Anemia - Ust 2007 (revised)

Anemia and Abnormalities of Red Blood Cells: Approach to Diagnosis and Treatment Section of Hematology-Oncology Department of Medicine University of Santo Tomas Faculty of Medicine and Surgery

Case 1-01-01: 35 year old premenopausic female with menorrhagia  

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housewife complains of progressive easy fatigability of about 3 months duration. (-) epigastric pain, (-) hematochezia nor melena menses – 28 days cycle, 7 days duration, 3 days profuse flow , 5-6 fully soaked pads/day (-) bruises/ecchymoses P.E. Pale, no jaundice (-) hepatosplenomegaly

Case 1-01-01 1.

2.

What other questions should you ask of this patient who presents with pallor? What other findings should you look for in the physical examination?

Case 1-01-01 3. What laboratory examinations would you request in this case? 4. What are red cell indices? 5. What information can you get from the examination of the peripheral smear? 6. What is the significance of the reticulocyte count?

Case 1-01-01: 

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CBC: Hb: 60g/L Hct: .21 MCV: 80fL MCH: 25 pg MCHC: 28% WBC: 6 x 109/L seg: 70% lymph: 25% eos: 3% mono: 2% Platelets: adequate Reticulocyte count:

Interpretation?      

Microcytic (MCV low) Hypochromic (MCH low) Normal WBC Platelets normal quantity Reticulocyte count normal Peripheral smear: hypochromic, microcytic red blood cells, varying sizes (anisocytosis), varying shapes (poikilocytosis), platelets adequate Back

Case 1 Patient

Normal value

Serum iron

10

TIBC

60

9 - 27 umol/L 50 – 150 μg/dL 54 – 64 umol/L 300 – 600 μg/dL 25 – 50%

% transferrin 16.6% saturation Serum ferritin 8ug/L

30 μg/L(female) 100

Interpretation? Serum iron low  TIBC normal  Transferrin saturation low  Serum ferritin low 

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Iron deficiency anemia

Anemia Reduction below normal in the concentration of hemoglobin or RBC’s in the blood  Anemia is not a diagnosis in itself, but merely an objective sign of disease  First step in its diagnosis is detection of its presence 

Symptoms of moderate to severe anemia           

Fatigue Breathlessness Loss of stamina Palpitations, especially with physical exertion Headache Vertigo Lack of mental concentration Drowsiness Tinnitus Paresthesias Pica

History Symptoms depend on: 2. Severity of the anemia 3. Rapidity of onset 4. Patient’s age and CV status - capacity of the CV & pulmonary system to compensate for the anemia 7. Associated manifestations of the underlying disorder - Endocrine disorder - Renal disorder - Hepatic disorder

History 

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Onset & Duration of symptoms  insiduous or acute Previous prescription for hematinics & response Medication history Occupation, household customs & hobbies Symptoms of hemolysis  jaundice, changes in urine color Symptoms of blood loss  melena, hematochezia, epigastric pain

History Obstetric & Gynecologic history  # of pads/day  duration  # of pregnancies, abortions interval  Concomitant bleeding manifestations  Dietary history Back to questions  Fever, Weight loss 

Vital signs Blood pressure  Hypotension  Orthostatic hypotension  Cardiac/pulse rate  Tachycardia  Respiratory rate  Tachypnea  Body temperature 

Cardiac Signs Hemic murmurs: mid or holosystolic often in the pulmonic or apical area, due to increased blood flow and turbulence  Gallop rhythms  Tachycardia/Cardiomegaly  Strong peripheral pulses with wide pulse pressure 

Skin 

Pallor: <8 to 10 mg/dL hemoglobin Affected by:

state of vasoconstriction/vasodilatation degree & nature of pigmentation nature & fluid content of the subcutaneous tissues Most constantly detected in: mucous membranes of the mouth, pharynx, conjunctivae, lips nailbeds

surface

* Areas where vessels are close to the skin

Skin Dry, Shriveled skin  Thinning, loss of luster, premature graying of hair  Brittle, lackluster nails, spooning 

