BIOL 2292: Lecture Notes

Lecture 1: Intro to Hemodynamics

Hemodynamics
Hemodynamics: flow of blood through blood vessels

 Purpose of blood flow:

o Deliver vital nutrients, gases, water, and hormones to tissues/cells
o Removes wastes
 Two routes in the circulatory system with one pump (heart)
o Pulmonary: supplies O2 to blood
o Systemic: supplies blood to the tissues
 Microcirculation
o Exchange of wastes and nutrients occurs in the capillaries
 Nutrients diffuse from vessels  into the interstitial fluid  capillaries
 Wastes diffuse from cells  into interstitial fluid  vessels
 Shit that can go wrong in blood
o Edema: increased in interstitial fluid because of changes in vascular permeability, blood pressure,
or blood osmolarity
 E.g., inflammation can make vessels more permeable
o Hyperemia/Congestion: Extra blood in vessels
o Inappropriate clotting
 Thrombosis  when there is no injury but a clot is there
 Can turn into embolism
 Embolism  when thrombosis starts to break off and go to other parts of the body
o Failure to clot when necessary  hemorrhage
o Hypertension  heart attack, stroke, kidney disease
o Hypotension  shock
 Not enough BP  tissues not being perfused sufficiently
 Primary problem
o Problem with the CV system itself
 E.g., direct damage to vasculature or systemic problem such as hypercoagulability
 Secondary problem
o Due to other problems; CV system is fine
 E.g., kidney disease or bacterial infection

Dynamics of Capillary Exchange

 The movement of water and solutes is influenced by BHP and BOCP

o BHP: force of fluid it exerts against walls inside a container (i.e., blood vessel)
 Drives fluid into the IF, because the force is stronger  fluid accumulates overtime, but
lymphatic system drains fluid and returns it back into the blood stream via thoracic duct
o BCOP: pressure exerted by the proteins (albumin, clotting factors, Abs) inside the blood
 Draws solids back into blood

Edema: I already explained what this was in the previous page

 Can be classified by location

o Localized – cerebral edema, ascites
 o Generalized – anasarca
 Can be classified by origin of fluid
o Transudate (watery, protein-poor fluid)
 Edema caused by increased BHP or decreased BOCP
 E.g., liver failure, renal failure
o Exudate (protein-rich fluid)
 Edema caused by leaky vessels or vascular damage
 E.g., trauma and infection  inflammation
 Causes
o Increases in vessel leakiness or increases in blood hydrostatic pressure
o Decreases BOCP
o Lymphatic blockages (almost always localized)
 Fluid cannot be drained from IF

Renin-Angiotensin-Aldosterone pathway (RAA)

 Regulates fluid balance

o Dehydration, sodium deficiency or hemorrhage leads to the kidneys secreting more renin
 Because the three things listed all lead to a decrease in blood volume  decrease in
blood pressure. The decreased blood pressure signals the kidneys to increase renin
o Renin converts angiotensinogen into angiotensin I
o And then ACE converts angiotensin I into angiotensin II
o Angiotensin II
 Vasoconstriction of the arterioles  increased BP until it returns to normal
 Sends signal to adrenal cortex to secrete more aldosterone  increased Na+ and water
reabsorption in the kidneys  increased blood volume  increased BP

 RAA pathway and Edema (in patients with CHF)

o Because there is low cardiac output there is reduced renal perfusion, this leads to activation of the
RAA pathway  Na+ and water reabsorption  fluid accumulates in veins because the pump
isn’t circulating it  increased venous BHP  more fluid forced into the tissues
o There is also reduced liver perfusion  reduced aldosterone breakdown  Na+ and water
reabsorption  fluid accumulates in the veins  diluted blood proteins  decreased BCOP 
less fluid is reabsorbed because not enough BCOP can pull the fluid back into the veins
o Combined leads to edema

