to Remember the Cascade
Common Pathway = Factors of 10: Factors X, V, II, I
Extrinsic Pathway = sEvEn = Factor VII
Intrinsic Pathway = Other factors above 7 not used = Factor XII, XI, IX, VIII
Complicated Vs Simplified
You may have seen complicated diagrams of the coagulation cascade like the one below.
These diagrams have extra arrows to depict activated factors activating the next factor from its inactive form to its active form.
Image - Busy coagulation cascade diagrams like above can be confusing. However, it accurately depicts each activated factor activating the next.
The extra arrows can create a busy diagram, so there is also a simplified version below.
The simplified diagram below takes away those extra arrows.
Just remember in the simplified version that each arrow represents the preceding activated factor activating the next factor from its inactive form to its active form.
**The arrow does not mean the previous factor is turning into a different factor!
For example, activated factor XII is activating factor XI; it is not turning into factor XI.
Image - A much more simplified version of the coagulation cascade diagram. Just remember that each activated factor is activating the next, and that is not turning into a different factor.
Primary vs Secondary Hemostasis
We now know the end result of the coagulation cascade is for thrombin to cleave fibrinogen into its active form fibrin.
If you remember from the primary hemostasis lecture, fibrinogen binds to GPIIb/IIIa receptors on platelets during platelet aggregation.
During secondary hemostasis, the coagulation cascade then converts the fibrinogen into fibrin.
So we can start to see how primary and secondary hemostasis interact with each other.
As fibrin is created, another coagulation factor called factor XIII will cross-link the fibrin strands together to form a fibrin mesh-like structure.
The fibrin mesh will lay over the platelet plug that was formed during primary hemostasis and help stabilize it.
Details of platelet plug formation seen in the above picture can be found in the primary hemostasis lecture.
The coagulation cascade ultimately creates a fibrin mesh that will further solidify the initial primary platelet plug.
Vitamin K
There are several factors and proteins in the coagulation cascade that require vitamin K to become mature and active.
The vitamin K dependent components are factor II, factor VII, factor IX, factor X, protein C, and protein S.
The vitamin K dependent components are important for warfarin, which is an anticoagulant (blood thinner).
The mechanism of action of warfarin is to inhibit the formation of active vitamin K.
Without active vitamin K, the vitamin K dependent factors will not mature.
If the coagulation cascade has missing factors, then coagulation or blood clotting cannot occur.
As a result, warfarin serves as an anticoagulant.
Memory Trick
The trick to remember the vitamin K dependent components of the coagulation cascade is to use the following phrase:
“TWO plus SEVEN CalculateS to NINE not TEN”
The important parts of the phrase are: TWO, SEVEN, C, S, NINE, and TEN.
This will help you remember factor II, factor VII, protein C, protein S, factor IX, and factor X.
Vitamin K Dependent Factors
Factor II
Factor VII
Factor IX
Factor X
Protein C and S
“TWO plus SEVEN CalculateS to NINE not TEN”
Regulators
The coagulation cascade has several regulators to prevent excessive thrombosis and clot formation from occurring.
While forming a blood clot is important to stop bleeding, overproduction of blood clots can lead to problems as well.
The major regulators of the coagulation cascade include:
Protein C and Protein S
Antithrombin
Tissue Factor Pathway Inhibitor
Plasmin
Thrombomodulin
Protein C and Protein S
Protein C and protein S inhibit factors V and VIII, the two “helper factors”.
Remember factor V helps factor X activate factor II.
Remember factor VIII helps factor IX activate factor X.
By inhibiting factors V and VIII, proteins C and S can prevent excessive thrombosis from occurring.
Antithrombin
As the name suggests, antithrombin inhibits thrombin.
Antithrombin also inhibits much of the intrinsic pathway including factors XII, XI, IX, and X (of the common pathway).
Tissue Factor Pathway Inhibitor
As the name suggests, tissue factor pathway inhibitor will inhibit the extrinsic/tissue factor pathway.
It does so by limiting the ability of tissue factor to activate factor VII.
Plasmin
Plasmin inhibits excessive fibrin formation.
Plasmin is also involved in fibrinolysis (the breakdown of fibrin), especially when the blood clot is no longer needed once the blood vessel heals.
Plasmin degrades fibrin into fibrin split products, thereby breaking down the clot.
The inactive form of plasmin is plasminogen.
Plasminogen is converted into plasmin (the active form) by tissue plasminogen activator (tPA).
Thrombomodulin
Thrombomodulin is present on the endothelium of blood vessels.
Thrombomodulin has a high affinity for thrombin, and it modulates or converts thrombin into an anticoagulant form capable of activating protein C (which helps inhibit factors V and VIII).
Memory Tricks
Here are some tricks to remember the different modulators!
Protein C and Protein S:
Protein C and protein S inhibit factors V and VIII.
So you can remember there are 2 proteins and they inhibit 2 factors.
Which 2 factors do they inhibit?
The 2 helper factors, which are factors V and VIII.
Antithrombin:
Antithrombin inhibits thrombin and factors of the intrinsic pathway.
Use the suffix “thrombin” in antiTHROMBIN to remember THROMBIN.
