The correct diagnosis of anemia can often be determined by combining a thorough history and physical examination with review of the CBC, concentrating particularly on the MCV and RDW, along with review of the reticulocyte count and the peripheral blood smear.

History and Physical Examination

Anemia can be a primary disorder of the erythron or secondary to other systemic processes, thus a careful history and physical examination provide valuable insight into the potential cause. Fatigue often accompanies anemia, but it is very nonspecific and may be related to systemic illness. Nonetheless, determining the concomitant presence of a systemic inflammatory disorder, infection, or malignancy that may be associated with fatigue can be critical in determining the underlying causes of anemia in both adults and children. The medical history may also be quite informative. For example, a history of diabetes mellitus can be associated with significantly impaired renal production of erythropoietin, even in the setting of only a mildly elevated creatinine level. Because certain medications may be associated with BM depression or, alternatively, the development of autoimmune hemolytic anemia, all pharmacologic agents, including those prescribed and over the counter, including alternative medicines, should be reviewed. Occupational history is occasionally relevant, as in the case of individuals, such as welders, who might have been exposed to lead or other potentially BM-toxic agents. Social history can be important. A history of intravenous drug use might suggest the possibility of virally transmitted diseases, such as human immunodeficiency virus (HIV), which may be associated with anemia. Dietary history is also very important, particularly in young and elderly individuals with anemia. The finding of pica in adults (most commonly ice chips or cornstarch) is well known to be associated with iron-deficiency anemia. Ingestion of paint chips may suggest the need to investigate the possibility of toxic lead ingestion. A family history of anemia is highly relevant in the evaluation of children with anemia. However, it is also relevant in adults because certain congenital anemias, such as milder forms of sickle β+-thalassemia and  hereditary spherocytosis, occasionally first become clinically apparent in adulthood.

The significance of pallor on physical examination is in many ways similar to the historic feature of fatigue: it is a common but nonspecific finding. More specific findings may be found in certain types of anemia. For example, angular cheilitis (cracking at the edges of the lips) and koilonychia (spooning of the nails) may accompany iron-deficiency anemia. Splenomegaly may be present in patients with anemia arising from a wide variety of different causes. When present early in life, it is suggestive of a congenital hemolytic anemia, such as thalassemia, sickle cell disease, or hereditary spherocytosis. When found for the first time later in life, splenomegaly may indicate an acquired disorder, such as autoimmune hemolytic anemia, lymphoproliferative disease, or a myeloproliferative disease such as myelofibrosis. Other physical findings can also sometimes provide insight relevant to the investigation of anemia when combined with historical features and laboratory data. Although anemia itself may lead to the presence of systolic cardiac murmurs, the finding of an increased cardiac murmur in an anemic patient with a prosthetic aortic valve and new microangiopathic change on peripheral smear may indicate that investigation into the possibility of perivalvular leak or prosthetic dysfunction is in order. Finally, because neurologic manifestations can accompany or even predate the anemia associated with vitamin B12 deficiency, findings such as loss of vibration or position sense in the extremities may be relevant.

Reticulocyte Count

As a marker of RBC production, the reticulocyte count provides essential information in directing the initial investigation of anemia. Modern flow cytometers accurately determine the reticulocyte count using fluorescent probes that bind to the residual ribonucleic acid present in newly released RBCs. These measurements are useful, accurate, and reflect the state of erythropoiesis. However, when significant numbers of nucleated RBCs or nuclear debris are present in the peripheral blood, this diagnostic accuracy declines, and manual counting methods are generally preferable.

When the reticulocyte count is reported as a percentage, it needs to be adjusted for the total number of RBCs present. This correction can be made by multiplying the reticulocyte count by the patient’s hematocrit divided by an age- and sex-appropriate normal hematocrit. No such correction is necessary when the reticulocyte count is reported as an absolute number or when it is converted to an absolute number by multiplying the percentage by the RBC number (in RBC/μL).

In the absence of anemia, the normal absolute reticulocyte count is between 25,000 and 75,000/μL. In the presence of anemia, an absolute reticulocyte count of less than 75,000/μL is indicative of a hypoproliferative process, and an absolute reticulocyte count of greater than 100,000/μL is indicative of hemolysis or an appropriate erythropoietic response to blood loss (see Table 1). Reticulocyte counts between 75,000 and 100,000/μL require interpretation in the context of other available clinical data, including the severity of anemia present.

