Heme/Onc 3 Flashcards
What are 2 classic findings on blood smear in G6PD deficiency?
Heinz bodies and bite cells
What test is used to diagnose G6PD deficiency?
Fluorescent spot test
Detects generation of NADPH from NADP, positive test if blood spot fails to fluoresce under UV light.
What is the treatment for G6PD deficiency?
Avoid triggers
What are spherocytes?
Slightly smaller and spherical RBCs that lack central pallor
What is the underlying mechanism of Hereditary Spherocytosis?
Abnormal proteins that tie cytoskeleton to RBC membrane, leading to chronic destruction in spleen.
What is the O2 carrying function of spherocytes?
Normal
What proteins are commonly involved in Hereditary Spherocytosis?
Spectrin, ankyrin
What diagnosis is suggested for a patient from Africa presenting with jaundice, dark urine, anemia, and back pain after an infection?
G6PD Deficiency
Hereditary Spherocytosis results in a [low/high] Red Cell distribution Width (RDW). Why?
High RDW, due to progressive loss of cell membrane.
What is the MCHC in Hereditary Spherocytosis?
High (smaller volume but same amount of hemoglobin)
What is the MCV in Hereditary Spherocytosis?
Normal or low (may be normal due to increased reticulocytes)
What is the consequence of loss of membrane flexibility in Hereditary Spherocytosis?
More rigid cells and high resistance to blood flow in small vessels (increased viscosity)
Patients with Hereditary Spherocytosis are at risk of aplastic crisis with what infection?
Parvovirus B19 (hemolysis is compensated until B19 exposure)
What does the Rule of 3 state regarding RBC count, Hgb, and Hct?
Hgb = 3 x Red Blood Cell Count; Hct = 3 x Hgb
What is the suggested diagnosis for a child with infection showing signs of anemia and spherocytes on blood smear?
Hereditary Spherocytosis
What test is used to diagnose Hereditary Spherocytosis?
Osmotic fragility test
Spherocytes will lyse in hypotonic solution and release Hgb.
What is the treatment for Hereditary Spherocytosis?
Splenectomy
Howell-Jolly bodies may appear on blood smear after this treatment.
What are Howell-Jolly bodies?
RBCs with nuclear remnants, normally cleared by the spleen
What is hematocrit?
Volume % of red cells
What are the 3 components of RBC indices?
MVC: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular Hgb concentration
How do RBCs in Microcytic Anemias usually appear?
Hypochromic (low hemoglobin)
What are the 3 underlying mechanisms of Microcytic Anemias?
Loss of iron; Loss of globins; Loss of heme
How is non-heme iron absorbed?
Fe3+ is converted to Fe2+ with help of Vitamin C, then absorbed by duodenal epithelial cell.
What is ferroportin?
Transports iron out of enterocytes and other cells so it can enter the circulation.
Transferrin levels are [increased/decreased] when iron stores are low.
Increased
Where is ferritin stored?
Intracellularly in macrophages of liver and bone.
Total Iron binding capacity is the:
Amount of transferrin in serum.
Iron deficiency is common in what age group? Why?
Babies, iron stores depleted ~6 months.
What can exclusive breast feeding in an infant lead to?
Iron deficiency
Malabsorption of iron can result from the loss of:
Acid (increases Fe3+)
What must an adult or post-menopausal female with iron deficiency have work-up for?
Colon cancer
What are 3 causes of bleeding that can lead to iron deficiency?
Menorrhagia; Peptic ulcers; Colon cancer
Prenatal vitamins often contain what?
Iron and folate
How to calculate % saturation of transferrin?
Iron/transferrin
What is often used to diagnose iron deficiency in pregnancy? Why?
Low ferritin
There is an increase in plasma transferrin which leads to a low % saturation.
What are 2 rare causes of iron deficiency?
Hookworms: Ancylostoma duodenale, Necator americanus; Plummer-Vinson syndrome
What is the clinical triad seen in Plummer-Vinson syndrome?
