Aplastic anemia, or aplastic crisis is the inability of the bone marrow to produce new blood cells. Aplastic anemia symptoms may show slowly, but can be fatal.

Aplastic Anemia

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Ismail Munir

Overview

Aplastic anemia is a rare condition in which blood cell production is compromised. The defect lies in the bone marrow (the soft, spongy tissue within the center of bone) which is responsible for the formation of blood cells of all lineages, such as red blood cells, white blood cells, and platelets.<a href="#accordion">[1]</a>Symptoms signaling the low levels of these cells in the blood appear when their production is disrupted due to aplastic anemia.

&nbsp;

However, in order to understand the symptoms of this blood disorder, it&rsquo;s important to first know the role of the different types of blood cells that are affected by this blood disorder:<a href="#accordion">[1]</a>

<ul>
	<li>Red Blood Cells -&nbsp;They carry oxygen across the bloodstream to the tissues that need it.</li>
	<li>White Blood Cells -&nbsp;They generate the defense response against any foreign offender, for instance, germs and bacteria.&nbsp;</li>
	<li>Platelets -&nbsp;These help the blood clot and, thereby, control bleeding.</li>
</ul>

So, when new blood cells aren&#39;t formed due to bone marrow failure, it can cause several other issues. Firstly, the body becomes susceptible to bleeding as a result of low platelets, a condition known as thrombocytopenia. Secondly, poor immune functioning makes the individual prone to infections since the white blood cell count is very low. Thirdly, individuals may exhibit signs of anemia, such as fatigue, because of decreased red blood cells.

Aplastic anemia can develop in anyone, irrespective of their age and gender. It can either progress gradually and worsen over time or it can happen suddenly producing severe symptoms of the disease.<a href="#accordion">[2]</a>

Aplastic anemia is not cancer, yet it is treated like other blood cancers such as leukemia since the defect lies in the bone marrow.<a href="#accordion">[3]</a>&nbsp;Treatment involves medications, bone marrow transplant, blood transfusion, and stem cell transplant.<a href="#accordion">[2]</a> 
&nbsp;

Aplastic anemia is a rare condition; approximately, 2 out of every 1 million people in the United States are affected each year.<a href="#accordion">[4]</a>&nbsp;However, aplastic anemia is more common in low-income countries.<a href="#accordion">[5]</a>

In Pakistan, the incidence of aplastic anemia is estimated to be 3.5 cases per million people.<a href="#accordion">[6]</a>&nbsp;In the West, the peak age associated with aplastic anemia is noted to be 15-29 years and greater than 60 years, whereas, in Asia, the age group associated with the highest cases of aplastic anemia is noted to be 15-24 years. This condition is observed to be more common in males since they are exposed to toxic agents in their occupational settings that increase the risk of aplastic anemia.<a href="#accordion">[6]</a>

Aplastic anemia has a case fatality rate of 34% which indicates the proportion of people who die after being diagnosed with this condition.<a href="#accordion">[6]</a>&nbsp; 
&nbsp;

Aplastic anemia is divided into:

<h5>1. Inherited Aplastic Anemia&nbsp;</h5>

This type of aplastic anemia is caused by a defect in a gene and is commonly seen in children and young adults. Individuals with this type of anemia have a higher likelihood of having leukemia and other types of blood cancer, therefore, it is recommended that they visit a specialist regularly.<a href="#accordion">[5]</a>&nbsp;Roughly 25% of cases in children and 10% of cases in adults are inherited aplastic anemia.<a href="#accordion">[7]</a> 
&nbsp;

<h5>2. Acquired Aplastic Anemia&nbsp;</h5>

This type of anemia is commonly seen in adults. Researchers believe that an immune trigger is responsible for destroying the stem cells in the bone marrow and, consequently, for the failure of the production of different blood cell types. The following factors can result in acquired aplastic anemia:<a href="#accordion">[5]</a>

