anemia case study

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Critical iron deficiency anemia with record low hemoglobin: a case report

• Audrey L. Chai   ORCID: orcid.org/0000-0002-5009-0468 1 ,
• Owen Y. Huang 1 ,
• Rastko Rakočević 2 &
• Peter Chung 2  

Journal of Medical Case Reports volume  15 , Article number:  472 ( 2021 ) Cite this article

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Anemia is a serious global health problem that affects individuals of all ages but particularly women of reproductive age. Iron deficiency anemia is one of the most common causes of anemia seen in women, with menstruation being one of the leading causes. Excessive, prolonged, and irregular uterine bleeding, also known as menometrorrhagia, can lead to severe anemia. In this case report, we present a case of a premenopausal woman with menometrorrhagia leading to severe iron deficiency anemia with record low hemoglobin.

Case presentation

A 42-year-old Hispanic woman with no known past medical history presented with a chief complaint of increasing fatigue and dizziness for 2 weeks. Initial vitals revealed temperature of 36.1 °C, blood pressure 107/47 mmHg, heart rate 87 beats/minute, respiratory rate 17 breaths/minute, and oxygen saturation 100% on room air. She was fully alert and oriented without any neurological deficits. Physical examination was otherwise notable for findings typical of anemia, including: marked pallor with pale mucous membranes and conjunctiva, a systolic flow murmur, and koilonychia of her fingernails. Her initial laboratory results showed a critically low hemoglobin of 1.4 g/dL and severe iron deficiency. After further diagnostic workup, her profound anemia was likely attributed to a long history of menometrorrhagia, and her remarkably stable presentation was due to impressive, years-long compensation. Over the course of her hospital stay, she received blood transfusions and intravenous iron repletion. Her symptoms of fatigue and dizziness resolved by the end of her hospital course, and she returned to her baseline ambulatory and activity level upon discharge.

Conclusions

Critically low hemoglobin levels are typically associated with significant symptoms, physical examination findings, and hemodynamic instability. To our knowledge, this is the lowest recorded hemoglobin in a hemodynamically stable patient not requiring cardiac or supplemental oxygen support.

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Anemia and menometrorrhagia are common and co-occurring conditions in women of premenopausal age [ 1 , 2 ]. Analysis of the global anemia burden from 1990 to 2010 revealed that the prevalence of iron deficiency anemia, although declining every year, remained significantly high, affecting almost one in every five women [ 1 ]. Menstruation is considered largely responsible for the depletion of body iron stores in premenopausal women, and it has been estimated that the proportion of menstruating women in the USA who have minimal-to-absent iron reserves ranges from 20% to 65% [ 3 ]. Studies have quantified that a premenopausal woman’s iron storage levels could be approximately two to three times lower than those in a woman 10 years post-menopause [ 4 ]. Excessive and prolonged uterine bleeding that occurs at irregular and frequent intervals (menometrorrhagia) can be seen in almost a quarter of women who are 40–50 years old [ 2 ]. Women with menometrorrhagia usually bleed more than 80 mL, or 3 ounces, during a menstrual cycle and are therefore at greater risk for developing iron deficiency and iron deficiency anemia. Here, we report an unusual case of a 42-year-old woman with a long history of menometrorrhagia who presented with severe anemia and was found to have a record low hemoglobin level.

A 42-year-old Hispanic woman with no known past medical history presented to our emergency department with the chief complaint of increasing fatigue and dizziness for 2 weeks and mechanical fall at home on day of presentation.

On physical examination, she was afebrile (36.1 °C), blood pressure was 107/47 mmHg with a mean arterial pressure of 69 mmHg, heart rate was 87 beats per minute (bpm), respiratory rate was 17 breaths per minute, and oxygen saturation was 100% on room air. Her height was 143 cm and weight was 45 kg (body mass index 22). She was fully alert and oriented to person, place, time, and situation without any neurological deficits and was speaking in clear, full sentences. She had marked pallor with pale mucous membranes and conjunctiva. She had no palpable lymphadenopathy. She was breathing comfortably on room air and displayed no signs of shortness of breath. Her cardiac examination was notable for a grade 2 systolic flow murmur. Her abdominal examination was unremarkable without palpable masses. On musculoskeletal examination, her extremities were thin, and her fingernails demonstrated koilonychia (Fig. 1 ). She had full strength in lower and upper extremities bilaterally, even though she required assistance with ambulation secondary to weakness and used a wheelchair for mobility for 2 weeks prior to admission. She declined a pelvic examination. No bleeding was noted in any part of her physical examination.

Koilonychia, as seen in our patient above, is a nail disease commonly seen in hypochromic anemia, especially iron deficiency anemia, and refers to abnormally thin nails that have lost their convexity, becoming flat and sometimes concave in shape

She was admitted directly to the intensive care unit after her hemoglobin was found to be critically low at 1.4 g/dL on two consecutive measurements with an unclear etiology of blood loss at the time of presentation. Note that no intravenous fluids were administered prior to obtaining the hemoglobin levels. Upon collecting further history from the patient, she revealed that she has had a lifetime history of extremely heavy menstrual periods: Since menarche at the age of 10 years when her periods started, she has been having irregular menstruation, with periods occurring every 2–3 weeks, sometimes more often. She bled heavily for the entire 5–7 day duration of her periods; she quantified soaking at least seven heavy flow pads each day with bright red blood as well as large-sized blood clots. Since the age of 30 years, her periods had also become increasingly heavier, with intermittent bleeding in between cycles, stating that lately she bled for “half of the month.” She denied any other sources of bleeding.

Initial laboratory data are summarized in Table 1 . Her hemoglobin (Hgb) level was critically low at 1.4 g/dL on arrival, with a low mean corpuscular volume (MCV) of < 50.0 fL. Hematocrit was also critically low at 5.8%. Red blood cell distribution width (RDW) was elevated to 34.5%, and absolute reticulocyte count was elevated to 31 × 10 9 /L. Iron panel results were consistent with iron deficiency anemia, showing a low serum iron level of 9 μg/dL, elevated total iron-binding capacity (TIBC) of 441 μg/dL, low Fe Sat of 2%, and low ferritin of 4 ng/mL. Vitamin B12, folate, hemolysis labs [lactate dehydrogenase (LDH), haptoglobin, bilirubin], and disseminated intravascular coagulation (DIC) labs [prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, d -dimer] were all unremarkable. Platelet count was 232,000/mm 3 . Peripheral smear showed erythrocytes with marked microcytosis, anisocytosis, and hypochromia (Fig. 2 ). Of note, the patient did have a positive indirect antiglobulin test (IAT); however, she denied any history of pregnancy, prior transfusions, intravenous drug use, or intravenous immunoglobulin (IVIG). Her direct antiglobulin test (DAT) was negative.

A peripheral smear from the patient after receiving one packed red blood cell transfusion is shown. Small microcytic red blood cells are seen, many of which are hypochromic and have a large zone of pallor with a thin pink peripheral rim. A few characteristic poikilocytes (small elongated red cells also known as pencil cells) are also seen in addition to normal red blood cells (RBCs) likely from transfusion

A transvaginal ultrasound and endometrial biopsy were offered, but the patient declined. Instead, a computed tomography (CT) abdomen and pelvis with contrast was performed, which showed a 3.5-cm mass protruding into the endometrium, favored to represent an intracavitary submucosal leiomyoma (Fig. 3 ). Aside from her abnormal uterine bleeding (AUB), the patient was without any other significant personal history, family history, or lab abnormalities to explain her severe anemia.

