Aplastic anemia

Last updated
Aplastic anemia
Specialty Oncology, hematology
Symptoms pale skin, fatigue, fast heart rate, rash, dizziness, headache, frequent or prolonged infections, nosebleeds, bleeding gums, prolonged bleeding from cuts, unexplained or easy bruising, [1] hematoma
Risk factors Smoking, family history, ionizing radiation, some chemicals, prior chemotherapy, Down syndrome
Diagnostic method bone marrow biopsy
Treatment bone marrow transplant, chemotherapy, radiotherapy, targeted therapy
Prognosis five-year survival rate 45%
Frequency3.83 million (2015)
Deaths563,000 (2015)

Aplastic anemia [2] (AA) [3] is a severe hematologic condition in which the body fails to make blood cells in sufficient numbers. Aplastic anemia is associated with cancer and various cancer syndromes. Blood cells are produced in the bone marrow by stem cells that reside there. [4] Aplastic anemia causes a deficiency of all blood cell types: red blood cells, white blood cells, and platelets. [5] [6]

Contents

It occurs most frequently in people in their teens and twenties but is also common among the elderly. It can be caused by heredity, immune disease, or exposure to chemicals, drugs, or radiation. However, in about half of cases, the cause is unknown. [5] [6]

Aplastic anemia can be definitively diagnosed by bone marrow biopsy. Normal bone marrow has 30–70% blood stem cells, but in aplastic anemia, these cells are mostly gone and are replaced by fat. [5] [6]

First-line treatment for aplastic anemia consists of immunosuppressive drugs—typically either anti-lymphocyte globulin or anti-thymocyte globulin—combined with corticosteroids, chemotherapy, and ciclosporin. Hematopoietic stem cell transplantation is also used, especially for patients under 30 years of age with a related, matched marrow donor. [5] [6]

Aplastic anemia is known to have caused the deaths of Marie Curie, [7] Eleanor Roosevelt, [8] Luana Reyes, and Molly Holzschlag.

Signs and symptoms

Anemia may lead to fatigue, pale skin, severe bruising, and a fast heart rate. [9]

Low platelets are associated with an increased risk of bleeding, bruising, and petechiae, with lower blood counts that impact the ability of the blood to clot. Low white blood cells increase the risk of infections. [9]

Causes

Aplastic anemia can be caused by immune disease or exposure to certain chemicals, drugs, radiation, or infection; in about half the cases, a definitive cause is unknown. It is not a hereditary condition, nor is it contagious. [5] [6]

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. However, the probability that these drugs will lead to aplastic anemia in a given patient is very low. Chloramphenicol treatment is associated with aplasia in less than one in 40,000 treatment courses, and carbamazepine aplasia is even rarer. [10]

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; the damaging effects of ionizing radiation were not then known. [11]

Aplastic anemia is present in up to 2% of patients with acute viral hepatitis. [12]

One known cause is an autoimmune disorder in which white blood cells attack the bone marrow. [2] Acquired aplastic anemia is a T-cell mediated autoimmune disease, in which regulatory T cells are decreased and T-bet, a transcription factor and key regulator of Th1 development and function, is upregulated in affected T-cells. As a result of active transcription of the interferon gamma (IFN-gamma) gene by T-bet, IFN-gamma levels are increased, which reduces colony formation of hematopoietic progenitor cells in vitro by inducing apoptosis of CD34+ cells in the bone marrow. [13]

Short-lived aplastic anemia can also be a result of parvovirus infection. [14] In humans, the P antigen (also known as globoside), one of many cellular receptors that contribute to a person's blood type, is the cellular receptor for parvovirus B19, which causes erythema infectiosum (fifth disease) in children. Because it infects red blood cells as a result of the affinity for the P antigen, parvovirus causes complete cessation of red blood cell production. In most cases, this goes unnoticed, as red blood cells live on average 120 days, and the drop in production does not significantly affect the total number of circulating cells. However, in people with conditions where the cells die early (such as sickle cell disease), parvovirus infection can lead to severe anemia. [15] [16]

More frequently, parvovirus B19 is associated with aplastic crisis, which involves only red blood cells (despite the name). Aplastic anemia involves all cell lines.

