General Pathology 300 (thrombi, emboli, infarcts) Flashcards
thrombosis define
local coagulation or clotting of the blood in a part of the circulatory system.
thrombosis define.
Transformation of a fluid into a solid
Clotting of whole blood into an aggregate of blood cells & fibrin
fibrin define
Fibrin – a polymerized fibrinogen
fibrinogen define
a soluble protein present in blood plasma, from which fibrin is produced by the action of the enzyme thrombin.
fibrin function
Forms mesh network of thin filaments binding blood cells to form thrombus or hemostatic plug
thrombus define
a blood clot formed in situ within the vascular system of the body and impeding blood flow
“pathogenesis” of thrombi
..
where do thrombi form
Thrombi form only in living organisms
what is thrombi formation part of
End products of the coagulation sequence
what is normal function of thrombi
Normally activated to prevent blood loss from disrupted vessels
how does pathological thrombosis occur?
If coagulation sequence activated in intact vessels pathological thromboses develop
coagulation sequence activated in intact vessels
pathological thrombosis
normal blood?
consists of protein-rich fluid (plasma) and blood cells (formed elements)
blood circulating depends on
blood must be fluid and blood cells must be freely suspended
Fluidity results from
factors that promote coagulation and those that inhibit it
clotting vs anti-clotting –> homeostasis
Under normal conditions, clotting and anti-clotting are in balance
which mechanisms promote / counter-act thrombosis
Clotting factors and platelets promote thrombosis
and endothelial cells and plasmin counteract it
which THREE factors determine intravascular coagulation
Intravascular coagulation is the result of interaction between:
- Coagulation proteins
- Endothelial cells
- Platelets
- Coagulation proteins
Cascade sequence of activation
culminates in thrombin
what does thrombin do
Thrombin is a catalyst, promoting polymerization of fibrinogen into fibrin
what does fibrin do
Meshwork of fibrin is the framework for the clot which includes blood cells and proteins
intrinstic pathway, extrinsic pathway –> common pathway
..
- Endothelial Cells
Normal resting endothelial cells have antithrombotic function, but if activated will initiate coagulation.
resting vs activated endothelial cells
resting endothelial cells have antithrombotic function, but if activated will initiate coagulation.
how are endothelial cells “activated”
Can be activated by inflammation or trauma
what activates endothelial cells
Cytokines activate endothelial cells
E.g. of cytokines that activate endothelial cells
Can initiate thrombosis
E.g. IL-1 and TNF
IL-1
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses
TNF
Tumor necrosis factor is a cytokine and member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain
- Platelets
Neutralize heparin and other anticoagulation factors
heparin define
Heparin is an anticoagulant (“blood thinner”) that stops your blood from forming blood clots or making them bigger.
It can help a blood clot dissolve faster, but it can’t break it down
heparin vs warfarin
Heparin: Heparin works to inhibit the blood clotting reactions caused by thrombin and fibrin by inactivating these proteins.
Warfarin: Warfarin functions as a vitamin K antagonist. Vitamin K functions to regulate the production of the cofactors, and warfarin functions to prevent vitamin K from performing this function.
what do platelets release
Secrete thromboxane
Coagulation stimulation
thromboxane define
Thromboxanes, a substance produced by platelets, lead to occlusion of blood vessels by fueling blood clots inside the vascular system.
Thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2
what about small thrombi
Small thrombi wash away easily
Degraded by thrombolytic chemicals like plasmin
about pathologic thrombus formation
Virchow’s Triad (predisposing factors)
Virchow’s Triad
Virchow’s triad or the triad of Virchow describes the three broad categories of factors that are thought to contribute to thrombosis.
Virchow’s Triad:
- Endothelial cell injury
- Hemodynamic changes
- Hypercoagulability of whole blood
- Endothelial Cell Injury
Intact endothelium has anticoagulant properties
Under influence of inflammatory mediators, endothelium loses antithrombotic properties
(becomes coagulant)
- Hemodynamic Changes
Disturbed normal laminar flow resulting in turbulence and margination
laminar flow define
Laminar flow is the property of fluid particles in fluid dynamics to follow smooth paths in layers, with each layer moving smoothly past the adjacent layers with little or no mixing.
margination define
- : the act or process of forming a margin. specifically : the adhesion of white blood cells to the walls of damaged blood vessels.
velocity vs laminar flow
Slow blood flow results in sedimentation & blood eddies
blood eddies define
a circular movement of water, counter to a main current, causing a small whirlpool.
