Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
152 Cards in this Set
- Front
- Back
|
CENTRAL TOLERANCE
- when - how |
During lymphocyte development, self- reactive lymphocytes are eliminated via NEGATIVE SELECTION in thymus or bone marrow (primary immune organs)
BUT, not all self-Ags are represented in primary immune organs --> escape |
|
|
PERIPHERAL TOLERANCE
- major mechanisms |
Undergone by mature lymphocytes in the periph
1. Anergy: inactivation 2' to lack of co-stimulatory molecules (CD28-B7) 2. Activation induced cell death: Fas-FasL & CTL-mediated 3. Treg Suppression: CD4+CD25+ Tcells with FoxP3 tsc factor. - cytokines, unduce cytolysis, modulate DC fxn, disrupt metabolism |
|
|
HOW IS IMMUNE TOLERANCE TO SELF BROKEN?
- mechanisms of autoimmunity |
1. Impaired Tregs: in number or suppressive fxn
- Self-reactive effector Tcells may also become RESISTANT to Tregs 2. Release of sequestered "self" Ags - From privileged sites 2' trauma or apoptotic/necrotic cells 3. Structural changes to AutoAgs - drugs, viruses, proteolysis 4. Molecular Mimicry: cross-reactive Ags 5. Polyclonal B cell Activation: Nonspecific, from LPS, superAgs, etc. 6. Defective Apoptosis of autoreactive lypmhocytes: Defective FasL or Fas 7. Abnormal T cell fxn: drug-induced autoimmunity (DNA hypomethylation) 8. Inappropriate expression of MHC molecules: 2' to IFN-y secretion during viral infxn. - ex// MHC class II on thyroid or CNS (abnormal) |
|
|
Mechanism of Autoimmunity in:
- Rheumatic Fever - Cryptic Epitopes (Topoisomerase) - ALPS (Canale-Smith Syndrome) |
Rheumatic Fever: Cross-reactivity
Beta-hemolytic streptococcus Group A bacteria Abs react against Cardiac myofibrils = valve malfxn TopoIsomerase: Defective clearance of apoptoic cells --> necrosis --> proteolytic processing of enzymes = modified self-Ags presented by DCs ALPS: Pediatric condition of lymphadenopathy, splenomegaly, etc 2' to defective apoptosis of autoreactive lymphocytes |
|
|
Factors Contributing to the development of autoimmunity/dx
|
1. Genetic Predisposition
- esp Ankylosing Spondylitis (specific HLA) 2. Environment/Extrinsic - Infxns = cross-reactive or damage to privileged sites - drugs: procainamide - Mercury & silica = scleroderma 3. Hormones: 90% lupus & 95% hashimoto's hypothyroidism are female (child-bearing age) |
|
|
Immunological Mechanisms leading to tissue/organ damage in Autoimmuniy
|
1. Immune-Complex Formation & Deposition: MOST COMMON, esp. SYSTEMIC
2. CTL-mediated killing: lymphocyte infiltration ex// DMI, Hashimoto's Thyroiditis, Sjogren's Syn. 3. AutoAb binding to cell-surface Receptor: ex// Myastehnia gravis (inhibit) & Graves' (activate) 4. Complement fixing Abs: - activation of complement --> cytolysis ex// Autoimmune hemolytic anemia |
|
|
IC FORMATION
- normal - during complement def. - ANA |
Normal defense mechanism:
Form in blood, RBCs with C3b-C4b R take them to liver/spleen Most common basis of SYSTEMIC autoimmune disease (ex//SLE) - multi-organ dz because of high blood flow During complement deficiency, ICs go to wrong place --> initiate complement mediated injury & draw neutrophils = more injury **renal & heart failure due to IC accumulation** ANA = AntiNuclear Abs - frequent in systemic autoimmune diseases - Antigens are nuclear proteins & DNA |
|
|
SYSTEMIC AUTOIMMUNE DISEASES
- general characteristics - common features |
1. Immune response to a BROAD RANGE of target Ags not specific to an organ/tissue (ANAs)
2. Hyperactivity of T&B cells 3. Widespread tissue damage caused by IC, CD8+ CTLs, & auto-Abs. COMMONS: 1. ANA production 2. Systemic involvement 3. Arthritis - joint pain/destruction 4. Accum of autoreactive T & B cells classic: sle, scleroderma, sjogren's, mixed CT dz. |
|
|
SLE = SYSTEMIC LUPUS ERYTHEMATOSUS
- affected parts - diagnosis |
CHRONIC, MULTISYSTEM INFLAMM DZ
- usually affects joints, kidneys, cns, serosal membranes, skin DX: 4+ OF... (#1 & 2 = most common) 1. Malar rash (NOT on upper eyelids 2. Discoid rash - IC deposits in BM of skin in lesions & "normal" skin 3. Photosensitivity 4. Oral ulcers - painless 5. Arthritis - WITHOUT deformity 6. Serositis: of pleura, pericard 7. Renal disorder: proteinuria, protein casts - glomerular disease 8. Neuro: seizures, psychoses - NO vasculitis (only narrowing) 9. ALL HAVE BLOOD DISORDER - AIHA (anemia), leukopenia, etc. 10.Immune disorder: auto-Ab **Anti-dsDNA & Anti-Sm Ab = DIAGNOSTIC, VERY specific for lupus ( Anti-RNP) 11. abnormally HIGH titer of ANA present in all cases 8. |
|
|
SLE
- pathophys |
Abnormal Th cells drive B-cell hyperreactivity --> auto-Abs (ANAs)
- POSITIVE charge of anti-DSDNA Ab lets it cross BM of vasculature --> activate C' & attract leukocytes ** Cationic ANA complexes are from oligoclonal T cells** - ICs eat up all the C' = hypocomplementemia **some pts also have some sort of C' deficiency inherited* |
|
|
LE CELLS
|
Specific to SLE
- Macros or neutrophils ingesting (nuclear) material from apoptotic cells |
|
|
SLE
- Genetic? - incidence - prognosis |
- + genetic predisposition
- Females 9:1, esp af-am most die from renal or cns dz - others from opportunistic infxn |
|
|
CHRONIC DISCOID LUPUS ERYTHEMATOSUS
|
+ SKIN LESIONS
but not usually multi-system - only 35% are ANA+ (don't have Anti-Sm **IC deposits in BM are ONLY in lesions (not normal areas)** |
|
|
DRUG-INDUCED LUPUS ERYTHEMATOSUS
- hwat drugs? - incidence? |
NO SKIN INVOLVEMENT
- genders equally affected - Anti-Sm rare DRUGS: procainamide, isoniazid, D-penicillamine cessation of drug will resolve symptoms |
|
|
18 yo African-American female with purply malar rash, bruises easily, anemic, complains of joint pain (but no deformities), positive for ANA (what type?) , also experiencing seizures and foamy urine
|
SLE
- proteinuria - CNS dz - anemia - arthritis |
|
|
SJOGREN'S SYNDROME
- types - symptoms - incidence |
1. Primary (isolated): sicca syndrome
2. Secondary: assc'd with other autoimmune dz (esp RA) 1. DRY EYES: keratoconjunctivitis sicca 2. DRY MOUTH: xerostomia 3. Looks like lymphoma: massive infiltration of lacrimal & salivary glands by lymphocytes *90% females 40-60 yo |
|
|
SJOGREN'S
- pathophy - aff'd organs - Abs |
Similar to Rheumatoid Arthritis:
Marked periductal & perivasc infiltration by CD4 Th cells 1st - recruited B cells --> lymphoid follicle formation --> destruction of glandular tissue by organ-specific inflammation ALSO: - Lung: no bronchial glands --> ^ infxn - Kidney: Tubulo-interstitial nephritis, NOT glomerular dz **ALSO AT 40X ^^^^ RISK OF LYMPHOMA*** Abs: - highest rate of Anti-RNP - 75% are RA-Factor positive, even if not symptomatic (Ab to a Ab) - GENETIC: hLA-DR3, DW3 |
|
|
50 yo female, also with rheumatoid arthritis. Frequent hospital visits for bronchitis or pneumonia. Complains of dry eyes and cotton mouth. always thirsty. has nasty periodontal dz. Sister also has similar symptoms
|
Sjogren's
- check for lymphoma (40x ^ risk) |
|
|
PROGRESSIVE SYSTEMIC SCLEROSIS/ PSS / SCLERODERMA
- pathophys |
Environmental damage = fibroblastic response in endothelium --> SCARRING (excess collagen)
- in skin, GI tract, kidneys, heart, lung 1st: edema, perivasc CD4+ lymphocytosis & collagen degen 2. Endothelial injury and platelet activation --> (tgf-b & pdgf ) intimal fibrosis --> narrow lumen --> OCCLUSION & REGIONAL FIBROSIS **many die of lung or renal dz** |
|
|
CREST VARIANT OF SCLERODERMA
|
MILDER - 3/6 for dx
1. Calinosis 2. Raynaud's 3. Esophageal dysfxn: "lead pipe" 4. sclerodactyly 5. Telangiectasia 6. anTI-CENTROMERE ab = very specific & sensitive for crest variant **THICK TIGHT SKIN - no sweat glands and skin is fULL of collagen |
|
|
DIFFUSE SCLERODERMA
NO HLA assc, but 96% have chromosomal abnormalities from serum breaking factor |
CREST + widespread sin involvement & early visceral involvement
- stone facies & claw hands - renal failure = #1 cause of death **NOT glomerular nephritis (IC accum), but ONION SKINNING of renal arterioles** - #2 COD = PULM HTN - Anti-Scl-70 = TopoI, very specific for pulmonary fibrosis/vasc dz (?) |
|
|
MIXED CT DZ
|
NO ANTI-DSDNA Ab
- combo of scleroderma & lupus good prognosis: - no renal dz - tx'd well w/ steroids *high titers of anti-RNP |
|
|
POLYMYOSITIS
- CELL TYPE - ANA |
CD8+ INFILTRATION into skeletal mm (not the case in derm)
- PROXIMAL MM ANAs against tRNA synthetases --> LUNG DISEASE *TYPE 4 Hypersensitivity reaction* |
|
|
DERMATOMYOSITIS
|
LILAC RASH, EVEN ON UPPER EYELIDS
- microvasculopathy CD4+ CELLS & B CELLS (neuro says b cells) LINKED TO LUNG CA ESP IN OLD MALES |
|
|
ORGAN SPECIFIC AUTIMMUNITY
|
1. Directd to target Ag unique to single organ/gland
2. Mediated by DIRECT cellular damage or stimulating/blocking auto-Abs - direct damage = DMI & hashimoto's - pernicious anemia: parietal cells - Autoimmune hemolytic anemia: liver & spleen (RBC) |
|
|
HASHIMOTO'S
- Auto-Abs |
Abs to thyroglobulin & thyroid peroxidase (involved in iodine uptake)
- CTL attacks thyroid epithelial cells - Thyroid is INFILTRATED with white cells |
|
|
GRAVES' DZ / THYROTOXICOSIS / HYPERTHYROIDISM
- AB? |
Ab (IgG) to TSH-R
ACTIVATES IT = EXCESS TH GOITER CAN occur simulatenous or subsequent to hashimoto's |
|
|
HALLMARK OF IMMUNODEFICIENCY
- Types of infxns assc'd with ImmunoD type **primary deficiencies are RARE - B & B/T deficiencies are most common** |
UNUSUAL & RECCURENT INFXNS
- B cell / Ab = Bacterial - T cell = Fungal, Protozoal, VIral - Phagocytic = systemic bact opport, skin, pyogenic (bacterial) - C' = pyogenic (bact) |
|
|
SOME PRIMARY IMMUNODEFS OF
- B CELLS - T CELLS - BOTH B&T - PHAGs - C' |
B.
- XLA/Bruton's - Transient hypogammaglobulinemia - Common variable " - Selective Ig Def. T. DiGeorge syn (cong. thymic aplasia) Chronic mucocutaneous candidiasis B&T: - reticular dysgenesis - SCID - WASP - Ataxia-tELANGEICTASIA PHags: - CGD - Chediak-Higashi syn C': Hereditary Angioedema |
|
|
X-LNKED INFANTILE AGAMMABLOBULINEMIA
X-LA , BRUTON'S DZ PROTOTYPE OF ALL IMMUNODEF. DZs |
-only males
- no mature B cells - defective B cell tyrosine kinase gene (btk gene) nec. for B cell maturation - ALL 5 Ig isotypes are decreased - small/absent tonsils & lymph nodes - MANY infxns after 6-9 mos: esp H. influenza, strep. pneumo, and ECHOVIRUS **DON'T USE LIVE VIRUS - CAN KLL BABY* |
|
|
8 mo. old baby boy, with h/o frequent ED visits & hospitalizations for bacterial infections. small, absent tonsils & no lymphadenopathy on PE. Vaccines never seem to work
blood test = No Abs |
x-la / bruton's
tx: abx & pooled IgG |
|
|
Transient Vs. common variable hypo-y-globulinemia
|
TRANSIENT: delay in B cells making IgG
- ONLY IgG is LOW - NO HELP FROM CD4 Th - no tx COMMON: Acquired, 15-35 yo - B cells don't differentiate into plasmacytes - 1+ IgG/A/M are deficiet - high freq of autoimmune dz & malignancy - also lotsa infxns like X-LA - same tx as x-la |
|
|
20 yo suddenly experiencing increased frequency of bacterial infxns. also has RA and malignant tumor had a biopsy for. Sister was diagnosed with IgA deficiency
- blood test = IgG & A def |
common variable hypo-y-globuinemia (older brother of bruton's)
- tx: ABX and pooled IgG * ^^^ risk of Gastric CA and lymphoma in females* *relatives of these pts are also at ^ risk of isolated IgA def* |
|
|
Selective Ig Deficiencies
|
Mostly due to failure in terminal differentiation of B cells
IgA: most common (esp in those w/ allergies) - chronic diarrhea - sinus infxns - **anti-IgA Abs can be common in pts --> blood transfusion can cause TYPE 1 transfusion rxns** IgG HIGH-M: B cells can't switch from making IgM to other isotypes - High igM levels, but def in others - LIVER abnlities - IgM auto-Abs can appear. - no CD40 ligand on Tcells or CD40-R on B cell/APC= no signal from Th cells to switch |
|
|
CONGENITAL THYMIC APLASIA
(DIGEORGE) *In severest form of T cell depletion, B cell activation is also impaired --> bacterial infxns become a problem* |
CAUSE: interference in the development of pharyngeal pouches 3&4
- No thymus = no t cells - no Parathyroid gland = hypocalcemia --> tetany, seizures - learning disabilities **FACE, HEART, BLOOD VESSEL MALFORMATIONS** Freq infxn: candida albicans, p. jirovecii, viral vacc (live) can be FATAL! |
|
|
1 mo. old infant with seizures, tetany, and recurrent infxns. Fish mouth, notched ears, cleft lip, and droopy eyes. grows up to be mildly retarded
|
DiGeorge's syn (congenital thymic aplasia)
- T cell tx: fetal thymus transplant, cardiac sx, ca supplement, abx |
|
|
Crhonic mucocutaneous candidiasis
|
CHRONIC infxn of skin & mucous membranes w/ candida
- SELECTIVE T CELL DEFECT (NORMAL T & B CELL REAXN TO OTHERS) TX: ANTIFUNGAL DRUGS |
|
|
RETICULAR DYSGENESIS
|
DEVELOPMENTAL ARREST OF PRECURSOR CELLS @ UBER EARLY STAGE