Types of Edema

 Subcutaneous edema
 Cerebral edema
 Pulmonary edema
 Dependent edema – depends on gravity
 Periorbital edema
 Anasarca
- Pitting is a common sign

Consequences of Edema

 Can impair wound healing

  Increases risk for infections
 Compression of vital tissues
o E.g., brain or lungs
 Compression of vascular supplies

Cerebral Edema

 Dangerous because brain is confined in cranium that is not flexible  increase pressure in the brain
 3 kinds of edema
o Vasogenic – increased permeability of vasculature
 Fluid accumulates in extracellular spaces
 E.g., neoplasms, infections, toxins, hemorrhage
o Cytotoxic edema – neurons swell with fluid
 Fluid accumulates within brain cells
 E.g., ischemia
o Interstitial edema – fluid accumulates in ventricles
 Problem with cerebral spinal fluid (CSF) flow (hydrocephalus)
 E.g., congenital, neoplasms, infections
 Characteristics of brain with edema
o Flattened gyri and narrow sulci
o Affected persons experience nausea, vomiting, disorientation, and seizures
 Intracranial pressure can force the brainstem downward, through the foramen magnum (not a condom
brand)
o This is fatal because the brain stem controls our basic functions that let’s us live laugh love (i.e.,
resp, heart rate, consciousness, BP and sleep) so if it gets squished or gets moved, these functions
can be altered and may cause fatal complications

Edema in other body spaces

 Heart, lungs and abdominal organs are surrounded by serous membranes – i.e., pericardium, pleura, and
peritoneum
o Serous membranes line the internal cavities
 Accumulation of fluids in the serous membranes leads to impaired organ function
 Pleural effusion: fluid accumulation in pleural space
o Can be caused by; CHF, liver cirrhosis, kidney disease
o Can lead to lung compression and collapse
o Patient experience dyspnea, painful cough
 Pericardial effusion: fluid accumulation in the pericardium
o Can be caused by; neoplasms, infection, autoimmune
o Hemopericardium: accumulation of blood in the pericardium due to hemorrhage
 The blood leaks into the pericardium space (blood from the chambers)
o Can cause cardiac tamponade (compression of cardiac chambers)
 Because the fluid in the pericardium squishes the heart and prevents it from pumping
 Ascites: fluid accumulation in the peritoneal cavity
o Caused by; neoplasms, liver cirrhosis, inflammation, CHF
o Abdomen can become extremely distended
o Patients show loss of appetite, vomiting, shortness of breath
o Chylous ascites: accumulation of lipid-rich lymph fluid in peritoneal cavity if thoracic duct is
blocked
Hyperemia

 Hyperemia is a higher than normal amount of blood in a tissue or organ

 Active hyperemia: physiological response to body’s needs
o E.g., skeletal muscles needing more oxygen when pumping those guns and pressing those benches
o Or increased flow to skin to dissipate heat
 Arteriole dilation increases blood flow to the capillaries
 Tissue becomes red (erythema)
 Passive hyperemia: due to impaired venous flow
o Blood not leaving because of possible clot blocking it or heart is not pumping
o Blood backs up in tissue
o Increased pressure may cause edema, or rupture of capillaries leading to hemorrhagic foci
 Can occur systemically due to heart failure, or locally in cases of venous blockage
 If condition persists, affected tissues appear cyanotic due to accumulation of deoxygenated blood in
affected vessels
o Can lead to hypoxia and necrosis in affected tissues

Hemorrhage

 Escape of blood from a ruptured vessel

 Failure of large vessels most often caused by trauma, invasion by tumour, atherosclerosis, inflammation
 Can also be caused by improper coagulation
o E.g., genetic disorders, drugs, vitamin deficiencies (i.e., Vitamin K), liver failure (not making
fibrinogen), blood malignancies, chemo
 Some hematomas (blood collecting in a tissue) can be large enough to be fatal
 Large bleeds are named by location
o E.g., hemothorax, hemopericardium, hemoperitoneum, hemarthrosis
 Petechia = 1-2 mm hemorrhages into the skin caused by platelet disturbances, infections
 Purpura = >3 mm can be due to the same as the girly above or result of trauma, vasculitis, vascular fragility
 Ecchymosis = 1-2 cm subcutaneous hematomas that change in colour as blood is degraded

