clinical problem solvers normocytic anemia

JOHN R. BRILL, M.D., AND DENNIS J. BAUMGARDNER, M.D.

Am Fam Physician. 2000;62(10):2255-2263

See related patient information handout on normocytic anemia , written by the authors of this article..

Anemia is a common problem that is often discovered on routine laboratory tests. Its prevalence increases with age, reaching 44 percent in men older than 85 years. Normocytic anemia is the most frequently encountered type of anemia. Anemia of chronic disease, the most common normocytic anemia, is found in 6 percent of adult patients hospitalized by family physicians. The goals of evaluation and management are to make an accurate and efficient diagnosis, avoid unnecessary testing, correct underlying treatable causes and ameliorate symptoms when necessary. The evaluation begins with a thorough history and a careful physical examination. Basic diagnostic studies include the red blood cell distribution width, corrected reticulocyte index and peripheral blood smear; further testing is guided by the results of these studies. Treatment should be directed at correcting the underlying cause of the anemia. A recent advance in treatment is the use of recombinant human erythropoietin.

Anemia is defined as a decrease in the circulating red blood cell mass to below age-specific and gender-specific limits. In normocytic anemias, the mean corpuscular volume (MCV) is within defined normal limits, but the hemoglobin and hematocrit are decreased. The MCV is also age-specific ( Figure 1 ) , 1 with normal values ranging from 70 femtoliter (fL) at one year of age to 80 fL at seven years and older. 2

Most patients with anemia are asymptomatic. Therefore, the condition is most often discovered by laboratory evaluation, usually on routine testing as part of the general physical examination or for reasons other than suspected anemia. Anemia should be considered a sign, not a disease. 3 It can be caused by a variety of systemic disorders and diseases, as well as primary hematologic disorders.

Approximately 4.7 million Americans have anemia. 4 Population-based estimates indicate that this condition affects 6.6 percent of males and 12.4 percent of females. The prevalence of anemia increases with age and is 44.4 percent in men 85 years and older. 5 Although the elderly are more prone to develop anemia, older age is not of itself a cause of the condition. 6

Normocytic anemias may be thought of as representing any of the following: a decreased production of normal-sized red blood cells (e.g., anemia of chronic disease, aplastic anemia); an increased destruction or loss of red blood cells (e.g., hemolysis, posthemorrhagic anemia); an uncompensated increase in plasma volume (e.g., pregnancy, fluid overload); or a mixture of conditions producing microcytic and macrocytic anemias.

It should be noted that in the initial stage, nearly all anemias are normocytic. The major primary causes of normocytic anemia are given in Table 1 .

Decreased Red Blood Cell Production

Anemia of chronic disease.

Anemia of chronic disease is the most common normocytic anemia and the second most common form of anemia worldwide (after iron deficiency anemia). 7 The MCV may be low in some patients with this type of anemia. The pathogenesis of anemia of chronic disease is multifactorial and is related to hypo-activity of the bone marrow, with relatively inadequate production of erythropoietin or a poor response to erythropoietin, as well as slightly shortened red blood cell survival.

Anemia of chronic disease is associated with a wide variety of chronic disorders, including inflammatory conditions, infections, neoplasms and various systemic diseases. The diagnosis of anemia of chronic disease is not usually applied to the anemias associated with renal, hepatic or endocrine disorders. Patients with these disorders may not display the hallmark ferrokinetic profile of anemia of chronic disease (i.e., decreased serum iron level, decreased transferrin level, or normal or elevated ferritin levels, all of which result in iron being present but inaccessible for use). 3 , 8 – 10

ENDOCRINE DEFICIENCY

Endocrine deficiency states, including hypothyroidism, adrenal or pituitary insufficiency, and hypogonadism, may cause secondary bone marrow failure because of reduced stimulation of erythropoietin secretion. Hyperthyroidism may also cause normocytic anemia. 3 , 9

RENAL FAILURE

Anemia occurs in acute and chronic renal failure. The anemia is usually normocytic but may be microcytic. In renal failure, anemia occurs in part because uremic metabolites decrease the lifespan of circulating red blood cells and reduce erythropoiesis.

Anemia secondary to uremia is characterized by inappropriately low erythropoietin levels, in contrast to the normal or high levels that occur with most other causes of anemia. To further confuse the presentation, serum iron levels and the percentage of iron saturation are often low, apparently because of negative acute-phase reactions. 10 Furthermore, the serum creatinine level and the degree of anemia may not correlate well. 3

OTHER CAUSES

Other causes of decreased red blood cell production include bone marrow infiltration, fibrosis, various myeloproliferative diseases and sideroblastic anemias. These uncommon disorders are generally diagnosed by bone marrow biopsy.

Increased Red Blood Cell Destruction or Loss

Hemolytic anemias.

Hemolytic anemias other than the alloimmune hemolytic anemias of newborns (e.g., Rh or ABO incompatibility) can be categorized as congenital or acquired ( Table 2 ) . 3 , 9 , 11 – 13

Congenital hemolytic anemias include the hemoglobinopathies (homozygous sickle cell disease [hemoglobin SS disease], heterozygous sickle hemoglobin C disease [hemoglobin SC disease]), red blood cell membrane disorders and red blood cell enzyme deficiencies. 11 , 12

Homozygous sickle cell disease is the most common cause of hemolytic normocytic anemias in children. Because of longevity, this disease is also becoming an increasingly prevalent cause of these anemias in adults. 11 – 13

Hereditary spherocytosis is the most common red blood cell membrane disorder. It usually presents in childhood with anemia, jaundice and splenomegaly. Pigment gallstones, delayed growth and dysmorphic features may occur. Hereditary elliptocytosis ranges from an asymptomatic carrier state to severe hemolytic anemia. 11 – 13

Red blood cell enzyme deficiencies include glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase deficiencies. More than 300 varieties of G6PD deficiency have been identified. The southern Mediterranean variety, referred to as “favism,” is best known, but the most common variant in the United States is a less severe X-linked disorder that affects 10 percent of black males. Persons with the U.S. variant may experience an acute, self-limited hemolytic episode after exposure to causes of oxidative stress, including sulfa drugs, nitrofurantoin (Furadantin), phenazopyridine (Pyridium) and antimalarial drugs. 11 , 12

Acquired hemolytic anemias include autoimmune hemolytic anemias, mechanical hemolysis and paroxysmal nocturnal hemoglobinuria. 12 Autoimmune hemolytic anemias primarily occur in persons older than 40 years. The most common and typically most severe of these anemias are those caused by warm-reactive antibodies. Autoimmune hemolytic anemias caused by cold-reactive antibodies most commonly follow Mycoplasma pneumonia or infectious mononucleosis.

Drugs that induce autoimmune hemolytic anemias include methyldopa (Aldomet), penicillins, cephalosporins, erythromycin, acetaminophen (e.g., Tylenol) and procainamide (Pronestyl).

Paroxysmal nocturnal hemoglobinuria generally presents as a chronic hemolytic anemia. Classic nocturnal hemoglobinuria is seldom seen. 12

UNCOMPENSATED BLOOD LOSS

Acute posthemorrhagic anemia occurs with gastrointestinal bleeding, bleeding from an external wound or, less obviously, retroperitoneal bleeding or bleeding into a hip fracture. A healthy young person would be expected to tolerate rapid loss of 500 to 1,000 mL of blood (10 to 20 percent of the total blood volume) with few or no symptoms, although about 5 percent of the general population would have a vasovagal reaction. 14 Indeed, healthy young persons at rest may tolerate an acute isovolemic reduction of hemoglobin volume to a level of 5 g per dL (50 g per L) without impairment of critical oxygen delivery. 15

HYPERSPLENISM

Hypersplenism leads to anemia only after the spleen reaches three to four times its normal size, as may occur in cirrhosis, chronic infections and myeloproliferative diseases. The anemia is primarily caused by the removal of red blood cells from the circulation, but increased destruction of red blood cells is usually a contributing factor. 16

Normocytic Anemia in Children

The prevalence of anemias caused by iron deficiency or lead toxicity continues to decline in the United States. 17 As a result, normocytic anemias are constituting a larger proportion of cases in the pediatric age group.

Iron deficiency, which in its early stages is usually characterized by a normal MCV, is still a common cause of mild normocytic anemia in children beyond the neonatal period. Other common childhood normocytic anemias are the result of acute bleeding, sickle cell anemia, red blood cell membrane disorders and current or recent infections (particularly in younger children). 2 , 17 Aplastic crises in patients of any age who have chronic hemolytic anemias are frequently precipitated by human parvovirus B19 infection. 2 , 12 , 13 , 18

Most anemias in children can be diagnosed with a basic work-up that includes a complete blood cell count (CBC), a corrected reticulocyte index, a peripheral blood smear and targeted studies of the peripheral blood (e.g., hemoglobin electrophoresis).

Although bone marrow examinations are generally unnecessary, one study found that when the basic laboratory studies and historical and physical evidence were unrevealing, bone marrow specimens yielded a specific diagnosis in 92 percent of children. 18 The most frequent diagnosis in this study was transient erythroblastopenia of childhood, a common, generally mild, self-limited red blood cell aplasia of unknown etiology. This entity must be distinguished from Blackfan-Diamond syndrome, a rare, usually macrocytic and probably genetic disorder of infants. Blackfan-Diamond syndrome is a congenital erythroid hypoplasia that usually does not spontaneously remit. 3 , 9

Physicians are sometimes inefficient in their evaluation of normocytic anemia, either ordering an excessive battery of tests or foregoing testing entirely in the belief that a cause is not likely to be found. 19 The first step in the evaluation of anemia is to correlate the finding of anemia with the information obtained from the patient's history and physical examination. In many instances, this approach allows a working diagnosis to be made and many disorders to be eliminated.

Most published algorithms for the diagnosis of normocytic anemia begin with an examination of the peripheral blood smear 20 or a corrected reticulocyte index. 2 , 9 , 21 The red blood cell distribution width is a measure of the variability of the size (anisocytosis) of the cells and is usually reported as a component of automated CBCs. Therefore, a practical and useful first step is to use the red blood cell distribution width to help categorize the normocytic anemia as heterogeneous (e.g., hemolytic anemia) or homogeneous (e.g., anemia of chronic disease). 2 In patients with a mild homogeneous normocytic anemia (hematocrit of 30 percent or greater) and a known chronic disease, anemia of chronic disease is highly likely, and bone marrow biopsy may not be necessary ( Figure 2 ) . 21

‘DRAW AND HOLD’ STRATEGY

Because the diagnosis of normocytic anemia usually proceeds in a step-wise fashion that begins with the corrected reticulocyte index and examination of the peripheral blood smear, a patient-friendly, cost-effective and time-efficient strategy is to use a “draw and hold” order for possible later testing. Most laboratories do not charge to hold tubes, and tests can usually be added up to one week after specimens are obtained. The physician should check with the local laboratory to determine the number and type of specimens that need to be obtained.

PERIPHERAL BLOOD SMEAR

The examination of the peripheral blood smear often yields diagnostic clues or confirmatory evidence. Easily recognized red blood cell findings related to normocytic anemias include the following: large polychromatic “shift cells,” which represent reticulocytosis; target cells, which may be found in liver disease; basophilic stippling, which may be present in hemolytic anemias; and mixtures of large and small red blood cells, which may suggest the presence of mixed microcytic and macrocytic disease processes (a finding that should be suggested by an elevated red blood cell distribution width).

Other findings include burr cells (uremia), spherocytes (hereditary spherocytosis, autoimmune hemolysis, G6PD deficiency), elliptocytes (hereditary elliptocytosis), schistocytes (microangiopathic processes), bite or blister cells (where all of the hemoglobin appears to be pushed to one side of the cell, G6PD deficiency) and nucleated red blood cells (hemolytic anemia, acute blood loss). These findings may be present in other anemias and in other conditions. 3 , 9 , 10

The corrected reticulocyte index, along with the white blood cell and platelet counts, indicates whether the bone marrow is functioning appropriately. The corrected reticulocyte index should be elevated in patients with an acute anemia but a competent bone marrow.

ILLUSTRATIVE CASES

Case 1 . A 50-year-old woman who had been taking aspirin for a flare of rheumatoid arthritis presented with mild epigastric pain. A CBC was ordered, and a guaiac test for occult blood was performed. The guaiac test was negative.

The CBC revealed a normocytic anemia (hemoglobin count, 11 per mm 3 [11 × 10 6 per L]; hematocrit, 33 percent [0.33]; MCV, 84 fL), with a red blood cell distribution width of 41 fL (normal range: 39 to 47 fL). A reticulocyte count and “draw and hold” specimens were ordered. The corrected reticulocyte index was 1.0 percent.

Ferritin and serum iron levels were obtained from the stored specimens. These tests revealed an elevated ferritin level and a low serum iron level, findings consistent with a diagnosis of anemia of chronic disease related to the patient's rheumatoid arthritis.

Case 2 . A 44-year-old woman presented with the complaint of fatigue. Her physical examination was unremarkable.

A CBC revealed normocytic anemia (hemoglobin count, 11 per mm 3 [11 × 10 6 per L]; hematocrit, 33 percent [0.33]; MCV, 84 fL), with an elevated red blood cell distribution width of 53 fL. A reticulocyte count and “draw and hold” specimens were ordered. The corrected reticulocyte index was elevated (3.6 percent).

Examination of a peripheral blood smear from the stored specimens was normal. A direct antiglobulin test (direct Coombs' test) was positive, and a preliminary diagnosis of autoimmune hemolytic anemia was made.

The treatment of a normocytic anemia begins with timely identification of its cause. In most patients, therapy is individualized to the underlying disorder. Treatments may include avoidance of trigger exposure in patients with hemolytic anemia, correction of iron, folate or vitamin B 12 deficiency in patients with mixed disorders, or splenectomy in patients with hypersplenism. 12 , 13

Anemia of renal disease is associated with a relative underproduction of erythropoietin, and inappropriate erythropoietin levels appear to contribute significantly to anemia of chronic disease. With the development of recombinant human erythropoietin (r-HuEPO; epoetin alfa [Epogen]), there has been considerable interest in finding out whether exogenous erythropoietin administration would improve anemia.

