Lecture 11: Hemostasis, thrombosis

Question 1

What are the primary and secondary stages of Hemostasis?

Answer 1

Primary: Initial vascular and platelet response to injury

Secondary: Formation of fibrin

Question 2

In Primary Hemostasis, what happens in vasoconstriction?

This question is as straightforward as it sounds.

Answer 2

In vasocontriction, the vascular space becomes more narrow.

Question 3

In Primary Hemostasis, what happens in the formation of a platelet plug?

Answer 3

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

Question 4

Through which two pathways is the formation and deposition of fibrin achieved?

Answer 4

Achieved through the intrinsic and extrinsic pathways of coagulation, and in some cases, both.

Question 5

What is hemostasis?

Answer 5

Hemostasis is the arrest of bleeding from a defect in a blood vessel.

Question 6

What are the regulators or hemostasis?

Answer 6

1. The vessel wall
2. Platelets
3. Coagulation

Question 7

How does the vessel wall regulate hemostasis?

Answer 7

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

Question 8

How do platelets regulate hemostasis?

Answer 8

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.

Question 9

How does coagulation regulate hemostasis?

Answer 9

Whole purpose is to generate fibrin

Fibrin is what holds the platelets together, holds them in a strong fashion to the vascular wall.

Question 10

During hemostasis, there are both _____________ and ______________ events happening to maintain the complex homeostatic mechanism.

Answer 10

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.

Question 11

This is a diagram of what an area of platelet formation and fibrin deposition might look like. Walk me through it.

Answer 11

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

Question 12

What does the complex homeostatic mechanism of hemostasis allow for?

Answer 12

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

Question 13

What 4 basic events follow a vessel injury?

Answer 13

1. Vessel contriction
2. Platelet activation and aggregation
3. Coagulation cascase forms fibrin
4. Fibrinolysis

Question 14

What is the main purpose of laying down fibrin, during the coagulation cascase in hemostasis?

Answer 14

The fibrin serves to lay down a meshwork, which stabilizes the primary platelet plug.

Question 15

Why is fibrinolysis an important final step in hemostasis?

Answer 15

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.

Question 16

What are we looking at here?

Answer 16

The clotting cascade!

Goal: to make fibrin

Intrinsic component and Extrinsic component

Either one can then activate the common pathway

Question 17

Where does the intrinsic pathway occur?

Answer 17

In the vascular lumen

Question 18

What initiates the extrinsic pathway?

Answer 18

Initiated by loss on endothelial cells; that exposure of the subendothelial substrate will initiate the extrinsic pathway

Question 19

What does thrombin have a role in?

Answer 19

• Platelet aggregation
• Fibrin
• Neutrophil adhesion
• Monocyte activation
• Lymphocyte activation
• Endothelium activation

Question 20

Thrombin is a component in what part of the clotting cascade?

Answer 20

Thrombin is a component in the intrinsic and the common pathway. The more thrombin that’s generated, the more upstream components are activated.

Question 21

In fibrinolysis, how is a clot broken down?

Answer 21

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.

Question 22

Is plasminogen active in the bloodstream?

Answer 22

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.

Question 23

Do endothelial cells help with the formation of fibrin clots, help in their break down, or both?

Answer 23

Both.

It’s in an endothelial cell’s best interest to keep blood moving across them.

Question 24

What is a hemorrhage?

Answer 24

The escape of blood from the blood vascular system

Question 25

Hemorrhage can be caused by rupture. What are the potential causes of this rupture?

Answer 25

• Trauma
• Vessel wall necrosis
• Vessel wall invasion by a neoplasm
• Primary vascular disease

Question 26

When would vessel wall necrosis happen?

Answer 26

An animal that’s had some sort of an ischemic event

Muscles, skin, liver lobules, vessels in the area could all be affected

Question 27

What’s an example of a primary vascular disease? The example Dr. F-W gave was for humans.

Answer 27

Humans: atherosclerosis

Parrots are also often afflicted by this, as well as certain strains of mice, rats, pigeons

Question 28

What does hemorrhage look like?

Answer 28

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

Question 29

What are the two main ways that hemorrhage can occur?

Answer 29

Via rupture of the blood vessels, or via diapedesis.

Question 30

Refresh my memory, what’s diapedesis?

Answer 30

Diapedesis is the passage of RBC’s through an intact vascular wall

Question 31

Can diapedesis of RBC’s happen in sites of extremely high pressure?

Answer 31

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.

Question 32

Once RBC’s leave the vascular space, can they return?

What happens to them once they leave the vascular space?

Answer 32

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.

Question 33

What are we looking at here? What is the arrow pointing to?

Answer 33

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.

Question 34

What are the types, or patterns, of hemorrhage?