<ul>
	<li>Certain medications, including some antibiotics and some medicines that are used to treat <a href="https://www.merisehat.pk/disease/rheumatoid-arthritis" target="_blank">rheumatoid arthritis&nbsp;</a></li>
	<li>Radiation or chemotherapy for cancer treatment&nbsp;</li>
	<li>Viruses such as <a href="https://www.merisehat.pk/disease/hiv-61" target="_blank">HIV </a>or Epstein-Barr virus&nbsp;</li>
	<li>Toxic chemicals&nbsp;</li>
</ul>

The clinical presentation of the 2 types is almost similar and it is a challenge to differentiate them on clinical grounds. However, 80% of cases of aplastic anemia are acquired due to external insults as mentioned above.<a href="#accordion">[7]</a> 
&nbsp;

Signs And Symptoms

Aplastic anemia symptoms depend upon the type of blood cells that are low. Mostly, all three of the blood cell types are low, a condition referred to as pancytopenia. However, it&rsquo;s also possible to classify the symptoms according to each cell type.&nbsp;

&nbsp;

Aplastic anemia symptoms due to low red blood cells include:

<ul>
	<li>Shortness of breath&nbsp;</li>
	<li>Fatigue&nbsp;</li>
	<li>Tiredness&nbsp;</li>
	<li><a href="https://www.merisehat.pk/disease/angina" target="_blank">Chest pain</a></li>
	<li>Headaches&nbsp;</li>
	<li>Pale skin</li>
	<li>Dizziness</li>
	<li>Irregular heartbeat&nbsp; 
	&nbsp;</li>
</ul>

Aplastic anemia symptoms due to low white blood cells include:

<ul>
	<li>Fever&nbsp;</li>
	<li>Recurrent infection<a href="#accordion">[7]</a>&nbsp; 
	&nbsp;</li>
</ul>

Aplastic anemia symptoms due to low platelets include:

<ul>
	<li>Bleeding from the nose (epistaxis)</li>
	<li>Easy bruising and bleeding&nbsp;&nbsp;</li>
	<li>Gum bleeding<a href="#accordion">[7]</a>&nbsp;</li>
</ul>

A small fraction also get <a href="https://www.merisehat.pk/disease/jaundice-65" target="_blank">jaundice</a>, which is the yellow discoloration of the skin and sclera (white part of the eye) or they may present with signs of <a href="https://merisehat.pk/disease/hepatitis-a&amp;e" target="_blank">hepatitis </a>(inflammation of the liver).<a href="#accordion">[7]</a>&nbsp; 
&nbsp;

Causes

Aplastic anemia develops when the stem cells within the bone marrow are depleted. Stem cells are present in the bone marrow and have the potential to develop into blood cells of any of the three lineages &ndash; red blood cells, white blood cells, or platelets. Thus, we say that the stem is pluripotent, which means it has the potential to give rise to different types of cells.

When the stem cells are affected, the bone marrow becomes either aplastic (empty) or hypoplastic (has few blood cells).<a href="#accordion">[7]</a>&nbsp;According to research, the most common reason aplastic anemia may develop is when the immune system attacks the stem cells in the bone marrow.&nbsp;

&nbsp;

Apart from an immune-mediated cause, other factors known to affect the production of blood cells include:<a href="#accordion">[2]</a>&nbsp;

<ul>
	<li>Exposure To Toxic Chemicals: These can be pesticides, insecticides, and benzene compounds. The individual&rsquo;s condition visibly improves once the offending agent is removed from their environment.&nbsp;</li>
</ul>

&nbsp;

<ul>
	<li>Chemotherapy And Radiation Treatment: While radiation and chemotherapy are targeted at cancer cells, there are normal healthy cells in the body such as the stem cells in the bone marrow that also get killed during the process. In this case, aplastic anemia is a temporary adverse effect of the treatment plan and the individual can recover later when repeated exposure to chemotherapy or radiation is stopped.</li>
</ul>

