Anemia Overview

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Anemia Overview

• Anu Thummala, M.D.
• Hematology/Oncology and Internal Medicine
• Comprehensive Cancer Centers of Nevada

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Anemia

• Three main mechanisms
• DECREASED PRODUCTION OF RBC
• (HYPOPROLIFERATION)
• 2. INCREASED DESTRUCTION OF RBC
• (HEMOLYSIS)
• 3. ACUTE BLOOD LOSS

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The most important first step in the diagnosis
of Anemias.
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The Peripheral Smear
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?

• Young women with surgery as child and was told
  that she could be at risk for developing
  infections.
• CBC normal

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?

• 74 male presents with neuropathy, loss of
  balance, WBC 1.9, HGB 7, PLT 120,000

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?

• A 20 YO woman presents with increasing weakness
  over six weeks,fever and Hb 5.9 g/dl., white
  cells 18.0 x10ˆ9/l., platelets 35 x10ˆ9/l.

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?

• Young man with recent travel presents with fever
  of unknown origin. WBC 18K, HGB 8 g, PLT 461,000

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?

• Elderly gentleman presents with fatigue, pallor
  and SOB. WBC 3K, HGB 6g, PLT 566,000

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?

• 70 YO male admitted to ICU with severe
  pancytopenia, bleeding, hypotensive. Patient is
  intubated
• PT 15, PTT 40, PLT 36,000, WBC 2.2, HGB 8 g.

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?

• 46 YO presents with history of alcohol abuse,
  hypotension.
• WBC 3.2, HGB 10g, PLT 72,000
• T. Bili 2.0, creatinine 4, BUN 68

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Anemia
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Case 1

• 51 YO female presents with fatigue, occasional
  tingling of her hand and feet. She reports
  decrease in concentration and memory
• PSHx cholecystectomy, gastric bypass
• Social Hx negative for drug, tobacco and alcohol

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Case 1

• LABS
• WBC 1.7
• HGB 8.9 G/DL
• PLATELETS 109,000
• MCV 109
• SEGS 52
• LYMPHS 40
• MONO 5
• EOS 2
• METAMYELOCYTES 1

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Case 1

• Additional tests

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SMEAR
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Macrocytic Anemia

• Abnormal maturation of nucleus in RBC precursors
• CAUSES
• - Alcoholism
• Pernicious Anemia (Vit B12 deficiency)
• Folic Acid deficiency
• Tropical Sprue
• Scandinavia - Fish tapeworm

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Macrocytic Anemia

• Megaloblastic
• Vitamin B12 (Cobalamin) Deficiency
• Folate Deficiency
• MDS
• Chemotherapy (Methotrexate, Hydroxyurea,
  Azathioprine
• SPURIOUS
• Alcohol, Hypothyroidism, MM, Liver disease, MDS,
  Aplastic Anemia

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MEGALOBLASTIC DISEASE

• Diagnosis MCVgt 100
• Macrocytosis may be blunted in presence of Fe
  deficiency or thalasemia
• Low Reticulocyte count
• Neutropenia and Thrombocytopenia
• WBC Hypersegmentation. Almost always
  pathognomonic

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Macrocytic Anemia
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FOLIC ACID

• FOLIC ACID (pteroylmonoglutamic acid)
• Natural Source fruits / vegetables
• May be destroyed by cooking
• Minimum daily requirement 50 micrograms/day
• Deficiency can develop within months
• FDA ordered Folic acid supplementation (January,
  1998) to all enriched grains

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FOLATE DEFICIENCY

• Inadequate Intake
• Malabsortion due to Sprue, Celiac disease

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FOLATE DEFICIENCY

• Increased Demand
• Cells with high rate of turnover
• Chronic hemolytic anemias
• Pregnancy
• Deficiency in first few weeks - - gt neural tube
  defects in fetus
• Malignancy
• Chronic Exfoliative Skin Disorders
• Hemodialysis pts

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FOLATE DEFICIENCY

• Medications
• 6 thioguanine, azathiprine, 6 mercaptopurine
• 5 FU, cytosine, arabinoside
• Hydroxyurea, procarbazine, AZT
• Folate Antagonists - Methotrexate, pentamidine,
  trimethoprim, triamterene, pyrimethamine, Dilantin

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COBALAMIN (VIT B12)

• Cobalt cannot be synthesized - required in diet !
  