- b, t cells, and granulocytes are affected DIE WITHIN A FEW WEEKS - INFECTED BY EVERYTHING, UNREMITTING, diarrhea, etc. - everything "-penia" |
|
|
SCID = SEVERE COMBINED IMMUNODEFICIENCY DISEASE
** know the ADA form for exams - purine metabolism is defective ** no live vaccines = fatal |
BUBBLE BOY (usually have rashes too)
Defective lymphoid stem cells = NO t & b cells (and some have no NK cells) many types: ex// - Defective gene for gamma chain of IL-2 Receptor = no growth signals - ADA enzyme def: ATP & dATP accum to toxic levels in lymphoid stem cells - Bare lymphocyte syn: no HLA I / II 2' lack of transporter protein |
|
|
2 wk old baby with candida albicans infxn, pneumonia, constant diarrhea, and viral infxn. Treated with abx, but continues to come back. severe lymphopenia, granulocytopenia, and low Igs
- dies at 3 weeks |
reticular dysgenesis
|
|
|
WAS = WISKOTT-ALDRICH SYNDROME
(B & T CELLS) |
Mtts in gene encoding WASP
- x-linked, MALES only - T cell count in kids can be normal but decrease LATER - IgM level low (2' high catabolism rate) - bleeding, eczema - abnormal platelets - thrombocytopenia **needs bone marrow transplant |
|
|
ATAXIA-TELANGIECTASIA
(B & T CELLS) |
SLOW PROGRESSION
- defective ATM gene (DNA repair) --> broken T cell antigen receptor gene & h chain gene in Abs - low IgA - high incidence of CAs - High susceptibility to radiation - SEVERE cerebellar ATAXIA - telangiectasia ** look at whites of eyes and ears ** bone marrow & thymus transplantation |
|
|
CHRONIC GRANULOMATOUS DISEASE (CGD)
PHAGOCYTE DZ |
Mtts in genes assc'd with NADPH OXIDASE
- Necessary to break down free radicals = granulomatous abscesses, esp in nodes, lungs, and liver - vulnerable to infxn tx: bone marrow transplant & tx infxn |
|
|
Chediak-Higashi syndrome
scary lady with light eyes |
Mtt in LYST (lysosomal trafficking)
- enzymes don't enter phagolysosoes - DELAYED killing by phagocytes (NK and T cells kill a little) **Oculocutaneous albinism** - grey hair, light eyes - extreme photophobia, - REM, cns problems *bone marrow transplant |
|
|
Complement deficiencies
|
EARLY = C1, C2, C4
C3 = Part of all 3 pathways, most abundant C' = increased chance of autoimmune dz & bact. infxns Late = C5-C9 **GRAM NEGATIVE BACTERIA = MOST COMMON TYPE OF INFXN IN C3, 5-9 DEF** - C' interacts w/ OM of gram- bacteria |
|
|
HEREDITARY ANGIOEDEMA
|
C1 Esterase Inhibitor = increased vascular permeability
1. uncontrolled C1qrs activation 2. Kinin-related proteins attacks of skin & mucous membrane swelling (not continuous) - swelling of larynx = die (1/3) - hives in stomach can cause vomiting, diarrhea, etc. - NO increase in infxns!!! C1 is part of coagulation cascade - symptoms can be INDUCED |
|
|
SECONDARY IMMUNODEFICIENCIES
|
3rd world = poor nutrition
young, old USA = immunosuppressant drugs/autoimmune dzs Protein loss Infxns: - HIV = cd4+ - EBV = B cells - Measles & m. tuberculosis, m. leprae other chronic dzs and agents |
|
|
EVALUATION OF IMMUNE COMPETENCE
|
1. SCREENING:
- hx: eczema, retard, FMH, freq/weird infxns - CBC with 3-pt diff - ELISA (HIV) - Skin tests: delayed hypersens - Serum Proteins - Auto-Abs, Igs - Total hemolytic C' eval 2. T cell - chest x-ray for thymus/tumors - Quantify lymphs (Abs for CD3,4,8 - Node biopsy = look at T cell #, dist, morphology - In vitro tests of competence 3. B cell (Ab) eval: - Ab titers before & after vacc - Quantify IgG subclasses - EBV - Bone marrow eval of pre-B & plasma cells - LN biopsy - In vitro test of competence 4. Phagocytes & Complement - Test for O2 radical production - Quanitfy specific C' components - Test for monocyte chemotaxis - Eval for presence of specific intracell enzymes - quantitative tests of bacterial killing |
|
|
HYPERSENSITIVITY REACTIONS
TYPES I-IV type 2 rxn = anemia |
1. immediate rxns triggered by IgE bound to mast cells
--> histamine release = local wheals or systemic anaphylaxis 2. Cytotoxic rxn mediated by Abs against Ag on cell or in tissue - very organ specific - C'-dep reactions (IgM & IgG) 3. Deposition of IC = #1 basis of AI dz --> complement fixation & inflammation 4. Cellular immune response - NO ANTIBODY INVOLVEMENT - t-cells |
|
|
TYPE I HYPERSENSITIVITY RXNS
|
IMMEDIATE
1. IgE Ab Production/Sensitization CD4 Th2 makes: - IL4 to switch IgM --> IgE synthesis - IL5 = increases eosinophil production 2. Mast cELL ACTIVATION - IgE binds to mast cells --> histamine release - Allergen exposure crosslinks mast cell IgE - Prformed mediators are released & PGs & LKs are made/released - Desensitization = increased allergen amts cause IgG to be released, replacing mast cells CLINICAL - ATOPY: HIVES, ASTHAM, ETC. - ANAPHYLAXIS |
|
|
TYPE II HYPERSENSITIVITY RXNS
|
Ab-Ag rxn in cell or tissue
C'-DEP: needs IgM - Cell lysis (MAC): ex// wrong blood transfusion - Tissue damage: IgG activates C5a --> monocytes & neutrophils --> proteases & O2 radicals ex// acute rheumatic fever (cross-reactive) & glomerular antibasement membrane dz - Phagocytosis: IgG or C3b opsonization C'-INDEP: need IgG - Anti-cell receptor IgG ex// MG (-) & Hyperthyroidism (+) |
|
|
TYPE III HYPERSENSITIVITY RXN
|
Rich vasculature = ^ deposition of IC
- kidney, lung, CNS - IC deposition attracts c' and inflammation & increases vasc perm. - attracts C5a --> neutrophils ex// SLE & glomerulonephritis after strep infxn |
|
|
TYPE IV HYPERSENSITIVITY
- cd4 vs cd8 |
CELLULAR IMMUNE RESPONSE
1. CD4, Th1 - interact w/ macros - delayed hypersensitivity rxn --> macros release IFN-y --> caseous necrosis of TB & MS - direct damage: CD4 release cytokines --> fibrosis --> scleroderma CD8 - interact w/ altered MHC I -ex// Polymyositis, contact dermatitis (poison ivy) |
|
|
MCV & MCHC (PART OF CBC)
- MEANING - SIGNIFICANCE |
MCV = Mean corpuscular volume: average size of the RBC
Hct / RBC x 10 LOW MCV = microcytosis MCHC = mean corpuscular [Hgb]: color of the cell MCHC = Hgb / Hct x 100 |
|
|
RDW (part of cbc)
- anisocytosis vs. poikilocytosis - iron def vs. thalassemia |
RED CELL DISTRIBUTION WIDTH:
Degree of variation of size (anisocytosis) & shape (poikilocytosis) - low MCV & high RDW = iron deficiency - Low MCV & normal RDW = thalassemia (abnl Hb) |
|
|
LIFE CYCLE OF RED CELL:
- ERYTHROPOIESIS - REGULATION - TURNOVER - retic count |
RBC precursor loses nucleus --> retic