Other viruses that have been linked to the development of aplastic anemia include hepatitis, Epstein-Barr, cytomegalovirus, and HIV.

In some animals, aplastic anemia may have other causes. For example, in the ferret (Mustela putorius furo), it is caused by estrogen toxicity, because female ferrets are induced ovulators, 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. [17] [18]

Diagnosis

Aplastic anemia must be differentiated from pure red cell aplasia. In aplastic anemia, the patient has pancytopenia (i.e., also leukopenia and thrombocytopenia) resulting in a decrease of all formed elements. In contrast, pure red cell aplasia is characterized by a reduction in red cells only. The diagnosis can only be confirmed with a bone marrow examination.[ citation needed ]

Before this procedure is undertaken, a patient will generally have had other blood tests to find diagnostic clues, including a complete blood count, renal function and electrolytes, liver enzymes, thyroid function tests, vitamin B12 and folic acid levels.

Tests that may aid in determining an etiology for aplastic anemia include:

  1. History of iatrogenic exposure to cytotoxic chemotherapy: transient bone marrow suppression
  2. Vitamin B12 and folate levels: vitamin deficiency
  3. Liver tests: liver diseases
  4. Viral studies: viral infections
  5. Chest X-ray: infections
  6. 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)
  7. Antibody test: immune competency
  8. Blood tests for paroxysmal nocturnal hemoglobinuria
  9. Bone marrow aspirate and biopsy: to rule out other causes of pancytopenia (i.e., neoplastic infiltration or significant myelofibrosis).

Pathogenesis

For many years, the cause of acquired aplastic anemia was not clear. Now, autoimmune processes are considered to be responsible. [19] The majority of cases are hypothesized to be the result of T-cell-mediated autoimmunity and destruction of the bone marrow, which leads to defective or nearly absent hematopoiesis. It is suggested that unidentified antigens cause a polyclonal expansion of dysregulated CD4+ T cells and overproduction of pro-inflammatory cytokines, such as interferon-γ and tumor necrosis factor-α. Ex vivo bone marrow models show an expansion of dysregulated CD8+ T cell populations. [20] Activated T cells also induce apoptosis in hematopoietic stem cells. [21]

Aplastic anemia is associated with increased levels of Th17 cells—which produce pro-inflammatory cytokine IL-17—and interferon-γ-producing cells in the peripheral blood and bone marrow. Th17 cell populations also negatively correlate with regulatory T-cell populations, suppressing auto-reactivity to normal tissues, including the bone marrow. [22] Deep phenotyping of regulatory T-cells showed two subpopulations with specific phenotypes, gene expression signatures, and functions. [23]

Studies in patients who responded to immunosuppressive therapy found dominant subpopulations characterized by higher expression of HLA‐DR2 and HLA‐DR15 (mean age of two groups: 34 and 21 years), [24] FOXP3, CD95, and CCR4; lower expression of CD45RA (mean age: 45 years); [23] and expression of the IL‐2/STAT5 pathway. Higher frequency of HLA‐DR2 and HLA‐DR15 may cause augmented presentation of antigens to CD4+ T-cells, resulting in immune‐mediated destruction of the stem cells. [25] In addition, HLA‐DR2-expressing cells augment the release of tumor necrosis factor-α, which plays a role in disease pathology. [26]

The hypothesis of aberrant, disordered T‐cell populations as the initiators of aplastic anemia is supported by findings that immunosuppressive therapy for T-cells (for example, anti-thymocyte globulin and ciclosporin) results in a response in up to 80% of severe aplastic anemia patients. [27]