• ONLY SOURCE Animal products (meat and dairy)
• Minimum daily requirement 2.5 micrograms/day

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COBALAMIN DEFICIENCY

• Inadequate intake vegetarian
• Malabsorption
• Defective Release of Cobalamin from Food
• Inadequate Production of Intrinsic Factor

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COBALAMIN DEFICIENCY

• Disorders of the terminal ileum
• Tropical and Non Tropical Sprue
• Regional Enteritis, Crohns Disease
• Intestinal Resection
• Competition for cobalamin
• Fish Tapeworm (Scandinavian countries)
• Bacteria (blind loop syndrome)
• Drugs
• p-aminosalicylic acid, colchicine, neomycin

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COBALAMIN DEFICIENCY

• Blood
• Macrocytic Anemia
• Pancytopenia, elevated LDH/ Indirect Bilirubin
• Clin Sx weakness, dizziness, vertigo, tinnitus,
  angina, palpitations and CHF
• Physical Exam pale, icteric, rapid pulse,
  enlarged heart, systolic flow murmur
• GI
• Based on rapidly proliferating GI epithelium
• SORE TONGUE
• ANOREXIA / WEIGHT LOSS
• DIARRHEA

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COBALAMIN DEFICIENCY

• NEURO (may be permanent)
• Demyelination -gt axonal degeneration -gt neuronal
  death
• Peripheral nerves, spinal cord (posterior and
  lateral columns) , cerebrum
• SX EARLY Numbness and parethesias in
  extremities
• LATER weakness, ataxia, sphincter disturbances,
• Decreased vibratory sensation
• mild irritability --gt dementia or psychosis
• NEURO SX MAY BE PRESENT IN A PATIENT WHO IS NOT
  ANEMIC

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COBALAMIN DEFICIENCY PERNICIOUS ANEMIA

• Autoimmune destruction or gastric mucosal atrophy
• Etio Lack of Intrinsic Factor (IF) secreted by
  parietal cells
• EPIDEMIOLGY
• Males females, often age gt60
• See in pts from Northern Europe or African
  Americans
• OTHER DISEASE ASSOCIATIONS
• Graves Disease Myxedema
• Thyroiditis Vitiligo
• Hypoparathyroidism
  Agammaglobulinemia
• Adrenocortical Insufficiency

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PERNICIOUS ANEMIA

• ABNORMAL LABS
• Anti parietal cell antibody (anti Na,K ATPase
  (90)
• Anti IF antibody (60)
• RX Glucocorticoids may reverse disease
• H Pylori does NOT cause parietal cell destruction
  
• ANATOMY Gastric atrophy --gt antrum is spared
• Tx All reversible except neurological changes
• Complications Gastric polyps 2x incidence of
  cancer

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Schilling Test (Cobalamin Deficiency
verification)

• STAGE 1
• STAGE 2
• Give Radioactive Cobalamin bound to IF by mouth
• IM injection of nonradioactive B12
• Measure 24 hour urine
• Will still be diminished if
• Bacterial Overgrowth Syndrome, Blind Loop,
  Pancreatic insufficiency, Celiac Sprue

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FOLATE v COBALAMIN DEFICIENCY STATES
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TREATMENT

• COBALAMIN DEFICIENCY
• IM Cbl 1000 µg (1 mg) every day x week,
  followed by 1 mg every week x four weeks.
• If the underlying disorder persists (PA) 1 mg
  every month for life
• Oral 1000 to 2000 mcg/day.
• May not be effective for PA (malabsorption)
• Do not use timed release preparations
• Transfusion- watch for CHF

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• COBALAMIN DEFICIENCY
• Laboratory response
• Anemia--- reticulocytosis in 3-4 days Severe
  Anemia--- serum iron and LDH levels fall
• Hypokalemia
• Hypersegmented neutrophils disappear at 10 to 14
  days.
• Neurologic abnormalities often improve but may
  not reverse fully

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TREATMENT

• Folate Deficiency
• Exclude Cobalamin deficiency !!
• A dose of 1 mg/day is usually sufficient, even if
  malabsorption is present.
• Neuro symptoms may be exacerbated with therapy

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Case 2

• 70 YO male presents with fatigue, weight loss,
  palpitations
• Unremarkable PMHx, PSHx
• WBC 1.9, HGB 8, PLT 79,000, MCV 100, ANC 1.0
• Normal B12/folate and iron levels

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Case 2

• What is the next diagnostic test..

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Case 2

• Smear
• Bone Marrow Biopsy
• Ultrasound to evaluate Liver and Spleen
• Hepatitis / Viral panel

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Case 2
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Case 2
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Myelodysplasia

• Clonal stem cell disorder resulting in
  multilineage dysplasia
• Can transform to acute leukemia
• Under diagnosed disorder
• Can be secondary to therapy
• Multiple bone marrow biopsies required
• Cytogenetic abnormalities

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Myelodysplasia

• WHO system includes
• Refractory anemia (RA)
• Refractory anemia with ringed sideroblasts (RARS)
  
• Refractory cytopenia with multilineage dysplasia
  (RCMD)
• Refractory cytopenia with multilineage dysplasia
  and ringed sideroblasts (RCMD-RS)
• Refractory anemia with excess blasts I and II
• 5q- syndrome
• Myelodysplasia unclassifiable (seen in those
  cases of megakaryocyte dysplasia with fibrosis
  and others

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IPSS SCORE

• Unfavorable cytogenetics 1
• Age gt 60 years 2
• Hgb lt10 (g dl-1) 1
• Plt lt50 2
• Plt gt50 -250 1
• 1BM blasts gt4 1
• diploid and 5q only were favorable cytogenetic,
  all others were considered as unfavorable
  cytogenetics.