Retic ---> 24 hrs in blood --> RBC (no stainable RNA) *hypoxia of kidney cells = EP production DEATH: - Phag'd by macros in marrow & spleen NORMAL = 1% OF RBC REPLACED BY RETICs every day * retic count = measure of RBCs made in last 24 HOURS: normal = 0.5-1.5% |
|
|
ABSOLUTE RETIC COUNT vs. raw retic count
|
Raw retic count: ratio of retics/RBCs
Absolute retic count: RAW retic ratio MULTIPLIED by RBC * raw count may be misleading in context of anermia (doubled) * |
|
|
ANEMIA WORKUP
- BASIC QUESTIONS TO ASK WITH CBC RESULTS |
1. Failure of marrow production (LOW retic) or of survival (HIGH retic)
2. RED CELL FEATURES - MCV: marrow failure - red cell shapes ( sickle cell) anemia from: Failed survival: - blood loss - hemolysis Failed production: - no marrow precursors - ineffective erythropoiesis |
|
|
ANEMIA WORKUP
- BASIC QUESTIONS TO ASK WITH CBC RESULTS |
1. Failure of marrow production (LOW retic) or of survival (HIGH retic)
2. RED CELL FEATURES - MCV: marrow failure - red cell shapes ( sickle cell) anemia from: Failed survival: - blood loss - hemolysis Failed production: - no marrow precursors - ineffective erythropoiesis |
|
|
ANEMIA
- BLOOD LOSS (reticulocytosis? time frame) |
Anemia occurs when rate of loss > rate of RBC production
- marrow can increase RBC production x4 --> reticulocytosis possible 1. Retic count is NORMAL in first 48 hours 2. Hb & HCT does NOT drop during the first 12hours (unless fluids are given) |
|
|
ANEMIA
- FAILURE OF SURVIVAL - types - retic count |
HIGH RETIC COUNT
1. Extrinsic damage to NORMAL red cells: DIC, malaria 2. Immune Hemolytic Anemia: Abs destroy RBCs - use Coombs test (Anti-human Ab) ex// AIHA, Blood transfusion, pregnancy 3. Hypersplenism: big spleen eats up RBCs - also thalassemia (only microcytic anemia with ^ retic |
|
|
COOMBS TEST
- anti-human globulin test - direct vs. indirect |
Postive reaction = RBC agglutination or lysis
DIRECT (DCT): Detects human anti-red cell Abs on patient's RBCELLS INDIRECT (ICT): human anti-RBC Abs in patient's plasma or serum - the serum is mixed w/ normal (donor's) RBCs *ICT used b4 transfusion & Rh- mom w/ Rh+ fetus |
|
|
COOMBS TEST RESULTS IN Rh-/+ family
- mom - fetus - dad |
mom: - DCT, + ICT
FETUS: + DCT, + ICT DAD: - DCT, - ICT |
|
|
ANEMIA:
- Failure to survive: intrinsically defective cells |
HIGH RETIC COUNT
1. Defective membrane - inherited (pherocytosis, ovalocytosis) or acquired (PNH - neoplastic mtt of C'-mediated lysis) 2. Defective Hb: do Hb electrophoresis - Thalassemia: decreased synthesis of Hb alpha or beta chain ( no AA mtt) --> excess chains precipitate --> phag'd --> microcytosis - Hemoglobinopathy: AA mtt ex// sickle cell - crystallized hb alters shape & membrane --> hemolysis & vascular occlusion 3. Defective enzymes - degrade Hb --> precipitates --> hemolysis |
|
|
ANEMIA
- FAIL 2 PRODUCE - retic count? |
LOW RETIC COUNT: lack of precursors
1. Aplastic: pancytopenia - lost ALL blood cell line precursors (only fat in marrow) 2. Pure red cell aplasia: only anemia 3. Renal failure: no EP - only anemia 4. Myelophthisis: pancytopenia - marrow replaced w/ tumor/fibrosis/granuloma OR "ineffective EP" - still have precursors, just destroyed in marrow - iron def (microcytosis) - anemia of chronic dz (normocytic anemia) - megaloblastic (folate/B12 def) - macrocytosis - Meds/toxin effect: inhibits precursors - Myelodysplasia: marrow precursor neoplasm (destoryed in marrow) - Hypothyroidism: T3/4 controls rate of cellular replication |
|
|
CELLS DERIVED FROM LYMPHOID & HEMOPOIETIC STEM CELLS
|
lymphoid: NKs, T, & B
Hematopoietic/Myeloid stem cell: - magakaryocyte --> Platelet - RBC - Mast cell - Myeloblast --> baso, eso, neutro, mono/macros |
|
|
MARROW CELLULARITY & M/E RATIO
- inflamm - hemolytic anemia **used to eval a cytopenia?* |
marrow cellularity = 100% - pt's age
(marrow occupied by precursors vs. fat) - plateaus at 30% Myeloid/Erythroid ratio = 3/1 granulocytic precursors / erythroid INFLAMM: M/E ^ HEMOLYTIC ANEMIA: M/E Decreases |
|
|
APLASTIC ANEMIA
|
low retic, normal MCV
NO STEM CELLS IN MARROW - hypoplastic marrow (mostly fat) - Pancytopenia (cytopenia or everything) CAUSES: - HEP C - chemicals/radiation - idiopathic *no splenomegaly * marrow transplant or immunosuppression (Tcells) |
|
|
MYELODYSPLASIA
|
low retic, HIGH MCV
NEOPLASTIC MTT of hemopoietic cells - defective differentiation --> apoptosis - can have pancytopenia *also suppresses normal stem cells |
|
|
PURE RED CELL APLASIA (PRCA)
= FAILURE OF PROGENITOR CELLS - acute - chronic |
LOW RETIC, NORMAL MCV
ACUTE: - KIDS - parvovirus: duration 2-3 weeks *only problem if hemolytic anemia (sickle cell dz) bc rbc life span is only 2-3 weeks in those pts (norma = 3 mo) CHRONIC - Adults - thymoma, thymic hyperplasia (immunologic dz) *both can be induced by drug rxns* |
|
|
anemia of chronic renal failure
(other normocytic anemias?) |
decreased EP production or toxic suppression by uremia
- low retic - normal MCV --> normocytic anemia tx w/ erythropoietin other normocytic anemias: - chronic dz anemia, early iron def, aplasia, PRCA, and myelopthisis (myelodysplasia = HIGH MCV) |
|
|
MYELOPHTHISIS:
|
bone marrow infiltrated by:
- tumor - granulomas - fibrosis (no room for precursors) - Leukoerythroblastemia: immature cells in periph - tear drop-shaped red cell (dacryocytes) in periph blood - pancytopenia possible |
|
|
IRON METABOLISM BASICS
- normal amts / losses /absorption |
normal adult male: 4g (3g in Hb unstained, 1g in macros (stained))
LOSSES: - GUT/SKIN: 1 mg/day - Menses: 15 mg/mo & pregnancy = 1g ABSORPTION: MALES: 1 mg/day Females: 2 mg/day - in duodenum & upper intestine (folate - jejunum & vit b12 - ileum) *boys = GI loss by ulcers & CAs *girls = gynecologic (inadequate intake/malabsorption problems are rare) |
|
|
tests for iron stores vs. iron transportation
- prussian blue / serum ferritin - serum iron, TIBC, % sat of TIBC - IRON DEF VS. ANEMIA OF CHRONIC DZ |
PRUSSIAN BLUE STAIN OF MARROW FOR IRON = gold std
(blue = hemosiderin = partly degraded ferritin) Serum ferritin: parallels STORAGE iron - but liver dz can elevate ferritin (even in iron def.) Serum iron: iron being TRANSPORTED by protein (transferrin) = 100microg/dL - normally only 1/3 binding sites filled --> TIBC = total iron binding capacity = 300 microg/dL %sat = (100% x serum iron) / TIBC = 33% |
|
|
IRON DEF VS. ANEMIA OF CHRONIC DZ
