Patho-Exam 2
CHAPTER 11
Have a working knowledge of these terms:
Viruses: protein coat surrounding nucleic acid core – no metabolic enzymes of their own; rely on host.
Bacteria: cells without membrane-bound organelles (prokaryotes); can live independently: release exotoxins or endotoxins when destroyed (gram neg).
Fungi: most require a cooler temperature than human core body temp – most infections on surface of body.
Parasites:
Protozoa: malaria, amoebic dysentery, giardiasis.
Helminths: roundworms, tapeworms, flukes.
Athropods: ticks, mosquitoes, mites, lice, fleas.
…itis (suffix): indicates INFLAMMATION or INFECTION.
…emia (suffix): abnormal blood condition.
Sepsis or septicemia: bacterial toxins in the blood.
Virulence: make an infection more likely to cause disease.
Toxins – endo/exo.
Adhesion factors help infective organism stick to the body.
Evasive factors help keep immune system from killing agent.
Pathogen: cause disease.
Opportunistic pathogen: microflora that can cause disease if your health/immunity are weakened.
Microflora: microorganisms NORMALLY living in or on body – some useful, many no effect.
Epitopes: small part of an antigen; ex: spike protein.
Antigen: foreign substance; a marker that tells immune system if something is harmful or not.
Active immunity: results when body produces antibodies in response to antigen.
Passive immunity: results when a person is given antibodies to a disease.
Cytokines: primary means of communication between cells.
Chemokines: subset of cytokines – direct movement of leukocytes – secreted by macrophages and T-Cells.
Opsonin / Opsonization: marks or targets a substance/pathogen for phagocytosis.
Describe infectious process in terms of:
How humans may be infected:
Direct contact with a pathogen.
Ingestion of a pathogen.
Inhalation of a pathogen.
Contact with zoonosis – animal pathogens that can jump to humans.
Contact with nosocomial – hospital acquired.
Contact with a fomite – objects capable of harboring pathogens.
Five stages of infection:
Incubation: active replication without symptoms.
Prodromal: early signs and symptoms like fever and fatigue.
Acute: maximum manifestations – tissue damage and inflammation.
Convalescent: contain infection, eliminate pathogen, repair damage.
Resolution: total elimination, no residual manifestations.
Barriers that protect humans from infection:
Skin – physical barrier.
Stomach acid.
Mucus and cilia – particularly in respiratory tract.
Earwax.
Tears.
Compare/contrast innate and adaptive immunity in terms of:
Cells involved including each cell’s role in immunity:
Innate – myeloid line from bone marrow.
Macrophages, NK cells, dendritic cells, neutrophil, eosinophil, basophil.
Adaptive – lymphoid line.
B cells – eliminate extracellular microbes, create memory for faster response.
Memory cells – prepare for subsequent antigen exposure.
Plasma cells – create immunoglobulins (antibodies) that perform opsonization.
T cells (CD4 – helper) – binds to MHC II.
CD8 (cytotoxic) – binds to MHC 1.
Both – T cells and Natural Killer T cells.
Lymphocytes without antigen specificity.
Macrophages and Dendritic cells act as APCs and present epitopes to CD4 on MHC II.
Natural killer cells – kill cells not expressing MHC 1 receptor – activated by CD8.
How pathogens are recognized:
Innate – Antigen presenting cells – Macrophage and Dendritic cells.
Toll-Like receptors (TLR) recognize PAMPs.
Adaptive – B cells and antibodies.
Epitope detected on MHC II receptor.
APCs present epitopes from phagocytized antigens to CD4 via MHC 2.
CD4 does a cross-check with B cells.
Absence of MHC 1 receptor – CD8 cells direct NKC to destroy.
Absence of MHC 1 indicates intracellular infection.
Mediators:
Innate – cytokines, chemokines, complement.
Adaptive – cytokines, chemokines, complement.
Pathogens targeted:
Innate - nonspecific.
Adaptive - specific.
Describe how each type of T-cell recognizes ‘self’ antigens.
CD8 – cytotoxic:
Recognize all nucleated cells and will destroy them if they present something that is non-self.
Associates with MHC I.
CD4 – helper:
Recognize only professional APC – macrophages and dendritic cells.
Associates with MHC II.
Discuss the significance of MHC proteins in transplanted tissue and autoimmune disease.
Transplant: act as “self-recognition” markers on cell surfaces. If a recipient's immune system detects a mismatch in MHC on transplanted organ: trigger immune response and reject organ.
Autoimmune: MHC alleles are associated with increased risk of autoimmune disease.
Immune system attacks own body tissues due to misinterpreting MHC.
Describe each of these immune cells. Your description should include where they originate, which type of immunity they are involved in, and their specific role in the immune response.
Cytotoxic T cells (CD8 cells):
Originate in marrow, mature in Thymus.
Adaptive immunity.
Destroy any nucleated cell expressing non-self.
Associates with MHC-1.
Helper T cells (CD4 cells):
Originate in marrow, mature in Thymus.
Adaptive immunity.
Recognize Professional APCs.
Associates with MHC – 2.
Check in with B-cells; keep B-cells from launching antibody response when not needed; both must agree epitope is non-self.
If CD4 recognizes antigen as non-self; clone themselves to make more.
B cells:
Originate and mature in bone marrow/blood.
Adaptive immunity.
Humoral response – pathogen floating in fluids; has not entered cells.
Have receptors that will ONLY bind to non-self.
If they find something non-self, phagocytose and express antigens on MHC-2.
Check in with CD4 helper T cells.
B-cell with its specific receptor turns into plasma cells – release receptors as antibodies.
Antibodies bind to pathogen – tag for phagocytosis – opsonization.
Compare/contrast active and passive immunity.
Active immunity: occurs when the lymphocytes are exposed to foreign antigens in the body.
Body then makes its own antibodies.
Passive immunity: occurs when we receive antibodies made elsewhere.
Vaccines; breastmilk, placenta, etc.
Describe age-related immunity considerations for:
Elderly:
Less ability to recognize foreign antigens; immune response is slower; tend to have more autoimmune diseases and cancer; reaction to vaccines is not as robust; thymus shrinks – producing fewer T cells, smaller amounts of cytokines; B cells lose function with age.
