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What are the basic steps in coagulation?
- Primary hemostasis
- Secondary hemostasis (Clotting cascade)
What basic steps are involved if it's just a small hole in the vessel?
- Small hole
- Vasoconstriction & primary hemostasis (platelet plug) will take care of it.
- Big blood clot isn't needed
How quickly does secondary hemostasis happen if there is a small or big breach in the blood vessel?
- Small breach the process starts in 1-2min.
- If major trauma, big breach in blood vessel, then the whole process begins in about 15-20sec.
Describe the Mechanism of vasoconstriction
- Myogenic spasm (local)
- Endothelin (from injured vessel) which is a vasoconstrictor
- Thromboxane A-2 (released from platelets) also contributes to vasoconstriction
What are platelets? (where are they from?)
Platelets are fragments of a large cell from bone marrow called megakaryocytes
Do platelets have a nucleus?
No nucleus just cytoplasm.
What causes platelets to contract?
- Do contain actin and myosin filaments, contractile proteins found in muscle cells.
- Also contains thrombosthenin which is another contractile protein
What do platelets contain?
- Actin and myosin filaments
- Leftover ER and Golgi apparatus (Where various enzymes and Ca+ are stored)
- Mitochondria (site of ATP synthesis)
- Can also synthesis prostaglandins, etc.
How do platelets know where they should and should stick??
- Platelets surface has a coat of glycoproteins.
- The platelets get activated by these glycoproteins and that causes the platelets to stick onto the exposed endothelial surface where there has been a breach in the blood vessel.
- Same mediators will prevent the platelets from adhering when they shouldn't be adhering.
- Won’t stick to normal endothelial lining, only where there is a breach.
Platelets have ½ life of __-___ days.
Normal count of platelets: ___________-_______. How much is sequestered in the spleen
- 1/3 are sequestered in the spleen.
What are the three processes responsible creating platelet plug (3A's)
- Activation (results in release of granules that have things in them to further along the process)
Like other membranes, platelet membranes have __________ that are also involved in the activation of the coagulation process.
If there is an injured endothelial surface, a platelet plug will be formed. Describe this process
- sub endothelium matrix is exposed & that becomes the surface for platelet adhesion and activation.
- When platelet adhere to that exposed subendothelial surface, they change their characteristics, swell and form pseudopods, reach out, contractile proteins contract and release granules (activation part).
- So platelet will stick to the collagen and to vWF.
- vWF actually leaks into the damaged tissue from the plasma.
- Also platelets secrete large amounts of ADP and form that vasoconstrictor (thromboxane A2)
- All together causes more and more platelets to come together to add to platelet plug to plug hole in the blood vessel.
What two molecular interactions will mediate platelet adhesion?
Describe the molecular interaction w/vWF that mediates platelet adhesion
- vWF is a large protein secreted both by activated platelets and injured endothelium (So coming in from plasma and secreted by activated platelets).
- It acts as a bridge. It will bind the surface receptors on platelet membrane to exposed areas of collagen (Subendothelial matrix) T
- These surface receptors have designations (become more important when we talk about some drugs) Glycoprotein 1B (GP1b) is the surface receptor that’s most readily bound to vWF.
Describe the molecular interaction w/GPV1 that mediates platelet adhesion
Platelet glycoprotein 6 (GPV1) that will interact directly w/the collagen.
When platelet stick to subendothelial collagen and get activated by these locally generated mediators.What happens w/activation?
platelet change shape, form pseudopods and get contracted.
What things will mediate platelet recruitment?
- ADP and thromboxane A2.
- During platelet aggregation the fibrinogen will cross link the platelets to one another by binding the GP2B3A receptor (becomes important when we look at the drugs)
So platelet activation can be initiated by that exposure of the sub endothelial collagen but can also have secondary pathway of activation. What initiates this?
- Initiated by tissue factor(also called thromboplastin when we get into clotting cascade)
- Its activated by WBC, it’s a critical component of the clotting cascade actually.
Ultimately the membranes of activated platelet are really important to number of critical reaction in clotting cascade by.......
converting prothrombin to thrombin
What are the mediators of platelet aggregation?