&nbsp;

<ul>
	<li>Autoimmune Disorders: This refers to the condition where the immune cells of the body attack the healthy cells such as the stem cells in bone marrow.</li>
</ul>

&nbsp;

<ul>
	<li>Viral Infections:&nbsp;Infections, like HIV, hepatitis, Epstein-Barr virus, parvovirus B19, and cytomegalovirus, can cause aplastic anemia by affecting the bone marrow.&nbsp;</li>
</ul>

&nbsp;

<ul>
	<li>Pregnancy: The individual is vulnerable in this state and the immune cells may attack the healthy cells of the body and cause aplastic anemia.&nbsp;</li>
</ul>

&nbsp;

<ul>
	<li>Paroxysmal Nocturnal Hemoglobinuria: This is a rare disorder that causes red blood cells to break down early. It can progress to aplastic anemia. Alternatively, aplastic anemia can also lead to paroxysmal nocturnal hemoglobinuria.</li>
</ul>

&nbsp;

<ul>
	<li>Fanconi&#39;s Anemia: This is another rare and inherited condition that can lead to aplastic anemia. Children who inherit this disease are small in size and are born with birth defects, like underdeveloped limbs.&nbsp;</li>
</ul>

&nbsp;

<ul>
	<li>Unidentifiable Factors: There are certain cases in which the cause of the disease isn&#39;t known. They are labeled as idiopathic aplastic anemia.&nbsp; 
	&nbsp;</li>
</ul>

Individuals who are 30 and over and have any of&nbsp; the risk factors of aplastic anemia should be screened for this blood disorder.<a href="#accordion">[6]</a> 
&nbsp;

Diagnosis

The following tests can help with the diagnosis of patients with suspected aplastic anemia:<a href="#accordion">[8]</a>

<ul>
	<li>Blood Tests: In a normal, healthy individual the level of red blood cells, white blood cells, and platelets should be within the normal range. However, in a rare condition like aplastic anemia, all three blood cell types will be low.</li>
	<li>Bone Marrow Biopsy: A needle is used to withdraw a sample of bone marrow from any of the large bones in the individual&rsquo;s body. The sample is then examined under the microscope to look for any abnormality signaling a blood disorder. In aplastic anemia, the marrow will have fewer than normal cells.&nbsp;</li>
</ul>

Once aplastic anemia is diagnosed, the doctor may order some other tests to determine the etiology (cause) of this disease.&nbsp; 
&nbsp;

Treatment

Aplastic anemia treatment is based on the severity of the disease and the age and overall health of the patient. Treatment generally includes blood transfusion, medications, bone marrow transplantation, or simply observation. In severe aplastic anemia, however, in which the levels of all blood cell types are critically low, immediate hospitalization is needed as it&#39;s a life-threatening condition.&nbsp; 
&nbsp;

<ul>
	<li>
	<h5>Blood Transfusions</h5>
	</li>
</ul>

Although blood transfusions are not a cure for aplastic anemia, it&rsquo;s preferred to treat the symptoms that develop due to low blood cell levels. For instance, platelet infusion can help control excessive bleeding. Additionally, red blood cell transfusion can raise the count of red blood cells and, hence, relieve fatigue and other symptoms of anemia.&nbsp;

Individuals with aplastic anemia receive blood transfusions multiple times to treat the symptoms and also because there&#39;s no set limit to the number of transfusions an individual can have.&nbsp;

However, one of the drawbacks of red blood cell transfusion is that iron starts accumulating within the patient&#39;s body and damages vital organs if the iron overload isn&#39;t treated. This complication then requires further medications, such as iron chelators, that can be used to remove the excess iron from the patient&#39;s body.&nbsp;

Sometimes, a patient&#39;s body develops antibodies to the transfused blood which renders the transfused blood ineffective at relieving symptoms. To avoid this from happening, doctors prescribe immunosuppressants which are medications that suppress the immune system to prevent it from attacking the transfused blood.<a href="#accordion">[8]</a>

