PA 603 Blood Fall 2023 Lecture Topics PDF

 PA603- Lecture Topics/Obectives TOPICS INSTRUCTIONAL OBJECTIVES Describe the genesis of RBC’s, WBC’s, & platelets Blood Cells Immunity Explain hematopoiesis and lineage of mature...

 PA603- Lecture Topics/Obectives TOPICS INSTRUCTIONAL OBJECTIVES Describe the genesis of RBC’s, WBC’s, & platelets Blood Cells Immunity Explain hematopoiesis and lineage of mature blood cell Coagulation Explain factors which raise and lower RBC Neoplasia production. Explain role of erythropoietin in stimulating RBC production Discuss steps in platelet plug formation, blood coagulation, and clot retraction  Instructional Objectives Cont’d Discuss the extrinsic and intrinsic pathways for clot initiation and the factors involved Explain the significance of immunity, particularly with respect to defending the body against microbial invaders Define the circulating and tissue cell types that contribute to immune and inflammatory responses List the risk factors for the development of neoplasia Define the molecular and biochemical basis for the development of neoplasia  What is Blood? Blood consists of protein rich fluid known as plasma and cells ( WBC’s, RBC’s, and platelets). Total blood volume makes up about 6-8 percent of the body’s weight. 70 kg person will have approximately 5-6 L of blood. Blood functions as transport, pH buffer, temperature or thermal maintenance, and immunity and defense. Hematopoiesis occurs(blood cell formation)in red bone marrow  Blood- Constituents Element 1- (Plasma- Element 2- (Cellular- 45 % of 55% of Blood Blood Volume) Volume) 6. Cell types- Erythrocytes (4-6 1.H20 million) 2. Ions - Blood 7. WBC’s-Neutrophils, Electrolytes Lymphocytes, Monocytes, 3. Plasma Proteins – Eosinophils, Basophils (4- ex. Albumin 11,000) Fibrinogen- clotting 8. Platelets- (250- 500,000) 4. Immunoglobulins - 9. Cellular component = antibodies for hematocrit defense Blood Constituents  Blood -Function Ensures homeostasis - cellular metabolism Body’s principal ECF- transports O2, hormones, nutrients, heat Roles in hemostasis/hematocrit (plasma and blood cells) Differentiates and proliferates (bone marrow, liver, and spleen) Maintenance of acid- base balance Defense against invading microorganisms and injury  Blood Pressure BP Importance (Perfusionàdrive blood flow through tissues Systolic/Diastolic- > hb synthesis, 7)reticulocyte, Mature RBCs- smaller) Erythropoietin (EPO)primary regulator Mature RBC’s- (Required Factors): - Iron - Folic acid - Vitamin B12 Erythropoiesis Cont’d  Hemoglobin Structure Hemoglobin=pigmentàred 4 heme molecules(inorganic) and protein=1 globin Cral molecule of hemeàFe2+ Alpha globin & Beta globin Types: embryo Hb1, 2, Portland,Fetus-different Hb (HbF)à2 alpha and 2 gamma HbA- adult = 2 alpha and 2 beta Hemoglobinopathies  RBC Destruction RBC death (110-120 days)à phagocytosis 1. Hgb breakdown à bilirubinà liver conjugationà bile 2. Anemia-decreased cell mass vs Polycythemia –increased cell mass Ex. Iron deficiency MCV=index of RBC size100=macrocytic RBC  Hematocrit Hematocrit = (ratio)size of total red cell mass(Hb,Hct,RBC) Hct = volume of red cells: volume of whole blood Size of RBC-(Hb,Hct,RBC) microcytosis vs macrocytosis Hb synthesis(MCH,MCHC) MCV=(%HCT /100)/RBCL= 82-98 MCH=27-33 MCHC-30-35  Peripheral Blood Smear Blood smear – red cell indices -variations in cell size/shape -Reticulocyte count-red cell production Other labs- measurements of nutrients: 1.Iron 2. Vitamin B12 3. Folic Acid Lab Values  Cellular Elements of Blood - Leukocytes Leukocytes (WBC’s)neutrophils(phagocytic), lymphocytes, monocytes (enter tissueà (macrophages), eosinophils, &basophils} 5000-10,000/L Derived from hematopoietic stem cells Primarily responsible to defend against infectious organisms & remove debris Classified according to structure & function: - Structure à Granulocytes vs Agranulocytes - Function àPhagocytes or Immunocytes Histology- WBC’s  Leukocytes Cont’d Granulocytes= neutrophils, basophils, & eosinophils = phagocytes - Have membrane bound granules(enzymes catabolize & ingest debris, biochemical mediators) - Have ameboid movement- migrate through vessel walls  Leukocyte- Neutrophils Neutrophil( Polymorphonuclear neutrophil –PMN) - Constitute 55% total leukocyte count in adults - Acute Inflammation-Chief phagocytes of early phase - Diapedesis - Tissue injuryà migrate out capillaries à inflamed siteà ingest/kill microorganismsà prepare site for healing  Leukocyte- Eosinophils Eosinophilsà Innate Immunity - Constitute ~3-5 % of normal leukocyte count, - BM maturation 2-5 days, 8-18 hrs.