Computed tomography (CT) of the abdomen and pelvis with contrast was obtained revealing an approximately 3.5 × 3.0 cm heterogeneously enhancing mass protruding into the endometrial canal favored to represent an intracavitary submucosal leiomyoma

The patient’s presenting symptoms of fatigue and dizziness are common and nonspecific symptoms with a wide range of etiologies. Based on her physical presentation—overall well-appearing nature with normal vital signs—as well as the duration of her symptoms, we focused our investigation on chronic subacute causes of fatigue and dizziness rather than acute medical causes. We initially considered a range of chronic medical conditions from cardiopulmonary to endocrinologic, metabolic, malignancy, rheumatologic, and neurological conditions, especially given her reported history of fall. However, once the patient’s lab work revealed a significantly abnormal complete blood count and iron panel, the direction of our workup shifted towards evaluating hematologic causes.

With such a critically low Hgb on presentation (1.4 g/dL), we evaluated for potential sources of blood loss and wanted to first rule out emergent, dangerous causes: the patient’s physical examination and reported history did not elicit any concern for traumatic hemorrhage or common gastrointestinal bleeding. She denied recent or current pregnancy. Her CT scan of abdomen and pelvis was unremarkable for any pathology other than a uterine fibroid. The microcytic nature of her anemia pointed away from nutritional deficiencies, and she lacked any other medical comorbidities such as alcohol use disorder, liver disease, or history of substance use. There was also no personal or family history of autoimmune disorders, and the patient denied any history of gastrointestinal or extraintestinal signs and/or symptoms concerning for absorptive disorders such as celiac disease. We also eliminated hemolytic causes of anemia as hemolysis labs were all normal. We considered the possibility of inherited or acquired bleeding disorders, but the patient denied any prior signs or symptoms of bleeding diatheses in her or her family. The patient’s reported history of menometrorrhagia led to the likely cause of her significant microcytic anemia as chronic blood loss from menstruation leading to iron deficiency.

Over the course of her 4-day hospital stay, she was transfused 5 units of packed red blood cells and received 2 g of intravenous iron dextran. Hematology and Gynecology were consulted, and the patient was administered a medroxyprogesterone (150 mg) intramuscular injection on hospital day 2. On hospital day 4, she was discharged home with follow-up plans. Her hemoglobin and hematocrit on discharge were 8.1 g/dL and 24.3%, respectively. Her symptoms of fatigue and dizziness had resolved, and she was back to her normal baseline ambulatory and activity level.

Discussion and conclusions

This patient presented with all the classic signs and symptoms of iron deficiency: anemia, fatigue, pallor, koilonychia, and labs revealing marked iron deficiency, microcytosis, elevated RDW, and low hemoglobin. To the best of our knowledge, this is the lowest recorded hemoglobin in an awake and alert patient breathing ambient air. There have been previous reports describing patients with critically low Hgb levels of < 2 g/dL: A case of a 21-year old woman with a history of long-lasting menorrhagia who presented with a Hgb of 1.7 g/dL was reported in 2013 [ 5 ]. This woman, although younger than our patient, was more hemodynamically unstable with a heart rate (HR) of 125 beats per minute. Her menorrhagia was also shorter lasting and presumably of larger volume, leading to this hemoglobin level. It is likely that her physiological regulatory mechanisms did not have a chance to fully compensate. A 29-year-old woman with celiac disease and bulimia nervosa was found to have a Hgb of 1.7 g/dL: she presented more dramatically with severe fatigue, abdominal pain and inability to stand or ambulate. She had a body mass index (BMI) of 15 along with other vitamin and micronutrient deficiencies, leading to a mixed picture of iron deficiency and non-iron deficiency anemia [ 6 ]. Both of these cases were of reproductive-age females; however, our patient was notably older (age difference of > 20 years) and had a longer period for physiologic adjustment and compensation.

Lower hemoglobin, though in the intraoperative setting, has also been reported in two cases—a patient undergoing cadaveric liver transplantation who suffered massive bleeding with associated hemodilution leading to a Hgb of 0.6 g/dL [ 7 ] and a patient with hemorrhagic shock and extreme hemodilution secondary to multiple stab wounds leading to a Hgb of 0.7 g/dL [ 8 ]. Both patients were hemodynamically unstable requiring inotropic and vasopressor support, had higher preoperative hemoglobin, and were resuscitated with large volumes of colloids and crystalloids leading to significant hemodilution. Both were intubated and received 100% supplemental oxygen, increasing both hemoglobin-bound and dissolved oxygen. Furthermore, it should be emphasized that the deep anesthesia and decreased body temperature in both these patients minimized oxygen consumption and increased the available oxygen in arterial blood [ 9 ].

Our case is remarkably unique with the lowest recorded hemoglobin not requiring cardiac or supplemental oxygen support. The patient was hemodynamically stable with a critically low hemoglobin likely due to chronic, decades-long iron deficiency anemia of blood loss. Confirmatory workup in the outpatient setting is ongoing. The degree of compensation our patient had undergone is impressive as she reported living a very active lifestyle prior to the onset of her symptoms (2 weeks prior to presentation), she routinely biked to work every day, and maintained a high level of daily physical activity without issue.

In addition, while the first priority during our patient’s hospital stay was treating her severe anemia, her education became an equally important component of her treatment plan. Our institution is the county hospital for the most populous county in the USA and serves as a safety-net hospital for many vulnerable populations, most of whom have low health literacy and a lack of awareness of when to seek care. This patient had been experiencing irregular menstrual periods for more than three decades and never sought care for her heavy bleeding. She, in fact, had not seen a primary care doctor for many years nor visited a gynecologist before. We emphasized the importance of close follow-up, self-monitoring of her symptoms, and risks with continued heavy bleeding. It is important to note that, despite the compensatory mechanisms, complications of chronic anemia left untreated are not minor and can negatively impact cardiovascular function, cause worsening of chronic conditions, and eventually lead to the development of multiorgan failure and even death [ 10 , 11 ].

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

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Department of Medicine, University of Southern California, Los Angeles, CA, USA

Audrey L. Chai & Owen Y. Huang

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA

Rastko Rakočević & Peter Chung

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AC, OH, RR, and PC managed the presented case. AC performed the literature search. AC, OH, and RR collected all data and images. AC and OH drafted the article. RR and PC provided critical revision of the article. All authors read and approved the final manuscript.

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Correspondence to Audrey L. Chai .

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Chai, A.L., Huang, O.Y., Rakočević, R. et al. Critical iron deficiency anemia with record low hemoglobin: a case report. J Med Case Reports 15 , 472 (2021). https://doi.org/10.1186/s13256-021-03024-9

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Published : 13 September 2021

DOI : https://doi.org/10.1186/s13256-021-03024-9

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Patient Case Presentation

Patient  Overview

M.J. is a 25-year-old, African American female presenting to her PCP with complaints of fatigue, weakness, and shortness of breath with minimal activity. Her friends and family have told her she appears pale, and combined with her recent symptoms she has decided to get checked out. She also states that she has noticed her hair and fingernails becoming extremely thin and brittle, causing even more concern. The patient first started noticing these symptoms a few months ago and they have been getting progressively worse. Upon initial assessment, her mucosal membranes and conjunctivae are pale. She denies pain at this time, but describes an intermittent dry, soreness of her tongue.