CD34+ progenitor cells and lymphocytes in the bone marrow over-express the Fas receptor, the main element in apoptotic signaling. A significant increase in the proportion of apoptotic cells in the bone marrow of aplastic anemia patients has been demonstrated. This suggests that cytokine‐induced and Fas‐mediated apoptosis play roles in bone marrow failure because annihilation of CD34+ progenitor cells leads to hematopoietic stem cell deficiency. [28]

Frequently detected autoantibodies

A study of blood and bone marrow samples obtained from 18 aplastic anemia patients revealed more than 30 potential specific candidate autoantigens after the serologic screening of a fetal liver library with sera from 8 patients. The human fetal liver cDNA library (chosen because of its high enrichment of CD34+ cells), compared with peripheral blood or the bone marrow, significantly increased the likelihood of detection of possible stem cell autoantigens.

ELISA and Western blot analysis revealed that an IgG antibody response to one of the candidate autoantigens, kinectin, was present in a significant number of patients (39%). In contrast, no antibody was detected in 35 healthy volunteers. Antibody was detected in both transfused and transfusion-naive patients, suggesting that antikinectin autoantibody development was not due to transfusion-related alloreactivity. Negative sera from patients with other autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis) showed a specific association of antikinectin antibodies with aplastic anemia. These results support the hypothesis that immune response to kinectin may be involved in the pathophysiology of the disease.

Kinectin is a large molecule (1,300 amino acid residues) expressed by CD34+ cells. Several kinectin-derived peptides can be processed and presented by HLA I and can induce antigen-specific CD8+ T-cell responses. [29]

Bone marrow microenvironment

A critical factor for healthy stem cell production is the bone marrow microenvironment. Important components are stromal cells, the extracellular matrix, and local cytokine gradients. The hematopoietic and non-hematopoietic elements of the bone marrow closely interact with each other and sustain and maintain the balance of hematopoiesis.

In addition to low numbers of hematopoietic stem cells, aplastic anemia patients have altered hematopoietic niche [30]

Treatment

Treating immune-mediated aplastic anemia involves suppression of the immune system, an effect achieved by daily medicine or, in more severe cases, a bone marrow transplant, a potential cure. [31] 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").

In young patients with an HLA-matched sibling donor, bone marrow transplant can be considered as a first-line treatment. Patients lacking a matched sibling donor typically pursue immunosuppression as a first-line treatment, and matched, unrelated donor transplants are considered second-line therapy.

Treatment often includes a course of antithymocyte globulin (ATG) and several months of treatment with ciclosporin to modulate the immune system. Chemotherapy with agents such as cyclophosphamide may also be effective but is more toxic than ATG. Antibody therapy such as ATG targets T cells, which are believed to attack the bone marrow. Corticosteroids are generally ineffective, [32] though they are used to ameliorate serum sickness caused by ATG. Normally, success is judged by bone marrow biopsy six months after initial treatment with ATG. [33]

One prospective study involving cyclophosphamide was terminated early due to a high incidence of mortality from severe infections as a result of prolonged neutropenia. [33]

Before the above treatments became available, patients with low leukocyte counts were often confined to a sterile room or bubble (to reduce risk of infection), as in the case of Ted DeVita. [34]

Follow-up

Full blood counts are required on a regular basis to determine whether the patient is still in remission.

Many patients with aplastic anemia also have clones of cells characteristic of paroxysmal nocturnal hemoglobinuria (PNH), a rare disease that causes anemia with thrombocytopenia and/or thrombosis and is sometimes referred to as AA/PNH. Occasionally PNH dominates over time, with the major manifestation of intravascular hemolysis. The overlap of AA and PNH has been speculated to be 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. [35]

Prognosis

Untreated, severe aplastic anemia has a high risk of death. [36] Modern treatment produces a five-year survival rate that exceeds 85%, with younger age associated with higher survival. [37]