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Myelodysplasia

• IPSS Score
• Low risk0
• Intermediate risk 1 0.5 1
• Intermediate risk 2 1.5 2
• High risk  gt2.5

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Myelodysplasia

• Low Risk MDS
• -Neutropenia or thrombocytopenia
• -symptomatic anemia is usually the initial
  problem
• - Erythropoietin highest response rate seen in
  patients with lower endogenous erythropoietin
  levels (lt 500 IU) and lower transfusion
  requirements.
• -low-dose granulocyte colony-stimulating factor
  (G-CSF)
• -Erythropoietin resistance
• -Red blood cell transfusions

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Erythropoietic Growth Factors

• Caution in patients with uncontrolled
  hypertension
• Risk of thrombosis
• Lack of response
• Survival benefit in patients with malignancy

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Myelodysplasia

• High Risk MDS
• -Refractory anemia/ thrmbocytopenia and
  neutropenia
• -Higher Blast percentage but less than 20
• -Multiple Karyotypic abnormalities

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Myelodysplasia

• High Risk MDS
• - Supportive Care
• -Bone Marrow Transplant
• -Hypomethylating Agents
• --5 Azacitadine
• --Decitabine

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Case 3

• 47 YO African American Female presents with
  fatigue, heavy menstrual bleeding, body aches.
• FHx anemia of unknown etiology
• Social Hx, PMHx is unremarkable
• WBC 5K, HGB 9.8 g, PLT 166,000, MCV 56
• How do you approach this case?

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Case 3

• Serum Ferritin 15
• Iron saturation 9
• TIBC 470
• B12 and folate are normal
• Retic 2.6
• Bone marrow biopsy

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Iron DeficiencyAnemia
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Iron Deficiency Anemia

• Etiology
• Dietary deficiency
• Malabsorption (Subtotal gastrectomy, celiac
  sprue)
• Bleeding (Gastrointestinal, Genitourinary,
  Hemoptysis, Epistaxis, Pregnancy)
• Intravascular hemolysis (PNH, Trauma,
  Hemosiderinuria)
• Chronic renal failure

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Iron DeficiencyAnemia

• Poor correlation between hemoglobin level and
  symptoms
• Symptoms may include
• Pica - geophagia, pagophagia, amylophagia
• Pallor
• Smooth tongue
• Stomatitis
• Cheilosis
• Koilonychia (spoon nails)
• Paresthesias
• Splenomegaly

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Iron DeficiencyAnemia

• LABORATORY
• Low iron, high TIBC, low ferritin, high serum
  transferrin receptor
• Absent marrow iron
• Thrombocytosis
• TREATMENT
• 1. Oral
• 2. Parenteral
• Iron dextran lt 70 utilized
• Need Test dose
• Total dose (mg) deficit in Hb (gm/100ml) x
  weight (lb) 1000mg
• Watch for anaphylaxis
• 3. Treat underlying

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Case 3

• Patient was treated with oral iron for 3 months
  and follow-up labs showed
• WBC 5.2, HGB 11, MCV 60, PLT 222,000
• What is your next step

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Case 3

• Patient was treated with oral iron for 3 months
  and follow-up labs showed
• WBC 5.2, HGB 11, MCV 60, PLT 222,000
• Ferritin 50, TIBC 300, Saturation 15
• What is the next step.

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Target cells Seen in ETOH, Liver Disease,
Hemoglobinopathies
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THALASSEMIAA Defect in Hemoglobin Synthesis

• Definition defect in Hemoglobin subunit
  synthesis (2a and 2ß)
• Inadequate hemoglobin accumulation ?
  Hypochromia/microcytosis and a host of clinical
  manifestations.
• Severe anemia will present in childhood
• Three main variants African, Asian,
  Mediterranean

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THALASSEMIA TYPE a (alpha)

• TYPES
• a-Thalassemia alpha globin unit synthesis
  decreased or absent
• b subunits will ppt
• Four subtypes
• Hydrops fetalis (4 loci)
• Hemoglobin H (3 loci)
• a-Thalassemia Minor (2 loci) mild anemia,
  microcytosis
• a-Thalassemia Minima (1 loci) no significant
  anemia

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Thalassemia
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THALASSEMIAA Defect in Hemoglobin Synthesis

• b-Thalassemia - beta globin unit synthesis
  decreased or absent, a subunits will ppt
• Beta two Loci/ one Gene
• Major Homozygous Severe Anemia, Jaundice,
  Hepatosplenomegaly, Fe Overload (High Ferritin),
  CHF
• Onset first year of life, transfusion dependent)
• Minor Heterozygous Hypochromic, Often Mild
• Microcytic Anemia ?HgB A, ?HgB F, ?HgB A2

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THALASSEMIAA Defect in Hemoglobin Synthesis

• Beta Major These pts will be symptomatic only
  after 4 6 months because in Fetal Hb (a2 d2),
  the d subunit is not replaced with the b subunit
  until after birth

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THALASSEMIAClinical Manifestations

• Skeletal-
• Osteoporosis vertebral compression Fx (next
  slide)
• Skull has a hot cross bun configuration
• Pneumatization of the sinuses is delayed (next
  slide)
• Distortion of the maxillary bones, as well as
  poor development of the sinus cavities
• Hand Metacarpals. Metatarsals, phalange make it
  look rectangular and convex shaped.

