2. Pathogenesis- sequence of events in the response of cells or tissues to the etiologic event
3. Morphologic change - structural alteration in cells or tissues that are either characteristic of the disease or diagnostic of the etiologic event.
4. Clinical manifestation - The nature of the morphologic changes and their distribution in different organs or tissues influence normal function and determine the clinical features, course, and prognosis of the disease.
The increase in the number of cells?
An increase in the size of individual cells?
A decrease in cell size and function?
The normal stages of cellular response to stress and injury
During times of stress and increased demand the cell adapts, if there is an inability to adapt the cell will die. If the stimulus is injurious the cell will die. Cell injury is reversible up to a certain point but if the stimulus persists the cell reaches the point of no return and suffers irreversible cell injury and death.
What are the two principle patterns of cell death?
1. Necrosis - Response to abnormal stresses such as ischemia and chemical injury. Always pathologic.
2. Apoptosis - Cell dies through activation of an internally controlled suicide program. Eliminates unwanted cells in embryogenisis and also occurs in some pathologic events.
What is deposited at the site of cell death?
Metabolic derangements cause what?
The intercellular accumulation of a number of substances.
Increased physiologic demand or increased tropic stimulus?
Decreased nutrients or stimulation?
Chronic irritation (chemical or physical)
Reduced oxygen supply, chemical injury, or microbial infection? Acute
Acute reversible injury
Reduced oxygen supply, chemical injury, or microbial infection? Progressive and severe
Irreversible injury leading to cell death- necrosis or apoptosis
Reduced oxygen supply, chemical injury, or microbial infection? Mild chronic injury
Subcellular alterations in various organelles
Induction of adaptation?
factors produced by the cell or surrounding cells
activation of cell surface receptors and downstream signaling molecules
Requirement for cells to undergo hyperplasia?
Capable of DNA synthesis and cell division
Two divisions of physiologic hyperplasia?
hormonal - increase of the female breast at puberty and uterus during pregnancy
compensatory - increase tissue mass after damage or resection. The liver can regenerate. After nephrectomy the other kidney enlarges and makes up for the lose.
Mechanism of hyperplasia?
Increase in local production of growth factors, increase in the number of growth factor receptors, or activation of intercellular signaling pathways.
-All lead to in increase production of transcription factors leading to cellular proliferation.
Liver stem cells only proliferate if hepatocytes proliferation is compromised.
Pathologic hyperplasia constitutes a fertile soil in which cancerous proliferation may occur.
Causes of Pathologic hyperplasia?
excessive hormonal stimulation or growth factors acting on a target.
Increased size of cells is due to what?
Synthesis of more structural components.
Increase or decrease in cellular DNA during hypertrophy?
Increase do to the arrest of the cell cycle without undergoing mitosis
Cause of hypertrophy?
Increased functional demand or by specific hormonal stimulation.
Genes induced during CARDIAC hypertrophy?
Induction of embryonic genes - Beta myosin in place of alpha myosin.
Transcription factors -
Growth factors - TGF-B, IGF-1, FGF
Vasoactive agents- alpha adrenergic agonists, endothelin-1, angiotensin II.
Atrial natriuretic factor ANF?
Secreted by the fetal atrium and ventricle and then by the adult atrium, response to pressure and volume change by regulating salt excretion to regulate volume and pressure.
ex. increased atrial pressure due to excess venous return leads to higher levels of ANF excretion and an increase in urine production by the kidneys.
Two types of hypertrophic triggers for the heart.
1. mechanical - stretch
2. trophic- growth factors and vasoactive agents secreted by non myocytes.
When does cardiac failure happen?
when the muscle reaches it limit for enlargement and is no longer able to compensate.
Common causes of atrophy? physiological and pathological
1. Decreased workload
2. Loss of innervation
3. Diminished blood supply
4. Inadequate nutrition- use of muscle for energy after fat stores are used up.
5. Loss of endocrine stimulation- loss of estrogen after menopause results in atrophy of the endometrium, breast, and vaginal epithelium.
