Mean Corpuscular Volume

Etiology

Clinicians use MCV to definitively diagnose the type of anemia—microcytic, normocytic, and macrocytic. Microcytic anemia is characterized by erythrocytes smaller than normal and significantly smaller than leukocytes. On a complete blood count (CBC), the MCV measure is below 80 fL, whereas a normal MCV ranges between 80 and 100 fL. This type of anemia is commonly associated with chronic iron-deficiency anemia, sideroblastic anemia, and thalassemias, although the anemia can also occur in other conditions. Microcytic cells may exhibit a larger area of central pallor, particularly in the context of iron-deficiency anemia and anemia of chronic disease.

Macrocytic anemia is characterized by an increased average RBC volume compared to normal levels, with an MCV measurement exceeding 100 fL on a CBC. Megaloblastic anemia is further categorized into megaloblastic, characterized by impaired DNA synthesis, or non-megaloblastic, where DNA synthesis remains normal. Megaloblastic anemia is commonly caused by folate deficiencies (folic acid or vitamin B9), cobalamin/vitamin B12, or orotic aciduria. This autosomal recessive disorder hinders the conversion of orotic acid to uridine monophosphate. On the other hand, non-megaloblastic anemia can result from hepatic insufficiency, chronic alcoholism, or a rare congenital disease known as Diamond-Blackfan anemia.

Normocytic anemia has a low hemoglobin and hematocrit range, but MCV is in the normal range of 80 to 100 fL. This type of anemia can be subclassified into hemolytic or non-hemolytic. Normocytic hemolytic anemia can occur intravascularly and extravascularly due to various underlying causes. Other laboratory values on the CBC further indicate the type of anemia, aiding in diagnosis. Non-hemolytic normocytic anemias may present in conditions such as early anemia of chronic disease, early iron-deficiency anemia, aplastic anemia, microangiopathic hemolytic anemias, and certain plasmodial infections.

Epidemiology

The MCV gradually increases with age, following 2 linear subsets in patients aged 1 to 25 and 26 to 88. Among individuals aged 40 to 80, women typically display lower MCV values compared to men. The demographics affected by various types of anemias vary depending on the MCV and underlying etiologies. Microcytic anemia has epidemiological variations in the underlying causes, with iron-deficiency anemia being the most common cause of microcytic anemia. Iron-deficiency anemia frequently occurs in premenopausal, menstruating women due to menorrhagia and chronic blood loss without adequate iron supplementation. However, for men and postmenopausal women aged 50 or older, the primary concern is colorectal cancer until ruled out, necessitating prompt colonoscopy evaluation.[1]

Anemia of chronic disease is the second most common type of anemia worldwide.[2] This type of anemia primarily affects patients with chronic inflammatory conditions, leading to disruptions in iron homeostasis.[3] The demographics range between men and women of all ages. Anemia of chronic disease can occur across demographics, affecting both men and women of all age groups, and is associated with a wide range of underlying conditions, including diabetes, rheumatologic diseases, and malignancies. Sideroblastic anemia can either be congenital or acquired, with potential causes such as lead exposure, myelodysplastic disorders, myeloproliferative neoplasms, vitamin B6 deficiency, isoniazid use, chronic alcoholism, or copper deficiency. By investigating spliceosome mutations, visualizations of ringed sideroblasts aid clinicians in narrowing the diagnosis, particularly towards myelodysplastic disorders or myeloproliferative neoplasms.

