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78 Cards in this Set
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What is the pathogenesis of type I hypersensitivity reactions?
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1. IgE antibody production (sensitization): allergens are first processed by APCs. APCs interact with CD4 Th2 cells, causing ILs to stimulate B-cell maturation.
2. Mast cell activation (re-exposure): allergen-specific IgE antibodies are bound to mast cells. Allergens cross-link IgE antibodies on mast cell membranes. IgE triggering causes mast cell release of preformed mediators (histamine, chemotactic factors for eosinophils, proteases). Produces tissue swelling and bronchoconstriction. Late phase reaction (mast cells synthesize and release prostaglandins and leukotrienes). |
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What are the different types of type II hypersensitivity reactions?
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1. Complement-dependent reactions
- IgM mediated - IgG mediated 2. Complement-independent reactions - Antibody (IgG)-dependent cell-mediated cytotoxicity - Antibody (IgE)-dependent cell-mediated cytotoxicity - Impairment or stimulation of receptors |
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What are some examples of type II hypersensitivity reactions?
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Complement-dependent reactions:
Lysis (IgM mediated): ABO mismatch, cold immune hemolytic anemia Lysis (IgG mediated): Goodpasture's syndrome, pernicious anemia, rheumatic fever Phagocytosis: warm (IgG) autoimmune hemolytic anemia, ABO and Rh hemolytic disease of newborn, ITP Complement-independent reactions: IgG-dependent: NK cell destruction of neoplastic and virus-infected cells IgE-dependent: eosinophil destruction of helminths Receptor targeting: myasthenia gravis, Grave's disease |
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What is the pathogenesis of type III hypersensitivity reactions?
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Type III: activation of the complement system by circulating antigen-antibody complexes
1. First exposure to antigen -> creation of antibodies 2. Second exposure to antigen -> deposition of antigen-antibody complexes -> complement activation, producing C5a, which attracts neutrophils -> tissue damage |
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What are some examples of type III hypersensitivity reactions?
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SLE (DNA-anti DNA)
Serum sickness Poststreptococcal glomerulonephritis Arthus reaction (swelling and inflammation following tetanus vaccine) |
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What is the pathogenesis of type IV hypersensitivity reactions?
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Antibody-independent T cell-mediated reactions
Sensitized T lymphocytes encounter antigen and then release lymphokines (leads to macrophage activation; no antibody involved). |
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What are the different types and examples of type IV hypersensitivity reactions?
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Delayed type: tuberculous granuloma; PPD reaction, multiple sclerosis
Cell-mediated cytotoxicity: killing of tumor cells and virus-infected cells; contact dermatitis (e.g. poison ivy, nickel) |
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What causes acute rejection? Chronic rejection?
What are the time frames for each? |
Acute rejection is due to cytotoxic T lymphocytes reacting against foreign MHCs. Occurs weeks to months after transplantation.
Chronic rejection is caused by both T cell and antibody mediated vascular damage. This occurs months to years after transplantation. |
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What type of infections would be recurrent with a congenital B-cell disorder?
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Recurrent encapsulated bacterial infections (e.g. Streptococcus pneumoniae).
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What types of infections would be recurrent with a congenital T-cell disorder?
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Recurrent infections caused by intracellular pathogens (fungi, viruses, protozoa).
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What are the congenital B-cell disorders?
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Bruton’s agammaglobulinemia, IgA deficiency, Hyper-IgM syndrome, Common variable immunodeficiency (CVID)
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What are the congenital T-cell disorders?
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DiGeorge syndrome, Il-12 receptor deficiency, Hyper-IgE syndrome, Chronic mucocutaneous candidiasis
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What are the combined B- and T-cell disorders?
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SCID, Wiskott-Aldrich syndrome, Ataxia-telangiectasia
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What is the pathogenesis of Bruton’s agammaglobulinemia? What is the hereditary pattern?
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A defect in BTK, a tyrosine kinase gene, results in the failure of pre-B cells to become mature B cells. X-linked recessive.
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What is the presentation and lab features of Bruton’s agammaglobulinemia?
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Recurrent bacterial infections after 6 months (decreased maternal IgG) due to opsonization defect. Normal pro-B, decreased number of B cells, decreased immunoglobulins of all classes.
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What is the pathogenesis of IgA deficiency? What happens if exposed to blood products that contain IgA?
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In selective Ig deficiencies, a defect in isotype switching leads to a deficiency in a specific class of Ig. IgA deficiency is the most common, which results in a failure of IgA B cells to mature into plasma cells.
If exposed to blood products that contain IgA, anaphylaxis may occur. |
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What is the pathogenesis and presentation of Hyper-IgM syndrome?
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Defective CD40L on helper T cells leads to an inability to class switch. Increased IgM, severely decreased IgG, IgA, and IgE.
