Lecture 11: Hemostasis, thrombosis Flashcards
What are the primary and secondary stages of Hemostasis?
Primary: Initial vascular and platelet response to injury
Secondary: Formation of fibrin
In Primary Hemostasis, what happens in vasoconstriction?
This question is as straightforward as it sounds.
In vasocontriction, the vascular space becomes more narrow.
In Primary Hemostasis, what happens in the formation of a platelet plug?
Platelet plugs aggregate to form a platelet plug.
Platelets, migrate to the area. Adhered to exposed area and to each other.
There’s a weak link in between platelets
Through which two pathways is the formation and deposition of fibrin achieved?
Achieved through the intrinsic and extrinsic pathways of coagulation, and in some cases, both.
What is hemostasis?
Hemostasis is the arrest of bleeding from a defect in a blood vessel.
What are the regulators or hemostasis?
- The vessel wall
- Platelets
- Coagulation
How does the vessel wall regulate hemostasis?
Endothelial cells are a major component; they are on the site, can reach immediately, in a local space or can be made to react systemically by systemic mediators
How do platelets regulate hemostasis?
Thrombocytes, like the bricks and mortar. They are living structures; they are reactive structures, they are fragments of megakaryocytes.
Bone marrow assessment? One of the things we’re looking for are the # of megakaryocytes. Huge cells, multiple nuclei. Generation of platelets from megakaryocytes is essentially just fragmentation
Decreased number of platelets in peripheral blood is called thrombocytopenia. Variety of syndromes in which an animal is thrombocytopenic and that animal is at risk for bleeding out if platelets are too low.
How does coagulation regulate hemostasis?
Whole purpose is to generate fibrin
Fibrin is what holds the platelets together, holds them in a strong fashion to the vascular wall.
During hemostasis, there are both _____________ and ______________ events happening to maintain the complex homeostatic mechanism.
During hemostasis, there are both thrombus and antithrombotic events happening to maintain the complex homeostatic mechanism.
Hemostasis is a complex thing, as a thrombus or platelet plug is being formed, simultaneously other factors are being released to help break it down.
This is a diagram of what an area of platelet formation and fibrin deposition might look like. Walk me through it.
Endothelial cells are missing, due to some trauma
Platelets have been laid down
Fibrin is represented by the blue squiggles
This fibrin will also entrap anything that comes by. RBC, neutrophils, whatever. For some time, this will project out into the vascular lumen. If it stays there for too long, it can cause a problem. That’s why we want to have fibrinolysis also working to reduce that risk
What does the complex homeostatic mechanism of hemostasis allow for?
It allows clotting when necessary, and to keep blood flowing.
There are many factors work to keep blood flowing, there’s also factors to break down the clots as soon as they are no longer necessary.
We don’t want to bleed out, but we also don’t want to die of a thrombotic event just because we’re a klutz
What 4 basic events follow a vessel injury?
- Vessel contriction
- Platelet activation and aggregation
- Coagulation cascase forms fibrin
- Fibrinolysis
What is the main purpose of laying down fibrin, during the coagulation cascase in hemostasis?
The fibrin serves to lay down a meshwork, which stabilizes the primary platelet plug.
Why is fibrinolysis an important final step in hemostasis?
The long the clot stays, the more potential it has to generate a systemic clotting situation, which isn’t a good thing.
Fibrinolysis is the final step, to break down fibrin
Can measure it as FDP’s, or fibrin degradation products. Normally have some basal levels of these, at anytime.
Become critical when we have an animal that is throwing clots, or an animal that is in DIC. Will measure the level of FDP to determine what’s going on.
What are we looking at here?
The clotting cascade!
Goal: to make fibrin
Intrinsic component and Extrinsic component
Either one can then activate the common pathway
Where does the intrinsic pathway occur?
In the vascular lumen
What initiates the extrinsic pathway?
Initiated by loss on endothelial cells; that exposure of the subendothelial substrate will initiate the extrinsic pathway
What does thrombin have a role in?
- Platelet aggregation
- Fibrin
- Neutrophil adhesion
- Monocyte activation
- Lymphocyte activation
- Endothelium activation
Thrombin is a component in what part of the clotting cascade?
