APPROACH TO ANEMIA

APPROACH TO ANEMIA

Dr. Sumanth K1st year post graduate

Department of general medicine

TOPICS RBC Life cycle Definition of Anemia Clinical Features of Anemia History taking and physical examination Basic Lab investigations for evaluation of anemia Peripheral Smear findings Anemia Evaluation – Where to start? Evaluation of Macrocytic Anemia Evaluation of Microcytic Anemias Evaluation of Normocytic Anemias Evaluation of Anemias with Bone Marrow Failure Evaluation of Hemolytic Anemia

RBC LIFE CYCLE

ERYTHROPOIETINGlycoprotein hormoneProduced by peritubular capillary lining of cells in kidney

Small amount in liverEPO gene regulation is by Hypoxia inducible factor 1α

Normal levels 10 – 25 U/lT1/2 – 6-9 hrs

Sites of Hematopoiesis

Parameters that can define Anemia

1.Haemoglobin2.Hematocrit (Packed Cell Volume)3.RBC Count

Adult male<13

Adult Female<12

Pregnant Female

<11Newborn

<14

Let’s Define

Clinical Features

Depends on the magnitude and rate of reduction in oxygen carrying capacity of the blood

Cardio Vascular and Pulmonary features:

Exertional Fatigue, Dizziness, Faintness, PalpitationsSevere Anemia can lead to CCF, Angina pectoris and Intermittent ClaudicationOn Examination- systolic flow murmurs can be heard

Skin And Mucosal Changes:Pallor- Where to examine – Palpebral conjunctiva Tongue Mucous membrane of mouth and pharynx Nail Bed Skin and Creases of the palms

Nails may become Brittle and early graying of hair

Associated Jaundice – Can be suggestive of Hemolytic anemias, some malignancies

Associated Petechiae - May suggest Bone marrow failure or Anemia due to bleeding disorder

Spoon shaped nails – May suggest Iron deficiency Anemia

Chronic Leg Ulcers – Sickle cell anemias and Hereditary spherocytosis

Glossitis – Pernicious anemia

Knuckle Hyperpigmentation – Megaloblastic anemia

NeuroMuscular Features: Headache, vertigo, tinnitus, scotoma, Lack of concentration muscular weakness

Ophthalmologic findings:Flame shaped hemorhages, Cotton wool spots, And in severe cases Papilledema

Gastro Intestinal Changes:Dysphagia can be seen in Iron deficiency anemiaOccult GI blood loss can cause Iron deficiency anemiaPainful ulcerative lesions in mouth and pharynx can be seen as a part of associated neutropenia

HISTORY Family History of Hemoglobinopathies, Bleeding Disorders History of Jaundice, Gallstones, Splenectomy and Bleeding Travel History Drug History Dietary History History of any major surgeries History of any worm in stool and dark tarry stools History of Fever – can be seen in Infections, Malignancies and Connective tissue disorders Menstrual History (Defined as excessive flow – Duration exceeds 7 days More than 12 pads used Clots after 1st day of menstruation)

PHYSICAL EXAMINATION Scleral icterus Lymphadenopathy Sternal Tenderness Palpation of Liver and Spleen Fundus Examination Thorough examination of other systems

EVALUATION OF BASIC HEMATOLOGY LABORATORY

DATA Haemoglobin Hematocrit RBC count Reticulocyte count MCV MCHC MCH RDW TC and DC Platelets Peripheral Smear

PERIPHERAL SMEAR FINDINGS

Hb H Cabot ring

RPI<2.5% RPI>2.5%

RPI<2.5% RPI>2.5%

RPI <2.5 PERCENT – GO FOR MCV• Microcytic Anemia<80

• Normocytic Anemia

80-100

• Macrocytic Anemia>100

EVALUATION OF MACROCYTIC ANEMIA

MCV 110-130 MCV 100-110

Hypersegmented Neutrophil

Ovalocytes

DRUGS CAUSING MEGALOBLASTIC ANEMIA

Folate antagonists (e.g., methotrexate) Purine antagonists (e.g., 6-mercaptopurine) Pyrimidine antagonists (e.g., cytosine arabinoside) Alkylating agents (e.g., cyclophosphamide) Zidovudine (AZT, Retrovir) Trimethoprim Oral contraceptives Nitrous oxide Arsenic

MICROCYTIC ANEMIA

Serum Iron – Measures Iron bound to Transferrin – 70 – 200 ug/dlTIBC- Total Iron binding capacity- a measure of transferrin - 250 – 435ug/dlTIBC saturation – (Transferrin saturation) – 20% - 45%Serum Ferritin level – Males 20 – 500 ug/L Females 10 – 200 ug/dlBone Marrow Iron Stores Graded 0 to 6Transferrin receptorsZinc erythro protoporphyrin