- Thromboxane A-2
What are the ADP receptors in platelet aggregation?
- P2Y –target for antiplt meds (Ticlopidine, Clopidogrel, & Prasugrel)
What is important about the activation of ADP receptors?
- Activation of ADP receptors will mediate that shape change in the platelets and cause these ADP receptors to be functional.
- ADP receptors are on the platelets.
Another important receptor in platelet aggregation is the GP IIb/IIIa receptors. This GP2B3A-firbiringoen connection is critical for platelet aggregation.
What are the inhibitors of this receptor?
- Eptifibatide (Integrilin)
- Abciximab (ReoPro)
- Tirofiban (Aggrastat)
Describe the basic steps in the coagulation mechansim
- Prothombin activator is formed as a result of damage to a blood vessel.
- Prothrombin activator causes conversion of prothrombin to thrombin as long as there is enough ionized Ca
- Thrombin causes conversion of fibrinogen to fibrin by polymerization and that takes about 10-15seconds.
How long does it take for the conversion of fibrinogen to fibrin??
According to Guyton, the rate limiting step in all the coagulation mechanism is the....
is prothombin activator (1st step). The rest happens quickly in order to form a clot.
Why are platelets so important in the coagulation mechanism?
- Remember platelet are already stuck onto damaged tissue.
- There are receptors for prothrombin on the platelets, those receptors will cause prothrombin to bind.
There is something called fibrin stabilizing factor that gets released from platelets. It's also activated by thrombin. What is important about the fibrin stabilizing factor?
- And without the fibrin stabilizing factor, all the fibrin fibers are kind of held loosely together by hydrogen bonds.
- With activation by thrombin, fibrin stabilizing factor causes those bonds to become covalent so now really tightly held, making the clot much stronger.
- The clot will contain blood cells as well as platelet and fibrin strands all of which acts to prevent further blood loss.
How long does clot retraction take and what does it require??
- Process of clot retraction occurs in about 20-60min and requires adequate platelets.
- It’s when the serum gets expressed from the clot
- Think of lab draw and not picked up & no anticoagulant in the tube, the clotted part of the blood (cells, fibirin) will sort of retract and come away from the walls of the test tube and just the liquid serum will stay.
- Clot retraction helps to bring the vessels sides together in the healing process.
What are the 1st 4 factors in the clotting cascade and their common names
- I: Fibrinogen
- II: Prothrombin
- III: Tissue factor. thromboplastin
- IV: Calcium ion
What is factor 6?
There isn't one! Actually activated Factor 5
There are two other clotting factors not on original list, what are they??
Prekallikrein and high molecular weight kininogen
Clotting itself will begin by 3 mechanisms. What are they?
- Trauma to vessel wall an other tissues
- Trauma to blood itself
- Contact between the blood and damaged endothelial cells (collagen)
- *All of those will form the prothrombin activator.
Describe the extrinsic pathway of the coagulation mechanism
- Starts w/trauma to vessel wall and any surrounding tissues.
- 1) Tissue factor (Thromboplastin) is released.
- 2) Tissue factor will combine w/factor 7 in the presence of Ca+ ions (necessary!)and it will activate factor 10.
- 3) Activated Factor 10 (10a) combines w/tissue factor and phospholipids from platelets which along w/factor 5, to form prothrombin activator.
Bottom line: it forms prothrombin activator essential to convert prothrombin to thrombin
So the bottom line of the whole extrinsic pathway of the coagulatin mechanism is that it forms prothrombin activator which is essential to convert prothrombin to thrombin. What else does THROMBIN so that helps this pathway??
- Thrombin is also necessary here in activating factor 5.
- Factor 5 in the prothombin activator complex is initially inactivate until it’s activated thrombin.
- Thrombin that gets made by prothrombin activator comes up and activates factor 5.
- Activated actor 5 will accelerate the process.
- Helps to speed up the process once it gets started.
What begins the intrinsic pathway
- Begins w/trauma to the blood instead of vessel or surrounding tissues.
- Or in the case of collagen (subendothelial matrix) gets exposed to the blood.
Describe the intrinsic pathway of the coagulation mechanism
- Blood trauma, contact of blood w/collagen first.