Table1. Usefulness of the Reticulocyte Count in the Diagnosis of Anemia ^a

Mean Corpuscular Volume and Red Blood Cell Distribution Width From the Complete Blood Count Automated cell counters provide a wealth of information regarding the size, shape, and hemoglobin content of RBCs. The two parameters most useful in classifying anemia are the MCV and the RDW. MCV is reported in femtoliters (fL) and reflects average cell size. RDW is often reported in percent and represents the standard deviation of RBC volume divided by the mean volume. It reflects the variation in cell size in the population of RBCs. These two parameters are useful because relatively reproducible changes in the MCV and RDW are associated with certain types of anemia (Table 2). The MCV and RDW can significantly narrow the differential diagnosis, particularly when combined with the reticulocyte count (Table 3).

Table2. Usefulness of the Mean Corpuscular Value and Red Blood Cell Distribution Width in the Diagnosis of Anemia

Table3. Combining the Reticulocyte Count and Red Blood Cell Parameters for Diagnosis

SYSTEMATIC APPROACH TO THE DIAGNOSIS OF ANEMIA

Integration of historic features and physical findings with thoughtful review of the results of the automated complete blood cell count and peripheral smear often significantly narrows down the differential diagnosis of anemia. For example, a patient who has had a gastric bypass eating a normal diet who presents with gradual onset of fatigue accompanied by the more recent onset of distal paresthesias and a finding of decreased vibration sense in the setting of anemia with significantly elevated mean corpuscular volume and red blood cell (RBC) distribution width values and numerous six-lobed polymorphonuclear leukocytes on peripheral blood smear almost certainly has vitamin B12 deficiency. This is suggested even before the return of specific laboratory testing because of the relatively narrow differential diagnosis for megaloblastic anemia and the fact that neurologic abnormalities are not associated with folate deficiency. For the purposes of diagnostic efficiency, the rewards of correlation of historic features and physical findings with a careful review of the peripheral blood smear cannot be overstated.

Special stains of the peripheral blood smear can be helpful in elucidating the cause of anemia. If there is significant nuclear debris present, the reticulocyte count obtained by automated methods can be inaccurate. In such cases, manual counting after staining with new methylene blue, which stains residual ribonucleic acid (RNA) in reticulocytes, permits accurate enumeration. If bite cells are detected on peripheral smear, supravital staining with methyl crystal violet can reveal Heinz bodies. These are aggregates of denatured hemoglobin reflecting an oxidative insult, most commonly caused by glucose-6-phosphate dehydrogenase deficiency or, less frequently, by the presence of an unstable hemoglobin (see Fig. 1H).

Several commonly encountered findings can be seen in RBCs on the peripheral blood smear (Table 3 and Fig. 1). Whereas microcytic, hypochromic RBCs are suggestive of iron-deficiency anemia or thalassemia (see Fig. 1F) macrocytic RBCs with ovalocytes (oval RBCs) are suggestive of megaloblastic anemias (see Fig. 1G). Some findings reflect organ dysfunction, such as echinocytes (burr cells) in uremia (see Fig. 1R) or acanthocytes (spur cells) in severe liver disease (see Fig. 1S), although acanthocytes may also be seen in rare conditions such as abetalipoproteinemia. Target cells may be seen in cases of liver disease but may also be present in hemoglobinopathies, including sickle cell disease and thalassemia (see Fig. 1W). The presence of schistocytes or RBC fragmentation often reflects systemic disease, such as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), or hemolytic uremic syndrome (HUS) (see Fig.1P). Finding spherocytes on a smear is suggestive of autoimmune hemolytic anemia or hereditary spherocytosis (see Fig. 1H). Occasionally, the clue to the correct diagnosis of a systemic illness comes in the form of the observation of intraerythrocytic inclusions, such as malarial or babesial forms, and examination of a thick blood smear may be useful for the diagnosis of these disorders when a low parasite burden is suspected.