Infant:
Functionally immature immune system. Passive immunity (IgG from placenta and IgA from breast milk).
CHAPTER 12
Have a working knowledge of these terms:
Anaphylaxis: systemic response to inflammatory mediators (type 1).
Anergy: body fails to react to antigen.
HIV (Human Immunodeficiency Virus): retrovirus – uploads into host dna.
Attacks CD4 – helper cells – and macrophages and dendritic cells.
Transmitted by body fluids – sex, breastmilk, blood-to-blood.
AIDS (Acquired Immunodeficiency Syndrome): CD4 count <200 (Normal count is 500-1500).
Compare/contrast 4 hypersensitivity reactions in terms of:
Type 1 – ALLERGIC REACTION:
Mechanism:
Initial exposures – no allergic response.
T-Helper (CD4) are exposed to antigen (allergen).
Cause B-Cells to produce IgE antibody.
IgE coats surface of Mast Cells.
Subsequent allergen binds:
Mast cells releases mediators.
Leads to local or systemic issues.
Immunoglobulins or mediator involved:
IgE mediated.
IgE produced by plasma cells and inserted into mast cells.
Histamine, cytokines, others.
Expected physiologic response:
Elevated WBC; fever; vasodilation; bronchoconstriction.
Local: Urticaria (hives), rhinitis, atopic dermatitis, bronchial allergic asthma, food allergies.
May result in systemic or anaphylactic reactions.
EFFECTS OF MEDIATORS ON ORGANS AND CELLS THAT CAUSE SYMPTOMS OF ALLERGIC REACTIONS.
Expected time lines:
1st phase – initial/early:
Occurs in 5-30 minutes, lasts about 60 minutes.
Mast cell degranulation.
Vasodilation, vascular leakage, smooth muscle contraction.
2nd phase – secondary/late:
Occurs in 2-8 hours, lasts days.
Lipid mediators – prostaglandins/leukotrienes.
Increase infiltration of eosinophils – leads to destruction of epithelial cell components.
Examples:
Local – hayfever.
Systemic – anaphylaxis – bee sting, etc.
Type 2:
Mechanism:
Tissue-specific reactions.
Leads to complement mediated phagocytosis, inflammation, and cell injury or physiologic responses without cell injury.
ANTIBODIES ATTACK ANTIGENS PRESENT ON CELL SURFACES.
Immunoglobulins or mediator involved:
Antibody mediated: IgG or IgM – attack antigens on cell surfaces.
COMPLEMENT mediated.
Expected physiologic response:
Depends on cells involved.
Expected time lines:
(Not specified in note).
Examples:
Transfusion reactions, Rh disease, Drug reactions.
Graves disease – antibodies stimulate thyroid hormone release.
Myasthenia gravis – acetylcholine receptors on muscle are blocked by antibody.
Goodpasture syndrome – glomerulus and alveoli are attacked.
Red (AB or Rh) or white blood cells.
Type 3:
Mechanism:
No fixed target.
Antigens – drugs, stings from insects or bites.
ANTIGEN-ANTIBODY COMPLEXES FLOATING IN PLASMA, CAN TRIGGER INFLAMMATION WHEREVER THEY ATTACH.
Circulating immune complexes deposit on walls of blood vessels and activate complement.
Leads to recruitment and activation of inflammatory cells that release tissue-damaging products.
Blood vessels damaged.
Immunoglobulins or mediator involved:
Free-floating antigen + antibody = circulating immune complex.
IMMUNE COMPLEX MEDIATED.
Expected physiologic response:
(Not specified in note).
Expected time lines:
(Not specified in note).
Examples:
Type 3 responsible for many AUTO-IMMUNE: Glomerulonephritis, systemic lupus, rheumatoid arthritis.
Type 4:
Mechanism:
Delayed – T cells have to travel to location.
CD4 (helper) delayed or CD8 cytolysis.
Leads to sensitized T cells which cause cell and tissue injury.
Release of inflammatory factors.
Immunoglobulins or mediator involved:
CD4 cells delayed or CD8 cytolysis.
Cell mediated – delayed.
ONLY HYPERSENSITIVITY THAT DOES NOT INVOLVE ANTIBODIES.
Expected physiologic response:
(Not specified in note).
Expected time lines:
(Not specified in note).
Examples:
Contact dermatitis – poison ivy, nickel jewelry.
PPD – TB test.
Multiple Sclerosis.
Describe cellular events involved in an allergic reaction.
Initial exposures – no allergic response.
T-Helper (CD4) are exposed to antigen (allergen).
Cause B-Cells to produce IgE antibody.
IgE coats surface of Mast Cells.
Subsequent allergen binds:
Mast cells releases mediators (like histamine).
Leads to local or systemic issues.
Explain how allergy shots work.
Allergy shots desensitize by turning down immune response to antigen.
Shot contains the actual allergen.
Antibodies (IgG) against allergen will form.
Next exposure to antigen leads to less severe allergic reactions.
Plasma cells decrease IgE and increase IgG and IgA; less cytokines; less degranulation.
IgG attacking the allergen makes it less able to bind to IgE on mast cells.
Describe what happens in solid organ rejection.
Recipient’s system sees unfamiliar protein (HLA) displayed on MHC.
Recognizes graft as foreign, mounts an immunological response and destroys it.
Cell mediated – T lymphocytes.
Antibody mediated – B lymphocytes.
Combination of both.
T-cell response: lead to ENDOTHELIAL CELL DEATH, leads to ischemia of the organ and triggers inflammation with increased vascular permeability, local accumulation of lymphocytes and macrophages.
HYPERACUTE: existing circulating antibodies react with graft; may show up during surgery.
Accidental ABO mismatch.
TYPE 2 HYPERSENSITIVITY.
Acute: most common – takes weeks and months.
Destruction can be from antibody or cell mediated or complement or inflammation, BUT the target is usually the blood vessels.
TYPE 4 HYPERSENSITIVITY.
T cells move to the location and release signals to trigger other immune response.
Chronic rejections: slow and progressive – type 3 and 4 hypersensitivity.
Takes months to years.
Organ atrophy over time.
No treatment.
Discuss Graft vs. Host disease (GVHD) in terms of:
Typical patients affected:
Recipient is immunocompromised.