Gastrointestinal manifestations Glossitis  Atrophy of the papillae of the tongue  Dysphagia  Oral ulcers  Gingival hyperplasia  Hepatosplenomegaly 

Sternal tenderness  Lymphadenopathy  Retinal hemorrhage 

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Complete blood count 

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Red cells  Hemoglobin  Hematocrit  Red cell count  Morphology  Red cell indices: MCV, MCH, MCHC White blood cells  Total count  Differential count Platelet count

Changes in Normal Hemoglobin/Hematocrit Values with Age and Pregnancy Age/Sex At birth Childhood Adolescence Adult man Adult woman

12

(menstruating)

Hgb (g/dl) 17

Hct (%) 52 36 13 40 16(+2) 47(+6) 13(+2) 40(+6)

Adult woman

14(+2)

42(+6)

During pregnancy

12(+2)

37(+6)

(postmenopausal)

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Red cell indices Index

Normal Value

Mean Cell Volume(MCV) (hematocrit x 10)/(red cell ct. x 106) Mean Cell Hemoglobin (MCH) (hemoglobin x 10)/ (red cell ct. x 106) pg Mean Cell Hemoglobin Concentration (hemoglobin x 10)/ hematocrit, or MCH/MCV Back to questions

90 + 8 fL 30 + 3 33 + 2%

Morphology

Morphology

APPROACH TO THE DIAGNOSIS OF ANEMIA

Reticulocyte count  

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Measure of bone marrow compensation for anemia Normal Value  0.5 – 1.5% (old)  5 – 15 x 10-3 (SI) Corrected Reticulocyte ct =Patient’s Hct x Reticulocyte 45 count (%) Reticulocyte production index Corrected Reticulocyte 2

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Back to case 1

Diagnosis of microcytic anemias Tests

Iron deficiency

Inflammatio Thalassem Sideroblas n ia tic anemia

Smear

Micro/hypo

Normal, micro/hypo

Micro/hypo variable with target

Serum iron

<30

<50

Normal to high

Normal to high

TIBC

>360

<300

normal

norml

% <10 saturation

10-20

30-80

30-80

Ferritin

30-200

50-300

50-300

normal

abnormal

normal

<15

Hemoglob normal in pattern

Adamson, J in Harrison’s Principles of Internal Medicine, 15th ed., 2001

Iron studies Serum iron: amount of circulating iron bound to transferrin  Total iron binding capacity: indirect measurement of bound transferrin  Percent transferrin saturation:  Serum iron level x 100 TIBC  Serum ferritin: estimate of iron stores 

Stages of Iron Deficiency Normal

Negative iron balance

Iron deficient Iron erythropoiesi deficiency s anemia

1–3+

0-1+

0

0

Serum ferritin 50- 200 (ug/L)

<20

<15

<15

TIBC (ug/dL)

300-360

>360

>380

>400

SI (ug/dL)

50-150

NL

<50

<30

Saturation (%) Marrow sideroblasts (%)

30-50

NL

<20

<10

40-60

NL

<10

<10

RBC morphology

NL

NL

NL

Microcytic hypochrom ic

Marrow iron stores

Treatment 

Severity and cause determine approach to treament  Elderly+/- cardiovasular instability: RBC transfusions  Younger individuals with compensated anemia: iron replacement

Oral Iron Therapy    

Optimal response occurs when about 200 mg of elemental iron given per day Absorption more complete on empty stomach With or after a meal, absorption decreases by 40 to 50% However gastric irritation is common, hence, advisingpt to take tablet immediately after a meal may increase compliance

Oral Iron Therapy   

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Absorption enhanced by orange juice, meat, poultry, fish Absorption inhibited by cereals, tea, milk Side Effects of Oral Iron: gastrointestinal: heartburn, nausea, abdominal cramps, diarrhea  Related to dose Continue iron treatment 3 to 6 months after anemia resolves  Allows repletion of iron stores

Oral Iron Preparations Preparation

Size

Iron Content

Usual Adult daily dose

Ferrous sulfate tablets (hydrated)

300 mg

60 mg

3 tablets

tablets (exsiccated)