Myelodysplastic disorders affect approximately 10,000 individuals annually, predominantly affecting adult men aged 65 or older.[4][5] Myeloproliferative diseases include acquired and familial types. Thalassemia is categorized into β and α types, varying in severity and distribution. Alpha-thalassemia is more prevalent in African, Southern Chinese, Malaysian, and Thai populations, whereas β-thalassemia is prominent in African and Mediterranean populations. Both types are congenital.[6][7]

Macrocytic anemia is common, with a prevalence ranging from 1.7% to 3.6%.[8] Folate and vitamin B12 deficiencies can affect diverse demographics globally due to dietary imbalances; however, vitamin B12 deficiency is more common in individuals with vegan diets due to the primary source of animal products. Moreover, vitamin B12 deficiency can also occur in malabsorptive diseases, Diphyllobothrium latum infection, pernicious anemia, and gastrectomy. Organic acidemias affect approximately 1 in 784 live births in the United Kingdom.[9] Hepatic insufficiency demonstrates demographic variability, with chronic alcoholism showing a prevalence range of 20% to 36%.[10] Diamond-Blackfan anemia is a congenital condition that typically manifests within the first year of life, with an estimated prevalence ranging from 1 per 100,000 to 1 per 200,000 live births, affecting diverse races and ethnicities.[11] However, the epidemiology of normocytic anemia varies widely across all ethnicities, ages, and genders due to the numerous causes, many of which are acquired.

Pathophysiology

Microcytic Anemia

Microcytosis can result from a deficiency in a hemoglobin component, leading to noticeably smaller cells on a peripheral blood smear. Hemoglobin is composed of heme and globin molecules. For instance, the ferrochelatase enzyme is critical in heme synthesis by incorporating iron into the protoporphyrin ring structure to form the heme molecule.[12] As a result, the lack of iron from chronic iron-deficiency anemia can make the protoporphyrin rings in the heme molecules defective.

Anemia of chronic disease is due to an evolutionary response aimed at safeguarding iron from bacteria that utilize iron for growth. Bacterial infections trigger inflammation, leading to elevated levels of acute-phase reactants such as hepcidin, which sequesters iron in macrophages and reduces iron absorption in the gastrointestinal tract. This effect is similar to the presentation of iron-deficiency anemia.[8] In cases of iron-deficiency anemia, anemia of chronic disease, or sideroblastic anemia secondary to lead poisoning, impaired synthesis of heme and hemoglobin results in significantly smaller erythrocytes. Thalassemias, characterized by mutations in the α- or β-globin chains, also disrupts hemoglobin synthesis, leading to microcytic erythrocytes in these hemoglobinopathies.

Macrocytic Anemia

Macrocytic anemia can be categorized into either megaloblastic or non-megaloblastic anemia. During pyrimidine synthesis, folate undergoes hydrogenation to tetrahydrofolate and contributes a carbon group. Vitamin B12, or cobalamin, is a cofactor for the enzyme that transfers the carbon group from tetrahydrofolate. Deficiencies in either folate or vitamin B12 enzymes disrupt the division of erythrocytes to their normal size. Consequently, erythrocytes cease dividing due to deficient pyrimidines, resulting in enlarged cells. Elevated MCV is believed to contribute to venous thromboembolic disease through 1 or more mechanisms.[13] One theory suggests that as the MCV increases, the hematocrit also increases. An elevated hematocrit promotes the margination of platelets, increasing the risk of venous thromboembolic disease. Another theory suggests that a higher MCV increases blood viscosity, especially in large vessels. Blood flow decreases exponentially, predisposing to clots. The increased MCV is believed to exert a rheological disequilibrium with subsequent thrombosis.

Sunitinib, a chemotherapy agent (tyrosine kinase inhibitor), elevates MCV levels without affecting B12 or folate levels.[14] This tyrosine kinase inhibitor targets multiple intracellular signaling pathways, including the stem cell growth receptor (ckit) pathway, leading to ckit inhibition and increased MCV. Retrospective analyses have shown that a baseline macrocytosis correlates with increased progression-free survival in patients treated with pazopanib, a tyrosine kinase inhibitor.[15]  An increase in the MCV during sunitinib treatment also correlates with an increased progression-free survival. Generally, a high MCV predicts a high overall response rate. Non-megaloblastic anemia affects macrocytes differently. Liver disease can hinder lipid production, compromising the integrity of erythrocyte phospholipid bilayers due to liver failure.[16] Moreover, chronic alcoholism leading to alcoholic cirrhosis may impair folate absorption, exacerbating the development of macrocytic anemia.[17]

Normocytic Anemia

Normocytic anemia commonly arises due to either intravascular or extravascular hemolysis. However, another cause of normocytic anemia is aplastic anemia, which involves destroying myeloid stem cells responsible for producing erythrocytes.