The effects of r-HuEPO administration have been studied in a variety of disorders. In a trial conducted in 1990, 22 all 11 patients with anemia related to rheumatoid arthritis reached a normal hematocrit after 24 weeks. Since then, r-HuEPO has been tested in patients with anemia of chronic disease secondary to acquired immunodeficiency syndrome, malignancy, inflammatory bowel disease, renal disease and other disorders. 23 , 24 Quality-of-life parameters in responders improved significantly.

Therapy with r-HuEPO is very expensive and should never replace treatment of the underlying cause of an anemia. R-HuEPO is an indicated therapy for anemia of renal disease. In this situation, its use should be based on clinical and quality-of-life issues rather than specific hemoglobin levels. 10 There are no consistent guidelines for r-HuEPO therapy in patients with anemia of chronic disease, although response rates of 40 to 80 percent may be achieved. 8

Erythropoietin also appears to be useful prophylactically in patients undergoing autologous blood donation and certain surgical procedures. 25

In all patients, treatment of anemia should include the provision of optimal nutrition and supportive care.

Dallman PR, Siimes MA. Percentile curves for hemoglobin and red cell volume in infancy and childhood. J Pediatr. 1979;94:26-31.

Bessman JD, Gilmer PR, Gardner FH. Improved classification of anemias by MCV and RDW. Am J Clin Pathol. 1983;80:322-6.

Schnall SF, Berliner N, Duffy TP, Benz EF Jr. Approach to the adult and child with anemia. In: Hoffman R, et al., eds. Hematology: basic principles and practice. 3d ed. New York: Churchill Livingstone, 2000:367–82.

Adams PF, Marano MA. Current estimates from the National Health Interview Survey, 1994. Hyattsville, Md.: U.S. Dept. of Health and Human Services, Public Health Service, Centers for Disease Control, National Center for Health Statistics, 1995. Vital and health statistics. Series 10: Data from the National Health Survey; no. 193; DDHS publication no. (PHS) 95–1521.

Ania BJ, Suman VJ, Fairbanks VF, Melton LJ. Prevalence of anemia in medical practice: community versus referral patients. Mayo Clin Proc. 1994;69:730-5.

Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. JAMA. 1999;281:1714-7.

Krantz SB. Pathogenesis and treatment of the anemia of chronic disease. Am J Med Sci. 1994;307:353-9.

Gardner LB, Benz EJ Jr. Anemia of chronic diseases. In: Hoffman R, et al., eds. Hematology: basic principles and practice. 3d ed. New York: Churchill Livingstone, 2000:383–8.

Lee GR. Anemia: a diagnostic strategy. In: Lee GR, et al., eds. Wintrobe's Clinical hematology. 10th ed. Baltimore: Williams &Wilkins, 1999:908–40.

Abramson SD, Abramson N. ‘Common’ uncommon anemias. Am Fam Physician. 1999;59:851-8.

Weatherall DJ. ABC of clinical haematology. The hereditary anaemias. BMJ. 1997;314:492-6.

Sackey K. Hemolytic anemia: Part 1. Pediatr Rev. 1999;20:152-8.

Sackey K. Hemolytic anemia: Part 2. Pediatr Rev. 1999;20:204-8.

Levine E, Rosen A, Sehgal L, Gould S, Sehgal H, Moss G. Physiologic effects of acute anemia: implications for a reduced transfusion trigger. Transfusion. 1990;30:11-4.

Weiskopf RB, Viele MK, Feiner J, Kelley S, Lieberman J, Noorani M, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998;279:217-21 [Published erratum appears in JAMA 1998;280:1404]

Erslev AJ. Hypersplenism and hyposplenism. In: Beutler E, Lichtman MA, et al., eds. Williams Hematology. 5th ed. New York: McGraw-Hill, Health Professions Division, 1995:709–14.

Sherry B, Bister D, Yip R. Continuation of decline in prevalence of anemia in low-income children: the Vermont experience. Arch Pediatr Adolesc Med. 1997;151:928-30.

Abshire TC. The anemia of inflammation. A common cause of childhood anemia. Pediatr Clin North Am. 1996;43:623-37.

Meyers FJ, Welborn JL, Lewis JP. Improved approach to patients with normocytic anemia. Am Fam Physician. 1988;38(2):191-5.

Farhi DC, Luebbers EL, Rosenthal NS. Bone marrow biopsy findings in childhood anemia: prevalence of transient erythroblastopenia of childhood. Arch Pathol Lab Med. 1998;122:638-41.

Brown RG. Normocytic and macrocytic anemias. Postgrad Med. 1991;89(8):125-32.

Pincus T, Olsen NJ, Russell IJ, Wolfe F, Harris ER, Schnitzer TJ, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med. 1990;89:161-8.

Krantz SB. Erythropoietin and the anaemia of chronic disease. Nephrol Dial Transplant. 1995;10(suppl 2):10-7.

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What Causes Normocytic Anemia?

Blood loss or certain health conditions can cause a low red blood cell count

What Is Normocytic Anemia?

Normocytic anemia happens when you have a low number of red blood cells, which carry oxygen through the body. The causes of normocytic anemia include heavy bleeding, COPD, certain cancers, sickle cell disease, and hemolysis (a condition in which the red blood cells break open and are destroyed).

This common type of anemia can be identified with a blood test. Identifying the cause and getting treatment are important aspects of managing normocytic anemia. 

This article will explore symptoms of normocytic anemia as well as causes, diagnosis, treatment, and prognosis.

Verywell / Jessica Olah

Normocytic anemia occurs when you have a lower-than-normal amount of red blood cells. However, the blood cells are still typically normal size. The condition is also marked by low hemoglobin levels.

In contrast, some types of anemia are microcytic (the red blood cells are small), and some are macrocytic (the red blood cells are large). These changes in size are usually due to different underlying issues than the causes of normocytic anemia, so the size of the red blood cells can help determine the cause of anemia.

For example, iron deficiency is a common cause of microcytic anemia (the red blood cells are small), while vitamin B12 deficiency is a common cause of macrocytic anemia (the red blood cells are too big).

What Are the Symptoms of Normocytic Anemia? 

The effects of normocytic anemia can range from mild to severe, depending on the red blood cell count and other medical conditions that can add to your symptoms. You may experience symptoms gradually if the anemia is slowly progressive, but the symptoms can worsen abruptly if the anemia develops rapidly. 

Common symptoms of normocytic anemia include: 

• Fatigue, low energy 
• A general feeling of being weak 
• Brain fog (difficulty with concentration and memory)
• Lack of motivation

You can expect several of these symptoms with normocytic anemia, and some people only experience a few of the effects, especially if the anemia is mild. 

You may also experience other symptoms that aren’t necessarily directly related to the anemia, but they can signal the cause of the anemia.  

Associated symptoms can include:

• Fever can occur due to an infection. 
• Blood in the stool or dark stools can occur due to gastrointestinal (digestive tract) disease.
• Coughing up blood can occur with lung cancer or esophageal (food tube) cancer. 
• Weight loss can occur with cancer or chronic disease. 
• Shortness of breath can occur if you also have chronic obstructive pulmonary disease (COPD, irreversible inflammatory lung disease) or heart disease. 

Normocytic anemia is a common complication of many different illnesses, and the associated symptoms can begin before or after the symptoms of anemia.

Normocytic anemia can happen due to bleeding, chronic disease, or low red blood cell production. Some people are born with the disorder.

There are many different causes, and the condition can be more severe if you have more than one cause. Chronic inflammation can lead to reduced production of red blood cells.

Common causes of normocytic anemia include:

• Heavy menstrual bleeding 
• Chronic bleeding, usually due to a gastrointestinal problem 
• Bleeding from an injury 
• Chronic kidney, heart, or liver disease 
• Hemolysis (premature destruction of the red blood cells) due to sickle cell disease or an infection
• Cancer or cancer treatment, particularly gastrointestinal forms of cancer
• Bone marrow disease 
• Aplastic anemia

Chronic disease may shorten red blood cells' lifespan, contributing to anemia.

Sometimes, the cause and risk of low red blood cells are known before normocytic anemia becomes symptomatic. Symptoms of anemia may begin, or the red blood cell count can be used to diagnose anemia before the causative condition is known. 

If you are at a known risk of anemia, your doctor may order blood tests to monitor your red blood cell count.

How Is Normocytic Anemia Diagnosed? 

The diagnosis of normocytic anemia is established with blood tests. If you have a serious injury with substantial blood loss, you would have a complete blood count (CBC) , which would provide quick information about whether you have anemia. 

You may have a blood test to evaluate your red blood cell count if symptoms or physical examination findings raise concerns that you could have anemia. Sometimes, normocytic anemia is diagnosed incidentally due to a routine CBC blood test done for a checkup.

Pale skin, a rapid pulse , a weak pulse, or low blood pressure are signs of anemia that your doctor may detect on your physical examination. 

Blood tests that detect anemia:

• CBC : This blood test provides a count of your red blood cells, white blood cells, and platelets, as well as a general assessment of the average red blood cell size. According to the World Health Organization, a normal hemoglobin level for adult males is above 130 grams per deciliter (g/dL). For adult females and children over age 12, it is above 120 grams per deciliter, for children aged 5 to 11, it is over 115 grams per deciliter, and for children under age five, it is above 110 grams per deciliter.
• Blood smear : This is a microscopic evaluation of the cells in a blood sample . Laboratory analysis of the sample will describe the shape and size of your red blood cells and the characteristics of the other cells in the sample. 

The diagnosis of normocytic anemia often involves a search for the cause if it isn’t already known. 

Tests you might have during your assessment may include:

• Electrolyte tests : This blood test may show signs of systemic diseases like kidney disease. 
• Liver function tests : These blood tests may show signs of liver disease. 
• Urinalysis (urine test) : This test can show signs of blood or infection in your urine. 
• Stool sample or rectal examination : These tests can detect bleeding in the gastrointestinal tract. 
• A cervical examination : This test would be considered for people with a uterus (womb) if there is concern about excessive uterine bleeding. 
• Imaging tests : Imaging tests, such as an abdominal computerized tomography (CT) scan, may show tumors or other structural problems or sources of bleeding. 

Your symptoms, medical history, and physical examination would guide the diagnostic tests that your doctor would order during your anemia assessment. 

What Are the Treatments for Normocytic Anemia? 

Treatment of normocytic anemia can include controlling blood loss, treatment of underlying disease, blood transfusion, and medication to promote red blood cell production. You would likely benefit from one or more of these treatments, and most people do not need all of them. 

• Blood transfusion : This therapy is a direct infusion of donor blood. It is needed when the red blood count is very low. If you have developed anemia due to trauma, for example, your red blood cell count might normalize after your transfusion and after your bleeding stops. 
• Surgical repair : Large traumatic wounds might not heal on their own and may need to be urgently surgically repaired to stop blood loss.
• Erythropoietin : The kidneys naturally produce this hormone to stimulate red blood cell production in the bone marrow. In some situations, such as chronic kidney disease or cancer, it can also be used as a medication to help increase red blood cells.  
• Treatment of underlying disease : If your anemia is due to a medical condition, such as COPD, liver disease, heart disease, kidney disease, or cancer, treatment of the underlying condition may help with symptoms of anemia, and your red blood cell count may improve as well. 

Treatment for anemia is important, even if you don't have symptoms. Anemia can worsen your overall health and make it harder for you to recover from illnesses.

Prognosis: What to Expect? 

Red blood cells last for an average of 120 days. Your red blood cell count should improve within a few weeks with treatment. 

If the cause of your anemia is acute (sudden and short-term), such as trauma, then you are likely to have lasting improvement after short-term treatment to alleviate blood loss and after a blood transfusion if your anemia is severe. 

Chronic normocytic anemia may require consistent treatment of the underlying cause so the red blood cell count will become normal and prevent anemia's recurrence.  Lifestyle approaches can also help maintain a healthy red blood cell count.

Anemia is low red blood cell number or function. Normocytic anemia is a common type of anemia with a low red blood cell count and normal-sized red blood cells. It can develop due to blood loss, low red blood cell production, or chronic disease.

Red blood cell loss can often be stopped with medical or surgical interventions. The symptoms and red blood cell count will usually improve with treatment of the cause of anemia. 

World Health Organization, Haemolglobin concentrations for the diagnosis of anemia and assessment of severity .

Agravat AH, Pujara K, Kothari RK, Dhruva GA. A clinico-pathological study of geriatric anemias . Aging Med (Milton). 2021;4(2):128-134. doi:10.1002/agm2.12150

Spazzafumo L, Olivieri F, Sabbatinelli J, et al. Prognostic relevance of normocytic anemia in elderly patients affected by cardiovascular disease . J Geriatr Cardiol. 2021;18(8):654-662. doi:10.11909/j.issn.1671-5411.2021.08.008

American Family Physician. Normocytic anemia.

Diagnostic Pathology: Blood and Bone Marrow. Normochromic normocytic anemia - an overview . Elsevier. 2018. doi:10.1016/B978-0-323-39254-9.50024-6

McSorley ST, Johnstone M, Steele CW, et al. Normocytic anaemia is associated with systemic inflammation and poorer survival in patients with colorectal cancer treated with curative intent . Int J Colorectal Dis . 2019;34(3):401-408. 10.1007/s00384-018-3211-7

Merck Manual Professional Version. Anemia of chronic disease .

de Las Cuevas Allende R, Díaz de Entresotos L, Conde Díez S. Anaemia of chronic diseases: Pathophysiology, diagnosis and treatment . Med Clin (Barc). 2021;156(5):235-242. doi:10.1016/j.medcli.2020.07.035

By Heidi Moawad, MD Dr. Moawad is a neurologist and expert in brain health. She regularly writes and edits health content for medical books and publications.