“An eddy is a movement of fluid that deviates from the general flow of the fluid. An example for an eddy is a vortex which produces such deviation.”
thrombi in slow/sluggish bloodstream
Small thrombi not dissolved by thrombolytic substances tend to persist or even grow in sluggish bloodstream
- Hypercoagulability
Blood is hypercoagulable in severe burn victims probably due to severe fluid loss and hemoconcentration
hemoconcentration
An increase in the concentration of blood cells resulting from the loss of plasma or water from the blood stream.
why else can blood be hypercoagulable
Also in cancer, chronic cardiac failure and pregnancy
pregnancy, hypercoagulability
Pregnancy-induced hypercoagulability is probably a physiologically adaptive mechanism to prevent post partum hemorrhage.
Pregnancy changes the plasma levels of many clotting factors, such as fibrinogen, which can rise up to three times its normal value.
Thrombin levels increase. Protein S, an anticoagulant, decreases.
cancer hypercoagulability
A hypercoagulable or prothrombotic state of malignancy occurs due to the ability of tumor cells to activate the coagulation system.
cardiac failure, hypercoagulability
Several studies have shown that patients with heart failure have increased plasma concentrations of beta-thromboglobulin, a marker of platelet activation.
Classification of thrombi: based on location
…
Intramural thrombi
mural endocardium – attached to wall of heart chambers and commonly found overlying myocardial infarction
mural define
MEDICINE
relating to or occurring in the wall of a body cavity or blood vessel.
(intra)mural thrombi
Mural thrombi are thrombi that attach to the wall of a blood vessel and cardiac chamber.
Mural thrombus occurrence in a normal or minimally atherosclerotic vessel is a rare entity in the absence of a hypercoagulative state or inflammatory, infectious, or familial aortic ailments.
Valvular thrombi
“attaches to valves”
fibrinous growths in debilitated persons
mimics endocarditis
aka non-bacterial (marantic) or sterile thrombotic endocarditis
marantic endocarditis
Formerly known as marantic endocarditis, which comes from the Greek marantikos, meaning “wasting away”.
The term “marantic endocarditis” is still sometimes used to emphasize the association with a wasting state such as cancer.
Nonbacterial thrombotic endocarditis.
aka “sterile thrombotic endocarditis”
what does Endocarditis do to heart valves
Bacterial endocarditis causes clumps of bacteria and cells start to form on the heart valves.
These clumps can break free into the bloodstream.
They can then cause damage by blocking other blood vessels.
They can also spread the infection to other organs.
non-bacterial (thrombotic) endocarditis
Non-bacterial thrombotic endocarditis (NBTE) is a disease characterised by the presence of vegetations on cardiac valves, which consist of fibrin and platelet aggregates and devoid of inflammation or bacteria.
Arterial thrombi
attached to arterial wall
cover ulcerated atheromas in aorta or coronary arteries
atherosclerosis / aneurysms
atheroma define
Atheroma refers to the fatty material that clogs your arteries. It builds up over time and can lead to complications.
Atheroma (plaque) is the defining feature of a disease called atherosclerosis.
When you have atherosclerosis, you have plaque buildup in your arteries.
venous thrombi
common in varicose veins
chronic may lead to organized granulation tissue and inflammation (thrombophlebitis)
granulation tissue define
Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process.
Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size.
thrombophlebitis
thrombus
vein
inflammation
“Thrombophlebitis is swelling (inflammation) of a vein, often caused by a blood clot (thrombus) in the vein.”
Microvascular thrombi
in arterioles, capillaries, venules
Typical of Disseminated Intravascular Coagulation (DIC)
Disseminated Intravascular Coagulation (DIC)
“Disseminated intravascular coagulation is a condition in which blood clots form throughout the body, blocking small blood vessels.
Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts of the body.
As clotting factors and platelets are used up, bleeding may occur.”
Thrombi can also be classified on the basis of their gross (external) appearance:
Red (conglutination) thrombi
Thrombi in small vessels are red
composed of tightly intermixed RBCs and fibrin
conglutination
to unite by or as if by a glutinous substance.
to become conglutinated. blood platelets conglutinate in blood clotting.
Layered (sedimentation) thrombi
distinct layering of cellular elements and fibrin
white lines – Lines of Zahn
Thrombi in large arteries, veins, mural thrombi
Lines of Zahn
Lines of Zahn are a characteristic of thrombi.
They have layers,
with lighter layers of platelets and fibrin,
and darker layers of red blood cells.
why in larger arteries/veins?
They are more present on thrombi formed with faster blood flow, more so on thrombi from the heart and aorta.