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THALASSEMIAA Defect in Hemoglobin Synthesis
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THALASSEMIA CHF/ CARDIOMEGALY Chest radiograph
typical of severe ß-thalassemia. widening of the
rib ends and cardiac dilation.
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THALASSEMIA Clinical Manifestations

• Shortened RBC survival
• DECREASED MCV
• Iron- normal !!
• Heart Cardiomegaly
• Growth Development is retarded both
  skeletal and dental ages.
• Secondary Iron Overload

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THALASSEMIA Clinical Manifestations

• Liver Hepatomegaly due to extramedullary
  hematopoiesis.
• Later in disease hepatomegaly is associated with
  cirrhosis.
• Iron deposited in Kupffer cells ? may look like
  idiopathic hemochromatosis.
• Viral Hepatitis may augment liver damage.

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THALASSEMIA Therapy

• Trait None indicated
• Splenectomy
• ChelationDeferoxamine / Fe Chelation (Keep
  Iron Saturation lt50)
• Iron Supplementation Contraindicated

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THALASSEMIA Therapy

• Genetic Counseling recommended.
• Autosomal Recessive pattern of inheritance

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Hemolytic AnemiaHemoglobinopathies

• Sickle Cell Disease (HgB SS)
• 1 in 400 American Blacks
• Valine for Glutamate at position 6 in b Chain
• Gelation of HgB ? Deoxygenation ? Sickled
  Irreversibly
• Electrophoresis Required for Differentiation
• Trait- often no clinical symptoms

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What is Sickle cell disease

• An inherited disease of red blood cells
• Abnormal hemoglobin.
• Sickle-shaped red cells interrupt blood flow by
  blocking small blood vessels
• Tissue damage due to lack of blood flow and
  severe pain due to tissue hypoxia

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Hemolytic AnemiaSickle Cell Disease

• Microinfarction
• Pulmonary (Acute Chest), Avascular Necrosis, CVA,
  CHF, RF, Skin ulcerations
• Pain
• Joint, Musculoskeletal, Abdominal
• Asplenism
• Sepsis, Recurrent Infection
• Fetal loss, high Maternal Morbidity
• Aplasic Crisis - Infection, Folate Deficiency
• Sequestration Crisis - ?? HgB, ?Retics.,
  Hepatosplenomegaly

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Hemolytic AnemiaSickle Cell Disease - TREATMENT

• Treatment
• PAIN CRISIS
• Supportive, Conservative Expectant
• Treat Infections Early Pneumococcal Vaccine
• Folate Supplementation Daily
• Opiod Analgesics PRN Dependence Common in
  advanced Stages

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Hemolytic AnemiaSickle Cell Disease - TREATMENT

• Treatment
• CHEST SYNDROME
• Supportive, Conservative Expectant
• Folate Supplementation Daily
• Opiod Analgesics
• Oxygen / Hyperbaric
• Correct Dehydration
• Hypertransfusion in Crisis
• Hydrea- reduce ulcers, transfusion, crises

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Case 5

• 36 YO female presents with history of URI
  symptoms, ear ache, fever.
• Unremarkable past medical history
• WBC 11 K, HGB 5 g, PLT 202,000
• What is the next step

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Case 5

• Iron studies are normal except for ferritin 988
• B12/Folate are normal
• Additional laboratory data requested

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Case 5

• Iron studies are normal except for ferritin 988
• B12/Folate are normal
• Peripheral Smear
• Additional laboratory data requested
• LDH 1000, Haptoglobin 5, T.Bili 3, Retic 12

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Hemolytic Anemia
Increased RI, LDH, Indirect Bilirubin Decreased
Haptoglobin Urine Hemoglobin- severe cases Direct
Antiglobulin test Indirect Antiglobulin
test Peripheral Smear
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Hemolytic AnemiaAcquired
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Hemolytic Anemia Immune

• Antibodies to Red Cell or Drug Interaction
• Direct Coombs Detects IgA/G or Complement (C3)
• Indirect Coombs Detects Antibody in Serum of
  Recipient Against Donor

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Hemolytic Anemia Immune Mediated
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Hemolytic AnemiaAlloantibody Immune

• Transfusion Reactions
• Recipient Antibody to Donor Antigen
• Increased Risk with Transfusions
• Single Donor Donation Decreases
• Erythroblastosis Fetalis IgG-Anti-Rh
• Rh- Mother Carrying Rh Fetus
• RhoGam (IgM-Anti-Rh) at Delivery/Miscarry