People who have received blood products with HLA-incompatible lymphocytes.
Cellular activity:
Donor T cells and NK cells attack host cells with incompatible HLA antigens.
Presenting symptoms:
Depends on cells targeted.
Skin – pruritic (itchy) sometimes painful rash with sloughing.
GI tract – severe abdominal pain, diarrhea, N/V, blood in stool.
Liver - Jaundice.
Necessary conditions:
Must be BONE MARROW.
Transplanted tissue has functional cellular immune component.
Host tissue has foreign antigens to donor.
Recipient immunity compromised so it cannot destroy the transplanted cells.
Type 4 HYPERSENSITIVITY.
Describe the basic pathophysiologic mechanism of autoimmune diseases.
Genetic predisposition and a trigger event (infection, stress, tobacco, etc.).
Breakdown in T-Cell anergy – body fails to react to antigen.
Release of sequestered antigens.
Molecular mimicry – foreign antigen closely resembles a self-antigen.
Antibodies formed against the foreign antigen.
Superantigens – activate immune response without processing or presentation.
Inflammatory reaction at mucosa leads to local auto-antibodies.
Compare/contrast primary and acquired immunodeficiency.
Primary: inherited.
Secondary: result of disease.
Describe the intracellular changes associated with HIV.
1. Virus binds to CD4 cell and attaches to surface molecules.
2. Fusion to CD4 cell membrane and uncoating of virus.
3. DNA synthesis – changes from single strand RNA to double strand DNA (using Reverse transcriptase enzyme).
4. Integrations where the newly formed DNA enters the nucleus of CD4 cell (using Integrase enzyme).
Becomes part of that cell’s DNA.
5. Transcription to mRNA.
6. Translation – rRNA uses message from mRNA to create virus protein chain.
7. Cleavage of that chain into parts that will make new virus (using Protease enzyme).
8. Proteins and viral RNA reassemble to make new viruses that are released from CD4.
This kills the CD4 cell and releases the viral particles into the bloodstream to invade more CD4 cells and make more viruses.
Describe the clinical course (phases) of the HIV infection.
Primary infection phase: signs of systemic infection.
Seroconversion – immune system response and antibodies against HIV appear.
1 – 6 months.
Latency phase: may last 10 years or longer.
Virus is replicating; CD4 count gradually falls.
No signs or symptoms.
Over AIDS phase:
CD4 cell count less than 200 cells/mL.
List the usual manifestations of uncontrolled HIV infection in terms of:
T-Cell immunodeficiency:
Immediate symptoms:
Fevers – especially at night.
Night sweats.
Diarrhea.
Fatigue.
Weight loss.
Lymphadenopathy.
AIDS associated illnesses:
Opportunistic infections – respiratory, GI, Nervous system.
Malignancies.
Wasting syndrome.
Metabolic disorders.
Explain the aims of pharmacology treatment for patients infected with HIV.
Most treatments are a combination of drugs.
Most block reverse transcriptase.
Entry/fusion inhibitors may reduce further progression by preventing entry into cells.
Post attachment inhibitors, NRTIs, integrase inhibitors, protease inhibitors.
GOALS:
Reduce viral load below detectable levels.
Increase CD4 count.
Reduce HIV-associated morbidity and mortality.
Improve quality of life.
Discuss risk factors for HIV/AIDS.
Unprotected sex, sharing needles/syringes, substance use/abuse, STIs.
CHAPTER 22
Have a working knowledge of these terms:
Megakaryocytes:
Thrombopoietin: activating factor that causes platelet production.
Made in liver, kidney, smooth muscle, and bone marrow.
Regulated by number of platelets in circulation.
Thrombocytes (platelets): made in bone marrow; fragments of megakaryocytes.
Live 8-9 days in circulation – do not leave bloodstream.
Many stored in spleen (up to 1/3) and released when needed.
Thrombocytopenia: not enough thrombocytes.
Symptoms: spontaneous bleeding of mucous membranes, GI tract, uterus, etc.
Cutaneous bleeding – petechia.
Drug induced – heparin.
Thrombocytosis: too many thrombocytes.
Describe thrombocytes (platelets) including:
Hormonal triggers:
Estrogen, progesterone, adrenaline/epinephrine, thrombopoietin.
Lifespan: 8-9 days.
Location:
Circulate – up to 1/3 stored in spleen.
Made in liver, kidney, smooth muscle, and bone marrow.
Seven key granular components (discussed in lecture) and significance of each:
Fibrinogen: leads to fibrin mesh formation to form plug – turns into fibrin.
Thromboxane A2 (TXA2): signaling molecule (prostaglandin) - triggers aggregation.
Plasminogen activator inhibitors: prevents clot dissolution.
Plasminogen: triggers dissolution – turns into plasmin.
Growth factors: stimulate injury repair.
Serotonin and histamine: trigger adhesion and inflammatory processes; Vasoconstriction/vasodilation.
ALSO: GPIIB.IIA: glycoprotein on outside of platelet; Binds fibrinogen and helps platelets bind to each other.
Discuss the role of fibrin in clotting.
Forms a stable framework that strengthens platelet plugs and stops blood loss.
In the coagulation cascade, describe the general differences between the intrinsic and extrinsic pathways in terms of triggers.
Coagulation cascade: 13 blood clotting proteins.
Circulate as inactive procoagulation factors.
Most are synthesized by the liver.
Von Willebrand factor:
Made by megakaryocytes and endothelium of vessels.
Carries Factor 8.
Intrinsic pathway:
Cascades of protein interactions activated by intravascular trauma.
Damage IN the vessel.
Slower process – 1-6 minutes.
Begins in the blood – blood contacting collagen in injured vessel wall.
Triggered by blood clotting factors.
Extrinsic pathway:
Cascades of protein interaction activated by damaged external surfaces.
Damage to surrounding tissues.
Faster process – 15 seconds.
Triggered by tissue factor.
Common pathway:
Begins with factor X.
In presence of FACTOR TEN: prothrombin > thrombin.
In presence of THROMBIN: fibrinogen > fibrin.
Describe the terminal steps of both the intrinsic and extrinsic pathways.
Activation of factor X (common pathway).
Prothrombin converted to thrombin, which converts fibrinogen into fibrin, forming a blood clot.
