Table of Contents
Definition of Aplastic Anemia
Aplastic anemia is an anemia that involves a reduced hematopoiesis and is based on a maturation defect of the pluripotent, hematopoietic stem cells. The underlying cause is bone marrow failure, which is distinguished from other bone marrow diseases by a cell count of the bone marrow of under 25 %, i.e., by a marked hypoplasia or aplasia of the bone marrow.
Etiology and Pathogenesis of Aplastic Anemia
The exact cause of aplastic anemia has not yet been definitively confirmed, which is why about half of all diseased cases are classified as idiopathic. The only secured fact regarding its pathogenesis is that this disorder is always related to a large reduction of the number of pluripotent, hematopoietic stem cells. Beyond that, an autoimmune reaction with the involvement of T-cells is being discussed as a likely explanation.
The disease can be divided into congenital (primary) and acquired (secondary) causes:
|Primary Causes||Secondary Causes|
|Blackfan-Diamond anemia, Fanconi anemia||Medication, chemicals (benzene), ionizing radiation, infections, autoimmune disease, heavy metals|
Congenital Aplastic Anemia (Primary Form)
Fanconi anemia is a disorder of autosomal-recessive inheritance and can be subdivided into seven subtypes, which will however not be the subject here. The disease usually manifests at the age of 5 to 10 years. The underlying cause is assumed to be a DNA repair defect. It can manifest in form of microcephaly, absent radii or thumbs, pelvic or horseshoe kidney, hyperpigmentation or hypopigmentation of the skin, and in some rare cases even mental retardation.
Treatment of choice is a bone marrow transplant. Furthermore, treatment with androgens is an option; however, the side-effects can be considerable (virilization, liver anomalies), and the remission that can be achieved lasts only for about 2 years.
Blackfan-Diamond anemia is the hereditary form of pure red-cell aplasia. It involves a primary erythroid aplasia in the bone marrow without affecting any other cell lines. Unlike other forms of aplastic anemia, it does not involve pancytopenia.
The leukocyte and thrombocyte numbers are in the normal range. However, the erythroblasts in the bone marrow are markedly reduced or not present at all. Clinical manifestations begin already in infancy with the typical symptoms of anemia. In addition, multiple somatic dysmorphias like genital malformations or dysphalangia develop.
Treatment consists in the administration of glucocorticoids and possibly a bone marrow transplant.
Acquired Aplastic Anemia (Secondary Form)
Acquired aplastic anemia is usually the result of a direct damage to the hematopoietic bone marrow. Factors known for having a negative impact on the bone marrow are mainly radiation and medication with cytotoxic effects. Also chemical substances like benzene disturb the functioning of the bone marrow. Furthermore, viral infections can lead to the development of aplastic anemia.
But it is not always possible to find a causative factor. For instance, the acquired chronic form of pure red-cell aplasia cannot always be traced back to one of the mentioned causes.
Pure Red-Cell Aplasia
Chronic Acquired Form of Pure Red-Cell Aplasia
Pure red-cell aplasia is a rare syndrome that can be inherited (see Blackfan-Diamond syndrome) or secondarily acquired. Unlike most of the other forms of aplastic anemia, the chronic form of pure red-cell aplasia does not involve pancytopenia. Only the number of the erythroblasts is markedly reduced. It is thus an isolated aplasia of erythropoiesis.
Since in many cases, the causative factor cannot be determined, most cases are classified as idiopathic. But it can also develop within the scope of an autoimmune disease like systemic lupus erythematosus (SLE).
Treatment of the acquired red-cell aplasia is similar to that of the congenital form. It can be treated with corticosteroids as well as with immunosuppressants.
Acute Transient Form of Pure Red-Cell Aplasia
The acute transient form of pure red-cell aplasia refers to a temporary aplastic impairment of erythropoiesis that is usually caused by parvoviruses or certain drugs.
Drug-Induced Aplastic Anemia
A series of cytotoxic medications is known for increasing the risk of developing aplastic anemia. Here, an important distinction is to be made: antimetabolites such as methothrexate and mitotic inhibitors like daunorubicin both provoke only a temporary aplasia, while alkylating agents like busulfan cause chronic aplasia.