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Which B-cell disorder can be acquired as an adult? What is the presentation?
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Common variable immunodeficiency (CVID). Normal numbers of B cells, but decreased plasma cells and immunoglobulins.
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What is the pathogenesis of DiGeorge syndrome?
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22q11 deletion leads to failure to develop 3rd and 4th pharyngeal pouches. This results in thymic aplasia as well as absent parathyroids.
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What is the presentation of DiGeorge syndrome?
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Hypoparathyroidism -> hypocalcemia -> tetany; Recurrent viral/fungal infections, congenital heart and great vessel defects. Absent thymic shadow on CXR.
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What are the lab findings of DiGeorge syndrome?
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Decreased T cells, decreased PTH, decreased Ca2+.
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What is the result of IL-12 receptor deficiency?
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Decreased Th1 response.
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What happens when Th cells fail to produce IFN-gamma?
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Neutrophils are unable to respond to chemotactic stimuli, leading to Hyper-IgE (Job’s) syndrome. This presents with (FATED) coarse Facies, cold staph Abscesses, retained primary Teeth, increased IgE, Dermatologic problems (eczema)
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What defects can lead to Severe Combined Immunodeficiency (SCID)?
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Defective IL-2 receptor (most common, X-linked), adenosine deaminase deficiency, failure to synthesize MHC II antigens.
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What is the treatment for SCID?
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Bone marrow transplant (no allograft rejection)
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What are the lab values for SCID?
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For defective IL-2 receptor, decreased T cell activation.
For adenosine deaminase deficiency, increased adenine (which is toxic to B and T cells.) Decreased Ig. |
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What is Wiskott-Aldrich syndrome?
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X-linked recessive disorder that leads to progressive deletion of B and T cells.
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What is the Wiskott-Aldrich triad of symptoms? What are the lab values?
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TIE
Thrombocytopenic purpura, Infections, Eczema Increased IgE and IgA. Decreased IgM. Normal IgG. |
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What is Ataxia-telangiectasia caused by? Symptoms?
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A mutation in DNA repair enzymes. Cerebellar defects (ataxia), spider angiomas (telengiectasia), IgA deficiency
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What are the microcytic, hypochromic anemias?
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Iron deficiency (most common)
Anemia of chronic disease Thalassemia (α and β) Sideroblastic anemias (least common; including lead poisoning) |
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What are the macrocytic anemias?
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Megaloblastic anemia caused by folate and B12 deficiency
Nonmegaloblastic macrocytic anemias - Liver disease Alcoholism Reticulocytosis Metabolic disorder (e.g. orotic aciduria) Drugs |
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What drugs can cause nonmegaloblastic macrocytic anemia?
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5-FU
AZT (Zidovudine) hydroxyurea |
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What are the normocytic, nonhemolytic anemias?
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Anemia of chronic disease (can become microcytic in long-standing disease)
Aplastic anemia Kidney disease (deficient EPO) |
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What are the intrinsic hemolytic normocytic anemias?
Are they extravascular or intravascular? |
Hereditary spherocytosis (E)
G6PD deficiency (I) Pyruvate kinase deficiency (E) Sickle cells anemia (E) HbC defect (?) Paroxysmal nocturnal hemoglobinuria (I) |
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What are the extrinsic hemolytic normocytic anemias?
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Autoimmune hemolytic anemia
Microangiopathic anemia Macroangiopathic anemia Infections |
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What are the lab values for intravascular hemolysis?
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Decreased haptoglobin
Increased LDH Hemoglobin in urine |
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What are the lab values for extravascular hemolysis?
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Macrophage in spleen clears RBC.
Increased LDH, UCB (causes jaundice) |
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What is caused by chronic iron deficiency? What are the symptoms?
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Plummer-Vinson syndrome
Symptoms: Esophageal web Achlorhydria (absent acid in stomach) Glossitis Spoon nails (koilonychia) |
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What are the lab findings of iron deficiency?
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Decreased MCV
Decreased serum iron, iron saturation Decreased serum ferritin Increased TIBC, RDW Cells with increased central area of pallor Increased serum free erythrocyte protoporphyrin (FEP) Thrombocytosis Normal leukocyte count |
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What is the pathogenesis of anemia of chronic disease?
What are the lab values? |
Chronic inflammation leads to decreased synthesis of heme.
Liver synthesis and release of hepcidin. Hepcidin enters macrophages and prevents release of iron from macrophages. Decreased iron Decreased TIBC Increased ferritin |
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What is Hb Barts?
HbH? |
Hemoglobin γ4
Deletion of 4 α-globin genes, incompatible with life. Causes hydrops fetalis. HbH is caused by deletion of 3 genes. Leads to β4 |
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What is the treatment for α-Thalassemia?
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There is no treatment. Do not treat with iron; danger of iron overload.
