Macrocytosis is a common clinical condition with multiple potential diagnoses. Complete blood counts typically reveal this condition, which is generally characterised as a mean corpuscular volume of more than 100 fL.1 The presence of abnormally large blood cells can significantly impact and reflect underlying bone marrow disease. Insufficient production of platelets, red blood cells, and white blood cells due to a lack of homeostatic hematopoiesis is referred to as bone marrow failure. Macrocytosis frequently indicates that the bone marrow is generating aberrant or immature red blood cells. Acute myeloid leukaemia (AML) and other bone marrow disorders, including myelodysplastic syndromes (MDS), may be to blame for this, as they interfere with normal cell production.2,3
Classification
Classification of Macrocytosis and Bone Marrow Disorder.
Figure No. 1: Types of Macrocytosis and Bone Marrow Disorders8,9,10,11
Aetiology
Macrocytosis
- Vitamin B12 and folate deficiencies
- Alcoholism
- Medications (Chemotherapy drugs, Antiretrovirals and some Anticonvulsants and Antibiotics)
- Liver disease
- Hypothyroidism
- Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML)4,5
Bone marrow disease
- Genetic Mutations: Inherited Disorder conditions like Fanconi anaemia and Diamond-Blackfan anaemia result from inherited genetic mutations affecting bone marrow function, and Acquired Mutations in specific genes (e.g., JAK2 in polycythemia vera) can lead to bone marrow diseases
- Exposure to Toxins: Chemicals like benzene and radiation exposure can damage bone marrow
- Previous Chemotherapy or Radiation Therapy: Treatments for other cancers can increase the risk of developing secondary bone marrow diseases
- Drugs and chemicals (cytotoxic agents, Chloramphenicol, non-steroidal antiinflammatory drugs, antiepileptics, gold salts, benzene)
- Autoimmune Disorders: Conditions where the immune system attacks the bone marrow, such as aplastic anaemia, eosinophilic fasciitis, and thymoma, can lead to bone marrow failure
- Infections: Viral infections like hepatitis, HIV, parvovirus B1, and Epstein Barr can directly or indirectly affect bone marrow function
- Chronic Kidney Disease Can lead to reduced erythropoietin production, impacting red blood cell production
- Chronic Liver Disease affects the overall metabolism and can lead to changes in bone marrow function
- Nutritional Deficiencies in essential nutrients like iron, vitamin B12, and folate can impair bone marrow function
- Idiopathic Causes: In many cases, especially with conditions like aplastic anaemia and myelodysplastic syndromes, the exact cause may remain unknown despite extensive investigation6,7
Pathophysiology
Macrocytosis refers to the presence of abnormally large red blood cells in the bloodstream. The pathophysiology involves impaired DNA synthesis due to vitamin B12 or folate deficiency that leads to the production of large, immature red blood cells. Increased red cell production, as seen in reticulocytosis, can also cause macrocytosis in response to anaemia or hemolysis. Bone marrow disorders like myelodysplastic syndromes (MDS) result in ineffective haematopoiesis and dysplasia, producing macrocytic red blood cells. Alcoholism and liver disease can directly affect bone marrow and red blood cell membrane composition, leading to macrocytosis. Additionally, hypothyroidism and certain medications, such as chemotherapy agents and antiretrovirals, can cause macrocytosis.1,20,21
Bone marrow diseases lead to disrupted production and function of blood cells through various mechanisms. In aplastic anaemia, damage to haematopoietic stem cells, often from autoimmune destruction or toxins, results in pancytopenia and hypocellular bone marrow. Myelodysplastic syndromes (MDS) involve genetic mutations causing ineffective haematopoiesis and dysplasia. Leukemias feature an uncontrolled proliferation of malignant haematopoietic stem cells, which outcompete normal cells, causing anaemia, thrombocytopenia, and leukopenia. Lymphomas infiltrate the bone marrow with malignant lymphoid cells, disrupting normal haematopoiesis. Multiple myeloma involves clonal plasma cell proliferation, leading to bone destruction, anaemia, hypercalcemia, and renal dysfunction. Myeloproliferative neoplasms (MPNs) are characterised by excessive blood cell production due to clonal expansion of hematopoietic stem cells, often driven by JAK2 mutations.22,23
Connection between macrocytosis and bone marrow disease
