Aplastic anemia
Encyclopedia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cell
s to replenish blood cells. The condition, per its name, involves both aplasia
and anemia
. Typically, anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types: red blood cell
s, white blood cell
s, and platelets, termed pancytopenia
.
is considered to be idiopathic
(without a known cause), but one known cause is an autoimmune disorder in which white blood cell
s attack the bone marrow.
Aplastic anemia is also sometimes associated with exposure to toxins such as benzene
, or with the use of certain drugs, including chloramphenicol
, carbamazepine
, felbamate
, phenytoin
, quinine
, and phenylbutazone
. Many drugs are associated with aplasia mainly according to case reports but at a very low probability. As an example, chloramphenicol treatment is followed by aplasia in less than 1 in 40,000 treatment courses, and carbamazepine aplasia is even more rare.
Exposure to ionizing radiation
from radioactive materials or radiation-producing devices is also associated with the development of aplastic anemia. Marie Curie
, famous for her pioneering work in the field of radioactivity, died of aplastic anemia after working unprotected with radioactive materials for a long period of time; damaging effects of ionizing radiation were not then known.
Aplastic anemia is present in up to 2% of patients with acute viral hepatitis
.
In some animals aplastic anemia may have other causes. For example, in the ferret
(Mustela putorius furo) aplastic anemia is caused by estrogen
toxicity. This is because female ferrets are induced ovulator
s, so mating is required to bring the female out of heat. Intact females, if not mated, will remain in heat, and after some time the high levels of estrogen will cause the bone marrow to stop producing red blood cells.
Short-lived aplastic anemia can also be a result of parvovirus
infection. In humans the P antigen (also known as globoside) is the cellular receptor for parvovirus B19 virus that causes erythema infectiosum (fifth disease) in children. Parvovirus causes complete cessation of red blood cell production. In most cases, this goes unnoticed, as red blood cells live for up to 180 days, and the drop in production does not significantly affect the total number of circulating red blood cells. In people with conditions where the cells die early (such as sickle cell disease), however, parvovirus infection can lead to severe anemia.
s to find diagnostic clues, including a complete blood count
(CBC), renal function
and electrolyte
s, liver enzymes, thyroid
function tests, vitamin B12
and folic acid
levels.
The following tests aid in determining differential diagnosis for aplastic anemia:
, an effect achieved by daily medicine
intake, or, in more severe cases, a bone marrow transplant
, a potential cure. The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The multipotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body ("graft-versus-host disease
").
Medical therapy of aplastic anemia often includes a short course of anti-thymocyte globulin
(ATG) or anti-lymphocyte globulin
(ALG) and several months of treatment with cyclosporin to modulate the immune system
. Mild chemotherapy
with agents such as cyclophosphamide
and vincristine
may also be effective. Antibody
therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. Steroids are generally ineffective, though are often used to combat serum sickness
caused by ATG use.
One prospective study involving cyclophosphamide was terminated early due to a high incidence of mortality, due to severe infections as a result of prolonged neutropenia
.
In the past, before the above treatments became available, patients with low leukocyte counts were often confined to a sterile room or bubble (to reduce risk of infections), as in the famed case of Ted DeVita
.
10-33% of all patients develop the rare disease
paroxysmal nocturnal hemoglobinuria
(PNH, anemia with thrombopenia and/or thrombosis
), which has been explained as an escape mechanism by the bone marrow against destruction by the immune system. Flow cytometry
testing is performed regularly in people with previous aplastic anemia to monitor for the development of PNH.
Occasionally, milder cases of the disease resolve on their own. Relapses of previously controlled disease are, however, much more common. Relapse following ATG/ciclosporin use can sometimes be treated with a repeated course of therapy.
Well-matched bone marrow transplants from siblings have been successful in young, otherwise healthy people, with a long-term survival rate of 80%-90%. Most successful BMT recipients eventually reach a point where they consider themselves cured for all practical purposes, although they need to be compliant with follow-up care permanently.
Older people (who are generally too frail to undergo bone marrow transplants) and people who are unable to find a good bone marrow match, who undergo immune suppression have five year survival rates of up to 75%.
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s to replenish blood cells. The condition, per its name, involves both aplasia
Aplasia
Aplasia is defined in general as "defective development or congenital absence of an organ or tissue." In the field of hematology, the term refers to "incomplete, retarded, or defective development, or cessation of the usual regenerative process."-Examples:*Acquired pure red cell aplasia*Aplasia...
and anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. Typically, anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types: red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s, white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s, and platelets, termed pancytopenia
Pancytopenia
Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
.