Table3. Features of the Peripheral Blood Smear

Fig1. USEFUL PERIPHERAL BLOOD AND RED BLOOD CELL FEATURES IN THE EVALUATION OF ANEMIA. (A) Normal red blood cells (RBCs). Note the central pallor is one-third the diameter of the entire cell. (B) Rouleaux formation is indicative of increased plasma protein. (C) Agglutination indicates an antibody-mediated process such as cold agglutinin disease. (D) Polychromatophilic cell. The gray-blue color is attributable to RNA and the cell is equivalent to a reticulocyte, which must be identified with a reticulocyte stain. (E) Basophilic stippling. This also is attributable to increased RNA caused either by a left shift in erythroid cells or lead toxicity. (F) Hypochromic microcytic cells typical of iron-deficiency anemia. Note the widened central pallor and the “pencil” cell in the lower left. (G) Macroovalocyte as can be seen in either megaloblastic anemia or myelodysplastic syndrome. (H) Microspherocytes typical of hereditary spherocytosis. (I) Elliptocytes (ovalocytes) from a patient with hereditary elliptocytosis. (J) RBC fragments from thermal injury (burn patient). (K) Nucleated RBC. (L) Howell-Jolly bodies indicative of splenic dysfunction or absence. (M) Pappenheimer bodies from a patient with sideroblastic anemia. (N) Cabot ring, as can be seen in megaloblastic anemia or MDS. (O) Malarial parasites (Plasmodium falciparum). (P) Schistocyte typical of a microangiopathic hemolytic anemia. (Q) Tear-drop form indicates marrow fibrosis and extramedullary hematopoiesis. (R) Echinocyte (Burr cell) with rounded edges. (S) Acanthocyte (spur cell) with more irregular pointed ends. This was from a patient with neuroacanthocytosis. They can also be seen in patients with liver disease and lipid abnormalities. (T) “Bite” cell from a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency. (U) Sickle cell, from a patient with homozygous sickle cell disease. (V) Hemoglobin C crystal. (W) Target cells. (X) Hemoglobin C disease. Note that the RBC in center has condensed hemoglobin at each pole. (Y) Heinz body preparation (supravital stain) from a patient with G6PD deficiency. Note that the cells to the right have increased precipitated hemoglobin.

Examination of the Peripheral Blood

Smear Despite the development and availability of more sophisticated diagnostic testing, review of a well-made peripheral blood smear remains one of the most informative and rewarding diagnostic procedures. It offers the chance to confirm the findings of the automated CBC count, which can be inaccurate in the presence of nucleated RBCs or rouleaux formation. Review of the blood smear also allows for evaluation of other cell lineages, which might suggest a primary BM or infiltrative disease. For example, the finding of hypersegmented neutrophils suggests a megaloblastic process, and this morphologic abnormality can be seen in the blood smear before there are significant changes in the hemoglobin or MCV (see box on Systematic Approach to the Diagnosis of Anemia). Also, only the blood smear reveals the unique morphologic changes occurring with several of the various hemolytic disorders.

Bone Marrow Examination

Bone marrow aspiration and biopsy permit evaluation of cellular morphology and BM architecture, respectively. Special stains, flow cytometry, cytogenetic analysis, fluorescence in situ hybridization (FISH), and molecular testing performed on the BM can provide a wealth of diagnostic information. Because of the discomfort involved in the procedure, however, careful consideration should be given to deter mining the array of tests required, so that repeated BM aspirates or biopsies need not be performed. If there is any consideration of the possibility of myelodysplasia, leukemia, or lymphoma, an aliquot of anticoagulated aspirate should be set aside at the time of the initial procedure that can be sent, if necessary, for flow cytometry or cytogenetics after review of the aspirate smear. It should be noted that even when properly performed, difficulty obtaining a BM aspirate is commonly observed in certain situations, including myelofibrosis, erythroblastic leukemia (M6), and hairy cell leukemia. In these cases, touch preps of the BM biopsy may help expedite diagnosis.

Diagnostic uncertainty in the setting of hypoproliferative anemia is an indication for BM biopsy. Hematologic disorders such as myelodysplasia, leukemia, lymphoma, or myeloma may be identified. Myelodysplasia in the marrow classically includes megaloblastic change and nuclear budding in maturing erythroblasts, as well as morphologic abnormalities in other lineages, such as hypolobated megakaryocytes and hypogranulation of the myeloid lineage. A variety of infiltrative (myelophthisic) processes may be observed. These include malignancies such as small-cell lung, breast, and prostate cancers, which frequently can appear in advanced stages with BM involvement. Alternatively, granulomas may be present, suggesting the possible presence of mycobacterial disease. In children, disseminated neuroblastoma and rhabdomyosarcoma occasionally can appear as a myelophthisic anemia.

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هرمون الذكورة يفاقم عدوى خطيرة تهدد حياة الرجال

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ما الدور الذي يلعبه الـ AI في "حروب أميركا"؟

المزيد

مواضيع ذات صلة

Comparison of Etiologies of Anemia in Adults and Children

Mechanisms of Anemia

Peptic Ulcer Disease

Nosology of Hemoglobinopathies

Infections of the Urinary Tract: Types of Infection and Their Clinical Manifestations

Toxic Goitre

Infections of the Urinary Tract : Pathogenesis

Infections of the Urinary Tract : Etiologic Agents

Infections of the Sinuses

Pathology of Acromegaly

clinical Features of Hyperprolactinaemia and Prolactinomas

Infections of the Ears : Diseases, Epidemiology, and Etiology of Disease