Thrombin is a component in the intrinsic and the common pathway. The more thrombin that’s generated, the more upstream components are activated.
In fibrinolysis, how is a clot broken down?
Plasminogen is activated (via numerous activators, including histamine and ATIII) to plasmin. Plasmin is one of the main players in the breakdown of fibrin, which leads to fibrin degradation products, or FDP’s.
Is plasminogen active in the bloodstream?
No, it has to be activated by numerous activators, including histamine and ATIII, to become plasmin.
Plasmin then gets all up in Fibrin’s bidness, breaks it down, and generates FDP’s.
Do endothelial cells help with the formation of fibrin clots, help in their break down, or both?
Both.
It’s in an endothelial cell’s best interest to keep blood moving across them.
What is a hemorrhage?
The escape of blood from the blood vascular system
Hemorrhage can be caused by rupture. What are the potential causes of this rupture?
- Trauma
- Vessel wall necrosis
- Vessel wall invasion by a neoplasm
- Primary vascular disease
When would vessel wall necrosis happen?
An animal that’s had some sort of an ischemic event
Muscles, skin, liver lobules, vessels in the area could all be affected
What’s an example of a primary vascular disease? The example Dr. F-W gave was for humans.
Humans: atherosclerosis
Parrots are also often afflicted by this, as well as certain strains of mice, rats, pigeons
What does hemorrhage look like?
This image shows a severe area of hemorrhage, affecting whole right leg
Can see an expansion of the leg
Dark red, more than just the skin is involved, also the muscles
All the subq tissues
Color change - pale, shiny to a swollen, dark red/black color
What are the two main ways that hemorrhage can occur?
Via rupture of the blood vessels, or via diapedesis.
Refresh my memory, what’s diapedesis?
Diapedesis is the passage of RBC’s through an intact vascular wall
Can diapedesis of RBC’s happen in sites of extremely high pressure?
Totally. Think about left heart failure.
Blood is leaving the right heart, going into lungs for oxygen and then it needs to travel back into the left heat. But if there’s left heart failure, there will be stasis in the lung. You’ll eventually get increased intravascular pressure in the pulmonary capillaries, and boom. Hemorrhage by diapedesis. RBC’s will exit the vascular space due to the increased pressure.
Once RBC’s leave the vascular space, can they return?
What happens to them once they leave the vascular space?
Nope, it’s a one way trip. Once they leave, they can’t rejoin the vascular space.
Once RBC’s are outside the vascular space, they are engulfed and broken down by macrophages. We can see this grossly as hemosiderin.
What are we looking at here? What is the arrow pointing to?
We’re looking at alveoli, and alveolar macrophages that have taken up RBC that were floating around. The arrow is pointing to a macrophage; they all have dark brown, punctate to globular pigment in them.
Can see free RBC’s in the alveolar spaces that haven’t been eating by a macrophage yet. Those RBC’s aren’t supposed to be in these alveolar spaces. Their death is inevitable.
What are the types, or patterns, of hemorrhage?
- Petechiae
- Ecchmyoses
- Purpura
- Paint brush, suffusive
Petechiae? What?
Tiny little red dots on the skin surface
May see them on serousal surfaces
Ecchymoses? You just made that word up.
Ecchymoses are similar to petechiae, just larger. Blotchier. 2-3 cm, red.
Tell me more about this “purpura”.
Purpura is widespread ecchymotic or petechial hemorrhages over multiple organs.
Paint brush, or suffusive, hemorrhage? You mean like Bob Ross?
Paint brush or suffusive hemorrhage is long streaky hemorrhagic lines over the serousal surfaces
What is this image showing?
This image shows both ecchymoses (larger red spots) and petechiae (small, pinpoint red dots).
What are the major mechanisms of hemorrhage?
- Endothelial/vessel injury
- Platelet dysfunction or thrombocytopenia
- Coagulation disorders, both acquired and inherited
What are some examples of acquired coagulation disorders?