Vital Signs:

Temperature – 37 C (98.8 F)

HR – 95

BP – 110/70 (83)

Lab Values:

Hgb- 7 g/dL

Serum Iron – 40 mcg/dL

Transferrin Saturation – 15%

Medical History

• Diagnosed with peptic ulcer disease at age 21 – controlled with PPI pharmacotherapy
• IUD placement 3 months ago – reports an increase in menstrual bleeding since placement

Surgical History

• No past surgical history reported

Family History

• Diagnosis of iron deficiency anemia at 24 years old during pregnancy with patient – on daily supplement
• Otherwise healthy
• Diagnosis of hypertension – controlled with diet and exercise
• No siblings

Social History

• Vegetarian – patient states she has been having weird cravings for ice cubes lately
• Living alone in an apartment close to work in a lower-income community
• Works full time at a clothing department store

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Chapter 6-1:  Approach to the Patient with Anemia - Case 1

Jeremy Smith

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Chief complaint, constructing a differential diagnosis.

• RANKING THE DIFFERENTIAL DIAGNOSIS
• MAKING A DIAGNOSIS
• CASE RESOLUTION
• FOLLOW-UP OF MRS. A
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Mrs. A is a 48-year-old white woman who has had fatigue for 2 months due to anemia.

Figure 6-1.

Diagnostic approach: anemia.

Anemia can occur in isolation, or as a consequence of a process causing pancytopenia, the reduction of all 3 cell lines (white blood cells [WBCs], platelets, and red blood cells [RBCs]). This chapter focuses on the approach to isolated anemia, although a brief list of causes of pancytopenia appears in Figure 6-1 . The first step in determining the cause of anemia is to identify the general mechanism of the anemia and organize the mechanisms using a pathophysiologic framework:

Acute blood loss: this is generally clinically obvious.

Underproduction of RBCs by the bone marrow; chronic blood loss is included in this category because it leads to iron deficiency, which ultimately results in underproduction.

Increased destruction of RBCs, called hemolysis.

Signs of acute blood loss

Hypotension

Tachycardia

Large ecchymoses

Symptoms of acute blood loss

Hematemesis

Rectal bleeding

Vaginal bleeding

After excluding acute blood loss, the next pivotal step is to distinguish underproduction from hemolysis by checking the reticulocyte count:

Low or normal reticulocyte counts are seen in underproduction anemias.

High reticulocyte counts occur when the bone marrow is responding normally to blood loss; hemolysis; or replacement of iron, vitamin B 12 , or folate.

Reticulocyte measures include:

The reticulocyte count: the percentage of circulating RBCs that are reticulocytes (normally 0.5–1.5%).

The absolute reticulocyte count; the number of reticulocytes actually circulating, normally 25,000–75,000/mcL (multiply the percentage of reticulocytes by the total number of RBCs).

The reticulocyte production index (RPI)

Corrects the reticulocyte count for the degree of anemia and for the prolonged peripheral maturation of reticulocytes that occurs in anemia.

Normally, the first 3–3.5 days of reticulocyte maturation occurs in the bone marrow and the last 24 hours in the peripheral blood.

When the bone marrow is stimulated, reticulocytes are released prematurely, leading to longer maturation times in the periphery, and larger numbers of reticulocytes are present at any given time.

For an HCT of 25%, the peripheral blood maturation time is 2 days, and for an HCT of 15%, it is 2.5 days; the value of 2 is generally used in the RPI calculation.

The normal RPI is about 1.0.

However, in patients with anemia, RPI < 2.0 indicates underproduction; RPI > 2.0 indicates hemolysis or an adequate bone marrow response to acute blood loss or replacement of iron or vitamins.

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Case Study: A 12-Year-Old Boy With Normocytic Anemia and Bone Pain

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The following case study focuses on a 12-year-old boy from Guyana who is referred by his family physician for jaundice, normocytic anemia, and recurrent acute bone pains. Test your knowledge by reading the background information below and making the proper selections.

Complete blood count (CBC) reveals a hemoglobin of 6.5 g/dL, MCV 82.3 fL, platelet count 465,000 /µL, white blood cell count 9,800 /µL, absolute neutrophil count 8,500 /µL, reticulocyte count 7 percent, and bilirubin 84 mg/dL. Blood film revealed numerous sickle cells. Sickle solubility test is positive. Alkaline and acid electrophoresis reveal the following (The patient’s sample is denoted by red arrow.):

What is the patient’s hemoglobinopathy genotype based on these results?

• Hb SC compound heterozygote
• Hb SS homozygote
• Hb S/beta-0-thalassemia compound heterozygote
• Hb S/C-Harlem (aka C-Georgetown) compound heterozygote
• Hb S/D-Punjab

Two years later, at age 14, the patient presented to the emergency department with acute onset (3 hours) of left hemiparesis. Non-contrast computed tomography of the brain demonstrated an acute right MCA infarct. The patient has no history of thromboembolic disease, no family history of venous or arterial thrombosis, and no artherosclerotic risk factors for stroke. His CBC at the time demonstrated a hemoglobin of 87 g/dL, hematocrit 0.240, MCV 89.0 fL, platelet count 650,000 /µL, white blood cell count 11,200 /µL, and ANC 9,800 /µL. You are consulted as the hematologist on call along with stroke team.

What would be the best treatment option for this patient?

• Acetylsalicylic acid 160 mg chewable
• Thrombolytic therapy (e.g., tissue plasminogen activator)
• Red cell “top-up” transfusion with target hematocrit of 0.300
• Red cell exchange transfusion with target hematocrit of 0.300 and hemoglobin S of less than 30 percent
• Unfractionated heparin IV infusion 

Answers:  1. B; 2. D

Explanation

The combination of the patient’s ethnic origin, medical history, current presentation, CBC, and peripheral blood film findings are most suggestive of a sickling disorder. High-performance liquid chromatography (HPLC) and hemoglobin gel electrophoresis are the two most commonly employed techniques in the investigation of hemoglobinopathies. The diagnosis of any sickling disorder, however, requires two laboratory investigations, one of which must be the sickle solubility test. The lower limit of detection of hemoglobin S in a sickle solubility test is approximately 15 to 20 percent. All possibilities listed in question 1 will result in a positive sickle solubility test, provided that it is not performed under the following conditions: infant &lt; 6 months or post-transfusion, both of which may result in a false negative result.

Hemoglobin gel electrophoresis separates hemoglobin variants based on the overall charge of the hemoglobin molecule. There is a single band aligned at the S position on the alkaline gel (pH 8.6), given that the orientation of the reference marker from anode (positive) to cathode (negative) is A F S C. Several other hemoglobin variants co-migrate with the S on the alkaline electrophoresis, the most notable of which are hemoglobin D, G, and Lepore. Similarly E, O-Arab, and A2 co-migrate with C. On the acid gel (pH 6.8), there is also one band aligned at the S position, given that the orientation of the reference marker from cathode (negative) to anode (cathode) is F A S C. O-Arab co-migrates with S on the acid gel, and D, G, Lepore, E, A2 co-migrate with A. The interpretation most compatible with the evidence provided above is that the patient is an Hb SS homozygote. He cannot be an Hb SC compound heterozygote, or there would be two bands on the alkaline and acid gel, at the S and C positions, respectively. If he is an Hb S/C-Harlem (aka C-Georgetown) compound heterozygote, he would have a band at the S and C positions (C-Harlem co-migrate with C), respectively, on the alkaline gel and a band in the S position on the acid gel. Interestingly, Hb C-Harlem is actually a hemoglobin variant with two mutations on the β-globin chain and was thought to have risen from a crossover between an Hb S ( Glutamic acid to Valine substitution at the 6th position) and Hb Korle-Bu (Aspartic acid to Asparagine at the 73 rd position) β-globin gene. Thus Hb C-Harlem was thought to have arisen from a cross-over between an Hb S and Hb Korle-Bu beta-globin gene. Also, he cannot have Hb S/D-Punjab, since this would produce two bands on the acid gel, one at the A position (Hb D-Punjab co-migrates with Hb A) and the other at the S position. Finally, he is very unlikely to be an Hb S/β-0-thalassemia compound heterozygote given his normal MCV.