-in blood, tissue ~5 days - Large/coarse granules(contain histaminase) - FXN: 1)migrate/digest invading germs, 2)create inflammatory response,3)phagocyt. complex - Induced by Ig E mediated hypersensitivity reactions - Eosinophilia- ex. Type 1 hypersensitivity, allergic rxns,& asthma, parasitic/fungal - Diurnal variation  Leukocyte- Basophils Basophils Make up less than 1% of the leukocytes Circulate ~ 12hrs. Cytoplasmic granules: contain vasoactive amines(histamine) contain anticoagulant (heparin) -leave capillariesà enter connective tissueà structured similarly & functions as mast cells -promote healing Degranulation à Allergic Rxn via IgE  Agranulocyte- Monocytes Monocytes - Immature macrophages - Formed & released by bone borrow into bloodstream - Maturing monocytesà migrate into tissueà Fully matured into tissue macrophages  Agranulocytes Agranulocytes - Includes- lymphocytes, monocytes, macrophages - Monocytes & macrophages = Mononuclear phagocyte system - Monocytes & macrophages ingest dead or defective host cells(ex. Blood cells)  Agranulocyte- Lymphocytes Lymphocytes - Primary cells of immune response - Constitute 36% of total leukocyte count - Initially transiently circulate in blood à then reside in lymphoid tissue as mature T cells, B cells or plasma cells Natural Killer cells(NK cells) resemble lymphocytes - Kill some types of tumor cells (in vitro) & virus infected cells w/o prior exposure  Spleen Spleen Largest lymphatic organ, LUQ Fibrous capsule, protein fibers compartments, venous sinuses(RBC’s)=red pulp, WBC’s= white pulp Contains macrophages & lymphocytes Fxn: Filtered by lymphocytes & macrophages Blood reservoir  Thymus Gland Bilobed gland,thoracic cavity Lymphoid tissue, clusters of lobules Fxn: Adaptive immunity - Rapid development of immune response (ex. 6mths-5 y/o Promote maturity of lymphocytesàT cellsàbloodstream Atrophy by adolescenceà replaced fibrous/fatty tissue  Tonsils Tonsils Located in pharyx Based on location:1) palatine tonsils 2)Pharyngeal tosils,3) lingual tonsils Fxn: Phagocytose microorganisms in mouth & throat regions Tonsillectomy-chronic infections  Peyer’s Patches Peyer’s Patches Distal end- Small intestines Extend mucosaà submucosa layer Follicles –B cellsà differentiate IgA -->plasma cells Fxn-macrophages - defensive barrier, identify microorganisms  Macrophages/Locations Liverà Kupffer cells Boneà osteoclasts Skin (epidermis)à Langerhaan cells Bone marrow/blood à monocytes CNS à microglia Kidney àmesangial cells  Lymph Node Lymph Node-”Filters” Most lymphocytes formed-lymph node, thymus, & spleen Precursor cells BMàB cells(cortical follicles) Precursor cells BMà T cells (Paracortical) processed in thymus Lymphocytes enter bloodstream via lymphatics majority in lymphoid organs Swollen- infection  Lymph Formation Pressure Gradients Interstitial fluid formed-protein extravasation from microcirculation into interstitial fluid Lymph-clear, H2O,WBC’s,- lymphocytes Role: immunologic tolerance, autoimmunity, inflammation, cancer metastasis, cardio/metabolic d/o  Lymphatic Trunks/Collecting Ducts Lymphatic Trunks Formed from merging lymphatic vessels Drains lymph from large regions of body Collecting Ducts 1. Thoracic Ducts (cysterna chyli à upper chest) Main collecting vessel for network Drains-left side(head, neck, thorax, Lt. upper limb entire body below diaphragm, fatty chyle from intestines 2. Right Lymphatic Duct- rt. head, neck, thorax, rt. upper limb  Antigen Recognition Markers On Surface of Lymphocytes Assigned clusters of differentiation-CD #’s = rxn’s to panel of monoclonal antibodies Most Cytotoxic T cellsà display glycoprotein CD8àrecognize MHC Class I Helper T cellsà CD4à recognize antigens presented by MHC Class II APC’s= dendritic cells in lymph nodes, skin, spleen  T-cell Sensitization What Event Sensitizes a T-Cell? Immunocompetent- before or after birth à adult life (Migrate thymus àlymphoid tissue (ex. Lymph nodes, spleen, bone marrow) Sensitization=Activation of mature incompetent macrophage in circulationà identifies antigen à phagocytized & processed in cytoplasm with MHC proteins à Clones T cell lines= Killer T cells, helper T cells, suppressor T cells, and memory T cells B- Cell Activation MHC I & MHC II  Clonal Diversity & Clonal Selection Clonal Selection Antigen recognition nonspecific & specific response Cells stimulated to divideà form clones cellsà respond to antigen Spleen & lymph nodes activation Generate diversity & antibody specifity, memory Fast secondary reponse  Types of helper T Cells T Cells Cytotoxic T cells helper/effector T cells Subtypes helper T cells Destroy transplanted 1. Th1àIL-2 and gamma-interferon cells & virally infected 2. 