Discuss how platelets are activated.
Activated by agonists – collagen, thrombin, ADP, TXA2.
Depict each of the five steps of hemostasis. Incorporate the following concepts in your pictures:
1. Vessel Spasm:
Neural reflexes immediately trigger smooth muscle contraction.
Spreads to nearby vessels by TXA2 release.
Vasoconstriction acts to quickly reduce blood flow.
Usually lasts less than 1 minute.
2. Platelet plug formation:
Von Willebrand factor is released which binds to platelets causing them to stick together.
Thromboxane is released from platelets.
Increases aggregation, stimulates production of new platelets, vasoconstrictor.
3. Blood coagulation:
Activation of factors in the blood:
Activation of factor TEN converts prothrombin to thrombin.
Thrombin converts fibrinogen to fibrin.
Fibrin is a fiber that creates the mesh of platelets and blood cells.
4. Clot retraction:
Actin and myosin in platelets cause the platelets to contract.
Squeezes serum from the clot, causing it to shrink.
5. Clot dissolution or lysis:
Plasminogen activators are slowly released.
Plasminogen trapped in the clot is converted or activated to form PLASMIN.
Plasmin breaks down fibrin.
The role of smooth muscle in the vascular wall:
Regulate blood pressure and flow by contracting and dilating.
Procoagulation factors, their origin, triggers and their functions:
Factor 7, Factor 9, Factor 10, Prothrombin.
Von Willebrand factor: produced by endothelium; Carries factor 8.
Thromboxane: released from platelets; Increases aggregation, stimulates production of new platelets, vasoconstrictor.
Anticoagulation factors, their origin, triggers and their functions:
Plasminogen: activates plasmin.
t-PA released by platelet and endothelium activate into plasmin.
Plasmin: digests fibrin strands.
Actin and myosin: cause platelets to contract, squeezing serum out.
Discuss two main causes of hypercoagulability.
Hypercoagulability: too much clotting resulting in unwanted (dangerous) thrombus.
Arterial thrombi: usually due to turbulence – directly leads to platelet aggregation.
Venous thrombi: usually due to stasis of flow – platelet aggregation and fibrin complexes caused by coagulation factors.
1. Conditions that increase platelet function:
Increased platelet counts = thrombocytosis.
Thrombopoietin stimulates production.
Linked to disease that increases thrombopoietin production.
Atherosclerosis, diabetes mellitus, elevated blood lipid/cholesterol levels.
Often related to lesions on vessel wall and turbulent blood flow.
2. Accelerated coagulation system activity:
Increased procoagulation factors in blood.
Decreased anticoagulation factors in blood.
Differentiate between inherited and acquired causes of hypercoagulability.
Inherited: usually involves coagulation factors (e.g., Factor V Leiden).
Acquired: bed rest, immobility, oral contraception use (estrogen).
Describe how aspirin interferes with coagulation and discuss the implications.
Aspirin binds irreversibly to COX (arachidonic acid pathway) so its effects last for the lifespan of the platelet – 8-10 days.
Blocks production of TXA2.
Describe how NSAIDs (ibuprofen) interferes with coagulation and discuss the implications.
NSAIDs effects are reversible and last only for the duration of drug action – also blocks COX.
Blocks production of TXA2.
Discuss hereditary bleeding disorders (causes and manifestations/symptoms):
Von Willebrand’s disease:
Most common hereditary bleeding disorder.
Deficiency of or defect in von Willebrand factor (vWF) leading to REDUCED PLATELET ADHESION.
Not enough or defective von Willebrand factor.
Because vWF carries factor 8, defective clot formation may also be present.
Type 1 and 2 – autosomal dominant. Type 3 – autosomal recessive.
Symptoms: bruising, excessive menstrual flow, spontaneous bleeding from: nose, mouth, and GI tract.
Avoid aspirin.
Hemophilia:
Not enough factor 8.
Impaired ability to make clots.
X-linked recessive disorder – primarily males.
Faulty factor 8 – not enough.
Severity of bleeding depends on how much normal factor 8 is produced.
Manifestations:
Bleeding in soft tissues and GI tract and joints.
Joint pain and swelling.
Severe cases bleeding occurs in childhood.
Prevent trauma.
Describe potential causes of bleeding disorders including:
Disorders of the platelets:
ITP (Immune thrombocytopenic purpura) – idiopathic T.P - T-cell dysfunction.
Autoimmune disorder – formation of antibodies against platelets.
Leads to excessive destruction of platelets, increasing bleeding.
Symptoms – bleeding, skin: petechia and purpura, epistaxis, gums, splenomegaly, low platelet counts.
Treatment – treat with corticosteroids to stop immune attack (not everyone needs treatment).
Primary: affects both genders, children and adults (highest incidence female 30-59 and those over 60).
Secondary: associated with other autoimmune disorders; Chronic infections: hepatitis, HIV, H-Pylori.
TTP (Thrombotic Thrombocytopenic Purpura):
Combination of thrombocytopenia, hemolytic anemia, renal failure, and neurologic dysfunction.
Unusually large von Willebrand proteins.
Absence of enzymes leaves large vWF molecules.
Abnormal processing of vWF – antibodies against vWF cleaving enzyme.
Causes intravascular clotting (consuming clotting factors) and microvascular occlusions with organ ischemia (heart, brain, kidneys).
Abrupt onset – high mortality.
Signs and symptoms:
Consumption of clotting factors and purpura (bleeding into tissues), fragmented RBC, anemia, hemolysis (jaundice).
Treatment – plasmapheresis – remove plasma, replace with fresh frozen plasma.
Primary: autosomal recessive; very rare – infancy and early childhood typically.
Secondary (acquired): late childhood or early adult.
Triggers: pregnancy, surgery, infection.
Endothelial damage – activation of intravascular thrombosis.
DIC (Disseminated Intravascular Coagulation):
Caused by massive activation of coagulation due to production of thrombin and formation of fibrin.
Widespread intravascular coagulation and bleeding.
High clot formation consumes available coagulation proteins and platelets – leads to severe hemorrhage.
Often results in multiple organ failure.
LOSS OF CLOTTING FACTOR DISTINGUISHES THIS FROM TTP.