FEP/ZPP – Free erythrocyte protoporphyrin / Zinc protoporphyrin

Mentzer IndexMCV/RBC >14 - S/O IRON DEFICIENCY

12-14 - INDETERMINATE <12 - THALASSEMIA TRAIT

RDW 13.4+/- 1.2 (Normal)RDW 16.3 +/- 1.8 (IRON DEF)

THALASSEMIAS AND OTHER HAEMOGLOBINOPATHIESGo for Haemoglobin electrophoresis- Done in Alkaline pH.To distinguish HbA2 and Hb C also do in Acidic pHBeta Thalassemias have increased HbF and HbA2Alpha Thalassemias are not diagnosed in Hb electrophoresis unless 3 genes are deletedAlpha Thalassemia trait is diagnosed by exclusion of Beta Thalasemia and Iron deficiency Anemia

SIDEROBLASTIC ANEMIA

HereditaryX-linked - ALA synthetase deficiencyAutosomal – Disorder in Glycine transport to MitochondriaAcquiredPrimary sideroblastic anemia (refractory)Secondary sideroblastic anemias caused by drugs and bone marrowToxinsPyridoxine deficiency and Zinc excess• Isoniazid • Chloramphenicol• Alcohol• Lead• Chemotherapeutic agents

NORMOCYTIC ANEMIA

Anemia associated with appropriately increased erythrocyte productionPosthemorrhagic anemiaHemolytic anemiaDecreased erythropoietin secretionRenal: anemia of renal insufficiencyHepatic: anemia of liver diseaseAnemia of endocrine deficiencyProtein-calorie malnutritionAnemia of chronic disordersAnemia with impaired marrow responseRed blood cell aplasiaAcquired pure red cell aplasia in adultsTransient aplastic crises associated with hemolysisAplastic anemia (pancytopenia)Bone marrow infiltrative disordersLeukemiaMyelomaMyelodysplastic anemiasCongenital dyserythropoietic anemia ([CDA] type II)

ANEMIA OF CHRONIC DISEASE

Chronic InfectionsPulmonary infections: abscesses, TB, pneumoniaSubacute bacterial endocarditisPelvic inflammatory diseaseOsteomyelitisChronic urinary tract infectionsChronic fungal diseaseMeningitisHuman immunodeficiency virus

Chronic, Noninfectious InflammationsRheumatoid arthritisRheumatic feverSystemic lupus erythematosusSevere traumaThermal injuryVasculitis

Malignant DiseasesCarcinomaHodgkin diseaseNon-Hodgkin lymphomaLeukemiaMultiple myeloma

MiscellaneousAlcoholic liver diseaseCongestive heart failureThrombophlebitisIschemic heart diseaseIdiopathic

ANEMIA DUE TO IMPAIRED BONE MARROW RESPONSE

Red blood cell aplasia Aplastic anemia Myelodysplasia Leukemias Myelophthisic anemia Marrow infiltration Myeloma Congenital Dyserythropoietic Anemias

When to do Bone marrow cytology or biopsy in a case of anemia?

reticulocytopenicanemias, particularly when there is more than one hematopoieticcell line affected.

Bone marrow was done to detect Iron stores. Not done these days

HEMOLYTIC ANEMIAS

Marrow compensation occurs in Hemolytic Anemia Anemia manifests if Mean RBC Life span falls to 15 to 20 days

In congenital Hemolytic Anemias expansion of erythroid bone marrow occurs featuring as tower shaped skull , frontal bossing, maxillary and dental abnormalities Pigmented gallstones, splenomegaly may also be present in congenital haemolytic anemias

Acquired haemolytic anemias have associated icterus , fever and aching pains of back, abdomen and limbs

Laboratory signs of Hemolysis Increased Indirect Bilirubin Increased serum LDH Decreased Serum Haptoglobin Increased Carbon Monoxide

Production Intravascular Hemolysis Haemoglobinemia Haemoglobinuria Methaemalbuminaemia Reticulocytosis Peripheral smear Polychromatophilia Basophilic stippling Erythroblastosis Schistocytes

RBC LIFE CYCLE

Laboratory signs of Hemolysis Increased Indirect Bilirubin Increased serum LDH Decreased Serum Haptoglobin Increased Carbon Monoxide

Production Intravascular Hemolysis Haemoglobinemia Haemoglobinuria Methaemalbuminaemia Reticulocytosis Peripheral smear Polychromatophilia Basophilic stippling Erythroblastosis Schistocytes

