---start path.lec.04.18.97---

Dr. Chacko
circulatory disturbances
handout given a while ago.

dr chacko will read the note service notes and add to them as needed, so 
no need to write down everything he says (ha ha).

review of the vascular system:

we had this in anatomy, histology, physiology.
think of biology of vascular system. what does it look like, how does it 
function.

aorta leaves heart - this is an ELASTIC ARTERY because there is a lot of 
elastic fibers in the wall. also smooth muscle cells. there is a tunica 
intima (endothelium, basement membrane, and elastic lamina)- if you peel 
off endothelial cells will see the "internal elastic lamina" -the 
thickness of intima varies with size of artery, tunica media- muscular 
layer, and adventitia- contains a lot of mesenchymal cells eg 
fibroblasts/myoblasts. also, the thick arteries like aorta need their own 
blood supply. the blood from the lumen can feed the inner part, but the 
outer part has its own arteries penetrating into it - those are the vasa 
vasorum. small branches of arteries supplying the larger arterial walls. 
why are there all those elastic laminae? needs to be strong, have recoil 
pressure. less elastic tissue in abdominal aorta and more distal 
branches. 

distributing aka muscular arteries: on section you see less elastic 
tissue/no elastic tissue, more collagen, and more smooth muscle

smaller branches have endothelium, internal elastic lamina, and some 
layers of smooth muscle

arterioles: lumen, endothelium, one layer of smooth muscle

capillary: endothelium and basement membrane with a few smooth muscle 
cells and pericytes which can become smooth muscle.

note:
you would consider that the smooth muscle is all the same, but they are 
different cells. there is only one gene that makes myosin, but there are 
different myosin isoforms. aortic smooth muscle has one kind, muscular 
arteries have a different myosin isoform - the ATP binding site is 
different, has twice the ATPase activity, can work twice as hard. elastic 
arteries have myosin with less atpase activity. aorta doesn't have to 
contract as much, has good recoil and is high pressure system. but 
muscular arteries have to contract, as do arterioles - vasomotion, etc. 
if arterioles just opened up, capillaries would burst.

large veins: not much but some elastic fibers, collagen, smooth muscle 
cells.
as veins get smaller, wall thickness decreases. always thinner than 
aorta; veins often are collapsed if not full at the moment.
venule - smallest veins

don't worry about this too much, try to understand the biology so you can 
understand the pathology.

from physio we know it is important that blood constituents can clot, in 
case of injury - we need to stop bleeding to maintain circulatory 
homeostasis. but when we get clotting in a living animal inside the 
cardiovascular system, anytime this happens, we call it a thrombus. 

thrombus components are the same as a blood clot, but a clot forms 
rapidly and a thrombus forms gradually.

what prevents thrombus formation in normal animal?

endothelial cells: provide smooth lumenal surface for vasculature. are 
contact inhibited. are arranged in one layer. if there is damage to one 
endothelial cell, the neighboring cells will divide, when they touch a 
neighbor cell, will stop dividing (contact inhibition). so very smooth 
surface. but endothelial cells aren't just passive. they have an active 
function. 

endothelial cell surface has a glycocalyx that contains heparan sulfate 
which prevents platelet aggregation - important. prevents clotting. also, 
endo cells make prostacyclin, which prevents platelet aggregation. so 
blood is constantly exposed to prostacyclin. endo cells ALSO convert ADP 
to adenosine. so, in vicinity of endo cells you have more adenosine, less 
ADP, and ADP is needed for platelet aggreggation. so an intact 
endothelium is extremely important in prevention of thrombus formation. 
if endothelium is damaged, clot will form.
also, the clotting components we learned about need to be normal. if we 
get them out of balance, there can be spontaneous clots or other weird 
problem.

also, circulation is important. blood flow should be constant, not become 
stagnant. stagnation can damage endothelium and cause clotting to occur.

HOW IS THROMBUS FORMED:
if there is damage to endothelial lining, platelets will aggregate. we 
get a fibrin network, cells get caught in it, thrombus starts to form. 
it's a gradual process. blood flows through and gets caught. artery tries 
to correct this a number of ways. the endothelial cells start dividing 
and try to cover the endothelial defect. in some cases, that works. they 
cover the thrombus, that is. so no more thrombus forms. also, sometimes, 
thrombus will "organize". So thrombus formation is nothing more than 
gradual formation of the clot. some books mention "lines of zahn" - we 
don't need to know that name. but understand that the line of zahn 
distinguishes thrombus from clot. clot forms fast. is homogenous, red, 
kinda elastic. but thrombus forms gradually. if you section it, there are 
lines in it. not homogenous. this is because it forms gradually. it is 
firmer, and can break up more easily - isn't elastic like a clot. it is 
kind of dry, very dry. then, the platelets, when they contract, liberate 
granules with PDF, stimulating the cells in the wall - causing 
proliferation of smooth muscle or other myogenic cells, which proliferate 
and migrate to this area, and at the same time, causes infiltration of 
inflammatory cells - PMNs and mphages, which try to phagocytose the 
thrombus and lyse the thrombus. so we have a stage of resolution. know 
difference between formation - formation of thrombus - and organization - 
what happens as it is forming. thne you get resolution: PMNs break down 
fibrin, mphages too. new collagen and elastin is made by fibroblasts, 
smooth msucle cells proliferate - this is happening at base of thrombus - 
this is organization of the thrombus. the endothelial cells still try to 
proliferate and cover the thrombus - "re-endothelialization".