 Consequences of Hemorrhage

o A person could lose 20% of blood volume without major impact (even more if the loss is slower)
 Greater loss leads to hemorrhagic (hypovolemic) shock
o Site of hemorrhage also important
 Even small accumulations in closed spaces of skull can be deadly
o Chronic blood loss can lead to anemia
 E.g., small gastrointestinal bleeds

Hemostasis and Thrombosis

 Hemostasis = ‘still blood’

o Clotting to prevent blood loss during vascular injury
 Thrombosis = pathological hemostasis
o Clotting when there is no vascular injury that needs to be plugged
o Thrombus forms within a vessel
 Homeostasis involves tightly controlled system of enzymes and cofactors
 Hemostasis and thrombosis depend on three key players
o Blood vessel endothelium
o Platelets
 o Coagulation cascade

Lecture 2: Hemodynamic Disorders

Hemostasis and Thrombosis

Hemostasis: a physiological response to injury to vasculature

Thrombosis: no injury to vasculature

 Hemostasis and thrombosis depend on:

o Blood vessel endothelium
o Platelets
o Coagulation cascade

Endothelial Cells

 Express anticoagulant and procoagulant factors to regulate hemostasis

Platelets

 Come from bone marrow; they are not cells

 Platelets are normally circulating in the bloodstream
o They get activated once they come into contact with collagen (found under the endothelium layer):
 Adhesion – bind to extracellular matrix
 Activation – change shape and release of granule contents and other factors e.g., Ca2+,
ADP, thromboxane A2 (these activate more platelets)
 The change in shape helps them stick to each other easier
 Aggregation – platelets fuse together to form platelet plug
 The plug fills in the hole
 Continuous positive feedback loop until platelet plug forms

Coagulation Cascade

 Intrinsic and Extrinsic converge into one Common pathway

o Intrinsic – trigger is the collagen that sets off the cascade
 I.e., damage within the blood vessel
o Extrinsic – triggered by TF; released by tissues
 i.e., happens outside the blood vessels
o in reality both pathways will be activated, making clotting more efficient
 if one pathway is not working properly clotting will take longer
o Common pathway
 Converts prothrombin  thrombin converts fibrinogen  fibrin
o Requires cofactors like Ca2+ and vitamin K

Clinical Assessment of Coagulation

 Prothrombin time (PT)

o How long it takes for blood sample to clot through extrinsic pathway and common pathway
 Takes citrated plasma and add tissue factor, phospholipids and Ca2+ and measure time to
clot (normally 11-13)
 Used to derive INR
 If PT is long it means they are more prone to bleeding; if short. They are clotting faster
  Activated partial thromboplastin time (aPTT)
o Assesses function of proteins in intrinsic and common pathways
 Same thing as above but they add negative charge (glass) instead of TF (normally 30-40
seconds)
 Thrombin time (TT)
o Strictly assessing function or levels of fibrinogen
 Add excess thrombin to citrated plasma and measure time to clot (normally 15-20
seconds)

 Platelet count, as part of CBC

o Normal range = 150 000 – 450 000 / uL
o < 150 000 – thrombocytopenia
o > 450 000 – thrombocytosis
 Peripheral smear
o Number of platelets
o Gross morphological characteristics of platelet functions

