Problems in Family Practice

The Common

Ralph 0. Wallerstein, MD San Francisco, C alifornia

Anemia is a common clinical problem requiring precise diagnosis of its Stippled cells are young cells, still con­ underlying etiology in order to provide effective . Most com­ taining RNA like reticulocytes, but the mon anemias are characterized by discrete hematologic patterns. The RNA is denatured and precipitated by most useful laboratory studies in most instances are red cell indices, Wright’s stain, unlike the reticulocytes , reticulocyte count, platelet count, serum and total whose RNA is precipitated only by supravital stain. Prominent stippling is iron binding capacity. This paper presents simple guidelines for the seen in or rational use of common laboratory tests in the diagnostic assessment minor. Howell-Jolly bodies are nuclear of anem ia. remnants and are characteristic of sple- nectomized patients. Tables 3 and 4 summarize the important elements in is a common clinical find­ Laboratory Work-up of Anemia the blood films of anemic patients and ing that requires explanation. Before When history and physical examina­ their diagnostic significance. appropriate therapy can begin, its eti­ tion have not explained the anemia, The reticulocyte count is a most ology must be established. In practice the following baseline data should be useful test in the evaluation of anemia, all anemias are due to one, or some­ obtained before ordering other tests: as illustrated in Table 5. A very high times a combination of the following (1) Red cell indices, (2) A look at the reticulocyte count (50 percent or mechanisms: blood film, (3) Reticulocyte count, (4) more) means autoimmune hemolytic 1. , ie, blood loss Platelet count, and (5) Serum iron and anemia when the Coombs’ test is posi­ 2. Marrow failure total iron binding capacity. tive; on very rare occasions it means a) relative — anemias of chronic Red cell indices (Table 2) are usual­ pyruvate kinase deficiency, a red cell disease ly supplied automatically if a Coulter enzyme defect associated with a nega­ b) absolute — , S is used. Sometimes they make an im­ tive Coombs’ test. Moderate elevation myelofibrosis, leukemia, lym­ mediate diagnosis. MCV above 120 of the reticulocyte count (ten to 20 phoma, myeloma usually means or megalo­ percent) usually means hemolysis but c) ineffective erythropoiesis — blastic anemia. MCV above 110 strong­ occasionally indicates other underlying refractory normoblastic ane­ ly argues against anemia of chronic dis­ problems. Acute blood loss can bring mia ease or acute blood loss. MCV below the count this high and patients with 3. 100 is not pernicious anemia, and pernicious anemia or folic acid defi­ 4. MCV below 80 is either iron deficien­ ciency may have counts at this level or Table 1 gives the approximate fre­ cy or thalassemia minor. MCHC above higher a week after specific therapy quency of anemias in practice. These 36 means hereditary , was started; their counts, however, frequencies change, of course, in a uni­ and MCHC below 32.5 usually means show an orderly rise, peak at one week versity setting and in subspecialty iron deficiency or thalassemia minor. and decline at two weeks, unlike a practice where hemolytic anemias and Inspection of the blood film should hem olytic anemia, whose counts, the anemias of leukemia, lymphoma, include a specific check for hypochro­ while fluctuating, stay high. If the re­ and myeloma are more common. mic microcytes, oval macrocytes, ticulocyte count is under five percent, spherocytes, , target cells, the patient probably does not have hypersegmented P.M.N.’s and abnor­ hemolytic anemia. Very low counts, mal white blood cells. Spherocytes especially in absolute terms, are char­

From the Departments of and indicate or acteristic of aplastic anemia and perni­ mical P a th o lo g y , U n iv e rs ity o f C a lifo rn ia autoimmune hemolytic anemia. Schis­ cious anemia. ennce, San Francisco General Hospital, San Francisco, C a lifo rn ia . R eq u e sts f o r re p rin ts tocytes (contracted cells, helmet cells, The platelet count is also a useful snould be addressed to Dr. Ralph O. Walier- laboratory test in the initial workup of s'ein, 3838 California Street, Suite 707, San triangular cells) usually suggest damage Francisco, C a lif 94118. to blood vessels by fibrosis or cancer. anemia. (Table 6) A low platelet count

