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Hematology and Oncology > Heme Pathology > Flashcards

Heme Pathology Flashcards

1
Q

Anemia

A 
P: signs/symptoms of hypoxia
Weakness, fatigue, dyspnea
Pale conjunctiva, skin
Headache and lightheaded
Angina (prexisting CAD)

Hb, Hct and RBC count as surrogates

Hb < 13.5 in males, <12.5 in females

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2
Q

Microcytic Anemia

A

MCV < 80
Decreased in production of hemoglobin (defective heme or globin synthesis)
heme = iron + protoporphyrin

Iron deficiency, anemia of chronic disease, sideroblastic anemia, thalassemia

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3
Q

Iron deficiency anemia and Causes

A

Cause: decrease iron -> decrease hemoglobin synthesis

Most common type of anemia (most common nutritional deficiency)

Deficiency from dietary lack/blood loss
Infants - breast-feeding
Children - poor diet
Adults - peptic ulcer; menorrhagia/pregnancy
Elderly - colon polyps/carcinoma; hookworm (Ancylostoma duodenale/Necator americanus)

Other causes: malnutrition, malabsorption, gastrectomy (acid aids iron absorption by maintaining Fe2+ state)

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4
Q

Iron absorption and transport

A

Absorption in duodenum

Enterocytes have heme/non-heme (DMT1) transporters

Enterocytes transport iron across cell membrane through ferroportin

Transferrin transports iron in bood and delivers to liver/bone marrow macrophages for storage

Intracellular iron bound to ferritin (prevent fenton reaction - free radical)

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5
Q 
Lab Measurements of iron status:
Serum iron
Total iron-binding capacity
% Saturation
Serum ferritin
A

Serum iron: iron in blood
Total iron-binding capacity: transferrin
% Sat: % transferrin bound to iron
Serum ferritin: iron stored in liver/macrophages

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6
Q

Iron deficiency: Stages and Histology

A

deplete storage iron (decrease ferritin, increase TIBC) -> deplete serum iron (decrease serum iron, decrease %sat) -> normocytic anemia (make fewer, but normal RBC) -> microcytic, hypochromic anemia (smaller and fewer cells)

P: anemia, koilonychia (spoon-shaped nails), pica

Lab: microcytic, hypochromic RBC with increased red cell distribution width
Decreased ferritin, increased TIBC; decreased serum iron and % saturation

Tx: supplemental iron (ferrous sulfate)

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7
Q

Plummer-Vinson syndrome

A

Iron deficiency anemia with esophageal web and atrophic glossitis

Anemia, dysphagia, beefy-red tongue

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8
Q

Anemia of Chronic Disease

A

Anemia assoc. with chronic inflammation (endocarditis, autoimmune conditions) or cancer; most common anemia in hospitalized patients

initially normocytic -> progress to microcytic, hypochromic

Increased production of acute phase reactants from liver (hepcidin)

Lab: high ferritin, low TIBC, low serum iron, low % saturation
increased free erythrocyte proptoporphyrin (FEP)

Tx: underlying cause; exogenous EPO (cancer patients)

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9
Q

Role of Hepcidin

A

1) Limits iron transfer from macrophages to erythroid precursors
2) Supresses erythropoietin (EPO) production
3) binds ferroportin on intestinal mucosal

Prevent bacteria from accessing iron (necessary for their survival)

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10
Q

Heme synthesis pathway

A

(Mitochondria) Rate limiting step
1) glycine + succinyl coA + B6 -> delta-aminolevulinic acid (ALA Synthase) inhibited by glucose, heme

(Cytoplasm)
2) ALA is converted to porphobilinogen (ALA Dehydratase)

3) Porphobilinogen -> hydroxymethylbilane (Porphobilinogen deaminase)
4) Hydroxymethylbilane -> Uroporphyrinogen III
5) Uroporphyrinogen III -> Coproporphyrinogen III (Uroporphyrinogen decarboxylase)

(Mitochondria)
6) Protoporphyrin + Fe2+ -> Heme (Ferrochelatase)

Iron is transferred to erythroid precursors and enters mitochondria from heme. If protoporphyrin is deficient, iron remains trapped - ringed sideroblasts

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11
Q

Lead poisoning

A

P: Child exposed to lead paint - mental retardation
Adults - battery/ammunition/radiator factory - headache, memory loss, demyelination
lead lines on gingivae (burton’s lines) and on metaphyses of long bones on x-ray; encephalopathy; abdominal colic; wrist/foot drop

Microcytic anemia, GI, kidney disease

Inhibits ALAD and ferrochelatase; inhibits rRNA degradation, causing RBC to retain aggregates of rRNA (basophilic stippling)
Increased ALA, protoporphyrin in blood

Tx: Dimercaprol and EDTA; Succimer for chelation for kids

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12
Q

Acute intermittent porphyria

A

Defective porphobilinogen deaminase
Autosomal dominant
Build up of porphobilinogen, ALA, uroporphyrin