Histopathology

A peripheral blood smear examination typically follows the MCV findings. This smear helps determine the size of erythrocytes relative to leukocytes. Microcytes are smaller and often exhibit a larger central area of pallor compared to normal erythrocytes, especially in cases of iron-deficiency anemia or anemia of chronic disease. Depending on the underlying cause of microcytosis, microcytic erythrocytes may also display features such as target cells and anisopoikilocytosis in thalassemia or basophilic stippling, characteristic of lead poisoning. Sideroblasts, on the other hand, are observed exclusively in bone marrow aspirates.

Megaloblastic macrocytosis refers to enlarged erythrocytes that are comparable in size to leukocytes. Due to DNA and RNA synthesis disruptions, this condition is often associated with hypersegmented polymorphonuclear neutrophils. However, patients with liver failure may exhibit acanthocytes or spur cells, along with macro-ovalocytes, stemming from lipid dysfunction from hepatic insufficiency. Various histopathological findings may be observed in normocytic anemia resulting from hemolysis, including sickled cells in sickle cell anemia; spherocytes in conditions, such as hereditary spherocytosis and autoimmune hemolytic anemia; Heinz bodies; Howell-Jolly bodies; degmacytes; and schistocytes. The specific presentations depend on the intrinsic or extrinsic factors contributing to normocytic anemia. Diagnosing aplastic anemia necessitates a bone marrow aspirate, which typically appears dry due to the absence of cells or may contain multiple white adipocytes lacking erythrocytes, leukocytes, or progenitor cells.

History and Physical

Mean Corpuscular Volume Below 80 fL

Iron-deficiency anemia presents with symptoms such as conjunctival pallor, fatigue, cold intolerance, cold distal extremities, koilonychia, occasionally pica, glossitis, dry, cracked lips, and cheilosis. Patients with iron-deficiency anemia report a history of chronic blood loss, chronic inflammation, exposure to lead paint, or a family history of thalassemia. In contrast, anemia of chronic disease presents with disease-causing chronic inflammation, such as arthritis in rheumatoid arthritis or malignancy. Also, these patients may remain asymptomatic. A family history of cancer, autoimmune disease, or rheumatologic conditions can provide valuable diagnostic clues in such cases. Furthermore, thalassemias can present with characteristic chipmunk facies resulting from bone marrow expansion and extramedullary hematopoiesis. Upon physical examination, this process may also lead to hepatomegaly and splenomegaly, whereas x-rays can reveal additional skeletal deformities. Patients with thalassemias typically have a family history of the condition, often inherited from 1 or both parents.

Patients with lead exposure are frequently exposed to lead paints, notably children in older homes where lead-based paints are common. Adults with lead exposure may report occupational exposures such as mining, pipefitting, auto repair work, and ceramic glazing. Lead poisoning can present with characteristic lead lines on the gums and metaphyses of long bones, along with symptoms such as abdominal pain, peripheral neuropathy (most commonly affecting the fibular and radial nerves), and fatigue. In severe cases, children can develop encephalopathy. Sideroblastic anemia can occur as a result of lead poisoning or chronic alcohol use, serving as the underlying etiology in some cases. Studies have shown a correlation between a low (pre-surgical) MCV and advanced stages (III or IV) of endometriosis.[18] These lower indices are believed to reflect dysregulated iron metabolism. 

Mean Corpuscular Volume Above 100 fL

Vitamin B12 deficiency typically develops over several years due to hepatic storage lasting approximately 3 to 6 years. Consequently, when symptoms do appear, they often involve the nervous system, as fatty acid synthesis is important for myelin sheath formation.

