HemOnc 03

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Direct Coombs test: detects RBCs coated with small amounts of antibody and/or complement
Indirect Coombs test: detects antibodies present in serum which under test conditions coat test RBCs in vitro
compare warm and cold autoimmune hemolytic anemias with respect to - Ig Class - Complement activation - Hemolysis: Warm AIHA

- Ig Class = IgG
- Complement activation = Maybe
- Hemolysis = Extravascular (opsonization)

Cold AIHA

- Ig Class = IgM (except PCH)
- Complement activation = Yes
- Hemolysis = Intravascular (lysis)
Drug Induced Hemolytic Anemia: Hapten Type B Model "The Innocent Bystander": medication or its metabolites react with antibody and the med-Ab combo binds to the RBC surface

Med-Ab complex sensitizes the RBC to immune destruction

e.g. quinine and quinidine
Drug Induced Hemolytic Anemia: Hapten Type A Model: medication or its metabolite bind directly to RBC

anti-drug antibody (usually IgG) reacts with cell bound drug and sensitizes cell for immune clearance

e.g. penicillin
Drug Induced Hemolytic Anemia: "Aldomet" Model: medicine or its metabolite cause a patient to generate antibodies against an RBC antigen; usually IgG antibodies
treatment for Neonatal Isoimmune Hemolytic Anemia: prevention with Rhogam (anti-Rh IgG) -- passive immunization of the mother preventing her from mounting an amnestic response

exchange transfusion (as newborn or intrauterine)
spectrin: comprises 76% of the RBC plasma membrane skeleton; consists of 2 parallel twisted a and b chains; form tetramers and oligomers at the "head end"
actin: attached to spectrin chains at their tail end
ankryn (Band 2.1): anchors the spectrin network at the region of head-head interaction to the integral membrane Protein 3
RBC volume and water content is maintained by:: active transport of Na+ out and K+ in
name four factors that can lead to RBC rigidity: (1) dehydration

(2) intracellular debris

(3) membrane rigidity

(4) DEC RBC surface-to-volume ratio (spherocytes)
spherocytes: RBCs with DEC surface:volume ratio

can expand their surface by no more than 3% before rupturing; effect more pronounced in the spleen
name three defects involved in the pathogenesis of Hereditary Spherocytosis (HS): (1) abnormal spectrin with defective binding to Protein Band 4.1

(2) defect in the structure of function of ankryn

(3) Band 4.2 deficiency
T/F Splenomagaly is a prominent clinical feature of Hereditary Spherocytosis (HS): T
Key to diagnosing Hereditary Spherocytosis: clinical triad of anemia (+/-) crises, jaundice, and splenomegaly
how do you make a definitive diagnosis of Hereditary Spherocytosis?: by osmotic fragility and/or autohemolysis tests
osmotic fragility test: HS RBCs show INC osmotic lysis compared to normal RBCs (red curve shifted to right) in hypotonic saline solutions
autohemolysis: HS cells demonstrate autohemolysis after incubation in saline at 37C for 48 hours
treatment for Hereditary Spherocytosis: - supportive care

- splenectomy (associated with INC susceptibility to encapsulated bacteria)
Hereditary Elliptocytosis (HE) - genetics: Autosomal Dominant inheritance
what four defects are associated with the pathogenesis of Hereditary Elliptocytosis (HE)?: (1) defects in spectrin self association (head end) leading to fewer tetramers / oligomers and more dimers

(2) partial deficiency in Protein Band 4.1

(3) defective binding of ankryn by Protein band 3

(4) elliptical shape is acquired in circulation, as reticulocytes are normal disk-shaped cells
what are the two manifestations of Heriditary Elliptocytosis (HE)?: (1) mild HE

- fully compensated hemolysis without anemia
- no splenomegaly

(2) Hemolytic HE with spherocytosis

- elliptocytes less prominent and more rounded
- spherocytes prominent
what is the treatment for Hemolytic HE with spherocytosis?: (same as for HS)

- supportive care
- splenectomy
main metabolic substrate of RBC for energy: glucose
two pathways of glucose metabolism for RBCs: (1) Embden-Meyerhof (EM) pathway (90%); generates ATP, 2,3-DPG, NADH

(2) Hexose monophosphate (HMP) shunt: generates NADPH and GSH
for defects in the Embden-Meyerhof (EM) pathway, is the anemia episodic or chronic?: chronic
what condition accounts for 90% of EM defects causing HA?: Pyruvate Kinase (PK) deficiency