#52: Anemia: Tips and tools for diagnosis and treatment

August 14, 2017 | By Matthew Watto, MD

Master the anemia algorithm, and take a deep dive on iron deficiency, anemia of chronic kidney disease, anemia of chronic inflammation, causes of macrocytic anemia, plus random clinical pearls in this discussion with international expert, Dr. David P. Steensma, Senior Physician from Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School.

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Cases from Kashlak Memorial:

• 62 yo M with diabetes and chronic kidney disease, asymptomatic hemoglobin (Hgb) 10, mean corpuscular (MCV) 90, and Creatinine (Cr) 1.9?
• 72 yo F with hypertension, asymptomatic Hgb of 11, MCV 85 and Cr 0.6.
• 72 yo F with breast cancer in remission after lumpectomy, adjuvant chemo, and radiation therapy treated 6 years ago presents with fatigue and some dyspnea on exertion. Hgb 9.6, MCV 102.

Clinical Pearls:

• Anemia defined: 1968 WHO criteria used in epidemiologic studies = Hemoglobin (Hgb) under 12 gm/dL in women and under 13 gm/dL in men. Values don’t account for race, altitude, or other patient factors. Anemia is more common with advanced age, but NOT normal and should be worked up!
• Anemia Algorithm: Dr. Watto’s anemia algorithm adapted from this interview (see below)
• Mean corpuscular (cell) volume (MCV): Average RBC size. Under 80 = microcytic. Between 80-95 (up to 100) = normocytic. Above 95 (or 100) is macrocytic.
• Red cell distribution width: Measures degree of variation among size of RBCs. Normal range 11.5% to 14.5%. Above 14.5% suggests wide range of RBC sizes.
• Reticulocyte count: Measures percentage of reticulocytes (immature RBCs) in peripheral blood. High in acute blood loss, hemolysis, exogenous erythropoietin (EPO), iron or B12 repletion. Low in bone marrow (BM) ablative disorders, lack of substrate (e.g. iron), low EPO, and conditions that impair erythropoiesis.
• Corrected reticulocyte count = reticulocyte count x (patient Hct/goal Hct).
• Reticulocyte index = accounts for increased RBC survival in patients who are anemic. Correction factor applied based on degree of anemia.
• Microcytic anemia: MCV close to or under 80. Think iron deficiency, thalassemia, and sometimes anemia of chronic inflammation.
• Normocytic anemia: MCV 80-100. Most difficult differential, but usually anemia of CKD, or chronic inflammation. If no acute bleeding, then check reticulocyte count. Consider checking  serum EPO level. If low, then patient might respond to an erythropoietin stimulating agent (ESA).
• Macrocytic anemia: Things to consider: alcohol use (or liver disease), culprit medications (e.g. methotrexate, azathioprine, hydroxyurea, metformin, proton pump inhibitors), check B12, folate, TSH.  If no answer, then refer for BM biopsy.
• Iron deficiency anemia: Ferritin <20 suggests iron deficiency. Soluble transferrin receptor (sTfR) is inversely related to iron levels in blood. It is NOT sensitive to inflammation. High sTfR level indicates iron deficiency even if ferritin elevated.
• Anemia of CKD: Hypoproliferative, normocytic (usually), and normochromic anemia. Must rule out other causes. Etiology = decreased renal erythropoietin synthesis +/- decrease RBC half life +/- absolute or functional iron deficiency (e.g. bleeding or inflammation respectively).
• Anemia of Chronic Inflammation: High ferritin, low TIBC, normal serum iron, and normal or slightly high transferrin saturation (serum iron divided by TIBC). These patients rarely respond to oral iron therapy. IV iron recommended by Dr. Steensma.
• Erythropoiesis-stimulating agents: E.g. darbepoetin, or erythropoietin. Correct iron deficiency prior to use. Goal iron saturation above 20%. KDIGO recommends iron saturation above 30% and ferritin above 500 in patients with CKD (weak recommendation). Ferritin cut-off is controversial. If >800, then person is clearly iron replete. Keep Hgb between 10-12 gm/dL in CKD not requiring dialysis, and above 9 gm/dL in CKD requiring dialysis.
• Oral versus IV iron: Oral iron poorly tolerated. IV iron more costly, but safe and effective. Dr. Steensma still recommends oral iron daily NOT every other day.
• Vitamin C and oral iron absorption: Evidence that Vitamin C modestly boosts absorption, but clinical benefit unclear and more expensive. Consider for patients with low acidity (e.g. on PPI therapy).
• Vitamin B12 deficiency: Check serum or urine methylmalonic acid (MMA). If level below 400, then treat to normalize Hgb. Use intramuscular B12 (cyanocobalamin) if neurologic involvement.
• Elevated Vitamin B12 level: If high in patient NOT on supplementation, then consider myeloproliferative neoplasm! These are associated with increased production of transcobalamin, a B12 binding protein.
• Myelodysplastic syndrome: Likely diagnosis if unexplained macrocytic anemia. Commonly treated with Azacitidine, Decitabine, or Lenalidomide. All three meds are FDA approved for MDS. Side effects include cytopenias. Lenalidomide can also cause rash, and neuropathy.

Goal: Listeners will apply a basic algorithmic approach to the diagnosis and classification of anemia.

Learning objectives: After listening to this episode listeners will…

• Recognize anemia elderly men and women
• Diagnose and manage the most common causes of anemia (iron deficiency, CKD, anemia of chronic inflammation)
• Classify anemia by MCV
• Determine the most important lab values reported in a CBC
• Interpret iron studies
• Identify when to order additional testing like EPO, TSH, B12, folate
• Utilize and interpret reticulocyte count for normocytic anemias
• Determine dose and route for iron repletion
• Determine dose and route for B12 repletion
• Identify patients with macrocytic anemia requiring a bone marrow biopsy
• Recall the three FDA approved agents for myelodysplastic syndrome and their common side effects

Disclosures: Dr. Steensma is on the data safety monitoring committee for Janssen, and has clinical trials sponsored by Amgen.

Time Stamps 00:00 Intro 01:18 Listener feedback 04:05 Announcement: We’re looking for on air correspondents to join The Curbsiders 05:05 Picks of the week 11:12 Getting to know our guest 17:50 Case #1 Normocytic anemia 19:15 Defining anemia (WHO criteria) 21:10 Epidemiology of anemia 23:45 Normocytic anemia 25:55 Erythropoietin for diagnosis and treatment 28:22 Anemia of CKD or chronic inflammation? 31:37 Discussion of ferritin and soluble transferrin receptor 33:47 Case #1 Conclusion 35:45 Hemoglobin targets in CKD 36:53 Case #2 Microcytic anemia 37:43 Correct reticulocyte count and reticulocyte index 40:45 Deciding on dose and route for iron repletion 43:44 Does vitamin C improve iron absorption? 45:27 Case #3 Macrocytic anemia 46:54 Vitamin B12 deficiency 51:54 Medication related B12 deficiency 52:35 Myelodysplastic syndrome 55:00 Side effects of common MDS treatments 56:18 Take home points 57:35 The Curbsiders post game analysis 64:16 Outro

Links from the show:

• Colossal (film) by Nacho Vigalondo 2016
• Pulgasari (1985) North Korean Giant Monster film with english subtitle on YouTube
• Master of None (TV show) by Aziz Ansari on Netflix
• When Breath Becomes Air (book) by Paul Kalanithi
• Anemia algorithm app (FREE) by Dr. Steensma on iTunes
• Improving outcomes in geriatric anemia: a guide to the differential diagnosis of treatable causes by Dr. Steensma and Dr. Koffman from Medscape
• Nomogram for EPO level versus Hemoglobin. Kidney International 2004
• Calculator: Absolute Reticulocyte Count & Reticulocyte Index from MDCalc
• Vitamin C and oral iron absorption. Scand J Haematol 1980.
• KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease 2012
• Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood 2015

Responding to the Listener Feedback from the ID doctor. I disagree wholeheartedly with his take on interviewing generalists. As a Family Physician, I enjoy personal growth and continued education and sharing information between colleagues (mostly "generalists"), but there is a significant service to be gained from a consultant's point of view - editorialized information. It's what differentiates one doctor from another, clinical experience. It's what makes this podcast standout from the crowd of written topics online and often times from shorter audio/video learning materials and activities online extrapolated from guidelines. The Curbsiders' approach to date is superior. I can attest to significantly learning more in this past year of listening to the podcast, even about topics I delved in to by myself due to caveats and pearls that may have been just a second or minute long. Its the small details in a long show that find its way into the conversation that make the difference and that can only be elicited by challenged a learned mind - the consultant / expert in a field.

Excellent podcast! I don't see any link to the anemia app in the show notes. Could you please provide the link? Thanks.

I have just seen the link in the show notes Thanks

So helpful! Thank you!

Great podcast! Quick question: when your iron level is low but your ferritin is within the normal range, why can't you just use transferrin saturation % to determine the degree of iron deficiency co-existing with anemia of inflammation? So if the iron is low, the transferrin saturation is <15-20%, and your ferritin is in the normal range, isn't that sufficient information to label this patient as having both iron deficiency and anemia of inflammation? I'm trying to figure out when I need to use the soluble transferrin receptor....Thanks in advance!

CME Partner

The Curbsiders are partnering with VCU Health Continuing Education to offer FREE continuing education credits for physicians and other healthcare professionals. Visit curbsiders.vcuhealth.org and search for this episode to claim credit.

anemia , assistant , B12 , care , chronic , deficiency , Doctor , education , family , ferritin , foam , FOAMed , Health , hemoglobin , hospital , Hospitalist , inflammation , internal , Internist , iron , kidney , medical , Medicine , myelodysplastic , nurse , oral , physician , primary , resident , student , supplementation , syndrome , therapy , vitamin

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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Acute anemia.

Robert B. Killeen ; Ajay Tambe .

Affiliations

Last Update: May 1, 2024 .

• Continuing Education Activity

Acute anemia is a critical condition characterized by a rapid decrease in red blood cell count, leading to impaired oxygen delivery to tissues and organs. This can result from sudden blood loss due to trauma, hemorrhage, or hemolysis, necessitating immediate intervention to stabilize the patient's condition and address the underlying cause. Effective management requires prompt recognition, accurate diagnosis, and timely implementation of resuscitative measures to restore adequate tissue perfusion and prevent further complications. Collaboration among healthcare professionals from various specialties is essential to optimize patient care and outcomes in acute anemia cases.

This activity allows healthcare professionals to stay abreast of the latest advancements in the diagnosis, management, and collaborative care of acute anemia. Participants will enhance their knowledge and skills in differentiating etiologies, implementing resuscitation measures, and applying evidence-based guidelines. Additionally, this activity aims to foster effective collaboration with specialists in hematology/oncology, gastroenterology, and surgery to provide comprehensive care to patients with acute anemia. By improving healthcare providers' competence and coordination, this activity enhances patient outcomes and mitigates the healthcare burden associated with acute anemia.

• Identify different etiologies of acute anemia based on clinical presentation, laboratory findings, and patient history.
• Implement resuscitation measures promptly for patients with acute anemia following the ABC ( (airway, breathing, circulation) approach as indicated based on the severity of anemia and the underlying cause.
• Apply evidence-based guidelines for managing acute anemia, including appropriate use of blood products, pharmacological interventions, and referral to specialist care when necessary.
• Collaborate with other healthcare professionals, including specialists in hematology/oncology, gastroenterology, and surgery, to provide comprehensive care for patients with acute anemia and address their unique needs.
• Introduction

Anemia is characterized by a deficiency in the number of circulating red blood cells (RBCs), the amount of hemoglobin, or the volume of packed RBCs, known as hematocrit. [1]  The World Health Organization (WHO) defines anemia as a hemoglobin level below 13 g/dL in men and below 12 g/dL in women. [2]  

Anemia can be classified into 2 main types: 

• Acute anemia involves a sudden and rapid decrease in RBCs, typically caused by hemolysis or acute hemorrhage.
• Chronic anemia is characterized by a gradual decline in RBCs over time. Its causes are varied and may include conditions such as iron or other nutritional deficiencies, chronic diseases, drug-induced factors, and other underlying health issues.

Anemia can result from various events and underlying conditions. Blood loss is among the most prevalent causes, resulting in decreased RBCs. This occurrence is widespread in cases of acute anemia observed in emergency room settings. Emergent conditions leading to acute anemia include traumatic injury causing arterial bleeding, ruptured aneurysms, massive upper or lower gastrointestinal (GI) hemorrhages, ruptured ectopic pregnancies, and disseminated intravascular coagulation (DIC).

Hemolytic anemias can also contribute to acute and chronic anemia, characterized by the destruction or reduced survival of RBCs. They are typically classified into 2 main categories: intracorpuscular and extracorpuscular. 

Intracorpuscular   Hemolytic Anemias

Intracorpuscular hemolytic anemias encompass conditions where the defect or issue originates within the RBC itself. These abnormalities can involve defects in the RBC's membrane, enzymes, or hemoglobin molecules, leading to premature cell breakdown and subsequent anemia.

Hemoglobinopathies affect the structure or function of hemoglobin.

• Sickle cell disease arises from a point mutation in the beta-globin chain's DNA, producing abnormal hemoglobin known as hemoglobin S (Hgb S). Under oxidative stress conditions, the Hgb S molecules polymerize and cause the RBCs to assume a sickle shape, which is less flexible and can block blood vessels, leading to tissue damage, pain crises, and other complications.
• Thalassemias involve reduced alpha or beta globin chain production, leading to imbalanced hemoglobin synthesis. Due to the abnormal structure or function of hemoglobin, these conditions can cause various complications, including tissue damage and pain crises. 

Enzymopathies  refer to conditions characterized by abnormalities in specific enzymes within RBCs (see Table.  Enzymopathies Causing Hemolytic Anemia). These enzyme defects can disrupt normal cellular processes and lead to various clinical manifestations, including hemolysis and anemia.

