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• Published: 13 September 2021

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.

Peer Review reports

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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Received : 25 March 2021

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Published : 13 September 2021

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

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

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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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History of Present Illness

• Review of Systems
• Past Medical History
• Physical Examination
• Differential Diagnosis
• Relevant Next Steps
• Test Results
• Interim Differential Diagnoses
• Relevant Next Steps 2
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• Treatment Orders
• About the Case

Anemia in a 42-year-old woman

A 42-year-old woman comes to the office for evaluation of significant anemia. She was diagnosed the previous week at an urgent care center during an evaluation for a 2-week history of progressive fatigue and dyspnea on exertion. She had a negative workup for cardiac and pulmonary disease, including normal pulse oximetry, chest x-ray, ECG, and point-of-care cardiac ultrasound. However, at that visit her hemoglobin was discovered to be 7.0 gm/dL (70 gm/L). Today in the office, she is still dyspneic with exertion, is unable to climb a flight of stairs without stopping, but she denies any other current symptoms. She has noted no bloody or dark stools or excessive vaginal bleeding. Her menses are regular, lasting 4 days, and she describes them as "not heavy." She has been told in the past that she had a "low blood count" that her previous doctor attributed to her periods and her vegetarian diet. She was sometimes treated with iron supplements but has had no other treatment or workup.

She brings her CBC results from the urgent care center:

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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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Iron deficiency anemia-a case study.

Case Details

An 18 –year- old female reported to the physician for consultation. She complained of generalized weakness, lethargy, and inability to do the routine work from the previous few months. On further questioning, she revealed that she was having excessive bleeding during menstruation for the previous six months. She complained of breathlessness and palpitations while climbing stairs for her house. She also had experienced periods of light-headedness, though not to the point of fainting. Other changes she had noticed were cramping in her legs, a desire to crunch on ice, There was no history of any fever, drug intake or abdominal discomfort. Her appetite had also decreased and she was taking meals only once a day.

Upon examination, her physician found that she had tachycardia, pale gums, and nail beds, and her tongue was swollen. Given her history and the findings on her physical examination, the physician suspected that the patient was anemic and ordered a sample of her blood for examination. The results were as shown below:

Red Blood Cell Count -3.5 million/mm 3

Hemoglobin (Hb) -7 g/dl

Hematocrit (Hct)- 30%

Serum Iron – low

Mean Corpuscular Volume (MCV) – low

Mean Corpuscular Hb Concentration (MCHC)- low

Total Iron Binding Capacity in the Blood (TIBC)- high

What is the cause of anemia in this patient?

What are the possible complications in the untreated cases?

Case Discussion-  The most likely diagnosis is iron deficiency anemia.

Generalized weakness, exercise intolerance, dyspnea, palpitations, history of blood loss during menstruation, tachycardia and low Hb, all are suggestive of iron deficiency anemia. Iron deficiency is the most prevalent single deficiency state on a worldwide basis. Iron deficiency is related in part to abnormal iron metabolism

Overview of iron metabolism

The balance of iron in humans is tightly controlled and designed to conserve iron for reutilization. There is no regulated excretory pathway for iron, and the only mechanisms by which iron is lost from the body are blood loss (via gastrointestinal bleeding, menses, or other forms of bleeding) and the loss of epithelial cells from the skin, gut, and genitourinary tract. Normally, the only route by which iron comes into the body is via absorption from food or from medicinal iron taken orally. Iron may also enter the body through red-cell transfusions or injection of iron complexes. The margin between the amount of iron available for absorption and the requirement for iron in growing infants and the adult female is narrow; this accounts for the great prevalence of iron deficiency worldwide—currently estimated at one-half billion people.

  Iron requirement

The amount of iron required from the diet to replace losses averages about 10% of body iron content a year in men and 15% in women of childbearing age. Dietary iron content is closely related to total caloric intake (approximately 6 mg of elemental iron per 1000 calories). Iron bioavailability is affected by the nature of the foodstuff, with heme iron (e.g., red meat) being most readily absorbed. Certain foodstuffs that include phytates and phosphates reduce iron absorption by about 50%.

Infants, children, and adolescents may be unable to maintain normal iron balance because of the demands of body growth and lower dietary intake of iron. During the last two trimesters of pregnancy, daily iron requirements increase to 5–6 mg. That is the reason why iron supplements are strongly recommended for pregnant women in developed countries.

Iron absorption

Iron absorption takes place largely in the proximal small intestine and is a carefully regulated process. In general, there is no regulation of the amounts of nutrients absorbed from the gastrointestinal tract. A notable exception is an iron, the reason that absorption must be carefully regulated is that the body does not possess a physiological mechanism to eliminate much iron from the body. The small amount of iron that is lost each day (about 1-2 mg) is matched by dietary absorption of iron.