Symptoms:
Petechia, purpura, oozing from puncture sites, severe hemorrhage.
Conditions associated with DIC:
OB complications, cancers, severe infections, shock (septic and hypovolemic), trauma/surgery, blood transfusion reactions.
Treatment:
Supportive – replace clotting factors – use heparin to prevent intravascular coagulation.
Describe the liver’s role in coagulation.
The liver synthesizes many coagulation proteins (factors).
CHAPTER 23
Have a working knowledge of these terms:
Reticulocytes: immature RBC.
Erythropoiesis: production of RBCs.
Decreased blood oxygen triggers the release of erythropoietin from the kidney.
Erythropoietin stimulates the bone marrow to produce RBCs.
Immature RBCs (nucleated) > Reticulocytes (contain ER) > mature RBC.
Unconjugated: not bound to another molecule.
Conjugated: bound to another molecule.
Jaundice: results from destruction of RBC/Hgb - excess bilirubin – makes yellow.
Build up of unconjugated bilirubin.
Discuss the red blood cell including:
Erythropoiesis:
Normal characteristics:
Biconcave disk - flexible and more surface area.
Carry O2 to cells – via hemoglobin.
Last about 120 days.
No nucleus or other organelles – no ability to regenerate proteins or repair damage.
Potentially abnormal characteristics:
Membrane deformation (e.g., sickle cell).
Lifespan: 120 DAYS.
Relationship to iron:
On Hgb, O2 binds to the iron (Fe).
65% of all iron in body found in Hgb.
Relationship to hemoglobin:
Adult: HbA – two ALPHA chains, two BETA chains.
Fetal: HbF – Two ALPHA chains, two GAMMA chains (instead of beta).
Usual pattern of destruction:
Membranes weaken as they age, weakened RBCs can break as they squeeze through small spleen capillaries.
Phagocytes from the spleen, liver, bone marrow, lymph nodes ingest and destroy RBC.
Byproducts of destruction:
Heme is separated from the Hgb protein chains.
Iron is removed from the heme and recycled.
Heme is further broken down to bilirubin.
Usual lab tests associated with RBC/RBC production including significance of each:
(Not specified in note).
Describe the iron cycle.
The rate hemoglobin can be synthesized depends on availability of iron.
Less iron means less Hgb in RBC = less O2 carrying capacity.
Dietary iron is absorbed in the small intestine.
Carried on TRANSFERRIN in blood plasma (support protein in circulation that carries iron; Prevents reactions between iron, oxygen, and water).
Most Iron is bound to Hgb (60-80%).
Some stored in liver as FERRITIN – protein that holds iron & prevents reactions.
Some stored in bone marrow.
The body recycles iron.
Destroyed RBC release iron back to the bone marrow – reused.
Less than 1 mg per day is lost – urine, sweat, epithelial sloughing.
Describe ways iron is lost.
Urine, sweat, sloughed off from epithelial cells in feces.
Differentiate red cell antigens from antibodies in people with A, B, AB, or O blood.
Type A: A antigens, B antibodies.
Type B: B antigens, A antibodies.
Type AB: A and B antigens, No antibodies.
Type O: No antigens, A and B antibodies.
Explain the significance of Rh factor.
Express D antigen = RH POSITIVE.
Don’t express = RH NEGATIVE.
Antibodies are not made spontaneously (like in ABO), require exposure (sensitization).
Pregnancy: second pregnancy at risk – now antibodies exist.
Transfusion: problems with subsequent transfusions.
Recognize signs and symptoms of these transfusion reactions:
Acute hemolytic:
Host antibodies attack donor cell resulting in lysis of RBC.
Rare but life-threatening reaction.
ABO incompatibility.
Occurs within 24 hours – or within minutes.
Signs and symptoms:
Back/flank pain; oliguria; hematuria, rash, itching, urticaria.
Severe: hypotension, respiratory distress.
Delayed hemolytic:
Antibodies were not detected at time of transfusion – symptoms 1-2 weeks later.
S&S: fall in hemoglobin; jaundice.
Febrile reactions:
Happens relatively frequently – 0.1-1% of transfusions.
Host antibodies are reacting to donor WBCs.
S&S: fever >100.4^{\circ}\text{F}; 2-4 hours after onset of transfusion.
Allergic reactions:
Most common type of reaction – 1-3%.
Host antibodies attack donor proteins.
Occurs during transfusion – within 4 hours.
S&S: facial edema, itching, rash and flushing – can manage with antihistamines.
SEVERE: anaphylaxis.
Transfusion Related Lung Injury (TRALI):
Immune reaction to donor HLA causes acute lung injury.
S&S: pulmonary edema; hypoxemia: hypotension within 6 hours of transfusion.
Transfusion Associated Circulatory Overload (TACO):
Fluid volume overload; more frequent in at-risk patients.
Heart failure, kidney problems, over age of 60.
S&S: acute dyspnea.
Manage by: slow transfusion; diuretics; supplemental oxygen; high fowler’s.
List the causes of anemia.
Abnormally low number of RBC, Hgb, or both – diminished O2 carrying capacity.
Results from:
Blood loss, internal or external, chronic or acute.
Hemolysis: cells die early (less than 120 days).
Primary: defective cell membranes (Sickle cell, spherocytosis, thalassemias).
Secondary: antibody mediated lysis (Drugs, chemicals, venoms, transfusion reaction).
Impaired RBC production – lack of nutrients or bone marrow failure.
List the effects of anemia.
Impaired O2 transport, reduction in RBC indices and Hgb levels, signs and symptoms associated with the pathologic process that is causing the anemia, compensation may occur if the person is otherwise healthy.
Increased CO, ventilation rate, plasma volume.
Indices - cytic – cell (size); chromic - color.
Classify the following list of anemias by cause (either insufficient RBC production or hemolysis).
Iron deficiency anemia: Insufficient production.
Megaloblastic anemias (pernicious – B12 and folic acid deficiencies):
B12 – deficient RBC production.
Folic acid – deficient RBC production.
Aplastic anemia: Deficient RBC production.
Hereditary spherocytosis: Hemolysis – membrane disorder.
Acquired hemolytic anemias: Hemolysis – membrane disorder – immune associated.