- cells lose ATP, are unable to maintain water and anion homeostasis, and become rigid
what is the most important defect to remember with regards to HMP Shunt Defects?: G6PD deficiency
pathogenesis of HMP Shunt Defect: G6PD deficiency: oxidants produced during infections or with exposure to oxidant drugs are usually detoxified by the GSH pathway

in G6PD deficiency the glutathione (GSH) levels are not maintained due to inadequate NADPH --> results in oxidation of Hb to methemoglobin, and formation of Heinz bodies

during conditioning of the spleen, Heinz bodies are "pitted" from the cells, resulting in "bite cells" and loss of membrane (spherocytes), leading to INC rigidity and shortened lifespan
main clinical features of G6PD deficiency: episodic hemolysis with infections or oxidant drug use
G6PD Deficiency therapy: - minimize potential sources of oxidant stress by avoiding oxidant drugs

- most hemolytic episodes are caused by infection

- use supportive care (transfusion, hydration, etc) during hemolytic episodes
what reaction is the rate limiting process in heme synthesis?: the first rxn: Succinyl CoA + glycine --> delta-ALA
what do penicillamine and isoniazid do to the 1st rxn of heme synthesis?: antagonistic to co-factor B-6, inhibit this rxn
what is the 2nd rxn of heme synth and what does it have to do with lead poisoning?: delta-ALA X 2 = PBG (via ALA dehydratase)

ALA dehydratase inhibited by lead --> therefore INC urinary excretion of delta-ALA is a good indicator of lead poisoning
6 steps of Heme Synth -- just the abbreviations, no enzymes: ALA --> PBG --> U --> C --> P --> Heme

"I'll a Pee the Bee Gees. You see P? Heme"
acute intermittent porphyria is a result of deficiency of what enzyme?: uroporphyrinogen I synthase (leads to elevated levels of PBG)
what 4 precipitating events can lead to acute intermittent porphyria?: (1) drugs that stimulate the cytochrome P-450 system (especially barbituates and birth control pills)

(2) menstruation

(3) infection

(4) acidosis
treatment for acute intermittent porphyria: - suppress ALA synthetase
- high carb load
- heme infusions
hereditary coporphyria: deficient copropporphyrinogen oxidase activity results in elevated levels of coproporphyrinogen III --> neurological symptoms & skin lesions & photosensitivity
sideroblastic anemia - what does peripheral blood smear look like?: dual population of red cells: one relatively normal-to-slightly macrocytic and the other hypochromic and microcytic
sideroblastic anemia - what does bone marrow look like?: hypercellular with erthyoid hyperplasia, increased iron stores and ringed sideroblasts
what drugs / substances can cause sideroblastic anemia?: ethanol, anti-TB drugs, lead
therapy for sideroblastic anemia: pyridoxine (a cofactor for the ALA synthetase enzyme) is often tried unless an offending drug can be identified and withdrawn
lead toxicity & heme synthesis: lead inhibits PBG synthetase and later steps in the heme synthetic pathway, thus heme precursors can accumulate
biliverdin: breakdown product of hemoglobin; water-soluble, non-toxic, will not cross the placenta
where is biliverdin metabolized to bilirubin?: primarily in reticuloendothelial tissues
bilirubin: water-insoluble, toxic; must be transported in blood by a carrier -- albumin
what happens to bilirubin in intestine?: - converted to urobilinogen by bacterial flora

- converted to stercobilin, excreted in feces
what are the four forms of bilirubin that exist in the bloodstream?: (1) conjugated bilirubin

(2) unconjugated bilirubin (noncovalently adsorbed to albumin)

(3) delta bilirubin (covalent linkage to albumin; long half-life in blood)

(4) "free" bilirubin (this form only exists when the conjugation mechanism is not functioning properly)
prehepatic jaundice: bilirubin formation in reticuloendothelial cells is excessive and overwhelm's the liver's capacity to process it

usually hemolytic in origin
hepatic jaundice: disorders of bilirubin metabolism and transport within the hepatocytes; may be due to a viral infection, drugs taken therapeutically, or the abuse of drugs and alcohol
extravascular hemolysis: an acceleration of normal mechanisms of red cell removal, which occurs primarily in the spleen

hypertrophy of spleen, inc in RBC production in bone marrow, inc Hb breakdown
intravascular hemolysis: refers to the process of cell rupture during circulation
in what two ways is presentation of intravascular hemolysis different from extravascular hemolysis?: (1) splenomegaly usually does not occur