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What is the treatment for β-Thalassemia minor? β-Thalassemia major?
What lab values are seen in both? |
For β-Thal minor, there is no treatment. Do not treat with iron, as there is a danger of iron overload.
For β-Thal major, there is a long-term transfusion requirement. This can lead to iron overload (hemosiderosis). Decreased (or no) HbA Increased HbA2, HbF |
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What is the pathogenesis of sideroblastic anemia?
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1) Chronic Alcoholism: alcohol is a mitochondrial toxin -> damages heme biosynthetic pathway in mitochondria
2) Pyridoxine (vitamin B6) deficiency: B6 is a cofactor for δ-aminolevulinic acid synthase (rate-limiting reaction of heme synthesis) 3) Lead poisoning: Pb denatures ferrochelatase (heme synthase), aminolevulinic acid (ALA) dehydrase, and ribonuclease (causes basophilic stippling) |
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What is the most common cause of Pyridoxine deficiency?
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Isoniazid (INH) therapy
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What is the pathogenesis of vitamin B12 and folate deficiency?
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Impaired DNA synthesis -> delayed nuclear maturation.
Causes a block in cell division leading to large, nucleated hematopoietic cells called megaloblasts. Ineffective erythropoiesis: Megaloblastic precursors outside the bone marrow sinusoids are phagocytosed by macrophages -> apoptosis -> pancytopenia. |
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What are the presentations of pernicious anemia?
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Achlorhydria (lack of gastic acid) due to destruction of parietal cells
Chronic atrophic gastritis of the body and fundus of stomach (antibody destruction of parietal cells) |
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Which megaloblastic anemia is associated with neurologic disorders? What are the symptoms?
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Vitamin B 12 deficiency, which leads to subacute combined degeneration: peripheral neuropathy with sensorimotor dysfunction; posterior columns, lateral corticospinal; dementia
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What is the mechanism that Vitamin B12 deficiency causes neurologic disorders?
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Propionyl CoA is convereted to methylmalonyl CoA. Vitamin B12 is a cofactor for methylmalonyl CoA mutase, involved in odd-chain fatty acid metabolism. This enzyme converts Methylmalonyl CoA to Succinyl CoA. Vitamin B12 deficiency causes an increase in propionyl and methylmalonyl CoA and their corresponding acids. Propionyl CoA replaces acetyl CoA in neuronal membranes resulting in demyelination.
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What is the pathogenesis of aplastic anemia?
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Antigenic alteration of myeloid stem cells causes T-cell activation and release of cytokines that suppress myeloid stem cells
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What are the clinical findings of aplastic anemia?
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Fever due to infection associated with neutropenia
Bleeding due to thrombocytopenia Fatigue due to anemia |
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What is myelophthisic anemia? What is a leukoerythroblastic smear?
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When cancer cells metastasize to the bone marrow, the malignant cells displace normal marrow hematopoietic cells into peripheral blood.
Presence of nucleated RBCs and immature myeloid cells into the peripheral blood is called leukoerythroblastic smear. |
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What are some causes of extravascular hemolysis?
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In extravascular hemolysis, RBCs are phagocytosed by macrophages in the psleen and liver. The RBCs may be coated with IgG (with or without C3b), or they may be abnormally shaped (i.e. spherocytes, sickle cells)
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What are some causes of intravascular hemolysis?
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In intravascular hemolysis, RBCs are lysed within blood vessels.
Enzyme deficiencies (e.g. G6PD) Complement destruction (e.g. IgM-mediated hemolysis) Mechanical damage (e.g. calcific aortic valve stenosis) |
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What is the pathogenesis of spherocytosis?
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A membrane protein defect results in the loss of RBC membrane and spherocyte formation. Mutation in ankrin is the most common defect. This results in premature removal of RBCs by spleen.
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When might aplastic anemia be associated with spherocytosis?
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Children with spherocytosis may develop aplastic anemia after a viral infection (parvovirus B19).
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What disease is caused by a mutation that causes loss of the anchor for decay accelerating factor (DAF)? What does DAF do?
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Paroxysmal noctural hemoglobinuria
DAF normally destabilizes C3 and C5 convertase adhering to RBCs, platelets, and neutrophils, which prevents activation of the membrane attack complex (MAC) and subsequent lysis of RBCs, neutrophils, and platelets. |
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What is the mutation that leads to sickle cell anemia?
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Missense point mutation: substitution of valine for glutamic acid at 6th position of β-globin chain.
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What three infections are associated with complications in sickle cell disease?
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Parvovirus B19: aplastic crisis
Pneumonia: Acute chest syndrome Salmonella: Osteomyelitis |
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What is the pathogenesis of G6PD deficiency?
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Decreased synthesis of reduced form on NADPH and GSH (glutathione) in the pentose phosphate pathway.