7. pressure - enlarged benign tumor can compress and cause atrophy of surrounding tissue.
Atrophied cells may have a diminished function but are not dead.
can die if blood supply is inadequate for even the atrophied cell.
Function of the ubiquin-proteasome pathway?
degradation of cytosolic and nuclear proteins.
Proteins are first conjugated to ubiquin then degraded within protease's.
Stimulated by glucocorticoids and thyroid hormones
Inhibited by insulin.
Cytokines such ad TNF are capable of increasing muscle proteolysis in this way.
reversible change from one cell type to another. May represent an adaptive substitution where one cell type is better suited to withstand an adverse environment.
-most common is columnar to squamous, in the respiratory tract in response to chronic irritation. The new cells can survive but the special feature of mucus secretion is lost.
Esophageal squamous cells are changed to columnar under the influence of refluxed gastric acid.
Bone formation in muscle after bone fracture
Mechanism of metaplasia?
Not a change in the phenotype but reprogramming of the stem cells in the tissue or of undifferentiated mesenchymal cells in connective tissue.
BMP's induce chondrogenic or osteogenic expression of stem cells while repressing differentiation to muscle of fat.
Causes of cell injury?
1. oxygen deprivation-
Family pulmonary hypertension?
BMP-2 receptor mutation,
Largest resistance of air flow ( anatomy), healthy vs disease?
Healthy- large bronchi
Disease - bronchioles
-cleave surface gp of Va and VIIIa
-stimulates the release of t-PA
-inactivates inhibitors of t-PA
-can not bind clot bound plasmin
-allows the destruction of a fibrin clot without the destruction of fibrinogen in circulation
not an enzyme but an allosteric modifier of human plasminogen that allows plasminogen to autocatylitically activate itself
Plasminotigen activator release
- bleeding into soft tissues (hematomas)
cofactor in the gamma carboxilation of factors 2,7,9,10
the carboxilation is of the glutamate side chain
carboxilated side chains bin to calcium and then to activates platelets
mostly thrombin but has some activity on 8,9,10,11
High molecular wieght heparin
Will bind to other plasma protein then AT3, this can cause the active amount in the blood to be reduced and spontaneous thrombi can be generated
heparin binds to platelet factor four
induces a conformational change in PF4 causing the immune system to not recognize it
antibodies are made against heparin PF4 complex
when antibodies bind the platelets become activated
bines vit K reductase enzyme needes to regenerate vit K
reduced gamma carboxilation, factors can not bind calcium or form complexes after coagulation is initiated
also blocks protein S and C
pentasaccharide that enhances AT3 interaction with Xa
HIT is not a complication since fondaparinux does not bind for PF4
Direct thrombin inhibitors?
Hirudin- discovered in leeches
bivalrudin, high binding aftinity for thrombin with a transient affect
Glucocorticoids inhibit collogen synthesis
Factor released by platelets to cause vasoconstriction?
Four mechanisms to hemostasis?
1. vascular constriction
2. platelet plug
3. blood coagulation
4. growth of fibrous tissue
Contactile fibers contained in platelets
actin, myosin, thombosthenin
Ion stored by platelets?
Calcium, dence granual
Functions of platelet derived growth factor
causes vascular smooth muscle, vascular endothelial cells, and fibroblasts to grow and multiply
Molecule on platelet surface that activates clotting (generic)
Half life of platelets and method of distraction
8-12 days, tissue macrophages, mainly spleen
when platelets bind to the endothelium what causes the release of granolas?
three location of vWF
platelets, endothelium, circulation
Two secretions of platelets that activate more platelets?
ADP, thromboxan A2
Responsible for plugging thousands of vascular holes daily?
major functional unit of clot retraction?
Two outcomes of a blood clot?