200 mg

60 mg

3 tablets

syrup & elixirs

40 mg/ml 300 mg

8 mg/ ml

25 ml

37 mg

5 tablets

200 mg 300 mg

67 mg 100 mg

3 tablets 2 tablets

Ferrous gluconate Ferrous fumarate

Indications for Parenteral Iron       

Unable to tolerate iron compounds orally Poor compliance Persistent loss of blood or iron at a rate too rapid for oral intake to compensate for the loss Disorder of GI tract e.g. ulcerative colitis Malabsorption of iron Inability of maintain iron balance during treatment with hemodialysis Donating large amounts of blood for autotransfusion

Computing for the dose of parenteral iron = Body weight (kg) x 2.3 x (15 – patient’s Hgb, g/dL) + 500 or 1000 mg (for stores)

Case 1-02-01      

75 year old female consulted because of progressive weakness and loss of balance numbness and tingling sensation in all extremities no gastrointestinal complaints hypertensive on Felodipine 5 mg per day, but not a diabetic Diet consists of vegetables and fish because of poor dentition P.E. Vital signs: BP: 150/90, PR: 80/min, regular, RR: 21/min., regular, Temp: 35.5’C  pale, has slightly icteric sclerae  smooth, red tongue  no lymph nodes, nor anterior neck mass.  regular rate and rhythm, no murmurs  Lung examination is normal  no abdominal masses palpated  some problems with gait but has an otherwise normal neurologic examination

Case 1-02-01 1.

2.

What other questions should you ask of this patient who presents with pallor? What other findings should you look for in the physical examination?

Case 1-02 

CBC: Hb: 80 g/L Hct: .26 MCV: 102fL MCH: 36 pg MCHC: 38% WBC: 9 x 109/L seg: 74% lymph: 20% eos: 2% mono: 4% platelets: adequate

Case 1-02-01 3. What laboratory examinations would you request in this case? 4. What other differential diagnoses should be considered?

> 36 macrocytes Reticulocyte count INCREASED Increased

• prior hemolysis • prior hemorrhage • treated disease • deficiency of - Vit. B12 - Folate

32-36 normochromic normocytic

< 32 hypoochromic microcytic

Normal/Decreased NORMAL/DECREASED bone marrow megaloblasti YES c NO • deficiency of Vit. • hypothyroidism B12, Folate • hypoplastic • disorders of DNA marrow and misc. synthesis - drug-induced - inherited

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Diagnostic Tests: Megaloblastic Anemia    

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Reticulocyte index Unconjugated bilirubin may be increased LDH may be increased Serum levels of  Cobalamin (Vitamin B12) (NV: 300 – 900 pg/mL)  Folate (6 – 20 mg/mL) Red cell folate levels  not subject to fluctuations in folate intake  better indication of folate stores

Bone marrow findings: Megaloblastic anemia    

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Back to discussion

Hypercellular Decreased myeloid/erythroid ratio Abundant stainable iron RBC precursors abnormally large, nuclei less mature (nuclearcytoplasmic asynchrony) Nuclear chromatin more disperse and condenses in a fenestrated pattern Abnormal mitosis Granulocyte precursor larger than normal with giant bands and metas Megakaryocytes decreased, abnormal

Interpretation? MCV high (macrocytic)  MCH high (hyperchromic)  PS: macrocytic red cells, some hyperchromic red cells, hypersegmented neutrophils 

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Macrocytic anemia, probably megaloblastic anemia

Megaloblastic anemia disorder caused by impaired DNA synthesis  Cells primarily affected: blood cells, GI epithelial cells  slowed nuclear cell division with normal progression of cytoplasmic maturation megaloblastosis in bone marrow 

Causes of Megaloblastic anemia 

Cobalamin deficiency  Inadequate intake (vegans)  Malabsorption  Gastric achlorydia, partial gastrectomy, drugs that block acid secretion  Pernicious anemia, total gastrectomy  Terminal ileal disease: sprue, enteritis, resection, tumors  Competition of cobalamin: fish tapeworm, “blind loop” syndrome