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Hemolytic AnemiaAutoimmune

• Warm Antibody IgG or lt IgA
• Inefficient C3 C4 Fixation
• Active at 37oC, Nonagglutinating
• Evans Syndrome- associated thrombocytopenia
• Symptoms Inc RI, SM, Spherocytosis
• Destruction in Spleen
• Idiopathic 20
• CLL 20, Lymphoma 10, Misc. 10
• Collagen Vascular 15, Thyroid Disease 10
• GI Diseases (UC) 10
• Treatment
• Steroids, Immunosuppression, Splenectomy

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Case 5

• 36 YO female presents with history of URI
  symptoms, ear ache, fever.
• Unremarkable past medical history
• WBC 11 K, HGB 5 g, PLT 202,000

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Hemolytic AnemiaAutoimmune

• Cold Antibody IgM
• Efficient Complement Fixation (C3)
• Active at 4oC, Agglutinate Dissociate at 32oC
• Destruction in Liver, Intravascular
• Mycoplasma (5-10 days post recovery),viral
  illnesses
• Lymphoproliferative, Often Chronic
• MGUS
• Treatment
• Acute - Usually Self Limited, Warm Environment
• Chronic Steroids, Splenectomy not Helpful
  Immune Suppression

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Hemolytic AnemiaAcquired DIC

• Microangiopathic
• Disseminated Intravascular Coagulation (DIC)
• Obstetrical, Bacterial Sepsis, Carcinoma, Trauma
• Diffuse Microthrombi Followed by Fibrinolysis
  Consuming Coagulant Proteins
• Extensive Hemorrhage, Thrombocytopenia,
  Fragmented RBCs (Schistocytes), ?PT/PTT,
  ?Fibrin Split Products (FSP), Mod. Hemolysis
• Severe disease usually with low Plasma Fibrinogen
  Level
• TREATMENT Underlying Disorder

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Hemolytic AnemiaHereditary
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Hemolytic AnemiaMicroangiopathic TTP

• Thrombotic Thrombocytopenic Purpura (TTP)
• Etiology Unclear Immunologic, Microaneurysm
• Anemia with Fragmented RBCs, ?Retics, Moderate
  Thrombocytopenia, Jaundice, Petechiae lt ITP
• PT, PTT, Fibrinogen, FSP usually near NL
• Fever, Abdominal Pain, Arthralgias
• Bleeding Unusual Course Days to Weeks
• Death Due to Renal Failure, Cerebral Ischemia
• Plasmaphoresis, Steroids

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Transfusion Reactions
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Hemolytic AnemiaMicroangiopathic TTP

• Thrombotic Thrombocytopenic Purpura (TTP)
• Pentad FAT-RNs
• 40 Present with Pentad
• 30 of patients will relapse

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Hemolytic AnemiaMicroangiopathic HUS

• Hemolytic Uremic Syndrome (HUS)
• ASSOCIATED WITH E.COLI O-157-H7 infection
• (5-10 of infections)
• Intracorpuscular Defect Acquired in Stem Cells
• Viral Prodrome, Young Children
• Acute Hemolytic Anemia, Thrombocytopenic
  Purpura, Oliguria, Venous Thrombosis
• Blood Smear Coagulation Studies Similar ITP
• Neurologic Deficits Uncommon
• Dialysis, Transfusion
• Mortality 5 to 20

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REFERENCES

• References for Hematology lecture dated 9/25/08
• Myelodysplasia, Blood, 1 August 2008, Vol. 112,
  No. 3, pp. 479.
• BMJ 1998 / B12 Deficiency
• Appelbaum FR, Gundacker H, Head DR, et al. Age
  and acute myeloid leukemia. Blood.
  200610734813485
• Silverman LR, McKenzie DR, Peterson BL, et al
  Cancer and Leukemia Group B. Further analysis of
  trials with azacitidine in patients with
  myelodysplastic syndrome studies 8421, 8921, and
  9221 by the Cancer and Leukemia Group B. J Clin
  Oncol. 20062438953903.
• Kantarjian H, Gandhi V, Cortes J, et al. Phase 2
  clinical and pharmacologic study of clofarabine
  in patients with refractory or relapsed acute
  leukemia. Blood. 20031022379.
• Faderl S, Gandhi V, OBrien S, et al. Results of
  a phase 12 study of clofarabine in combination
  with cytarabine (ara-C) in relapsed and
  refractory acute leukemias. Blood. 2005105940
• Burnett AK, Mohite U. Treatment of older patients
  with acute myeloid leukemianew agents. Semin
  Hematol. 20064396106.
• Greenberg et al. International Scoring System for
  Evaluating Prognosis in Myelodysplastic
  Syndromes. Blood 1997892079-2088.
• Silverman LR, Demakos EP, Peterson BL, et al
  (2002). "Randomized controlled trial of
  azacitidine in patients with the myelodysplastic
  syndrome a study of the cancer and leukemia
  group B". J. Clin. Oncol. 20 (10) 242940.