- Disrupted Hematopoiesis: Many bone marrow diseases involve ineffective hematopoiesis, resulting in the production of abnormally large red blood cells (macrocytosis). Conditions like MDS and certain leukemias directly affect the bone marrow's ability to produce normal-sized red blood cells, leading to macrocytosis
- Compensatory Mechanisms: In response to bone marrow failure or increased red blood cell turnover (e.g., in haemolysis), the bone marrow may release more immature red blood cells (reticulocytes) into the bloodstream, contributing to macrocytosis
- Secondary Effects: Nutritional deficiencies (e.g., vitamin B12 and folate) are often seen in bone marrow disease patients due to poor diet, malabsorption, or increased cellular turnover, which can lead to macrocytosis
- Liver disease, often associated with bone marrow disorders, can also cause macrocytosis through altered lipid metabolism and red blood cell membrane composition
- Shared Etiological Factors: Both macrocytosis and bone marrow diseases can be caused by similar factors, such as alcohol abuse, certain medications, and underlying chronic diseases
Diagnosis
Clinical assessment, laboratory testing, and occasionally, bone marrow examination are used in a systematic manner to diagnose bone marrow diseases and macrocytosis. Patients deficient in CBL were diagnosed with pernicious anaemia if they exhibited serum antibodies against the intrinsic factor and/or distinctive Schilling test outcomes. Patients with megaloblastic hematopoiesis who had normal serum cobalamin (Cbl) and Serum methylmalonic acid (MMA) values were diagnosed with isolated "folate deficiency." In individuals without the usual morphological characteristics of megaloblastic haematopoiesis and with normal or high Cbl levels and higher and total homocysteine (HCYS) values, isolated folate insufficiency was not detected, but tissue vitamin deficiency.
Table no. 1: Diagnostic methods of Macrocytosis1,13,14
| Diagnosis of Macrocytosis | |
| Clinical evaluation | Laboratory Tests |
| History - Dietary habits (intake of B12 and folate)- Alcohol consumption - Medication history (methotrexate, zidovudine) - Family history of hematologic disorders - Symptoms of anaemia (fatigue, pallor) or underlying conditions (e.g., liver disease) Physical Examination - Signs of anaemia (pallor, tachycardia) - Neurological examination (for B12 deficiency) | Complete Blood Count (CBC) - Elevated mean corpuscular volume (MCV > 100 fL) - Haemoglobin and hematocrit levels - Red cell distribution width (RDW) Peripheral Blood Smear - Presence of macrocytes - Hyper segmented neutrophils Reticulocyte Count Serum Vitamin Levels - Vitamin B12 level - Folate level Liver Function Tests - To evaluate liver disease Thyroid Function Tests - To rule out hypothyroidism |
Only patients exhibiting conventional clinical features such as neutrophil hyper segmentation, macro-ovalocytosis, and, typically, a response to vitamin B12 and folic acid therapy are diagnosed with "megaloblastic haematopoiesis" in this situation.12
Table no. 1: Diagnostic methods of Bone Marrow Disease.15,16,17
| Diagnosis of Bone Marrow Disease | |
| Laboratory test | Bone Marrow Examination |
| Complete Blood Count (CBC) - Anaemia, leukopenia, thrombocytopenia, or pancytopenia - Abnormal white blood cell differential Peripheral Blood Smear - Abnormalities in red and white blood cells Biochemical Tests - Lactate dehydrogenase (LDH) is elevated in hemolysis and some bone marrow disorders Uric acid levels | Aspiration and Biopsy - Morphological evaluation of marrow cells - Assessment of cellularity, fibrosis, and abnormal cells Cytogenetic Analysis - Chromosomal abnormalities (e.g., Philadelphia chromosome in CML) Flow Cytometry - Immunophenotyping for leukaemia or lymphoma Molecular Testing - Specific genetic mutations (e.g., JAK2 mutation in myeloproliferative neoplasms) |
Treatment strategies
Numerous medications can lead to megaloblastic anaemia by preventing the body from using or absorbing folic acid or vitamin B12. The cause of this could be due to the physical destruction of the vitamins, competition for reducing enzymes, end-product inhibition of co-factor-mediated processes, or interference with folate or vitamin B12 absorption, plasma transport, or administration.18 Hydroxyurea, methotrexate, zidovudine, azathioprine, antiretroviral medications, valproic acid, and phenytoin are common medications that induce macrocytosis.