Causes of megaloblastic anemia  

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Folic acid deficiency Inadequate intake: unbalanced diet (alcoholics, teenagers, some infants) Increased requirements  Pregnancy  Infancy  Malignancy  Increased hematopoiesis (chronic hemolytic anemias)  Chronic exfoliative skin disorders  Hemodialysis Malabsorption Impaired metabolism

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Other causes of megaloblastic anemia 

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Drugs that impair DNA metabolism Purine antagonists: 6 mercaptopurine, azthioprine Pyrimidine antagonists: 5FU, cytosine arabinoside, others Others: procarbazine, hydroxyurea, zidovudine Metabolic disorders (rare) Hereditary orotic aciduria Lesch Nyhan syndrome Megaloblastic anemia of unknown etiiology Refractory megaloblastic anemia DiGuglielmo’s syndrome Congenital dyserythropoietic anemia

Treatment of Megaloblastic anemia Treat the cause  Cobalamin deficiency  IM cyanocobalamin: 1000 mcg per week for 8 weeks then monthly  Oral cobalamin: 2 mg crystalline B12 per day  Folic acid: 1 mg/day po 

Case 1-03-01   

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50 year old female was referred for evaluation of anemia easy fatigability about 5 weeks cough and fever and was diagnosed to have pneumonia. She was given antibiotics which included Cefuroxime 500 mg BID other symptoms  passage of highly colored urine  weight loss of about 5 lbs in the last 2 months P.E. Vital signs: BP: 120/70, PR: 110/min, regular, RR: 23/min, regular, Temp: 37’C  pale palpebral conjunctivae, icteric sclerae, small cervical lymph nodes on both sides,  no hepatomegaly and slight splenomegaly

Case 1-03 

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CBC: Hb: 70 g/L Hct: .21 MCV: 98fL MCH: 35pg MCHC: 36% WBC: 13x 109/L seg: 80% lymph: 20% platelets: adequate Reticulocyte count: 80 x 10-3/L

Case 1-03-01 1.

2.

What other questions should you ask of this patient who presents with pallor? What other findings should you look for in the physical examination?

Case 1-03-01 3. What is the most likely problem in this patient? 4. What diagnostic tests are important in this patient?

Diagnostic tests for hemolytic anemia  

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Peripheral smear Direct Coomb’s test (antiglobulin test)  Clue to immune (antibody-mediated) hemolysis of RBC Ham’s test (acid hemolysis); sucrose hemolysis test screens for paroxysmal nocturnal hemoglobinuria  Flow cytometry diagnostic Osmotic fragility test Hemoglobin electrophoresis for hemoglobinopathies (e.g. thalassemia)

Morphology in hemolytic anemias

Spherocytes: hereditary spherocytosis Autoimmune hemolytic anemia

Target cells: thalassemias

Schistocytes: microagiopathic hemolytic Anemia, intravascular prostheses

Causes of Hemolysis

INTRACORPUSCULAR

EXTRACORPUSCULAR

Abnormalities of RBC interior Enzyme defects Hemoglobinopathies RBC membrane abnormalities Hereditary spherocytosis, etc Paroxysmal nocturnal hemoglobinuria Spur cell anemia Extrinsic factors Hypersplenism Antibody: immune hemolysis Microangiopathic hemolysis Infections, toxins, etc.

HEREDITARY

ACQUIRED

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HEMOLYTIC ANEMIA COOMB’S TEST

NEGATIVE

POSITIVE EXTRACORPUSCULAR

AUTOIMMUNE HEMOLYTIC ANEMIA Primary Secondary (CT disease, drugs) Isoimmune Hemolytic Disease Rh,ABO, mismatched transfusion

HEMOLYTIC ANEMIA COOMB’S TEST

NEGATIVE CORPUSCULAR Hemoglobinopathies Enzymopathies Membrane Defects Morphology Autohemolysis Osmotic Fragility