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Malaria

• Clinical Manifestation
• 1 to 6 weeks after Innoculation
• P. vivax P. ovale Recurrent 6 12 Months
• Chills, Fever, Myalgia, Splenomegaly, Anemia
  Leukocytosis Rare
• P. falciparum Encephalitis, ARDS
• Blackwater Fever Massive Immune Hemolysis,
  Renal Failure
• Treatment
• P. falciparum - Chloroquine Resistant Quinine
  Doxycycline
• Others - Chloroquine Responsive
• P. vivax P. ovale Add Primaquine
• Prophylaxis Chloroquine, Mefloquine

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Hemolytic Anemia Infectious - Babesiosis

• Malaria-Like Intraerythrocyctic Parasite
• Eastern and Western Seaboard,
• Ixodidae Ticks Rodents, Pets
• Symptoms Febrile Hemolytic Anemia
• Incubation 1-3 weeks
• Flu like Symptoms, Myalgias, Dark Urine
• Asplenic individuals can have overwhelming
  disease
• Often co-infection with Borrelia burgdoferi

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Hemolytic Anemia Infectious - Babesiosis

• Diagnosis Blood Smears
• Similar to P Falciparum (Malaria) but these
  organisms produce no pigment.
• Maltese Cross
• Therapy Clindamycin Quinine
• Exchange Transfusion when Severe Disease

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Hemolytic AnemiaCongenital

• DAT negative
• Membrane Abnormalities
• Hereditary Spherocytosis
• Hemoglobinopathies
• Sickle Cell Anemia
• Hemoglobin C SC Disease
• Thalassemia
• Defective Metabolism
• Glucose-6-phosphate Dehydrogenase Deficiency

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Hemolytic AnemiaMembrane Abnormality

• Hereditary Spherocytosis
• Common Hemoglobinopathy in Whites
• Defective Fragile Red Cell Membrane Spherocytes
• Hemolysis in Spleen Splenomegaly, Common Skin
  Ulcers Over Ankles
• Mildly Reduced HgB, Increased Retics.
• Occasional Jaundice, Gallstones, Anemia is mild
  to severe, Increased MCHC, Aplastic Crisis in
  Viral Infection or ?Folate
• Splenectomy Curative (Dont forget vaccinations!)
• Lifelong Folate

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Hemolytic AnemiaAcquired Nonimmune

• Paroxysmal Nocturnal Hemoglobinuria
• Acquired stem cell disorder
• Susceptible to complement due to two missing
  membrane components of the complement system.
• Look for Specific assays for CD 55 and CD59 by
  Flow Cytometry
• Complication Thrombosis
• Treatment Steroids, Transfusions, Iron and
  folate replacement

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Hemolytic AnemiaEnzyme Deficiencies

• Glucose-6-Phosphate Dehydrogenase
• ? Glutathione-SH (in a series of biochem rxns)
• GSH Protects Oxidation Cysteine in Cell Wall,
  Oxidation MethHgB (Fe3 ? Fe2)
• X - Linked, gt 250 Variants
• Acute Hemolysis 2-4 days after drug exposure
• American Blacks African Variant (A-)
• 13 Males 20 Female Carriers, Variable Affect
• Self-Limited Retics NL G-6-PD Activity
• May Confer Malarial Protection
• Italian/Greek Mediterranean, More Severe

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Hemolytic AnemiaG6-PD Deficiency What causes a
crisis?

• Oxidative Drug-Induced Hemolysis
• Sulfonamides, Dapsone Nitrofurantoin
• Antimalarials Primaquine, Chloroquine
• Vitamin K (Water Soluble), Probenecid
• Occasional - Infection, Diabetic Ketoacidosis
• Mediterranean Variant
• Quinine, Quinidine Aspirin
• Favism Exposure to Fava Bean or Pollen

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Hemolytic AnemiaG6-PD Deficiency

• Laboratory Studies
• Heinz Bodies (Precipitated GS-SG HgB)
• Bite cells
• NL 50 Enzyme Decline in 120d RBC Life
• Black Variant (A-) ?RBC Survival, w/o Anemia
• Mediterranean ??Survival, Anemia w/o Exposure
• G6PD enzyme normal with active hemolysis
• Acute Phase
• ?RBC, ? 25 in A-, gt Mediterranean
• ?Plasma HgB, ?Uncong. Billi., ?Haptoglobin
• Hemoglobinuria
• Heinz Bodies Cleared After Day 1 ? Bite Cells

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Hemolytic AnemiaG6-PD Deficiency

• Treatment Maintain Hydration
• Black Variant Self-Limited
• Mediterranean
• Splenectomy not Effective
• RBC Transfusion Rarely Indicated
• Prevention
• Screening - Avoid Oxidant Drugs
• Prompt Treatment Infection

118
Other Anemias

• Blooms Syndrome AR, Ashkenazi Jews, Mild
  anemia, stunted growth, Photosensitivity, Mental
  Retardation, Facial erythema, Infertility (men)
• Dyskeratosis congenita Marrow aplasia,
  Dystrophic nails, Skin hyperpigmentation,
  Leukoplakia, Continuous lacrimation, Testicular
  atrophy