5P’s
Painful abdomen
Port wine-colored urine (turns dark upon standing)
Polyneuropathy
Psychological disturbances
Precipitated by drugs (sulfonamides, phenobarbital)

Tx: glucose and heme (inhibit ALAS)

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13
Q

Porphyria cutanea tarda

A

Defective uroporphyrinogen decarboxylase
Uroporphyrin (tea-colored urine)

Blistering cutaneous photosensitivity; most common porphyria

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14
Q

Sideroblastic anemia

A

X-linked
Defective delta-aminolevulinic acid synthase
Other causes: alcohol, lead, isoniazid, vit B6 deficiency

Lab: ringed sideroblasts with iron-laden mitochondria
High iron, high % sat, normal TIBC, high ferritin (iron overloaded state)

Tx: pyridoxine (B6 cofactor for d-ALA)

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15
Q

Thalassemia

A

Microcytic anemia

Decreased synthesis of globin chains of hemoglobin

Carriers protected against P. falciparum

Divided into alpha/beta based on decreased production of alpha/beta globin chains

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16
Q

Normal types of hemoglobin

A

HbF: alpha2 gamma 2
HbA: alpha 2 beta 2
HbA2: alpha 2 delta 2

HbH: beta 4 (seen in alpha-thalassemia -3)
Hb Barts: gamma 4 (alpha-thalassemia -4)

17
Q

Alpha-thalassemia

A

Deletion of alpha-globin (chromosome 16)

1 deletion: asymptomatic

2 deletions: mild anemia with increased RBC count; cis deletion increases risk of severe thalassemia in offspring

Cis - Asians; Trans - Africans

3 deletions: severe anemia; HbH (beta4)

4 deletions: lethal in utero (hydrops fetalis)
HbH (gamma 4) seen on electrophoresis

18
Q

Beta-thalassemia

A

Point mutation in splice sites/promoter sequences on chromosome 11 -> deletion (-) or reduced production (+)

African and Mediterranean descent

19
Q

Beta-thalassemia minor

A

Mildest form: Beta/Beta+

Microcytic, hypochromic RBC and target cells
Slightly decreased HbA with increased HbA2 (>3.5%) and HbF on electrophoresis

20
Q

Beta-thalassemia major

A

Beta(-)/Beta(-) most severe
Severe anemia a few months after birth (HbF temporarily protective)

Alpha tetramers aggregate and damage RBC -> ineffective erythropoiesis and extravascular hemolysis

Massive erythroid hyperplasia (crewcut skull, chipmunk facies)
Aplastic anemia with parvovirus B19

Little to no HbA; increased HbA2 and HbF; microcytic, hypochromic RBC with target cells and nucleated red blood cells

Tx: chronic transfusions (risk for secondary hemochromatosis)

HbS/Beta-thalassemia heterozygote: mild to moderate sickle cell depending on beta globin production

21
Q

Macrocytic anemia

A

Anemia with MCV > 100
Most commonly due to folate or vitamin B12 deficiency (megaloblastic anemia)

Impaired synthesis of DNA precursors -> impaired division and enlargement of RBC precursors

Impaired divisions of granulocytic precursors leads to hypersegmented neutrophils (megaloblastic changes also seen in rapidly-dividing epithelial cells like intestinal)

Other causes: alcoholism, liver diseases, drugs

22
Q

Folate Deficiency

A

Macrocytic, megaloblastic anemia
P: glossitis, decreased serum folate

Folate deficiency develops within months (minimal body storage); in green vegetables/fruits absorbed in jejunum

Causes: poor diet (alcoholics/elderly), increased demand (pregnancy, cancer, hemolytic anemia), folate antagonists (methotrexate)

Increased serum homocysteine
(THF gives methyl group to vitamin B12 -> gives to homocysteine to convert to methionine)

Normal methylmalonic acid

23
Q

Vitamin B12 Absorption

A

1) Salivary gland enzymes (amylases) liberate B12
2) B12 binds to R-binder (from salivary gland)
3) B12 liberated from R-binder in duodenum by pancreatic proteases
4) B12 binds to intrinsic factor (from gastric parietal cells)
5) B12 and intrinsic factor absorbed in ileum

Large hepatic store of vitamin B12; from animal-derived proteins

24
Q

Vitamin B12 Deficiency: Presentation and Causes

A

Macrocytic RBC with hypersegmented neutrophils; glossitis, subacute combined degeneration of spinal cord

Pernicious anemia (most common): autoimmune destruction of parietal cells - intrinsic factor deficiency

Other causes: pancreatic insufficiency, damage to terminal ileum (Crohn; diphyllobothrium), dietary deficiency (rare, except in vegans), proton-pump inhibitors

25
Q

Vitamin B12 Deficiency: Laboratory findings

A

Increased methylmalonic acid (Conversion of methylmalonic acid to succinyl coA by cofactor Vitamin B12)