Signs and symptoms
- AnemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
with malaiseMalaiseMalaise is a feeling of general discomfort or uneasiness, of being "out of sorts", often the first indication of an infection or other disease. Malaise is often defined in medicinal research as a "general feeling of being unwell"...
, pallorPallorPallor is a reduced amount of oxyhaemoglobin in skin or mucous membrane, a pale color which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to sunlight, anaemia or genetics....
and associated symptoms such as palpitations - ThrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(low platelet counts), leading to increased risk of hemorrhage, bruising and petechiae - LeukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
(low white blood cell count), leading to increased risk of infectionInfectionAn infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease... - ReticulocytopeniaReticulocytopeniaReticulocytopenia, or "aplastic crisis", is the medical term for an abnormal decrease of reticulocytes in the body. Reticulocytopenia can originate from congenital hemolytic anemia, especially when exacerbated by Parvovirus B19 infection...
(low reticulocyteReticulocyteReticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
counts)
Causes
In many cases, the etiologyEtiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
is considered to be idiopathic
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
(without a known cause), but one known cause is an autoimmune disorder in which white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s attack the bone marrow.
Aplastic anemia is also sometimes associated with exposure to toxins such as benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
, or with the use of certain drugs, including chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
, carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, felbamate
Felbamate
Felbamate is an anticonvulsant drug used in the treatment of epilepsy. It is used to treat partial seizures in adults and partial and generalized seizures associated with Lennox-Gastaut syndrome in children...
, phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
, quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
, and phenylbutazone
Phenylbutazone
Phenylbutazone, often referred to as bute, is a non-steroidal anti-inflammatory drug for the short-term treatment of pain and fever in animals. In the United States, it is no longer approved for human use.-In humans:...
. Many drugs are associated with aplasia mainly according to case reports but at a very low probability. As an example, chloramphenicol treatment is followed by aplasia in less than 1 in 40,000 treatment courses, and carbamazepine aplasia is even more rare.
Exposure to ionizing radiation
Ionizing radiation
Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...
from radioactive materials or radiation-producing devices is also associated with the development of aplastic anemia. Marie Curie
Marie Curie
Marie Skłodowska-Curie was a physicist and chemist famous for her pioneering research on radioactivity. She was the first person honored with two Nobel Prizes—in physics and chemistry...
, famous for her pioneering work in the field of radioactivity, died of aplastic anemia after working unprotected with radioactive materials for a long period of time; damaging effects of ionizing radiation were not then known.
Aplastic anemia is present in up to 2% of patients with acute viral hepatitis
Viral hepatitis
Viral hepatitis is liver inflammation due to a viral infection. It may present in acute or chronic forms. The most common causes of viral hepatitis are the five unrelated hepatotropic viruses Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, and Hepatitis E...
.
In some animals aplastic anemia may have other causes. For example, in the ferret
Ferret
The ferret is a domesticated mammal of the type Mustela putorius furo. Ferrets are sexually dimorphic predators with males being substantially larger than females. They typically have brown, black, white, or mixed fur...
(Mustela putorius furo) aplastic anemia is caused by estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
toxicity. This is because female ferrets are induced ovulator
Estrous cycle
The estrous cycle comprises the recurring physiologic changes that are induced by reproductive hormones in most mammalian placental females. Estrous cycles start after puberty in sexually mature females and are interrupted by anestrous phases or pregnancies...
s, so mating is required to bring the female out of heat. Intact females, if not mated, will remain in heat, and after some time the high levels of estrogen will cause the bone marrow to stop producing red blood cells.
Short-lived aplastic anemia can also be a result of parvovirus
Parvovirus
Parvovirus, often truncated to "parvo", is both the common name in English casually applied to all the viruses in the Parvoviridae taxonomic family, and also the taxonomic name of the Parvovirus genus within the Parvoviridae family...
infection. In humans the P antigen (also known as globoside) is the cellular receptor for parvovirus B19 virus that causes erythema infectiosum (fifth disease) in children. Parvovirus causes complete cessation of red blood cell production. In most cases, this goes unnoticed, as red blood cells live for up to 180 days, and the drop in production does not significantly affect the total number of circulating red blood cells. In people with conditions where the cells die early (such as sickle cell disease), however, parvovirus infection can lead to severe anemia.