The most likely cause of this patient’s right MCA territory cerebral infarction is sickle cell disease (SCD). The yearly stroke rate of a child with SCD is between 0.5 and 1.0 percent compared with 0.003 percent in a healthy child. Children with trans-cranial Doppler velocity of &gt; 200 cm/s are at even higher risk of stroke, between 10.0 and 13.0 percent yearly. Moreover, 22 percent of SCD patients have evidence of silent cerebral infarcts. Risk factors for stroke include prior transient ischemic attack, low steady-state hemoglobin, acute chest syndrome, and elevated systolic blood pressure. Transfusion with the goal of Hb S &gt; 30 percent and hematocrit of 0.300 is the only proven method of treating stroke in an acute setting and in primary and secondary prophylaxis against stroke in patients with SCD. In an acute setting, the only feasible means of achieving this goal is by exchange transfusion. Although transfusion has not been tested as part of a randomized control trial in SCD patients with acute stroke, retrospective cohort studies have demonstrated that transfusion can reduce the acute mortality and morbidity with the aggressive use of exchange transfusion at presentation. The STOP trial has shown that chronic transfusion therapy with a pre-transfusion Hb S target of &lt; 30 percent is effective in preventing stroke in SCD patients with high transcranial Doppler velocity (&gt; 200 cm/s) compared with no transfusion. STOP2 further shows that the discontinuation of transfusion for SCD patients with elevated transcranial Doppler velocity results in a reversion to high rate of stroke. Currently, the Silent Cerebral Infarct Transfusion (SIT) trial is evaluating whether transfusion will reduce the risk of overt strokes or further silent infarcts in patients with proven silent cerebral infarcts.

The author would like to acknowledge Dr. William F. Brien from Hospital for Sick Children, Toronto, Ontario, Canada, for providing the image of the alkaline and acid gel electrophoresis.

Further Reading

• Bain BJ. Haemoglobinopathy Diagnosis, 2nd ed. 2006. Blackwell Publishing. Oxford, UK.
• Adams RJ. Big strokes in small persons . Arch Neurol. 2007;64:1567-1574.
• Platt OS. Prevention and management of stroke in sickle cell anemia . Hematology 2006. 2006;1:54-57.
• Swerdlow PS. Red cell exchange in sickle cell disease . Hematology 2006. 2006;1:48-53. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography . N Engl J Med. 1998;339:5-11.
• Adams RJ, Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease . N Engl J Med. 2005;353:2769-2778.

Case study submitted by Kevin Kuo, MD, University of Toronto.

American Society of Hematology. (1). Case Study: A 12-Year-Old Boy With Normocytic Anemia and Bone Pain. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/child-normocytic-anemia-bone-pain .

American Society of Hematology. "Case Study: A 12-Year-Old Boy With Normocytic Anemia and Bone Pain." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/child-normocytic-anemia-bone-pain (label-accessed July 02, 2024).

"American Society of Hematology." Case Study: A 12-Year-Old Boy With Normocytic Anemia and Bone Pain, 02 Jul. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/child-normocytic-anemia-bone-pain .

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Case 2: Recurrent Anemia in a 10-year-old Girl

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Drs Rani, Imdad, and Beg have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

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Uzma Rani , Aamer Imdad , Mirza Beg; Case 2: Recurrent Anemia in a 10-year-old Girl. Pediatr Rev December 2015; 36 (12): 548–550. https://doi.org/10.1542/pir.36-12-548

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A 10-year-old premenarchal girl presents to the emergency department with an episode of syncope. She has been feeling progressively more tired for the last week, and her mother noticed that she was pale. The girl has had intermittent headaches but no complaints of palpitations, weight loss, abdominal pain, or rectal bleeding. Her diet consists of vegetables and meat. She is taking oral iron supplements because she presented with similar symptoms 4 months ago and was found to have severe anemia (hemoglobin of 4.9 g/dL [49.0 g/L]). The cause of the anemia at that time was determined to be iron deficiency, based on peripheral blood smear, iron studies, and bone marrow examination. A stool guaiac test was negative and hemoglobin electrophoresis yielded normal results. After packed red blood cell transfusion, she was started on ferrous sulfate supplements. Her anemia responded to iron supplements; her hemoglobin 3 months later measured 11 g/dL...

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Weyand AC , Chaitoff A , Freed GL , Sholzberg M , Choi SW , McGann PT. Prevalence of Iron Deficiency and Iron-Deficiency Anemia in US Females Aged 12-21 Years, 2003-2020. JAMA. 2023;329(24):2191–2193. doi:10.1001/jama.2023.8020

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Prevalence of Iron Deficiency and Iron-Deficiency Anemia in US Females Aged 12-21 Years, 2003-2020

• 1 Department of Pediatrics, University of Michigan Medical School, Ann Arbor
• 2 Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts
• 3 Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor
• 4 Department of Medicine, St Michaels Hospital, Toronto, Ontario, Canada
• 5 Department of Pediatrics, Alpert Medical School of Brown University, Providence, Rhode Island

Iron deficiency and iron-deficiency anemia are common, underappreciated conditions with significant morbidity and mortality despite widespread availability of effective treatment. Historically, the focus of screening has been preschool-aged and pregnant persons. The Centers for Disease Control and Prevention recommends anemia screening for nonpregnant female adolescents and women every 5 to 10 years, 1 whereas the US Preventive Services Task Force does not address screening for these populations. 1

Although screening for anemia by measurement of hemoglobin level is recommended, there is benefit in identifying and treating iron deficiency in those without anemia because supplementation improves exercise performance and reduces fatigue, and iron deficiency is associated with increased all-cause mortality. 2 , 3 We examined iron deficiency prevalence among females aged 12 to 21 years to inform future screening strategies.

This study used National Health and Nutrition Examination Survey (NHANES) cycles from 2003-2010 and 2015–March 2020 (ferritin level was not measured in 2011-2014). NHANES is a series of nationally representative surveys consisting of interviews and physical examinations. Response rates ranged from 51% to 80%. The study protocol was approved by the ethics review board of the National Center for Health Statistics and participants provided informed consent.

Data were extracted for nonpregnant females aged 12 to 21 years. Individuals were excluded for missing data, inflammation, and kidney or liver dysfunction (additional information appears in the eMethods in Supplement 1 ). The proportion of the population with iron deficiency (ferritin <25 μg/L) 4 was described; and the ferritin cutoffs of 15 μg/L and 50 μg/L were assessed as sensitivity analyses. The prevalence of iron-deficiency anemia (hemoglobin <12 mg/dL by World Health Organization definition and ferritin <25 μg/L) was examined as well as using the hemoglobin cutoffs of 12.5 mg/dL and 13 mg/dL, given debate around this definition. 5 Quasibinomial models were used to generate independent adjusted odds ratios to assess the associations among race and ethnicity, income, food security, menstruation, and body mass index and having iron deficiency or iron-deficiency anemia. Self-reported race and ethnicity (using categories defined by NHANES) were collected to evaluate for associations between social determinants of health and iron deficiency.