Table 1. Enzymopathies Causing Hemolytic Anemia.

Extracorpuscular Hemolytic Anemias

Extracorpuscular hemolytic anemias are a group of disorders where the defect leading to RBC destruction originates outside the RBC itself. These conditions typically involve factors in the bloodstream or external to the RBCs that cause their premature destruction.

Mechanical destruction (microangiopathic):

• Thrombotic thrombocytopenic purpura (TTP) is characterized by the formation of platelet-rich thrombi in small blood vessels, primarily caused by a deficiency in ADAMTS13, metalloprotease responsible for cleaving von Willebrand factor. The classic triad of TTP includes microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia. [6]
• Familial (atypical) hemolytic-uremic syndrome (HUS) results from gene mutations encoding complement regulatory proteins, leading to complement system dysregulation, immune system activation, and damage to small blood vessels. HUS also presents with a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure, though its lesions are primarily confined to the kidneys, distinguishing it from TTP. [7] [8] [7]

Complement-mediated thrombotic microangiopathy is defined by the abnormal activation of the complement system, resulting in the formation of small blood clots within the microvasculature. This phenomenon can manifest in various disorders, including HUS.

Immune thrombocytopenic purpura  is a condition in which IgG autoantibodies bind to platelets, marking them for destruction by the spleen. Consequently, platelet count decreases, raising the risk of bleeding, particularly when platelet levels plummet significantly.

Disseminated intravascular coagulation  is characterized by widespread systemic activation of coagulation throughout the body in response to various underlying causes, such as infections, severe trauma, or certain complications during pregnancy. DIC results in excessive formation of intravascular fibrin, causing thrombosis. However, as coagulation factors are consumed, bleeding complications can arise. [9]

Toxic agents and drugs can destroy RBCs and cause hemolysis. Exposure to substances such as hyperbaric oxygen (or 100% oxygen), certain medications (eg, methyldopa, nitrates, chlorates, methylene blue, dapsone, cisplatin), numerous aromatic (cyclic) compounds, and other chemicals (arsine, stibine, copper, and lead) can trigger this process.

Infectious causes of hemolytic anemia include malaria, the most prevalent worldwide, and in certain regions, infection with Shiga toxin-producing E. Coli O157:H7, which leads to HUS. Additionally, in specific clinical situations such as open wounds, septic abortion, or contaminated blood transfusions, Clostridium perfringens sepsis can induce life-threatening hemolysis through the action of a toxin with lecithinase activity.

Autoimmune hemolytic anemia  occurs when IgG antibodies target and bind to RBCs, leading to their destruction by macrophages, resulting in hemolysis. The affected RBCs often assume a rigid and nonelastic spherical shape known as spherocytes, making them more prone to rapid destruction. This type of anemia can be associated with autoimmune diseases (eg, lupus), certain types of lymphomas and leukemias, or can be drug-induced. In many cases, the cause remains unidentified. [10]

Hypersplenism is characterized by splenomegaly, resulting in increased destruction of blood cells, including RBCs. In acute conditions, such as infections or other causes of hemolysis, the spleen removes more RBCs, exacerbating the loss. [11]  When the rate of hypersplenic destruction surpasses the marrow's capacity to produce RBCs, the anemia becomes more severe.  

• Epidemiology

Anemia is a prevalent condition, affecting one-fourth of the general population. Its prevalence is even higher among hospitalized patients, with approximately 50% affected. Among older hospitalized patients, the rate of anemia can rise to as high as 75%. 

Data collected in 2000 from over 81,000 health plan members revealed varying rates of anemia across specific patient populations. Patients with chronic kidney disease exhibited the highest prevalence of anemia, at 34.5%. Anemia prevalence among patients with cancer was 21%, while those with chronic heart disease had a rate of 18%. Inflammatory bowel disease accounted for 13% of anemia cases, followed by rheumatoid arthritis at 10%. Additionally, individuals with HIV infection had a 10% prevalence of anemia. [12]    

• Pathophysiology

Acute anemia typically arises from 2 common causes: hemolysis or hemorrhage, both of which lead to a sudden decrease in RBCs. When the decline in RBCs is rapid, a hemoglobin level of 7 to 8 g/dL often triggers symptoms, as the body has insufficient time to compensate and replenish the lost volume. Healthy individuals can typically tolerate up to a 20% loss of blood volume without significant symptoms due to reflex vasospasm and the redistribution of blood flow.

However, when blood loss surpasses this threshold, patients start exhibiting signs and symptoms of hypovolemia. Compensatory mechanisms, like the redistribution of blood flow, become inadequate to sustain blood pressure, resulting in clinical manifestations such as postural hypotension, altered mental status, cool and clammy skin, tachycardia, and hyperventilation.

In cases of acute hemorrhage, hemoglobin and hematocrit levels may initially appear normal because both RBCs and plasma are lost concomitantly. This discrepancy becomes evident once intravenous fluids restore or replenish the patient’s plasma volume.

• Histopathology

When examining a peripheral blood smear under a microscope, specific findings can provide valuable insights into the underlying condition. Observations related to certain types of anemia are as follows:

• Microangiopathic hemolysis: In conditions characterized by microangiopathic hemolysis, such as TTP, immune thrombocytic purpura (ITP), HUS, and DIC, a peripheral blood smear examination may reveal several abnormal RBC shapes. These abnormalities include helmet cells (schistocytes), fragmented RBCs, and other RBC fragments. Spherocytes (small, round RBCs lacking central pallor) may also be present in some cases.
• Sickle cell disease: A hallmark finding in sickle cell disease is the presence of sickle-shaped cells, also known as sickle cells. These cells have a crescent or "sickle" shape due to the abnormal Hgb S in individuals with this genetic disorder. Another characteristic feature of sickle cell disease is Howell-Jolly bodies, which are small nuclear remnants within RBCs. Howell-Jolly bodies are typically seen in individuals with functional asplenia or hyposplenism.
• History and Physical

When evaluating a patient with anemia, obtaining a comprehensive yet focused medical history is essential for guiding further assessment and management. However, specific priorities should be addressed initially, including managing the patient's airway, breathing, and circulation (ABCs) are stable. If required, immediate resuscitation measures should be initiated to stabilize the patient.

In situations where the patient cannot communicate, obtaining as much information as possible from emergency medical services (EMS) personnel or individuals at the bedside is crucial. Additionally, reviewing previous medical charts, if available, can offer valuable insights into the patient's medical history and aid in understanding the underlying cause of anemia.

A focused history should also include identifying the potential source of bleeding. For example, if GI hemorrhage is suspected, obtaining a detailed GI history is essential, which may involve asking about any prior episodes of GI bleeding, symptoms of GI disorders, or known GI conditions. Similarly, if gynecological causes are suspected, a focused menstrual and pregnancy history should be taken to evaluate any potential gynecological sources of bleeding.

Physical Examination

In assessing a patient with anemia, regular monitoring of vital signs is essential to evaluate the patient's stability and response to interventions. As mentioned earlier, the initial physical examination should focus on the organ or system suspected to be the source of bleeding. If trauma is suspected, a thorough examination of the chest, abdomen, pelvis, and extremities is necessary, including assessing for signs of injury. Additionally, imaging studies may be conducted as clinically indicated to further evaluate potential injuries or sources of bleeding. 

The presentation of hemorrhagic shock can be categorized into different stages based on the amount of blood loss and the associated clinical signs. The various stages typically include:

• Mild tachycardia is usually the first sign
• Blood pressure remains within normal range
• The skin may start to feel cool to the touch
• Tachycardia continues, becoming more pronounced
• Tachypnea begins
• Pulse pressure decreases
• Tachycardia worsens, with a rapid and weak pulse
• The decrease in blood pressure becomes more significant
• Skin becomes cold and appears pale and mottled
• Urine output decreases significantly
• This stage is dangerous and carries a high mortality rate
• Tachycardia and decreased blood pressure continue to worsen and can lead to loss of consciousness
• The pulse can disappear if there is >50% blood loss

Additional findings during a skin examination can offer valuable insights into assessing a patient with potential bleeding disorders or hemorrhage. These may include:

• Flank ecchymosis (Grey-Turner sign): Bruising in the flank area can indicate retroperitoneal hemorrhage.
• Umbilical ecchymosis (Cullen sign): The appearance of bruising around the umbilicus can suggest intraperitoneal or retroperitoneal bleeding.
• Jaundiced, yellow skin: Jaundice can indicate liver disease, certain hemoglobinopathies, or other forms of hemolysis.
• Purpura and petechiae: The presence of purpura or petechiae can suggest platelet disorders or abnormalities in blood clotting.
• Hemarthrosis: Bleeding into joint spaces can indicate a bleeding disorder such as hemophilia.
• Diffuse bleeding from intravenous sites and mucous membranes: This may be a sign of DIC.

A further diagnostic workup is crucial to determining the etiology and severity of the bleeding. This comprehensive assessment may include a range of tests and procedures to identify the underlying cause and extent of the hemorrhage.

Blood typing and cross-matching involve promptly sending a blood sample to the laboratory for typing and cross-matching. This facilitates the preparation of blood products if transfusion is necessary, ensuring compatibility and safety during transfusion procedures. 

Complete blood count (CBC) provides essential insights into the patient's RBC count, hemoglobin, and hematocrit levels, aiding in evaluating blood loss and the severity of anemia. However, it is essential to recognize that in actively bleeding patients, the initial hematocrit level may not accurately reflect the true extent of blood loss due to temporary dilutional effects maintaining normal levels.

Serial CBC monitoring is crucial in acute bleeding cases, as it allows for tracking changes in hemoglobin and hematocrit levels over time. This ongoing assessment helps clinicians gauge the effectiveness of interventions and the patient's response to treatment.

Mean corpuscular volume (MCV) is a valuable parameter used to classify anemia into different types based on the average volume of RBCs.

• Thalassemia
• Anemia of chronic disease
• Iron deficiency anemia
• Lead poisoning
• Sideroblastic anemia/sickle cell disease
• Active bleeding
• Alcohol-related anemia
• Folate deficiency
• Vitamin B-12 deficiency
• Some preleukemic conditions

Lactate dehydrogenase (LDH), haptoglobin, and bilirubin can indicate hemolytic anemia with elevated LDH and indirect bilirubin levels and decreased haptoglobin levels.

Blood urea nitrogen (BUN) levels are commonly elevated in patients with upper GI bleeds due to undigested blood.

Reticulocyte count is increased due to an erythropoietic response by the bone marrow, suggesting active RBC production. Conversely, a low reticulocyte count may indicate an inadequate bone marrow response, as seen in conditions such as aplastic anemia, hematologic cancers, drugs, or toxins. Reticulocytosis often corresponds with an increased MCV in the blood count.

Screening labs for DIC typically include prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, fibrin split products, and platelet count. Diagnostic findings indicative of DIC comprise increased coagulation times, decreased platelets and fibrinogen levels, and fibrin split products. DIC should be considered in the diagnosis of patients experiencing severe sepsis, childbirth complications, burns, malignancies, or uncontrolled hemorrhage.

Additional studies for evaluating anemia include the following:

• Folate and vitamin B12 levels
• Lead levels
• Hemoglobin electrophoresis
• Factor deficiency tests
• Bleeding time
• Bone marrow aspiration
• Coombs test

Imaging studies are vital for assessing anemia and identifying the source of bleeding. Common imaging modalities and procedures used for this purpose include:

• Ultrasound: A quick and noninvasive tool for diagnosing intraperitoneal bleeding. In trauma settings, a focused abdominal sonography for trauma (FAST) examination is often performed to assess for intraabdominal hemorrhage, especially in unstable patients.
• Chest x-ray: Helpful in trauma patients to identify potential sources of bleeding such as hemothorax, pulmonary contusions, aortic rupture, or free air under the diaphragm associated with GI bleeding.
• Computed tomography scanning: Beneficial in patients with GI trauma or suspected GI bleeding.
• Esophagogastroduodenoscopy: Commonly employed for diagnostic and therapeutic purposes in cases of upper GI bleeding. 
• Sigmoidoscopy or colonoscopy: Valuable tools for diagnosing and sometimes treating lower GI bleeding. 
• Treatment / Management

The treatment and management of acute anemia are paramount in stabilizing the patient and addressing the condition's underlying cause. Acute anemia requires prompt intervention to restore adequate oxygen delivery to tissues and prevent further complications. Treatment strategies often involve a combination of measures aimed at stopping ongoing bleeding, replacing lost blood volume, and addressing the underlying cause of the anemia. 

Initial Management

• Evaluate the ABCs (airway, breathing, and circulation)
• Treat any life-threatening conditions immediately
• Administer supplemental oxygen
• Establish 2 large-bore intravenous lines
• Intravenous fluid resuscitation (crystalloid is the initial fluid of choice) 
• Apply direct pressure to any hemorrhage if possible 

Treatment 

The primary treatment for acute anemia involves administering packed red blood cells (pRBCs) to replenish the lost blood volume. Typically, each unit of pRBCs is expected to increase the hematocrit by approximately 3 points.

Transfusion thresholds

A restrictive transfusion strategy is generally followed for hospitalized, hemodynamically stable adult patients, those in critically care settings, with transfusion not recommended  until the hemoglobin concentration drops to 7 g/dL or lower. [13]  However, in patients with acute coronary syndrome, transfusion consideration arises when hemoglobin level equals or falls below 8 g/dL. [14]

For actively bleeding patients, transfusion decisions should be guided by clinical context and bleeding severity, with a more liberal approach potentially required to maintain hemodynamic stability during ongoing hemorrhage until bleeding control is achieved. In cases of massive hemorrhages, such as trauma or major surgical procedures, initiation of a massive transfusion protocol is warranted. This protocol involves promptly administering blood products, including pRBCs, fresh frozen plasma (FFP), platelets, and sometimes cryoprecipitate, to ensure hemodynamic stability and replenish coagulation factors.