2. Th2->Il-4 and IL-5 (Humoral imm.) targets 3. Th17- àIl6 and IL-17, recruitneutrophils 4. T reg cellsàIL10dampen T cell driven response Sensitization / Allergy  Thrombocytes (Platelets) Platelets - 140,000-340,000, an additional 1/3 reserved pool in spleen - Cytoplasmic fragments that lack a nucleus - Primarily essential for blood coagulation & control of bleeding - Contain cytoplasmic granules( alpha & dense granules) release biochemical mediators Alpha granules-VwF, Factor V, TGF- betaFactor VIII, Integrins Dense granules: ATP, serotonin, ADP) - A platelet circulates ~10 days à removed by macrophages (MPS) - Main regulator of circulating platelet massà Thrombopoietin (TPO)  Thrombopoiesis Thrombopoiesis- production of platelets. -occurs in common myeloid progenitor cell in bone marrowà differentiate promegakaryocytes & megakaryocyte Life span 3-10 days Rate of formation based on plasma concentration -TPO  Clotting Factors Factor I – Fibrinogen Factor VIII-Antihemophiliac factor A Factor II- Prothrombin Factor IX- Antihemoph fact. B Factor III-Tissue thromboplastin Factor X- Stuart factor Factor IV- Calcium Factor XI- Antihemoph fact. C Factor V- Proaccelerin Factor XII- Hageman fact. Factor VII- Proconvertin  Vessel Injury 1. Injury 2. Extrinsic & Intrinsic pathway 3. Factor 2 Activation 4. PTà Thrombin 5. Fibrinogenà Fibrin threads (RBC’s, plasma, platelet’s= clot) 6. Clot retraction Goal hemostasis-STOP bleeding  Type of Hemostasis- Primary Primary Hemostasis Plateletsà form plug Weak formation Damage collagen/membrane à Weibelpalade bodies (inside is VwF-”glue”)àVwF leak join to platelets via GpIa(platelet adhesion)à activated call for help by releasing ADP & TXA2à new platelets binding to other platelets=platelet aggregation via GpIIIIb/IIIA producing weak platelet plug Deficiency VwF- Bleeding GPIA defective(Bernard Soulier Syndrome)à platelet adhesion can’t occur(no platelet plug = bleeding GPIIb/IIIaà no platelet aggregation (Glanzman Thrombosthenia  Secondary Hemostasis Secondary Hemostasis Goal: Clotting factors àform clots Start with X in center Soluble (fibrinogenà insoluble fibrin Damage endothelial damage Intrinsic Pathway Extrinsic =(outside tissue damage) (3)Tissue Factor XIIàXIàIXàVIIIàXàVII 5 2-Thrombin Soluble fibrinogen 1 à insoluble fibrin (seals it)  Platelet Function-Hemostasis 1. Vasoconstriction àVascular spasm- endothelinà myogenic nocioceptor reflex/activation mechanism 2. Formation of Platelet plug (Intrinsic Prothrombin activation)via VWF+Gp1b, GpIIb/IIIaADP, TXA2, Serotonin 3. Coagulation Cascade –Phosphatidyl serine, activate liver-clotting factors Ca2+=activate X, X+V+prothrombin activator+IIa(Thrombin+fibrinogen)àfibrin(insoluble)+XIII + Ca2+(cross linkages of fibrin)Factor III reacts with Factor VIIa and becomes activeàIX(Extrinsic pathway) 4. Clot retraction-endothelial/platelet contraction, platelet derived growth factor (PDGF), Vascular endothelial GF(VEGF)à 5.Fibrinolysis-avoid occlusion àTPA=Plasminogen=Plasmin Coagulation Cascade Coagulation studies: –How quickly does your blood clot? (PT,PTT,INR) Prothrombin Time(PT)- evaluates plasma’s ability to clot(Extrinsic System& factors common to both systems) - Factors VII, V, and X, prothrombin and fibrinogen A Partial Thromboplastin Time (PTT) -How long it takes for blood to clot (Intrinsic System) - Factors VIII,IX,X1 and factor XII -if low can prevent clot from forming PT-(10-12 sec), PTT(30-45sec),INR(1-2)  Vitamin K/Aspirin Vitamin K initiates carboxylation of Factors II,VII,IX and X Warfarinà anticlotting inhibits clot formation Ex. cardiac pts, DVT, thrombolic event clot formation Aspirin= platelet aggregation inhibition  PT/PTT Time PT (prothrombin)=Extrinsic pathway PTT-Intrinsic pathway Hemostasis Overview Immunity, Blood cells, Coagulation and Neoplasia Part II  Immunity, Blood Cells, Coagulation and Neoplasia Understand pathophysiology of infectious diseases as a relationship between the host, the pathogen and the environment Describe types of microorganisms – pathogens vs normal flora vs colonization Levels of human defense against pathogens Understand main characteristics of innate and adaptive immunity, major differences and mechanism of action Infectious diseases: pathophysiology, clinical manifestations (examples: endocarditis, meningitis, pneumonia, infectious diarrhea); understand pathophysiology of sepsis and septic shock Describe the etiology, pathophysiology, clinical manifestations, and clinical course of the following immune disorders, including but not limited to: allergy and immunodeficiency and autoimmune disorders