*both can be nomocytic (normal MCV) in early stages) inflammatory cytokines (IL-6) --> liver --> ^ hepcidin --> STOPS ferroportin from releasing iron stores. |
BOTH LOW RETIC & LOW MCV
IRON DEF: - decreased serum ferritin (storage) - Decreased serum Fe (transported) - High TIBC (binding filled) - %Fe sat <10% *also inflamm & ^ ESR CHRONIC DISEASE: - NORMAL/HIGH serum ferritin** - Decreased Serum Fe - Decreased TIBC** - %Fe sat > 15%** |
|
|
FEP
- thalassemia vs. iron def/chronic dz anemia |
USE FEP WHEN WORKING UP A MICROCYTIC ANEMIA
Free erythrocytic protoporphyrin (FEP) - iron uses porphyrin to make Hgb Fe deficiency, Chronic dz, Lead Tox: iron is unavailable - EXCESS FEP thalassemia: no FEP excess - also, thal int/major has HIGH retic |
|
|
IRON DEFICIENCY ANEMIA
- causes -dx - evolution process - other signs (only if severe/chronic) - tx **always low retic count* |
CAUSES:
- iron loss > gain - malabsorption or inadequate intake (premies) *milk anemia, growth spurt, pregnancy DX: - LOW serum ferritin - LOW serum iron - HIGH TIBC (liver cells make more transferrin due to low iron) - ^ duodenal abs (no more hepcidin = ^ ferriportin channels = ^ iron in blood) EVOLUTION: - EARLY: normocytic, normochromic - moderate: icrocytosis - severe: hypochromasia w/ RBC shape change |
|
|
IRON DEFICIENCY ANEMIA
- other signs (only if severe/chronic) - tx **always low retic count* |
NONHEMATOLOGIC:
- CHEILOSIS/PERLECHE - LINGUAL DEPAPILLATION (smooth tongue) - koilonychia (spoon finger nails) - esophageal web+tongue, mouth lesions (plummer-vinson syndrome) - pica: eat weird stuff to get minerals TX: FIND CAUSE & TX IT - ORAL IRON: ferrous sulfate - if elderly/sever = give packed RBCs *poor compliance = #1 reason oral Fe therapy fails * Reticulocytosis should appear in 3-7 days *Hgb should ^ 2g every 3 weeks (normal w/in 4-6 months) |
|
|
ANEMIA OF CHRONIC DZ
|
LOW RETIC, LOW-NORMAL MCV
(microcytic, hypochromic) Chronic dz/inflamm = 1. IL-6 --> Liver 2. hepcidin 3. Ferriportin on macros OFF 4. Iron is trapped inside macros "functional iron deficiency?" classic: - adequate or ^ marrrow iron = reticulo-endothelial (RE) BLOCK DX: - LOW SERUM IRON & TIBC - % SAT IS NORMAL OR increased (>15%) - INCREASED SERUM FERRITIN |
|
|
THALASSEMIA
|
MICROCYTIC, HYPOCHROMIC ANEMIA
- iNHIBITION OF Hgb chain production --> less Hgb --> less iron needed --> more iron stays in macros DX: - Increased serum ferritin - ONLY microcytic anemia with ELEVATED retic count (compensating for anemia) *hemosiderosis can occur when transfusion are given = decreased hepcidin = open ferriportin in dudoenal cells = increased iron absorption. |
|
|
SIDEROBLASTIC ANEMIA
*marked white center* |
MICROCYTIC ANEMIA WITH RINGED SIDEROBLASTS
-iron granules of defective/poisoned mitos surround nucleus - iron in e-blast can't be used for Hgb --> microcytosis CAUSES: - mito toxins (ALCOHOL!!) - Idiopathic (usually myelodysplasia = neoplastic preleukemia state) |
|
|
LEAD POISONING ANEMIA
|
microcytosis
(POISONED porphyrin enzymes **CLASSIC = BASOPHILIC STIPPLING OF RED CELLS - poisoning of ferrochelatase cause ringed sideroblasts |
|
|
iINFECTIOUS MONONUCLEOSIS
- general - cause/ mechanism - labs |
Acute, viral, complete recovery
- old kids, young adults (richer) - kissing dz LABS: - slightly high WBC - increased circulating lymphocytes (atypical - transformed - T killers) - Liver enzymes may increase - Rarely jaundice - POSITIVE heterophile Ab Test - POISTIVE monospot test CAUSE: EBV (Herpes virus4) MECH: EBV attchs to C3d-R on B lymphocytes --> enters cell --> B cell expresses weird new Ags --> killed by Tkiller cells |
|
|
INFECTIOUS MONO
- SYMPTOMS - EBV ASSC'D WITH? |
Usu asymptomatic
- Fever, sore throat - enlarged posterior cervical lymph nodes*** - tender liver, splenomegaly, - malaise - eye problems EBV: burkitt's lymphoma, nasopharyngeal carcinoma, b-cell lymphoma, post-transplantation lymphoproliferative disorder |
|
|
INFECTIOUS MONO
- DIFF DX - COMPLICATIONS - TX |
DIFF DX:
- tonsillitis, viral hepatitis, leukemia, viral agents (cmv) COMPLICATIONS: AIHA, ruptured spleen tx: rest. recover 3-4 weeks |
|
|
AUTOIMMUNE HEMOLYTIC ANEMIA
AIHA |
WARM VS COLD TYPES
- dep on temperature at which Ab reacts - ALL have positive direct Coombs test 70% are 2' to another dz cause: red cell Abs with specificity for RBC membrane proteins |
|
|
WARM AIHAs
- gen - mechanism - periph smear |
80% of AIHAs
- IgG (or Rh) - females, pregnant, >40 yo MECH: IgG-coated RBCs bound to Fc-R on monocytes & splenic macros --> spheroidal transformation --> trapped in spleen --> destroyed = splenomegaly (50%) & hepatomegaly Periph smear: high retic, spherocytes |
|
|
WARM AIHA
- Symptoms - TX |
SIGNS: weakness, fever, dizzy, jaundice, anemia
tx: steroids (block RE phag & suppress Ab synth), splenectomy/immuran |
|
|
SIGNS OF HEMOLYTIC ANEMIA
|
1. Hemoglobinemia and/or hemoglobinuria (as evidenced by pink serum and/or urine)
2. Increased unconjugated bilirubin in the serum (this occurs when red cells are being destroyed faster than the liver can process the bilirubin) 3. Increased lactate dehydrogenase (LDH is an enzyme present in a lot of cells, including red cells; when you bust open red cells, their LDH is released) 4. Decreased haptoglobin (a protein that binds free hemoglobin; if there’s a lot of free hemoglobin around, the amount of free haptoglobin – without bound hemoglobin – goes down) *WEIRD SHAPED CELLS: spherocytes, schisocytes, bite cells* |
|
|
COLD AIHA
- gen -mech - labs |
20% of AIHA, females, >50 yo
MECH: distal capillaries (colder) -IgM (anti-I) agglutinates --> may bind C' --> intravasc hemolysis labs: spherocytes & retics, LOTSA RBC agglutination (IgM = pentamer), hemoglobinuria *fetal cells are not usually affected since they have i Ag) |
|
|
cold vs. warm aiha
|
WARM: mainly extravascular (splenic) hemolysis
--> splenomeg (but not really hemoglobinuria) COLD: mostly intravascular hemolysis --> hemoglobinuria (but no splenomegaly) |
|
|
COLD AIHA
- ASSC'D DZS - TX |
ASSC'D:
- MYCOPLASMA PNEUMONIA - INFECTIOUS MONO - b cell lymphoma tx: rest, keep warm, transfuse w/ washed RBCs (get rid of c') |
|
|
PAROXYSMAL COLD HEMOGLOBINURIA
- gen, signs, mech, tx (rare type of cold AIHA) |
any age, gender