Answer 34

• Petechiae
• Ecchmyoses
• Purpura
• Paint brush, suffusive

Question 35

Petechiae? What?

Answer 35

Tiny little red dots on the skin surface

May see them on serousal surfaces

Question 36

Ecchymoses? You just made that word up.

Answer 36

Ecchymoses are similar to petechiae, just larger. Blotchier. 2-3 cm, red.

Question 37

Tell me more about this “purpura”.

Answer 37

Purpura is widespread ecchymotic or petechial hemorrhages over multiple organs.

Question 38

Paint brush, or suffusive, hemorrhage? You mean like Bob Ross?

Answer 38

Paint brush or suffusive hemorrhage is long streaky hemorrhagic lines over the serousal surfaces

Question 39

What is this image showing?

Answer 39

This image shows both ecchymoses (larger red spots) and petechiae (small, pinpoint red dots).

Question 40

What are the major mechanisms of hemorrhage?

Answer 40

1. Endothelial/vessel injury
2. Platelet dysfunction or thrombocytopenia
3. Coagulation disorders, both acquired and inherited

Question 41

What are some examples of acquired coagulation disorders?

Answer 41

• 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

Question 42

What is an example of an inherited coagulation disorder?

Answer 42

Hemophilia. Seen in humans, dogs, cats, the occasional horse.

Question 43

The clinical significance of hemorrhage depends on a few things. What are they?

Answer 43

Depends on the amount of blood loss, the rate of the blood loss, the site of blood loss, and the duration.

Question 44

Tell me more about how the amount of blood loss plays a role in the clinical significance of hemorrhage.

Answer 44

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.

Question 45

Tell me more about how the rate of blood loss plays a role in the clinical significance of hemorrhage.

Answer 45

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.

Question 46

Tell me more about how the site of blood loss plays a role in the clinical significance of hemorrhage.

Answer 46

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

Question 47

Tell me more about how the duration of blood loss plays a role in the clinical significance of hemorrhage.

Answer 47

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.

Question 48

Other than clot formation, what’s another thing that can help the arrest of hemorrhage?

Answer 48

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

Question 49

What happens to blood once it’s escaped from, say, a small hemorrhage?

Answer 49

May not be all that noticeable

The serum gets reabsorbed, the macrophages show up, they clean up the RBC’s, and everything goes on

Question 50

What happens to blood once it’s escaped from, say, a large hemorrhage?

Answer 50

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.

Question 51

What happens to blood once it’s escaped from, say, a large hematoma?

Answer 51

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.

Question 52

What is thrombosis?

Answer 52

Thrombosis is the excessive or inappropriate intravascular blood coagulation in the living animal.

Question 53

What are the three main factors in the pathogenesis of thrombosis.

What is the combonation of these three factors called?

Answer 53

3 main factors in thrombosis:

• Endothelial injury
• Blood turbulence or stasis
• Hypercoagulability

These 3 factors together are termed “Virchow’s Triad”.

Question 54

How are the endothelial injury and blood turbulence/stasis in Virchow’s triad related?

Answer 54

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.

Question 55

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?

Answer 55

No, any one of these factors can result in the generation of thrombosis.

Virchow’s Triad:

• Endothelial injury
• Blood Turbulence or Stasis
• Hypercoagulability

Question 56

If there’s thrombosis of an artery/vein, what will be the downstream effects?

Answer 56

• Ischemia
• Embolism
• Infarction

Question 57

What do the effects of ischemia depend on?

Answer 57

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.

Question 58

Remind me what an embolism is…

Answer 58

The free floating of any mass in circulation, and in some cases, air.

Air bubbles in circulation can also serve as an embolism.

Question 59

What will infarction result in?

Answer 59

The blockage of blood flow to a region will result in ischemic necrosis.

Question 60

Once a thrombi is generated, what are some potential fates of it?

Answer 60

Fates of Thrombi:

• Propagation
• Embolism
• Fibrinolysis
• Organization/recanalization

Question 61

What does propagation of thrombi mean?

Answer 61

Thrombi can generate further thrombi. That’s one of the reasons we don’t like them hanging around the vascular system.

Question 62

I was with you with propagation, embolism, and fibrinolysis of thrombi, but organization and recanalization? What’s that?

Answer 62

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

Question 63

What are Lines of Zahn?

Answer 63

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

Question 64

What do Lines of Zahn look like?

Answer 64

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”.

Question 65

Why do we care about Lines of Zahn?

Answer 65

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.

Question 66

In what direction does a thrombi grow?

Answer 66

A thrombi will grow in the direction of blood flow.

Question 67

What are we looking at here?

Answer 67

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

Question 68

How awesome are you?

Answer 68

Totally awesome.