Describe the etiology, pathophysiology, clinical manifestations, and clinical course of the following blood disorders, including but not limited to: iron deficiency anemia, pernicious anemia, neutropenia, and thrombocytopenia, and coagulation disorders Describe the etiology, pathophysiology, clinical manifestations and clinical course of types of cancer including but not limited to: leukemia, and lymphoma, colon, breast, neuroendocrine, germ cell, sarcomas Innate vs Adaptive immune system Immune system: pathogen recognition/ initiate response/eliminate pathogen/memory Innate: Non-specific Fast response No memory Similar response to all pathogens (phagocytosis, degranulation) Adaptive: Highly specific to each pathogen Slow response Requires receptor specific to pathogen Recognizes numerous number of specific Ags and mounts specific response to each Immune cells need to be activated to differentiate Immunologic memory Repeated insult leads to stronger response each time pathogen appears Cell production: hematopoiesis Stem cellsà lymphoid progenitor cells (B and T cells) and myeloid progenitor cells Hematopoiesis  Innate immune system Polymorphic leukocytes (neutrophils) Cytoplasmic granules can create phagolysosome and low pH with acidity destroying pathogen Phagocytosis of multiple pathogens, oxidative burst releasing antimicrobial factors (oxidative metabolites, superoxide, hydrogen peroxide, myeloperoxidase, proteolytic enzymes (collagenase, elastase, cathepsin B) eliminating pathogen Attracted by chemotactic factors (plasma-activated complement C5a, leukotriene, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), IL-8, PAF (platelet activating factor) Eosinophils Not phagocytic, respond to parasites producing holes in pathogen membrane Contain granules with pro-inflammatory molecules; when stimulated, release inflammatory factors (MBP – major basic protein), destroy parasites Attracted to the site of AG/Ab reactions by PAF, C5a, chemokines, histamine, LTB4 (leukotriene B4) Role in development of airway hyperreactivity - impair ciliary beating, cause exfoliation of respiratory epithelial cells; may trigger histamine release from mast cells and basophils IL-5 – primary growth factor (inhibition – treatment of asthma and airway disease) Basophils Non phagocytic, contain granules when stimulated, release histamine, leukotrienes, prostaglandins (PG), PAF Similar to tissue mast cells (mast cells = basophilic cells that interface with the environment) High affinity receptors for IgE; mediate immediate and late-phase allergic responses Mast cells Non phagocytic, similar to basophils, reside in subcutaneous or connective tissue, not in blood, and involved in allergic response Contain granules with mediators of immediate hypersensitivity with receptors for Fc fragments of IgE ; mediators - histamine (vasoactive), prostaglandins/leukotrienes (lipid mediators), cytokines, proteases); contribute to tissue damage when activated promoting angiogenesis and fibrogenesis  Innate immune system Monocytes, Dendritic cells and Macrophages- phagocytic APC cells Monocytes Very long life span but spend only 3 days in circulation Differentiate into macrophages in tissues and engulf pathogens there Macrophages Tissue phagocytic cells; recognize PAMP; can release IL1, IL6 Derive from blood monocytes, abundant near mucosal surface Internalize pathogens and travel to lymphoid organs Dendritic cells Sentinel cells located on the sites exposed to external pathogens (skin, GI and respiratory mucosa) Langerhans cells (epidermis), Kupffer cells 9liver) Natural killer cells – large granular lymphocytes Cytotoxic lymphocytes, kill tumor and virus (endogenous pathogens) about 3 days after infection Unique - do not need MHC or Abs , able to recognize and kill without MHC Differentiate and mature in bone marrow, lymph nodes, spleen, tonsils, thymus; then circulate in blood and migrate to tissues Adaptive immune system: lymphocytes T-lymphocytes CD3, can differentiate into CD4 and CD8 (70-80% of circulating lymphocytes; migrate to thymus to mature) - cellular response CD4: T helper cells - TCR on surface; amplify B-cell production of immunoglobulins, recruit leukocyte Th1 – produce IFN gamma and TNF beta, IL2; fight intracellular bacteria Th2 – develop in presence of IL4, IL5, IL13 respond to infestations and eosinophil activation; responsible for strong Ab production stimulating activated B cell proliferation Th17 - produces IL17, highly inflammatory cytokine causing immune-mediating diseases (psoriasis, RA, MS, IBD, asthma, tumorigenesis and transplant rejection Treg – specialized cells acting