Primary Hemostasis: The Platelet Plug Steps and Diagram
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Example Case
A female patient presents after suffering from a laceration to her hand. Prior to arrival she was chopping up vegetables when she accidentally sliced her left hand. This occurred approximately 30 minutes ago and she continues to bleed.
She informs you that she has a history of von Willebrand disease. You recall how decreased levels of von Willebrand factor could impact hemostasis and begin to think through your next steps of management.
Primary Hemostasis: Platelet Plug
The body will take immediate action whenever there is damage to a blood vessel.
The endothelium is the inner lining of a blood vessel, and it normally separates the intravascular content from the extravascular space.
Damage to the endothelial lining of a blood vessel may cause blood to leak into the extravascular space where it does not belong.
The body tries to fix the leak by forming a clot over the damaged area of the blood vessel.
The process in which the body stops a damaged blood vessel from bleeding is called hemostasis.
There are 2 main phases to hemostasis:
Primary Hemostasis
Secondary Hemostasis
Primary hemostasis forms an initial platelet plug.
Secondary hemostasis uses the coagulation cascade to form fibrin, which strengthens the initial platelet plug.
This lecture will walk through primary hemostasis and platelet plug formation step-by-step.
Check out the secondary hemostasis lecture to learn more about the coagulation cascade and how it works to solidify the platelet plug!
Vasospasm
The body takes immediate action when the endothelial lining of a blood vessel is damaged.
The initial step that occurs is vasospasm.
Vasospasm is the sudden constriction of a blood vessel, thereby reducing its diameter and flow rate.
And this makes sense….
An injured blood vessel constricts in order to reduce blood flow and minimize bleeding from the damaged site.
How Does Vasospasm Occur?
How does vasospasm occur after an injury to a blood vessel?
Let’s find out!
The endothelial cells of a blood vessel normally release vasoactive hormones called nitric oxide and prostacylcin.
Nitric oxide and prostacyclin work synergistically to relax vascular smooth muscles.
Nitric oxide and prostacyclin also inhibit platelet activation and aggregation, which prevent unnecessary clotting (thrombosis) from occurring in healthy blood vessels.
If the endothelial cells become damaged, then they will be unable to release nitric oxide and prostacyclin.
Since these hormone normally relax vascular smooth muscles, the absence of them will lead to vasoconstriction.
Since these hormones also inhibit platelet activation and aggregation, the absence of them will allow platelets to adhere to the damaged site.
The endothelial cells also release a chemical peptide in response to an injury.
This chemical peptide is called endothelin.
Endothelin is a potent vasoconstrictor.
When endothelin binds to vascular smooth muscle, it leads to contraction and vasospasm.
Subendothelial collagen (white) is exposed after injury to the endothelial lining of a blood vessel (red line).
Endothelial cells normally release nitric oxide (NO) and prostacyclin to relax blood vessels and prevent platelet activation from occurring.
If endothelial cells are injured, then there will be a decrease in the release of NO and prostacyclin which will lead to vasoconstriction (vasospasm).
Endothelial cells also release endothelin (a potent vasoconstrictor) onto vascular smooth muscles which leads to smooth muscle contraction and vasoconstriction (vasospasm).
Primary Hemostasis = Platelet Plug
As previously mentioned, the body takes immediate action after an injury to the endothelial lining of a blood vessel occurs.
In order to prevent blood from leaking out of a damaged blood vessel into the extravascular space, the body forms a quick primary plug using platelets.
The process of forming an initial platelet plug is called primary hemostasis.
Primary hemostasis and the formation of a platelet plug involves 3 steps:
Platelet Adhesion
Platelet Activation
Platelet Aggregation
Memory Trick!
Adhesion, activation, and aggregation all start with the letter “A” which can make it challenging to remember the order of the steps.
Here is the trick….
You can remember the order of primary hemostasis by going from the shortest word to the longest word!
Adhesion (8 Letters)
Activation (10 Letters)
Aggregation (11 Letters)
**Of note, all three steps occur simultaneously once the platelet plug start to form.
Trick to Remember the Order of Platelet Plug Formation:
Go From Shortest Word to Longest Word
Adhesion (8 letters)
Activation (10 letters)
Aggregation (11 letters)
Step 1: Platelet Adhesion
Let’s walk through the steps of primary hemostasis and the formation of a platelet plug, starting with platelet adhesion.
Damage to the endothelium of a blood vessel will expose subendothelial collagen that would normally be unexposed.
Damaged endothelial cells release a glycoprotein, called von Willebrand factor (vWF).
The released vWF binds tightly to the exposed collagen.
The circulating intravascular platelets have receptors on them, called glycoprotein Ib (GPIb) receptors.
The GPIb receptors on platelets bind to the vWF that is bound to the collagen.
This process is called platelet adhesion.