THE JOURNAL OF FAM ILY PRACTICE, VOL. 2, NO. 3, 1975 in an anemic patient, who does not caused by iron deficiency, and finding and serum iron may even be mid.,,, have frank thrombocytopenic purpura, a low serum iron but high TIBC means ing. When a patient with p e r n S points to the marrow as the site of dis­ iron deficiency. If the serum iron is anemia is treated with vitamin B ease. In other words, this is not just not low, the patient does not have iron the serum iron plummets to very low iron deficiency or anemia of chronic deficiency; if the serum iron is low and levels and stays low for weeks, even disease, but possible leukemia, aplastic the TIBC is also low, one has learned with ample iron states. anemia, or some other malignancy. nothing because many of the anemias The Schilling test is not w orth do­ Hypersplenism may also present with of chronic disease may have a very low ing in patients with MCV below 100 moderate anemia, platelet count - of serum iron — as low as 10 meg/100 ml or in patients with elevated WBC and 70,000 and white count under 2,000. as seen in hemochromatosis, and often high reticulocyte counts or sphero­ The serum iron and total iron bind­ in megaloblastic anemias. cytes. Vitamin B, 2 level should, 0f ing capacity is worth doing early in the Some hematologic tests are fre­ course, not be done after a Schilling work-up because so many anemias are quently misapplied. The serum iron/ test. The Coombs’ test is usually not TIBC (Table 7) should not be done in worth doing with a normal reticulo­ a patient with fever or be­ cyte count. The osmotic fragility is Table 1. Relative Incidence of useful only in the diagnosis of heredi­ Anemia per 1,000 cause it will always be low. It should also not be done in a patient With a tary spherocytosis. It is no longer use­ high reticulocyte count because iron ful in the work-up of patients with Anem ia o f chronic disease 10 deficiency is not the patient’s problem hypochromic anemia. Iron deficiency 10 Sickle cell anemia 2 Black population Pernicious anemia .4 Table 4. Abnormal Red Cells on the Blood Film Hereditary anemia .2 Leukemia .05 Abnormal Cells Possible Causes M yeloma .03 Aplastic anemia .004 Spherocytes Hereditary spherocytosis Autoimmune hemolytic anemia Acute alcoholism Table 2. Red Cell Indices Hb C disease Burns ABO incompatibility MCV Oval cells Ovalocytosis Above 120 Liver disease Megaloblastic anemia Megaloblastic anemia Myelofibrosis Refractory normoblastic anemia Above 110 NOT anemia of chronic disease, chronic blood Microangiopathic cells Thrombotic thrombocytopenic purpura loss (fragmented, helmet M etastatic cancer (stomach, pancreas, ovary) NOT pernicious anemia Below 100 cells, etc) Postcardiotomy Below 80 Iron deficiency Calcific aortic stenosis (?) Thalassemia minor Drugs (± G6PD deficiency) Hemolytic-uremic syndrome of infants MCHC Acute nephritis (rare) Above 36 Hereditary spherocytosis Malignant hypertension (rare) Uremia Below 32.5 Iron deficiency Thalassemia minor Target cells Jaundice Thalassemia Iron deficiency Table 3. Blood Film Splenectomy Hem oglobi nopath ies

Look fo r: S tippling Lead poisoning Thalassemia minor Hypochromic microcytes Several severe anemias Oval macrocytes Spherocytes Spur cells Cirrhosis Schist ocytes Acanthocytosis Target cells PK deficiency

Hypersegmented P.M.N.'s Howell-Jolly bodies Splenectomy Abnormal WBC Megaloblastic anemia