to suppress immune response maintaining homeostasis and self-tolerance; together with co-stimulator B7 suppress T cell response CD8: directly kill cells infected with virus, tumor, graft or intracellular pathogen; differentiate based on cytokine milieu Secrete a pore-forming protein perforin, inserts in infected cell plasma protein with serine protease granzymes leading to osmotic lysis or induce apoptosis B- lymphocytes CD19 – humoral response 10-15% of circulating lymphocytes; plasma cells – activated B cells Humoral response (outside of the infected cells); memory cells Can be APC for T cells Ready for proliferation when signaled by interleukins released by Th2 cells causing clonal expansion  Major histocompatibility complex I and II MHC I (intracellular Ags): MHC II (extracellular Ags): - present on most of all healthy cell - present only on APC membranes (B membranes lymphocytes, macrophages, dendritic cells, monocytes) - lymphocytes do not touch “self” - presents “foreign” material to antigens and recognize “non-self” cells lymphocytes with MHC with fragments of cancer cells, viral components, damaged cell - recognized by CD4 helper cells fragments signaled for destruction - T helper cells release IL-2 which moves to T and B cells to force them to - binds only endogenous Ags synthesized differentiate in a cell - Presence of foreign antigens induces Ab - therefore, recognized by CD8 (cytotoxic) production and attracts immune cells to cells place of infection -presence of abundant antigen - B cells produce memory cells and plasma containing cells targets cell for cells with Abs to specific Ag destruction MHCI and MHC II MHC - group of genes encoded on chromosome 6 - proteins those genes are encoding for - Human leukocyte antigens (HLA) - HLA can be found on every cell of the body - MHCI and MHC II - genes aka HLAs  Mediators of inflammation Histamine: Bioactive amine packaged in dense intracellular granules which bind to membrane bound H1, H2, H3 receptors Muscular contraction, vasodilation, increased vascular permeability, stimuljation of nasal mucosal glands (H1) Increased gastric acid secretion, mucus secretion, leukocyte chemotaxis (H2) Allergic rhinitis, Allergic asthma, Anaphylaxis Others: Kinins (bradykinin – vasodilation and smooth muscle relaxation), PAF, Arachidonic acid metabolies, cytokines, complement cascade Prostaglandins: generated by almost all nucleated cells PGD2 (mast cells)– vasodilation, vascular permeability, airway constriction PGF2a (neutrophils and macrophages) – bronchoconstrictor , PGE2 – bronchodilator TXA2 - platelet aggregation, bronchial constriction PGI2 – platelet disaggregation Other mediators Types of hypersensitivity reactions  Selected immune disorders: Allergic rhinitis: pathophysiology Stimulation of the immune cells the nasal cavity causing inflammation leading to local tissue damage in upper and lower respiratory tract and causing nasal congestion, rhinorrhea, sneezing Type I hypersensitivity - IgE – mediated allergic airway disease with immediate hypersensitivity; mast cells - key cells of allergic inflammation Abnormal hypersensitivity immune response to environmental allergens: seasonal tree, grass, weed pollens or perennial inhalants (house dust mite or cockroach Ag, mold, animal dander) Inherited tendency to generate IgE Abs to environmental allergens with immune response after interaction of allergen with mast-cell bound IgE Interaction of mediators with various target organs and cells of airway with release of histamine and other mediators S&S: nasal, ocular, palatal pruritus, sneezing, rhinorrhea, nasal congestion Selected infectious disease syndromes: Infective endocarditis Bacterial or fungal infection of the cardiac valves Effects inner layer of the heart Requires presence of ü Bacteremia ü Injury to endocardium ü Bacterial adherence ü Vegetation formation  Infective endocarditis: pathophysiology Bacteremia or fungemia Translocation of bacteria from the infective source into a blood stream Dental procedures (transient bacteremia with normal oral flora Strep viridans) IVDU (introduction of skin bacteria into the blood with non-sterile needles – Staph aureus) Genitourinary infections (enterococci may lead to blood stream entrance) Prosthetic heart valves (skin flora Staph epidermidis or Staph aureus) Injury to endocardium Tubulant flow (regurgitation) Micro-abrasion from impurities present in the injected material with subsequent formation of sticky matrix with fibrin, platelet and adhesion proteins Chronic inflammation (autoimmune conditions) Mechanical injuries from devices (Swan-Ganz catheters) Bacterial