Week 9 - Clotting and Coagulation Cascade Flashcards
What is hemostasis?
The process by which the body maintains the delicate balance between bleeding and clotting
What are the three layers of the blood vessel?
Intimia –> Inner most
Media –> Thickest in arteries (smooth muscle)
Adventitia –> Thickest in veins (outer most layer)
What is the intimia layer composed of primarily?
Endothelial cells
What is the importance of the endothelial cells in blood vessels?
Synthesize and secrete many mediators in the clotting cascade –> Procoagulants (initiate clots), anticoagulants (inhibit coagulation), fibrinolytics (break down clots)
What mediator secreted and synthesized by the endothelial cells allows platelets to begin sticking to each other?
von Willebrand factor
What does Tissue factor do in regards to the clotting cascade?
Extrinsic –> Tissue factor (3) activates factor 7 –> this 7a can now activate factor X in the common pathway
When vessel injury occurs, what is the first step that takes place?
Endothelial cells secrete Thromboxane A2 and ADP to cause vasoconstriction at the injured site.
What mediators can cause vasodilation of the blood vessel?
Nitric oxide (NO) and prostacyclin
Although the endothelial cells within the intimia secrete many mediators contributing to the clotting cascade, what is another important job this tissue does?
Prevents the fluid contents of the blood from interacting with the sub endothelial space (media) –> This is where highly thrombogenic material is stored, collagen and procoagulants like fibronectin
Where do platelets tend to flow within the blood vessel?
Along the vessel surface –> The endothelial muscle physically repels bigger blood components away (RBCs and WBCs) while smaller components like Platelets get placed conveniently near their site of action
Why is the media layer of the vessel important to coagulation?
Sub endothelial layer –> Secretes collagen and fibronectin which aid in platelet plug formation
What layer of the blood vessel is responsible for the degree of contraction or dilation?
Adventitia –> Outer most layer, thickest in veins
What mediators act of the adventitia vessel layer?
Nitric oxide and prostacyclin –> Dilation
Thromboxane A2 and ADP –> Contraction
Where is nitric oxide and prostacyclin produced?
Endothelial cells
What is the purpose of nitric oxide and prostacyclin in regard to coagulation?
These mediators dilate the vessel, washing away procoagulants and prevents the formation of a clot
Where are platelets formed?
In the bone marrow from megakaryocytes –> They are round and disk like
Normal platelet count and average life span
150 - 300 K, 8 - 12 days
How can platelets participate in anaerobic and aerobic metabolism?
Contains a mitochondria –> Aerobic
Contains glycogen stores –> Anaerobic
What blood cell stores various contractile proteins, enzymes, and large amounts of calcium?
Platelets
Many granules stored within platelets synthesize prostaglandins which _______________
platelets to promote vascular and local tissue reactions
What blood cells can produce thrombin?
Platelets –> Thrombin’s role includes activating coagulation factors as well as recruiting more platelets to the site of injury
Do platelets contain DNA, RNA, or a nucleus?
NO –> So they don’t reproduce
Do platelets float around active?
NO –> Largely inactive until activated by vascular trauma
Do platelets work independent relying only on themselves for formation of a platelet plug?
NO –> They work in conjunction with plasma proteins and the coagulation cascade
What are some procoagulant mediators?
What are some fibrinolytic mediators?
What occurs downstream of a blood vessel that just constricted in response to a vascular injury?
The area adjacent to this vessel dilates to distribute blood to the surrounding organs and tissue
What three things occur AFTER constriction of a blood vessel due to vascular injury?
Formation of the platelet plug –>
1. Adhesion
2. Activation
3. Aggregation
What happens during the adhesion stage of platelet plug formation?
von Willebrand factor emerges from the endothelial cells and attaches to the wall of the damaged vessel –> vWF then attaches to platelets via the GP1b receptor site on the platelet
This activates platelets causing them to become “sticky” and adhere to the site of injury
What mediator activates platelets causing a conformational transformation?
Tissue factor (factor 3) –> The platelet swells and becomes irregularly shaped
What occurs during the aggregation stage of platelet plug formation?
Platelets express GP2b/GP3a –> Fibrinogen connects platelets together via these receptor sites. This forms the primary “unstable” plug
After platelet plug formation, why would the clotting cascade be initiated?
If the injury is large –> This secures this unstable plug into a more stable plug.