2 1 8 THE JOURNAL OF FAM ILY PRACTICE, VOL. 2, NO. 3,1975 electrophoresis is not worthwhile in ic anemia, such as hereditary sphero­ The anemia of cancer is sometimes patients with low platelets and white cytosis, can increase its output by six complicated by blood loss, sometimes cells or normal looking red blood cells. to ten times. it features contracted cells, schisto- Other abnormal findings have to do cytes, a sign of marrow invasion. Patterns of Common Anemias with impaired protein synthesis result1 Ineffective erythropoiesis or intra­ The most common anemias have ing in low transferrin, erythropoietin, medullary hemolysis refers to a phe­ their own hematologic patterns.1' 5 and albumin levels. The serum iron is nomenon that combines greatly in­ 1 iron deficiency anemia. This is usually also low because of impaired creased production of erythroblasts characterized by an MCHC below 32.5 reutilization of iron, that is, the reticu­ with destruction of these nucleated and MCV usually below 80, serum iron loendothelial cells do not readily re­ red cells right in the marrow, permit­ below 50, TIBC above 350, and an ab­ lease iron obtained from decaying red ting only few, and often misshapen sent marrow hemosiderin. In blood cells. Another example of the relative and poorly made red cells to reach the loss of recent onset (ie, within two to unavailability of iron is an increase in blood stream. Pernicious anemia is the four weeks) these laboratory devia­ red cell protoporphyrin in these condi­ best known example of this mecha­ tions from normal may not as yet have tions. nism; the also show this occurred. There are some subtle differences form of dyserythropoiesis. In the so- 2. Thalassemia minor must be dif­ between these entities. Anemia associ­ called refractory normoblastic anemias ferentiated from iron deficiency ane­ ated with cirrhosis is primarily he­ or sideroachrestic anemias, intramedul­ mia because both conditions feature molytic, frequently with target cells; lary hemolysis is a prominent feature hypochromic, microcytic red cells; spur cells are seen occasionally; the re­ and it is associated with characteristic thalassemia minor is a frequent diagno­ ticulocytes are usually slightly ele­ ring sideroblasts in the marrow. sis in those population areas where vated. 4. Hemolytic anemia. Most chronic many people of Mediterranean, espe­ Anemia of azotemia is primarily hemolytic anemias have an elevated re­ cially Italian, or Cantonese Chinese or­ hypoplastic; because of the striking de­ ticulocyte count, and slightly elevated igin reside. It is always a mild anemia; crease in the erythropoietin, few red indirect bilirubin; they may have an the hemoglobin is above 9 gm and usu­ cells are made. Sometimes a few burr elevated LDH, and an absent haptoglo­ ally between 10 and 13 gm, but the cells are seen on the peripheral blood bin. These general signs of hemolysis red cell count is often higher than nor­ film. Burr cells must be distinguished should be obtained first. After first es­ mal. The MCHC is only slightly low from spur cells. Spur cells, which are tablishing that hemolysis is present, but the MCV is well below 80 and may characteristically seen in jaundiced pa­ one goes on to specific tests, such as be below 60. The diagnosis of thalasse­ tients with liver disease, have a few osmotic fragility to establish heredi­ mia minor may be established definite­ long spikes emanating from the cell; tary spherocytosis, Coombs’ test to es­ ly by finding an elevated hemoglobin the spike is longer than the base is tablish autoimmune hemolytic anemia, A, or hemoglobin F on hemoglobin wide. Burrs are short; the bases are hemoglobin electrophoresis for diagno­ electrophoresis. wider than the length of the projec­ sis of , and enzyme 3. Marrow failure. In absolute mar­ tions. studies for diagnosis of hereditary non- row failure, the normal myeloid tissue has been replaced by fat (aplastic ane­ mia), fibrosis (myelofibrosis), or malig­