Patients with vitamin B12 deficiency may present with various symptoms, including:

• A strict vegan lifestyle without supplementation
• Short bowel syndrome with a history of small bowel resection
• Pernicious anemia, characterized by nausea, increased flatulence, diarrhea, weight loss, and anorexia
• Malabsorption symptoms such as steatorrhea, foul-smelling stools, diarrhea, weakness, and weight loss

Patients with MCV above 100 fL often exhibit signs of subacute combined degeneration, including cerebellar ataxia, bilateral hemiplegia, decreased vibration, and discriminative touch sensations. Folate deficiency may manifest with glossitis as a prominent symptom but typically lacks other specific symptoms. However, pregnant women with folate deficiency are at risk of fetal neural tube defects such as spina bifida occulta, especially if they do not use supplemental vitamins during pregnancy. Chronic alcoholism can contribute to folate deficiency, adding to the risk in such cases. Orotic aciduria typically presents early in life and is characterized by failure to thrive and delayed development, particularly in patients with a family history of the condition. Non-megaloblastic anemias often stem from underlying causes such as hepatic insufficiency, which can also be associated with chronic alcoholism, a prevalent contributing factor.

In addition, patients can report symptoms such as jaundice, fatigue, spider angiomas, palmar erythema, ascites, peripheral edema, easy bleeding, and bruising. Diamond-Blackfan anemia presents in the first year of life and is characterized by facial and hand malformations, growth retardation, and predisposition to malignancies.[19] An elevated MCV and increased mean corpuscular hemoglobin but not mean corpuscular hemoglobin concentration are associated with long-term cardiovascular events and elevated homocysteine levels—a proatherogenic risk factor.[20] An increased MCV is also associated with acute coronary syndrome and post-stroke depression, with a significant correlation observed between high MCV values and increased 30-day mortality from intracranial hemorrhage and major trauma, particularly in older people.

MCV is crucial in assessing esophageal cancer. Findings suggest that patients with locally advanced esophageal squamous cell carcinoma and an elevated MCV experience poor recurrence-free survival and overall survival rates. In this context, MCV establishes a harbinger of responsiveness for neoadjuvant chemotherapy. Furthermore, current findings support the idea that an increased MCV may indicate the presence of esophageal cancer.[21][22][23][24]

Mean Corpuscular Volume Between 80 and 100 fL

Both intrinsic and extrinsic hemolytic normocytic anemias can present with similar symptoms. Patients often experience darkened urine due to increased urobilinogen levels. In intravascular hemolysis caused by microangiopathic hemolytic anemias or paroxysmal nocturnal hemoglobinuria, hemoglobin and hemosiderin may also be detected in the urine.

The etiology of many of these diseases is spontaneous, but specific triggers or associations, as mentioned below, can provide diagnostic clues.

• Malaria may be suspected in patients who have recently traveled to endemic areas, participated in recent camping activities, or had Ixodes tick bites suggestive of babesiosis. Studies have suggested that children with a high or low MCV have a subsequent protective effect against malaria.
• Consumption of undercooked ground beef can raise suspicion for hemolytic uremic syndrome.
• In patients with systemic lupus erythematosus, symptoms such as foamy urine (indicative of proteinuria), along with epistaxis and hypertension in pregnant women beyond 20 weeks of gestation, may indicate HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count).

Aplastic anemia, characterized by pancytopenia, can present with pallor, purpura, petechiae, an increased risk of mucosal bleeding and infections, and fatigue secondary to pancytopenia.[25] 

Evaluation

A CBC, which includes hemoglobin, hematocrit, and MCV measurements, is essential for determining the type of anemia. The specific diagnostic approach for microcytic anemia depends on the patient's presentation. For instance, if a menstruating woman presents with an MCV below 80 fL and exhibits symptoms such as menorrhagia, further investigations such as a Von Willebrand factor assay and thyroid panel may be necessary to ascertain the underlying cause related to menstrual history. On the contrary, in patients with microcytic anemia aged 50 or older, a colonoscopy is typically recommended to investigate whether the iron deficiency originates from colonic polyps or neoplasms. Additional diagnostic steps may include a urea breath test and an upper endoscopy to assess for Helicobacter pylori, especially if the patient reports symptoms suggestive of gastritis-type pain.