Mechanism of iron absorption

Iron is found in the diet is present as ionic (non-haem) iron and haem iron. Absorption of these two forms of iron occurs by different mechanisms. Absorption is a multistep process involving the uptake of iron from the intestinal lumen across the apical cell surface of the villus enterocytes and the transfer out of the enterocyte across the basolateral membrane to the plasma. Ionic iron is present in the reduced (ferrous) or oxidized (ferric) state in the diet and the first step in the uptake of ionic iron involves the reduction of iron. Recently, a reductase that is capable of reducing iron from its ferric to ferrous state has been identified. It is a membrane-bound haem protein called Dcytb that is expressed in the brush border of the duodenum. Next, ferrous ion is transported across the lumen cell surface by a transporter called divalent metal transporter 1 (DMT1) that can transport a number of other metal ions including copper, cobalt, zinc, and lead.

Once inside the gut cell, iron may be stored as ferritin or transported through the cell to be released at the basolateral surface to plasma transferrin through the membrane-embedded iron exporter, ferroportin. The function of ferroportin is negatively regulated by hepcidin, the principal iron regulatory hormone. More the Hepcidin levels lesser is the iron absorption and vice versa. In the process of release, iron interacts with another ferroxidase, hephaestin, which oxidizes the iron to the ferric form for transferrin binding. Hephaestin is similar to ceruloplasmin, the copper-carrying protein.

Factors affecting iron absorption

Iron absorption is influenced by a number of physiologic states.

1)      Erythroid hyperplasia stimulates iron absorption, even in the face of normal or increased iron stores, and in this state hepcidin levels are inappropriately low. The molecular mechanism underlying this relationship is not known. Thus, patients with anemias associated with high levels of ineffective erythropoiesis absorb excess amounts of dietary iron. Over time, this may lead to iron overload and tissue damage. In iron deficiency, hepcidin levels are low and iron is much more efficiently absorbed from a given diet; the contrary is true in states of secondary iron overload.

2)      Hypoxia- Both the rate of erythropoiesis and hypoxia regulate iron absorption. Expression of ferroportin and Dcytb are increased in hypoxia, resulting in more iron absorption.

3)      Body Stores – Iron absorption is stimulated if the level in body stores is low.

Hepcidin is produced by hepatocytes when iron stores are full, hepcidin makes a complex with ferroportin resulting in its degradation and thus iron is not transported to the blood and remains in the enterocyte in the form of ferritin.

4)      Interfering substances- Iron absorption is decreased by phytic acid (in cereals) and oxalic acid(in leafy vegetables) due to the formation of insoluble salts.

5)      Other Minerals- Calcium, copper, zinc, lead, and phosphates also inhibit iron absorption

6)       Inflammation can also stimulate hepcidin production resulting in lower iron absorption.

Free Iron toxicity

Iron is a critical element in the function of all cells, although the amount of iron required by individual tissues varies during development. At the same time, the body must protect itself from free iron, which is highly toxic in that it participates in chemical reactions that generate free radicals such as singlet O 2 or OH – . Consequently, elaborate mechanisms have evolved that allow the iron to be made available for physiologic functions while at the same time conserving this element and handling it in such a way that toxicity is avoided.

Iron Transport

Iron absorbed from the diet or released from stores circulates in the plasma bound to transferrin , the iron transport protein. Transferrin (Tf) is a bilobed glycoprotein with two iron binding sites. Tf is normally about one-third saturated with iron Transferrin that carries iron exists in two forms— monoferric (one iron atom) or diferric (two iron atoms).  

The turnover (half-clearance time) of transferrin-bound iron is very rapid—typically 60–90 min.  The half-clearance time of iron in the presence of iron deficiency is as short as 10–15 min. With the suppression of erythropoiesis, the plasma iron level typically increases and the half-clearance time may be prolonged to several hours.

The iron-transferrin complex circulates in the plasma until it interacts with specific transferrin receptors on the surface of marrow erythroid cells. Diferric transferrin has the highest affinity for transferrin receptors; apo transferrin (transferrin not carrying iron) has very little affinity. While transferrin receptors are found on cells in many tissues within the body—and all cells at some time during development will display transferrin receptors—the cell having the greatest number of receptors (300,000 to 400,000/cell) is the developing erythroblast.

Utilization of iron

Once the iron-bearing transferrin interacts with its receptor, the complex is internalized via clathrin-coated pits and transported to an acidic endosome, where the iron is released at a low pH. The iron is then made available for heme synthesis while the transferrin-receptor complex is recycled to the surface of the cell, where the bulk of the transferrin is released back into circulation and the transferrin receptor re anchors in to the cell membrane. At this point, a certain amount of the transferrin receptor protein may be released into circulation and can be measured as soluble transferrin receptor protein. Within the erythroid cell, iron in excess of the amount needed for hemoglobin synthesis binds to a storage protein, apoferritin , forming ferritin . This mechanism of iron exchange also takes place in other cells of the body expressing transferrin receptors, especially liver parenchymal cells where the iron can be incorporated into heme-containing enzymes or stored. The iron incorporated into hemoglobin subsequently enters the circulation as new red cells are released from the bone marrow. The iron is then part of the red cell mass and will not become available for reutilization until the red cell dies.