Survival rates for stem cell transplants vary depending on the age and availability of a well-matched donor. They are better for patients who have donors that are matched siblings and worse for patients who receive their marrow from unrelated donors. [38] Overall, the five-year survival rate is higher than 75% among recipients of blood marrow transplantation. [39]

Older people (who are generally too frail to undergo bone marrow transplants) and people who are unable to find a good bone marrow match have five-year survival rates of up to 35% when undergoing immune suppression. [40]

Relapses are common. Relapse following ATG/ciclosporin use can sometimes be treated with a repeated course of therapy. In addition, 10–15% of severe aplastic anemia cases evolve into myelodysplastic syndrome and leukemia. [40] According to one study, 15.9% of children who responded to immunosuppressive therapy eventually relapsed. [41]

Milder disease may resolve on its own. [40]

Etymology

Aplastic is a combination of two ancient Greek elements: a- (meaning "not") and -plasis ("forming into a shape"). [42] Anemia is a combination of the ancient Greek element an- ("not") and -emia (Neo-Latin from the Greek -(h)aimia, meaning "blood"). [43]

Epidemiology

Aplastic anemia is a rare, noncancerous disorder in which the blood marrow is unable to adequately produce blood cells required for survival. [44] [45] It is estimated that the incidence of aplastic anemia is 0.7–4.1 cases per million people worldwide, with the prevalence between men and women being approximately equal. [46] The incidence rate of aplastic anemia in Asia is 2–3 times higher than it is in the West; the incidence in the United States is 300–900 cases per year. [45] [46] The disease most commonly affects adults aged 15–25 and over the age of 60, but it can be observed in all age groups. [45]

The disease is usually acquired during life and not inherited. [44] Acquired cases are often linked to environmental exposures such as chemicals, drugs, and infectious agents that damage the bone marrow and compromise its ability to generate new blood cells. [46] However, in many instances the underlying cause for the disease is not found. This is referred to as idiopathic aplastic anemia and accounts for 75% of cases. [45] This compromises the effectiveness of treatment since treatment of the disease is often aimed at the underlying cause. [39]

Those with a higher risk for aplastic anemia include individuals who are exposed to high-dose radiation or toxic chemicals, take certain prescription drugs, have pre-existing autoimmune disorders or blood diseases, or are pregnant. [47] No screening test currently exists for early detection of aplastic anemia. [45]

Notable cases

See also

Related Research Articles

<span class="mw-page-title-main">Bone marrow</span> Semi-solid tissue in the spongy portions of bones

Bone marrow is a semi-solid tissue found within the spongy portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production. It is composed of hematopoietic cells, marrow adipose tissue, and supportive stromal cells. In adult humans, bone marrow is primarily located in the ribs, vertebrae, sternum, and bones of the pelvis. Bone marrow comprises approximately 5% of total body mass in healthy adult humans, such that a man weighing 73 kg (161 lbs) will have around 3.7 kg (8 lbs) of bone marrow.

<span class="mw-page-title-main">Fanconi anemia</span> Medical condition

Fanconi anemia (FA) is a rare, AR, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.

<span class="mw-page-title-main">Paroxysmal nocturnal hemoglobinuria</span> Medical condition

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. There is ongoing research into other key features of the disease, such as the high incidence of venous blood clot formation. Research suggests that PNH thrombosis is caused by both the absence of GPI-anchored complement regulatory proteins on PNH platelets and the excessive consumption of nitric oxide (NO).

Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes). Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine. The risk is especially high in cytotoxic chemotherapy for leukemia. In the case of non-small-cell lung cancer, myelosuppression predisposition was shown to be modulated by enhancer mutations.

Anti-thymocyte globulin (ATG) is an infusion of horse or rabbit-derived antibodies against human T cells and their precursors (thymocytes), which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia due to bone marrow insufficiency.

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce additional normal blood cells. It may be autologous, allogeneic or syngeneic.

<span class="mw-page-title-main">Graft-versus-host disease</span> Medical condition

Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells.