Sickle cell disease: Hemolysis – hemoglobinopathy.
Thalassemia (alpha and beta): Hemolysis – hemoglobinopathy.
Alpha.
Beta.
Chronic renal failure: Deficient production of RBC.
Discuss causes, features, and consequences of these anemias:
Iron deficiency anemia:
Includes blood loss – iron can't be recycled.
Causes: dietary deficiencies; chronic blood loss (most common); increased demands during growth periods.
Manifestations – related to lack of Hgb and impaired O2 transport:
Fatigability, palpitations, dyspnea, angina, tachycardia.
Women: abnormal menses.
S&S and Labs: pica, spoon-shaped deformity of nails, elevated transferrins, RBCS are smaller and paler.
Treatment: (Not specified in note).
Pernicious anemia:
Vitamin B12 deficiency.
Malabsorption: GI disease, gastrectomy/gastric bypass; chronic PPI use.
Chief cells (parietal cells) - not producing intrinsic factor – needed to absorb B12.
Atrophic gastritis causes lack of intrinsic factor – antiparietal antibodies.
S&S: RBCs abnormally large (megaloblastic) low serum B12, red sore tongue, numbness/tingling.
Folic acid anemia:
Malnutrition; higher demand during pregnancy.
S&S and labs: like pernicious but no neuro S&S.
Aplastic anemia:
Bone marrow not working; aplastic means not producing enough of ALL blood cells (WBC, platelets, RBC, etc.).
Radiation, chemo, other toxins.
S&S and labs: WBCs and platelets also low.
Hereditary spherocytosis:
RBC membrane affected – makes it a sphere.
Acquired hemolytic anemias:
Hemolytic disease of newborn (immune associated).
RBC lysis as a result of turbulent blood flow.
Sickle cell disease:
Chronic hemolytic anemia.
Inherited disorder – mutation changes one amino acid.
Blood cells form an elongated shape and may adhere to vessel walls.
Often resulting in ischemia causing pain, organ failure.
Caused by a mutation in the beta-chain of hemoglobin (HbS).
Consequences: cells more likely to be destroyed: jaundice, pigment gallstones.
Block capillaries; pain, infarctions, etc.
Thalassemia (alpha and beta):
Mutation in gene that directs synthesis of chains.
Deficiency in Hgb, beta chains more soluble than alpha.
Excess production of unaffected chains.
Excess alpha = Heinz bodies; damage cell membranes.
Alpha: Affects both fetal and adult.
Beta: Doesn't affect fetal (gamma instead of beta).
Differentiate Primary polycythemia from Secondary polycythemia.
Primary (Polycythemia vera):
Neoplastic disease of bone marrow stem cells.
S&S: increased blood volume and viscosity.
HTN, decreased cerebral flow (dizziness, vision and hearing impaired), dusky redness of lips fingernails and mucous membranes, blood clots, hemorrhage.
Secondary:
RBC increase from hypoxia.
Live at high altitude, chronic heart/lung disease, smoking.
Neoplasm that stimulates release of erythropoietin.
CHAPTER 24
Have a working knowledge of these terms:
…penia (suffix): (Not specified in note).
…cytosis (suffix): (Not specified in note).
Leukopenia: decrease in all WBC count.
Neutropenia:
Agranulocytosis: virtual absence of neutrophils – common infections may become fatal.
Lymphadenopathy: swollen/infected/diseased lymph nodes.
Review the development of blood cells from a pluripotent stem cell.
Differentiate between lymphoid and myeloid cells.
Lymphoid: NK, T, and B cells.
Myeloid: Monocytes, all granulocytes, megakaryocytes, platelets, RBC.
Compare/contrast B and T cells.
T cells:
Thymus – produced in marrow, mature in thymus.
B cells:
Produced and mature in bone marrow.
Become plasma cells.
Categorize WBCs as either granulocyte or agranulocyte.
Granulocytes:
Neutrophils.
Eosinophils.
Basophils.
Mast cells.
Agranulocytes:
Lymphocytes – NK, T, B cells.
Monocytes.
Recite the types of granulocytes and agranulocytes:
(See above categorization).
State function of each granulocyte and agranulocyte.
Granulocytes:
Neutrophils: first responders; primary pathogen finders.
Eosinophils: allergic response and parasites.
Basophils: blood cells – release histamine and heparin.
Mast cells: tissue cells – release inflammatory mediators – allergic reactions.
Agranulocytes:
B cells: antibodies.
T cells:
CD4 – helper – activate immune response.
CD8 – cytotoxic – cell-mediated immune.
NK (Natural Killer) cells: kill antigenic cells.
Monocytes > macrophages: antigen presenting; produce inflammatory mediators.
Localize the key lymphatic tissue in the body:
Primary: thymus and bone marrow.
Secondary: tonsils, spleen, lymph nodes.
Mucosa Associated Lymphoid Tissue (MALT):
Not enclosed in a capsule.
Respiratory, genitourinary tract, alimentary canals.
Describe non-neoplastic WBC disorders:
Nonneoplastic = normal WBC count.
Decreased production or excessive removal.
Neutropenia (Congenital and Acquired):
Specific decrease in neutrophils – less than 1500.
Congenital: hereditary.
Acquired: pathology induced or drug induced.
Infectious mononucleosis including clinical course and complications:
Stays in B-cells for life.
Infected B cells become dormant.
Epstein-Barr virus.
Evades immune system – 90% of humans infected.
Spreads via saliva.
Transmissible even if asymptomatic.
Most prevalent in teens/young adults.
Symptoms:
Severe sore throat.
Painful and enlarged lymph nodes (cervical and axillary).
Compare/contrast acute and chronic leukemias in terms of:
Acute:
Rapid onset and progression.
High blast count (immature cells) - replace normal cells.
Depressed bone marrow function.
Infiltrate various organs.
Anemia and easy bruising.
Weight loss – hypermetabolism.
Bleeding – low platelets.
Bone pain – marrow expansion.
Abdominal pain/tenderness.
Nausea and vomiting.
Chronic:
Insidious, slow onset.
Prolonged.
Proliferation of MORE DIFFERENTIATED cells – myeloid or lymphoid.
Often discovered during other tests.
May withhold treatment until symptoms develop.