Diagnosis
The condition needs to be differentiated from pure red cell aplasia. In aplastic anemia the patient has pancytopenia (i.e., anemia, neutropenia and thrombocytopenia) resulting in decrease of all formed elements. In contrast, pure red cell aplasia is characterized by reduction in red cells only. The diagnosis can only be confirmed on bone marrow examination. Before this procedure is undertaken, a patient will generally have had other blood testBlood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s to find diagnostic clues, including a complete blood count
Complete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
(CBC), renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
and electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s, liver enzymes, thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
function tests, vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
and folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
levels.
The following tests aid in determining differential diagnosis for aplastic anemia:
- Bone marrow aspirate and biopsy: to rule out other causes of pancytopenia (i.e. neoplastic infiltration or significant myelofibrosis).
- History of iatrogenic exposure to cytotoxic chemotherapy: can cause transient bone marrow suppression
- X-rays, computed tomography (CT) scans, or ultrasound imaging tests: enlarged lymph nodes (sign of lymphoma), kidneys and bones in arms and hands (abnormal in Fanconi anemia)
- Chest X-ray: infections
- Liver tests: liver diseases
- Viral studies: viral infections
- Vitamin B12 and folate levels: vitamin deficiency
- Blood tests for paroxysmal nocturnal hemoglobinuriaParoxysmal nocturnal hemoglobinuriaParoxysmal nocturnal hemoglobinuria , sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia , red urine and thrombosis...
- Test for antibodies: immune competency
Treatment
Treating immune-mediated aplastic anemia involves suppression of the immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, an effect achieved by daily medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
intake, or, in more severe cases, a bone marrow transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
, a potential cure. The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The multipotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body ("graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
").
Medical therapy of aplastic anemia often includes a short course of anti-thymocyte globulin
Anti-thymocyte globulin
Anti-thymocyte globulin is an infusion of horse or rabbit-derived antibodies against human T cells which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia.-Uses:...
(ATG) or anti-lymphocyte globulin
Anti-lymphocyte globulin
Anti-lymphocyte globulin is an infusion of horse-derived or more commonly rabbit-derived antibodies against human T cells which is used in the treatment of acute rejection in organ transplantation, especially in kidney transplants. It was developed at the University of Minnesota by Dr...
(ALG) and several months of treatment with cyclosporin to modulate the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Mild chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
with agents such as cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
and vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
may also be effective. Antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. Steroids are generally ineffective, though are often used to combat serum sickness
Serum sickness
Serum sickness in humans is a reaction to proteins in antiserum derived from an non-human animal source. It is a type of hypersensitivity, specifically immune complex hypersensitivity . The term serum sickness–like reaction is occasionally used to refer to similar illnesses that arise from the...
caused by ATG use.
One prospective study involving cyclophosphamide was terminated early due to a high incidence of mortality, due to severe infections as a result of prolonged neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
.
In the past, before the above treatments became available, patients with low leukocyte counts were often confined to a sterile room or bubble (to reduce risk of infections), as in the famed case of Ted DeVita
Ted DeVita
Ted DeVita was a victim of severe aplastic anemia who was forced to live in a sterile hospital room for eight and a half years....
.
Follow-up
Regular full blood counts are required to determine whether the patient is still in a state of remission.10-33% of all patients develop the rare disease
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria , sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia , red urine and thrombosis...
(PNH, anemia with thrombopenia and/or thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
), which has been explained as an escape mechanism by the bone marrow against destruction by the immune system. Flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
testing is performed regularly in people with previous aplastic anemia to monitor for the development of PNH.
Prognosis
Untreated aplastic anemia is an illness that leads to rapid death, typically within six months. If the disease is diagnosed correctly and initial treatment is begun promptly, then the survival rate for the next five to ten years is substantially improved, and many patients live well beyond that length of time.Occasionally, milder cases of the disease resolve on their own. Relapses of previously controlled disease are, however, much more common. Relapse following ATG/ciclosporin use can sometimes be treated with a repeated course of therapy.
Well-matched bone marrow transplants from siblings have been successful in young, otherwise healthy people, with a long-term survival rate of 80%-90%. Most successful BMT recipients eventually reach a point where they consider themselves cured for all practical purposes, although they need to be compliant with follow-up care permanently.
Older people (who are generally too frail to undergo bone marrow transplants) and people who are unable to find a good bone marrow match, who undergo immune suppression have five year survival rates of up to 75%.
External links
- Aplastic Anemia & MDS International Foundation
- Mayo Clinic
- University of Texas -- Idiopathic aplastic anemia -- Secondary aplastic anemia
- The Aplastic Anaemia Trust
- Shannon's Trust, support for people with aplastic anemia