Hemodynamic Disorders – Friday September 8, 2006

Blood Circulation
~ depends on:
~ 1) Vessels
~ 2) Pressure – osmotic pressure vs. hydrostatic pressure
~ 3) Contents – plasma proteins, WBC, RBC, and platelets
~ 4) Viscosity – thickness of blood

Edema
~ 2/3 of fluids should be in cells
~ only 5% of fluid in blood pressure
Definition: abnormal accumulation of fluid in interstitial space
Causes:
~ 1) hydrostatic P  physically force fluid out of vessels
~ ex: venous obstruction
~ gravity dependant
~ 2) compression of vessels
~ 3) osmotic pressure – too little solute, fluid leaks out
~ 4) lymphatic flow – if problem with lymph flow, then the fluid filtered out of blood
vessels will not be returned  leads to decreased BP
~ also gravity dependent
~ ex: in breast CA
~ 5) concentration of NA in extracellular fluid – if too high, water will leak out
~ leads to systemic edema
Why do we care?
~ blood pressure
~ problems with oxygenation and blood flow
~ loss of function of pain
~ indicates deeper problem within the body
~ encapsulated tissues will be affected even more

Hyperemia and Congestion

~ often because of “backlog”
~ fluid stuck in vessels
Definition: local increased volume of blood in a particular tissue
Causes:
hyperemia – an active process, intentional increased blood flow to an area, drainage is
normal
~ more blood related, arteriolar dilation
~ very red blood, because the blood flow is highly oxygenated
congestion – can’t drain properly
~ more of a passive process, impaired venous return
~ end up decreasing oxygen (hypoxia) in the area, b/c the oxygen is already used up
but none is being brought there because there’s stagnation in the area
Hemorrhage
Definition: movement of an entire volume of blood outside of blood vessel wall,
extravasation of blood due to rupture of blood vessels
Causes: erosion or trauma of vessel wall
~ ex: gastric hemorrhage – bacteria in gastric wall cause erosion of the wall
Types:
~ hematoma: accumulation of blood
~ petechiae: minute hemorrhages (1-2mm) into skin, mucous membranes or serosal
sufarces
~ purpura: slightly larger hemorrhages (3-5mm)
~ ecchymoses: larger subcutaneous hematomas (bruises) from 1-2cm.

Hemostasis
Definition: accumulation of body of blood
Process:
~ endothelium:
~ when uninjured, they show antiplatelet, anticoagulant, and fibrinolytic properties
~ if injured or activated, they will show procoagulant functions
~ platelets:
~ when platelets come into contact with endothelium, they adhere to the membrane
and change shape. Next, they secrete granules causing the activation of an intrinsic
clotting pathway. Lastly, the platelets aggregate and a thrombin is generated
~ coagulation cascade:
~ enzymatic conversions that leads to formation of thrombin. Thrombin converts
fibrinogen into fibrin.

Thrombosis
Definition: inappropriate clotting, often uncontrollable, and when there is no injury to
wall
Causes: Virchow Triad (three primary influences that cause thrombus formation)
~ endothelial injury – the most important part (Ex: atherosclerosis)
~ keep in mind that there doesn’t need to be physical damage to the wall. If the
balance of prothrombotic and antithrombotic properties are disrupted, thrombosis
can occur
~ stasis or turbulence – disruption of blood flow can cause platelets to come into
contact with endothelium, prevent dilution of activated clotting factors, slow down
inflow of clotting factor inhibitors allow build up of thrombi, increase endothelial cell
activation
~ hypercoagulability – any alteration of coagulation pathways that predisposes to
thrombosis

Sequelae of Thrombi
Embolus: thrombus traveling downstream, it has propagated itself along with blood flow
~ pulmonary embolism – when an embolus travels to the heart, which can lead to MI
Occlusion: closure or blocking of blood vessel
Natural evolution:
~ propagation: thrombus may accumulate and eventually cause the obstruction of a
vessel
~ embolization: thrombi can dislodge and cause occlusion elsewhere
~ dissolution: thrombi can be removed by fibrinolytic activiy
~ organization and recanalization: thrombi can cause inflammation (organization), and
re-establish vascular flow (recanalization) leading it to be part of thickened vascular wall

Embolism
Definition: particle in blood that is not dissolved; detached mass (liquid, solid, or gas)
that is distant from its point of origin
~ most common: thromboembolism
~ usually block smaller vessels
Cause:
~ pulmonary – occulusion in heart, usually originating from deep leg veins
~ systemic – tend to start in heart, thrombus formed in heart and it flows into system

Infarction
Definition: death of tissue caused by occlusion of arterial supply or venous drainage in a
particular tissue
~ severity depends on availability of alternative blood supply, importance of oxygen to
that organ, and how fast the occlusion blocks off entire blood supply
Cause: usually from thrombus or embolus

Shock
Definition: systemic; reduction in cardiac output or circulating blood volume
Cause:
~ cardiogenic – myocardial pump failure
~ hypovolemic – loss of blood or plasma volume
~ septic – systemic microbial infection

Shock Compensation
~ through sympathetic nervous system – constriction of blood vessel to increase blood
pressure but DILATION of blood vessel to heart and brain
~ KI – retains water to increase blood pressure
~ ADH – pituitary system
~ increase blood flow to brain and heart