Thrombosis – Virchow’s Triad

 Virchow’s Triad include three predictors that will lead to thrombosis
o Abnormal blood flow
 Turbulence
 E.g., aneurysm – abnormal dilation of vessel walls
o Cause turbulence because it can disrupt the blood flow
 Stasis – blood sitting in blood vessel
 Means there is prolonged contact time to coagulation factors  clotting
o Hypercoagulability
 Primary (genetic)
 Secondary (acquired)
 E.g., oral contraceptives, pregnancy, HRT, cancer, aging, smoking, obesity
o Endothelial injury
 Loss of endothelial cells
 Exposes collagen (at this point you should know why this is bad)
 Disrupted balance between pro- and anti- coagulation factors
 o

Thrombosis

 You should know what a thrombosis is composed of (clot)

o They show lines of Zahn (alternating bands of light platelets + fibrin with darker red blood cells
 Thrombi are attached to underlying vascular surface but prone to fragmentation and embolization (you
should also know what embolization is)

Arterial Thrombi

 Most commonly found in the aorta and its major branches

o Coronary, cerebral, mesenteric, renal arteries
 This is because they are more prone to turbulence
 Main causes
o Damage to endothelium (e.g., ruptured atherosclerotic plaque)
o Turbulence or slowing of blood flow (e.g., aneurysm)
o Increased blood coagulability (e.g., polycythemia)

Venous Thrombi

 Most occur in the veins of legs

o E.g., sinuses above valves
 Main causes
o Reduce venous return (e.g., lack of exercise, heart failure, defective venous valves, age, bed rest
following surgery
o Hypercoagulability (e.g., genetics, oral contraceptives)
 Thrombi in superficial veins can cause pain and swelling but seldom form emboli
o Blocked vein  reduced flow through tissues  hypoxia
o Congestion can make skin in the area vulnerable to infections
 Not medical emergency because superficial veins don’t have much smooth muscles
around it that contracts and cause thrombi
 Deep vein thrombosis (DVT) is dangerous – e.g., femoral, popliteal
o often asymptomatic ( ~50%) because collateral vessels form
o possibility of embolism
 dangerous because they are more likely to embolize to the lungs and form a pulmonary
embolism

Fate of Thrombus

1. dissolution: clot may dissolve due to fibrinolysis

2. propagation: thrombus continues to grow
a. increased risk of blocking vessel or embolization
 3. Embolization
a. Embolus gets lodged in a vessel  ischemia  infarction
4. Organization and recanalization
a. Organization – connective tissue invades thrombus
b. Recanalization – blood vessels form through thrombus
i. Making alternate paths for blood to flow through
ii. Not ideal because its not as big as og vessel  decreased blood flow
c. Thrombus becomes incorporated into vessel wall

Treatment/Prevention of Thrombosis

 Diagnoses that might required anticoagulants:

o Patients at risk for developing clots
 Afib (irregular atrium rhythm  not sending blood efficiently  stasis  clot
formation), CAD, hypercoagulability disorders
o Patients who have had clots
 DVT, ischemic stroke, myocardial infarct, pulmonary embolism
 Major risk of treatment
o Bleeding
o Increased vascular calcification when vitamin K is inactivated
 Blocking vitamin K  Ca2+ gets deposited into CV system and impairs function
o Thrombolytic drugs can embolization
 Because they can cause the clot to breakdown into fragments

Disseminated intravascular coagulation (DIC)

 Complication of a variety of conditions associated with thrombin activation

o E.g., obstetric disorders, trauma, cancer, sepsis
 Sudden, insidious onset of widespread fibrin thrombi in the microcirculation
 Can cause diffuse circulatory insufficiency particularly in the brain, lungs, heart, and kidneys
 Platelet and coagulation protein consumption (by widespread thrombi)  bleeding catastrophe

Embolism

 Embolus: anything that can travel through the circulation, get stuck, and obstruct blood flow
 Blockage leads to ischemia which leads rapidly to necrosis (infarction)
 Thromboemboli are the most common
o Origin is thrombus
o Emboli can also be fat, nitrogen, bacteria, tumour fragments, bone marrow