Iron deficiency anemia, beef red tongue, esophageal webs
What type of anemia does Iron Deficiency Anemia cause?
Initially may be normocytic → microcytic, hypochromic anemia
What is the MCV, MCH, and MCHC in Iron Deficiency Anemia?
All decreased
Red Cell Distribution Width is often wider in what 3 deficiencies?
Iron, B12, folate
Heme is made of what 2 components?
Iron + protoporphyrin
Erythrocyte protoporphyrin level will be [increased/decreased] in iron deficiency.
Increased (No Fe for protoporphyrin to bind with)
Erythrocyte protoporphyrin level is elevated in what 2 conditions?
Lead poisoning, iron deficiency
What is used to screen for iron deficiency and lead poisoning?
Erythrocyte protoporphyrin level
What is the treatment for iron deficiency?
Iron supplementation
Symptoms from anemia in Anemia of Chronic disease are [common/rare].
Rare
What is the mechanism of Anemia of Chronic Disease?
Triggered by cytokines: decrease in RBC survival, inadequate EPO level/response, lack of availability of iron (trapped in storage form).
What is Hepcidin? How does it affect iron metabolism?
Acute phase reactant produced in the liver; Binds to ferroportin in enterocytes and macrophages → Iron trapped in cells as ferritin.
What is a key lab finding in Anemia of Chronic Disease?
↑ ferritin
Can iron supplementation be used to treat Anemia of Chronic Disease?
No
What type of anemia does Anemia of Chronic Disease produce?
Usually normocytic, 25% microcytic
What is the treatment for Anemia of Chronic Disease?
Treat underlying disease
What are the iron studies in Anemia of Chronic Disease?
Serum iron: low; Ferritin: high; Transferrin: decreased; % sat: normal
What is a common lead exposure in adults/children?
Adults: Inhalation from industrial work (battery factory); Children: Eating lead paint (old house)
Lead inhibits what 2 enzymes in heme synthesis?
Delta-aminolevulinic acid dehydratase (δ-ALAD) and Ferrochelatase
Lead poisoning leads to what type of anemia?
Microcytic, hypochromic
What can a patient with microcytic, hypochromic anemia and normal iron studies suggest?
Beta thalassemia or Lead poisoning
What are the iron studies in Lead poisoning?
Normal or low
What is the rate limiting step in heme synthesis?
ALA Synthase
What does lead poisoning lead to a buildup of?
δ-ALA, Protoporphyrin
What does low levels of heme increase the activity of?
ALA Synthase
What are 3 lab findings seen in Lead poisoning?
Plasma lead level; ↑δ-ALA; ↑ erythrocyte protoporphyrin
What is seen in a Lead poisoning blood smear?
Basophilic stippling
Besides δ-ALAD dehydratase and Ferrochelatase, what else does Lead poisoning inhibit?
Pyrimidine 5’ nucleotidase (leads to basophilic stippling)
What are symptoms seen in lead poisoning?
Abdominal pain (“lead colic”); Constipation; ‘Lead lines’: Blue pigment at gum-tooth line; Nephropathy: Fanconi-type syndrome, glucose, amino acids, and phosphate wasting; Neuropathy: drop wrist and foot, children may have behavioral issues/developmental delay.
What is Fanconi-type syndrome?
Injury to proximal tubules; Results in excess glucose, bicarbonate, phosphates, amino acid, etc loss.
What is the treatment for Lead poisoning?
Removal of exposure to lead; Chelation therapy
What are 3 chelating agents used in Lead poisoning?
Dimercaprol; Calcium disodium EDTA; DMSA
What are ‘lead lines’?
Blue pigment at gum-tooth line
What are Ring sideroblasts?
Nucleated red cell precursors that have iron-loaded mitochondria and perinuclear ring of blue granules.
Sideroblastic anemia usually causes what type of anemia?
Microcytic
What are the 2 underlying mechanisms of Sideroblastic anemia?