All these blood components are integral to treating specific conditions associated with anemia. They may be considered in instances as outlined (see Table.  Treatment Options for Acute Anemia): 

Table 2. Treatment Options for Acute Anemia.

Sickle cell anemia

Treatment options for sickle cell anemia focus on symptom management, complication prevention, and enhancing overall quality of life. A blood transfusion may be initiated based on the rate of hemoglobin decline and the patient's clinical condition, especially during aplastic crises characterized by low reticulocyte counts. An exchange transfusion may be performed in vaso-occlusive crises or severe complications, such as acute chest syndrome or stroke. This procedure involves gradually replacing the patient's blood with a donor or substitute, aiming to decrease sickle cell count, reduce blood viscosity, enhance circulation, and reduce further complications.

Hydroxyurea, oral medication, is a viable option for managing sickle cell anemia. Its mechanism involves stimulating fetal hemoglobin production, thereby inhibiting the sickling of RBCs. Hydroxyurea effectively reduces the frequency and severity of sickle cell crises, decreases the need for transfusions, and improves overall symptoms and quality of life.

Platelet disorders

Patients with thrombocytopenia and clinical evidence of bleeding warrant a platelet transfusion. Those with platelet counts below 10,000/μL face a risk of spontaneous cerebral hemorrhage and thus necessitate prophylactic transfusion. For conditions like HUS and TTP, large-volume plasmapheresis with FFP replacement is the preferred treatment, often requiring daily sessions. Treatment objectives include increasing platelet count, decreasing lactate dehydrogenase (LDH) levels, and reducing RBC fragments as positive indicators of treatment response. Complementary measures, such as high-dose glucocorticoids and antiplatelet agents like aspirin, are often employed alongside plasmapheresis in cases of inadequate response to plasmapheresis interventions such as splenectomy or immunosuppression may be considered. 

Initial management of atypical hemolytic uremic syndrome (aHUS) involves supportive care, similar to the approach used for Shiga toxin-producing Escherichia coli –associated HUS (STEC-HUS). However, for patients with severe complement-mediated HUS, particularly those at risk of death or end-stage renal disease (ESRD), eculizumab, a humanized monoclonal antibody to C5, is recommended. Emerging evidence suggests that early initiation of eculizumab can improve renal and nonrenal recovery.

The primary objective in treating ITP is to maintain a safe platelet count that mitigates clinically significant bleeding, rather than normalizing platelet counts. The bleeding risk occurs when the platelet counts fall below 10,000/µL. Immediate platelet transfusion is recommended for patients experiencing severe bleeding, such as intracranial or GI bleeding, and having a platelet count of less than 30,000/μL. In addition to platelet transfusion, specific therapies for ITP, including intravenous immune globulin (IVIG), glucocorticoids, and romiplostim, are commonly used.

Congenital bleeding disorders

Von Willebrand disease, characterized by deficient or defective von Willebrand factor, can be effectively managed using different approaches. Primary treatment options include desmopressin (DDAVP), recombinant von Willebrand factor (rVWF), and von Willebrand factor/factor VIII (vWF/FVIII) concentrates. These treatments aim to replenish or enhance the function of von Willebrand factor, thereby mitigating bleeding episodes and improving overall clinical outcomes.

Factor VIII and IX concentrates are employed to manage hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency), respectively. The dosage and administration of these concentrates vary depending on the site and severity of bleeding in each patient. This tailored approach ensures effective control of bleeding episodes while minimizing the risk of complications associated with hemophilia.

Disseminated intravascular coagulation

The management of DIC primarily focuses on addressing the underlying cause to eliminate the stimulus for ongoing coagulation and thrombosis. Prophylactic transfusion of platelets and coagulation factors is not recommended when the platelet count remains above or equal to 10,000/μL. However, treatment is warranted in patients with severe bleeding, those at high risk for bleeding complications, or those requiring invasive procedures. Notably, antifibrinolytic agents, such as tranexamic acid (TXA), epsilon-aminocaproic acid (EACA), or aprotinin, are contraindicated in managing DIC.

• Differential Diagnosis

The following conditions should not be overlooked when evaluating patients presenting with anemia. 

• Trauma or blood loss
• Noted GI bleed
• Nonsteroidal anti-inflammatory drug (NSAID) or corticosteroid use
• Alcohol use
• Anticoagulant use
• May present with sudden-onset tearing pain. Loss of consciousness may also occur.
• Recent surgery involving moderate blood loss
• History of bleeding disorders or excessive bruising
• Use of antibiotics
• Excessive menstrual bleeding lasting >7 days
• Iron, vitamin B12, or folate deficiency 
• Macrocytic anemia with leukopenia, macro-ovalocytes, and especially bilineage cytopenias
• Acute leukemias present with pancytopenia and the presence of 20% blasts on peripheral smear
• Chronic leukemias can cause normocytic anemia
• weight loss, malaise, fevers, fatigue
• Known or suspected ingestion of causative drug before the onset
• History of known chronic inflammatory, autoimmune, or infectious states
• Chronic kidney disease or chronic liver disease 
• Most notable in the later stages, such as the third semester 

The prognosis of acute anemia correlates with its severity, rate of development, and concurrent illnesses. [15] [16] [17] [18] [19]  Typically, anemia exacerbates a patient's overall condition, adding further stress to the body and potentially accelerating the progression of underlying diseases or conditions. 

Time is of the essence in managing acute anemia. Failure to promptly identify and address the underlying cause can have severe consequences, potentially resulting in a rapid deterioration of the patient's health. Therefore, timely intervention and appropriate management are paramount to mitigate adverse outcomes associated with acute anemia. 

• Complications

The most severe complication of acute anemia arises from hypovolemic shock caused by significant hemorrhage. Reduced blood volume can lead to tissue hypoxia, precipitating end-organ damage such as heart attack, heart failure, renal failure, acute hypoxic respiratory failure, or other manifestations of organ dysfunction.    

• Consultations

In the management of challenging-to-treat anemias, leukemia patients, or severe cases of ITP, TTP, or HUS, the expertise of a hematology/oncology specialist is essential. Their specialized knowledge and experience are crucial for accurately diagnosing and developing tailored treatment plans for these complex hematologic conditions.

Consultation with a gastroenterologist is essential for GI bleeding cases. Their expertise allows for using techniques like endoscopy to visualize and treat bleeding lesions or ulcers in the GI tract, significantly enhancing the management of GI bleeding.

A surgeon's involvement is crucial in instances of trauma or vascular aneurysm rupture. They possess the skill to execute essential surgical interventions, control bleeding, repair damaged blood vessels, and administer appropriate surgical care to patients in critical conditions.

• Deterrence and Patient Education

Chronic anemia can manifest silently, with the body gradually adapting to lower RBC and hemoglobin levels. Conversely, acute anemia may present with more pronounced signs and symptoms, explaining the underlying cause. However, in acute scenarios, time becomes paramount as healthcare practitioners must promptly identify and address the cause to prevent potential complications.

Collaboration and teamwork among healthcare staff are crucial when managing anemia. Equally important is the patient's cooperation and compliance.

• Pearls and Other Issues

Key facts to keep in mind about acute anemia are as follows:

• Acute anemia is a sudden decline in RBC count, typically precipitated by hemolysis or acute hemorrhage.
• Acute anemia can result from various causes, including trauma, hemorrhage (such as GI bleeding or trauma-related bleeding), hemolysis (such as autoimmune hemolytic anemia or hemolytic transfusion reaction), and other acute conditions.
• Patients with acute anemia may present with symptoms such as weakness, fatigue, pallor, tachycardia, hypotension, shortness of breath, and, in severe cases, shock.
• In cases of acute anemia, it is crucial to prioritize the ABCs and initiate resuscitation as necessary.
• Promptly collect a blood sample for typing and cross-matching and conduct serial CBCs to closely monitor hemoglobin and hematocrit levels throughout the patient's care.
• The initial steps in management involve administering supplemental oxygen, establishing large-bore intravenous access, initiating intravenous fluid resuscitation with crystalloid fluids, and applying direct pressure to any site of hemorrhage to control bleeding.
• Transfusion of pRBCs is indicated when hemoglobin levels drop below 7 g/dL or based on clinical judgment. Typically, each unit of pRBCs increases the hematocrit by about 3 percentage points and the hemoglobin level by 1 g/dL.
• Complications of acute anemia include hypovolemic shock, tissue hypoxia, end-organ damage, and death if left untreated or inadequately managed. Early recognition and intervention are crucial to prevent adverse outcomes.
• Enhancing Healthcare Team Outcomes

In the realm of acute anemia management, various healthcare professionals must collaborate effectively to ensure patient-centered care, optimal outcomes, and safety. Physicians, advanced practitioners, nurses, pharmacists, and other team members should possess proficient skills in recognizing anemia's signs and symptoms, conducting diagnostic tests, and implementing appropriate treatment strategies promptly.

Responsibilities are distributed among team members, with clear communication channels established to facilitate interprofessional collaboration and care coordination. Regular communication updates, shared decision-making, and mutual respect among team members enhance patient safety and contribute to improved outcomes.

The interprofessional team is pivotal in managing acute anemia to improve patient outcomes. Education is a vital component of the care plan, emphasizing patient adherence to prescribed medications like iron supplements and steroids, avoidance of known triggers such as alcohol consumption and NSAID use, and comprehension of the underlying cause of the anemia to prevent future episodes.

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Anemia is a commonly encountered problem in clinical medicine. Broadly categorized, the causes of anemia relate to acute loss, inadequate production, or destruction of red blood cells. Thoughtful review of the complete blood count (CBC) and reticulocyte count combined with examination of the peripheral blood smear leads to the creation of an appropriate differential diagnosis. The mean corpuscular volume, red cell distribution width, and reticulocyte count provide particularly useful information when considered together and sometimes point toward the specific cause of anemia present. This knowledge minimizes the amount of additional laboratory investigation required. Accurate and timely diagnosis facilitates appropriate therapeutic intervention.

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Marks, P.W. (2019). Anemia: Clinical Approach. In: Lazarus, H., Schmaier, A. (eds) Concise Guide to Hematology. Springer, Cham. https://doi.org/10.1007/978-3-319-97873-4_4

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Rational diagnostic work-up of anemia

Anemia is defined as a decrease in the hemoglobin concentration below the age- and sex-specific lower limit, established by WHO as 130 g/L in men and 120 g/L in women. In principle, there are many differential diagnoses which must be considered. The diagnostic evaluation furthermore is complicated by the fact that anemias are often multicausal. A rational evaluation of anemia should always take into account the epidemiological data and also the individual patient’s history. The classification according to the size and the hemoglobin content of the red blood cells based on the erythrocyte indices still plays a central diagnostic role. The worldwide most important cause of a hypochromic-microcytic anemia is iron deficiency. Anemia of chronic disease (ACD) and thalassemia are to be considered as differential diagnoses. Disorders of vitamin B12 and folic acid metabolism are clinically the most important causes of hyperchromic-macrocytic anemia. The normochromic-normocytic group includes most forms of anemias. In these cases one should not try to cover all possible causes by a fully comprehensive laboratory panel within the first blood sample already. It is more appropriate to proceed step-by-step to evaluate the most frequent and clinically most important reasons first. This especially applies to geriatric and multimorbid patients where the diagnostic effort must be adjusted to the individual needs and prognosis of the patient, not only from economical but also from ethical reasons. In unexplained anemias, consultation of a hematologist should be considered. In case of doubt, bone marrow biopsy is required to precisely evaluate the hematopoiesis and to exclude a hematological disorder.

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Introduction.

Anemia is defined as a decrease in hemoglobin concentration (Hb) below the age- and sex-specific reference values. Larger laboratories usually establish their own normative data based on regional measurements. Epidemiological studies mostly rely on the criteria set by a WHO expert group in 1968 [1]. According to this, the hemoglobin concentration depends on both age and sex with lower hemoglobin limits of 120 g/L for women and 130 g/L for men ( Table 1 ).

Lower hemoglobin limit depending on age and sex according to the WHO [1].

A low hemoglobin concentration can have negative effects on the cardiovascular system, cognitive functions and quality of life. However, rather than being a disease itself, anemia should be considered the result of an underlying congenital or acquired disease or disorder. Therefore, the clinical picture of anemia is coupled with a wide array of differential diagnoses which the clinician should consider carefully. Given the high prevalence of anemia [2, 3], the diagnosis should be based on sound reasoning in order to minimize laboratory investigations and costs. Although it is obviously desirable to have a diagnostic approach tailored for an individual patient, it may be best to follow a standardized protocol and modify that as required by individual circumstances.

Epidemiology

In clinical practice, this standard protocol starts with a patient-based evaluation of the epidemiological data that one keeps at the back of one’s mind. You will encounter frequently that which is frequent but only rarely that which is rare (“if it’s rare it’s not on my chair”). This applies not only to general practitioners, but also to hospitals and – except for specialist outpatient clinics – university hospitals.

In children and adolescents, iron deficiency anemia and thalassemia are by far the most common forms of anemia in Europe – at least an order of magnitude more common than any other form [1, 4, 5].

In adults, anemia is mostly caused by an impaired iron supply for erythropoiesis. Premenopausal women and pregnant women are primarily affected by genuine, absolute iron deficiency. In those aged 65 and older, anemia of chronic disease (ACD), pathophysiologically due to disturbed iron metabolism, is the most common type of anemia accounting for approximately 20% of cases. Other frequent causes of anemia in geriatric patients include malnutrition and chronic renal insufficiency [2, 6–11].

Case history

Considering the patient’s history is an essential part of diagnosing anemia. The cause of anemia can be identified more effectively and more cost-efficiently if one knows about the patient’s social background, eating habits, as well as family and medical history. In this context, the clinical assessment of the anemia symptoms is also important. In other words: is there also a clinical manifestation of the decreased hemoglobin level or could it be merely related to the applied reference value. Older men are a good example. The physiological drop in testosterone level results in a decrease in hemoglobin, a fact that is not considered in the WHO reference ranges. Thus, a hemoglobin level of 120 g/dL obtained in an asymptomatic 80-year-old man is usually no reason to initiate an extensive diagnostic work-up.