Figure-2 showing the internalization of Iron- Transferrin complex, utilization of iron and transport to other cells via Transferrin  from the hepatocyte

Conservation of iron

In a normal individual, the average red cell life span is 120 days. Thus, 0.8–1.0% of red cells turn over each day. At the end of its life span, the red cell is recognized as senescent by the cells of the reticuloendothelial (RE) system , and the cell undergoes phagocytosis. Once within the RE cell, the hemoglobin from the ingested red cell is broken down, the globin and other proteins are returned to the amino acid pool, and the iron is shuttled back to the surface of the RE cell, where it is presented to circulating transferrin. It is the efficient and highly conserved recycling of iron from senescent red cells that supports steady state (and even mildly accelerated) erythropoiesis. Persistent errors in iron balance lead to either iron deficiency anemia or hemosiderosis. Both are disorders with potential adverse consequences.

Storage of iron

Ferritin and Haemosiderin are iron-containing compounds meant for the storage of iron. Ferritin is a protein-bound, water-soluble, mobilizable storage compound and is the major source of storage iron. Haemosiderin is a water-insoluble form that is less readily available for use. When the amount of total body iron is relatively low, storage iron consists predominately of ferritin. When iron stores are high, Haemosiderin predominates. Unlike ferritin, Haemosiderin stains with the Prussian blue stain (Pens reaction) and may be observed in tissues. Storage forms normally comprise approximately 30% of total body iron. Iron stores provide a source of iron when physiologic demand is high, e.g., blood loss, pregnancy, and periods of rapid growth.

The metabolic role of iron

Iron is vital for all living organisms because it is essential for multiple metabolic processes, including oxygen transport, DNA synthesis, and electron transport.

The major role of iron in mammals is to carry O 2 as part of hemoglobin. O 2 is also bound by myoglobin in muscle. Iron is a critical element in iron-containing enzymes, including the cytochrome system in mitochondria. Without iron, cells lose their capacity for electron transport and energy metabolism. In erythroid cells, hemoglobin synthesis is impaired, resulting in anemia and reduced O 2 delivery to tissue.

Iron-containing Proteins

a) Haem containing proteins

Hemoglobin, Myoglobin, Cytochromes, Catalase, Peroxidase, Lactoperoxidase and tryptophan pyrrolase

b) Non-haem containing proteins

Aconitase, Phenyl alanine hydroxylase, Transferrin, Ferritin, and hemosiderin

c) Iron-sulfur complexes

Adrenodoxin, Complex-III of Electron transport chain, Succinate dehydrogenase and Xanthine oxidase

Demand and supply imbalance

Since each milliliter of red cells contains 1 mg of elemental iron, the amount of iron needed to replace those red cells lost through senescence amounts to 16–20 mg/d (assuming an adult with a red cell mass of 2 L). Any additional iron required for daily red cell production comes from the diet. Normally, an adult male will need to absorb at least 1 mg of elemental iron daily to meet needs, while females in the childbearing years will need to absorb an average of 1.4 mg/d. However, to achieve a maximum proliferative erythroid marrow response to anemia, additional iron must be available. With markedly stimulated erythropoiesis, demands for iron are increased by as much as six- to eightfold. With extravascular hemolytic anemia, the rate of red cell destruction is increased, but the iron recovered from the red cells is efficiently reutilized for hemoglobin synthesis. In contrast, with intravascular hemolysis or blood loss anemia, the rate of red cell production is limited by the amount of iron that can be mobilized from stores. Typically, the rate of mobilization under these circumstances will not support red cell production more than 2.5 times normal. If the delivery of iron to the stimulated marrow is suboptimal, the marrow’s proliferative response is blunted, and hemoglobin synthesis is impaired. The result is a hypoproliferative marrow accompanied by microcytic, hypochromic anemia.

Menstrual blood loss in women plays a major role in iron metabolism. The average monthly menstrual blood loss is approximately 50 mL, or about 0.7 mg/d. However, menstrual blood loss maybe five times the average. To maintain adequate iron stores, women with heavy menstrual losses must absorb 3–4 mg of iron from the diet each day. This strains the upper limit of what may reasonably be absorbed, and women with menorrhagia of this degree will almost always become iron deficient without iron supplementation.