adherence and proliferation Staph aureus can invade endocardium in the absence of preexisting valvular injury) Vegetation formation Growth of bacteria with enlargement with further deposition of platelets and fibrin and inflammation with activation of coagulation pathway Vegetation particles can detach leading to complications of infective endocarditis  Infective endocarditis: complications Cardiac Valvular insufficiency and Heart failure Cardiac abscess, aortic root abscess, MI CNS Ischemic and hemorrhagic stroke Cerebral abscess and Mycotic aneurysms (caused by arterial wall dilatation caused by infection) Renal Renal infarctions and Immune complex depositions, glomerulonephritis Pulmonary Septic PE (TV) Other Splenic infarctions and abscess formation Endothalmitis Persistent bacteremia with metastatic seeding of infection (abscesses or septic joints) Death is usually caused by hemodynamic collapse or by septic emboli to the CNS with brain abscesses or mycotic aneurysms and intracerebral hemorrhage  Infective endocarditis Predisposing factors: structurally abnormal cardiac valves history of rheumatic or congenital heart disease prosthetic heart valve history of prior endocarditis and IVDU The most common infectious agents : Gram-positive bacteria - Streptococcus viridans, Staphylococcus aureus, Enterococci, fungi – Candida Signs and Symptoms: Fever (often low grade) Night sweats Dyspnea Fatigue Chest pain Hematuria with renal involvement  Infective endocarditis: signs Fever and Regurgitant murmur Discoloration of the extremities: Janeway lesions (painless hemorrhagic lesions palms/soles 2/2 septic microemboli) Osler nodes (painful papules / pads of the fingers and toes 2/2 deposition of immune complexes 2/2 local immune response) Splinter hemorrhages at nail beds 2/2 capillary injury Roth spots on fundoscopy (white centered retinal hemorrhages) Selected infectious disease syndromes: Meningitis Inflammation of protective brain and spinal cord meninges - arachnoid mater and pia mater Separated by subarachnoid space with CSF providing nutrients and protective layer to the brain CSF contains glucose, low level plasma proteins, electrolytes, WBC (100 fL), increased homocysteine level, bone marrow study – megaloblastic changes in RBC precursors at various stages of differentiation Treatment: dietary intake, decreased alcohol consumption, discontinuation of medications  Pernicious anemia – B12 (cobalamin) deficiency anemia B12 is used to: synthesize DNA precursors essential for cell division B12 deficiency lead to: impaired cell division, increased homocysteine and methylmalonic acid in the body Pernicious anemia is a disease where large, immature, nucleated cells (megaloblasts) circulate in the blood, and do not function as blood cells; caused by impaired uptake of vitamin B-12 due to the lack of intrinsic factor (IF) in the gastric mucosa, thought to be related to autoimmune condition Cobalamin (aka B12): not produced by human body, received from animal and dairy products (meat, eggs, milk); broken down in stomach by pepsin to release B12; binds to intrinsic factor from parietal cells in the stomach, B12/intrinsic factor (IF) complex passes into intestine and terminal ileum where complex is absorbed by enterocytes by binding to transcobalamin; needed to form RBCs and DNA Some of transcobalamin-II/B12 complex is transported to the liver where B12 can be stored for several years  Pernicious anemia: clinical manifestations Causes: impaired absorption (increased production of antibodies against the intrinsic factor or parietal cells à intrinsic factor can’t bind vit B12) decreased dietary intake (vegetarian diet, non animal products) Crohn’s disease (damaged enterocytes in terminal ileum), B12 can’t bind transcobalamin Gastric bypass Parasitic infection and decreased absorption Signs and symptoms: Pallor, shortness of breath, fatigue, glossitis, ischemic heart disease, chest pain, and NEUROLOGICAL symptoms (loss of memory, decreased reflexes, psychosis Hypersegmented neutrophils –sign of megaloblastic anemia Treatment: supplement, diet Anemia*** Anemia***  White blood cell disorders Malignant Disorders: increased production of non- functioning cells Leukemia Lymphoma Benign disorders: Absolute neutropenia: neutrophil counts < than 1500–2000/μL Cyclic neutropenia: rare, lifetime history of neutrophil counts that decrease to zero or near zero for 3–5 days at a time every 3 weeks and then rebound Classic, childhood-onset cyclic neutropenia results from genetic mutations  Thrombocytopenia Decreased platelet count due to: Decreased production of platelets Congenital