Therapeutic classification of macrocytosis19
- Antineoplastic
- Azathioprine
- Capecitabine
- Cladribine
- Cyclophosphamide
- Cytosine arabinoside
- Hydroxyurea
- Imatinib
- Methotrexate
- Sunitinib
- 5-Fluorouracil
- 6-Mercaptopurine
- Antibacterial
- Sulfamethoxazole-trimethoprim
- Antimalarial
- Pyrimethamine
- Anticonvulsant
- Phenytoin
- Primidone
- Valproic acid
- Anti-inflammatory
- Sulfasalazine
- Antiviral
- d4T
- Lamivudine
- Valacyclovir
- Zidovudine
- Antidiabetic
- Metformin
- Diuretic
- Triamterene
Depending on the severity of your illness and your age, your doctor may recommend bone marrow transplants, blood transfusions, medication, or observation as treatments for aplastic anaemia. Your blood cell counts will be dangerously low if you have severe aplastic anaemia, which necessitates emergency hospitalisation.
General supportive treatments
- Blood Transfusions: To manage anaemia and thrombocytopenia
- Growth Factors: Granulocyte colony-stimulating factor (G-CSF) to stimulate white blood cell production
- Iron Chelation Therapy: For patients with iron overload due to frequent blood transfusions
- Antibiotics/Antifungals: To prevent and treat infections in immunocompromised patients
Aplastic anaemia
- Antithymocyte Globulin (ATG): An immunosuppressive therapy
- Cyclosporine: Another immunosuppressant often used in combination with ATG
- Eltrombopag: A thrombopoietin receptor agonist to stimulate platelet production
- Bone Marrow Transplant: For eligible patients, especially younger individuals
Myelodysplastic syndromes (MDS)
- Azacitidine and Decitabine: Hypomethylating agents that can help reduce abnormal cell proliferation
- Lenalidomide: This is Particularly effective for patients with a deletion 5q cytogenetic abnormality
- Erythropoiesis-Stimulating Agents (ESAs): Such as epoetin alfa or darbepoetin alfa to reduce the need for blood transfusions
- Supportive Care: Includes blood transfusions and iron chelation therapy
- Bone Marrow Transplant: For higher-risk patients or those who do not respond to other treatments
Leukaemias
- Chemotherapy: Standard treatment for many types of leukaemia (e.g., ALL and AML)
- Targeted Therapy: Imatinib, Dasatinib, Nilotinib. For chronic myeloid leukaemia (CML); Venetoclax. For certain subtypes of AML: Monoclonal Antibodies. Rituximab for certain lymphoid leukaemias
- Bone Marrow Transplant: Especially for relapsed or refractory leukaemia
Lymphomas
- Chemotherapy: Often combined with immunotherapy
- Monoclonal Antibodies: Rituximab and other targeted agents.
- Bone Marrow Transplant
Multiple myeloma
- Proteasome Inhibitors: Bortezomib and carfilzomib
- Immunomodulatory Drugs: Lenalidomide, thalidomide, and pomalidomide
- Monoclonal Antibodies: Daratumumab and elotuzumab
- Bone Marrow Transplant: Autologous stem cell transplant
- Bisphosphonates: To reduce bone damage.
Myeloproliferative neoplasms (MPNs)
- JAK Inhibitors: Ruxolitinib for myelofibrosis and polycythemia vera
- Hydroxyurea: To control blood counts in polycythemia vera and essential thrombocythemia
- Interferon-alpha: Used especially in younger patients or during pregnancy
Summary of macrocytosis and bone marrow disorders
Macrocytosis refers to the presence of abnormally large red blood cells, typically with a mean corpuscular volume (MCV) greater than 100 fL. It can indicate underlying bone marrow disorders like myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML). Key causes of macrocytosis include vitamin B12 and folate deficiencies, alcoholism, certain medications, liver disease, and hypothyroidism.
Bone marrow diseases can result from genetic mutations (e.g., Fanconi anemia, JAK2 mutations in polycythemia vera), toxins, autoimmune disorders, infections, and chronic diseases. These conditions disrupt normal blood cell production and can lead to pancytopenia, ineffective hematopoiesis, and dysplasia, contributing to macrocytosis.
Diagnosis involves clinical evaluation, complete blood count (CBC), peripheral blood smear, and specific tests for vitamin levels, liver and thyroid function, and bone marrow examination. Bone marrow diseases require further investigation using tests like cytogenetic analysis and bone marrow biopsy.
Treatment strategies vary depending on the underlying condition. General supportive treatments include blood transfusions, growth factors, and bone marrow transplants. Specific therapies include immunosuppressants for aplastic anaemia, hypomethylating agents for MDS, chemotherapy and targeted therapy for leukaemias, and JAK inhibitors for myeloproliferative neoplasms (MPNs).
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