Fate of thrombi – depends on:
Size, location, hemodynamics of vessel
Most small thrombi lysed without consequence
Larger thrombi remain attached to surface of vessel wall or endocardium
what can happen? What is attachment initially mediated by?
Attachment initially mediated by adhesion molecules such as fibronectin or fibrin
fibronectin atherosclerosis
Extra domain A of cellular fibronectin (FN-EDA) is known to cause insulin resistance, atherosclerosis, tissue fibrosis, ischemic stroke
ATTACHMENT VIA
adhesion molecules such as fibronectin or fibrin
what can thrombus stimulate
Eventually thrombus can stimulate ingrowth of inflammatory cells and vessels
granulation tissue, anchor – “organization”
Granulation tissue forms firmer anchorage - organization
“organization” define (thrombus)
Organization of the thrombus -
the vessel wall under the thrombus suffers hypoxia and undergoes necrosis, which is destroyed by reparative inflammation
(along the fibrin fibers penetrate blood vessels and fibroblasts, i.e. granulation tissue - the thrombus is organized by granulation tissue, resulting in thickening of the vessel wall under the thrombus).
other possible events
Inflammatory cells of granulation tissue dissolve the thrombus
Granulation tissue replaced by collagenous fibrous tissue
Occlusive thrombi can be recanalized
Can become break of and become emboli
Can block b.v. leading to infarction
granulation tissue vs fibrous (scar) tissue
During the next few weeks, the granulation tissue is gradually replaced by fibrous scar.
During this period, collagen type III is slowly replaced by collagen type I and the wound acquires tensile strength.
thrombotic occlusions of cardiac and cerebral arteries
Thrombotic occlusions of cardiac and cerebral arteries are a major cause of death in US
clinical Sx of thrombotic occlusion (?)
Clinical symptoms depend on site, extent of thrombi, rapidity with which they form, duration of thrombosis, widespread nature of disease, complications
occlusion of lumen causes
Occlusion of lumen of blood vessel causes ischemia
most common cause of Myocardial infarct
Sudden thrombotic occlusion of coronary arteries most common cause of myocardial infarction
Chronic Heart Failure (Congestive Heart Failure)
occlusion over time
Slowly narrowing of lumen of blood vessel and decrease in blood flow results in hypoxia and reduced function of affected organ over time (chronic heart failure)
thrombus vs embolus
Thrombus can become detached become free flowing in blood - embolus
chronic heart failure
Chronic heart failure, otherwise known as congestive heart failure or heart failure
what can emboli do
Emboli can become lodged in arteries and lead to infarct
cerebral infarct
Cerebral infarct - stroke
thrombus can accelerate the development of…
Thrombus can accelerate the development of atherosclerosis
thrombus vs infection
Thrombus can become infected
infected thrombus braeking off (?)
Can break off - septic emboli
Emboli
Embolus - a freely movable, intravascular mass that is carried from one anatomical site to another by blood
Emboli – plural
Embolism define
MEDICINE
obstruction of an artery, typically by a clot of blood or an air bubble.
“Embolism – infarct caused by embolus”
Classification of emboli
Thromboemboli
Liquid emboli
Gaseous emboli
Solid particle emboli
Thromboemboli
thrombi carried by venous or arterial blood
Liquid emboli
fat emboli following bone fracture;
amniotic fluid emboli in veins
amniotic fluid emboli
What is amniotic fluid embolism? Amniotic fluid embolism (AFE) is a rare and life-threatening complication that occurs when a pregnant person gets amniotic fluid into their bloodstream just before, during or immediately after childbirth.
bone fracture emboli
When you break a bone, fat tissue from the bone marrow can leak into your blood.
“Fat embolism syndrome is a rare condition that usually follows breaking a major bone. It most often happens when you break your pelvis or a bone in your legs, but can rarely occur with other medical conditions or circumstances.”
Gaseous emboli
air injected into veins;
air liberated under decreased pressure (caisson disease or decompression sickness)
air embolism
When an air bubble enters a vein, it’s called a venous air embolism. When an air bubble enters an artery, it’s called an arterial air embolism.
These air bubbles can travel to your brain, heart, or lungs and cause a heart attack, stroke, or respiratory failure.
Air embolisms are rather rare.
why air injected?
A syringe or IV can accidentally inject air into your veins.
Decompression sickness (Caisson disease)
Decompression sickness (DCS; also called divers’ disease, the bends, aerobullosis, and caisson disease) is a medical condition caused by dissolved gases emerging from solution as bubbles inside the body tissues during decompression.