Peripheral smear

Coombs test

Osmotic fragility

tests

Approach in a case of Hemolytic Anemia

SICKLE CELL ANEMIAClinical complications of sickle cell anemia

Toddlers Splenomegaly and sequestration Frequent infections DactylitisChildhood Painful crises Acute chest syndrome Osteonecrosis

Adolescence Painful crises Stroke Priapism Psychosocial problemsAdults Painful crises Pulmonary Hypertension Renal insufficiency Osteonecrosis Retinopathy Leg Ulcers

In a Hemolytic picture go for Coombs test and Osmotic fragility test

Osmotic Fragility Test

DISEASES OR CONDITIONS ASSOCIATED WITH WARMAUTOIMMUNE ANTIBODIES

Autoimmune disordersSystemic lupus erythematosusRheumatoid arthritisSclerodermaUlcerative colitisAntiphospholipid antibodiesLymphoproliferative disordersChronic lymphocytic leukemiaAcute myelocytic leukemiaHodgkin’s lymphomaNon-Hodgkin’s lymphomaWaldenström macroglobulinemiaOther lymphoproliferative disordersMultiple myeloma

Other Neoplastic disordersThymomaTeratomaKaposi sarcomaViral InfectionsEBVKIVHepatitis COtherDPT VaccinationBone Marrow TransplantationHypogammaglobulinemiaPregnancy

Disorders associated with Cold autoimmune antibodies

Idiopathic Cold agglutinin diseaseParoxysmal Cold HemoglobinuriaNeoplasmsWaldenstrom MacroglobulinemiaCLLMyelomaKaposi sarcoma

InfectionsMycoplasmaEBVAdenovirusInfluenzaRubellaMumpsVaricellaHIVE ColiLegionnaires diseaseMalariaTrypanasomiasisSyphilisTropical Eosinophilia

An 85-year-old slender, frail white woman was hospitalized for diagnosis and treatment of anemia suspected during aroutine examination by her physician. The physician noted that she appeared pale and inquired about fatigue and tiredness. Although the patient generally felt well, she admitted to feeling slightly tired when climbing stairs. A point-of-care haemoglobin performed in the physician’s office showed a dangerously low value of 3 g/dL, so the patient was hospitalized for further evaluation. Her hospital CBC results are as follows:

During a holiday visit, the children of a 76-year-old man noticed that he seemed more forgetful than usual and that he had difficulty walking. Concerned about the possibility of a mild stroke, the children insisted that he see his physician. The physician diagnosed a peripheral neuropathy affecting the father’s ability to walk. In addition, the physician noted that he was pale and ordered routine hematologic studies. The results were as follows

WBC differential: unremarkable with the exception of hypersegmentation of neutrophils RBC morphology: moderate anisocytosis, moderate poikilocytosis, macrocytes, oval macrocytes, few teardrop cells

A 16-year-old female presented to her pediatrician with jaundice. Her pediatrician checked liver enzyme and bilirubin levels, which were elevated. Hepatitis A, B, and C serologies were all negative. She was referred to a gastroenterologist, who diagnosed her with autoimmune hepatitis. With immunomodulatory treatment, her hepatitis improved. However, over the next several months, she noticed increasing fatigue and bruising. She also developed heavier menses, with menstrual cycles lasting up to 2 weeks in duration. Physical examination revealed pallor and scattered ecchymoses with petechiae on her chest and shoulders with no other abnormalities. Complete blood count results were as follows

Serum vitamin B12 and folate levels were within reference intervals. Bone marrow aspirate revealed mild dyserythropoiesis but normal myelopoiesis and megakaryopoiesis. Iron stain revealed normal stores. A bone marrow biopsy specimen was moderately hypocellular (15%) with a reduction in all three cell lines. There was no increase in reticulin or blasts. Cytogenetic testing revealed a normal karyotype, and results of flow cytometry for paroxysmal nocturnal hemoglobinuria (PNH) cells was negative

A 24-year-old male was found to have a hemoglobin level of 10.2 g/dL. He is not having any symptoms. He got this Haemoglobin value in a routine blood checkup. He was ordered other tests and results were as followed

Peripheral blood RBCs exhibited moderate microcytosis, slight hypochromia, and slight poikilocytosis with occasional target cells, and several RBCs had basophilic stippling. Hb A2 was 4.9% of total hemoglobin by high-performance liquid chromatography (reference interval, 0% to 3.5%). Serum ferritin level was 320 ng/mL (reference interval, 15 to 400 ng/mL).

REFERENCESHarrison’s principles of Internal MedicineWintrobe’s Clinical HematologyRodak’s HematologyManson’s Tropical Diseases

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