Pregnancy may also upset the iron balance since requirements increase to 2–5 mg of iron per day during pregnancy and lactation. Normal dietary iron cannot supply these requirements, and medicinal iron is needed during pregnancy and lactation. Repeated pregnancy (especially with breast-feeding) may cause iron deficiency if increased requirements are not met with supplemental medicinal iron.

Decreased iron absorption can on very rare occasions cause iron deficiency and usually occurs after gastric surgery, though concomitant bleeding is frequent.

By far the most important cause of iron deficiency anemia is blood loss, especially gastrointestinal blood loss. Chronic aspirin use may cause it even without a documented structural lesion. Iron deficiency demands a search for a source of gastrointestinal bleeding if other sites of blood loss (menorrhagia, other uterine bleeding, and repeated blood donations) are excluded.

Chronic hemoglobinuria may lead to iron deficiency since iron is lost in the urine; traumatic hemolysis due to a prosthetic cardiac valve and other causes of intravascular hemolysis (eg, paroxysmal nocturnal hemoglobinuria) should also be considered. Frequent blood donors may also be at risk for iron deficiency.

While blood loss or hemolysis places a demand on the iron supply, conditions associated with inflammation interfere with iron release from stores and can result in a rapid decrease in the serum iron level.

Summary of Causes of Iron Deficiency

Conditions that increase demand for iron, increase iron loss, or decrease iron intake or absorption can produce iron deficiency;

• rapid growth in infancy or adolescence
• erythropoietin therapy
• chronic blood loss
• acute blood loss
• blood donation
• Phlebotomy as a treatment for polycythemia vera.
• inadequate diet  
• malabsorption from disease (sprue, Crohn’s disease)
• malabsorption from surgery (post-gastrectomy)  
• acute or chronic inflammation

  Iron deficiency anemia

Iron deficiency is defined as decreased total iron body content. Iron deficiency anemia occurs when iron deficiency is sufficiently severe to diminish erythropoiesis and cause the development of anemia. Iron deficiency is the most prevalent single deficiency state on a worldwide basis. It is important economically because it diminishes the capability of individuals who are affected to perform physical labor, and it diminishes both growth and learning in children.

In countries where little meat is in the diet, iron deficiency anemia is 6-8 times more prevalent. This occurs despite the consumption of a diet that contains an equivalent amount of total dietary iron because heme iron is absorbed better from the diet than nonheme iron. In certain geographic areas, intestinal parasites, particularly hookworm, worsen the iron deficiency because of blood loss from the gastrointestinal tract. Anemia is more profound among children and premenopausal women in these environments.

Mortality/Morbidity

Chronic iron deficiency anemia is seldom a direct cause of death; however, moderate or severe iron deficiency anemia can produce sufficient hypoxia to aggravate underlying pulmonary and cardiovascular disorders. In children, the growth rate may be slowed, and a decreased capability to learn is reported.

Clinical Manifestations

As a rule, the only symptoms of iron deficiency anemia are those of the anemia itself (easy fatigability, tachycardia, palpitations, and tachypnea on exertion). Severe deficiency causes skin and mucosal changes, including a smooth tongue, brittle nails, and cheilosis. Dysphagia because of the formation of esophageal webs (Plummer–Vinson syndrome) also occurs. Many iron-deficient patients develop pica, craving for specific foods (ice chips, etc) often not rich in iron.

Laboratory Findings

• This documents the severity of the anemia. In chronic iron deficiency anemia, the cellular indices show a microcytic and hypochromic erythropoiesis, ie, both the mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) have values below the normal range for the laboratory performing the test. Reference range values for the MCV and MCHC are 83-97 fL and 32-36 g/dL, respectively.
• Often, the platelet count is elevated (>450,000/µL). This normalizes following iron therapy.
• The WBC count is usually within reference ranges (4500-11,000/µL).
• If the CBC count is obtained after blood loss, the cellular indices do not enter the abnormal range until most of the erythrocytes produced before the bleed are destroyed at the end of their normal lifespan (120 d).
• Peripheral smear
• In the early stages, the MCV remains normal. Subsequently, the MCV falls and the blood smear shows hypochromic microcytic cells (see blood smear). With further progression, anisocytosis (variations in red blood cell size) and poikilocytosis (variation in the shape of red cells) develop. Severe iron deficiency will produce a bizarre peripheral blood smear, with severely hypochromic cells, target cells, hypochromic pencil-shaped cells, and occasionally small numbers of nucleated red blood cells. The platelet count is commonly increased.(Figure-3)
• Combined folate deficiency and iron deficiency are commonplace in areas of the world with little fresh produce and meat. The peripheral smear reveals a population of macrocytes mixed among the microcytic hypochromic cells. This combination can normalize the MCV.