Laboratory diagnostics

The first steps in the evaluation of anemia depend on the laboratory screening panel initially used. Typically, this includes the complete blood count, consisting of hemoglobin, red blood cell count, hematocrit, the erythrocyte indices mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), the number of platelets and leukocytes, as well as the differential blood count. Reticulocytes usually have to be ordered separately and are not typically available at the initial evaluation.

First, one should look at the differential blood count. When blasts are detected, it is indicative of a serious, underlying hematological disease that requires immediate admission, or referral to a hematologist. Also with a white blood cell count of over 25×10 9 /L and in the absence of other obvious causes, the patient should be referred to a specialist in order to exclude a hematologic neoplasm. Although platelet counts above 500×10 9 /L can also occur reactively, for example, in the context of iron deficiency, a myeloproliferative neoplasm should be assumed unless proven otherwise.

In the case of an isolated anemia, the further diagnostic measures depend on the size and hemoglobin content of the erythrocytes. If the reticulocyte count is already available at this point, the anemia can be divided into a hyper-regenerative (reticulocytes >100/μL) and a hypo-regenerative form. This distinction is valuable because a hyper-regenerative anemia really only occurs, with the exception of therapy-related regenerations, in a subacute hemorrhage or hemolytic anemia. Both cases require immediate action in the form of further diagnostics or intensive medical care.

If the reticulocytes are not elevated, or they are not yet available, an initial diagnosis has to be based on the red cell indices , MCV and MCH. The classification is then made in favor of hypochromic-microcytic (MCH <27 pg, MCV <80 fL), normochromic-normocytic (MCH 27–34 pg; MCV 80–96 fL) or hyperchromic-macrocytic (MCH >34 pg; MCV >96 fL). This “time-honored” classification is still valid from the clinical perspective because it ensures that the most important types of anemia, and in particular those with the most severe consequences, are not being missed ( Figure 1 ). A hypochromic-microcytic anemia is to be considered the result of an iron deficiency, and to be investigated as such, until proven otherwise. In the case of a hyperchromic-macrocytic blood count, one initially assumes a vitamin B12/folic acid deficiency and acts accordingly in order to prevent permanent damage to the patient.

Classification of anemia according to the red cell indices.

Hypochromic-microcytic anemia

In theory, there are several possible causes of hypochromic-microcytic anemia ( Figure 1 ). But only three of them matter in clinical practice: iron deficiency anemia, ACD and thalassemia. What are the typical characteristics of these forms of anemia and how can one tell them apart most easily?

Iron deficiency anemia

A negative iron balance first causes a storage iron depletion (stage I), where the total body iron is decreased, without the synthesis of hemoglobin being affected. In this stage, there is no immediate clinical dysfunction. In stage II, the iron-deficient erythropoiesis, iron deficiency becomes a disease, as the amount of iron is no longer sufficient to meet the requirement of the erythropoietic precursors in bone marrow. The hemoglobin concentration, however, is still within the reference range. Finally, when the iron supply is insufficient to maintain a normal hemoglobin concentration, stage III of iron deficiency, the iron deficiency anemia ( Figure 2 ), is reached.

Peripheral blood film of a patient with an iron deficiency anemia.

The erythrocytes are smaller than normal red blood cells. As a result of the lack of hemoglobin, there is an increase in central pallor, which occupies more than the normal approximate one-third of the red cell diameter. Most erythrocytes appear ring-shaped, known as anulocytes.

There are several iron parameters that can be used to assess the iron metabolism of a person. It is, however, important always to bear in mind that these tests indicate something different in terms of iron deficiency [12]. The individual parameters do not measure a single entity called “iron deficiency” but they are related to a specific stage of iron deficiency ( Figure 3 ). Ferritin reflects the amount of iron stored, but says nothing about the iron supply for the red cell precursors in bone marrow. This requires other parameters which allow to monitor the supply of the erythropoiesis with iron. These include zinc protoporphyrin (ZPP), the soluble transferrin receptors (sTfR), the hypochromic erythrocytes (HYPO) and reticulocyte hemoglobin (CHr). An indirect indication of iron-deficient erythropoiesis is provided by a reduced transferrin saturation of ≤15%. Finally, a hemoglobin analysis is required to confirm the drop in hemoglobin below the lower limit and, thus, to diagnose the most severe form of iron deficiency, the iron deficiency anemia [13]. Consequently, there is no such thing as the “best iron parameter”. In detecting different stages, the various tests, however, efficiently complement one another in order to characterize the severity of the iron deficiency in the individual patient.

Laboratory parameters of iron metabolism and their sensitivity.

According to WHO recommendation, the best way to determine the iron status of an individual is to analyze the serum ferritin level [14]. From the theoretical point of view, this is correct, because ferritin is the only laboratory parameter that reflects the iron stores and, thus, captures iron deficiency at the earliest stage. A serum ferritin <12 μg/L is deemed proof of storage iron deficiency. However, even levels <22 μg/L seem to be associated with a clinically relevant storage iron depletion [15].

There is, however, a potential problem when using ferritin as a screening parameter of iron deficiency, because ferritin is also an acute-phase protein that co-reacts in connection with inflammatory disorders, as well as in liver diseases. Therefore, ferritin measurement is only of limited use in particular in multimorbid patients. Caution should be exercised in this regard also in the case of the elderly: Aging goes hand-in-hand with a subclinical inflammatory process that can elevate the serum ferritin concentration and, thus, mask an existing iron deficiency [16].

The general recommendation in connection with a normal or elevated ferritin level is that an additional acute-phase protein should be examined in order to rule out a false-normal ferritin concentration [17]. As a rule, the C-reactive protein (CRP) is used for this purpose. But this does not quite solve the problem yet, since ferritin exhibits a different dynamics than CRP in the inflammatory process, which causes that about 15% of cases of iron deficiency are not detected even when this tandem analysis is employed. Meanwhile, recommendations have been issued that suggest that the α1-acid glycoprotein should be used as a further acute-phase protein in addition to CRP. But this does not make the diagnostics any cheaper [18].

Given the diagnostic uncertainty of ferritin, there is a clear need for a diagnostic alternative, particularly in multimorbid patients. This alternative is provided by the parameters of iron-deficient erythropoiesis that monitor the iron supply for erythroid precursors. ZPP is of particular diagnostic value. It is produced instead of heme when the iron support to the erythropoiesis becomes insufficient and zinc, instead of iron, is incorporated into protoporphyrin IX. The measurement therefore captures all disturbances of the iron metabolism, not only the absolute iron deficiency [19, 20]. False-elevated levels, by contrast, are measured only in the very rare congenital, erythropoietic porphyria. The ZPP analysis prompts the clinician to the following question: “Does the anemia have anything to do with iron?” The clear answer: yes, or no. Values within the normal range rule out disorders of the iron metabolism except for an isolated depletion of the iron stores (stage I). Elevated levels provide proof of iron-deficient erythropoiesis, and also allow for an assessment of their clinical significance. Typically, you would consider an anemia when the ZPP reaches twice the standard value, ie ZPP >80 μmol/mol heme. In the case of severe forms of anemia with a hemoglobin level <90 g/L, ZPP is usually >200 μmol/mol heme, and a long-lasting iron-deficient erythropoiesis can produce concentrations of up to 1000 μmol/mol heme.

To proof the existence of an iron deficiency beyond doubt requires the analysis of one of the parameters of the iron-deficient erythropoiesis in addition to ferritin ( Table 2 ). Here, HYPO, CHr and sTfR have a key advantage over ZPP, because their analysis was automated. However, they do not solely depend on the iron metabolism, which means that other factors, too, must be considered when interpreting them. For HYPO and CHr, these are generally all factors that affect the erythrocytic hemoglobin concentration, but also, above all, those that cause a hyperchromic blood count. In the case of sTfR, it is especially the quality and quantity of erythropoiesis that is reflected in the measured serum levels, apart from the iron metabolism [21]. Chronic lymphocytic leukemia, too, causes an increase in the sTfR concentration in correlation with the tumor burden, even though there is no iron deficiency present [22].

Typical constellation of iron parameters at different stages of iron deficiency.

Depending on the desired sensitivity and specificity, different cut-off values were proposed for HYPO and CHr in the past. Now, the preferred proof of iron-deficient erythropoiesis is usually HYPO >5% and CHr <28 pg [23]. The situation is somewhat more complex for sTfR. The parameter is measured using different methods that use calibrators with varying degrees of transferrin affinity. This results in test-dependent reference values, some of which differ from each other quite considerably (e.g. 0.4–1.8 mg/L for Dade Behring and 0.7–4.2 mg/L for Nichols Institute). In addition, reference values were not always obtained from individuals whose iron metabolism had been studied carefully. Consequently, the “normal population” also included people with an iron deficiency. This can be seen when considering the different reference values for males and females, even though people without an iron deficiency do not exhibit any sex-specific differences in their sTfR concentration. Furthermore, the manufacturer’s reference values were partially revised on the basis of investigations done on a group of individuals whose iron status was defined precisely [15, 24]. In order to fully exploit the potential of this diagnostically superior parameter, it is therefore recommended to check the quality of the stated reference values against the literature, or even to derive one’s own reference values for the sTfR test used.

Anemia of chronic disease

Anemia of chronic disease (ACD) is also caused by an iron-deficient erythropoiesis. In contrast to the genuine, absolute iron deficiency, the iron deficiency in the context of ACD is only of a functional nature. The pathogenesis of ACD is complex and multifactorial. The focus is on hepcidin-triggered iron deprivation, which puts the body in a state of functional deficiency. Although iron is abundantly available in the body, to provide an unspecific defense mechanism, it is blocked within the reticulo-endothelial system. As a result, iron is unavailable to the pathogen or the inflammatory process – but unfortunately also to the erythropoiesis [25–27].

Any inflammatory or malignant process can induce ACD, but only if it persists for, typically, at least six to eight weeks. Particularly noteworthy here are autoimmune diseases (e.g. polymyalgia rheumatica, rheumatoid arthritis, systemic lupus erythematosus), chronic infections (e.g. tuberculosis, osteomyelitis, endocarditis) and malignancies. A substantial amount of the anemia of the elderly is also ACD, caused by cytokine imbalance. Acute inflammation also causes an iron blockade, but this is without clinical significance due to the short duration of the disease and the long life span of the erythrocytes.

ACD plays an important role in clinical practice. It is, in fact, regarded as the most common type of anemia in hospitalized patients and the elderly [6, 7, 10]. However, it must be emphasized that not every anemia occurring in a chronic disease is ACD; it is only those that can be linked pathophysiologically to a cytokine-induced derangement of iron metabolism. Therefore, the epidemiological surveys on ACD should be treated with caution, since the diagnosis in such cases is usually based only on a ferritin and/or CRP analysis.

ACD can only be proven beyond doubt by examination of a Prussian blue stain of a bone marrow smear. This can confirm both the sufficient amount of iron in reticulo-endothelial stores and the iron-deficient erythropoiesis, which becomes obvious by decrease of the iron-containing red cell precursors. A bone marrow biopsy is of course not always possible, nor is it necessary in most cases to arrive at a reliable ACD diagnosis.

The key task of ACD diagnostics consists in confirming iron-deficient erythropoiesis and ruling out an absolute iron deficiency. This can be done very easily with two parameters, ZPP and sTfR. ZPP captures all derangements of iron metabolism, including those related to ACD [28]. The sTfR concentration, on the other hand, is elevated only in the case of a genuine, absolute iron deficiency; with ACD, it remains within the reference range [29, 30]. Valuable information is also obtained from the ZPP level: levels >150 μmol/mol heme are observed only in connection with a very severe form of ACD. ZPP >200 μmol/mol heme virtually never occurs with ACD, and suggests an iron deficiency anemia. In other words, the insufficient iron supply for erythropoiesis in the case of ACD is not as pronounced as in an anemia that is caused by absolute iron deficiency. Accordingly, the ACD in most cases is normochromic-normocytic. A hypochromic-microcytic blood count develops only after a long and severe course of the chronic illness. However, MCV levels <70 fL are practically never reached.

Of course, one can ignore ZPP and sTfR and work only with the traditional parameters, but the diagnostics would then be more difficult and not entirely clear, particularly if the erythrocytes are only borderline microcytic. Decreased transferrin saturation in such cases points to an iron-deficient erythropoiesis. CHr <28 pg confirms a current insufficient supply for erythropoiesis, while an increase in HYPO >5% indicates that the insufficient supply has already persisted for some time. But none of this makes any difference between iron deficiency anemia and ACD. By this point, at the latest, one must analyze the sTfR, or rely on elevated ferritin. CRP does not really help much in this situation. Although elevated CRP is traditionally part of ACD, it also renders the assessment of elevated ferritin more difficult, by signaling that the ferritin might also be false-normal. In other words, iron deficiency anemia would produce precisely the same laboratory constellation in connection with an acute inflammation. To be honest, one must admit that in clinical practice, and when an underlying chronic disease is known, ACD diagnoses have been only assumptions more often than they have been confirmed beyond doubt. It would help diagnostically to know the serum level of hepcidin, which is reduced with iron deficiency anemia and elevated with ACD [31, 32]. Several laboratories now offer this parameter and we would expect that it will play a key role in the differential diagnosis in the future. It has not been standardized yet, which means that the measured values depend on the method (ELISA, mass spectrometry) and standard used and on the respective ability to capture the isoforms hepcidin-20 and hepcidin-22 in addition to the bioactive hepcidin-25 [33].

