Introduction

Aplastic anaemia (AA) is a rare but serious blood disorder that occurs due to the failure of bone marrow (found in the centre of the bones and responsible for the production of blood cells) to produce blood cells. Patients suffering from AA are often symptomatic and present with symptoms such as anaemia, bleeding, and infection resulting from a lack of RBCs, platelets, and WBCs. AA can be acquired or idiopathic (disease of unknown cause). It is immune-mediated. Treatment for AA depends on the underlying cause but consists of immunosuppressive therapy. 

Definition 

Acquired aplastic anaemia (aAA) is characterised by underdeveloped, fatty bone marrow (BM) with profound reductions in hematopoietic stem/progenitor cells (HSCs/HPCs) that lead to defective mature blood cell production and peripheral pancytopenia. 

AA is classified as inherited or acquired. Inherited bone marrow disorders can present early in childhood but can also be diagnosed later in life. In case no inherited syndrome is diagnosed, AA is considered acquired.¹

Let’s understand the acquired aplastic anaemia

Blood consists of red blood cells, white blood cells, platelets, and plasma. It transports oxygen and nutrients to different areas of the body. Blood cells also help in fighting infection and prevent bleeding disorders. These blood cells are formed in the bone marrow.² 

Conditions in which bone marrow cannot produce blood cells and platelets lead to aplastic anaemia. The bone marrow is replaced by fat cells leading to a decreased number of stem cells and hence the inability to produce blood cells. It is important to understand and be aware of this condition because people suffering from AA are more prone to infections, bleeding disorders, and poor health in general. Some individuals suffering from AA exhibit mild symptoms and can be stable throughout their life while some can develop life-threatening conditions.³ 

Symptoms of acquired aplastic anaemia

The clinical manifestations of aAA depend on the extent of pancytopenia present.⁴ A low level of circulating red blood cells, white blood cells, and platelets is called anaemia, leukopenia, and thrombocytopenia respectively.

Anaemia 

Individuals presenting with anaemia may suffer from weakness, lightheadedness, pale skin, tiredness, irritability, dizziness, headaches, breathlessness, and cardiac symptoms.

Leukopenia

Reduced white blood cells or leukopenia can make an individual prone to infections or sudden febrile illness.

Thrombocytopenia

A decrease in the number of platelets makes people susceptible to bruising even after minor injuries, spontaneous gum bleeding, nose bleeding, and bleeding disorders. 

Causes of acquired aplastic anaemia

The incidence of aAA has historically been associated with chemical and drug exposure in the environment. A discovery by Alice Hamilton and Harrison Martland in the United States in the 1930s, that workers exposed to benzene presented with bone marrow failure further strengthened this association. The introduction of chloramphenicol was also associated with increased cases of AA.

However, as medical science progressed, various other causative factors were found to be responsible for causing this condition. Bone marrow transplantation proving to be effective in the treatment of AA pointed towards a stem cell deficiency. A positive response to immunosuppressive therapies indicated an autoimmune mechanism. 

Acquired causes of AA include:⁵

• Infectious diseases
• Medicines like antibiotics and anticonvulsants
• Exposure to toxins and heavy metals
• Radiation exposure
• Autoimmune disorders

Diagnosis of acquired aplastic anaemia

Diagnosis of AA is confirmed by taking a detailed patient history, thorough clinical evaluation, and tests including bone marrow biopsy. Diagnosis of aAA should be confirmed after fulfilling at least two of the following criteria:⁶ 

• Haemoglobin <10 g/dL
• Platelets 20-50 x 10⁹/L
• Neutrophils 0.5-1.5 x 10⁹/L
• A hypocellular BM
• Absence of abnormal infiltrates or fibrosis 

Based on cell count and bone marrow cellularity aAA is classified into non-severe, severe, and very severe

Following are the laboratory findings in aAA:

Decreased 

• Absolute neutrophil count 
• Haemoglobin 
• Platelet count 
• Reticulocyte count 
• Reticulocyte production index 
• White blood cell count
• CD 34 cells

Increased/normal

• Mean cell volume
• Serum erythropoietin
• Growth factors
• Blood smear 

• Decreased neutrophils monocytes, and platelets 
• Normocytic or macrocytic red blood cells 
• Toxic granulation of neutrophils may be present
• Liver function tests may be abnormal

Differential diagnosis

It is important to distinguish AA from similar conditions so that appropriate treatment methods can be applied. Certain conditions such as PNH, MDS, and acute leukaemia present similar clinical features but require varied treatment. Thus, accurate diagnosis is important for appropriate treatment and management. 