sometimes, depending on size, endo cells can cover it, sometimes they 
can't. also, in this process, the thrombus is kind of dry, and at this 
stage of resolution we develop cracks or spaces in the thrombus during 
this organization. if you have a thrombus which is so big it occludes or 
nearly occludes the artery, the endothelial cells won't be able to cover 
it, but will go into the cracks in the thrombus, and will stop if/when 
they meet other endo cells on other side. so you can make a canal through 
the thrombus in this manner - "re-canalization". sometimes this will 
restore normal blood flow. sometimes you will form a nubmer of canals. so 
organization is resolution (removal of fibrin, necrotic cells), 
reendothelialization, recanalization. this is how thrombus becomes 
organized.

everyone get it? good. now, depending on - thrombus can form anywhere 
there is blood. in heart, valves, chambers, arteries, vein, anywhere 
there is blood and endothelial damage. depending on where it forms and 
how it forms, pathologists give them different names. if thrombus occurs 
on a heart valve, we call it valvular thrombosis. also arterial 
thrombosis, venous thrombosis, etc. if thrombus occludes an artery, it is 
an occluding thrombus. usually if it forms like that, there's no 
infective agent, just endothelial damage caused by a number of factors eg 
iatrogenic from injections, or whatever.

usually when thrombus forms there is no infectious agent - so we call it 
a BALD THROMBUS. or sterile thrombus. on the other hand, sometimes, you 
have say endocarditis, bacterial endocarditis, damaging valvular 
endothelium, causing thrombus to form. this thrombus will have bacteria 
in it. bacteria grow in it. so we call this a SEPTIC THROMBUS.

that's enough terminology. what does a thrombus do? occlude blood 
vessels, cause ischemia, hypoxia. causes tissue death. infarct. in heart, 
causes myocardial infarction, in brain, stroke, etc. so it cuts down or 
cuts off blood supply to an area. if small thrombus, may not occlude 
whole thing, maybe isn't a huge problem. or maybe will cause small 
infarct, but not affect organ function. so effects depend on size of 
artery, size of thrombus, etc. also, it depends on whether it is bald or 
septic. if it is septic, that produces more inflammation at the site, 
increasing size of the thrombus. another thing to think of wrt sequelae 
to thrombus, is - they form gradually, are dry, and can break off, 
causing embolism. again, if embolism comes from bald thrombus, will just 
cause occlusion and infarct.  if septic, can cause an infection at the 
site where it lodges - will often form abscess. 

about embolism...what is embolism? ANY foreign material that circulates 
in blood and gets lodged in a vessel. not only thromboemboli. here, we 
are talking about a piece of thrombus, but you could also have something 
else in there. a fat embolus - if fat animal has a bone fracture or 
something, fat can enter the circulation, or air embolism can also occur 
with trauma, or a parasitic embolus eg if a heartworm dies or something. 
a good example of air embolism is the use of air to euthanize an animal 
whch used to occur a long time ago. 20 cc of air injected by syringe can 
kill a rabbit. a small amt of air isn't significant, though. also, you 
can see tumor emboli - if you have a metastatic neoplasia, tumor cells 
can get into blood supply and occlude small arteries, and start new 
masses there.

often on a slide you see an artery with internal elastic lamina and 
surrounding muscle layer....and you see a vein near it, much smaller 
lumen since it is collapsed. often the way to tell a capillary is that it 
has blood in it. 

slide: dog with thrombus in heart. someetimes we see small thrombus form 
in LA, at a site of endothelial damage. it forms, attached to atrium, and 
it gets bigger, since there is some stagnation of blood, and then 
sometimes it gets detached, but still gets bigger, because it is sitting 
in the atrium...this is BALL THROMBUS. this can sometimes get out AV 
valve and lodge in the aorta. here we see one lodged in the aorta. once 
it lodges, more clot forms on top of it and it grows. this is a "saddle 
embolism" - it lodges where the iliacs come off the abdominal aorta. 

if you do autopsy, how do you tell thrombus from embolism? need to look 
for primary site. sometimes, if ball thrombus wsa origin, you can't see 
where it came from. if you look carefully, may be able to see increased 
fibrosis at site. also, if it is an embolism, if you lift it up, it will 
just come off, isn't attached. thrombus will be attached, because it has 
formed there. another way to check is to try lifting and checking for 
primary damage to endothelium. if there is an atherosclerotic lesion, you 
know that it is a thrombus that formed there, likely.  one problem - 
sometimes a large embolism will lodge in there and IT will damage the 
endothelium, so local reaction will occur, and then it is really hard to 
say if it formed there or came from somewhere else. then we call it maybe 
a thromboembolism - we aren't sure which. clot is darker than thrombus. 

atherosclerotic lesion causes stenosis, causing a mural thrombus - 
thrombus forms on wall of artery w/o occluding it. emboli can break off 
of it. if it grows to occlude the area, it becomes an occlusive thrombus.  
that can cause a stagnation thrombus behind it.

atherosclerotic lesions thmselves can rupture and cause emboli.

arteritis can cause thrombus formation as well (arterial inflammation).

slide; bacterial endocarditis - AV valve has large thrombus on it. this 
is valvular thrombosis or vegetative endocarditis. 
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