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Aplastic Anemia

Aplastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types ( AA AA Amyloidosis) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis. Aplastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types can be acquired or inherited, however, most cases of AA AA Amyloidosis are acquired and caused by autoimmune damage to hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis. Specifically known acquired causes and associations of AAs include medications, chemicals, high doses of whole-body radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma, viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, immune diseases, and pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care. Inherited or constitutional syndromes associated with AA AA Amyloidosis include Fanconi anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, dyskeratosis Dyskeratosis Dermatomyositis congenita, and Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down syndrome (Trisomy 21). Therapies include transfusion support, immunosuppression, and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow transplantation.

Last updated: Nov 1, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Epidemiology and Etiology

Epidemiology

  • Varying incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency worldwide 
    • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency in Europe: 2.35 per 1 million 
    • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency in Asia ASIA Spinal Cord Injuries: 7 per 1 million 
  • No sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria preference
  • Acquired aplastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types ( AA AA Amyloidosis): biphasic age distribution → major peak in the teens to twenties; 2nd peak in the elderly

Etiology

Inherited conditions: 

  • Intrinsic defect(s) in hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis
  • Fanconi anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
    • Autosomal recessive inheritance Autosomal recessive inheritance Autosomal Recessive and Autosomal Dominant Inheritance
    • Inability to repair certain types of damage to the DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
    • Cell damage occurs in multiple cell types, including hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis.
  • Dyskeratosis Dyskeratosis Dermatomyositis congenita: a telomere Telomere A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs. DNA Replication biology syndrome with different inheritance patterns involving multiple differing genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure
  • Shwachman-Diamond syndrome Shwachman-Diamond syndrome An inherited syndrome characterized by exocrine pancreatic insufficiency; hematologic abnormalities (e.g., bone marrow hypoplasia), and skeletal abnormalities (e.g., metaphyseal chondroplasia). Germline mutations in the sbds gene are associated with shwachman-diamond syndrome. Neutropenia: gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations affecting ribosome biogenesis and mitosis Mitosis A type of cell nucleus division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. Cell Cycle
  • Diamond-Blackfan anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types: gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations affecting ribosome synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Trisomy 21 Trisomy 21 Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down syndrome (Trisomy 21)/ Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down syndrome (Trisomy 21): can lead to multiple hematologic disorders ( AA AA Amyloidosis less often than myeloproliferative diseases or leukemia)