119
Acute Intermittent Porphyria

• AD, presents in adulthood
• Defect of porphobiligen deaminase activity,
  accumulate Aminolevulinic acid and
  porphobilinogen in urine
• Symptoms Abdominal pain, Autonomic (HTN,
  Tachycardia) and Peripheral Neuropathy,
  Hyponatremia, MS changes, Psychosis, Seizures,
  (No Skin changes like other porphyrias)
• Treatment High carb diet, IV Glucose, Hematin

120
Myeloproliferative Disorders
Polycythemia Vera Low EPO, Inc RBC Mass,
SM.Treat w/Phlebotomy, Hydrea, ASA Symptoms HA,
Visual Changes, Fatigue, Pruritus, Epistaxis,
DVT, High B12 levels If Hct gt54- rule out
secondary causes- Hypoxia, Carboxyhem, Tobacco,
EPO tumors). SHOULD GET BM BIOPSY Myelofibrosis E
ssential Thrombocythemia CML
121
MYELODYSPLASTIC DISORDERS

• MDS- Refractory anemia, RA with ringed
  sideroblasts, RA with excess blasts, RA with
  excess blasts in transformation, CMMOL
• Causes Environmental exposures, post
  chemotherapy, Aplastic anemia, Fanconis anemia
• Symptoms of Anemia, SM, increased MCV,
  Hyposegmented PMNs (Pelger Huet anomaly)
• Treatment SCT, Growth factors, Chemotherapy,
  Transfusions

122
Leukemia/Lymphoma

• CLL
• CML
• AML
• ALL
• Non-Hodgkins Lymphoma
• Hodgkins Lymphoma

123
CHRONIC LYMPHOCYTIC LEUKEMIA

• Most common form of Leukemia in US
• Usually seen in pts gt 50 yrs old
• Most pts are asymptomatic at presentation
• Diagnosis made by flow cytometry
• Abnormal cells resemble mature small lymphocytes
• Symptoms LA, SM, Anemia, Thrombocytopenia
• Associated with Autoimmune disorders
• Median Survival gt 10 years

124
CHRONIC LYMPHOCYTIC LEUKEMIAInfections and
Indications for Rx

• Hypogammoglobulinemia- Can give IVIG
• Staph Pneumoniae
• Staph Aureus
• Hemophilus influenza
• Indications for Treatment
• Anemia Hb lt 10
• Thrombocytopenia Platelets lt 100,000
• Constitutional Symptoms
• Bulky Lymphadenopathy
• Richters Tranformation

125
CHRONIC MYELOGENOUS LEUKEMIA

• 15 to 20 percent of cases of leukemia in adults
• Annual incidence of 1 to 2 cases per 100,000
• Male predominance
• Median age at presentation- 50 years
• Uncontrolled production of maturing granulocytes,
  predominantly neutrophils, but also eosinophils
  and basophils.
• Three phases Chronic phase (85 at Diagnosis),
  Accelerated phase, Blast crisis.

126
CHRONIC MYELOGENOUS LEUKEMIA
127
CHRONIC MYELOGENOUS LEUKEMIA

• Symptoms
• SM (60), leukocytosis, thrombocytosis, Blast
  crisis- fever, night sweats, bone pain,
  ecchymoses
• Diagnosis
• Philadelphia chromosome (922) translocation
• Treatment
• Tyrosine kinase inhibitors (Imatinib, Desatinib)
• Hydroxyurea
• Interferon Alpha with or without cytarabine
• Stem Cell Transplant

128
CHRONIC LYMPHOCYTIC LEUKEMIA

• Most common form of Leukemia in US
• Usually seen in pts gt 50 yrs old
• Most pts are asymptomatic at presentation
• Diagnosis made by flow cytometry
• Abnormal cells resemble mature small lymphocytes
• Symptoms LA, SM, Anemia, Thrombocytopenia
• Associated with Autoimmune disorders
• Median Survival gt 10 years

129
AMLDefinition, Manifestations, Outcome

• Uncontrolled clonal proliferation and
  accumulation of neoplastic hematopoietic
  precursors
• Inhibition of normal hematopoiesis
• Defective maturation
• Multilineage
• Extramedullary disease
• Outcome has improved in younger adults, but much
  less so for older adults

130
FAB Classification
Bennett et al, Br J Haematol, 1976
131
FAB Classification
Bennett et al, Br J Haematol, 1979
132
Leukemic Myeloblast
Auer Rod in Leukemic Myeloblast
133
M4
M5
134
M6
135

• AML- Acute Myelogenous Leukemia
• Risk factors
• Ionizing radiation
• Chemical exposure benzene
• Previous chemotherapy
• Melphalan, Cyclophosphamide, Etoposide
• Genetic factors
• Downs syndrome, Klinefelters, Fanconis anemia
• MDS

136

• AML- Acute Myelogenous Leukemia
• Prognosis
• Age
• Performance status
• Secondary AML
• Previous chemotherapy
• WBC gt20,000/µL

137

• 1)Good prognosis features
• cytogenetic interpretation (t1517, t821 or i16)
  
• 60 of patients are cured with multiple cycles
  of high dose AraC
• 2)For patients with normal cytogenetics
  (intermediate risk) approximately 70 achieve a
  complete remission and 40 of complete
  responders (i.e. 28 overall) are cured.
• 3)Poor prognostic features for AML include
  WBCgt10,000 or platelets lt40,000.
• -CALGB AML Study (gt1200 patients)
• 5-year survival for good risk cytogenetics 55.
• 5-year survival for intermediate risk 24.
• 5-year survival for poor risk 5.