When managing patients with anemia of chronic disease with an unknown cause, several diagnostic tests are necessary. These include assessments for rheumatoid factor, anti-double-stranded DNA antibodies, anti-neutrophil cytoplasmic antibodies, and anti-myeloperoxidase antibodies. In addition, a urine spot test should be conducted to evaluate renal function by measuring parameters such as glomerular filtration rate, creatinine, and blood urea nitrogen levels. Screening for HLA-B27 and rheumatologic antibodies is also crucial. Consideration may be given to malignancy screening using imaging modalities such as computed tomography (CT) scans or chest x-rays.

A blood lead level test is the gold-standard diagnostic tool for suspected lead poisoning. However, a bone marrow biopsy is necessary if other causes of sideroblastic anemia are possible. Obtaining a detailed medical history is crucial in identifying the underlying etiology, potentially avoiding a bone marrow biopsy. Suspected β-thalassemia cases can be further evaluated through hemoglobin electrophoresis to determine the proportions of hemoglobin A versus A2. For α-thalassemia, genetic analysis offers superior diagnostic accuracy. 

Peripheral blood smear and urine analysis are essential for distinguishing between intravascular and extravascular hemolysis in normocytic anemia. The presence of schistocytes and hemoglobin in the urine suggests microangiopathic hemolytic anemia. However, despite suspected hemolysis, the absence of schistocytes in the peripheral blood smear and the absence of hemoglobin in the urine warrant further investigation. Detection of spherocytes in the peripheral blood smear prompts a direct Coombs test to differentiate autoimmune hemolytic anemia from splenic sequestration in hereditary spherocytosis, aiding diagnosis.

Renal analysis demonstrates an inverse relationship between MCV and bone marrow density in patients on dialysis, observed with hemodialysis but not peritoneal dialysis. Reticulocyte mean corpuscular volume (MCVr), representing larger and younger cells, is typically elevated compared to mature RBCs. Monitoring MCVr can be instrumental in tracking recovery from various conditions, ranging from iron deficiency (microcytosis) to megaloblastic anemia, providing valuable clinical insights.

In cases of macrocytic anemia, obtaining a detailed history and performing a thorough physical examination are crucial for identifying potential causes, such as chronic alcoholism, liver failure, malabsorptive disorders, or dietary deficiencies, including veganism without vitamin supplementation. Notably, assessing vitamin B12 and folate levels is crucial, considering folate supplementation can mask underlying vitamin B12 deficiency. Suspected orotic aciduria necessitates urine analysis to detect orotic acid and ammonia levels. The ammonia test can differentiate a deficiency in ornithine transcarbamylase versus orotic aciduria. Due to the rarity of Diamond-Blackfan anemia, a detailed history, a thorough physical examination, and CBC are typically sufficient for diagnosis. However, due to associated predispositions, clinicians may opt for follow-up computed tomography (CT) scans to screen for potential malignancies.[19][26][27]

Treatment / Management

Microcytic Anemia

Treatment for microcytic anemia due to iron-deficiency anemia typically involves iron supplementation for premenopausal women. In some cases, women may also receive treatment with oral contraceptive pills to regulate menstrual cycles and reduce menstrual flow or levothyroxine if the cause is secondary to hypothyroidism.