The models restricted to menstruating individuals were generated to evaluate the association with years menstruating. The counts were unweighted and the percentages were weighted to account for nonresponse. A 2-sided α < .05 was considered statistically significant. Analyses were conducted using the survey package in R version 4.2.2 (R Foundation for Statistical Computing).

There were 4052 individuals who met inclusion criteria and 3490 who had complete data. Of these 3490 individuals, 188 were premenarchal (5.4% [95% CI, 4.2%-6.6%]) ( Table 1 ). The overall prevalence of iron deficiency was 38.6% (95% CI, 35.8%-40.9%); 17% (95% CI, 15.4%-19.2%) using a 15-μg/L ferritin cutoff and 77.5% (95% CI, 75.7%-79.3%) using a 50-μg/L cutoff. Premenarchal individuals had a prevalence of iron deficiency of 27.1% (95% CI, 17.1%-37.0%) using a 25-μg/L ferritin cutoff.

The overall prevalence of iron-deficiency anemia was 6.3% (95% CI, 5.2%-7.4%); 11.0% (95% CI, 9.5%-12.6%) using a 12.5-mg/dL hemoglobin cutoff and 17.2% (95% CI, 15.3%-19.1%) using a 13-mg/dL cutoff. Among individuals with iron deficiency, it was not associated with iron-deficiency anemia for 83.6% (95% CI, 80.8%-86.4%).

In multivariable analyses, non-White race, Hispanic ethnicity, and menstruation were associated with iron deficiency and iron-deficiency anemia. Lower body mass index and poverty were associated with iron deficiency. Food insecurity was associated with iron-deficiency anemia ( Table 2 ). When restricting models to menstruating individuals, the number of years menstruating was not associated with iron deficiency (adjusted odds ratio, 1.05 [95% CI, 0.98-1.13]) or iron-deficiency anemia (adjusted odds ratio, 1.05 [95% CI, 0.92-1.21]).

Among 12- to 21-year-old US females between 2003 and 2020, iron deficiency affected almost 40% and iron-deficiency anemia affected 6%, with variation by the ferritin or hemoglobin thresholds used. Menstruation was a risk factor for both, but more than one-quarter of premenarchal individuals had iron deficiency.

Limitations of this study include limited granularity of the race and ethnicity data and potential overfitting of the iron-deficiency anemia model because few premenarchal participants had iron-deficiency anemia. However, removing the menstruation variable from the model had minimal effects on other adjusted associations.

Given the high prevalence of iron deficiency found with the majority not associated with iron-deficiency anemia, current screening guidance may miss many individuals with iron deficiency. Although annual screening is recommended for higher-risk patients, risk factors (extensive menstrual blood loss, 6 low iron intake, prior diagnosis of iron deficiency) are not clearly defined and likely result in inconsistent screening.

The frequency of universal screening for iron deficiency and iron-deficiency anemia in menstruating persons and the best ferritin and hemoglobin thresholds should be evaluated. Further study is needed to identify risk factors and inform screening practices among premenarchal individuals.

Accepted for Publication: April 25, 2023.

Corresponding Author: Angela C. Weyand, MD, Department of Pediatrics, University of Michigan Medical School, 1500 E Medical Center Dr, Ann Arbor, MI 48109 ( [email protected] ).

Author Contributions: Drs Weyand and Chaitoff had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Weyand, Sholzberg, McGann.

Acquisition, analysis, or interpretation of data: Weyand, Chaitoff, Freed, Choi.

Drafting of the manuscript: Weyand, Chaitoff, McGann.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Weyand, Chaitoff.

Administrative, technical, or material support: Weyand, Sholzberg.

Supervision: Choi.

Conflict of Interest Disclosures: Dr Weyand reported receiving personal fees from Sanofi, Genzyme, Takeda, and Genentech for serving on advisory boards and consulting; receiving personal fees from Spark Therapeutics and Bayer for serving on advisory boards; receiving personal fees from Novo Nordisk for consulting; and receiving grant funding paid to her institution from Pfizer, Sanofi, Novo Nordisk, and Takeda. Dr Sholzberg reported receiving grants from Pfizer paid to her institution and receiving personal fees from Pfizer for speaking engagements. No other disclosures were reported.

Data Sharing Statement: See Supplement 2 .

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Case 2 diagnosis: megaloblastic anemia due to dietary cobalamin deficiency, clinical pearls, recommended reading.

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Case 2: A pale infant – not a typical case of iron deficiency

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Michelle P Wong, Louis Wadsworth, John K Wu, David Dix, Case 2: A pale infant – not a typical case of iron deficiency, Paediatrics & Child Health , Volume 13, Issue 6, July/August 2008, Pages 507–511, https://doi.org/10.1093/pch/13.6.507a

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A 15-month-old boy presented to his doctor when his mother became concerned about his diet. Despite the introduction of solids at six months of age, he was almost exclusively breastfed and a ‘picky eater’. His parents were partial vegetarians, with little meat intake. His mother had noticed that he was pale with gait disturbance and occasional falls. His developmental history was otherwise unremarkable. His past medical history included a term delivery with no complications and an uneventful postnatal period. After initial bloodwork, he was referred to a paediatric hematologist.

On examination, he was pale. His weight and height were between the 5th to 10th and 15th percentiles, respectively. A systolic murmur grade 2/6 was present. The patient's bloodwork included a complete blood count with white blood cell count 5.2×10 9 /L (normal 5.3×10 9 /L to 16×10 9 /L), neutrophils 1×10 9 /L (normal 1×10 9 /L to 6.5×10 9 /L), hemoglobin 83 g/L (normal 103 g/L to 135 g/L), mean corpuscular volume 107 fL (normal 70 fL to 86 fL) and platelet count 311×10 9 /L (normal 200×10 9 /L to 550×10 9 /L). His reticulocyte count was 31×10 9 /L (normal 40×10 9 /L to 120×10 9 /L), and his peripheral blood smear showed occasional oval macrocytes and hypersegmented neutrophils. A bone marrow aspirate was performed, and the images demonstrated classic findings of a particular diagnosis.

Additional investigations for macrocytic anemia included serum folate 33.3 nmol/L (normal greater than 6.8 nmol/L), and vitamin B 12 (cobalamin) 44 pmol/L (deficient range lower than 107 pmol/L). Based on the test results and the bone marrow aspirate findings of hypersegmented neutrophils, megaloblasts and giant metamyelocytes, a diagnosis of megaloblastic anemia (MA) was made.

Bloodwork was also performed on the mother. Serum folate was normal at 30.9 nmol/L (greater than 6.81 nmol/L) and serum vitamin B 12 was low-normal at 209 pmol/L (normal 133 pmol/L to 675 pmol/L). Maternal hemoglobin level and mean corpuscular volume (MCV) were normal.

Given the history, the likely cause of MA and cobalamin deficiency was reduced dietary intake. The toddler was treated with intramuscular cyanocobalamin injections (20 μg daily for seven days, then 100 μg weekly for four weeks) and a dietician was consulted. Oral cobalamin therapy was also an option and would have been effective, but for convenience and to ensure compliance, the parenteral route was chosen.