POSITIVE EXTRACORPUSCULAR Idiopathic Secondary Drugs Infection Microangiopathic

Immune-mediated hemolysis 

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Usually due to IgG or IgM antibodies with specificity to antigens on red cell membrane(autoantibodies) or with alloantigens on transfused RBC (alloantibodies) Diagnostic tool: Coomb’s antiglobulin test  Direct: ability of anti-IgG or anti-C3 sera to agglutinate patient’s RBC  Indirect: serum of patient incubated with normal RBC & antibody is detected with anti-IgG

Hemolysis due to Antibodies 

Warm-Antibody Immunohemolytic anemia  Idiopathic  Lymphomas  SLE & other collagen vascular disease  Drugs  Alpha methyl dopa  Penicillin  Quinidine  Postviral infections  Other tumors

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Cold-Antibody Immunohemolytic Anemia  Cold-agglutinin disease  Acute: Mycoplasma, infectious mononucleosis  Chronic: idiopathic, lymphoma  Paroxysmal cold hemoglobinuria

Treatment: Autoimmune hemolytic anemia Glucocorticoids: Prednisone  Splenectomy  Immunosuppressive drugs  Blood transfusion for severe anemia 

Case 1-04-01 48 year old male farmer with progressive weakness and pallor  no jaundice nor hepatosplenomegaly petechiae noted on both L.E.’s 

Case 1-04 

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CBC: Hb:7 gm/dl Hct: 21 WBC: 3,000 lymph: 48% segs: 52% Platelet count: 80,000 Reticulocyte Count:5 x 10-3

Interpretation? Pancytopenia (anemia, leukopenia, thrombocytopenia)  Reticulocyte index low  Peripheral smear: normocytic, slightly hypochromic RBC, leukopenia, platelets nil 

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Bone marrow failure Back to algorithm

Case 1-04-01 

What examination will establish the diagnosis in this case?

Diagnosis of hypoproliferative anemias Tests

Iron deficiency

Inflammatio n

Renal disease

Hypometaboli c states

anemia

Mildsevere 70-90

mild

mild

80-90

Mildsevere 90

morpholog Normoy micro Serum Iron <30

normo

normo

normo

<50

normal

normal

TIBC

>360

<300

normal

normal

Saturation % Serum ferritin

<10

10-20

normal

normal

<15

30-200

115-150

normal

Iron stores

0

2-4+

1-4+

normal

MCV (fl)

90

Adamson, J in Harrison’s Principles of Internal Medicine, 15 Back to Case 1-04-01

th

ed., 2001

Bone marrow examination 

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Bone marrow aspiration  Smear for morphology  Flow cytometry  Cytogenetics Bone marrow biopsy  cellularity

Normal bone marrow Fatty marrow: Aplastic anemia

Classification of Aplastic Anemia 

Acquired  Secondary  Radiation  Drugs/chemicals  Viruses • EBV • Hepatitis (non-A, non-B, non-C) • Parvovirus B19 • HIV1  Immune diseases • Eosinophilic fascitis • Hypoimmunoglob ulinemia • Thymoma/thymic ca • GVHD  PNH  Pregnancy  Idiopathic

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Inherited  Fanconi’s anemia  Dyskeratosis congenita  Shwachman-Diamond syndrome  Reticular dysgenesis  Amegakaryocytic thrombocytopenia  Familial aplastic anemias

Treatment: Aplastic Anemia  

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Treatment of identifiable cause Supportive care  Blood component therapy  Treatment of infections Severe acquired AA:  Stem cell transplantation  Immunosuppression  ALG or ATG + cyclosporine Moderate  Androgens

Summary  

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History and Physical examination are essential in the assessment of a patient who may have anemia CBC, done and reported correctly is an important tool in anemia  Confirms presence of anemia  Clues to the type and possible etiology of anemia Additional tests indicated depending on type of anemia  Bone marrow examination  Iron studies  Hemoglobin electrophoresis  Blood chemistries  Vitamin levels: B12, folic acid  Coomb’s test  Others Treatment depends on the cause

Acknowledgements: This presentation has been the collective effort of the following members of the staff of the Section:  Gina V. Panuncialman, MD  Priscilla B. Caguioa, MD  Irene D. Castillo, MD