Macrocytic Anemia

Treatment for macrocytic anemia varies depending on the underlying causes. For vitamin B12 and folate deficiencies, supplementation with folate and vitamin B12 is the standard therapeutic approach. Individuals who consume alcohol are advised to discontinue alcohol consumption and are often supplemented with folate. Patients diagnosed with orotic aciduria typically require supplementation with uridine monophosphate synthase to bypass the deficient enzyme and restore normal function.[28]

Normocytic Anemia 

Treatment for patients with paroxysmal nocturnal hemoglobinuria typically involves the use of eculizumab, which can effectively reduce hemolysis and prevent complications such as portal hypertension resulting from venous thromboses.[29] Blood transfusions may be necessary in severe anemia to restore hemoglobin levels. Patients with bone marrow failure may undergo hematopoietic stem cell transplantation as a potential treatment option. For patients with macroangiopathic hemolytic anemia secondary to conditions such as prosthetic heart valves or aortic stenosis, surgical interventions such as valve repair or replacement may be considered. Patients with intravascular hemolysis due to malaria or babesiosis require treatment with appropriate anti-malarial or babesiosis medications to manage the underlying infection effectively.(B3)

Microangiopathic hemolytic anemia can arise from thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, systemic lupus erythematosus, hypertensive emergency, and HELLP syndrome. Patients with thrombotic thrombocytopenic purpura are treated with plasmapheresis and corticosteroids. Patients with hemolytic uremic syndrome are treated with plasmapheresis, which is similar to thrombotic thrombocytopenic purpura. Patients with systemic lupus erythematosus are treated with prednisone to decrease flares, hydroxychloroquine, mycophenolate mofetil, and tumor necrosis factor (TNF)-α inhibitors. Patients with HELLP syndrome are treated with antihypertensives such as labetalol or hydralazine, magnesium sulfate to prevent convulsions, corticosteroids to further develop the baby's lung development before delivery, and blood transfusion if required due to thrombocytopenia.

Treatment for hereditary spherocytosis includes folate supplementation, blood transfusions if hemoglobin falls below 7 g/dL, and erythropoietin administration for infants up to 9 months old. Vaccination against encapsulated bacteria is recommended as a final step before splenectomy. Autoimmune hemolytic anemia is initially managed with glucocorticoids and then with cytotoxic drugs such as rituximab if the condition is refractory.[30] Aplastic anemia treatment involves identifying and removing any causative agents if possible. Hematopoietic stem cell transplants are commonly used for the management.[31]

Treatment for anemia of chronic disease commonly involves anti-inflammatories, corticosteroids, and TNF-α inhibitors unless malignancy is the underlying cause, in which case the malignancy requires a standard treatment protocol. Lead poisoning is managed with chelation therapy using dimercaprol, EDTA, and succimer for children. Copper deficiency requires copper supplementation. Patients taking isoniazid with vitamin B6 deficiency should receive vitamin B6 supplementation and discontinue isoniazid. Immediate cessation of chronic alcohol intake is necessary. Thalassemias are managed differently depending on severity; most cases do not require medication or transfusions, but therapy for β-thalassemia may include chronic blood transfusions.

Other types of thalassemia typically remain asymptomatic and do not necessitate treatment. Iron supplementation is contraindicated, especially in patients receiving chronic transfusions, due to concerns about acquired hemochromatosis. If H pylori is suspected, a urea breath test is necessary. An upper endoscopy can also be performed for biopsy and to assess severity, particularly because this bacterium is associated with premalignant conditions.

Differential Diagnosis

The differential diagnoses for microcytic, normocytic, and macrocytic anemias based on MCV findings in a CBC are outlined below. Differential diagnoses for MCV below 80 fL include iron-deficiency anemia, anemia of chronic disease, sideroblastic anemia, H pylori, and thalassemias. Iron-deficiency anemia can also present with various differential diagnoses such as menorrhagia, colorectal adenocarcinoma, bleeding colonic polyp, bleeding peptic ulcer disease, H pylori, hematemesis, chronic epistaxis, duodenal malabsorption, or resection. Anemia of chronic disease presents with a range of differential diagnoses, including malignancy; rheumatologic conditions, such as systemic lupus erythematosus and rheumatoid arthritis; autoimmune diseases, such as primary biliary cirrhosis or multiple sclerosis; chronic kidney disease; and chronic infections. Differential diagnoses for sideroblastic anemia, leading to microcytic anemia, include chronic alcoholism, vitamin B6 deficiency, isoniazid use, myelodysplastic disorder, lead poisoning, copper deficiency, and congenital sideroblastic anemia. The main types of thalassemia include α1, α2, α3/hemoglobin H disease, α4 (fatal), β-thalassemia minor and major, and HbS/β-thalassemia heterozygote.