- Causes activation of factor 12 and release of phospholipids from the platelets.
- Activated factor 12 will then activate factor 11 and the reaction requires those two new coagulation factors that don’t have roman numeral (Prekallikrein and high molecular weight kininogen) are mediators in that reaction.
- Activated Factor 11 will then activate factor 9.
- Activated factor 9 together with activated factor 8 (also platelet phospholipids) will activate factor 10.
- Activated factor 10 and factor 5 and platelet phospholipids or tissue factor, will form the prothrombin activator which goes on to split prothrombin into thrombin (this last step is the same as the extrinsic)
Which ion is CRITICAL to the coagulation cascade? (which steps are the exception to this???)
- Required for all steps in the process except steps 1 and 2 of intrinsic pathway.
Both extrinsic and intrinsic pathways of the coagulation mechanism occur simultaneously. What are they each initiated by?
- Extrinsic pathway initiated by tissue factor
- Intrinsic pathway initiated by contact between vascular wall collagen & Factor XII & platelets
What is an important difference between the intrinsic and extrinsic pathways of the coagulation mechanism according to Guyton?
- Extrinsic can be explosive.
- Meaning that once begun the only limiting factor in speed clot formation is the amount of tissue factor released, as well as the amount of factors, 10, 7, and 5 in the blood.
How long do the extrinsic and intrinsic pathways take to clot? Which is faster??
- Extrinsic: If the tissue trauma (trigger) is severe enough clotting can occur within 15 seconds.
- Intrinsic: takes about 1-6min for clotting to occur so it’s much slower
TRUE or FALSE. Most clotting factors circulate in active form
FALSE. they are mostly inactive!
Where are most clotting factors synthesized?
Most clotting factors are synthesized in the liver except factor VIII (has some extrahepatic synthesis)
What is special about Factor VIII?
Factor VIII is a large 2-molecule complex of vWF & coagulant factor VIII
Of the coagulation factors that are vitamin K dependent (2,7,9,10) which one has the shortest 1/2 life in vivo?
- Of those 4 factors, 7 as the shortest ½ life in vivo.
- Patient put on warfarin (Coumadin) or develops Vit. k deficiency, that’s the first factor to disappear from circulation.
Which coagulation factors are vitamin K dependent?
II, VII, IX, X (2,7,9,10)
- If no Vit K these factors are produced by won't work
- So the anticoagulant action of Vit K antagonist. Interfere w/final step in making those factors functional.
Factors ___& ___ have the shortest half-life in storage
- V & VIII
- They referred to as labile factors. Because they’re activity isn’t durable in stored blood.
What is vWF the carry protein for??
vWF is carry protein for the 8c (coagulant factor)
What important function does the vWF have in the formation of the platelet plug?
vWF has important function in formation of platelet plug (it connects the platelet to the collagen)
What is hemophilia A?
If the coagulant part of factor 8 is absent that is what is hemophilia A.
So if there is deficiency of vWF (factor 8) we have two hemostatic abnormalities. What are they?
- 1) defect in primary hemostasis (no bridge to collagen and platelet)
- 2) similar to hemophilia A because vWF is important of being part of that factor 8.
What is the purpose in regulation of homostasis?
- Restriction to site of injury
- Vessel remains patent
In regulation of homostasis, you need balance
of procoagulant and anticoagulant factors
- Major procoagulation is tissue factor (Thromboplastin) and is localized.
- Anticoagulation are generally secreted by endothelium and are soluble in the blood.
what is the 1st line of defense in regulation of hemostasis?
- 1st line of defense is vascular endothelium itself.
- It has built in antithrombotic properties that will limit platelet activation and aggregation (unless there is breach of the vessel) and will cause lysis of clot if it does form.
What are the Endothelium-mediated limitation of hemostatic process?
- Prostacyclin (PGI-2)
- Antithrombin III
- Proteins C & S
- Once there is an injury the endothelium will utilize all those factors and will limit the hemostatic process. Keep it localized just to the site of injury.
What does t-PA do?
limits clots formation -digests fibrin fibers and helps to lyse a clot