bone marrow failure Acquired bone marrow failure (aplastic anemia, leukemia) Exposure to chemotherapy, irradiation, medications) Nutritional deficiency (vitamin B12, folate) Increased destruction of platelets Immune thrombocytopenia Heparin-induced thrombocytopenia Disseminated intravascular coagulation Increased sequestration of platelets Hypersplenism (cirrhosis, lymphoma)  Coagulation factors and coagulation system Highly complex, regulated interaction of cells and plasma proteins Provides immediate activation when control of bleeding (hemostasis) is required and confines its activity to the site of blood loss The major components of hemostasis: Platelet aggregation Vasoconstriction / Endothelial cells Coagulation factors (plasma proteins) The end result of the activated coagulation system - the formation of a complex of cross-linked fibrin molecules and platelets that terminate hemorrhage after injury Main step: activation of factor X and activation of thrombin Coagulation cascade The factors were numbered in order of their discovery, and not in order of their functions (as blood researchers learned more about coagulation, they realized that there is not, in fact, a factor II, or IV, or VI). Primary homeostasis: platelet plug Secondary homeostasis: coagulation cascade Effects of multiple anticoagulant medications on coagulation cascade Laboratory testing of the coagulation process*** PT, aPTT – tests of coagulation function; both mean “seconds to form a clot” PT (Coumadin)– assesses the extrinsic, used to monitor the effects of warfarin; reported with companion test INR (the international normalized ratio – removes the impact of difference prothrombin batch purity on the result) aPTT (Heparin)– assesses the intrinsic pathway; prolonged easily with reduced factor VIII or IX  Coagulation disorders: pathophysiology Disorder of platelets and coagulation factors Hypocoagulable states: tendency to bleed Platelets and coagulation factors are low, clot can’t be formed Excessive bleeding/bruising from trauma Nasal bleeding Hematuria Bleeding into the joints Excessive bleeding during menstrual period Petechiae (pinpont red dot on the skin) or deep bleeding  Decreased coagulation factors Clotting factors are proteins synthesized in the liver; several of them (II, VII, IX, X) require vitamin K for synthesis Deficiency in clotting factors Liver failure Vitamin K deficiency Genetic mutation leading to dysfunctional protein Inadequate amount of proteins Hemophilia – genetic disease with clotting factor deficiencies Hemophilia A (classic) – factor VIII Hemophilia B (Christmas disease) – factor IX Von Willebrand disease – decreased in von Willebrand factor (protein stabilizing factor VIII and platelet adhesions) Factor V Leiden deficiency - mutated form of factor V with increased hyper coagulability  Hypercoagulable state Leads to clot formation (pulmonary embolism – clot in pulmonary artery, stroke – clot in cerebral vasculature, mesenteric ischemia – clot in the mesenteric vasculature) Anti-phospholipid antibodies (Lupus) Pregnancy Malignancy Oral contraceptives Turbulent flow (atrial fibrillation) Heart failure Stasis Checks in clotting system: protein C, protein S, antithrombin III Factor V Leiden – mutation of factor V so factor V cannot be inactivated by protein Cà hypercoagulability Coumadin interferes with pathway by affecting vitamin K-dependent factors (II, VII, IX, X) Heparin increases antithrombin III activity Medications do not break clots! Slow down coagulation tPa- tissue plasminogen activator – breaks clots  Cancer: pathophysiology Cancer is a disease caused when cells divide uncontrollably and spread into surrounding tissues; caused by changes to DNA; studied with use of immunohistochemistry, flow cytometry, molecular biologic approaches to cancer diagnosis Genetic changes: genes regulate growth, maturity and death of the cells; genetic changes – gain/loss of chromosomes Oncogenes (cancer causing genes): may be normal genes which are expressed at high levels or altered or changed normal genes due to mutation à cancerous changes in the tissues Tumor suppressor genes: normally inhibit cell division and prevent survival of cells damaging DNA; disabled in patients with cancer Genomic amplification: a cell gains many copies of a small chromosomal locus containing one or more oncogenes and adjacent genetic material Point mutations: occur at single nucleotides; may be deletions and insertions at the promoter region of the gene; changes the protein coded for by the particular gene Translocation: two separate chromosomal regions become abnormally fuse at