Evaluation of the anemic patient
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EVALUATION OF THE ANEMIC PATIENT. Is the patient really anemic?. Hemoglobin declines with advanced age African heritage - 0.5 g/dl lower hgb Hematocrit lower by a mean of 4 points in recumbent vs standing position Edematous pts have 12% drop in Hct/Hgb after one hour of recumbence.

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EVALUATION OF THE ANEMIC PATIENT

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Evaluation of the anemic patient

EVALUATION OF THE ANEMIC PATIENT


Is the patient really anemic

Is the patient really anemic?

  • Hemoglobin declines with advanced age

  • African heritage - 0.5 g/dl lower hgb

  • Hematocrit lower by a mean of 4 points in recumbent vs standing position

  • Edematous pts have 12% drop in Hct/Hgb after one hour of recumbence


Evaluation of the anemic patient

Blood 2004;104:2263-2268

  • Data from the Third National Health and Nutrition Examination Survey (1988-1994)

  • Prevalence of anemia rises rapidly after age 50, prevalence 20% over age 85

  • 11% of men, 10.2% of women over 65 anemic

  • 1/3 due to nutritional deficiency, 1/3 to chronic inflammation or renal disease, 1/3 unexplained

  • Most cases mild; only 2.8% of women and 1.6% of men had Hgb < 11 g

  • Unexplained mild “anemia” in elderly people may simply be an effect of aging in some cases


Clinical clues

History

Family history

Timing of symptoms

Medications

Occupation/Hobbies

Diet

Mouth problems

GI symptoms

Bruising/bleeding

GU symptoms

Exam

Mouth

Sternal tenderness

Lymph nodes

Cardiac murmurs

Liver/Spleen size

Skin exam

Pelvic/rectal

Clinical Clues

  • Always consider/rule out blood loss!


Look hardest for readily treatable causes of anemia

Look hardest for readily treatable causes of anemia

  • Nutritional deficiency (iron, B-12, folate)

  • Endocrinopathy (esp thyroid)

  • Low-EPO state (more common than you think)

  • GI blood loss

  • Most treatable causes of anemia can be diagnosed without marrow biopsy


Confirm laboratory data

Confirm laboratory data

  • CBC performed by machine, including differential

  • Quality of “flagging” abnormal values varies

  • All “flagged” results should be reviewed when diagnosis is not known.

  • Blood smear from abnormal CBC should be reviewed by a human


Kinetics of erythropoiesis

KINETICS OF ERYTHROPOIESIS

Hyporegenerative (marrow not working well)

Hyperregenerative (marrow working)

Calculating the reticulocyte index will usually tell you which category your patient is in


Reticulocytes

Reticulocytes

  • “Reticulin” - insoluble ribosomal RNA

  • Present after extrusion of nucleus until degradation of rRNA.

  • Retics normally spend 3.5 days in marrow, 1 day in blood

  • Normal 28 -115 thousand per microliter

Reticulocytes demonstrated by Crystal Violet stain of blood smear (most labs now use flourescent dye and automated cell counter)


Measuring reticulocytes

Measuring Reticulocytes

Maturation

Mature RBC

High fluorescence

Low fluorescence

* False positive - Howell-Jolly, Heinz, & Pappenheimer bodies , Malaria, Babesia, porphyria


Reticulocyte response

Reticulocyte Response

  • Reticulocyte count = % retics

  • Reticulocyte Index correlates best with RBC production

    • Correct for low RBC count (absolute retic count)

    • Correct for immature retics if present (factor of 2)

  • “Normal” RI = 1 but should go up in anemia if marrow function normal

    • Normal or low RI in anemia implies hyporegenerative state

    • Very high RI (>4) suggests hemolysis

    • Misleading results possible if not in steady state


Retic index

Retic Index

When Hct 25 or less, use 1/2 for maturation time term


Example

Example

  • 75 yo with osteomyelitis

    • receiving extended antibiotic therapy

    • poor appetite, weight loss

    • Labs:

      • Hct 25, WBC 12.0, Platelets 545, MCV 92,

      • Retic 5.8% (normal 0.5 to 2.2%)