Patients with ACD and a co-existing iron deficiency, not uncommon in rheumatoid arthritis, present a particularly challenging constellation. Diagnosis with conventional iron parameters was notoriously problematic and could generally only be made by bone marrow biopsy. In those cases, too, sTfR proved extremely helpful after it had been shown that it is able to detect absolute iron deficiency even in combination with a chronic inflammation. As long as sTfR is within the reference range, one assumes a “simple” ACD in patients with chronic inflammatory diseases. If, however, the sTfR concentration is elevated the diagnosis changes in favor of an ACD with a co-existing iron deficiency [15, 24]. This challenging differential diagnosis underlines the demand for a clear cut-off value to be applied to sTfR in order to differentiate between patients with and without iron deficiency.

To improve the diagnostic reliability of sTfR for confirming or ruling out iron deficiency in complex cases of anemia, the TfR-F index was introduced [15, 24]. This parameter represents a ratio of the serum sTfR value and the common logarithm of serum ferritin concentration. It can be used to distinguish between patients with iron deficiency and those without: patients with iron deficiency exceed a cut-off value. Our preference is in favor of separate interpretation of the individual parameters sTfR and ferritin. This is based on the following reasons. First, the index reduces two meaningful parameters to a single, imaginary value. Second, in our study we have not been able to show the superiority of the TfR-F index [22]. Finally, the cut-off values of the TfR-F index are test-dependent (see above) and in some cases differ substantially from each other (R&D Systems: >1.5; Dade Behring: >1.5; Orion Diagnostica: >2.2; Nichols Institute: >3.5; Roche Diagnostics: >3.8), which does not facilitate the diagnosis. When the interpretation of the sTfR results becomes problematic as in conditions with increased erythropoiesis or in chronic lymphocytic leukemia, the sTfR-F index does not provide any diagnostic help when compared to the sole sTfR analysis [34].

To estimate the proportion of the erythropoiesis on the concentration of sTfR, and to consider it in the differential diagnosis, the “Thomas plot” combines the TfR-F index with CHr as a second parameter of iron-deficient erythropoiesis that is independent of the erythropoietic activity [23]. Even though the above objections to the TfR-F index apply here as well, and the cut-off value of TfR-F is not only test-dependent, but also shifts relative to CRP, the four-quadrant plot provides a rough guide for classifying anemias: anemias can be assigned to one of the four quadrants depending on their cause. Quadrant 1 (TfR-F index <cut-off, CHr >28 pg) contains anemias with a normal hemoglobin content, with normal or reduced erythropoiesis (e.g. ACD, renal anemia, hypo-regenerative anemias, myelosuppression), while Quadrant 2 (TfR-F index >cut-off, CHr >28 pg) contains hyper-regenerative anemias and iron deficiency anemias undergoing substitution therapy and/or cases with slight iron-deficient erythropoiesis. Typical iron deficiency anemias are located in Quadrant 3 (TfR-F index >cut-off, CHr <28 pg) and anemias involving derangements of iron metabolism and disorders causing a reduced hemoglobin production (e.g. severe ACD, ACD combined with iron deficiency, thalassemia), in Quadrant 4 (TfR-F index <cut-off, CHr <28 pg).

Thalassemia

In the case of thalassemia, the hypochromic-microcytic blood count is due to a deficit in hemoglobin production, resulting from a genetically caused, reduced or absent function of one or more globin genes. Since hemoglobin, from the seventh month of life, physiologically consists of 95%–98% HbA 1 , composed of two α and two β chains, only the α and β thalassemias are important in clinical practice. The clinical picture and also the laboratory parameters may vary greatly depending on the respective genetic mutation and the number of affected genes.

β-Thalassemia major ( Figure 4 ) generally does not cause diagnostic problems. It is characterized by a severe, transfusion-dependent hypochromic-microcytic anemia (mostly since early infancy) that is caused by a severe reduction or total lack of synthesis of the β globin chains.

Smear of peripheral blood in the case of a transfusion-dependent β-thalassemia major.

One sees an abundance of hypochromic anulocytes whose cell membrane is only slightly covered with hemoglobin, as well as individual target cells. Howell-Jolly bodies are present in some erythrocytes due to a splenectomy in the past, as are numerous Pappenheimer bodies (siderocytes), which indicate derangement of iron metabolism. Between the patient’s own erythrocytes, one can see transfused donor erythrocytes, one erythroblast and numerous platelets. Laboratory, see Table 4 , patient 14.

More difficult is the recognition of a β-thalassemia minor , in which case the production of the β chains is only slightly reduced, so that often no or only mild anemia occurs. Nevertheless, it results in a hypochromic-microcytic blood count that does not match the marginally normal hemoglobin, therefore allowing the differential diagnosis from an iron deficiency anemia. Another difference from iron deficiency anemia is the mostly normal MCHC (normal: 32–36 g/dL) and minimal anisocytosis (red cell distribution width, RDW <15%). The disease is confirmed by hemoglobin electrophoresis or HPLC by detecting elevated HbA 2 (normal: <3.2%). However, it should be noted that the production of HbA 2 is selectively reduced in connection with iron deficiency, so that iron deficiency can mask a β-thalassemia minor. In this context, ZPP is helpful because it can exclude a significant iron-deficient erythropoiesis and substantiate the HbA 2 finding. However, the ZPP analysis is generally useful in cases of suspected thalassemia. In contrast to iron deficiency anemia, it is normal or only slightly elevated in thalassemia minor, and thus already resolves the differential diagnosis. Elevated ZPP value measured in a case of thalassemia minor points to additional iron deficiency. Ferritin does not help with the differential diagnosis. It does check the iron stores, but does not allow for any conclusions about the iron supply for erythropoiesis. In cases of β-thalassemia intermedia , ZPP of up to 100 μmol/mol heme can be observed. This increase is due to the significantly elevated, ineffective erythropoiesis when the system capacity for an optimal iron support is exceeded. Similar observations are made with other highly hyper-regenerative anemias.

In α-thalassemia , the situation is somewhat more complicated. The existence of the α chain (being the most important globin chain) is secured by four α genes. The failure of all four genes is incompatible with survival and ends in hydrops fetalis. The absence of three genes results in a chronic hemolytic anemia with hemoglobin levels of 60–100 g/L, as well as in a significant reduction in MCV, MCH and MCHC and a pronounced anisocytosis with elevated RDW. The diagnosis is confirmed by means of hemoglobin electrophoresis or HPLC with detection of hemoglobin H (HbH) consisting of four β chains. If so suspected, HbH-containing erythrocytes can be easily detected by their classic golf ball morphology using brilliant cresyl blue supravital staining. This requires, however, a staining incubation time of 3–4 h.

While the severe forms of α thalassemia can hardly be overlooked, the loss of one or two α genes, a condition known as α-thalassemia trait, poses a real diagnostic challenge. The patients are clinically asymptomatic and have normal hemoglobin levels. However, the red cell indices are usually lowered, which is often misinterpreted as iron deficiency. Thus, one should always suspect an α-thalassemia trait when a person of an appropriate ethnic group has a hypochromic-microcytic blood count, is not iron deficient and has a normal hemoglobin electrophoresis and normal HbA 2 – at least until proven otherwise. Real proof of the α-thalassemia trait can only be obtained by DNA analysis. Hemoglobin electrophoresis and HPLC yield normal readings, except during the neonatal period when a low amount of hemoglobin Bart’s (γ 4 ) and HbH may be detected.

Practical consequences

What are the consequences for clinical practice? An “all-inclusive panel” that allows for an adequate clarification of the main causes of hypochromic-microcytic anemia, in our view, would contain the following parameters: reticulocytes, ferritin, transferrin saturation, ZPP, sTfR, CRP, ALAT, hepcidin and hemoglobin electrophoresis. It is obviously of benefit to adapt or condense this panel for each patient. For example, in young women with hypochromic-microcytic anemia, a ferritin analysis is usually diagnostically sufficient. Hemoglobin electrophoresis is generally carried out only when there is a real suspicion of a hemoglobin abnormality, or in case of an unexplained anemia.

When determining an iron supply deficiency for the erythropoiesis, preference is frequently given to HYPO and CHr over ZPP, because ZPP analysis cannot yet be automated. Regardless, we prefer ZPP because it is the only parameter that detects directly, selectively and quantitatively an iron-deficient erythropoiesis and not only its consequences.

Hyperchromic-macrocytic anemia

The group of hyperchromic-macrocytic anemias comprises mainly the types of anemia that are caused by an impairment of cell division – primarily by an impairment of DNA synthesis. The most important clinical causes are vitamin B12 and folic acid deficiency [35–39].

Pathophysiological similar are anemias that are associated with medications that affect the folic acid metabolism as well as all those that impair DNA synthesis such as cytostatics or immunosuppressants. When it comes to minimal macrocytosis with only marginally increased MCV, one must also consider alcohol-induced anemia and, particularly, hyper-regenerative hemolytic anemia, because the reticulocytes are substantially larger than normal erythrocytes, which shifts the MCV up. Myelodysplastic syndromes (MDS) constitute an important differential diagnosis in geriatric patients. Macrocytic anemia, caused by impaired DNA synthesis and cell division, is also often observed in these cases. MDS is, however, rare in people younger than 50.

Vitamin B12 and folic acid

The clinically most important anemia in this group is caused by an impaired folic acid/B12 metabolism. Based on the characteristic bone marrow appearance with a predominance of conspicuous red cell precursors, known as megaloblasts, it has been given the generic name megaloblastic anemia. The DNA synthesis derangement in these cases is due to an impairment of thymidylate synthase, accompanied by a reduced conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. This reaction requires folic acid, which in turn needs vitamin B12. Vitamin B12 demethylates the folic acid and, thus, renders it functional. The separated methyl group is transferred to homocysteine, which is converted to methionine as a result. A serum analysis for homocysteine, therefore, offers a simple way of checking this, highly complex, metabolic pathway. Serum homocysteine is elevated ( Figure 5 ) if there is a lack or any other impairment of vitamin B12 and/or folic acid. However, with only borderline elevated levels, one must keep in mind that the increase in homocysteine can also have other causes, primarily renal failure, alcohol abuse and, in particular, technical problems in processing the blood sample [40]. The diagnostically more reliable alternative in checking the entire vitamin B12 metabolism is believed to be the measurement of the plasma concentration of methylmalonic acid (MMA) – the MMA analysis is more sensitive and more specific than that of homocysteine. But it is also significantly more expensive and not available everywhere. It is therefore used in clinical practice only in diagnostically problematic cases. As is true of homocysteine, the MMA concentration, too, can be false-elevated in renal insufficiency [40].

About 80% of vitamin B12 in peripheral blood is bound to a glycoprotein from the group of transcobalamins, haptocorrin (formerly transcobalamin I).

This complex is referred to as holo-haptocorrin (Holo-HC) and is biologically inactive. Its task presumably consists of returning excess vitamin B12 to the liver. The supply for the cells is the sole responsibility of holo-transcobalamin II (Holo-TC), which carries only around 20% of vitamin B12 in peripheral blood. Holo-TC binds to a specific transcobalamin II receptor (TCR). This is then absorbed into the cell as part of a vesicle. After this bond is broken down, the TCR is recycled, the transcobalamin II is broken down lysosomally, and vitamin B12 is supplied to the cell. The vitamin-B12-dependent reactions are impaired in the case of an intracellular lack of functional vitamin B12. From the diagnostic point of view, the impaired breakdown of homocysteine and methylmalonyl-CoA is significant, because one can analyze these parameters in peripheral blood to check the functionality of the entire vitamin B12 metabolism.

The preferred clinical practice is the serum analysis of the individual parameters vitamin B12 and folic acid, rather than doing a global check of the entire system. A cut-off of 200 ng/L has traditionally been applied to vitamin B12, upon several studies had shown that 60%–80% of people with a level <200 ng/L suffer from a clinically significant vitamin B12 deficiency [40]. However, higher levels do not rule out a clinically relevant vitamin B12 deficiency. This has to do with the fact that around 80% of the vitamin circulating in the blood is bound to haptocorrin, in a biologically inactive complex. Only a small fraction that is bound to transcobalamin II, known as holo-transcobalamin (Holo-TC), is biologically active and capable of supplying cells with vitamin B12. Holo-TC tests are now commercially available, and are offered and recommended particularly at the early stage of vitamin B12 deficiency. This test also makes sense in the context of an unexplained hyperchromic-macrocytic anemia in order to check the vitamin B12 supply for erythropoiesis. The reference range for Holo-TC is 40–200 pmol/L. Lower values indicate a deficiency of bioactive vitamin B12 [41].

In the case of folic acid, one must note that the serum folic acid concentration only reflects the situation of the last one to two weeks and that it does not rule out anemia caused by folic acid deficiency. To do so, one must examine the erythrocytic folic acid, which allows for an assessment of the last 2–3 months, according to the lifespan of the red cells. Considering that the folic acid in the erythrocytes represents 95% of the total folic acid in the blood, it is clear that even a minimal hemolysis can distort the folic acid concentration significantly.

The morphological findings of the vitamin B12/folic acid deficiency in the bone marrow, with markedly elevated, left-shifted, ineffective erythropoiesis, are reflected in the hemolysis parameters. LDH is considerably elevated and is mostly around 1000 U/L; bilirubin is slightly elevated, at around 2 mg/dL. Deficiency of vitamin B12 and folic acid does, however, not only affect erythropoiesis, but the entire hematopoiesis. Thus, the picture of a severe vitamin B12 and/or folic acid deficiency may also include leukopenia with hypersegmented neutrophils and thrombocytopenia with levels that can fall below 50×10 9 /L.

Given the rather complex metabolism ( Figure 6 ), a vitamin B12 deficiency can have a wide range of causes. First of all, one must rule out pernicious anemia, an autoimmune disease with type A gastritis and antibodies against the intrinsic factor and parietal cells. Gastric cancers are frequent with pernicious anemia, so that patients require regular gastroenterological monitoring. However, a vitamin B12 deficiency may also occur in other malabsorption disorders (atrophic gastritis, gastric resections, exocrine pancreatic insufficiency, bowel resections, vitamin-B12-consuming intestinal bacteria, fish tapeworm, Crohn’s disease, coeliac disease, Zollinger-Ellison syndrome, calcium deficiency). Other causes include inadequate intake (vegans, alcoholics, goat’s milk), increased demand (pregnancy, hemolysis, neoplasias, hyperthyroidism), medications (colchicine, neomycin, metformin), inactivation by nitrous oxide, or congenital problems (intrinsic factor abnormalities, transcobalamin deficiency, Imerslund-Gräsbeck syndrome).