The differential diagnoses of MCV above 100 include megaloblastic anemia and non-megaloblastic anemia. The causes of megaloblastic anemia include folate deficiency caused by chronic alcoholism, barbiturates, phenytoin, sulfasalazine, methotrexate, triamterene, trimethoprim/sulfamethoxazole, pyrimethamine, and duodenal or jejunal malabsorption or resection. The differential diagnoses for vitamin B12 deficiency include Crohn disease ileitis, short bowel syndrome, strict vegan diet without supplementation, D latum, chronic metformin, pernicious anemia, atrophic gastritis, orotic aciduria, and Diamond-Blackfan anemia. Non-megaloblastic differential diagnoses include conditions leading to hepatic insufficiency or cirrhosis secondary to chronic alcoholism, fulminant hepatitis secondary to drug toxicity, α-1-antitrypsin disease, galactosemia, Wilson disease, chronic hepatitis B viral infection, chronic hepatitis C infection, hemochromatosis, autoimmune hepatitis, amyloidosis, chronic decompensated right heart failure, and parasitic infections such as Schistosoma haematobium.

The differential diagnoses of MCV between 80 and 100 fL include conditions that can lead to intravascular hemolytic anemia, extravascular hemolytic anemia, and aplastic anemia. Intravascular hemolytic anemia may arise from paroxysmal nocturnal hemoglobinuria and micro- or macroangiopathic hemolytic anemia due to thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, HELLP syndrome, disseminated intravascular coagulation, aortic stenosis, and defective prosthetic cardiac valve. On the other hand, extravascular hemolytic anemia can be caused by disorders including hereditary spherocytosis, sickle cell anemia, glucose 6-phosphate dehydrogenase (G6PD) deficiency, infections such as malaria and babesiosis, and autoimmune hemolytic anemia. Some differential diagnoses for autoimmune hemolytic anemia causes include chronic lymphocytic leukemia, systemic lupus erythematosus, and hematopoietic stem cell transplant. Furthermore, differential diagnoses for aplastic anemia include Fanconi anemia; paroxysmal nocturnal hemoglobinuria; radiation exposure; drug toxicities, such as chloramphenicol, sulfonamides, and benzene exposure; viral infections, such as parvovirus B19 (especially in immunocompromised patients), HIV, Epstein-Barr virus; hairy cell leukemia; and myelodysplastic disorders. 

Pertinent Studies and Ongoing Trials

MCV and RBC distribution are believed to determine the risk of cardiovascular events after surgery or blood transfusions. Patients with macrocytic or microcytic anemia have a higher risk after surgery or blood transfusion compared to patients with normocytic anemia. These values may help prevent cardiovascular events due to closer monitoring after procedures. In addition, MCV can determine the risk of restenosis after stent placement into the coronary arteries. Microcytic erythrocytes were associated with restenosis of the coronary arteries with stent more than macrocytosis or normocytic erythrocytes.[3][32]

Prognosis

The prognosis for anemia may vary with changes in MCV. Iron-deficiency anemia has a good prognosis with iron supplementation. However, if iron deficiency is secondary to chronic blood loss from malignancy, the prognosis is poor and often fatal. The prognosis of anemia of chronic disease varies due to the underlying etiology. Chronic inflammation secondary to malignancy can have a poorer prognosis compared to a rheumatologic disease controlled by medication. However, sideroblastic anemia is relatively mild and easily treated with supplementation or withdrawal from the causal agent. Furthermore, thalassemias have varying prognoses. Hemoglobin Bart syndrome, or α-thalassemia major, is fatal, causing hydrops fetalis, with a poor prognosis in utero. β-thalassemia major has improved outcomes with increasing iron chelation treatment and chronic blood transfusions, allowing patients to live reasonably normal lives. However, the outlook is still poor due to the early mortality of these patients from restrictive diseases secondary to acquired hemochromatosis. Patients with other α- and β-thalassemias generally live normal lives without significant complications and have excellent prognoses.