138

• Clinical Presentation
• Fatigue, dyspnea, pallor
• Petechiae, hematoma, bleeding
• Recurrent infections
• Not common to see splenomegaly
• Leptomeningeal involvement
• Neurologic abnormalities- may be signal of
  intracranial bleed
• Tumor lysis syndrome

139
Major Clinical Features

• Incidence/Prevalence
• Estimated new cases in US in 2002 10,600
• 80 gt15 years old median age 70 years
• Estimated deaths in US in 2002 7,400
• Mortality in US 7/100,000/year
• Pancytopenia
• Extramedullary disease
• Skin, gingiva M5
• CNS M5, ? Increased in M4EO
• Orbit M2 with t(821) and CD56 expression

140
Major Clinical Features

• Hyperleukocytosis
• microgranular APL, monocytic differentiation
• 11q23 and inv(16)(p13q22)
• gt100,000 myeloblasts/?L
• leukostasis (obstruction, vascular injury,
  hypoxemia)
• leukaphoresis, hydroxyurea, RT, chemotherapy
• Coagulation abnormalities
• abn plt function
• consumption APL gt M5, M4
• Metabolic abnormalities
• tumor lysis syndrome
• renal tubular dysfunction
• Typhlitis (mimics appendicitis)

141
Chloroma
Gingival Hyperplasia in M5
142

• Diagnosis
• Peripheral smear
• Identification of myeloblasts
• Bone Marrow Biopsy
• CBC WBC can be high or low
• Blast count high or low
• Thrombocytopenia
• Anemia
• Increased LDH, Uric Acid, K, PO4

143
Common Induction Regimen

• Daunorubicin 45-60 mg/m2/d IV x 3 days
• Cytarabine 100 mg/m2/d CI x 7 days

144
Tumor Lysis Syndrome

• Rapid cell turnover
• Prevent with Fluids, Allopurinol, Sodium
  Bicarbonate

145
PLASMA CELL DISORDERS

• Multiple Myeloma
• Plasmacytoma
• MGUS (Monoclonal Gammopathy of Undetermined
  Significance)
• POEMS (Polyneuropathy w/Organomegaly,
  Endocrinopathy, M-Protein production, and Skin
  changes)
• Waldenstroms Macroglobulinemia
• Amyloidosis (ASSOCIATED WITH FACTOR X
  DEFICIENCY) types- AA, AL, Familial, Dx Fibers
  stain with Congo Red- Apple green Birefringence
• Cryoglobulinemia

146
PLASMA CELL DISORDERS

• If Suspected
• Quantitate Immunoglobulin production- SPEP, SIFE,
  UPEP, UIFE
• BM Biopsy
• Skeletal survey, Abdominal Fat Pad Biopsy if MM
  present (r/o Amyloid)

147
MULTIPLE MYELOMA

• Second most common hematologic malignancy
• More common in African Americans
• Associated with
• Monoclonal Spike
• Lytic Lesions increased risk of fracture, Cord
  Compression
• Renal insufficiency
• Bence Jones Proteinuria
• Hypercalcemia
• Hyperviscosity
• Peripheral Smear Rouleaux Formation
• Increased Risk of Bacterial Infections
• Treat with Stem Cell Transplant, Thalidomide,
  Thalidomide derivatives, Melphalan, Steroids,
  Bisphosphonates (watch for osteonecrosis of jaw)

148
MULTIPLE MYELOMA
149
MM Monoclonal Band
150
Multiple Myeloma
151
Multiple Myeloma

• Lytic lesions

152
Severe aplastic anemia

• Disease of bone marrow etiology either toxin,
  genetic, or autoimmune
• Incidence 3 per million per year
• Genetic include Fanconi anemia accounts for 20
• Radiation, chemicals, or viruses for toxin
  (Benzene, Radiation, Parvo B19, Hepatitis)

153
Treatment of SAA

• Bone Marrow Transplant if matched related donor
  around 70-85 cure and little chance of leukemia.
• Immunosuppressive therapy cyclosporin,
  antithymocyte globulin, and prednisone
• May add erythropoietin, and Neupogen
• Supportive with transfusion and chelation

154
Thalassemia Screening
MCV Fl
MCH pg
Hb pattern
gt 78
gt 27
AA2 lt 3
lt 78
lt 27
AF(0.1-7) A2 gt 3.5
ß-THAL Carrier