Acquired: Failure to make protoporphyrin usually secondary to a toxin (alcohol, Vitamin B deficiency); X-linked: Inherited deficiency of ALA synthase.
X linked Sideroblastic anemia often responds to what treatment?
Vitamin B6
What are the iron studies in Sideroblastic anemia?
Serum iron: increased; Ferritin: increased; Transferrin: decreased
What are 2 lab findings seen in Sideroblastic anemia?
Iron overload; Low erythrocyte protoporphyrin levels
What is thalassemia?
Decreased or absent production of globin chains (alpha or beta)
All Hgb has two ____ globins.
Alpha
What is an important diagnostic technique used to evaluate hemoglobinopathies?
Hgb Electrophoresis (Different hemoglobin move different distances)
How many genes code for alpha chains? Where are they located?
4 genes, 2 on each copy of chromosome 16
Alpha thalassemia commonly results from what type of mutation?
Gene deletion
What is Alpha Thalassemia Minima? Clinical presentation?
1/4 alpha globin genes mutated; Normal red cells, no symptoms/carrier state.
What is Alpha Thalassemia Minor? Clinical presentation?
2/4 alpha globin genes mutated; Sometimes mild anemia with ↓ MCV/MCH/MCHC.
Alpha Thalassemia Minor is common among what demographic?
Asians: cis (αα/–) type more common; Africans: trans (α-/α-) more common.
Which type of Alpha Thalassemia Minor is more risk to offspring?
Cis (αα/–)
What is HbH disease? What does this lead to?
3/4 alpha globin gene deletions; Leads to excess beta globin → HbH forms (4 beta chains) which are easily damaged and useless for O2 delivery.
HbH disease can lead to what type of hemolysis?
Extravascular hemolysis due to RBC deformity; HbH easily oxidized → intravascular hemolysis.
How can you diagnose HbH disease?
DNA testing (Electrophoresis insensitive)
What type of hemoglobin is formed in Hgb Barts? What is the consequence of this?
Four gamma globin chains form in utero; Cannot release O2 to tissues → hydrops fetalis → death.
How many genes code for β globin chains? Where are they located?
2 genes, one on each copy of chromosome 11
What is the clinical presentation of Beta Thalassemia Minor?
Asymptomatic; May see mild anemia on routine blood work.
How to diagnose Beta Thalassemia Minor? What result will you see?
↑ HgbA2 (no beta chains) on Electrophoresis.
Beta Thalassemia Major is also called?
Cooley’s Anemia
When does anemia begin in Beta Thalassemia Major? Why?
1st year of life, HgbF(α2γ2) production wanes.
Beta Thalassemia Major leads to the formation of ______. Clinical manifestations?
Alpha chain tetramers → precipitate and cause RBC damage → cleared by the spleen → splenomegaly.
What are 3 key features of Beta Thalassemia Major?
Abnormal red blood cell shapes; Erythroid hyperplasia; Extramedullary hematopoiesis.
What types of RBC abnormalities are seen in Beta Thalassemia Major?
Microcytosis; Hypochromia; Anisocytosis: Increased RDW; Poikilocytosis (abnormal shapes); Basophilic stippling; Nucleated RBCs; Target cells.
What is Basophilic Stippling? Is seen in what 2 conditions?
Residual RNA in red cells, seen in: Lead poisoning; Beta Thalassemia.
What are target cells? What conditions can this be seen?
Small dark area in center of cell due to ↑ surface area-to-volume ratio; Decreased cell volume: Thalassemia and iron deficiency.
What is Basophilic Stippling?
Residual RNA in red cells, seen in lead poisoning and beta thalassemia.
What are target cells?
Small dark area in center of cell due to ↑ surface area-to-volume ratio. Decreased cell volume seen in Thalassemia and iron deficiency; Increased cell membrane seen in liver disease and splenic dysfunction.
What is Erythroid Hyperplasia?
↑↑ EPO without normal response → massive expansion of bone marrow. Consequence of severe anemia in beta major disease.