Megaloblastic anemias secondary to folate and cobalamin deficiencies tend to have good prognoses with proper supplementation. However, vitamin B12 deficiency with severe subacute combined degeneration can be fatal and has a poor prognosis. This condition is preventable with appropriate supplementation through vitamins, food intake, or injections. Folate deficiency has a good prognosis in patients who are not pregnant. However, the prognosis for neonates with folate-deficient mothers is poor, depending on the etiology of the neural tube defect. Patients with spina bifida occulta have a good prognosis and are often unaware of their condition. However, patients with rachischisis have a poor prognosis and may not survive in utero.

Patients with orotic aciduria and Diamond-Blackfan anemia can have a good prognosis depending on chronic supplementation. If these patients are noncompliant with supplementation, their anemias can have a poor prognosis, leading to fatality. Patients with non-megaloblastic anemias tend to have poor prognoses. Patients with chronic alcoholism have many vitamin deficiencies ranging from folate to thiamine. These deficiencies can cause neurological issues, cerebellar damage, and hepatic insufficiency. Hepatic insufficiency and cirrhosis also have a poor prognosis, depending on their severity. Many of these patients suffer from portal hypertension and esophageal varices with the risk of rupture and hemorrhage. They can, in turn, develop hepatorenal syndrome and become encephalopathic, with additional life-threatening consequences. A preoperative high and low MCV is a poor prognostic factor. Studies revealed that the worst prognostic effect was in stage III. 

Normocytic anemias often have poorer prognoses due to their chronic hemolysis and deteriorating conditions. With newer treatments, intravascular hemolysis, such as paroxysmal nocturnal hemoglobinuria, has an improved prognosis. However, without treatment, the patient can develop pancytopenia and experience aplastic anemia, which can be fatal. If treated, the prognoses of microangiopathic hemolytic anemias are generally positive; however, patients must adhere to their treatments. Extravascular hemolytic diseases, such as sickle cell anemia, have a poor prognosis and a life expectancy ranging from 30 to 40 years. These patients may experience chronic vaso-occlusive crises, a common, fatal sequelae.[33] 

Complications

The lack of treatment and increased mortality are common complications for anemias with varying MCV. Patients with iron-deficiency anemia without supplementation can develop high-output heart failure. Lead poisoning can also be fatal without chelation therapy and removal of the causal agent. Untreated diseases such as systemic lupus erythematosus can lead to renal insufficiency, which is the most common cause of death in these patients. Patients with β-thalassemia major are prone to complications from treatment, such as acquired hemochromatosis. Without chronic chelation therapy, these patients are at risk of death from iron intoxication and restrictive pericarditis due to iron deposition in the pericardium. 

Folate deficiency can lead to complications in pregnant patients, causing neural tube defects in the developing fetus. Vitamin B12 deficiency can result in subacute combined degeneration of the nervous system. Unfortunately, without appropriate supplementation, conditions such as orotic aciduria and Diamond-Blackfan anemia can be fatal. Patients with hepatic insufficiency or cirrhosis face a spectrum of complications, including hyperammonemia, ascites, portal hypertension, cardiomegaly, esophageal varices with a risk of rupture and hemorrhage, internal hemorrhoids, hepatorenal syndrome, and hepatic encephalopathy. Chronic alcoholism can also contribute to these complications due to alcoholic cirrhosis, along with the development of Wernicke-Korsakoff syndrome resulting from thiamine deficiency. Normocytic anemia can lead to various complications such as hemoglobinuria, hematuria, syncope, petechial rashes, high fevers, and death. Timely and effective treatment is crucial in mitigating these potential complications and improving patient outcomes.