<span class="mw-page-title-main">Pure red cell aplasia</span> Medical condition

Pure red cell aplasia (PRCA) or erythroblastopenia refers to a type of aplastic anemia affecting the precursors to red blood cells but usually not to white blood cells. In PRCA, the bone marrow ceases to produce red blood cells. There are multiple etiologies that can cause PRCA. The condition has been first described by Paul Kaznelson in 1922.

Reticulocytopenia is the medical term for an abnormal decrease in circulating red blood cell precursors (reticulocytes) that can lead to anemia due to resulting low red blood cell (erythrocyte) production. Reticulocytopenia may be an isolated finding or it may not be associated with abnormalities in other hematopoietic cell lineages such as those that produce white blood cells (leukocytes) or platelets (thrombocytes), a decrease in all three of these lineages is referred to as pancytopenia.

The National Marrow Donor Program (NMDP) is a nonprofit organization founded in 1986 and based in Minneapolis, Minnesota, that operates the Be The Match Registry of volunteer hematopoietic cell donors and umbilical cord blood units in the United States.

<span class="mw-page-title-main">Congenital amegakaryocytic thrombocytopenia</span> Medical condition

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive bone marrow failure syndrome characterized by severe thrombocytopenia, which can progress to aplastic anemia and leukemia. CAMT usually manifests as thrombocytopenia in the initial month of life or in the fetal phase. Typically CAMPT presents with petechiae, cerebral bleeds, recurrent rectal bleeding, or pulmonary hemorrhage.

Bone marrow failure occurs in individuals who produce an insufficient amount of red blood cells, white blood cells or platelets. Red blood cells transport oxygen to be distributed throughout the body's tissue. White blood cells fight off infections that enter the body. Bone marrow also contains platelets, which trigger clotting, and thus help stop the blood flow when a wound occurs.

<span class="mw-page-title-main">Reticular dysgenesis</span> Medical condition

Reticular dysgenesis (RD) is a rare, inherited autosomal recessive disease that results in immunodeficiency. Individuals with RD have mutations in both copies of the AK2 gene. Mutations in this gene lead to absence of AK2 protein. AK2 protein allows hematopoietic stem cells to differentiate and proliferate. Hematopoietic stem cells give rise to blood cells.

Neal Stuart Young is an American physician and researcher, chief of the Hematology Branch of the National Institutes of Health (NIH), and Director of the Center for Human Immunology at the NIH in Bethesda, Maryland. He is primarily known for his work in the pathophysiology and treatment of aplastic anemia, and is also known for his contributions to the pathophysiology of parvovirus B19 infection.

Microtransplantation (MST) is an advanced technology to treat malignant hematological diseases and tumors by infusing patients with granulocyte colony-stimulating factor (G-CSF) mobilized human leukocyte antigen (HLA)-mismatched allogeneic peripheral blood stem cells following a reduced-intensity chemotherapy or targeted therapy. The term "microtransplantation" comes from its mechanism of reaching donor cell microchimerism.

Guo Mei is a hematologist and associate director of 307th Hospital of Chinese People’s Liberation Army and deputy director of Radiation Research Institute.

T-cell depletion (TCD) is the process of T cell removal or reduction, which alters the immune system and its responses. Depletion can occur naturally or be induced for treatment purposes. TCD can reduce the risk of graft-versus-host disease (GVHD), which is a common issue in transplants. The idea that TCD of the allograft can eliminate GVHD was first introduced in 1958. In humans the first TCD was performed in severe combined immunodeficiency patients.

<span class="mw-page-title-main">Shimon Slavin</span> Israeli professor of medicine

Shimon Slavin is an Israeli professor of medicine. Slavin pioneered the use of immunotherapy mediated by allogeneic donor lymphocytes and innovative methods for stem cell transplantation for the cure of hematological malignancies and solid tumors, and using hematopoietic stem cells for induction of transplantation tolerance to bone marrow and donor allografts.

References

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