Treatment options for acquired aplastic anaemia

Treatment for aAA depends upon the patient's age, general health, and disease severity. The treatment objective is to address the bone marrow failure and treat the patient's immediate signs and symptoms. 

The treatment strategy for acquired AA involves two main approaches:⁷ 

• Replacing the deficient or damaged stem cells in the bone marrow through transplantation
• Suppressing the autoimmune reaction targeting the stem cells

The following are the treatment options for aAA:

Bone marrow transplantation (BMT):

• Recommended for patients under 40 with an HLA-matched sibling donor
• Standard conditioning: cyclophosphamide and anti-thymocyte globulin (ATG)
• Graft-versus-host disease (GVHD) prophylaxis: cyclosporine A (CSA) and methotrexate
• Avoid irradiation due to increased risks of GVHD, pneumonitis, second tumours, and infertility

Immunosuppressive therapy:

• Indicated for patients over 40 or without an HLA-matched sibling donor
• Standard regimen: ATG and CSA
• Relapse or non-response may require a second course of immunosuppressive therapy

Use of granulocyte colony-stimulating factor (G-CSF):

• Controversial due to potential increased risks of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)
• G-CSF is used only in prospective clinical trials

Response and relapse:

• A second course of immunosuppressive therapy is for non-response or relapse after the first course
• Response rates for non-response vary between 30-70%; for relapse, rates are around 60-65%

Unrelated donor BMT:

• Improved outcomes in recent years, especially with younger patients
• Two approaches: low-dose total body irradiation (TBI) with cyclophosphamide and ATG or non-irradiation, fludarabine-based regimen with ATG and low-dose cyclophosphamide

Referral and assessment:

• Early transplant is crucial for better outcomes
• Prompt referral to a specialist centre for assessment and treatment is necessary for newly diagnosed patients

Supportive care 

• It is provided for thrombocytopenia and anaemia via platelet transfusions when platelet counts drop below 10 x 10^9/L (or 20 x 10^9/L in febrile patients) and red blood cell transfusions to ease symptoms of anaemia
• Antibiotics and antifungal medications are used prophylactically in patients experiencing prolonged neutropenia

Prognosis and living with acquired aplastic anaemia

The likely outcome of aAA depends on the severity of the disease.⁸ The survival rate is poor if treatment consists of only transfusion and antibiotics. Progression to conditions like PNH, MDS, and leukaemia is not rare. The patients need close monitoring for episodes of bleeding.

The propensity of infections requires special care concerning diet, especially dairy products, raw meat, and fruits and vegetables because of the risk of bacterial colonisation. Patients should know of the importance of maintaining good hand and personal hygiene due to their high risk of infections.

FAQs

What is the best treatment for acquired aplastic anaemia?

Bone marrow transplant is the best treatment for young patients while transfusion and supportive therapy work well for older patients.

What is the difference between acquired and inherited aplastic anaemia?

Acquired means you aren't born with the condition but you develop it. "Inherited" means your parents passed the gene for the condition on to you. Acquired aplastic anaemia is more common, and sometimes it's only temporary. Inherited aplastic anaemia is rare.

Is acquired aplastic anaemia a form of cancer?

It is not cancer but it has the risk of progression to leukaemia which is a type of blood cancer.

What is the differential diagnosis of acquired aplastic anaemia?

The three conditions most commonly included in the differential diagnosis of aplastic anaemia are inherited marrow-failure syndromes, paroxysmal nocturnal hemoglobinuria, and myelodysplastic syndrome (MDS). 

Summary 

AA is an uncommon but serious disorder caused by the failure of bone marrow to produce sufficient blood cells leading to pancytopenia. Treatment options and prognosis have greatly improved for people with AA over the last few decades. There is more clarity about the disease pathology and progress leading to a better quality of life for people suffering from this condition. Anyone experiencing these symptoms should immediately consult their healthcare provider for an accurate diagnosis and treatment.