1. can be invaded by fibroblasts and form connective tissue, promoted by PDGF, 1-2 weeks
Three essential steps of blood coagulation?
1. formation of a complex of activated substances called prothrombin activator, rate limiting step in blood coagulation
2. The activator catalyzes prothrombin to thrombin in the presence of calcium
3. Thrombin convers fibrinogen to fibrin
Prothrombin activator is formed in result of?
damage to special substances in the blood
Name and function of GPIIb/IIIa?
prothrombin receptor, on the cell membrane of platelets already bound to damaged tissues
prothrombin and bradykinin
Does fibrinogen leak of of vessels?
no, it is too large.
During pathological conditions vascular permeability can increase enough to let it out
Reticulum of a blood clot?
Long fibrin chain attached to clot
Fibrin stabilizing factor, site of storage and function.
released by activated platelets and cross links fibrin monomers by covalent bonds
Origin of serum?
after a clot is formed the platelets contract and squeeze out all the fluid, this fluid is serum.
does not contain clotting factors
Failure of a clot to retract indicates?
low platelet level
Platelets release what that cause clot contraction?
ATP and calcium to activate actin/myosin and thrombosthenin
Thrombin is proteolitic
factors activated thrombin act on
2, 8, 9, 10,11, and 12
three initiating events of prothrombin activator formation
1. trauma to vascular wall
2. trauma to blood
3. contact of blood with collagen
Two pathways of prothrombin activator?
Intrinsic- damage to blood
Extrinsic-damage to vascular wall
Factor that activates prothrombin activator?
What is released form damaged blood vessels to initiate the extrinsic pathway?
tissue factor, tissue throboplastin
Two main proteins of prothrombin activator
X and V and calcium
factor X is the protease in this complex, V accelerates the action
thrombin itself has posotive feedback on factor V
Initiation of the intrinsic pathway?
blood trauma, release of factor XII (activated when it contacts collagen surface or glass)
exposure of of blood to collagen
Cleavage of XI by XII needs?
HMW kininogen, accelerated by prekallikrein
Activation of X in the intrinsic pathway by?
VIII and IX
Steps on blood coagulation that do not need calcium
XII activating XI and XI activating IX
Function of citrate ion?
De-ionize calcium to stop coagulation in collected blood
Function of oxalate ion?
precipitate calcium out of solution to prevent clotting
Speed of two clotting pathways?
extrinsic is much faster then intrinsic
Three factors that prevent clotting in the normal endothelium?
1. smoothness of endothelium
2. layer of glycocalyx, mucopolysacharide
3. thrombomodulin and heparin on surface
Two function of thrombomodulin in anticoagulation?
binds thrombin and removes it from circulation
complex activates protein C which cleaves V and VIII and causes the release of t-PA
Two most powerful thrombin removers?
ATIII and fibrin mesh (prevents the spread of clot)
Largest site of heparin production?
mast cells, large amounts in lung and liver to stop the coagulation of slow moving venous blood
I, V, VIII, XII
Plasmin is caught in the fibrin mesh and combined into the clot
Disease or damage to what organ can cause bleeding problems
5 vit K dépendent coagulation factors?
II, VII, IX, X, protein c
Cause of vit K deficiency?
liver fails to secrete bile into the GI tract, obstruction of the bile duct or liver disease, prevents adqauate fat absorption
Inheritance of hemophilia A
two compound of factor VIII
factor VIII and von willebrands factor (protects factor 8 in circulation)
difference in bleeding with hemophilia a and thrombocytopenia?
thrombocytopenia is small vessels and hemophilia in large
spleenectomy and whole blood transfusion are helpful
widespread clotting in the circulation
usually occurs with large amounts of traumatized or dying tissue that releases tissue factor into the blood
can remove many clotting factors and eventually cause bleeding
Clotting disorder with septicemia
DIC, caused by bacteria or endotoxins, part of the reason septic shock is lethal.