Two months later, he had improved significantly with a normal hemoglobin level (107 g/L) and MCV (83 fl). He was more energetic and interactive. His gait had returned to normal and his falls had decreased. His diet had improved with increased intake of meats, eggs, milk, fruits and vegetables, supplemented with PediaSure (Abbott Nutrition, Canada). Eight months after presentation, his development was appropriate for age and he was not anemic, despite being off therapy for several months. Maintenance of normal counts after discontinuation of therapy and adherence to a balanced diet are consistent with a dietary etiology for MA.

MA describes a group of disorders characterized by defective DNA synthesis. Morphological hallmarks in the marrow are megaloblasts and giant metamyelocytes displaying nuclear to cytoplasmic asynchrony. A megaloblast has a nucleus that is immature relative to the cytoplasm because the nucleus has impaired DNA synthesis, but hemoglobinization, which is dependant on ribosomal function, continues normally in the cytoplasm. There are many causes of MA, some of which are listed in Table 1 .

Causes of megaloblastic anemia

The case described demonstrates MA in a paediatric patient who was a ‘picky eater’ and was found to have macrocytic anemia. The insidious onset can delay diagnosis. It is important to diagnose this condition early to avoid the symptoms of anemia, as well as the neurological sequelae, including loss of vibration sensation and potential progression to spastic ataxia due to demyelination of the dorsal and lateral columns of the spinal cord. An approach to the workup of suspected MA in paediatric patients is proposed.

History and physical examination

Many patients are asymptomatic, and a diagnosis of MA is made incidentally when macrocytosis is found on routine bloodwork. There may be a history of poor food intake, prolonged breastfeeding, and a maternal history of vegetarian and vegan diets or autoimmune disorders. Nonspecific symptoms include irritability, weight loss, diarrhea or constipation. The clinical features are primarily those of a classic ‘lemon yellow’ pallor because of the combination of anemia and jaundice. Severe cases may have marked anorexia, weight loss, glossitis and angular cheilosis. Neurological effects may be manifested by failure to reach developmental milestones and may include paresthesias, muscle weakness and impaired intellectual development.

Screening bloodwork

The complete blood count shows macrocytic anemia. The MCV can be normal when there is concomitant microcytosis (thalassemia trait or iron deficiency). The peripheral blood smear shows oval macrocytes and hypersegmented neutrophils (five or more lobes) ( Figure 1 ). If a child is being breastfed, maternal bloodwork must be performed to exclude maternal vitamin deficiencies.

Peripheral blood smear demonstrating a hypersegmented neutrophil

Diagnostic tests

Folate and cobalamin levels are critical diagnostic blood tests. Red blood cell folate levels may be a better indicator of body folate because recent changes in dietary intake and hemolysis of the specimen will interfere with serum folate levels. Patients deficient in folate have low assay results, but a significant proportion of cobalamin-deficient patients will also have low red cell folate assays because cobalamin is a cofactor in folate metabolism. Cobalamin assays have limitations when correlating clinical deficiency with low-normal assay levels in some patients. Concentrations of the cobalamin carrier protein transcobalamin 1 can influence serum levels of vitamin B 12 . The assays for folate and vitamin B 12 levels are generally robust and convenient for diagnosing deficient states.

A bone marrow biopsy is an invasive procedure and less frequently performed with the availability of diagnostic blood tests, but it can be warranted to expedite diagnosis. The marrow can provide a morphological diagnosis within a matter of minutes; however, it requires skilled physician resources. A bone marrow aspirate in MA shows hypercel-lularity with ineffective hematopoiesis and megaloblastic erythropoiesis ( Figure 2 ), giant myeloid precursors (giant metamyelocytes) ( Figures 2 and 3 ), increased iron stores and, less commonly, hyperpolyploid megakaryocytes. When no explanation for cytopenias is found, bone marrow studies must be performed to exclude bone marrow failure, hematological malignancy or metastatic tumour.

Bone marrow aspirate demonstrating megaloblastic hematopoiesis with a megaloblast (white arrow) and a giant metamye-locyte (black arrow)

Bone marrow aspirate demonstrating megaloblastic hematopoiesis with a giant metamyelocyte (black arrow)

Additional tests and special tests

Schilling test:.

When Addisonian pernicious anemia (PA) is suspected, a Schilling test may be performed to assess cobalamin absorption. The test measures urinary excretion of orally administered radioactive cobalamin, with and without added intrinsic factor. PA is rare in children. The Schilling test would be helpful, and should be performed when there is a need to distinguish PA from the rarer malabsorptive errors of cobalamin absorption that are listed in Table 1 .

Total plasma homocysteine, serum methylmalonate and urinary excretion of methylmalonate:

Vitamin B 12 , but not folate, is required in methylmalonate (MMA) metabolism. Increased total plasma homocysteine and MMA levels are associated with cobalamin deficiency. Total plasma homocysteine level is elevated in both folate and vitamin B 12 deficiency, and is less specific than MMA. These tests, however, may be useful in suspected presymptomatic deficiency when the patient is not anemic and cobalamin levels are in the low-normal range. Elevated total plasma homocysteine and MMA levels may signal functional vitamin B 12 deficiency ( 1 ). Availability of these tests may limit their diagnostic application.

The etiology of folate or cobalamin deficiency must be determined because most causes are preventable or treatable. In developed countries, MA is more commonly caused by cobalamin rather than folate deficiency because many foods are folate-supplemented. Cobalamin deficiency must be ruled out before administering folic acid because treatment with folic acid alone, in the presence of cobalamin deficiency, can cause or exacerbate irreversible neurological damage.

MA can occur in children when there is a history of ‘picky eating’, poverty, chronic hemolysis such as hereditary spherocytosis, diets low in animal products or prolonged breastfeeding. Human milk cobalamin concentrations have been found to be lower in vegetarian mothers compared with omnivorous mothers ( 2 ). Breastfeeding mothers can have clinical ( 3 ) or subclinical cobalamin deficiency, the latter having low-normal cobalamin levels ( 1 ). As such, infants of cobalamin-deficient mothers are at risk of developing MA. Cobalamin deficiency may also occur in infants born to mothers with PA; however, this risk is largely theoretical because women with PA are usually infertile ( 4 ).

Early diagnosis of MA in childhood is imperative to prevent neurological consequences in infants who remain untreated. Increased awareness leading to early diagnosis and appropriate, timely therapy can prevent irreversible neurological effects for the child with MA. This is especially important during the critical period of neurodevelopment in early childhood.

Prolonged breastfed infants may be at risk of developing MA, especially if the mother consumes a vegetarian or vegan diet.

Cobalamin deficiency must be ruled out before instituting folate therapy.

Cobalamin deficiency may have neuropsychiatric as well as hematological manifestations, and early diagnosis is imperative to prevent irreversible neurological damage.

Measurement of serum MMA is important in the detection of presymptomatic cobalamin deficiency.

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A Case of Severe Aplastic Anemia in a 35-Year-Old Male With a Good Response to Immunosuppressive Therapy

Ekaterina proskuriakova.

1 Internal Medicine, Mount Sinai Hospital, Chicago, USA

Ranjit B Jasaraj

Aleyda m san hernandez, anuradha sakhuja, mtanis khoury.