Pulmonary Embolism

 Most emboli form in the deep veins of the legs

 Venous thromboembolism most commonly present as DVT + pulmonary embolism
 Develops in surgery patients > age 40
o Risk increases with age, length of surgical procedure, obesity, cancer, pre-existing venous
problems
 Any prolonged inactivity puts person at risk
 Clinical manifestations depend on size and location of clot
o Small emboli can be asymptomatic
o Moderate sized emboli can cause dyspnea, tachypnea, hemorrhage, and hemoptysis (couging
blood with sputum)
o Large emboli can cause chest pain, heart failure, and shock
  Treatment
o Prevention by reducing risk of thrombosis
 E.g., anticoagulants
o Inferior vena cava filters
 But they introduce turbulence
o Thrombolytics
o Embolectomy

Other forms of emboli

 Fat and marrow embolism

o Fat released by marrow or adipose injury enters circulation
o Due to skeletal injuries, soft tissue trauma, burns, CPR
 Air embolism
o Surgical incision, intravascular catheters, laparoscopic procedures, chest wall injuries, scuba
diving
 Amniotic fluid embolism
o Amniotic fluid containing fetal epithelial cells and lanugo enters maternal circulation through open
uterine and cervical veins
o Can trigger systemic inflammation response, cardiorespiratory failure, DIC

Infarction

 Ischemic necrosis because of a blocked artery or impaired venous drainage

 Common cause of death when it occurs in the brain, heart or intestines
o If not fatal, scar tissue will form
 Mostly caused by arterial thrombosis or arterial embolism (because arteries deliver oxygenated blood)
o Flow is usually not completely blocked by venous thrombosis due to opening of collaterals
 Infarcts can be classified by colour (red vs white) and presence of infection (septic vs bland)

Hemorrhagic infarcts are red

 Occurs in organ with rich blood supply (e.g., lungs)

o Affected tissue turns necrotic and fills with blood form surrounding non-blocked vessels
o Tissue must be loose enough for blood to accumulate
 E.g., lungs, small intestines

Anemic infarcts are pale or white – absolute lack of blood

 Occur in solid organs with end-arterial circulation – only supplied by a single vessel
o Blockage occurs in the only artery that feeds the tissue
o Tissues is dense and does not have much space for blood to accumulate
 E.g., heart, kidney, spleen

Brain infarction

 Typically result in liquefactive necrosis  cysts becoming full of fluid

Factors that influence development of an infarct

 Nature of vascular supply

o Is tissue receiving dual or single blood supply
  Rate of occlusion development
o Slowly developing occlusions allow time for alternate perfusion pathways to form
 Vulnerability to hypoxia
o Neuronal cells undergo irreversible damage in 3-4 min without O2
o Myocardial cells die after 20-30 min
 Oxygen content of blood
o Anemic or cyanotic patients are at higher risk

Lecture 3: Hemodynamic Disorders

Blood Pressure

 BP: force exerted on vessel walls as blood is flowing through CV system

 Generated by ventricles of heart

Determinants of Blood Pressure

 BP = CO x SVR
o SVR – system vascular resistance
o CO – cardiac output
 HR x SV

Shock

 Happens when circulatory system fails

 Due to reduction in cardiac output, loss of blood of increase in vascular space
o This is because not enough pressure in cardiovascular system to push blood throughout the body
 Reduced delivery of oxygen and nutrients and impaired removal of wastes
o All lead to systemic hypotension and hypoperfusion
 If it happens to quickly or too long you DIE