But also non-cytotoxic medications such as chloramphenicol or gold can cause an aplastic anemia. Since the incidence with chloramphenicol is very high, this drug should only be given in very severe cases after all other medication has failed.
Medication that can produce damage to the bone marrow includes the following:
- Cytostatic agents
- Gold preparations
Chemical substances that are known to provoke damage to the bone marrow are:
- Hair dye products
Bone marrow failure can also occur as a consequence of radiation therapy. Therefore, when there is a suspicion of bone marrow failure, the medical history should take account of previous radiological examinations.
Since there is an etiological relation between aplastic anemia and autoimmune reactions, the correlation of certain autoimmune diseases with the development of aplastic anemia will not come as a surprise. Autoimmune diseases that represent an increased risk of developing aplastic anemia are:
- Systemic lupus erythematosus (SLE)
- Graft versus host disease (GVHD)
The viruses which are proven to have an influence on the development of aplastic anemia are:
- Parvovirus B19
- HIV virus (AIDS)
- Hepatitis viruses A and C
- Epstein-Barr virus (EBV)
- Cytomegalovirus (CMV)
Symptoms and Clinical Presentation of Aplastic Anemia
Aplastic anemia can have an insidious or an acute onset. First warning signs may be neutropenia or thrombocytopenia. In addition, there are the typical clinical signs of anemia, such as fatigue, exhaustion, overall weakness, pale skin and pale mucous membranes. There is also an increased occurrence of infections, especially in the mouth and cervical areas, and an increased bleeding tendency (epistaxis, menorrhagia).
Diagnosis and Differential Diagnosis of Aplastic Anemia
Since pancytopenia is typical of aplastic anemia, this finding should prompt (after excluding other more probable diseases) further investigations in the direction of bone marrow failure. Before that, the following diseases associated with pancytopenia have to be considered as differential diagnoses:
- Myelodysplastic syndrome (MDS)
- Acute myeloid leukemia (AML)
- Megaloblastic anemia
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Temporary pancytopenia after viral infections
Besides pancytopenia, the blood count will show a normochromic, normo-, or macrocytic anemia. The reticulocyte count will be reduced. Serological examinations of the blood should look for parvovirus B 19, hepatitis viruses, Epstein-Barr viruses, and cytomegaloviruses.
The actual confirmation of the suspicion is done by examining the bone marrow (trephine biopsy and aspiration). The cells taken from the iliac crest are examined cytologically and histologically. The detection of hypoplasia or aplasia of the hematopoietic marrow is to be expected due to it being replaced by non-hematopoietic fatty bone marrow. Also the absence of the precursor cells of other cell lines would be characteristic.
Treatment of Aplastic Anemia
If known, the causative factor of the anemia (radiation, chemicals, medication etc.) should be eliminated as a first step. The only promising and curative treatment, however, consists in allogeneic stem cell transplantation (age < 40 years), which is aimed at generating a completely new hematopoiesis.
Here, it is of importance that as few transfusions as possible are performed before the stem cell transplantation because every transfusion could lead to the alloimmunization of the patient and thus decrease the chances of success of a transplantation. Possible donors are siblings, and if these are not available, unrelated donors (in both cases, at least 10 HLA alleles should be a match).
Prognosis for Aplastic Anemia
If stem cell transplantation is done early, prognosis is good with a relatively low risk of recurrence. Patients treated with immunosuppressants, however, have an increased risk of recurrence with every third patient experiencing a relapse. In addition, there is an increased risk for these patients to develop over the following years a myelodysplastic syndrome (MDS), an acute myeloid leukemia (AML), or a paroxysmal nocturnal hemoglobinuria (PNH).
If left untreated, aplastic anemia is lethal in 75 % of the cases.
Anemia of Chronic Diseases
Anemia of chronic disease is a non-progressive anemia that occurs as part of chronic inflammatory, infectious, or neoplastic diseases. It is usually rather mild but its severity does correlate with the severity of the underlying disease.
After iron deficiency anemia, the anemia of chronic disease is with about 20 % the second most common type of anemia.
Etiology and Pathogenesis of Anemia of Chronic Disease
Typically, the organism reacts to infections, inflammatory system diseases and malignoma with an increased release of inflammatory mediators. These not only have a local but also a systemic effect. In this context, cytokines play a special role: when their systemic release is increased, they provoke an imbalance in the homeostasis of iron by influencing the physiological storage of iron in the macrophages of the bone marrow.