2 Hematology and Oncology, Mount Sinai Hospital, Chicago, USA

Aplastic anemia (AA) is a severe but rare hematologic condition associated with hematopoietic failure leading to decreased or total absent hematopoietic precursor cells in the bone marrow. AA presents at any age with equal distribution among gender and race. There are three known mechanisms of AA: direct injuries, immune-mediated disease, and bone marrow failure. The most common etiology of AA is considered to be idiopathic. Patients usually present with non-specific findings, such as easy fatigability, dyspnea on exertion, pallor, and mucosal bleeding. The primary treatment of AA is to remove the offending agent. In patients in whom the reversible cause was not found, patient management depends on age, disease severity, and donor availability. Here, we present a case of a 35-year-old male who presented to the emergency room with profuse bleeding after a deep dental cleaning. He was found to have pancytopenia on his laboratory panel and had an excellent response to immunosuppressive therapy.

Introduction

Aplastic anemia (AA) is a rare condition characterized by the combination of hypoplasia or aplasia of the bone marrow and pancytopenia in at least two of the three main lines of cells: red blood cells (RBCs), white blood cells (WBCs), and platelets [ 1 ]. An estimated incidence of this disease is 0.6 to 6.1/million per year with a sex ratio of about 1:1 [ 2 ]. AA is more common in Asia than in Western countries [ 3 ]. This could reflect the variability of exposure to different environmental factors, such as drugs, chemicals, viral pathogens, or genetic predisposition. Although this condition could be seen in any age group, two incidence peaks of AA are reported: in young adults (20-25 years old) and the elderly population with a peak after the age of 60 [ 4 , 5 ].

The three main mechanisms of AA are direct injuries, immune-mediated disease, and bone marrow failure (inherited or acquires) [ 1 ]. The most common etiology of AA is considered to be idiopathic, responsible for 65% of cases. Seronegative hepatitis accounts for about 10% of cases and tends to develop three months after the episode of acute hepatitis [ 6 ]. Telomerase abnormalities are found in approximately 5% of late-onset AA [ 7 ]. Among hereditary causes, Fanconi anemia is the most common, which presents in the first 10 years of life with pancytopenia, hypoplasia, and bone abnormalities [ 8 ].

The clinical manifestation of AA is usually some non-specific finding due to pancytopenia, such as fatigue, dyspnea on exertion due to anemia, mucosal bleeding like petechiae, heavy menses, gingival bleeding due to thrombocytopenia, or fever with neutropenia [ 9 ]. A bone marrow examination with a finding of aplastic or hypoplastic marrow is required to establish a diagnosis. In addition, cytogenetic studies, such as fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS), help make a diagnosis and rule out other hematologic abnormalities responsible for pancytopenia [ 9 ]. Peripheral blood-flow cytometry could be helpful in order to exclude paroxysmal nocturnal hemoglobinuria (PNH) [ 10 ].

Management of AA in patients without reversible causes depends on the age of the patient and disease severity. For young and healthy individuals under 50 years old, an allogeneic hematopoietic cell transplant (HCT) should be performed before initiation of immunosuppressive therapy (IST). Those who are older than 50 years old or younger individuals who cannot have HCT should start on full-dose IST, including eltrombopag, which is a thrombopoietin agonist, anti-thymocyte globulin (ATG) that eliminates antigen-reactive T-cells, cyclosporin A inhibiting interleukin-II (IL-2), and prednisone that leads to the destruction of immature T-lymphocytes [ 9 ]. Supportive treatment with transfusions of leukoreduced RBC for hemoglobin (Hgb) less than 7 mg/dL or platelets less than 10,000/microliters and infection treatment or prophylaxis is also indicated for patients with AA [ 1 ].

Here, we present a case of a 35-year-old male who presented to the emergency room with profuse bleeding after deep dental cleaning and was found to have pancytopenia on his laboratory panel.

Case presentation

A 35-year-old male presented to the emergency department (ED) of our hospital for persistent bleeding of his gums. He had been having episodes of minimal gum bleeding for a week that he attributed to an infection and had gone to a dentist on the day of admission for dental cleaning. He started having profuse bleeding after the dental procedure, which did not resolve with the application of pressure and was advised to go to the ED.

At the time of admission, he was in mild distress and concerned about the bleeding. The patient did not have any dizziness, headache, palpitations, or bleeding anywhere else. He denied similar episodes in the past or a family history of bleeding. The patient denied tobacco, alcohol, or illicit drug use and was not on any anticoagulants/anti-platelets. The patient migrated from Mexico 20 years ago and worked in construction. He denied any sick contact or recent travel. On examination, his vital signs were stable, but he was in mild distress. He was having profuse bleeding in his bilateral lower gums, both the buccal and lingual side, and in the buccal side of his upper gums. The rest of the examination was unremarkable.

Initial laboratory results were significant for pancytopenia (Table ​ (Table1). 1 ). The chemistry panel was significant for elevated blood urea nitrogen and mild hypokalemia (potassium = 3.4 mEq/L). The liver function test, renal function test, coagulation panel, and other electrolyte results were normal. The peripheral blood smear test showed normal WBC and platelet morphology, decreased platelet number, abnormal RBC morphology, marked hypochromasia, and slight schistocytes.

g/dL: grams per deciliter; mm 3 : cubic meter; µm 3 : cubic micrometer; pg/cell: picogram per cell

CBC: complete blood count; WBCs: white blood cells; RBCs: red blood cells; Hbg: hemoglobin; Hct: hematocrit; MCV: mean cell volume; MCH: mean cell hemoglobin; PT: prothrombin time; INR: international normalized ratio; PTT: partial thromboplastin time

Within two hours, the patient became hypotensive and developed hemorrhagic shock, and was admitted to the intensive care unit. The patient’s mouth was packed, and he received multiple transfusions of packed RBC and platelets. Further test results (Table ​ (Table2) 2 ) were negative for any infections. However, he was positive for parvovirus and cytomegalovirus IgG antibodies, which were likely from a previously cleared infection. The reticulocyte count was 0.9 after correction for hematocrit, and haptoglobin and lactate dehydrogenase (LDH) were both within normal limits, pointing toward the hypoproliferation of the bone marrow rather than hemolysis.

HIV: human immunodeficiency virus; HBVs Ag: hepatitis B surface antigen; HBVc IgM Ab: IgM antibody against hepatitis B core antigen; HBV cIgM: hepatitis B virus cytoplasmic IgM; HCV IgG Ab: IgG antibody against hepatitis C; HAV IgM: IgM antibody against hepatitis A; COVID-19: coronavirus disease 2019; CMV IgG Ab; IgG antibody against cytomegalovirus; CMV IgM Ab: IgM antibody against cytomegalovirus; parvovirus B19 IgG Ab: parvovirus B19 IgG antibody; parvovirus B19 IgM Ab: parvovirus B19 IgM antibody

The bone marrow biopsy showed a hypocellular bone marrow with 5-10% cellularity consistent with AA (Figure ​ (Figure1, 1 , Figure ​ Figure2 2 ).

PNH flow cytometry with fluorescein-labeled proaerolysin (FLAER), which is a high-sensitivity assay that assesses the glycosylphosphatidylinositol (GPI)-linked CD59 on erythrocytes, was abnormal with elevated PNH monocytes (2.001%) and polymorphonuclear neutrophil (PMNs) (0.381%). No circulating blasts and megakaryocytes were seen. The overall AA is associated with PNH.