- acute, intermittent, MASSIVE hemolysis post-cold exposure - IgG C' fixing Ab with anti-P specificity mech: BIPHASIC - attaches to RBC at low temp - C' mediated hemolysis at higher temp signs: chills, fever, pain in back/legs, hemoglobinuria tx: keep pt warm asscd: viral dz (measles/mumps), syphilis, mycoplasma pneumonia |
|
|
DRUG-INDUCED HEMOLYTIC ANEMIAS
- 3 MAIN MECH **cephalosporins are implicated in all three rxns** |
1. FIRM BINDING OF DRUG 2 RBC
- drug+protein --> RBC - IgG against drug-protein --> extravasc hemolysis - fast decrease in Hb, no bleeding, ^ retics - same symptoms as above 2. Immune ternary compex - drug+protein binds IgM - complex binds RBC --> C' intravascular hemolysis 3. AutoAb model ("TRUE" drug-induced) - drug alters RBC membrane - IgG Ab against normal red cell Ag --> extravasc hemolysis SIGNS: GRADUAL anemia (takes months), ^ retics, spherocytes - gradual improvement |
|
|
RBC INCOMPATIBILITY (TRANSFUSIONS)
-SIGNS - LABS |
SIGNS: hypervent, tachy, urticaria (hives), flush, deep back pain, chills, fever, ABRUPT fall in Hb
LABS: Hemoglobinuria (less severe if Rh incompatibility --> extravasc hemolysis) & microspherocytes tx: stop transfusion (dose-related severity) & increase hydration (renal) |
|
|
RBC INCOMPATIBILITY (TRANSFUSIONS)
-SIGNS - LABS |
SIGNS: hypervent, tachy, urticaria (hives), flush, deep back pain, chills, fever, ABRUPT fall in Hb
LABS: Hemoglobinuria (less severe if Rh incompatibility --> extravasc hemolysis) & microspherocytes tx: stop transfusion (dose-related severity) & increase hydration (renal) |
|
|
HEMOLYTIC DZ OF THE NEWBORN
(erythroblastosis fetalis) - abo - Rh |
IgG (transplacental)
signs: unexplained hyperbili in group A or B infant w/ group O mom, anemia, heart fail, erythropoiesis ABO: First born can be affected - not severe (IgM Ab can't cross placenta) - A & B antigens aren't fully formed or confined to RBCs (neutralized) tx: transfuse w/ group O blood Rh: 1st born NOT affected - decrease freq w/ concurrent ABO incompatibility, insufficient dose, 1st sensitization |
|
|
Rh incompatibility tx
|
bili > 7: transfuse (usually O-) w/ mother's serum compatible
bili 4-5: phototherapy (convert bili --> excreted) mom: Rhogam w/in 72 hours of delivery: prevent sensitization - gets rid of Rh Ags before she can make Abs |
|
|
MEGALOBLASTIC ANEMIAS
- peripheral smear - bone marrow |
PERIPH SMEAR:
- MACROCYTOSIS (macro-oval) - poikilocytosis & anisocytosis - Pancytopenia - HYPERSEGMENTED neutrophilic granulocytes (>5 lobes) BONE MARROW: - HYPERcellular - megaloblastic maturation of RBCs - nuclear/cytoplasmic asynchrony - parachromatin (lacy): "puffed ric" - ineffective erythroid production - GIANT, bizarre granulocytic precursors - disordered dev of ALL marrow cell lines |
|
|
MEGALOBLASTIC ANEMIAS
- DIFF DX |
95% = Vit B12 (cobalamine) & B9 (folate) deficiency
- Myxedema - LIVER DZ - reticulocytosis of any cause - aplastic anemia ** macrocytosis is NOT diagnostic of megaloblastic anemia** |
|
|
MGLB ANEMIA
- CHEMICAL BASIS - MECHANISMS |
Defective DNA synthesis --> weird nuclear maturation
N5,N10-methylene THF (folate) methylates uracil --> thymine - Vit B12 helps make N5,N10 methylene folate - DFHReductase turns DHF --> THF MECHANISMS: 1. folate - Dietary or absorption problem 2. Chemo (methotrexate): inhibit DHFR (can't reduce to FH4) 3. B12 deficiency: "methyl folate trap" ^ methyl THF can't be made into THF |
|
|
B12 DEFICIENCY
- CAUSES - SOURCES - Features |
Western: MALABSORPTION (several reasons for this)
India/Hindu (vegetarian) = Dietary source: microorganisms & animal products Features: - anemia (et al) - macrocytosis - hypersegmented granulocytes - neuro problems - decreased B12 - neuro features |
|
|
VIT B12
- ABSORPTION - PLASMA TRANSPORT |
Absorption:
- binds Intrinsic factor from parietal cells - absorbed in ileum - requires Ca2+ & neutral pH Plasma transport: - Transcobalamin II & I/III <-- major - I/III saturation is decreased in deficiency |
|
|
THE SCHILLING TEST
|
Measures urinary excretion of isotopically labeled B12 following oral admin
Levels <5% = absorption problem - must check serum B12 levels BEFORE doing test SCHILLING II: - administer hog IF with oral B12 to check for pernicious anemia Schilling I & II are abnormal if ileum is messed up or there is competitive B12 destruction by abnormal bacteria or parasites |
|
|
NEUROLOGICAL FEATURES OF B12 DEFICIENCY
|
CLASSIC: SUBACUTE, combine ddegen of the nervous system
- PN - posterior column damage - lateral column (UMN) = ^ DTRs - cerebral dysfxn **methionine synthesis defective - used in myelin basic protein synthesis **need to tx w/ B12; giving Folate will make anemia better, but WORSEN neuro symptoms** |
|
|
PERNICOUS ANEMIA
* tx = IM B12 - HIGH RISK OF GASTRIC CA |
PRIMARY CAUSE OF ANEMIA IN US
FAILURE OF IF synthesis (2' atrophy of gastric mucosa due to immune rxn) DX: - Megaloblastic anemia - SERUM ABS TO B12 OR PARIETAL CELLS - histamine-fast achlorhydria - radioimmunoassay or Schilling test - NEURO SYMPTOMS |
|
|
B12 MALABSORPTION NOT 2' PERNICIOUS ANEMIA
- CAUSES |
1. GASTRECTOMY (loss of parietal cells)
- B12 def. takes 3-4 yrs to manifest - Abnormal I, normal II test 2. Defective ileal absorptive surface - surgical resection - regional ileitic - sprue or celiac dz (inflamm / atrophy) - schilling I & II abnormal 3. Competitive B12 destruction by abnormal bacteria or parasites - blind loop syndrome (duodenum grows nasties) - fish tapeworm - competitive bacteria/parasites - schilling I&II abnormal tx all w/ parenteral B12 |
|
|
Folate deficiency
- sources - absorption - diagnosis of def |
SOURCE: grean leafies, fruits, liver, kidney
- 3-4 months storage capacity Absorption: duod & jejunum (rapid & fast) Dx: - megaloblastic anemia - ID Cause - decreased serum folate levels |
|
|
CAUSES OF FOLATE DEFICIENCY
|
1. DIETARY: old & debilitated
2. Malbsorption: - nontropical sprue - other malabsoprtive states 3. Drugs - DPH (phenytoin) - rarely birth conrol 4. Increased requirements: - pregnancy - hemolytic anemia - neoplasia 5. Folic acid antagonists - methotrexate & aminopterin (inhibit DHFR) TX: N5 formyl tetrahydrofolate (citrovorum factor) tx: oral/IM folate |
|
|
intravascular hemoglobin degradation
|
1. binds haptoglobin --> liver (degraded)
2. forms ab dimers --> excreted 3. other (methemoglobin, etc) **severe anemia - haptoglobin levels drop** SEVERE EXTRAVASC hemolysis may look like intravascular hemolysis when macros throw up hemoglobin |
|
|