  Figure –3- showing microcytic hypochromic cells in peripheral smear

• Serum iron, total iron-binding capacity (TIBC), and serum ferritin : Iron deficiency develops in stages. The first is depletion of iron stores. At this point, there is anemia and no change in red blood cell size. The serum ferritin will become abnormally low. A ferritin value less than 30 mcg/L is a highly reliable indicator of iron deficiency. The serum total iron-binding capacity (TIBC) rises. After iron stores have been depleted, red blood cell formation will continue with deficient supplies of iron. Serum iron values decline to less than 30 mcg/dL and transferrin saturation to less than 15%. A low serum iron and ferritin with an elevated TIBC are diagnostic of iron deficiency. While low serum ferritin is virtually diagnostic of iron deficiency, a normal serum ferritin can be seen in patients who are deficient in iron and have coexistent diseases (hepatitis, anemia of chronic disorders). These test findings are useful in distinguishing iron deficiency anemia from other microcytic anemias
• A bone marrow aspirate can be diagnostic of iron deficiency. Bone marrow biopsy for evaluation of iron stores is now rarely performed because of variation in its interpretation.
• Testing stool for the presence of hemoglobin is useful in establishing gastrointestinal bleeding as the etiology of iron deficiency anemia. Severe iron deficiency anemia can occur in patients with a persistent loss of less than 20 mL/d.
• Hemoglobinuria and hemosiderinuria can be detected by laboratory testing. This documents iron deficiency to be due to renal loss of iron and incriminates intravascular hemolysis as the etiology.
• Hemoglobin electrophoresis and measurement of hemoglobin A 2 and fetal hemoglobin are useful in establishing either beta-thalassemia or hemoglobin C or D as the etiology of the microcytic anemia. 
• Serum Levels of Transferrin Receptor Protein -Because erythroid cells have the highest numbers of transferrin receptors on their surface of any cell in the body, and because transferrin receptor protein (TRP) is released by cells into the circulation, serum levels of TRP reflect the total erythroid marrow mass. Another condition in which TRP levels are elevated is absolute iron deficiency. Normal values are 4–9 μg/L determined by immunoassay. This laboratory test is becoming increasingly available and, along with the serum ferritin, has been proposed to distinguish between iron deficiency and the anemia of chronic inflammation

Differential Diagnosis

Other causes of microcytic anemia include anemia of chronic disease, thalassemia, and sideroblastic anemia. Anemia of chronic disease is characterized by normal or increased iron stores in the bone marrow and a normal or elevated ferritin level; the serum iron is low, often drastically so, and the TIBC is either normal or low. Thalassemia produces a greater degree of microcytosis for any given level of anemia than does iron deficiency. Red blood cell morphology on the peripheral smear is abnormal earlier in the course of thalassemia.

The diagnosis of iron deficiency anemia can be made either by the laboratory demonstration an iron-deficient state or evaluating the response to a therapeutic trial of iron replacement.

Since the anemia itself is rarely life-threatening, the most important part of treatment is the identification of the cause—especially a source of occult blood loss.

Ferrous sulfate, 325 mg three times daily, which provides 180 mg of iron daily of which up to 10 mg is absorbed (through absorption may exceed this amount in cases of severe deficiency), is the preferred therapy.

Parenteral Iron

The indications are intolerance to oral iron, refractoriness to oral iron, gastrointestinal disease (usually inflammatory bowel disease) precluding the use of oral iron, and continued blood loss that cannot be corrected. Because of the possibility of anaphylactic reactions, parenteral iron therapy should be used only in cases of persistent anemia after a reasonable course of oral therapy. 

Red Cell Transfusion

Transfusion therapy is reserved for individuals who have symptoms of anemia, cardiovascular instability, continued and excessive blood loss from whatever source, and require immediate intervention. The management of these patients is less related to iron deficiency than it is to the consequences of the severe anemia. Not only do transfusions correct the anemia acutely, but the transfused red cells provide a source of iron for reutilization, assuming they are not lost through continued bleeding. Transfusion therapy will stabilize the patient while other options are reviewed.

Iron deficiency anemia is an easily treated disorder with an excellent outcome; however, it may be caused by an underlying condition with a poor prognosis, such as neoplasia. Similarly, the prognosis may be altered by a comorbid condition such as coronary artery disease.

• ferroportin
• Iron deficiency anemia
• transferrin

Reference Books By Dr. Namrata Chhabra

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Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia

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A 44-year-old man presents with fever, abdominal pain, and fatigue. His physical examination shows splenomegaly. His laboratory results are as follows:

The patient is transfused several units of packed red blood cells without significant correction of his anemia, and instead, his pancytopenia worsens. Peripheral smear shows pancytopenia without blasts, tear drop cells, or dysplasia. A bone marrow biopsy demonstrates the following:

• Aplastic anemia
• Acute promyelocytic leukemia
• Myelofibrosis
• Hemophagocytic lymphohistiocytosis
• Myelodysplastic syndrome

Explanation

The most likely diagnosis is hemophagocytic lymphohistiocytosis (HLH). The patient fulfills at least five of the main nine diagnostic criteria of HLH including fever, splenomegaly, cytopenia, elevated ferritin, low fibrinogen, and evidence of hemophagcytosis on bone marrow, as demonstrated in the pictures that a histiocytes engulfing a nucleated red cell (Figure 1) and a neutrophil (Figure 2).