nancy (lymphosarcoma, multiple mye­ Table 5. Reticulocytes in Anemia loma, or leukemia). The platelet count and absolute reticulocyte count are usually low. Morphologically abnormal Relative Count Type of Anemia Absolute Count* white cells help in the diagnosis. A bone marrow aspirate or biopsy is es­ Over 1,000,000/cu mm sential for specific diagnosis. Over 50% Autoimmune hemolytic anemia Pyruvate kinase deficiency Relative failure is exemplified by the anemias of chronic disease.' In gen­ 10 ± 5% Hem olytic anemias 2-500,000/cu mm eral, all these conditions have in com­ Acute blood loss mon normal red cell morphology. Escape from depression White cells and platelets are normal in eg, chloramphenicol number and appearance, and reticulo­ following specific therapy cytes are not elevated. The serum iron (eg, iron or vitam in B ,,) is low, and TIBC is not elevated. This Under 5% Probably not hemolytic anemia Under 100,000/cu mm group is characterized by relative mar­ row failure, ie, a moderately shortened Under 5% Primary marrow failure Under 50,000/cu mm red cell survival with only suboptimal Megaloblastic anemia compensatory increase in marrow ac­ tivity. The red cell survival is often 1 ± .59 Normals 25-75,000/cu mm one-sixth normal, but the marrow only compensates 1 Vi to two times. By con­ trast, marrow in chronic blood loss, or ‘ Obtained by multiplying the percent of reticulocytes by the red cell count. marrow in an uncomplicated hemolyt­

2 1 9 THE JOURNAL. OF FAM ILY PRACTICE, VOL. 2, NO. 3, 1975 spherocytic hemolytic anemia. oval macrocytes, hypersegme;ed Table 6. Platelets The are seen polymorphonuclear cells, the ch.ac' mostly in the black population; target teristic bone marrow findings, am?116 cells are common to all hemoglobin­ appropriately low vitamin B, ’ 0r)lic Below 150,000: opathies. Red cell indices are usually acid serum levels. Hypersplenistis Marrow involved normal. Sickle cell anemia is the most a syndrome which is usually second Megaloblastic anemia common, but other variants must be to some other disease, such as cirri’® considered. When red cell morphology of the liver, rheumatoid arthriticor Aplastic anemia is normal, hemoglobinopathy is un­ Gaucher’s disease. It is character Malignancy likely. by a large spleen, “empty” bloocfnd Hypersplenism 5. Megaloblastic anemia. This ane­ full marrow without morphologii.ab' mia is easily recognized by the large normalities of the red cells, white d*s’ or platelets. With these simple guidelines.^ Table 7. work-up of a patient with aneif is usually neither time-consuming ncex‘ pensive and is gratifying to the ^ s‘' Serum Iron TIBC cian in terms of precise diagnoS anemia as the basis for effective;aIe of the patient. Low Iron deficiency anemia Infection Infe ction Collagen disease References Cancer Rheumatoid arthritis 1. Adamson JW, Eschbach J, mcfl Renal disease Cancer CA: The kidney and erythropoiesis.'m J Med 44:725-734, 1967 Rheumatoid arthritis Hypoproteinemia 2. Cartwright GE, Lee GR: The , Collagen disease mia of chronic disorders. Br J Hat1310 21:147-152, 1971 Pregnancy 3. Eichner ER, Hillman RS: Th&olu. tion of anemia in alcoholic patients. m J Serum levels in the afternoon Med 50:218-232, 1971 4 . K u r n ic k J E , W ard HP, Picke,. : High Iron deficiency Mechanism o f the anemia of chronicIS0rh ders: Correlation of hematocrit valuwl Pregnancy a lb u m in , v ita m in B j 2 , tra n s fe rrin , an,q7« The p ill stores. Arch Intern Med 130:323-326^ 5. R a p a p o rt S I: I n tro d u c tio n to!j ma tology. New York, Harper & Row, 19

220 THE JOURNAL OF FAM ILY PRACTICE, VOL. 2, NO. 3,1975