(2) because free haptoglobin cannot usually dispose of all the degraded hemoglobin, free Hb is seen in the plasma
haptoglobin: a protein found in the plasma which binds with high affinity free Hb released by erythrocytes
thalassemia: an imbalance between the production of globin chains
gamma, delta, and beta chains (of hemoglobin) are located on which chromosome?: chromosome 11
Homozygous beta-thalassemia aka: aka thal major, Mediterranean anemia, Cooley's anemia
Homozygous beta-thalassemia - general - clinical features: both of the beta genes defective

- microcytic hypochromic anemia
Beta Thalassemia Intermedia - general: both beta genes defective, but at least one is B+
Beta Thalassemia Minor - general: one defective beta globin gene, one normal

patients mostly asymptomatic
how to distinguish beta thalassemia minor from iron deficiency anemia?: INC iron
Hemoglobin H: Beta-4
what would hemoglobin electrophoresis show for Beta Thalassemia Minor?: mildly INC Hgb A2 (5%) with slightly INC F
what is the hemoglobin electrophoresis picture for Homozygous Thalassemia?: â€“ No HgbA
â€“ Hgb A2: 5-10%
â€“ Hgb F: 90- 95%
basically, what is responsible for the clinical manifestations of sickle cell disease?: cellular injury secondary to vaso-occlusion from hemoglobin S polymerization
can oxygenated red cells sickle?: NO, only deoxygenated red cells can sickle
what are the normal %'s for HbA, HbF, and HBA2?: HbA = 97%
HbF = 1%
HbA2 = 2%
on which chromosome are the beta, delta, and gamma chains coded?: Chromosome 11
on which chromosome are the alpha chains of Hb coded?: Chromosome 16
how does Hb S occur?: gene mutation causing a substitution of valine for the normal glutamic acid in the 6th AA position of the beta globin chain of Hb
how is sickle cell disease inherited?: autosomal recessive
sickle cell trait (Hb AS): an individual who is a sickle cell carrier (heterozygotes for sickle cell gene)
what % of the African-American population in the US has sickle cell trait?: 8%
T/F Heterozygotes for Hemoglobin S have apparently increased resistance to malaria infection.: T
average lifespan of a sickled cell: 10-20 days
percentage of reticulocytes decreased or elevated in sickle cell disease?: elevated
pain crises (sickle cell anemia): vaso-occlusive episodes
what mnemonic is used to summarize the common complications seen in individuals with sickle cell disease?: HB SS PAIN CRISIS

H - Hemolysis, Hand-Foot syndrome
B - Bone Marrow Hyperplasia / Infarction
S - Stroke
S - Skin Ulcers (primarily leg venous ulcers)
P - Pain episodes,
A - Anemia, Aplastic crisis, Avascular necrosis
I - Infections
N - Nocturia
C - Cholelithiasis, Cardiomegaly, CHF, Chest syndrome
R - Retinopathy, Renal failure
I - Infarction
S - Sequestration crisis involving spleen or liver
I - Increased fetal loss during pregnancy
S - Sepsis
why is fetal Hemoglobin (HbF) protective in sickle cell disease?: because it interferes with intracellular Hb S polymerization
how does the chemotherapeutic agent hydroxyurea help in sickle cell disease?: stimulates the production of Hb F within the red cells
acute chest syndrome (of sickle cell anemia): fever and respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray
how does D5W administration help in sickle cell?: lower serum osmolarity --> water moves into RBC --> reduced concentration of sickle Hb in the cell
the definitive test used to diagnose sickle cell syndrome: hemoglobin electrophoresis
what does thrombopoietin do to platelet production?: thrombopoietin stimulates CFU-Meg division, megakaryocyte production, and platelet production from the megakaryocyte
GIIb/IIIa, CD41: platelet glycoprotein surface receptor (most abundant platelet cell surface protein)

receptor is nonfunctional on the resting platelet but binds fibrinogen, as well as fibronectin, vitronectin, collagen, and von Willebrand's factor when the cell is activated by agonists such as adenosine diphosphate and thrombin

is also the principal mediator of platelet-platelet cohesion
is bleeding time indicated for the preoperative screening for hemostatic defects?: NO
Glanzmann thrombasthenia: arises from an aberration in GPIIb/IIIa leading to moderate to severe bledding problems
Bernard-Soulier syndrome: arises from the absence of GPIb-V-IX

normal aggregation toi agonists requiring fibrinogen binding, but show a lack of response to agents requiring GP1b (i.e. thrombin, ristocetin plus von Willebrand factor)
most common lab method to measure vWF activity for the diagnosis and monitoring of von Willebrand disease: ristocetin cofactor assay
quantitative platelet abnormalities: platelet count is DEC (thrombocytopenia) or INC (thrombocytosis)

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