And use the suffix “in” in antithrombIN to remember INtrinsic pathway.
Tissue Factor Pathway Inhibitor:
Tissue factor pathway inhibitor will inhibit the extrinsic or tissue factor pathway.
Just use the name tissue factor pathway inhibitor to remember it inhibits the tissue factor pathway.
Plasmin:
Plasmin inhibits excessive fibrin formation and is involved in fibrinolysis (the breakdown of fibrin).
You can remember this because plasmin and fibrin rhyme.
Thrombomodulin:
Thrombomodulin converts or modulates thrombin into an anticoagulant form.
Break down the word “thrombomodulin” into “modulates thrombin”.
This will help you remember thrombomodulin modulates thrombin.
Tricks to Remember Regulators
Protein C and S = 2 proteins inhibit 2 factors, which 2 factors? The 2 helpers V and VIII
AntiTHROMBIN = inhibits THROMBIN and INtrinsic pathway factors
Tissue factor pathway inhibitor = inhibits tissue factor/extrinsic pathway
Plasmin = Degrades fibrin into fibrin split products (Plasmin and Fibrin rhyme)
Thrombomodulin - “Modulates thrombin” into anticoagulant form
Protein C and S inhibit factors V and VIII. Antithrombin inhibits thrombin and factors of the intrinsic pathway. Tissue factor pathway inhibitor inhibits the tissue factor/extrinsic pathway. Plasmin degrades fibrin. Thrombomodulin modulates thrombin into anticoagulant form.
Practical Applications
Let’s wrap this up with a few practical applications.
These will be discussed more in future lectures including how anticoagulation medications interact with the cascade, ways to reverse anticoagulation, and various diseases involving primary and secondary hemostasis.
However, here are a few brief examples.
Medications (Anticoagulation Reversal)
There are medications and blood products available that can reverse the effects of anticoagulation and help promote blood clotting.
Examples include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC).
These agents are often used in major or life threatening bleeding, particularly if an individual is on an anticoagulant/blood thinning medication (see next section).
Anticoagulant reversal agents contain coagulation factors and/or other various blood products that are important for promoting coagulation.
Medications (Anticoagulants)
There are medications that inhibit different parts of the coagulation cascade, and so they serve as anticoagulants or “blood thinners” as result.
Factor Xa inhibitors such as apixaban (eliquis) and rivaroxaban (xarelto) inhibit factor Xa activity.
Dabigatran (pradaxa) acts as a direct thrombin inhibitor.
Warfarin (coumadin) acts by inhibiting synthesis of vitamin K dependent factors (factors II, VII, IX, and X along with Protein C and S).
Heparin increases the activity of antithrombin which inhibits thrombin and intrinsic factor activity.
Fibrinolytics such as alteplase act as tissue plasminogen activators to convert plasminogen into plasmin resulting in degradation of fibrin.
Medications such as factor Xa inhibitors, direct thrombin inhibitors, antithrombin activators, and tissue plasminogen activators all function as blood thinners.
Bleeding Disorders
There are diseases involving the coagulation cascade that can make an individual prone to bleeding.
Hemophilia is a bleeding disorder from low levels of factor VIII (hemophilia A) or low levels of factor IX (hemophilia B).
Having lower than normal levels of coagulation factors can make an individual prone to bleeding.
Clotting Disorders
There are also diseases involving the coagulation cascade that can make an individual prone to forming clots (thrombosis).
Factor V leiden is a hypercoagulable (prone to forming blood clots) disease state in which a mutated variant of factor V is present.
Normally, protein C would inhibit factor V as a protective mechanism against overproduction of clot formation.
However, protein C does not recognize the mutated form of factor V in factor V leiden.
Factor V cannot be inhibited by protein C as a result, which leads to a hypercoagulable state making an individual prone to blood clots.
Protein C and protein S deficiencies will likewise lead to a similar hypercoagulable thrombotic state.
Disorders such as hemophilia result in a bleeding risk due to factor deficiencies. Disorders such as factor V leiden lead to a clotting risk due to inability to regulate/inhibit factor V.
Labs
There are blood tests that can be used to assess coagulation status.
They can be use to evaluate for unexplained bleeding or clotting, and they can be used to assess an individual’s coagulation status while on an anticoagulant (blood thinner).
Examples include prothrombin time (PT), partial thromboplastin time (PTT), and INR.
PT measures the integrity of the extrinsic pathway as well as the common pathway.
PTT measures the integrity of the intrinsic pathway as well as the common pathway.
INR is typically used to measure warfarin efficacy.
Summary
Hopefully this lecture provided you with a better understanding of secondary hemostasis and the coagulation cascade.
Secondary hemostasis involves the intrinsic pathway (factors XII, XI, IX, VIII) converging with the extrinsic pathway (factor VII) to form the common pathway and fibrin formation (factors X, V, II, I).
Use the memory tricks below to remember the coagulation cascade:
Common Pathway: Factors of 10 = X, V, II, I
Extrinsic Pathway: Factor sEvEn = VII
Intrinsic Pathway: Other factors above VII = XII, XI, IX, VIII
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