Acquired AA AA Amyloidosis

  • Autoimmune or other types of damage to hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis
  • Idiopathic Idiopathic Dermatomyositis
    • Most cases (80%–85%)
    • Immune-mediated: increased numbers of activated cytotoxic Cytotoxic Parvovirus B19 T cell clones
  • Medications and other agents: 
    • Allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs 
    • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
    • Antithyroid agents Antithyroid agents Antithyroid agents are used in the management of hyperthyroidism, particularly that due to Graves’ disease. This group of medications includes the thionamides (methimazole and propylthiouracil), potassium iodide, and radioactive iodine. Thionamides are currently the preferred choice for hyperthyroid management. Antithyroid Drugs
    • Antiprotozoals
    • Anticonvulsants
    • Cytotoxic Cytotoxic Parvovirus B19 chemotherapeutic drugs
    • Chloramphenicol Chloramphenicol Chloramphenicol, the only clinically relevant drug in the amphenicol class, is a potent inhibitor of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. Chloramphenicol is a broad-spectrum antibiotic with wide distribution; however, due to its toxicity, its use is limited to severe infections. Chloramphenicol
    • D-penicillamine D-penicillamine The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in wilson’s disease. Movement Disorder Drugs
    • NSAIDs NSAIDS Primary vs Secondary Headaches 
    • Sulfonamides Sulfonamides A group of compounds that contain the structure so2nh2. Sulfonamides and Trimethoprim
    • Other agents
      • Benzene
      • Estrogens 
      • Heavy metals: gold, arsenic Arsenic A shiny gray element with atomic symbol as, atomic number 33, and atomic weight 75. It occurs throughout the universe, mostly in the form of metallic arsenides. Most forms are toxic. According to the fourth annual report on carcinogens, arsenic and certain arsenic compounds have been listed as known carcinogens. Metal Poisoning (Lead, Arsenic, Iron), bismuth, mercury Mercury A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200. 59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. Renal Tubular Acidosis
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma to the whole body: 
    • Nuclear accidents → direct damage to DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
    • AA AA Amyloidosis is an acute sequela.
    • Myelodysplasia Myelodysplasia Non-Hodgkin Lymphomas and leukemia are late effects.
  • Viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology may alter antigens on stem cells activating a cytotoxic Cytotoxic Parvovirus B19 T cell clone, or initiating T cell release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response:
    • EBV EBV Epstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus
    • CMV
    • Human immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology ( HIV HIV Anti-HIV Drugs)-1, AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS
    • Parvovirus B19 Parvovirus B19 Primate erythroparvovirus 1 (generally referred to as parvovirus B19, B19 virus, or sometimes erythrovirus B19) ranks among the smallest DNA viruses. Parvovirus B19 is of the family Parvoviridae and genus Erythrovirus. In immunocompetent humans, parvovirus B19 classically results in erythema infectiosum (5th disease) or “slapped cheek syndrome.” Parvovirus B19 (transient AA AA Amyloidosis, more commonly causes pure red cell aplasia Aplasia Cranial Nerve Palsies)
    • Seronegative hepatitis (most likely due to a yet-unknown virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology)
  • Immune diseases (e.g., eosinophilic fasciitis, thymoma Thymoma A neoplasm originating from thymic tissue, usually benign, and frequently encapsulated. Although it is occasionally invasive, metastases are extremely rare. It consists of any type of thymic epithelial cell as well as lymphocytes that are usually abundant. Malignant lymphomas that involve the thymus, e.g., lymphosarcoma, Hodgkin’s disease (previously termed granulomatous thymoma), should not be regarded as thymoma. Primary Lymphatic Organs)
  • Clonal evolution ( AA AA Amyloidosis may be associated with another hematologic disorder):
    • Paroxysmal nocturnal hemoglobinuria Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is a rare but serious acquired hemolytic anemia with periodic exacerbations. This anemia is caused by nonmalignant clonal expansion of ≥ 1 hematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIG-A) gene. Paroxysmal Nocturnal Hemoglobinuria ( PNH PNH Paroxysmal nocturnal hemoglobinuria (PNH) is a rare but serious acquired hemolytic anemia with periodic exacerbations. This anemia is caused by nonmalignant clonal expansion of ≥ 1 hematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol n-acetylglucosaminyltransferase subunit a (pig-a) gene. Paroxysmal Nocturnal Hemoglobinuria):
      • Approximately 50% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with AA AA Amyloidosis show an expanded clonal population with the PNH PNH Paroxysmal nocturnal hemoglobinuria (PNH) is a rare but serious acquired hemolytic anemia with periodic exacerbations. This anemia is caused by nonmalignant clonal expansion of ≥ 1 hematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol n-acetylglucosaminyltransferase subunit a (pig-a) gene. Paroxysmal Nocturnal Hemoglobinuria defect by flow cytometry Flow cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. X-linked Agammaglobulinemia
      • Approximately 15% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with PNH PNH Paroxysmal nocturnal hemoglobinuria (PNH) is a rare but serious acquired hemolytic anemia with periodic exacerbations. This anemia is caused by nonmalignant clonal expansion of ≥ 1 hematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol n-acetylglucosaminyltransferase subunit a (pig-a) gene. Paroxysmal Nocturnal Hemoglobinuria develop pancytopenia at 8 years. 
    • Myelodysplastic syndrome
    • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care

Pathophysiology

Normal hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis

  • At birth: Hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis is present throughout the entire skeleton, with islands of residual hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis remaining in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy for 1 month.
  • After puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty: Hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis ceases in distal bones and becomes restricted to the axial Axial Computed Tomography (CT) skeleton ( skull Skull The skull (cranium) is the skeletal structure of the head supporting the face and forming a protective cavity for the brain. The skull consists of 22 bones divided into the viscerocranium (facial skeleton) and the neurocranium. Skull: Anatomy, sternum Sternum A long, narrow, and flat bone commonly known as breastbone occurring in the midsection of the anterior thoracic segment or chest region, which stabilizes the rib cage and serves as the point of origin for several muscles that move the arms, head, and neck. Chest Wall: Anatomy, ribs Ribs A set of twelve curved bones which connect to the vertebral column posteriorly, and terminate anteriorly as costal cartilage. Together, they form a protective cage around the internal thoracic organs. Chest Wall: Anatomy, vertebrae, head of humerus Humerus Bone in humans and primates extending from the shoulder joint to the elbow joint. Arm: Anatomy and femur, and pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 “hip” bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis: Anatomy).
    • In normal adults, only about half of the marrow space is hematopoietically active (red marrow); the inactive marrow is fatty (yellow marrow).
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow cellularity decreases 10% every decade.
Renal myelolipoma