Myelofibrosis can be associated with splenomegaly, but is less likely here since no marrow fibrosis or tear drop cells reported. Myelodysplastic syndrome is a possible cause of pancytopenia, but no dysplasia was noted on peripheral smear or in the bone marrow. Acute promyelocytic leukemia can be associated with DIC and low fibrinogen on presentation, but should have a hypercellular bone marrow with predominance of promyelocytes. Patients with aplastic anemia are found to have profound hypocellular bone marrow, but no hemophagocytes should be found.

Case study submitted by Tzu-Fei Wang, MD, The Ohio State University, Columbus, OH

American Society of Hematology. (1). Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/male-fever-abdominal-pain-pancytopenia .

American Society of Hematology. "Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/male-fever-abdominal-pain-pancytopenia (label-accessed April 08, 2024).

"American Society of Hematology." Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia, 08 Apr. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/male-fever-abdominal-pain-pancytopenia .

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Egyptian Child Mummies Reveal High Prevalence of an Ancient Sickness

A nemia was common in mummified ancient Egyptian children, according to a new study that analyzed child mummies in European museums.

Researchers used computed tomography (CT) scans to peer non-invasively through the mummies' dressings and discovered that one-third of them had signs of anemia; they found evidence of thalassemia in one case, too.

"Our study appears to be the first to illustrate radiological findings not only of the cranial vault but also of the facial bones and postcranial skeleton that indicate thalassemia in an ancient Egyptian child mummy," the team writes in their published paper .

Paleopathologist Stephanie Panzer and her colleagues from Germany, the US, and Italy, suggest that anemia was likely common in ancient Egypt, and it was probably caused by factors such as malnutrition, parasitic infections, and genetic disorders, which still cause the health problem today.

Researchers have even speculated that Tutankhamun died of sickle cell disease, a cause of anemia. However, as the researchers of this new study explain , "the direct evidence of anemia in human remains from ancient Egypt is rare."

Anemia is a condition where the body lacks enough healthy red blood cells to carry oxygen to the body's tissues. As Panzer and colleagues studied child mummies, the remains are more likely to show signs of anemia than adult mummies, due to their early death.

Whether or not anemia played a role in each of the children's deaths could not be determined from the CT scans, but the research team believes it is likely to have contributed. They also looked for signs of diseases that could have caused the anemia.

When ancient humans were mummified, their bodies were preserved in ways that kept more information than those buried. Although modern science doesn't let researchers remove the wrappings used in the mummification process, they often use scans to 'look' through the wrappings and see what's inside.

CT scans can look at the mummies' bones, which can provide evidence of anemia because the bone marrow makes red blood cells.

Chronic hemolytic anemia and iron deficiency anemia are often accompanied by an enlargement of the cranial vault (the area of the skull that houses the brain). The researchers hoped to look for this along with further indicators of anemia in the bones, such as porosity, thinning, and changes in shape.

Measuring the porosity and thinness of bones requires a certain level of contrast – often reduced in the CT scans by the density of the preserved tissue and surrounding embalming. After consideration, this assessment, as the authors explain in their paper, "was not feasible in this study because of insufficient CT image quality."

Overall, the team found that 7 of the 21 child mummies they examined in German, Italian, and Swiss museums had measurable signs of anemia, specifically an enlarged frontal cranial vault.

Moreover, one child – referred to as case 2 – had facial and other bone changes present in thalassemia, a genetic disease in which the body can't make enough hemoglobin. Case 2 also had a tongue that was larger than usual, which the authors say "probably indicated Beckwith–Wiedemann syndrome ."

This genetically unlucky child probably died from thalassemia's many symptoms, which can include anemia, within 1.5 years of birth.

The mummified children, estimated to be aged between 1 and 14 years when they died, lived during multiple periods.

"The chronologically oldest mummy dated back to the time span between the Old Kingdom (2686–2160 BCE) and the First Intermediate Period (2160–2055 BCE). Most mummies dated to the Ptolemaic (332–30 BCE) and Roman Periods (30 BCE–395 CE)," the researchers state .

As sad as this discovery is, ancient Egyptian mummified remains certainly have revealed some interesting facts and insights about their lives and deaths . While it adds to our understanding, a small-scale study like this does have limitations.