GSH normally neutralizes H2O2. In G6PD deficiency, peroxide oxidizes Hb, which precipitates in the form of Heinz bodies. Heinz bodies damage the RBC membranes casing intravascular hemolysis, and are removed by splenic macrophages, producing bite cells. |
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What are some forms of oxidant stress that can exacerbate G6PD deficiency?
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Infection
Drugs (primaquine, chloroquine, sulfonamides) Fava beans |
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What is the pathogenesis and presentation of pyruvate kinase deficiency?
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PK normally converts PEP to pyruvate leading to a net gain of 2 ATP. A chronic lack of ATP causes membrane damage.
This presents with jaundice beginning at birth. |
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What is the most common cause of autoimmune hemolytic anemia?
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Systemic lupus erythematosis
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What is cold type and warm type AIHA?
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Cold type AIHA: IgM antibodies (e.g. Mycoplasma pneumoniae)
Warm type AIHA: IgG antibodies (e.g. SLE) |
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What is the most important marker of immune hemolytic anemia?
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Direct antihuman globulin test (DAT; Coomb’s test)
Positive: anti-Ig antibody added to patient’s RBCs agglutinate if RBCs are coated with Ig. Indirect antihuman globulin test (indirect Coomb’s test) Positive: normal RBCs added to patient’s serum agglutinate if serum has anti-RBC surface Ig. |
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What is the difference between microangiopathic anemia and macroangiopathic anemia?
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Microangiopathic anemia occurs when RBCs are damaged passing through obstructed or narrowed vessel lumina. This occurs in DIC, TTP-HUS, SLE, and malignant hypertension.
Macroangiopathic anemia occurs with prosthetic heart valves and aortic stenosis. |
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What are the disorders that result in an increased bleeding time?
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Bernard-Soulier disease
Glanzmann’s thrombasthenia Idiopathic thrombocytopenic purpura (ITP) Thrombotic thrombocytopenic purpura (TTP) Von Willebrand’s disease Scurvy |
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What is the difference between Bernard-Soulier disease and Glanzmann’s thrombasthenia?
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Both are defects in platelet plug formation.
Bernard-Soulier disease is due to absent Gp1b, resulting in defective platelet-to-collage adhesion. Glanzmann’s thrombasthenia is due to absent GpIIb/GpIIIa, resulting in defective platelet-to-platelet aggregation |
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What is the pathogenesis of ITP?
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IgG antibodies directed against GpIIb/IIIa receptors -> peripheral platelet destruction
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What is the pathogenesis of TTP?
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Deficiency of ADAMTS13 (vWF metalloprotease) -> decreased degradation of vWF multimers -> increased large vWF multimers -> increased platelet aggregation and thrombosis.
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What is the clinical pentad of symptoms of TTP?
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Fever, thrombocytopenia, renal failure, microangiopathic hemolytic anemia, CNS deficits
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What causes hemolytic uremic syndrome (HUS)? What are the findings?
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Infection by shiga-toxin producing organisms (E. coli, Shigella) -> endothelial damage at arteriole-capillary junction.
Findings similar to TTP: decreased Platelet Count, increased Bleeding Time, microangiopathic hemolytic anemia, renal failure, thrombocytopenia, CNS findings less frequent. |
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What are the intrinsic pathway defects? What is elevated in intrinsic pathway defects?
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Hemophilia A or B, von Willebrand’s syndrome
Increased PTT |
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What is the pathogenesis of Hemophilia A and B?
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Hemophilia A: Deficiency of factor VIII -> Increased PTT
Hemophilia B: Deficiency of factor IX -> increased PTT |
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What is the pathogenesis of von Willebrand’s disease?
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vWF acts to carry/protect factor VIII. Decreased vWF -> defect in platelet-to-collagen adhesion. Increased PTT, Increased BT.
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What are some causes of Vitamin K deficiency? What is the function of Vitamin K?
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Decreased synthesis of vitamin K by colonic bacteria: newborns lack bacteria; prolonged treatment with antibiotics
Decreased small bowel reabsorption of vitamin K Decreased activation of vitamin K by epoxide reductase Vitamin K γ-carboxylates vitamin K-dependent factors II, VII, IX, X, and proteins C and S. |
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What type of organisms are Chronic Granulomatous Disease patients susceptible to? Why?
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Myeloperoxidase is able to use the H2O2 produced by bacteria to create bleach and destroy the bacteria. Catalase-positive organisms are able to destroy the H2O2, and phagocytes are not able to create HOCl to destroy those organisms.
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What test is used to diagnose Chronic granulomatous disease?
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Nitroblue tetrazolium dye reduction test. If the test is positive (purple-blue) the NADPH oxidase is present. If the test is negative (yellow), there is no NADPH oxidase and patient has CGD.
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