DCS most commonly occurs during or soon after a decompression ascent from underwater diving, but can also result from other causes of depressurisation, such as emerging from a caisson, decompression from saturation, flying in an unpressurised aircraft at high altitude, and extravehicular activity from spacecraft.
DCS and arterial gas embolism are collectively referred to as decompression illness.
Solid particle emboli
cholesterol, tumour cells, bone marrow
MOST COMMON EMBOLI (most clinically significant)
Thromboemboli are the only clinically significant emboli; all others are rare
what can all emboli do
All emboli can occlude blood vessels resulting in decreased blood supply to organ (ischemia)
VENOUS EMBOLI
Originate in veins
Carried by venous circulation
Typically lodge in pulmonary artery and cause pulmonary embolism
Smaller emboli cause pulmonary infarcts —> subpleural pain
pulmonary embolism
A pulmonary embolism (PE) occurs when a blood clot gets stuck in an artery in the lung, blocking blood flow to part of the lung.
NOTE:
Different from Bronchial arteries (from descending aorta) that supply O2/nutrients to lung tissue itself
pulmonary infarct
Pulmonary infarction is one of the key complications of pulmonary embolism (PE).
“It is important to note that infarction invariably occurs in a subpleural location, whilst malignancy or pneumonia can occur centrally.”
Arterial emboli
Common cause of ischemia in spleen, kidney, intestines
Usually originate from cardiac A) mural or B) valvular thrombi
Can also originate from aorta
ARTERIAL EMBOLI FRAGMENTATION
THEREFORE tend to…
Arterial emboli mechanically fragmented inside vessels because arterial blood flows fast and disrupts them
THEREFORE?
Therefore tend to lodge in small and medium-sized arteries
THEREFORE, where is greatest risk?
Greatest risk in cerebral circulations
“mechanically fragmented”
—> “Therefore tend to lodge in small and medium-sized arteries”
most common cerebral artery and infarct
Typically lodge in middle cerebral artery and cause infarcts of BASAL GANGLIA
morality of “
Associated with high mortality and neurological defects
Splenic emboli/infarcts can cause this SSx
Infarcts that develop from splenic emboli cause sharp subcostal pain
Renal infarct/emboli
Renal infarcts are painful and associated with hematuria
(blood in urine)
Intestinal infarct/emboli
Intestinal infarct – medical emergency; can cause gangrene of intestines
renal infarct prognosis
Outlook. Renal infarction 30-day mortality was 11.4% in a retrospective analysis of 44 individuals with atrial fibrillation and renal infarction.
pulmonary embolism SSx
dyspnea
hemoptysis (coughing blood)
pain
sudden death
Infarction
Sudden insufficiency of blood supply resulting in an area of necrosis
most infarction caused by
Most are caused by thrombi or thromboemboli
classification of infarction (origin)
May be classified by origin as arterial or venous
classificaiton of infarction (appearance)
Can be further classified by appearance as white or red
White or pale infarcts
Typical of solid organs
E.g. heart, kidney, spleen
Ischemic necrosis paler than surrounding tissues
marble skin / mottled appearance (White Infarcts)
Blood may infiltrate from collateral arteries resulting in mottled appearance
mottled
mottle:
marked with spots or smears of color.
Red infarct
Typical of venous infarction
E.g. Particularly of intestines or testes
Circulation can be interrupted by twisting organ
E.g. torsion of testes
Why Red ?
It happens due to the inability of blood to exit the infarcted area.
The area becomes congested, causing an accumulation of blood around the site.
Red infarcts occur in organs with multiple blood supplies, such as the lungs, liver, intestines, and testes.
E.g. of location (Red Infarct)
organs with multiple blood supplies,
such as lungs, liver, intestines, and testes.
Fate of infarcts – depends on…
Anatomic site
Circulatory status
Capacity for repair
mitotic vs post-mitotic tissue –> regeneration capabilities of necrotic tissue after infarct
Ischemic necrosis of post-mitotic cells (e.g. heart) cannot be repaired - only replaced with fibrous tissue (scarring)
Necrotic brain cells also not repaired, but liquefactive necrotic tissue resorbed
—-> leaves clear fluid-filled cyst
mitotic tissues / facultative mitotic tissues – after infarcts
Mitotic tissues and facultative mitotic tissue heal with relatively few defects – e.g. liver
exception even with mitotic tissues
However, large infarcts may be impossible to regenerate completely
—> Leaves scarring
—> Loss of function