Four main types of shock

1. Cardiogenic shock  achy breaky heart

a. Damage to the heart leads it to not being able to pump enough blood
i. Myocardial infarction and arrhythmias
2. Obstructive shock
a. Blockage that prevents adequate filling or output
i. Pulmonary embolism, cardiac tamponade (you should know what both of these hoes do)
3. Hypovolemic shock
a. Blood volume low so not enough blood to fill the vessels
i. Hemorrhage, diarrhea, burns, dehydration
4. Distributive shock
a. Systemic vasodilation resulting in impaired distribution of blood – the entire vessels in the system
are dilated
 i. Normally our body prioritizes which tissue should be getting more blood and which don’t
– by dilating or constricting vessels in that tissue
ii. Anaphylactic shock – type I hypersensitivity  histamine release  vasodilation and
increased vascular permeability
iii. Neurogenic shock – brain or spinal cord injury  impaired SNS  vasodilation
iv. Septic shock – systemic inflammatory response to microbial infection  vasodilation
 Blood vessels become leaky

Pathophysiology of shock

 Failure of myocardial pump (idk why she just doesn’t say heart), decrease in blood volume or systemic
dilation  hypoperfusion  hypoxia
 Hypoxia leads to formation of free radicals (remember what Father Paul taught you)
 Endothelial cell damage
o Increases vascular permeability, further decreasing volume
 Impaired function of multiple systems
o Acidosis, hypercoagulability
 Acidosis occurs because cells acid is a by product of glycolysis which cells use to make
ATP since there is no more oxygen
 Multiple organ dysfunction  morbidity and DIE

Three Stages of Shock

 Non-progressive stage
o Body’s compensatory mechanisms work to maintain adequate perfusion
o Falling BP triggers compensatory mechanisms
 Capillary BHP drops  less fluid being pushed out of vessels
 Hormones (e.g., ADH, RAA pathway) act on kidneys to increase blood volume
 By reabsorption of sodium
 Auto-regulation in brain and heart to dilate blood vessels to maintain perfusion
 Baroreceptors detect reduction in pressure and signal cardiovascular center in medulla
oblongata via sympathetic NS
 Increase heart rate and contractility
 Vasoconstriction (V/c) in peripheral blood vessels, directing blood to heart and
brain
 Progressive stage
o Compensatory mechanisms begin to fail
o Situation is still reversible, but worsening
o In the lungs
 Tachypnea and dyspnea as lungs try to compensate for hypoxia
 Gradual onset of pulmonary edema
o In the kidneys
 Extensive vasoconstriction (to reduce urine production)  reduced GFR  oliguria
(reduced urine output)
o As lungs and kidneys fail, acidosis develops
 You should know why acidosis develops
o Acidosis interferes with normal vasomotor response – vasoconstriction and vasodilation
 Small blood vessels dilate and blood begins accumulating
  Further decrease in cardiac output
 Accumulating blood becomes hypoxic
 Endothelial cell injury sets in
 Disruption to normal coagulation pathways  DIC
o Acidosis may also effect mental function, leading to confusion
o Tissues become hypoperfused
o Circulatory and metabolic problems get worse
 Irreversible stage
o Game over for the girlies
o Widespread cell death
 Lysosomal contents leak out, causing further damage
 Ability of heart muscles to contract gets worse
 Necrosis in large intestine may allow bacteria into circulation, increasing risk of septic
shock
 Tubular necrosis in kidneys leads to kidney failure
o DIC leads to infarctions in organs
o Death is inevitable

 Clinical manifestation of shock

o Clinical manifestations
 Tachycardia – to compensate for reduced cardiac output
 Pale and cool skin – because body is prioritizing sending blood to heart and brain instead
of skin
 Peripheral vasoconstriction
 Oliguria
 Reduced blood being sent to the kidneys  reduced urine production

Treating Shock

 Severity and outcome depends on immune status, presence of co-morbidities, pattern of pathogenesis,
extent and virulence of infection
 Management can include:
o Antibiotics, fluids, epinephrine
o Securing airway, blood transfusions
 Goal of treatment is to increase urine output (shows that we are back to perfusing organs, also helps to
restore body’s pH) and blood pressure
 Prognosis
o Survival is ~90% in young, healthy peeps
o Poor outcome for cardiogenic and septic shock