characteristic location (Philadelphia chromosome or translocation of chromosomes 9 and 22 in CML) Tumor: can be due to inflammation, infection, cysts or fluid filled lesions or due to benign growth. Cancerous tumor has the capacity to grown rapidly and metastasize Tumor development: 1) parenchyma containing cancer tissue 2) stroma induced by neoplastic cells in which they are dispersed; new blood vessel formation  Leukemia: pathophysiology Uncontrolled proliferation of partially developed white blood cells (also called blast cells) which interferes with development and function of healthy WBCs; ***term leukemia can be attributed to any of the blood cells (RBC and platelets) Stem cells: myeloblasts (myeloid cell precursor) à RBC, platelets, leukocytes (granulocytes (neutrophils, basophils or eosinophils) or monocytes) lymphoblasts (lymphoid cell precursor) à pre B cells and pre-T cells (develop into B and T lymphocytes) Once cells are formed à get to blood, tissues, lymph nodes, spleen Genetic mutation: Loss of ability of precursor blood cells to differentiate into mature blood cells (constantly in the blast stage of development without normal function) Uncontrollable division of the blast cells taking up space and nutrition in a bone marrow so other bone marrow cells cannot develop à cytopenia (anemia, thrombocytopenia, leukopenia Blast cells in bloodstream, settle down like normal cells in organs and tissues (liver, spleen, thymus (pre-T cells) à structure enlargement  Acute leukemia Acute leukemia - mutation in the precursor blood cells in the bone marrow Acute myeloid leukemia (AML) – more common in elderly, occurs due to chromosomal translocations used to classify AML into different typesà AML without maturation, AML with minimal maturation, AML with maturation, Acute promyelocytic leukemia, Acute myelomonocytic leukemia, Acute monocytic leukemia, Acute erythroid leukemia, Acute megakaryoblastic leukemia. Myelodysplastic syndrome: defective maturation of myeloid cells and development of blasts in the bone marrow à can progress to AML with myelodysplasia Down syndrome (associated with AML and CML; trisomy 21) Exposure to radiation Exposure to alkylating chemotherapy for treatment of other type of cancer Acute lymphoblastic leukemia (ALL) – more common in children, due to chromosomal translocation (12 and 21 and 9 and 22) or abnormal number of chromosome à production of abnormal proteins affecting cell function and division T-cell ALL: proliferation of Tcell precursors B-cell ALL: proliferation of B cell precursors  Leukemia: clinical manifestations Signs and symptoms: Fatigue (anemia) Bleeding (thrombocytopenia) Risk if infections (neutropenia) Pain and tenderness in the bones (expanison of bone marrow) Hepatsplenomegaly and feeling of abdominal fullness Pain in the lymph nodes (lymphadenopathy) Gingival swelling (monocytic infiltration in monocytic AML) Mediastinal growth (thymus enlargement in ALL) Diagnosis: peripheral blood smear (myeloblasts and lymphoblasts; bone marrow biopsy (increased in blast cells), immunophenotyping (TdT – DNA polymerase present only in the nucleus of the lymphoblasts and CD10 – surface marker for pre-B cells) Treatment: goal is to reduce a number of blast cells; chemotherapy, stem cell or bone marrow transplant  Chronic leukemia Increase in abnormal partially developed white blood cells over a long period of time which interfere with function and development of healthy RBCs, WBCs, and platelets Partial maturation (while in acute leukemia cells do not mature at all) à rapid division or delayed cell death with too many premature cells à weaker immunity Most common cause – chromosomal abnormality in stem cells destined to become leukocytes Chronic Myeloid leukemia (CML): chromosomal translocation affecting granulocytes (Philadelphia chromosome: abnormally short chromosome 22 --- and 9 translocation t(9;22)à rapid cell division can progress to acute leukemia with blast crisis Chronic Lymphocytic leukemia (CLL): chromosomal mutations affecting lymphocytes  Lymphoma A collection of white blood cells: they are either not dying and collecting or there is a dysfunction in the way the immune system allows cells replicate out of control (Hodgkin / Non- Hodgkin types - based on the type of lymphocyte affected Hodgkin (presence of the Reed-Sternberg cell) B lymphocytes (CD19 – marker for B cells) T lymphocytes (CD4 or CD8 cells) Dendritic Langerhans cells (APCs) Non-Hodgkins lymphoma (85% of all lymphomas) 80% - B cell lymphoma 20% - T cell lymphoma, always diffuse Burkitt lymphoma – aggressive, B-type, fast growing, can affect CNS Thank you!!!