What symptoms can Erythroid Hyperplasia lead to?
Abnormalities of skull and facial bones: ‘Chipmunk facies’, Crew cut appearance of skull on x-ray, delayed skeletal maturation, widening of marrow spaces → osteoporosis.
What physical exam finding is associated with Extramedullary hematopoiesis?
Hepatosplenomegaly.
What virus can cause an aplastic crisis in Beta thalassemia patients?
Parvovirus B19.
How do you diagnose Beta Thalassemia Major?
Electrophoresis: increased HbA2 and HbF, decreased or absent HbA.
What is the treatment for Beta Thalassemia Major?
Blood transfusion. Complication: iron overload.
What is Beta Thalassemia Intermedia?
Symptomatic beta thalassemia that does not require transfusions.
What do Alpha and beta thalassemia protect against?
Malaria (↓ growth of plasmodium falciparum in RBC).
How can Red Cell Distribution Width be used?
To distinguish iron deficiency and mild thalassemia (normal RDW).
What is the inheritance pattern of Sickle Cell Anemia?
Autosomal recessive disorder.
What is the underlying mechanism of Sickle Cell Anemia?
Single base substitution of β gene → substitution of valine (hydrophobic) for glutamate (hydrophilic) → Abnormal beta chains (HbS).
What is the problem with HbS?
Deoxygenated HbS is poorly soluble and leads to polymerization when O2 low, also in dehydration and acidosis.
What RBC appearance is associated with Sickle Cell Anemia?
Crescent/sickle shaped.
What effect does Sickle Cell Anemia have on ESR?
Decreases.
What are the two major problems that result from sickle cells?
Hemolytic anemia and vaso-occlusion of small blood vessels.
What type of hemolysis does Sickle Cell Anemia cause?
Mostly extravascular due to continuous sickling/de-sickling leading to RBC membrane damage.
What are clinical features of Sickle Cell Anemia?
Erythroid Hyperplasia, swollen hands (‘dactylitis’), acute pain crises, spleen failure, splenic sequestration crisis, avascular necrosis, acute chest syndrome, renal dysfunction.
What is the treatment for Acute pain crises in Sickle Cell Anemia?
Hydration and pain medication.
What is a common initial symptom of Sickle Cell Anemia among children?
Dactylitis, fingers may look like ‘sausage’ digits.
Infection with Parvovirus B19 may lead to aplastic anemia in what conditions?
Sickle cell anemia, spherocytosis, thalassemia.
What bacteria should Sickle Cell Anemia patients be vaccinated against?
Strep pneumoniae and H influenza.
What is the common pathogen responsible for osteomyelitis in Sickle Cell Anemia?
Salmonella species.
What is the leading cause of death in adults with Sickle Cell Disease?
Acute chest syndrome.
How does Acute chest syndrome present in Sickle Cell Disease?
Chest pain and SOB, infiltrates on CXR (looks like pneumonia).
What is the treatment for Acute chest syndrome in Sickle Cell Disease?
Fluids and pain medication, antibiotics, oxygen, bronchodilators, transfusions as needed.
What are four treatments for Sickle Cell Anemia?
Immunizations, hydroxyurea (raises amount of HbF), transfusion, bone marrow transplant (curative).
What is the Sickle Cell trait?
Only 1 mutated beta globin gene, usually no sickling present. Renal medulla may have loss of concentrating ability and ↑ risk of renal medullary carcinoma.
How to diagnose Sickle Cell Disease or trait?
Electrophoresis: presence of HbS and sickling test.
How is the Sickling test performed?
Blood sample + Sodium metabisulphite → HbS becomes insoluble and is easily visualized.
What is the protective effect of Sickle trait?
Protective against Plasmodium falciparum, infection tends to be milder.
What is Hemoglobin C?
Mutation of beta gene → Glutamic acid replaced by lysine.
What do heterozygotes with Hemoglobin C present with?
Mild anemia (extravascular hemolysis).