"The collection of investigated child mummies did not represent a population," the authors note in their paper .

"The purpose of this study was to estimate the prevalence of anemia in ancient Egyptian child mummies and to provide comparative data for future studies."

The study has been published in the International Journal of Osteoarchaeology .

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• v.1(1); Jan-Jun 2009

Immune Hemolytic Anemia: A Report of Two Cases

Paramjit kaur.

Department of Transfusion Medicine, Government Medical College and Hospital, Chandigarh, India

Sabita Basu

Ravneet kaur, gagandeep kaur.

The transfusion-medicine specialists and physicians are often in a difficult situation when the patient has severe worsening anemia and all the blood is mismatched. This situation can arise in patients with red cell autoantibodies or alloantibodies due to previous transfusions. We report two cases of immune hemolysis – one due to warm auto antibodies and the second due to alloimmunization from multiple transfusions.

INTRODUCTION

Immune hemolysis is a shortening of red blood cell survival due, directly or indirectly to antibodies. These antibodies may be autoantibodies or alloantibodies. It is necessary to identify these atypical antibodies in the patient’s serum in order to select appropriate blood for transfusion. Even in the most vexing situation encountered by a transfusion specialist where no compatible units are available for a patient with severe anemia, transfusion should not be denied. In such cases, transfusion requirement should be considered as a medical emergency even if serologic testing is incomplete.[ 1 ]

CASE REPORT

A 20-year-old female was referred to our hospital with complaints of icterus and breathlessness. She had similar complaints one year back and was treated for jaundice by a local physician. Prior to her referral, she had been transfused three units of AB positive blood over one week. On general physical examination, there was marked pallor, icterus, tachycardia and tachypnea. She had mild hepatosplenomegaly. Hematological investigations revealed severe anemia (Hb – 2.7 gm/dl). There was mild leucocytosis and blood film showed autoagglutination with the presence of nucleated red cells (19/100 WBCs). Plasma and urine hemoglobin were raised. Liver function tests were deranged with indirect hyperbilirubinemia. Blood urea was also elevated (55 mg/dl). X-ray of the chest showed cardiomegaly. Patient had adequate urine output. The patient's sample was received in the blood bank for crossmatching. Cell and serum grouping showed a discrepancy with strong positive auto-control. Patient was typed as A Rh-positive with autoantibodies. Direct antiglobulin test with poly-specific Coomb's reagent (IgG + C3d) (Tulip diagnostics) was positive. Patient also had a positive antibody screen with all three reagent cells in the anti-human globulin test (Ortho cell panel, Ortho Diagnostics). Since the patient had life-threatening anemia with urgent requirement for transfusion, detailed phenotyping was not done and crossmatching was performed with several random A Rh-positive packed red cells but no compatible unit was detected. She received three ‘least incompatible’ A Rh-positive non-leuco reduced packed red cell units over three days as a life-saving measure after informed consent. No adverse events were reported during or after transfusion. Besides, she was also started on steroid therapy, antibiotics and diuretics. However, she developed sudden cardiorespiratory arrest on fifth day and could not be revived.

A 57-year-old male presented with chest pain and breathlessness. The patient was a case of coronary artery disease with off and on gastric bleed and a recipient of multiple transfusions in the past. Initial hemogram showed anemia (Hemoglobin 7.7 gm/dl). Peripheral blood smear showed dimorphic blood picture with moderate anisocytosis and poikilocytosis with mild hypochromia, microcytes, macro-ovalocytes and polychromasia. Reticulocyte count was 12%. Liver and renal function tests were normal. Blood group was O Rh-positive and two units of O Rh-positive packed cells were transfused. Since there was not much improvement in hemoglobin, another transfusion was requested but crossmatch was incompatible and antibody screen was positive. There was a difference in the strength of reaction at different phases and auto-control was negative. Direct Antiglobulin Test (DAT) was negative. Antibody identification studies suggested anti E, JKa and s as the implicating antibodies (Patient E-, JKa- and s-). Strong possibility of anti E was considered on 11 cell identification panel results. Meanwhile, patient improved clinically and was discharged at hemoglobin of 10.5 gm/dl with no further requirement for transfusion. Advice for future transfusions was given. Subsequently, he was readmitted with another bout of hematemesis and hemoglobin of 6.4 gm/dl. Patient received two transfusions by standard compatibility testing procedure since the blood bank was not informed about his previous immuno-hematological work up and hence a phenotypically matched blood was not given. However, there was a reaction with the first unit in the form of fever and mild jaundice (serum bilirubin 2.2 mg/dl), which recovered subsequently. Besides blood transfusion, the patient also received hematinics, antianginal drugs and diuretics.