- Hepatic dysfunction - big. Factor 7 is produced by the liver and if the liver is dysfunctioning, one of the first things to go is the extrinsic clotting cascade
- Vitamin K antagonism. Vitamin K is required for clotting factors 2, 7, 9, and 10. Rat baits are good at antagonizing Vitamin K, and thereby eliminating these clotting factors.
- Disseminated Intravascular Coagulation, or DIC
What is an example of an inherited coagulation disorder?
Hemophilia. Seen in humans, dogs, cats, the occasional horse.
The clinical significance of hemorrhage depends on a few things. What are they?
Depends on the amount of blood loss, the rate of the blood loss, the site of blood loss, and the duration.
Tell me more about how the amount of blood loss plays a role in the clinical significance of hemorrhage.
Loss of 40% or more of your blood puts you at risk for hypovolemic shock
Can withstand a 20-40% blood loss; the body can tolerate that without going into shock.
Tell me more about how the rate of blood loss plays a role in the clinical significance of hemorrhage.
Slow rate is preferable than losing it all at once
That is reflective of the fluid redistribution that has to occur
If you’re looking a large volume of blood, not only are you losing the RBC’s that carry oxygen, you’re also losing the fluid that is moving that whole tissue around the vascular system, over a very large space. You’re losing that ability to move things around.
Tell me more about how the site of blood loss plays a role in the clinical significance of hemorrhage.
Site of the hemorrhage can be important; depends on what is being damaged at the hemorrhage site
Into your spleen, because you’re been kicked or have a small tumor? Not that big of a deal, may actually make that into circulation.
20 mls into your brain stem? Can be fatal, quickly
Tell me more about how the duration of blood loss plays a role in the clinical significance of hemorrhage.
Bone marrow is awesome. It regenerates stuff for us all the time. But, there is a lag time. There’s a 3-4 day lag time for hematopoiesis. So, if you sustained an acute blood loss today, the regen process won’t be fully in effect until 3-4 days from now. If we lose blood rapidly, we have limited powers of regeneration
What if we had a chronic loss of blood? We might still be anemic but the bone marrow is able to try and keep up, until we get to a point of iron deficiency.
If we’re losing enough blood over time, we’re not able to replace the iron that’s lost, then your bone marrow will have a challenge. It won’t be able to replace RBC’s quickly, if it doesn’t have enough iron.
Other than clot formation, what’s another thing that can help the arrest of hemorrhage?
Pressure of surrounding tissue
If you’re suddenly got a clot forming inside and outside of a vessel, now you’ve got some swelling going on, the pressure of the surrounding tissues actually contributes to the strength of that clot.
Works great unless you’ve had massive blood loss. Then you have decreased vascular pressure and tone. That can be something that contributes to the stasis of blood, if there’s isn’t enough exterior pressure being exerted on that space.
Decreased blood pressure -> blood flow slows -> stasis -> death
What happens to blood once it’s escaped from, say, a small hemorrhage?
May not be all that noticeable
The serum gets reabsorbed, the macrophages show up, they clean up the RBC’s, and everything goes on
What happens to blood once it’s escaped from, say, a large hemorrhage?
Clot formation -> contraction of that clot will happen -> squeezes all the fluid that’s left in that clot back out into the surrounding tissue
That fluids that in the surrounding tissue will eventually drain into the lymphatics.
Macrophages and fibroblasts have are the main cell types that contribute to this process.
What happens to blood once it’s escaped from, say, a large hematoma?
Really large hematoma? Think an auricular hematoma.
Over time, the RBC are removed or broken down, but you still have a pocket of fluid. It’s called a seroma. It’s great if there’s fibrosis around that; fibrosis serves to help constrict things, tighten things down. But in the case of an auricular hematoma, there’s constant trauma. The animal is always shaking its head.
Seroma’s can be a problem, depending on where they are located. If something (like a seroma) is gravity dependent, it can be really hard to get that fluid reabsorbed.
May have a large fluid filled space on the ventrum of a horse/cow that will be hard to clean up. What if it gets injured again, or bacteria is introduced? Now you’ve got a nice bacterial playground. No bueno.
What is thrombosis?
Thrombosis is the excessive or inappropriate intravascular blood coagulation in the living animal.