You can appreciate how von Willebrand factor is important for platelet adhesion, as it helps bind platelets to the collagen at the injured site of the blood vessel.
Von Willebrand factor (vWF) is secreted by damaged endothelial cells and will bind to the exposed subendothelial collagen (white lines) at the site of injury.
GPIb receptors on platelets (PLT) bind to vWF that is bound to the collagen.
Step 2. Platelet Activation
Now that the platelets have undergone platelet adhesion and are bound to the vWF on exposed collagen, the next step is platelet activation.
The interaction between vWF and GPIb receptors during platelet adhesion will activate the platelets.
During platelet activation, the platelets will degranulate or release their content into the intravascular space.
The platelets release cytokines, ADP, thromboxane A2, vWF, platelet-activating factor (PAF), vascular endothelial growth factor (VEGF), coagulation factors, serotonin, and other chemical mediators that facilitate activation and recruitment of additional platelets.
Platelet activation can quickly recruit other platelets to the injured site in an exponential fashion.
At this point, platelet adhesion and activation are occurring simultaneously.
Platelet aggregation starts to occur as well, which will be discussed next.
ADP and thromboxane A2, which are released by platelets during platelet activation, will bind to other platelets and recruit them to the site of injury.
Thromboxane and serotonin also act as vasoconstrictors to reduce bleeding.
Coagulation factors are also released during platelet activation, and this will become important during secondary hemostasis and the coagulation cascade (see coagulation cascade lecture).
The release of VEGF promotes angiogenesis (the development of new blood vessels).
In summary, activation of platelets leads to platelet degranulation of content that will serve as platelet recruiters, promote angiogenesis, cause vasoconstriction, and release coagulation factors that will be important during secondary hemostasis.
The interaction between GPIb platelet receptors and vWF during platelet adhesion, leads to platelets (PLT) activation and degranulation of content (yellow circles) to further facilitate platelet adhesion and activation along with other functions to augment hemostasis.
Step 3. Platelet Aggregation
The final step in forming a platelet plug is platelet aggregation.
As platelet adhesion and platelet activation continue at the site of injury, the platelets need a method to bind to each other in order to strengthen the platelet plug.
When platelets are activated they will express GPIIb/IIIa receptors.
GPIIb/IIIa receptors bind fibrinogen to create a cross-link between 2 or more platelets.
The cross-linking of platelets will further solidify and strengthen the platelet plug.
The process of clumping or cross-linking two or more platelets via fibrinogen is called platelet aggregation.
As more platelets become activated, they too will express the GPIIb/IIIa receptors and platelet aggregation will continue.
Activated platelets express GPIIb/IIIa receptors that bind fibrinogen to form a cross-link between 2 platelets to further solidify the platelet plug through platelet aggregation.
Practical Applications
Platelet plug formation can be inhibited by certain antiplatelet medications.
For example, clopidogrel inhibits ADP activity and aspirin inhibits thromboxane formation.
Reminder: ADP and thromboxane are released during platelet activation and bind to other platelets to activate and recruit them to the site of injury.
Clopidogrel and aspirin inhibit this process, which will impede platelet aggregation.
This becomes clinically important in conditions such as acute coronary syndrome, in which platelet aggregation in the coronary arteries could be detrimental.
There are also diseases that impact the normal process of primary hemostasis.
For example, von Willebrand disease results in vWF dysfunction and/or decreased levels of vWF.
As we learned above, vWF is important in the formation of a platelet plug.
Dysfunction and/or decreased levels of vWF could negatively impact hemostasis.
Clopidogrel inhibits the function of ADP and aspirin inhibits thromboxane formation. Both impede platelet aggregation and serve as antiplatelet medications.
Summary
Hopefully this helped you better understand primary hemostasis and the formation of a platelet plug.
Damage to the endothelial lining of a blood vessel will lead to vasospasm through:
Endothelin release from damaged endothelial cells
Decreased levels of nitric oxide and prostacyclin
There are 3 steps to platelet plug formation:
Platelet Adhesion
Platelet Activation
Platelet Aggregation
Platelet adhesion occurs when GPIb receptors on platelets bind to von Willebrand factor on the exposed subendothelial collagen.
The interaction between von Willebrand factor and GPIb platelet receptors will activate platelets, leading to degranulation of platelet content into the intravascular space. This will recruit more platelets to the site of injury, along with other effects that facilitate hemostasis.
Platelet aggregation occurs when activated platelets express GPIIb/IIIa receptors that bind fibrinogen to cross-link platelets together and further solidify the platelet plug.
Antiplatelet medications such as clopidogrel and aspirin act by inhibiting the function of ADP and the formation of thromboxane respectively.
Von Willebrand disease can result in decreased levels of vWF and impede hemostasis.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159913/
https://www.ncbi.nlm.nih.gov/pubmed/16368572
https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/expphysiol.2007.038588