LYMPHOID:
Acute - ALL (Acute Lymphoblastic Leukemia):
10% of all leukemias.
Most common leukemia in children (75%) - less common in adults.
Composed of lymphoblasts.
85% are B cells.
Sudden onset of symptoms and hypermetabolism.
Chronic - CLL (Chronic Lymphocytic Leukemia):
Clonal malignancy of B cells.
1/3 of all leukemias.
Most common adult leukemia.
2 forms: one is more aggressive.
Often asymptomatic.
B – lymphocytes.
Proliferation of more mature cells.
MYELOID:
Acute – AML (Acute Myeloid Leukemia):
Most common leukemia of all 4 types – 45%.
Most acute leukemias are myeloid.
Mainly affects older adults.
Myeloid cells don't mature – blasts replace normal cells.
Myeloblasts.
Chronic – CML (Chronic Myeloid Leukemia):
95% have PHILADELPHIA CHROMOSOME.
Affects hematopoietic progenitor cells.
Problems making granulocytes and megakaryocytes.
Affects adults in 60s – average age is 67.
Prevalence:
Cells of origin (myeloid vs. lymphoid):
Cell characteristics:
Progression:
Proliferation:
Signs/symptoms:
Type of patient typically affected:
Include discussion of the Philadelphia Chromosome. What does it mean in terms of diagnosis and prognosis?
5 year survival rate with treatment is 65% - pretty good.
Compare/contrast Hodgkin and non-Hodgkin’s lymphomas in terms of:
Lymphoma: Solid tumors of lymphoid tissue.
Non-Hodgkin:
Three times more common than Hodgkin.
1 in 50 people will be diagnosed.
Most are B-cell – but can also affect T cell.
Risk factors:
EBV, human T-cell virus, HIV, H Pylori.
Several subtypes of B cell (Follicular, large B-cell, Burkitt, mantle cell, marginal zone).
Signs and symptoms:
Most frequent is painless lymphadenopathy – isolated or widespread.
Abd/chest pain = pressure from enlarged nodes.
Unexplained fever, night sweats, fatigue, weight loss, itchy red patches on skin.
Diagnosed:
With lymph node biopsy – specific surface markers.
Expected spread:
Does not spread in a pattern – could go anywhere.
Hodgkin:
Reed-Sternberg cells are present – unknown origin – owl eyes.
Arises in singular node or chain.
Spread:
Spreads to first anatomically contiguous tissue.
Goes to things right next to it.
Affects 15-40 y/o and then 55+ (NOT FOUND IN 40-55 Y/O).
Manifestations:
Painless lymphadenopathy (USUALLY ABOVE DIAPHRAGM).
Mediastinal mass.
Chest pain/pressure.
Heart and lymph chains here.
Typical patient age:
How diagnosed:
Location:
Expected spread:
Symptoms:
Describe key features and consequences of multiple myeloma include:
Most common blood cancer.
Affects plasma cells – B cell origin.
CRAB symptoms:
Calcium increase.
Renal dysfunction – Bence-Jones.
Anemia.
Bone lesions.
1% of all cancers.
Proliferation in bone marrow = bone pain.
Osteolytic bone lesions.
Activation of osteoclasts – bone reabsorption.
Calcium goes to blood.
Interrupts calcium homeostasis.
Weakens bones.
Proteinuria – overproduction of antibodies.
Bence Jones proteins.
Normal function of bone marrow affected.
Decreased production of other blood cells.
Anemia and neutropenia.
Cell origin:
Prevalence:
Pathophysiology:
Symptoms:
CHAPTER 41
Have a working knowledge of these terms:
Anabolism: building up.
Catabolism: breaking down.
Metabolism: chemical reactions to produce energy.
Gluconeogenesis: making glucose from non-carbs; glycerol, amino acids.
Glycogenolysis: breaking down glycogen into glucose.
Lipolysis: break down of fat for energy.
Diabetes: metabolic disorders; hyperglycemia – imbalance between insulin and response.
Insulin resistance: producing insulin but little or no effect.
So much sugar in blood, but can’t enter cells; cells starving.
Metabolic syndrome: combination of disorders; three of:
Elevated fasting glucose.
Reduced HDL.
Increased triglycerides.
Elevated BP.
Central obesity.
Glycosated hemoglobin (HbA1c): amount of Hgb that glucose has entered.
Measures glucose on Hgb.
The rate hemoglobin takes up glucose:
Does not depend on insulin.
Depends on level of blood glucose.
Is irreversible.
Oral glucose tolerance test (OGTT):
Drink glucose solution.
Check blood sugar 2-3 hours later.
Body's response to glucose.
Tests how well insulin works to move glucose from blood to cells.
>140 is normal; at risk, >200 diabetes.
Somogyi effect: hypoglycemia during sleep.
Dawn phenomenon: unexplained rise of blood glucose in the morning.
Pre-breakfast higher than pre-bedtime.
Describe the pathophysiology and expected symptoms of:
Grave’s disease (hyperthyroidism):
Overstimulation of thyroid; increase in metabolism.
Thyroid tumors.
T3 and T4 are HIGH.
Autoimmune disease – type 2 hypersensitivity – activates TSH receptors.
Makes auto-antibodies to TSH receptor.
Binding of autoantibodies mimics TSH with no regulation.
Symptoms: weight loss (increased appetite), hair loss, arrhythmia, bone loss, heat intolerance, sleep disturbances, goiter, exophthalmos.
Hypothyroidism (Hashimoto, iodine deficiency, and surgical removal of thyroid): decreased metabolism.
Hashimoto: autoimmune – most common – thyroid destroyed, type 2 hypersensitivity.
High TSH – low t4, more stimulating but not enough thyroid hormone.
Hypometabolic state.
Symptoms: weight gain (no appetite), goiter (thyroid hormones collect), iodine deficiency, cold intolerance, reduced HR, high cholesterol, fatigue.
Myxedema: swelling of skin and underlying tissue. Mild or life threatening. Could result in coma.
Disorders/diseases of adrenal glands:
Cushing’s syndrome:
Excess cortisol.
Disease = pituitary disease – too much ACTH.
Syndrome – from medications.
Addison’s disease:
Insufficient cortisol.
Can be autoimmune, TB, or adrenal glands removed (cancer).