EXTRAVASC HEMOLYSIS LABS
|
1. JAUNDICE: ^ unconjugated hemoglobin
2. Poikilocytosis (shape) 3. ^ urobilinogen 4. reticulocytosis urine color doesn't change |
|
|
INTRAVASC HEMOLYSIS LABS
|
1. DARK URINE = hemoglobinuria
2. uRINE Hemosiderin (trapped in renal tubular cells) 3. ^ SERUM LACTATE DEHYDROGENASE 4 ^ Serum Hgb 5. Decreased serum haptoglobin 6. Reticulocytosis |
|
|
ACUTE ANEMIC CRISIS
FROM FAILURE OF ERYTHROPOIESIS in severe chronic hemolytic anemia |
1. Kids - HUMAN PARVOVIRUS INFXN
- 5th dz / "slapped cheeks" dz (red facial rash) - can cause pancytopenia or just aplasia of erythropoiesis - recover in 12 days - only hits kids with chronic hemolytic anemia (RBC life span = 20-30 days instead of 3 mo) 2. Adults: folate deficiency - ^ erythropoiesis & short RBC half life |
|
|
INTRINSIC CAUSES OF HEMOLYSIS
- mostly hereditary (except PNH) |
dEFECT IN 1+:
1. Membrane - hereditary spherocytosis, ovalocytosis, PNH 2. Enzymes - G6PD deficiency 3. Hemoglobin - Hemoglobinopathy & thalassemia |
|
|
HEREDITARY SPHEROCYTOSIS
- PATHOPHYS - tests |
Premature loss of membrane lipids due to ankyrin +/- spectrin deficiency
= ^ osmotic fragility Tests: - Smear: ^ retics & spherocytes - Family hx (autosomal dominant): splenectomy? - Osmotic fragility test - Autohemolysis test (w/ & w/o Glucose) |
|
|
H. SPHEROCYTOSIS
- TX - CONCERNS |
TX:
- Splenectomy *don't get rid of spherocytes* CONCERNS: - S. pnemuo & H. flu vaccines before spleen out - thrombocytopenia & bleeding |
|
|
HEREDITARY ELLIPTOCYTOSIS/OVALOCYTOSIS
-pathophys - v. h. spherocytosis |
Autosomal dominant
- similar abnormalities as spherocytosis - Membrane problem - NOT as leaky --> splenectomy only 15% cause: Impaired associationg of spectrin dimers --> tetramers smear: oval RBCs |
|
|
PAROXYSMAL NOCTURNAL HEMOGLOBINURA
incidence: YOUNG ADULTS!!! *variable severity* - all but lab tests |
DARK URINE in morning after nocturnal hemolysis
(25% pts - only when haptoglobin can't keep up) NEOPLASM (acquired) - usually after marrow aplasia - defective PIG A anchor = lack of membrane proteins *CD55 & CD59* = inhibit C' PANCYTOPENIA!! Nocturnal: hemolytic C' activity better at low plasma pH - sleeping, exercise, acidotic thing COD: - VENOUS THROMBOSIS (pulm embolism) - pulm HTN tx: TRANSFUSE W/ WASHED RED CELLS (C') |
|
|
PNH
- LABS |
SMEAR: PANCYTOPENIA
- HYPOcellular marrow (precursors are lysed too) - Hemoglobinuria (episodic) - Hemosiderinuria - DECREASED LEUKOCYTE ALKALINE PHOSPHATASE** TESTS: #1. FLOW CYTOMETRY FOR CD55 & CD59 older, C' sensitivity tests: 2. HAM test or acid serum hemolysis test 3. Sucrose hemolysis test *these tests only used for PNH |
|
|
G-6-PD DEFICIENCY
(Defect of hexose monophosphate shunt) - pathophys |
VERY COMMON RBC Defect (esp in malarial endemic countries)
G6PD needed to reduce glutathione --> H2O2 --> H2O *Accumulation of H2O2 = Hgb degradation & clumping = HEINZ BODIES - macros eat the heinz X-LINKED DZ (MALES ONLY) Af-am type: normal unless exposed to oxidant drug (antimalarial/antibiotic) - still recover ok |
|
|
G6PD DEFICIENCY
symptoms, labs, **acute anemia, self-resolving once you make new RBCs** - splenic macros are eating heinz bodies = extravasc hemolysis |
SYMPTOMS:
- Weakness - scleral icterus - hemoglobinuria --> dark urine & back/abd pain (kidneys) * extravasc hemolysis looking like intravascular** LABS: - Reticulocytosis (after hemolysis) - Anemia - high unconjugated bili (jaundice) - low haptoglobin - hemoglobinuria - DECREASED RBC G6PD (maybe normal if new RBCs are replaced) Blood smear: heinz bodies in RBC - bite cells |
|
|
ENZYME DEFICIENCY IN EMBDEN-MYERHOFF PATHWAY
|
AUTOSOMAL RECESSIVE
- many types - most common = pyruvate kinase deficiency = chronic hemolytic anemia w/ splenomegaly tx: splenectomy *can't make lactate in states of poor perfusion** |
|
|
CAUSES OF EXTRINSIC HEMOLYSIS
- Abs - Infxns - mechanical |
AIHA
MALARIA, BABESIA, BORRELIA SCHISTOCYTES: DIC: Fibrin strands ARTIFICAL HEART VALVES flappers Clostridial toxins |
|
|
HEMOGLOBIN
- GENETICS - types |
Alpha chain: 2 genes on each chromosome
Non-alpha chain: 1 gene each chromosome (beta, gamma, delta) *Ferrous 2+ binds O2, ferric 3+ does NOT* Hgb types: Gower = fetal = zeta, epsilon, gamma A: 2a, 2 b A2: 2a, 2d A1C: Glycosylated hgbA |
|
|
Hgb pattern of appearance
- onset of beta vs alpha chain disorders |
Hgb F peaks at 3-6 mo gestation
- decreases as beta chain is made more (Hgb A) 3-6mo, Hgb A 95% in baby *Alpha chain disorders appear at birth* - but beta chain disorders appear >3mo (ex// thalassemia?) |
|
|
o2 dissociation curve
- factors shifting L or R |
RIGHT SHIFT/DECREASE AFFINITY
- low pH - high Temp - high 2,3-DPG - ANEMIA/Hypoxia *causes ^ 2,3-DPG LEFT SHIFT/INCREASED AFFINITY - high pH - low TEMP - low 2,3-DPG - Hgb F - POLYCYTHEMIA: need ^ RBCs because the Hgb affinity is high (CO: HgCO) |
|
|
ALTERED HEMOGLOBIN AFFINITY
|
1. ^ 2,3-DPG lowers affinity
- 2' chronic anemia or hypoxia 2. CO poisoning: carboxyhemoglobin increases affinity *cherry pink blood & skin* 3. Methemoglobinemia (^ Fe3+) decreases O2 affinity = cyanosis - congenital Met-Hgb reductase deficiency - antifreez/antimalarials = oxidants - Hgb w/ a or b chain mtts |
|
|
Hgb ELECTROPHORESIS
- CSFA - LOOK AT PTS to decide bw C,A2,E *C = BLACK; E = ASIAN, A2 = beta thalassemia* |
-Crawl SLOW FAST ACC'D+
(C,E,A2 Sickle fetal normal) Normal: A & a little C Sickle Trait: S & a Sickle DZ: S & F SC Dz: S & C E DZ: ONLY E cord blood: F & a little A Charlem: C & A only 2 genes/cell for beta chains: - sickle cell & Hgb C dz will have NO hgbA band |
|
|
POLYCYTHEMIA
- Criteria - causes -perfusion issues |
sustained ^blood Hgb & RBC
HCT >55% ^ RBC mass or decrease in plasma volume (relative) = INCREASED VISCOSITY & decreased perfusion - circulatory stagnation (redness) - headaches/thrombosis - HTN, CHF, cor pulmonale |
|
|
CLASSIFICATION OF POLYCYTHEMIA
**plethora/ruddy complexion** - Relative - 2' absolute - primary/essential |
relative: decreased plasma volume
- Gasboeck's syn: chronic stress - dehydration - diuretics SECONDARY ABSOLUTE: ^EP - Appropriate/hypoxic: lung dz, cyanotic heart dz, abnormal Hgb - Inappropriate: renal/liver tumors Primary (polycythemia rubra vera) = RBC NEOPLASM *JAK2 V617F = GENE MTT **EP LEVELS ARE LOW** |
|
|
HEMOGLOBIN TYPES IN NORMAL ADULT
& gene clusters for globin synthesis |
MAJOR: HbA