&nbsp;

<ul>
	<li>
	<h5>Stem Cell Transplant&nbsp;</h5>
	</li>
</ul>

People with severe aplastic anemia benefit greatly from stem cell transplant, also known as bone marrow transplant. In this treatment, healthy stem cells from a donor are transplanted to a patient with aplastic anemia who has little to no stem cells in their bone marrow.&nbsp;

The ideal candidates for stem cell transplants are individuals who are young and have a matching donor, mostly a sibling. When a donor has been found, the existing, diseased bone marrow of the patient is completely depleted by means of chemotherapy or radiation. Following this, healthy stem cells from the donor are then introduced and injected into the bloodstream intravenously. These healthy stem cells reach the bone marrow where they reside and start creating all the blood cell types.&nbsp;

This procedure takes place in a hospital and requires immunosuppressant drugs after the transplant to prevent the possibility of rejection of the healthy stem cells by the patient&#39;s body.<a href="#accordion">[8]</a>&nbsp;This is because if the patient&#39;s body rejects the transplanted stem cells, it can result in life-threatening complications. 
&nbsp;

<ul>
	<li>
	<h5>Immunosuppressants</h5>
	</li>
</ul>

Individuals who have aplastic anemia due to an autoimmune reaction or those who cannot undergo bone marrow transplant will be prescribed certain medications to suppress their immune system.&nbsp;

Some of the commonly known immunosuppressive medications include cyclosporine and anti-thymocyte globulin, which are often used together to limit the immune-mediated activity of the body and, thus, prevent the damage of bone marrow by the cells of the immune system.&nbsp;Corticosteroids like methylprednisolone are often combined with these drugs.&nbsp;

This treatment is effective, but it greatly weakens the immune system and there&rsquo;s also the possibility that anemia will recur once these drugs are stopped.<a href="#accordion">[8]</a>

&nbsp;

<ul>
	<li>
	<h5>Bone Marrow Stimulants&nbsp;</h5>
	</li>
</ul>

There are certain drugs that promote the growth of stem cells within the bone marrow and help in the production of new blood cells. These drugs include colony-stimulating factor, epoetin alfa, and eltrombopag among others to stimulate the healthy growth of the bone marrow.<a href="#accordion">[8]</a>

&nbsp;

<ul>
	<li>
	<h5>Antibiotics And Antivirals</h5>
	</li>
</ul>

Individuals with aplastic anemia have weakened immune systems due to the medications they take for treatment. This makes them prone to severe infections. Therefore, these individuals should see their doctor as soon as they develop a fever, which is usually the first sign of an infection, to prevent any life-threatening complications from developing. Doctors may prescribe antibiotics and antivirals to severe aplastic anemia patients.<a href="#accordion">[8]</a>&nbsp;

&nbsp;

<ul>
	<li>
	<h5>Other Treatment Options&nbsp;</h5>
	</li>
</ul>

Individuals who develop aplastic anemia as a consequence of radiation and chemotherapy see an improvement in their symptoms of anemia after the treatment stops. Similarly, aplastic anemia due to any drug will also improve once the drug is withdrawn.&nbsp;

Moreover, aplastic anemia that develops in pregnancy is treated with blood transfusions. Most women with aplastic anemia due to pregnancy improve once the pregnancy is over and those who don&#39;t improve should be provided with a treatment plan according to their condition.<a href="#accordion">[8]</a>&nbsp; 
&nbsp;

If aplastic anemia is not treated, it can result in serious complications, such as:

<ul>
	<li>Bleeding</li>
	<li>Heart complications (e.g., heart failure or arrhythmia)&nbsp;</li>
	<li>Severe infections (e.g., bacterial, viral, or fungal)</li>
	<li>Blood cancer (e.g., leukemia)<a href="#accordion">[1]</a>&nbsp;</li>
</ul>