What are two key findings in Hemoglobin C?
Presence of HbC crystals on smear and ↑ MCHC.
What is Hemoglobin SC?
One HbS gene plus one HbC gene, same complications as sickle cell disease but at a lower frequency.
What are the three underlying mechanisms of Non-hemolytic normocytic anemia?
Low iron, low EPO, abnormal marrow.
Where is Erythropoietin synthesized?
Interstitial cells of the peritubular capillary, in the cortex of the kidney.
What type of anemia results from low EPO?
Normocytic.
What are two EPO injections given to patients with severe anemia of chronic kidney disease?
Darbepoetin alfa (Aranesp) and Epoetin alfa (Epogen).
What is aplastic anemia?
Defective stem cells → Loss of hematopoietic precursors in bone marrow → acellular/hypocellular bone marrow, results in pancytopenia.
What is ‘Myelophthisis’?
Displacement of bone-marrow tissue.
What is the hallmark of Aplastic anemia in bone marrow biopsy?
Acellular or hypocellular bone marrow + replacement with fat.
What are the symptoms of Aplastic anemia?
Anemia → Fatigue, pallor; Thrombocytopenia → Bleeding; Leukopenia → Infections.
What is the most common cause of Aplastic anemia?
Idiopathic.
What are five possible causes of Aplastic anemia?
Idiopathic, radiation, chemicals, drugs, viruses, inherited (Fanconi anemia).
What is the suggested mechanism of Idiopathic Aplastic anemia?
T-cell mediated destruction of stem cells.
What are the two treatments for Idiopathic Aplastic anemia?
Anti-thymocyte globulin and cyclosporine (both immunosuppressants).
What chemical can cause aplastic anemia?
Benzene, found in rubber factor and shoe repair shops.
What are four drugs that can cause aplastic anemia?
Chloramphenicol, methimazole, propylthiouracil (PTU), phenylbutazone.
What are five viruses that can cause aplastic anemia?
Parvovirus B19, acute viral hepatitis, HIV, EBV, CMV.
What is Fanconi Anemia?
Inherited aplastic anemia.
When does Fanconi anemia usually present?
In children <16 y/o.
What physical deformities are associated with Fanconi anemia?
Short stature, cafe-au-lait spots, malformed thumbs, etc.
What mutations are commonly involved in Fanconi anemia?
Mutations in DNA repair enzymes, leading to hypersensitivity to DNA damage.
What malignancies are associated with Fanconi anemia?
Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), squamous cell carcinoma of head, neck or vulva.
What are five treatments for Aplastic anemia?
Stop offending agent, transfusions (red cells, platelets), bone marrow stimulation (EPO, GM-CSF, G-CSF), immunosuppression (antithymocyte globulin, cyclosporine), bone marrow transplant.
What is Pure Red Cell Aplasia?
Absence of erythroid precursors in bone marrow, usually idiopathic.
What condition is Pure Red Cell Aplasia associated with?
Thymoma.
What is Megaloblastic anemia?
Red blood cell precursors grow but cannot divide leading to large size, results from abnormal DNA synthesis.
What are two findings in Megaloblastic anemia?
Large RBCs (↑MCV) and hypersegmented neutrophils (>5 lobes).
What are five causes of Megaloblastic Anemias?
Folate deficiency, B12 deficiency, orotic aciduria, drugs (MTX, 5-FU, hydroxyurea), zidovudine (HIV NRTIs).
What are three causes of Non-megaloblastic Macrocytic anemia?
Liver disease, alcoholism, reticulocytosis.
What type of antibodies are A and B antibodies?
IgM, cannot cross the placenta.
What are the antigens part of the Rh system?
All transmembrane proteins.
Which Rh antigen is highly immunogenic?
D antigen.
What does ‘Rh positive’ mean?
‘Rh positive’ has D antigen; ‘Rh negative’ lacks D antigen.
When may a Rh negative individual develop anti-D antibodies?
During pregnancy.
