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Macrocytosis Workup

  • Author: Vincent E Herrin, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
Updated: Jul 14, 2016

Laboratory Studies

A complete blood count (CBC) with platelet count is indicated. The hemoglobin concentration and hematocrit may help guide diagnosis and determine the presence and severity of anemia. White blood cell (WBC) and platelet counts may be decreased in primary marrow disturbances. Mean cell volume (MCV) is a calculated average red blood cell (RBC) volume. An MCV greater than 100 fL is macrocytosis by definition. Because evaluation of RBC size is key to the diagnosis of an anemia, the MCV is considered to be the most important of the RBC indices.

Peripheral blood smear morphology may be helpful. Round macrocytes suggest liver or marrow infiltrative disease, whereas oval macrocytes tend to suggest a megaloblastic disorder. This study provides clues to the etiology of macrocytosis. Hypersegmented neutrophils and macro-ovalocytes strongly suggest megaloblastic anemia. Nucleated RBCs, teardrop cells, decreased or large platelets, and immature WBCs are often present in myelophthisic disease and leukemias.

The reticulocyte count helps determine whether hemolysis is present; it can also indicate malfunctioning bone marrow. Marked reticulocytosis (>4%) is to be expected in hemolytic anemias. A reticulocyte count lower than 1% indicates inadequate marrow production. The reticulocyte count must be corrected for the degree of anemia present.

If the reticulocyte count is elevated, a Coombs test should be performed to aid in identifying the cause of hemolysis. A positive direct Coombs test finding is to be expected in autoimmune hemolytic anemias, hemolytic transfusion reactions, and some drug-induced anemias (eg, those caused by penicillin, methyldopa, some cephalosporins, or sulfonamides).

Lactate dehydrogenase (LDH) levels are elevated in both intravascular and extravascular hemolysis, including the ineffective erythropoiesis that occurs in megaloblastic anemias.

Because the haptoglobin binds free hemoglobin, a low or absent haptoglobin level indicates intravascular hemolysis.

If macro-ovalocytes and hypersegmented neutrophils are noted on peripheral smear, the vitamin B-12 level may be low. If folate deficiency is the cause of the macrocytosis, the RBC folate level likely will be decreased. As in vitamin B-12 deficiency, peripheral smear may reveal hypersegmented neutrophils and macro-ovalocytes.

Serum total homocysteine levels are almost always elevated in patients with folate deficiency because folate is required in the remethylation step that converts homocysteine to methionine.[18] Serum methylmalonic acid and homocysteine levels are increased early in vitamin B-12 deficiency, even before hematologic manifestations or decreases in B-12 levels are noted.[19]

Serum unconjugated bilirubin is expected to be elevated in hemolysis.

If vitamin B-12 deficiency is the cause of the macrocytosis, the serum vitamin B-12 level likely will be decreased. A Schilling test was previously considered the criterion standard for further investigation of a low vitamin B-12 level. However, many institutions no longer offer the Schilling test. Alternative tests to the Schilling test are antibodies to parietal cells and intrinsic factor antibodies.

A serum folate level may be obtained,[20] although an RBC folate level is more reliable because it reflects the level over the lifespan of the RBC.

A study designed to identify the underlying causes of macrocytosis by analyzing hematological features concluded that complete medical histories, analysis of red cell parameters, and peripheral blood smears were simple and inexpensive tools that can be helpful in settings with limited resources.[21]


Bone Marrow Biopsy and Aspiration

Bone marrow biopsy and aspiration are performed to determine whether the marrow is functioning adequately and also may reveal replacement of marrow with tumor, granuloma, or fibrosis. The bone marrow should be obtained before any vitamin B-12 or folate therapy or blood transfusion because megaloblastic changes may reverse rapidly.

The bone marrow in megaloblastic anemias is usually hypercellular, with all cell lines proliferating. Marked erythroid hyperplasia may occur to the point at which the myeloid-erythroid ratio is reversed. Nuclear-chromatin dissociation with a young-appearing nucleus and abundant mature-appearing cytoplasm may occur. Granulocytic hyperplasia with giant metamyelocytes and bands is often noted.


Histologic Findings

On peripheral blood smear, large RBCs are evident. Depending on the etiology of the macrocytosis, peripheral smear may reveal nucleated RBCs, target cells, RBC fragments, hypersegmentation of neutrophils, immature WBCs, large platelets, or pancytopenia.

Depending on the etiology of the macrocytosis, the marrow may reveal hypercellularity, megaloblastic changes, fibrosis, infiltration by tumor or granulomatous disease, leukemic changes, or erythroid hyperplasia.

Contributor Information and Disclosures

Vincent E Herrin, MD, FACP Professor of Medicine, Division of Hematology and Medical Oncology, Director, Medicine Residency Program, University of Mississippi School of Medicine

Vincent E Herrin, MD, FACP is a member of the following medical societies: American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Society of Clinical Oncology, Southern Society for Clinical Investigation, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.


Russell Burgess, MD (Retired) Chief, Division of Hematology/Oncology, Eastern Carolina Internal Medicine, PA

Russell Burgess, MD is a member of the following medical societies: American College of Physicians and American Medical Association

Disclosure: Nothing to disclose.

Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

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