Rare disease.
Need lifetime hormonal replacement.
Poor stress tolerance.
Detail the hormonal processes within the hypothalamo-pituitary-adrenal axis.
Negative feedback.
Hypothalamus makes CRH > Anterior Pituitary makes ACTH > adrenal cortex > cortisol.
Cortisol influences hypothalamus and anterior pituitary.
Low blood cortisol stimulates pituitary to produce ACTH.
ACTH stimulates adrenal gland to produce cortisol.
Once cortisol levels are sufficient, negative feedback system decreases cortisol production by slowing ACTH.
Recognize examples of positive and negative feedback loops for hormonal regulation.
TRH released by hypothalamus; TSH released by pituitary gland; Thyroid releases T3, T4.
Increased T3 and T4 levels provide negative feedback.
Stops release of TRH and TSH.
Discuss the production and storage of energy (ATP):
Carbohydrates: glucose is cells preferred energy.
Fatty acids: most efficient form of energy.
Proteins/amino acids: least preferred energy source.
Role of the liver in metabolism:
Stores, processes, and metabolizes: triglycerides, cholesterol, amino acids, etc.
Hormones:
Insulin: made in pancreas – beta cells into bloodstream.
Adipose tissue: increases glucose uptake, increases triglyceride synthesis, decreases lipolysis.
Skeletal muscle: increases glucose uptake, increases glycogen storage, increases protein synthesis.
Liver: increases glycogen synthesis, increases triglyceride synthesis, decreases gluconeogenesis.
Glucagon: “when glucose is gone.”
Alpha cells of pancreas release glucagon into blood – islets of Langerhans.
Maintain blood glucose between meals.
Initiate glycogenolysis in liver.
Stimulate gluconeogenesis in liver – build glucose from amino and fatty acids.
Regulated by blood glucose levels.
1. Glycogen > Glucose = glycogenolysis.
2. Fat > fatty acids for energy = lipolysis.
3. Amino acids > glucose = gluconeogenesis.
Cortisol: glucocorticoid.
In response to stress: fight or flight.
Stimulates gluconeogenesis.
Increases protein breakdown.
Mobilizes fatty acids.
Suppresses immune response.
Thyroid hormones (T3-T4): increase blood glucose.
Epinephrine:
Maintains glucose during stress.
Stimulates gluconeogenesis in liver (glycogen > glucose).
Inhibits insulin secretion.
Lipolytic effect.
Growth hormones:
Increase in protein synthesis.
Mobilizes fatty acids.
Antagonizes effects of insulin.
Glucocorticoid hormones:
Stimulates gluconeogenesis in liver.
Describe how blood glucose is managed/impacted by:
Alpha cells: release glucagon when detect low blood glucose.
Between meals.
Beta cells: release insulin when detect high blood sugar.
Or when triggered by gut hormone after eating.
Glucagon: when glucose is gone.
Maintains blood glucose between meals – initiate glycogenolysis in liver – stimulate gluconeogenesis in liver.
Other hormonal influences:
Effects of insulin:
Adipose tissue: increase triglyceride synthesis, decrease lipolysis.
Skeletal muscle: increase glycogen storage, increase protein synthesis.
Liver: increase glycogen synthesis, increase triglyceride synthesis.
The role of glucose transporters (GLUT) in glucose metabolism.
Cell membranes are impermeable to glucose.
Insulin binds to and activates a receptor on target cells.
Intracellular signals are generated that result in the insertion of a GLUT (glucose transporter) into the cell membranes.
Glucose is transported across the cell membrane through the GLUT.
Compare/contrast Type I, Type II, and gestational diabetes in terms of:
Type 1:
Can’t release insulin.
Insulin dependent diabetes mellitus.
Absolute deficiency of insulin.
Usually autoimmune process destroys beta cells (pancreas).
May be genetic predisposition with environmental trigger.
Symptoms: The polys – polyphagia, polydipsia, polyuria.
Type 2:
Usually occurs in persons over 30 – 90% of newly diagnosed are type 2.
Can’t respond to insulin.
PROBLEMS WITH GLUT TRANSPORTERS.
Highly associated with obesity.
Beta cells eventually become dysfunctional.
Exercise seems to help muscles take up more glucose.
Insulin resistance better with weight loss.
Insulin resistance – high serum glucose but insulin doesn't work: cells starved.
Causes liver to produce more glucose.
High levels of circulating insulin effect:
Adipose: increased triglycerides, decreased lipolysis.
Skeletal muscle: increased glycogen storage, increased protein synthesis.
Liver: increased glycogen synthesis, increased triglyceride synthesis.
Gestational:
Glucose intolerance during pregnancy.
Increases pregnancy complications.
Women likely to develop type 2 within 5-10 years.
Cause:
Pathophysiology:
Prevalence (Type 1 compared to Type 2):
Potential complications:
Chronic:
Neuropathy.
Nephropathy.
Retinopathy.
Cardio and cerebrovascular disease.
Foot ulcers.
Acute – usually in insulin dependent diabetes:
Hypoglycemia:
Not enough intake, insulin dose error, alcohol decreases gluconeogenesis, rapid onset and progression of symptoms, altered cerebral function.
Acute hyperglycemia – hyperglycemic hyperosmotic state – HHS:
MORE COMMON IN TYPE 2.
Hyperglycemia >600 mg/dL.
Hyperosmolarity – pulls water from cells (dehydrates them).
Too much extracellular “stuff.”
Symptoms – often mistaken for a stroke.
Neuro – decreased LOC, seizures, hemiparesis, aphasia, and visual disturbances.
NO KETOACIDOSIS.
Acute Hyperglycemia - diabetic ketoacidosis – DKA:
MORE COMMON IN TYPE 1.
Lack of insulin and release of glucagon.
Body begins to breakdown triglycerides.
Use fatty acids as energy source.
Ketones are produced (“fruity breath”).
Recognize dangerously abnormal blood glucose levels and identify a treatment:
(Not specified in note).
Describe metabolic syndrome:
Combination of disorders (at least three).
Elevated fasting glucose.
Reduced HDL levels.
Elevated blood pressure.
Central obesity.
INCREASES RISK OF:
Cardiovascular disease.
Type 2 diabetes.