Autoimmune hemolytic anemia is a fairly uncommon disorder with estimates of the incidence at 1–3 cases per 100 000 per year.[ 2 , 3 ] In contrast, alloimmune hemolytic anemia requires exposure to allogeneic red cells through pregnancy, transfusion or transplantation. The incidence of acute hemolytic transfusion reactions has been estimated to be 0.003–0.008%, while 0.05–0.07% of transfused patients develop a clinically recognized delayed hemolytic transfusion reaction.[ 4 – 6 ] Delayed serologic transfusion reactions are more common and are a frequent finding in patients who receive multiple transfusions.[ 7 ]

Warm autoantibodies are responsible for 48–70% of autoimmune hemolytic anemia cases.[ 8 , 9 ] Positive direct antiglobulin test may be the first serological evidence. Anemia is of variable severity and some patients present with fulminant hemolysis, jaundice, pallor, hemoglobinuria and hepatosplenomegaly.[ 10 ] In the first case, the patient was erroneously grouped and transfused AB positive blood before referral to our center. She presented with severe life-threatening anemia, jaundice, mild hepatosplenomegaly and evidence of hemolysis. The direct and indirect antiglobulin tests were positive. Initial antibody screen and auto-control was also strongly positive. Approximately 57% of patients with warm autoimmune hemolytic anemia have free serum autoantibody and a positive indirect antiglobulin test.[ 11 ] Due to pan agglutinin in the serum of patients with autoimmune hemolytic anemia, crossmatching blood is a difficult and time-consuming process since the pan agglutinin reacts with all donors’ red blood cells.. Moreover, the most pressing problem is detection and identification of RBC alloantibodies that may be masked by the autoantibodies.[ 12 ] In our patient, the anemia was life threatening with time constraints to perform adsorption studies with subsequent identification of underlying alloantibodies.

Even after thorough serological evaluation, the optimal blood for transfusion is still likely to be mismatched. Clinical reluctance to administer transfusions to such patients due to serological mismatch or an incomplete workup can have devastating consequences. Factors such as rate of onset of hemolysis and anemia, presence or absence of accompanying hypovolemia and the underlying health status and cardiorespiratory reserve must be taken into account to determine the transfusion trigger.[ 12 ] Our patient had received ‘least incompatible” transfusions due to severe anemia with imminent clinical deterioration. When a decision to transfuse mismatched blood is taken, transfusion of small aliquots to provide relief of symptoms and avoid fluid overload has been recommended.[ 12 ] It has also been recommended to transfuse using leucocyte-reduced blood products and pre-medication with antihistaminics and antipyretics to prevent febrile and allergic reactions, respectively, in patients with multiple antibodies.[ 13 ] Provision of prophylactic antigen-matched donor blood where feasible has also been advocated.[ 14 ]

The second patient was a recipient of multiple transfusions with difficulty in finding a compatible unit. Antibody screen was positive with difference in the strength of reaction in immediate spin, 37°C, and in the antihuman globulin phase. The patient had multiple alloantibodies, which did not cause any clinical evidence of delayed hemolytic transfusion reaction except mild subclinical jaundice. However, in spite of repeated transfusions, there was not much improvement in the hemoglobin. The reason could be that the antibody titer was low initially but subsequent to transfusion, an anamnestic response led to rise in antibody titer and hence subsequent crossmatching did not give a compatible unit. When the patient's sample was received in the first instance, crossmatch was compatible. Antibody screening was done with a subsequent request for blood when crossmatching yielded incompatibility. The incidence of alloimmunization in random multi-transfused patients has been reported to be 0–34%.[ 15 – 19 ] It is more in transfusion-dependent patients, such as those with sickle cell disease, aplastic anemia, myelodysplastic syndrome and other congenital or acquired anemia.[ 20 ] In a prospective study on the incidence of red cell alloimmunization following transfusion, 8.4% of patients developed antibodies within 24 weeks of transfusion.[ 21 ]

However, all alloantibodies are not clinically significant.[ 22 ] Takeuchi and coworkers[ 23 ] have reported a delayed hemolytic transfusion reaction due to anti E, anti C and anti JKa that are clinically significant antibodies. Such patients present a challenge for elective transfusions particularly if multiple clinically significant alloantibodies are present. If such a situation arises, transfusion should be withheld until suitable antigen-negative donor units are located. Patients with multiple alloantibodies should receive phenotypically matched red blood cells to avoid transfusion reaction and they should be given a card indicating the antibody specificities so that he can receive antigen negative blood.

In either case, a good communication must be established between the clinician and the transfusion specialist to assess the clinical urgency and the complexity of serological studies. The final decision to transfuse should depend on the evaluation of the patient's clinical status and the benefits must be weighed to the potential risks of transfusion.

ACKNOWLEDGMENT

Department of Transfusion Medicine, PGIMER, Chandigarh for technical assistance.

Source of Support: Nil

Conflict of Interest: None declared.