Time for warfarin effect
12 hours 50%
24 hours 20% clotting power
oxalate is toxic to the body
can citrated blood be re-infused
yes the liver will convert the citrate to glucose within a couple minutes
what is hyperemia?
increased blood flow to activated tissues
PT time is a measure of what?
concentration of prothrombin in the blood
bacteria membrane receptor
Toll like receptor
How does renal failure cause metastatic calcification?
secondary hyperparathyroidism due to phosphate retention.
Cause of movement of gas from one point to another?
partial pressure difference
pO2 of alveolar and pulmonary arterial blood and blood leaving the aorta
104 and 40 and 95
Two reasons for increase in oxygen diffusion capacity during exercise?
increase in open pulmonary capillaries, more ideal retaliation perfusion ratio
blood is fully oxygenated about 1/3 of the way through the capillary
ejection volume of rt ventricle to lt
left ejects 2-3% more volume due to addition of bronchial circulation
an increase in blood flow through a tissue will increase the tissues pO2
vita B deficiency that affects cell oxygen utilization
disables cytochrome oxidase activity, cell can not utilize oxygen
End effect of an increase in tissue metabolism on interstitial pCO2
as pO2 rises so does the saturation of Hb
amount of oxygen 1g of Hb can combine with?
amount of O2 (ml) in 100ml of blood
under normal conditions how much oxygen is delivered to the tissues per 100 ml of blood?
5ml, can increase to 15ml during heavy exercise
What factors cause muscle pO2 to stay constantly at 40mmHg during exercise
increase in cardiac output
decrease in affinity for Hb, raise in temp CO2, 2.3DPG and decrease in pH
percentage of blood that gives up its oxygen as it passes through the capillaries
as oxygen is delivered to the tissue Hb releases more oxygen into the blood
chronic hypoxic condition increase what?
2,3, DPG (poor tissue blood flow)
What is the main limiting factor what blood pO2 is greater then one for tissue metabolism?
effects of oxygen poisoning?
brain convolutions and death
What binds to the same site on Hb and oxygen but with a high affinity?
CO, partial pressure of 0.4 will allow CO to equally compete with O2 for binding to Hb. 0.6 is lethal
In CO poisoning what is the affect on blood pO2?
normal, no obvious signs of hypoxia
since pO2 is not depressed there is no low O2 feedback mechanism to increase respiration
can treat with pure oxygen and CO2 in the blood to increase breathing
amount of CO2 transported from the tissues to the lungs in the blood per 100ml blood
CO2 is higher in the venous blood causing an increase in production of H2CO3, this then dissociates and the H is buffered by Hb and the bicarb is exchanged for Cl. The chloride content of venous blood is less then arterial blood
Water moves into the cell to maintain the osmotic equilibrium and causes the cell to swell.
carbonic anhydrase inhibitor, can cause tissue pCO2 to reach 80
what is carbaminohemaglobin?
CO2 bound to the terminal amine group of Hb
pKa is around 7 so 50% is available at blood pH
volume percent change for CO2
52in venous blood to 48 in arterial, 4ml/100ml blood
What is the Haldane effect?
the binding of oxygen to Hb displaces CO2 from the blood in the lungs
The combination of oxygen with Hb causes Hb to become a stronger acid
The more acidic Hb has less affinity for CO2 at the terminal amine group
The increased acidity of Hb causes it to release more H that in turn bind with bicarb and form water and CO2, the CO2 is released from the lungs
This effect doubles the amount of CO2 released from the blood in the lungs and double the amount picked up in the tissues. from 2ml to 4ml.
Normal pH of arterial and venous blood?
7.41 and 7.37
Respiratory exchange ratio?
volume percent of CO2 over the volume percent of O2
Usually in the range of 82 %
using mainly carbohydrates for metabolism increases
using fates for metabolism decreases
Decreases in the fasting and starved states
Disease states that promote pulmonary embolism in situ?