Normal hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis (all 3 cell lines present) with a megakaryocyte Megakaryocyte Very large bone marrow cells which release mature blood platelets. Platelets: Histology near the center of the field (H&E, 200x)

Image: “Histologic findings” by Department of Pathology, Ibn Sina University Hospital, Rabat, Morocco. License: CC BY 2.0

Aplastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types

  • Peripheral blood: 
    • Decrease in all 3 cell lines, e.g., WBCs, RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology, and platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology (= pancytopenia)
    • No abnormal (e.g., dysplastic or leukemic) cells present and no evidence of hemolysis
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow: hypocellular for age; no abnormal cells or marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans
  • Various degrees of severity

Clinical Presentation

  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types: pallor, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, palpitations Palpitations Ebstein’s Anomaly, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
  • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia: mucosal and gingival bleeding or petechial rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes
  • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia: overt infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, recurrent infections Recurrent infections Common Variable Immunodeficiency (CVID), fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, oropharyngeal ulcers
  • May see congenital malformations Congenital malformations Congenital malformations or teratogenic birth defects are developmental disorders that arise before birth during the embryonic or fetal period. The rate of incidence for children born alive is approximately 3%. Teratogenic Birth Defects in the associated inherited disorders
Features of aplastic anemia

Fanconi anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types malformation:
A: Fanconi facies with tapering jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint: Anatomy
B: Polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn
C: Chromosomal breaks in lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology in peripheral blood

Image: “Figure 1” by Shabneez Hussain, Salman Naseem Adil. License: CC BY 2.0

Diagnosis

History and physical exam

  • Check for exposure Exposure ABCDE Assessment to drugs or chemicals.
  • Check for viral infection.
  • Family history Family History Adult Health Maintenance: cytopenias Cytopenias IPEX Syndrome and/or somatic findings suggestive of an inherited disorder 
  • Physical findings:
    • Associated with pancytopenia, especially pallor and petechiae Petechiae Primary Skin Lesions
    • Complications of the cytopenias Cytopenias IPEX Syndrome (e.g., cardiovascular system, infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease)
    • Manifestations of inherited disorders (e.g., cutaneous/nail findings, short stature, skeletal or genitourinary abnormalities, eye/ear findings)
    • Enlargement of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy, or lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy suggests negative for AA AA Amyloidosis.

Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

Pancytopenia with a hypocellular bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow showing:

  • No abnormal infiltrates (no leukemic blasts Blasts Injuries resulting when a person is struck by particles impelled with violent force from an explosion. Blast causes pulmonary contusion and hemorrhage, laceration of other thoracic and abdominal viscera, ruptured ear drums, and minor effects in the central nervous system. Blunt Chest Trauma or evidence of megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types)
  • No marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans (as seen in myeloproliferative disorders)
  • No myeloid dysplasia Dysplasia Cellular Adaptation (as seen in myelodysplastic syndrome)
  • Only 1 cell line may be suppressed before profound pancytopenia arrives!

Laboratory studies

  • Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy function tests, lactate dehydrogenase Lactate Dehydrogenase Osteosarcoma, renal function tests
  • Serum vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 and RBC folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 level to exclude megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • Flow cytometry Flow cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. X-linked Agammaglobulinemia to detect PNH PNH Paroxysmal nocturnal hemoglobinuria (PNH) is a rare but serious acquired hemolytic anemia with periodic exacerbations. This anemia is caused by nonmalignant clonal expansion of ≥ 1 hematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol n-acetylglucosaminyltransferase subunit a (pig-a) gene. Paroxysmal Nocturnal Hemoglobinuria (absence of CD59 and CD55 on blood cells) 
  • Cytogenetic and molecular testing of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow to exclude certain inherited disorders

Categories of severity

  • Severe AA AA Amyloidosis:
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow cellularity < 25%
    • At least 2 of the following in the peripheral blood count: 
      • Absolute neutrophil count Absolute neutrophil count The number of neutrophils (as opposed to the percentage of WBCs) circulating per µL of blood . Neutropenia < 500/μL 
      • Platelet count < 20,000/μL 
      • Reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count < 20,000/μL
  • Very severe AA AA Amyloidosis:
  • Non-severe AA AA Amyloidosis: bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow hypocellularity and peripheral blood cytopenias Cytopenias IPEX Syndrome not fulfilling criteria for severe or very severe AA AA Amyloidosis

Management

Moderate aplastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types

  • Remove potential causative drugs or agents.
  • Transfusions and antiinfective therapy if needed
  • Wait to treat since spontaneous remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches may occur (if caused by a virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology or a drug).
  • Treat if AA AA Amyloidosis transforms to a more severe form or becomes transfusion-dependent.