What are the three main factors in the pathogenesis of thrombosis.
What is the combonation of these three factors called?
3 main factors in thrombosis:
- Endothelial injury
- Blood turbulence or stasis
- Hypercoagulability
These 3 factors together are termed “Virchow’s Triad”.
How are the endothelial injury and blood turbulence/stasis in Virchow’s triad related?
Abnormal blood flow? Say you’re a cat, with hypertrophic cardiomyopathy. The clinical abnormality there is that the left ventricular lumen is very small. There’s virtually no space for blood to enter that left ventricle, and then exit through the aorta. So blood coming back from the lung goes into the left atria as normal, and would really like to go into the ventricle, but it can’t as only a small fraction is allowed. So it shoots back up through the left AV valve, back into the atrium, and now you have blood flow coming in and going out. That’s turbulence.
The result is that it will increase that space, which is not a good thing, and every time endothelial cells are subjected to that trauma, they get a little irritated. They may be blasted off of the endothelial space. What happens when we remove endothelial cells? And there’s exposure of the subendothelium? Clot formation.
Is the left atrium a good place to have clots forming? NO.
So, abnormal blood flow can end up with endothelial injury, and vice versa.
Do you need all three of the factors of Virchow’s Triad present at the same time, to generate thrombosis?
What are those three factors again?
No, any one of these factors can result in the generation of thrombosis.
Virchow’s Triad:
- Endothelial injury
- Blood Turbulence or Stasis
- Hypercoagulability
If there’s thrombosis of an artery/vein, what will be the downstream effects?
- Ischemia
- Embolism
- Infarction
What do the effects of ischemia depend on?
The location of the ischemia, and the collateral circulation of the organ
Lung and liver have a lot of collateral blood flow
Kidney, brain, heart, spleen, testes… They have less collateral supply. A thrombotic event in one of these organs could have a more immediate and damaging effect.
Remind me what an embolism is…
The free floating of any mass in circulation, and in some cases, air.
Air bubbles in circulation can also serve as an embolism.
What will infarction result in?
The blockage of blood flow to a region will result in ischemic necrosis.
Once a thrombi is generated, what are some potential fates of it?
Fates of Thrombi:
- Propagation
- Embolism
- Fibrinolysis
- Organization/recanalization
What does propagation of thrombi mean?
Thrombi can generate further thrombi. That’s one of the reasons we don’t like them hanging around the vascular system.
I was with you with propagation, embolism, and fibrinolysis of thrombi, but organization and recanalization? What’s that?
Organization and recanalization involves the ingrowth of smooth muscle cells, fibroblasts and endothelium into the fibrin-rich thrombus. If recanalization proceeds it provides capillary-sized channels through the thrombus for continuity of blood flow through the entire thrombus but may not restore sufficient blood flow for the metabolic needs of the downstream tissue.
Taken from Wikipedia
What are Lines of Zahn?
Lines of Zahn are a characteristic of thrombi that appear particularly when formed in the heart or aorta. They have visible and microscopic alternating layers (laminations) of platelets mixed with fibrin, which appear lighter, and darker layers of red blood cells. Their presence implies thrombosis at a site of rapid blood flow that happened before death. In veins or smaller arteries, where flow is not as constant, they are less apparent.
From Wikipedia
What do Lines of Zahn look like?
This is thrombus, expanding an arteriole. Do you see the pale areas, like the rings of tree? Those are the Line of Zahn. Dr. F-W described them as “pale areas of aggregated fibrin”.
Why do we care about Lines of Zahn?
Lines of Zahn are a way for us to know that that’s truly a thrombus, and not just aggregation of fibrin that happened postmortem.
In what direction does a thrombi grow?
A thrombi will grow in the direction of blood flow.
What are we looking at here?
This is recanalization of a an occlusive mural thrombus.
Large pink area? That’s fibrin. There’s been some organization
Purple - fibroblasts that are helping to organize, arrange
Can see that RBC’s are actually passing through this structure thanks to recanalization and the relining of endothelial cells of that vascular space
Results in a more narrow space; still functional but not ideal
How awesome are you?
Totally awesome.