Scheme of the vitamin B12 metabolism.

The dietary supply of vitamin B12 is through animal source foods, broken down in the stomach (if digestion works properly) and bound to haptocorrin. In the duodenum, this compound is cleaved by pancreatic enzymes and vitamin B12 is transferred to the intrinsic factor, under the protection of which it reaches the terminal ileum. Here, at a pH >5.4 and in the presence of Ca 2+ , it binds to intrinsic factor receptors and is absorbed. The absorbed vitamin B12 is first taken up by transcobalamin II. Most of the vitamin, however, is transferred in the liver to haptocorrin and secreted via the bile into the duodenum, creating an enterohepatic circulation. Thanks to the enterohepatic circulation, the human organism is able to compensate a complete lack of vitamin B12 intake for 3–6 years, although the physiological body stores of vitamin B12 are only 2–5 mg.

Apart from an insufficient supply, folic acid deficiency can be caused particularly by an increased demand (pregnancy, hemolysis, neoplasias, stress). Other causes include drugs (barbiturates, anticonvulsants, contraceptives, sulfasalazine) and in particular folic acid antagonists used for therapeutic purposes (methotrexate, pemetrexed, sulfonamides, trimethoprim, pyrimethamine, triamterene). Congenital causes (dihydrofolate reductase deficiency, formiminotransferase deficiency), however, are rare.

Myelodysplastic syndromes

Myelodysplastic syndromes (MDS) represent a heterogeneous group of diseases that are predominantly diagnosed in the elderly [42]. The peak incidence is between 70 and 80 years of age; before 50 years of age, MDS is rare. The common feature of MDS is an ineffective hematopoiesis, which affects one or more cell lines. The bone marrow is usually normocellular, or even hypercellular, while cytopenias are found in peripheral blood. The clinical picture depends on the affected cell line and on the degree of cytopenia. The full picture of MDS is characterized by a pronounced pancytopenia with transfusion-dependency, susceptibility to infection and bleeding. In 20%–30% of cases, a transformation to acute myeloid leukemia occurs.

Most MDS patients present with a more or less severe anemia, which is typically normochromic and normocytic or macrocytic. The number of reticulocytes may be normal or reduced. This also applies to sTfR, where serum concentration is typically normal, or even decreased, in spite of the increased erythropoiesis due to the poor maturation of the red cells. A particular MDS entity is the so-called 5q – syndrome, which is cytogenetically characterized by a deletion of the short arm on chromosome 5. The disease affects mainly older women and is characterized by a mostly isolated, macrocytic anemia.

In the presence of hyperchromic-macrocytic anemia, vitamin B12 and folic acid deficiency must initially be excluded. The laboratory panel used should include at least reticulocytes, LDH, bilirubin, vitamin B12 serum level and erythrocytic folic acid. To also identify more complex disorders, we recommend serum homocysteine to be added to the battery of laboratory tests. In the case of a vitamin B12 deficiency, it is necessary to confirm or rule out a pernicious anemia (gastroscopy, antibodies). If the cause of a macrocytic anemia remains unclear and also not be explained on the basis of a patient’s history regarding eating habits, comorbidities and medication, the patient should be referred to a hematologist in light of the required substantial diagnostic effort.

Macrocytic anemia in people aged 50 or older warrants special attention. If the blood count in this patients group can neither be explained by a vitamin B12 and/or folic acid deficiency, nor normalized by way of substitution, one should first (and foremost) assume MDS. Here, too, the patient should be referred to a hematologist, because even a suspected diagnosis already warrants a timely bone marrow biopsy, including cytology, histology, flow cytometry, cytogenetics and molecular testing.

Normochromic-normocytic anemia

In contrast to hypochromic-microcytic and hyperchromic-macrocytic anemias, which are usually relatively easy to clarify, normochromic-normocytic anemias frequently pose a real diagnostic challenge to the clinician. On the one hand, this has to do with the fact that this group comprises most types of anemia. On the other hand, anemias often have more than one cause. In fact, they are multfactorial in about 30% of cases [9]. If several components co-exist, they can mask classical types of anemia, so that also iron deficiency, or vitamin B12 and/or folic acid deficiency can give rise to a normochromic-normocytic anemia.

There is one diagnostically important question that should be answered right at the start of doing a work-up on this anemia group: Is the anemia hyper- or hypo-regenerative? Traditionally, this question is answered by the measurement of the reticulocytes. Hyper-regenerative anemias are characterized by a reticulocyte count >100/μL, the counts are lower in hypo-regenerative types. A hyper-regenerative anemia may be caused by an elevated erythropoiesis during or following therapy (chemotherapy, erythropoietin substitution, vitamin B12 or iron substitution), but also by a subacute hemorrhage or hemolysis. A subacute hemorrhage requires immediate referral and consideration by internal and particularly gastroenterological specialists.

The suspected diagnosis of hemolysis is substantiated by an increase in LDH and indirect bilirubin, as well as by a reduction in haptoglobin. In the presence of hemolysis, one should first look at the patient’s history and find out whether a congenital disorder of the red blood cells (disorder of hemoglobin synthesis, enzyme defect, defective membrane) could be the underlying cause ( Figure 7 ). The assessment of the peripheral blood smear is then followed by hemoglobin electrophoresis in these cases, as well as by measurement of the erythrocyte enzymes (G6PDH, pyruvate kinase), analysis of osmotic fragility and the EMA test (spherocytosis). Given the costs of these specialized tests, they are usually ordered by a hematologist.

Work-up of hemolytic anemia.

If congenital anemia is unlikely, the next step should be about ruling out fragmentocytes and, thus, a microangiopathic anemia in connection with thrombotic thrombocytopenic purpura (TTP) or a hemolytic uremic syndrome (HUS), because it constitutes a therapeutic emergency that must be treated immediately by plasmapheresis [43, 44]. This diagnosis should be considered first and foremost when the patient is young and has thrombocytopenia. If microangiopathic anemia is suspected, it is recommended to measure the activity of metalloprotease ADAMTS13 before starting the treatment [45].

Exclusion of microangiopathic anemia is followed by the Coombs test to verify an immunohemolysis [46]. In this context, one should keep in mind that five to ten percent of immunohemolytic anemias are Coombs test negative [47]. This can be the result of a range of causes. Generally, though, this is due to the fact that the autoantibodies in these cases are more effective than the Coombs serum used in the test, which reacts only once there is a load of 500 IgG molecules per erythrocyte. IgG 3 and IgA autoantibodies, in particular, cause hemolysis at significantly lower loads. Even low-affinity IgG can trigger hemolysis by complement activation, which is not detected by a conventional Coombs test.

Before considering rare causes of hemolysis, such as mechanical hemolysis (march hemolysis, heart valve), hemolysis in connection with infectious diseases (malaria, gas gangrene) or due to toxic exposure (chemicals, drugs, animal poisons), one should first order a flow cytometry analysis (FACS) of peripheral blood to rule out a monoclonal lymphoid population and, thus, an underlying hematological neoplasia. The diagnosis of the only acquired corpuscular hemolytic anemia, the paroxysmal nocturnal hemoglobinuria (PNH), which is characterized by sudden-onset hemolysis with dark morning urine, as well as by thrombophilia, has meanwhile also become a domain of FACS. The low expression of the glycosylphosphatidylinositol (GPI)-anchored surface molecules CD55 and CD59 can be established not only on the erythrocytes, but also on neutrophils and on monocytes, which allows an unequivocal diagnosis even after a hemolytic episode, when the erythrocytic PNH clone has largely disappeared [48, 49].

After excluding a hyper-regenerative anemia, the entire range of hypo-regenerative types remains as differential diagnosis. The most common ones are combined anemias, recent ACD, myelosuppression and especially the renal anemia. In order to clarify these cases, the measurement of sTfR proved itself valuable, particularly when performed in tandem with its natural diagnostic partner, ZPP [50]. The sTfR concentration depends on the iron metabolism, as well as on the quantity and quality of the erythropoiesis. Elevated sTfR is measured not only in iron deficiency, but also when the erythropoiesis is increased. A tandem analysis of sTfR and ZPP thus provides valuable information, especially if the erythropoietin level is measured at the same time. This way, it is possible to confirm or rule out an iron-deficient erythropoiesis, while also diagnosing ACD, which typically starts as a normochromic-normocytic anemia before turning into the hypochrom-microcytic form as the disease progresses.

Normal ZPP values exclude any relevant problem of the iron metabolism. In these cases, the quantity and quality of erythropoiesis can be derived directly from the sTfR concentration ( Table 3 ). A hyper-regenerative anemia in hemolysis is associated with elevated sTfR. Elevated levels are also observed with megaloblastic anemias, which are associated with an increased, relatively well maturing erythropoiesis. MDS, by contrast, exhibit normal or reduced sTfR concentrations, despite the elevated erythropoiesis, because the erythropoiesis matures poorly, and because the immature red cell precursors carry substantially fewer transferrin receptors than the more mature erythroblasts. Hypoplasia and aplasia of erythropoiesis can be recognized by a significantly decreased sTfR. This relates to therapeutically induced myelosuppression following chemotherapy, but also to the pure red cell aplasia (PRCA), which is characterized by virtually absent sTfR coupled with extremely high erythropoietin levels ( Table 4 ).

Clarification of anemias based on ZPP and sTfR [50]. IDE, iron-deficient erythropoiesis; EP, erythropoiesis; ACD, anemia of chronic disease.

Examples of individual patients with various types of anemia, including the relevant laboratory parameters. Key differential-diagnostic parameters are, in particular, zinc protoporphyrin (ZPP), the soluble transferrin receptors (sTfR) and serum erythropoietin (EPO), because they allow for an assessment of the iron metabolism and of erythropoietic activity in the bone marrow.

Reference values: Lactate dehydrogenase, LDH [109–250 U/L]; Vitamin B12 [182–625 ng/L]; Bilirubin [0.1–1.2 mg/dL]; Haptoglobin [0.3–2.0 g/L]; Hb, Hemoglobin; MCV, mean corpuscular volume; Reti, reticulocytes; CHr, reticulocyte hemoglobin; EP, erythropoiesis; PK, pyruvate kinase; NHL, Non-Hodgkin lymphoma; PMF, Primary Myelofibrosis; EK, erythrocyte concentrate; GFR, glomerular filtration rate; AIHA, autoimmune hemolytic anemia.

Renal anemia deserves special mention, given its high clinical significance especially in the elderly. Renal anemia has, in fact, been described in several studies as the most frequent form of anemia in geriatric patients [9]. The loss of functional renal tissue in elderly impairs the kidney’s excretory function as well as the production of erythropoietin. When assessing on the basis of creatinine alone, the renal function of the elderly tends to be rated too positive, often resulting in a failure to recognize the renal component of the anemia. Creatinine and erythropoietin levels within the normal range do not rule out renal anemia. The creatinine is often normal as a result of reduced muscle mass, so that the assessment of the renal function should be based on a creatinine clearance instead. A Cockroft clearance is sufficient. Renal anemia can already occur at a creatinine clearance of 50 mL/min; at levels <30 mL/min, it is virtually a certainty [51, 52]. In line with the decreased erythropoiesis, the sTfR levels are in the lower reference range in the case of renal anemia. The erythropoietin level is normal or slightly elevated, but the increase is inadequate with respect to the hemoglobin concentration ( Table 4 ).

Myelosuppression in patients after chemotherapy, or patients with bone marrow infiltration by a hematological neoplasia or carcinoma, is also very frequently associated with an anemia that generally is normochromic-normocytic. It is said to be the second most common presentation of anemia in general practice [9]. In this context, it makes sense to check first whether nucleated red cells (erythroblasts) and neutrophil precursors are released into the blood-stream. The presence of a leukoerythroblastic anemia is suggestive of a severe bone marrow damage. It is most commonly seen in association with marrow fibrosis and malignant infiltration of bone marrow, especially in patients with carcinomas of the breast, prostate gland and lung. In addition to the differential blood count, a FACS analysis of peripheral blood is required in unexplained cases in order to detect any monoclonal lymphoid population.

In view of the wide array of differential diagnoses of a normochromic-normocytic anemia, it is best not to be too ambitious by trying to cover all possible causes with the first blood sample. It makes more sense to proceed step by step in the clarification and initially cover only the most important causes diagnostically. The first laboratory panel should include reticulocytes, LDH, serum creatinine, creatinine clearance, ferritin, transferrin saturation, bilirubin, ALAT and CRP. The analysis of sTfR, ZPP and erythropoietin will undoubtly facilitate the clarification. The further diagnostic procedure depends on the results obtained with the initial screening. One should not be too disappointed if the initial findings do not yield a clear result. After all, normochromic-normocytic anemias are very often not monocausal, but multifactorial, especially when it comes to older multimorbid patients. In such cases, it is not critical to identify all of the components that have contributed to the anemia. Instead, one should focus on isolating the principal cause. In addition, it is necessary to confirm or rule out all those components that can be easily treated, such as substrate or erythropoietin deficiency.

Some consider the microscopic examination of peripheral blood film an anachronism. In our view, it is the basis of every work-up of anemia that has not been clarified through a laboratory’s routine panel of tests. With regards to the immunohemolytic anemia, one should be aware that it frequently occurs in the context of a hematologic neoplasia. Arguably, these cases benefit from a referral to a hematologist. This also applies to other unexplained anemias, because in case of doubt, a bone marrow biopsy must be done to assess the hematopoiesis accurately and to reliably rule out an underlying hematological disorder.

Acknowledgments:

The authors thank Prof. G. Löffler for critically reading the manuscript.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Article note:

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