Severe aplastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types

  • Remove potential causative drugs or agents.
  • Transfusions and antiinfective therapy if needed
  • If under 50 years old and medically fit:
    • Triple therapy: includes 2 immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants + 1 bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow stimulant
      • Horse anti-thymocyte globulin
      • Cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants 
      • Eltrombopag Eltrombopag Hematopoietic Growth Factors ( thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors agonist)
    • Allogeneic hematopoietic cell transplantation (HCT)
  • If > 50 years old, or if not medically fit: only triple therapy

Differential Diagnosis

  • Reversible bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow suppression Suppression Defense Mechanisms: predictable, dose-dependent effects of cytotoxic Cytotoxic Parvovirus B19 chemotherapy Chemotherapy Osteosarcoma, accidental radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy, severe sepsis Severe Sepsis Sepsis in Children, or acute viral infection. Diagnosis is made by history, microbiological testing, and serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus testing. Blood counts are expected to improve over days to weeks.
  • Megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types: due to deficiencies of vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 ( pernicious anemia Pernicious anemia A megaloblastic anemia occurring in children but more commonly in later life, characterized by histamine-fast achlorhydria, in which the laboratory and clinical manifestations are based on malabsorption of vitamin B12 due to a failure of the gastric mucosa to secrete adequate and potent intrinsic factor. Megaloblastic Anemia) and/or folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 ( malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries). Peripheral blood smear Peripheral Blood Smear Anemia: Overview and Types shows hypersegmented neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation and macro-ovalocytes; bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow shows megaloblasts. Low serum levels of vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 (or methylmalonic acid) and/or folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 can confirm the diagnosis. The patient is managed with vitamin supplementation.
  • Infiltrative disorders of the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow: can be due to fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans (e.g., myelofibrosis), malignancies, or infectious Infectious Febrile Infant agents (e.g., tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology). Peripheral blood smear Peripheral Blood Smear Anemia: Overview and Types often shows abnormally shaped cells (poikilocytes), tear-drop cells, and leukoerythroblastic changes (i.e., both immature WBCs and immature/nucleated RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology). Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow is usually diagnostic of infectious Infectious Febrile Infant cases, or abnormalities seen in malignancies.
  • Hypersplenism Hypersplenism Condition characterized by splenomegaly, some reduction in the number of circulating blood cells in the presence of a normal or hyperactive bone marrow, and the potential for reversal by splenectomy. Splenomegaly: Cytopenias Cytopenias IPEX Syndrome due to sequestration associated with splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly may be caused by liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, portal vein Portal vein A short thick vein formed by union of the superior mesenteric vein and the splenic vein. Liver: Anatomy thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus, and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow infiltrative disorders. The cytopenia is not as severe as seen in AA AA Amyloidosis or other disorders. Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow exam reveals normal or increased hematopoietic activity.
  • Myelodysplastic syndrome: usually shows a full marrow with peripheral cytopenia. Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow shows cellular dysplastic changes and/or characteristic myelodysplastic syndrome cytogenetic or molecular abnormalities. Myelodysplastic syndrome may respond to the same triple therapy used for AA AA Amyloidosis.
  • Large granular lymphocyte leukemia: a leukemia characterized by cytopenias Cytopenias IPEX Syndrome, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, and infiltration of peripheral blood and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow by large granular lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology, which may coexist with AA AA Amyloidosis. Diagnosis is possible with flow cytometry Flow cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. X-linked Agammaglobulinemia and molecular testing.

References

  1. Montané, E., Ibáñez, L., Vidal, X., Ballarín, E., Puig, R., García, N., Laporte, J. R., & Catalan Group for Study of Agranulocytosis and Aplastic Anemia (2008). Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica, 93(4), 518–523. https://doi.org/10.3324/haematol.12020
  2. Olson, T.S. (2019). Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis. Uptodate. Retrieved November 23, 2020, from https://www.uptodate.com/contents/aplastic-anemia-pathogenesis-clinical-manifestations-and-diagnosis
  3. Young, N.S. (2018). Bone marrow failure syndromes including aplastic anemia and myelodysplasia. In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. Vol 1, pp. 723–728. 
  4. Red Blood Cell and Bleeding Disorders (2020). In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.). Robbins & Cotran Pathologic Basis of Disease, 10th ed. pp. 659–660.

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