RI = 1.6

too low


Hyporegenerative anemia

Hyporegenerative anemia

Retic index not appropriately increased

  • Nutritional deficiency (iron, B-12, folate)

  • Marrow dyscrasia (leukemia, myelodysplasia, aplastic anemia etc)

  • Thalassemia

  • Low EPO state (renal disease, inflammation, endocrinopathy, ? old age)


Hyperregenerative anemia

Hyperregenerative anemia

Retic index increased

  • Hemolysis

  • Blood loss

    • Retic count increase generally less striking than in hemolysis


Interpreting the mcv

Interpreting the MCV

  • The MCV reflects the average size of RBC

    • Macrocytic (MCV >95)

    • Microcytic (MCV <82)

    • Normocytic


Evaluation of the anemic patient

Pernicious anemia

Aplastic anemia

Myelodysplasia

Hemolysis

Normal

inflammation

Thal trait

Iron deficiency


Blood smear

BLOOD SMEAR

  • RBC size, shape

  • Polychromasia (young retics)

  • RBC inclusions (nucleated rbc, Howell-Jolly bodies, etc)

  • Rouleaux

  • Abnormal/immature leukocytes

  • Platelet number/morphology


Evaluation of the anemic patient

Normal

Polychromasia


Evaluation of the anemic patient

Microcytosis, hypochromia

Normal rbc


Evaluation of the anemic patient

Normal

Macrocytic/megaloblastic


Evaluation of the anemic patient

Spur cell anemia (liver disease)

Microangiopathic hemolytic anemia


Evaluation of the anemic patient

Hereditary spherocytosis


Evaluation of the anemic patient

Rouleaux (myeloma, Waldenstroms)


Evaluation of the anemic patient

Neutrophil hyposegmentation (myelodysplastic syndrome)

Leukoerythroblastic (marrow infiltration)


Differential diagnosis guided by retic index mcv

DIFFERENTIAL DIAGNOSIS GUIDED BY RETIC INDEX, MCV

  • Hyporegenerative

    • Microcytic

    • Macrocytic

    • Normocytic

  • Hyperregenerative


Microcytic hyporegenerative anemia

Microcytic, hyporegenerative anemia

  • Iron deficiency (R/O GI bleeding!)

  • Thalassemia

  • Inflammation

  • Sideroblastic anemia (myelodysplasia, lead poisoning etc)

Microcytosis implies defective hemoglobin production


Laboratory assessment of microcytic anemia

Laboratory assessment of microcytic anemia

*best discriminators of Fe defic vs anemia of inflammation


Tests of iron status practical aspects

TESTS OF IRON STATUSPractical aspects

  • Low serum ferritin almost always indicates iron deficiency

  • Low serum iron and high TIBC almost always indicate iron deficiency

  • Ferritin > 100 rarely found in iron deficiency

    • Exception - liver inflammation/necrosis

  • Normal serum iron rarely found in iron deficiency

    • Exception - iron deficiency recently treated with oral iron

  • When TIBC is low or normal, low serum iron not a reliable indicator of iron deficiency!

  • Iron deficiency may be hard to diagnose via blood tests in setting of inflammation (eg, low iron, low TIBC, intermediate ferritin level)

    • Therapeutic trial of iron +/- EPO a reasonable alternative to marrow biopsy


Macrocytic hyporegenerative anemia

Macrocytic, hyporegenerative anemia

Megaloblastic:

B12/folate deficiency

Myelodysplastic syndrome

Drug-induced

Non-megaloblastic:

Liver disease

Alcohol

Hypothyroidism

Reticulocytosis


Macrocytic anemia causes

Macrocytic Anemia - Causes

Colon-Othero; Med Clin North Am: 581, 1992


B 12 folate deficiency

B-12/Folate deficiency

  • Therapeutic trial reasonable if blood level of vitamin borderline

  • In equivocal cases consider confirmatory tests:


Megaloblastic anemia drugs

Folate antagonists

methotrexate

trimethoprim

Most cancer chemotherapy

Anti-retroviral agents

zidovudine

delavirdine

lamivudine

zalcitabine

Nitrous oxide

Arsenic

Chlordane

Anticonvulsants

Dilantin

Valproate

Lamotrigine

Megaloblastic Anemia - Drugs


Normocytic hyporegenerative anemia

Normocytic, hyporegenerative anemia

Marrow disorders

Aplastic anemia

Pure red cell aplasia

Inherited anemia (Diamond-Blackfan)