The patient was not accepted for the Allogenic Hematopoietic Stem Cell Transplant (HSTC) Center due to the lack of insurance. The patient was started on triple immune suppression therapy: ATG, cyclosporine (CsA), and prednisone. The patient was started on equine ATG 40 mg/kg/day IV for four consecutive days in combination with CsA 10 mg/kg every 12 hours and prednisolone (0.5 mg/kg/day). In addition, he received eltrombopag 150 mg per oral (PO) once per day, an oral thrombopoietin-receptor agonist, and diphenhydramine 25 mg to prevent serum sickness from ATG. The patient continued to be on neutropenic precautions and close monitoring of all cell line levels, with goals of Hgb 7 g/dL and platelet count 10,000/mm 3 .

The patient was discharged home to continue outpatient chemotherapy. On the last follow-up at the outpatient clinic, three months after admission, recovery of all the three cell lines was noted (Table ​ (Table3 3 ).

CBC: complete blood count; WBCs; white blood cells; RBCs: red blood cells; Hbg: hemoglobin; Hct: hematocrit; MCV: mean cell volume; MCH: mean cell hemoglobin

The 35-year-old patient with no significant past medical history presented to the hospital with oropharyngeal bleeding. The severity of his thrombocytopenia expanded and the bleeding worsened upon his presentation to the hospital. His decreased WBC count and neutropenia put him at a high risk of infection. Low Hgb and below-normal reticulocytes showed that his RBC production was profoundly impaired. The bone marrow biopsy ruled out other differential diagnoses, but the cause of AA development was still questionable. In addition, the patient was found to have PNH, which could be associated with AA in 40% of patients. However, there are contradictory data in the literature about the impact of PNH clones on patients with AA undergoing immunosuppressive treatment.

AA can be associated with a broad spectrum of pathologies that could lead to the loss of progenitor cells and pancytopenia. There are three main mechanisms of its development: disrupting extrinsic factors, expression of familial genetic mutations, or damage by an autoimmune attack on hematologic cells [ 1 ]. The extrinsic mechanisms of AA are usually apparent and include exposure to therapeutic radiation, benzene, chemotherapy [ 11 ], several medications, or pesticides, such as organophosphates [ 7 ]. Nevertheless, this patient did not take any medications or have no known history of radiation or chemotherapy.

A genetic abnormality that is mainly associated with AA is Fanconi anemia, a condition attributed to DNA repair abnormalities. This syndrome is usually manifested in patients during the first or second decade with other congenital defects, such as thumb or facial abnormalities and short stature [ 12 ]. Dyskeratosis congenita is another common mechanism, a condition caused by mutations in genes responsible for the repair of telomeres. Patients can present with skin pigmentations, oral leukoplakia, and dystrophic nails [ 13 ]. Congenital abnormality was highly unlikely in this patient; he did not have any family history of such conditions, nor had a clinical manifestation.

Another common cause of AA can be seronegative hepatitis, which can develop in up to 10% of cases approximately three months before the manifestation of AA [ 14 ]. It usually occurs in the younger population. However, this patient did not have any risk factors or any history related to the development of hepatitis. Other viruses that could predispose to AA include HIV or parvovirus B19 [ 15 ]. IgG usually develops two weeks after infection and persists for life, with an increase in level post-re-exposure. Transient aplastic crisis (TAC) is characterized by the abrupt onset of anemia with absent or low-level reticulocytes and can be associated with B19 in patients with hematologic abnormalities. TAC and B19 can also lead to other cytopenias in other blood lineages [ 16 ]. TAC could be a potential explanation for the patient’s symptoms as his blood tests revealed elevated IgG levels to B19. This finding can reflect only previous infections and has no association with AA in this patient. Nevertheless, regardless of the trigger, the patient’s presentation and the severity of his AA were associated with a high chance of death without urgent management.

Management of AA depends on the severity of the condition, the age of a person, access to the treatment or availability of a matched stem-cell donor, and the presence of other comorbidities that decrease the chance of getting a cell transplant [ 17 ]. The patient’s laboratory values met the criteria for severe AA, which are defined by bone marrow hypocellularity of less than 30% and involvement of at least two out of the three criteria: absolute reticulocyte count less than <60 ×109/L, absolute neutrophil count less than 0.5×109/L, or platelet count less than 20 ×109/L. Younger age (less than 40) and the presence of a matched sibling donor favor the use of the allogeneic HSCT. Usually, older patients (>40 years) and those who do not have access to HSCT are treated with IST, which includes a combination of ATG and CsA with response rates up to 80% and survival rates the same as those after HSCT [ 18 ]. However, rates of relapse and evolution to myelodysplastic syndromes are higher with IST treatment [ 19 ]. Bacigalupo et al. showed an overall survival rate of 87% and a response rate of 77% in 100 patients treated with CsA, ATG, prednisone, and filgrastim [ 20 ]. Nevertheless, the patient did not have access to the treatment with an allogeneic stem cell transplant. He was commenced on full IST with eltrombopag, ATG, and CsA with prednisone and diphenhydramine to prevent serum sickness from ATG.

Some studies have revealed factors that predict a better response to IST, such as younger age, high absolute reticulocyte and lymphocyte count, and mutations in the PIGA, BCOR, or BCORL1 genes [ 21 ]. Mutations in the PIGA gene lead to the lack of the GPI-anchored proteins, CD59, and decay-accelerating factor (DAF or CD55) in patients with PNH. Deficiency of these GPI-anchoring proteins in WBCs and RBCs leads to the development of the so-called escape clones of PNH in AA [ 22 ].

The explanation of this immune escape mechanism is proposed to be associated with cytotoxic T cells that target normal hematopoietic stem cells (HSCs), and PNH-positive HSCs are protected from this immune attack. These T cells’ target can most likely be GPI anchors in patients with AA [ 23 , 24 ].

PNH escape clones can be found in more than 50% of patients with AA at the time of diagnosis, as in this patient. According to the AA guidelines of the British Society for Standards in Haematology, all patients with AA should be screened for PNH clones [ 17 ]. The impact of PNH clones on the treatment outcome of patients treated with IST has been discussed in the recent meta-analysis that showed a better response rate in the group diagnosed with PNH [ 25 ].

Apart from IST, patients with AA usually require supportive care that includes prophylaxis and treatment of infections, transfusions of leukoreduced packed RBC if the level of Hgb is less than 7 mg/dL, or platelets if their level drops below 10 x 109/L, or less than 50 x 109/L with active bleeding [ 1 ]. The patient presented with a platelet count of 4 x 109/L; therefore, he received multiple platelet transfusions before being discharged home.

The patient gradually improved on IST and was eventually discharged home to continue outpatient chemotherapy. On the last follow-up at the outpatient clinic, three months after admission, recovery of all the three cell lines was noted.

Conclusions

In this case report, we described a case of a healthy young man with no medical history who presented to the hospital with persistent bleeding from his gums and was found to have AA. The patient’s laboratory values met the criteria for severe AA, and he was also found to have PNH that could be associated with AA in 40% of patients. Patients with age less than 40 and the presence of a matched sibling donor favor the use of HSCT. Our patient did not have access to the bone marrow transplant. Therefore, he was commenced on full IST with ATG, prednisone, and CsA. In addition to IST, the patient was also receiving eltrombopag. The patient with severe AA responded excellently to the therapy, recovering all the three cell lines after three months of management. Therefore, young age, no significant past medical history, and concomitant diagnosis with PNH can be the main factors leading to a better response rate to IST in patients diagnosed with severe AA.

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained or waived by all participants in this study