Shock Progression
See course notes (flow chart)

Neoplasia – Friday September 8, 2006

~ can often predict where neoplasia is more likely to happen because of anatomy

Definitions
Neoplasia – new growth, generally used to describe abnormal growth that is out of
proportion, uncoordinated with surrounding normal tissues, and continues after the
removal of the stimuli that caused the growth
~ usually the same type of cell
~ there is a loss of responsiveness to normal growth controls
Benign – localized, generally not harmful, can be removed
~ well-differentiated, resembles normal cells
~ slow growth, few exhibit mitosis
~ tend to be encapsulated, unable to metastasize
Malignant – cancerous, implies that the neoplasm will invade and destroy adjacent
structures, spread to distant sites to cause death
~ poorly differentiated, abnormal cells
~ fast growth, many mitoses
~ invades local tissues, not encapsulated, ability to metastasize
~ “oma” = benign, sarcoma = cancerous

Epidemiology
~ stress
~ genetics
~ diet
~ emotional stage
~ environment
~ age
~ anything that is at an ongoing attempt to repair

Carcinogenesis
~ nonlethal genetic damage therefore apoptosis does not happen (if it was lethal genetic
damage, the cell would undergo apoptosis)
~ involves: growth promoting and inhibiting genes, apoptosis genes, and repair genes

Autonomous Cell Growth

protooncogene – gene that regulates cell division and growth
oncogene – mutation of protooncogene and promote inappropriate cell division and
growth
Explanation of diagram:
~ starts with binding of growth factor to its receptor on cell membrane
~ activation of growth factor receptor, which activates signal0transducing proteins (RAS)
~ the signal is transmitted across cytosol into the nucleus via second messengers
~ causes induction and activation of nuclear regulatory factions that initiate DNA
transcription
~ eventually process enters cell cycle, causing cell division and growth

Insensitivity of Growth Inhibition

Tumour suppressor genes
~ responsible for moving cells into quiescence (non-proliferative)
~ responsible for moving cells into post-mitosis (differentiated and looses replicative
potential)
TP53 – tumor suppressor gene, one of the most commonly mutated genes in human
cancer
~ signals cell to fix itself or to undergo apoptosis
~ if TP53 senses DNA damage, it will initiate cell cycle arrest
~ if DNA damage is not successfully repaired, then TP53 will direct the cell to
undergo apoptosis
~ so if TP53 is damaged, then cell with DNA damage will continue to grow and
replicate

Lack of Apoptosis
Overexpression of genes can protect cancer cells from undergoing apoptosis

Infinite Replication
~ with each cell division telomeres (located at ends of chromosomes) are shortened
~ after 60-70 doublings, the loss of telomeres leads to massive chromosomal
abnormalities and death of cell
~ to avoid dying, cancerous cells activate telomerase (enzyme) which can maintain
normal telomere length
~ telomerase is in stem cells but not in somatic cells

Angiogenesis
Required for nutrition and metastasis
Angiogenic factors produced by:
~ cancer cells themselves
~ inflammatory response

Metastasis
Not all cells in a tumour can metastasize
Metastatic cascade is divided into two phases: invasion of ECM and vascular
dissemination
1) Invasion of ECM
~ detachment of cells from tumour
~ attachment to matrix
~ degradation of matrix
~ migration of cells
2) Vascular dissemination

Tumour Progression
Increasing malignancy over time – because the strongest ones stay, treatment will kill off
weaker malignant cells

Carcinogens
1) chemicals – damage cells via free radical damage
2) radiation – UV rays / X-rays
3) viruses and infections

Host Reaction
CD8+ cytotoxic T cells – label Ag, activate NK cells
NK cells – try to attack tumour cells
Macrophages – engulf and consume
Antibodies – mediated by T cells and NK cells, and also use NK cells to mark tumour
cell for destruction

Clinical Assessment
Physical exams and pathological evaluation
Location – crucial depending on where the tumor is located (can cause other problems
such as blocked ducts or compressed gland tissues)
Ulceration – consequent bleeding and lead to secondary infection
~ if protrudes into gut lumen, it can get dislodged and travel elsewhere causing
occlusion
Cachexia – wasting syndrome (loss of body fat and lean body mass with profound
weakness, anorexia, anemia)
Paraneoplastic syndromes – symptoms other than cachexia that can’t be explained by
local or distant spread of tumour
~ important to note these because they can represent early manifestation of neoplasm,
because they can represent other clinical, maybe lethal, problems, and because they
can mimic metastatic disease and interfere with treatment

Grading and Staging

Important for prognosis and tracking
Grading  microscopic
Staging  macrosopic
~ T – tumour (size 1 – 4)
~ N – involvement of nymph nodes? (1 – 3)
~ M – presence or absence of metastasis (0 or 1)
Worth noting: staging has proved to be a greater clinical value than grading

Laboratory Diagnosis
Tumor sample and testing
~ morphological testing
Biochemistry
~ biochemical assays for tumor-associated enzymes, hormones, tumor markers
~ can not be a modality for diagnosis of cancer, but can help in determining the
effectiveness of therapy
Molecular analysis
~ using molecular techniques to diagnose tumours and predict their behaviour