Build up of methylmalonic acid impairs spinal cord myelinization -> decreased proprioception/vibratory sensation (posterior column); spastic paresis (lateral corticospinal tract)

Increased homocysteine (increases risk for thrombosis)

26
Q

Orotic aciduria

A

Defective orotic acid -> uridine
Megaloblastic anemia not cured by folate/B12

Hypersegmented neutrophils, glossitis, orotic acid in urine

Tx: uridine monophosphate

27
Q

Nonmegaloblastic macrocytic anemias

A

DNA synthesis is impaired

Causes: liver disease, alcoholism
reticulocytes -> Increased MCV

Drugs: 5-FU, AZT, hydroxyurea

Macrocytosis and bone marrow suppression can occur in the absence of folate/B12 deficiency

28
Q

Normocytic anemia

A

Anemia with normal-sized RBC (MCV 80-100)

Increased peripheral destruction or underproduction (use reticulocytes to distinguish)

29
Q

Reticulocytes: Correction

A

Baby RBC - Larger cells with bluish cytoplasm (residual RNA)

Normal - 1-2% count

Decrease in total RBC falsely elevates percentage of reticulocytes
Correct count = retic count x Hct/45
>3% - good response (destruction)
<3% - underproduction

30
Q

Extravascular Hemolysis

A

Normocytic anemia
Destruction by reticuloendothelial system (spleen, liver, lymph nodes)

Macrophages consume RBC and break down hemoglobin
Globin -> Amino acids
Iron -> recycled
Protoporphyin -> unconjugated bilirubin -> binds to albumin -> liver for conjugation -> excretion in bile

Anemia with splenomegaly, jaundice (unconjugated bilirubin), increased risk for bilirubin gallstone

Marrow hyperplasia (>3%)

Examples: hereditary spherocytosis, sickle cell anemia, hemoglobin C

31
Q

Intravascular Hemolysis

A

Destruction of RBC in vessels

Hemoglobinemia, hemoglobinuria, hemosiderinuria (renal tubular cells pick up hemoglobin filtered in urine and breaks down iron -> hemosiderin; then shed)

Decreased serum haptoglobin (binds to hemoglobin)

Examples: PNH, G6PD, immune hemolytic anemia, microangiopathic hemolytic anemia, malaria

32
Q

Hereditary spherocytosis

A

Defective RBC cytoskeleton-membrane tethering proteins (spectrin, ankyrin, band 3.1)

Loss of membrane causes small/round RBC with no central pallor (increased MCHC, RDW)
Splenomegaly, jaundice with unconjugated bilirubin, increased risk for bilirubin gallstones

Increased risk for aplastic crisis with parvovirus B19

Dx: positive osmotic fragility test (increased spherocyte fragility in hypotonic solution)

Tx: splenectomy - spherocytes persist and howell-jolly bodies (fragments of nuclear RBC); but anemia resolves

33
Q

Sickle cell anemia: Epidemiology and Causes

A

Autosomal recessive (glutamic acid to valine in beta chain of hemoglobin) at position 6

African descent (F. malaria protection)

Polymers aggregate into needle-like structures when deoxygenated (hypoxemia, dehydration, acidosis)

HbF protective against sickling (first few months)

Lab: Sickle cells, target cells on blood smear in sickle cell disease
Metabisulfite screen (both disease and trait to sickle)
Hb electrophoresis to confirm

Tx: hydroxyurea (increases HbF)

34
Q

Sickle cell anemia: Complications

A

Extravascular hemolysis (RE system removes damaged RBC) -> jaundice with unconjugated hyperbilirubinemia, anemia, increased risk of bilirubin gallstone

Intravascular hemolysis (damaged membranes dehydrate) -> decreased haptoglobin and target cells

Expansion of hematopoiesis into skull (crewcut, chipmunk); hepatomegaly; Risk of Parvo B19 virus

Irreversible sickling leads to complications of vaso-occlusions

35
Q

Sickle cell anemia: Vaso-occlusion

A
  • Dactylitis (swollen hands/feets from vaso-occlusive infarcts in bones) in infants
  • autosplenectomy (increased risk of encapsulated organism - most common death in children; salmonella paratyphi osteomyelitis); howell-jolly bodies
  • Acute chest syndrome (pulmonary microcirculations) - chest pain, shortness of breath, lung infiltrates; precipitated by pneumonia
    most common death in adults
  • pain crisis
  • renal papillary necrosis - results in gross hematuria/proteinuria
36
Q

Sickle cell trait

A

One mutated and one normal beta chain

microinfarction leading to microscopic hematuria

37
Q

Hemoglobin C

A

Autosomal recessive mutation in beta chain (glutamic acid to lysine)
Less common than sickle cell disease

Mild anemia due to extravascular hemolysis

HbC Crystals in RBC

Hemoglobin to positive charge - migrates slowest

Hematology and Oncology (4 decks)

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