<div>&nbsp;</div>

Following factors increase the risk of aplastic anemia:<a href="#accordion">[1]</a><a href="#accordion">[2]</a>

<ul>
	<li>Being an Asian-American or Asian&nbsp;</li>
	<li>Being a teenager or young adult&nbsp;</li>
	<li>Being over the age of 65&nbsp;</li>
	<li>Being exposed to toxic chemicals, such as pesticides, insecticides, etc.</li>
	<li>Being treated with chemotherapy or high-dose radiation&nbsp;</li>
	<li>Being prone to autoimmune diseases, blood diseases, and viral infections</li>
	<li>Being pregnant (this rarely happens) 
	&nbsp;</li>
</ul>

There are no known prevention techniques for aplastic anemia. However, certain known triggers, like exposure to insecticides and pesticides, should be avoided to lower the risk of aplastic anemia.<a href="#accordion">[2]</a> 
 
&nbsp;

Severe aplastic anemia requires bone marrow transplantation for complete remission of the disease. There is a 25% probability of finding a Human Leukocyte Antigen (HLA) donor matched from a sibling and even though it is a successful treatment option, only a minority of patients are able to benefit from this treatment plan.&nbsp;

The next best option is to start treatment with immunosuppressive drugs, such as anti-thymocyte globulin (ATG) and Cyclosporin A (CsA). The hematopoietic response rate after ATG/CsA is 60&ndash;70% and the probability of survival at 5 years ranges from 60 to 85%. However, up to 40% of patients eventually relapse.&nbsp;

Recently, a clinical trial with another immunosuppressive agent, cyclophosphamide was observed to be successful. The response with cyclophosphamide and cyclosporine A was similar to treatment with CsA and ATG, however, the risk of development of serious hematological disorders seen with the latter wasn&#39;t seen with cyclophosphamide treatment when a follow-up of patients was done over a period of 10 years. Moreover, patients who are treated with cyclophosphamide do not go into disease relapse, which is another positive aspect of the newfound potent immunosuppressive agent in the treatment of aplastic anemia<a href="#accordion">[9]</a>.

<div>&nbsp;</div>

Key Points

<ul>
	<li>Aplastic anemia is a rare hematological disorder with failure of stem cells in the bone marrow.</li>
	<li>Aplastic anemia results in the disruption of blood cell production, i.e., the patient has low levels of red blood cells, white blood cells, and platelets.&nbsp;</li>
	<li>Aplastic anemia can be either due to a genetic defect or it can be acquired due to an immune trigger.</li>
	<li>Symptoms of aplastic anemia include fatigue, bleeding, and recurrent infections.&nbsp;</li>
	<li>Viral infections, exposure to toxins, radiation, and chemotherapy for cancer treatment can all lead to aplastic anemia.&nbsp;</li>
	<li>Aplastic anemia diagnosis is done through complete blood count and bone marrow biopsy.&nbsp;</li>
	<li>Aplastic anemia treatment options include bone marrow transplant, immunosuppressants, blood transfusion, antibiotics and antivirals, etc.&nbsp;</li>
</ul>

[1] Aplastic Anemia: Bone Marrow Transplant, Treatment, Causes. Cleveland Clinic.

[2] Aplastic anemia - Symptoms and causes. Mayo Clinic.

[3] Arrendell A. Aplastic anemia: Johns Hopkins Kimmel Cancer Center. Aplastic Anemia | Johns Hopkins Kimmel Cancer Center.

[4] Syndromes D, Health N. Definition & Facts for Aplastic Anemia & Myelodysplastic Syndromes | NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases.

[5] Gardner A. Aplastic Anemia: What You Need to Know. WebMD.

[6] Syed M, Rahman A, Ghani A et al. An Investigation of Selected Socio-Demographic Factors with Aplastic Anemia in Pakistan: A Case-Control Study. Int J Gen Med. 2021;Volume 14:8929-8934. doi:10.2147/ijgm.s335961