If the injury in small and minute, the primary unstable plug is enough to maintain hemostasis and the clotting cascade won’t be needed
Do coagulation factors circulate the blood in an active or inactive state?
Inactive state
What are the two clotting pathways that lead to the common pathway?
Intrinsic –> Damage WITHIN the vessel
Extrinsic –> Damage OUTSIDE the vessel
Describe the extrinsic pathway
Factor 3 (tissue factor) activates this pathway by activating factor 7 (proconvertin) –> 7a now goes and activates the common pathway, starting with factor 10 (Stuart-Prower)
Describe the common pathway
The intrinsic or extrinsic pathway can activate this…
Factor X is activated via 7a (extrinsic) or 8 (intrinsic) and turns in Xa –> Xa, Factor 5 (proaccelerin), and calcium activate factor 2 (prothrombin) and turn it into factor 2a (thrombin) –> Factor 2a (thrombin) now activates Factor 1 (fibrinogen) and turns in into 1a (fibrin)
Factor 1a and Factor 13 (fibrin stabilizing factor) secure the primary unstable clot.
What initiates the intrinsic pathway?
Prekallikrein
What clotting factors are dependent on vitamin K?
2, 7, 9, and 10
What factors are synthesized in the liver?
All but 3 (tissue factor), 4 (calcium), and 6 which non existent
Which factors are part of the common pathway?
10, 5, 2, and 1
What is the name of factor 12?
What is the name of factor 8?
Describe the intrinsic pathway
Prekallikren activates factor 12 (hageman) –> Factor 12 (hageman) with factor 4 (calcium) cause a domino effect and activates Factor 11 (plasma thromboplasmin antecedent) which activates Factor 9 (christmas) which activates Factor 8 (anti-hemophiliac) –> This now activates the common pathway, Factor 10 (Stuart-Prower)
Platelets can release thrombin, or it can be activated via the common pathway (factor 2a). What other factors can this thrombin now activate?
It activates factors 5, 8, 1, and 13. It also recruits more platelets to the site of injury
What happens in the extrinsic pathway immediately after factor 3 (tissue factor) activates factor 7 (proconvertin)?
TF pathway inhibitor prevents more factor 7 from being activated so only a preset limit remains activated.
Factor 2a (thrombin) acts as both a __________ and ___________
coagulant, anticoagulant
When thrombin is acting as an anticoagulant, what three things does it cause?
- Releases tPA from endothelial cells –> prevents “run away” clots
- Stimulates proteins C and S –> inhibits clotting
- Forms a relationship with anti thrombin III –> Anti-thrombin III inhibits thrombin activity by inhibiting factors 12, 11, 10, and 9
Heparin only works in the presence of ____________
Anti thrombin III
Someone has heparin resistance, what do you suspect is the likely cause
Anti thrombin III deficiency
What factors are ultimately responsible for turning a primary unstable clot into a stable clot during a large injury?
Factors 13 (fibrin stabilizing factor) and Factor 1a (fibrin)
After a clot is made, it retracts. What does this do to the vessel.
Eliminates it serum –> Retracting causes weaving of the edges of the vessel together, healing the site of injury.
What are the three steps of coagulation within the cell based theory model?
- Initiation
- Amplification
- Propagation
What is the purpose of the fibrinolytic system?
Degrade fibrin –> Breaks down the clot
What initially occurs during activation of the fibrinolytic system?
Endothelial cells secrete nitric oxide and prostacyclin to cause dilation of the vessel to wash away procoagulant mediators such as ADP and thromboxane A2.
After dilation of the vessel, what occurs next in the fibrinolytic system?
THROMBIN changes roles into an anticoagulant now –> This ONLY stops further production of the clot, not breakdown
1. TFPI inhibits TF
2. Proteins C and S inhibit factors 3, 5, and 8
3. Anti Thrombin III inhibits 12, 11, 10, and 9
What is the purpose of plasminogen in a clot and where does it come from?
This is inactivated plasmin, synthesized by the liver –> It incorporates itself into the clot. Once activated however, it can now break the clot from within by degrading fibrin
How does the incorporated plasminogen in the clot become activated thus enabling it to begin breaking down fibrin holding the clot together?
Endogenous urokinase and tPA
After the clot has been completely dissolved, what mediators shut off the fibrinolytic system?
alpha antiplasmin and tissue plasminogen activator inhibitor
What factor is used specifically to position the other factors in correct orientation on the surface of the platelet?
Factor 4 (calcium)