Myelophthisic state

Myelodysplasia

Leukemia and other heme malignancy

Low EPO state

Uremia, inflammation, endocrinopathy, HIV infection, etc

Relatively common in elderly


Expected epo levels in uncomplicated anemia

Expected EPO Levels in Uncomplicated Anemia

Serum EPO→

Hematocrit→


Anemia of renal insufficiency

Anemia of Renal Insufficiency

  • Due to low EPO, shortened RBC survival, and altered iron kinetics.

  • Anemia begins to develop when CrCl is below 40ml/min/1.73M2

  • Common problem in elderly, can be improved with EPO, often given with po or iv iron

  • Example: 70yo woman, 5’2”, 110 lbs, Cr 1.6

    CrCl = 22ml/min/1.73M2


Anemia with impaired erythropoietin response in diabetic patients

ANEMIA WITH IMPAIRED ERYTHROPOIETIN RESPONSE IN DIABETIC PATIENTS

Arch Intern Med. 2005;165:466-469

  • Subjects: 722 patients with diabetes mellitus

  • Measurements/data collection: Clinical data, lab measurements including CBC, iron studies, EPO

  • Findings: 23.3% of patients were anemic. 77.4% of these had inappropriately low (ie, normal) EPO levels

  • EPO levels inappropriately low in 69% of anemic diabetic patients with apparently normal renal function. Most of these patients had albuminuria and only mild anemia.

  • CONCLUSIONS: Diabetic renal disease can cause mild anemia in the absence of renal impairment. Most diabetics with anemia could benefit from EPO treatment


Erythropoietin and aging

ERYTHROPOIETIN AND AGING

In 143 initially healthy subjects followed for 8-30 years, serum erythropoietin levels rose steadily with age, while hemoglobin levels remained constant or declined slightly.

This suggests that older individuals are more dependent on EPO to maintain the Hgb, and are at greater risk for anemia if there is even slight impairment in EPO production.

Ershler et al, J Am Geriatr Soc 2005;53:1360


Hyperregenerative anemia1

Hyperregenerative anemia

Blood loss

Hemolysis

Immune

Mechanical/microangiopathic

Hereditary (hemoglobinopathy, membrane defect, enzyme deficiency)

Acquired membrane defect (PNH, spur cells)

Infection (malaria, Clostridia, babesiosis)


Hemolytic anemia laboratory evaluation

Hemolytic anemia – laboratory evaluation

  • Blood smear (fragments, spherocytes, sickle cells, malaria, etc)

  • Nonspecific indicators of hemolysis: LDH, bilirubin

  • Direct Coombs test

    • Warm antibody = IgG  C3

    • Cold antibody = C3 only (cold agglutinin)

  • Indicators of intravascular hemolysis: haptoglobin, urine hemosiderin, plasma or urine hemoglobin

  • Other: Hgb electrophoresis, rbc enzyme levels, G6PD, osmotic fragility, PNH testing etc


Indications for bone marrow biopsy

INDICATIONS FOR BONE MARROW BIOPSY

  • Retic index not appropriately increased

  • No evidence of iron/B-12/folate deficiency, renal failure, endocrinopathy, inflammation or other low EPO state

  • Poor response to EPO, iron or vitamin replacement

  • WBC/plts/diff abnormal, monoclonal gammopathy, or other peripheral blood evidence of marrow disorder

  • Would you treat leukemia/MDS or other neoplastic disorder if you found it?


Algorithm for evaluation of anemia

ALGORITHM FOR EVALUATION OF ANEMIA

ANEMIC PATIENT

Retic index

Hyper-regenerative

Hypo-regenerative

Evaluate for hemolysis

and bleeding

Rule out treatable

nutritional deficiency,

endocrinopathy, etc

Epo level

Low-EPO

High-EPO

Continue EPO

Trial of EPO

Consider BMBx

Response

No

response


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