minor: Hb A2 (delta instead of beta) & HbF a-gene cluster: 2a & 1zeta b-gene: 1 b, 2 y, 1 d, 1 e - per chromosome Hb embryonic --> HbF --> HbA |
|
|
Major diff bw thalassemia syndromes & hemoglobinopathies
|
THALASSEMIA: PRODUCTION DEFICIT
- shortage of specific globin chain - but chains made are normal Hgbopathies: GENE PROBLEM - Globin chain is effed up. |
|
|
HISTOLOGY OF THALASSEMIAS
- gen - beta thal |
Microcytic, hypochromatic, anemia
- target cell - nucleated RBC = severe - "floppy" cell (less hgb) Beta: a chains are INSOLUBLE *HEINZ BODIES* --> hemolytic anemia |
|
|
GENETICS OF A-THALASSEMIA
*prevent excess Fe tx in heterozygous states* |
usually due to gene DELETION
- stepwise gradation of severity bw types 1. delete single: NO PROB 2. delete 2: a-thal MINOR; asympt - asian type: both genes on 1 chrom are blasted. sucks more - african type: 1 gene on each chrom is blasted 3. Hgb H dz = delete 3 - excess b-chains = heinz bodies - mild hemolytic anemia 4. Bart's hgb dz: delete ALL 4 = fatal - hydrops fetalis, intrauterine death - Y chains only = Hb Bart's (crappy) --> preeclampsia *only asian types can do this* |
|
|
ETIOLOGY OF BETA-THAL
**never hydrops fetalis at birth** switch y --> b chain occurs after birth (6mo) |
Usually due to tsc or tsl problem b+ (NOT gene deletion - b0)
MINOR: INTERMEDIA: still no transf MAJOR: COMPLETELY dep on transfusions for survival |
|
|
beta-thalassemia major
- findings - prognosis - tx |
b+/b+ = both beta genes severely affected
Severe hemolytic anemia - hepatosplenomegaly - growth retard, sex dev delayed - new bone formation = skeletal malformations Prognosis: die ~30 yo from heart dz (hemochromatosis) - 2' numerous transfusion - increased Fe absorption (hepcidin) TX: rbc transf - Bone marrow transplant - drug-induced HbF production - chelation tx (remove Fe) = mandatory *only way to remove Fe = bleeding & chelation* |
|
|
THALASSEMIAS
- LAB FINDINGS high retic count? |
1. Microcytic, hypochromatic anemia
2.. HUGE RBC count >6million (regardless of severity) 3.Hgb Electrophoresis & quantification of HbF & HbA2 (both ^^) - useful in beta-thal 4. Heinz bodies (nonspec) a-thal: need molecular dx hetero b/b+ = high RBC count & microcytic, target cell, basophilic stippling, high Fe |
|
|
HEMOGLOBINOPATHIES
- usually etiology - gen |
*QUALITATIVE*
- usually point substitutions resulting in DIFFERENT globin chain being made (in normal amts) (thal = QUANTITY issue) - most are asymptomatic |
|
|
SICKLE CELL ANEMIA
- genetics / etiology |
Hereditary hemoglobinopathy
Glutamate --> valine (beta chain) Sickling of cells occurs HbS polymerizes --> highly viscous gel --> reduced RBC deformability (stuck in spleen) Sickle cell dz = homozygous HbS Sickle trait = hetero; <50% HbS |
|
|
SICKLING OF THE RBC
REVERSIBLE --> IRREV (effects on cell) |
Reversible: HbS polymerized--> depol
- after repeated sickling, it becomes irrev Membrane damage: ^ Ca2+ - opens K+ channel - lose K+ & h2o (dehydrate) - ^ sickling Unstable Hgb: ^ oxidative damage on cell **RBCs get really STICKY and stick to endothelium** |
|
|
Hb A/F/C and HbS interactions
|
HbA: weak interaction w HbS
HbF: INHIBITS polymerization of HbS - newborns don't show symptoms until 5-6mo HbC: >interaxn than HbA - HbS/HbC (HbSC dz): milder anemia; symptomatic sickling |
|
|
FACTORS PROMOTING SICKLING
|
1. ^ MCHC = [Hgb]
- dehydration / major exertion - decreased solubility = ^ sickling 2. Acidosis: ^ deoxyhemoglobin 3. Decreased blood flow in microcirc 4. Infections (inflamm - ^ transit time) 5. low pO2: ^ deoxyHgb 6. Vascular Stasis (venous pO2 drops) |
|
|
Sickle cells --> anemia & ischemia
how? |
Trapped in microcirculation (esp spleen)
--> extravasc hemolysis also intravasc hemolysis (fragile) Occlude blood vessels = ischemia & infarction 1. ^ adhesion (sticky) 2. log-jamming |
|
|
SICKLE CELL TRAIT SYMPTOMS
|
Mostly asymptomatic except:
1. hYPOSTHENURIA: can't concentrate urine 2. Hematuria 3. Peripheral blood normal, but can be INDUCED to sickle (chemical hypoxia) |
|
|
VASO-OCCLUSIVE PROBLEMS OF SICKLE CELL DISEASE
- acute chest syn - hand-foot - abd crisis/stroke - aplastic crisis, acute splenic seq, megaloblastic crisis - hematuria, hyposthenuria - hematochromatosis |
PAIN: Bones, chest, abdomen
Brain: seizures & strokes Kidneys: sp. gravity 1.010 (ten-ten) - papillary necrosis Priapism: looong erection;hurts Auto-splenectomy: huge spleen 2' fibrosis; nonfxnal Ocular problems: even blindness *nonhealing leg ulcers* *pregnancy: high mortality* |
|
|
SICKLE CELL DZ &
- HAND & FOOT SYN - ACUTE CHEST SYN - ABDOMINAL CRISIS |
HAND&FOOT:
small bones peak @ 1yo - low environmental temps = infarction of extended bone marrow space - ostenoecrosis @ femur/humerus --> osteomyelitis (esp from salmonella) ABDOMINAL CRISIS: Ischemia/bowel infarct - like acute appendicitis - multiple abd scars (many sx's) ACUTE CHEST SYN: - Pulmonary infarcts - can get infected fever/cough/chest pain/infiltrates |
|
|
HEMATOLOGIC PROBLEMS OF SICKLE CELL DZ
- aplastic crisis - acute splenic sequestration - megaloblastic crisis |
APLASTIC CRISIS: parvo B19 infxn & folate def (esp late pregnancy)
ACUTE SPLENIC: massive RBC trapping in spleen; kids - hypovolemia & shock --> die - tx w/ transfusions ANAPLASTIC/megalo crisis: - assc'd w/ (viral) infxn - 2' bone marrow depression - dont' really get it?? =( |
|
|
Other issues of sickle cell anemia
- cardiac - liver - gallstones - height |
Shorter, delayed puberty
CARDIAC: - hemochromatosis - high output fail 2' chronic anemia ^ gallstones (pigmented - bili derived) LIVER: nodular cirrhosis - viral hep - vaso-occlusion - rbc sequestration |
|
|
SICKLE CELL DISEASE TX:
|
1. PREVENT SICKLING EPISODES:
2. hypertransfusion of normal RBC 3. chelation therapy 4. bone marrow transplant 5. Prophylactic penicillin (hasta 5 yo) 6. daily folic acid supp (kids) |
|
|
Hb C
- etiology - pathology |
glutamine --> LYSINE
2-3% blacks hetero: clincially silent microcytic mild anemia homo: mild disorder - abdominal discomf - arhtralgias - headaches HbC crystals (rhomboid) seen in blood films of HOMOZYGOUS |
|
|
HbE
|
SECOND MOST PREVALENT HGBOPATHY
- southeast asian mainland Hetero: silent, but same old, erythrocytosis, low MCV, target cell HOMO: Mild, hemolytic anemia & splenomeg |
|
|
HbS & severe beta-thal
|
CLINICALLY LOOKS LIKE HOMOZYGOUS HbS (milder)
|