In addition, the mediators trigger the production of hepcidin in the hepatocytes. Hepcidin inhibits the iron uptake in the intestines and lowers the availability of iron for erythropoiesis. This results in an increased iron retention and insufficient iron output.
The consequence is a relative insufficiency of iron, which from a pathophysiological perspective leads to a defective composition of the heme molecule and clinically manifests as anemia.
In addition to the imbalanced iron homeostasis, the increased release of cytokines also provokes the suppression of erythropoietin production. So not only is there a relative insufficiency of iron but also of erythropoietin. Moreover, under the influence of the cytokines, the life-span of the red blood cells is shortened to about 80 – 90 days.
Some of the underlying diseases that may involve anemia of chronic disease are:
- Infektious: Pneumonia, tuberculosis, osteomyelitis, bacterial endocarditis, pulmonary abscesses
- Non-infectious: Systemic lupus erythematosus (SLE), Crohn’s disease, ulcerative colitis, vasculitides, rheumatoid arthritis, sarcoidosis
- Malign diseases: Carcinoma, lymphoma, sarcoma, multiple myeloma
Clinical Presentation and Symptoms of Anemia of Chronic Disease
Unspecific general symptoms like fever and weight loss in combination with other, typical signs of anemia like fatigue, weakness, tachycardia, or visual impairments should be considered as a possible indication of anemia of chronic inflammation. Since anemia of inflammation is the consequence of an underlying disease, it is also important to look out for the specific symptoms of the respective underlying disease.
Diagnosis and Differential Diagnosis of Anemia of Chronic Disease
If the underlying disease is known and accompanied by signs of anemia, suspecting an anemia of chronic diseases stands to reason but it has to be further verified.
Laboratory tests will initially show a hyporegenerative, normochromic, normocytic anemia. Only in the further course of the disease, this will change to a hypochromic, microcytic anemia.
Hematocrit, erythrocyte, and reticulocyte levels are reduced. Hemoglobin is also reduced, but the level usually does not fall below 9.0 g/dl. In contrast, ferritin will be increased since the iron insufficiency is not absolute and it is primarily a dysfunction of iron homeostasis. It is crucial to identify this circumstance because this is a way to exclude iron sufficiency anemia as a differential diagnosis.
Furthermore, measurement of the inflammatory markers is indicative. Patients with anemia of chronic inflammation have increased BSR and CRP. A bone marrow examination would detect normal or increased iron storage.
The causes of anemia can be diverse. Since different triggers such as hemorrhages or hemolysis could be present simultaneously during the course of a disease and since this could always change the clinical manifestation of an already diagnosed anemia, such a diagnosis will have to be reassessed regularly. It is a diagnosis of exclusion.
The first priority is treating the underlying disease. Additionally, an erythropoietin substitution might be considered. Oral iron therapy is ineffective, and due to the relative iron insufficiency which cannot be remedied by oral intake of iron, it is contraindicated!
If the underlying disease can be treated successfully, the anemia will also subside.
Popular Exam Questions on Aplastic Anemia and Anemia of Chronic Disease
Solutions can be found below the references.
1. A reduced erythropoietin concentration in the plasma found in anemia patients is most likely due to:
- Iron deficiency
- Cobalamin (vitamin B12) deficiency
- Kidney insufficiency
- Differentiation defect of hematopoietic precursor cells
2. A 34-year-old woman complains of a lack of physical strength and performance. Skin and mucosas are pale. A blood panel shows: hemoglobin concentration 120 g/l; hematocrit 0.35; reticulocyte count, MCH, and MCV are reduced. Which diagnosis is most likely?
- Vitamin B12 deficiency
- Folate deficiency
- Kidney-related anemia
- Iron deficiency anemia
- Aplastic anemia
3. A left shift of the oxygen dissociation curve of hemoglobin…
- …means a decrease in oxygen affinity of hemoglobin.
- …is achieved by binding 2, 3-biphosphoglycerate to hemoglobin.
- …impedes the release oxygen into the tissue.
- …is the result of an increased CO2 partial pressure in the blood.
- …can be due to an increase in body temperature to more than 37° C.