Kembara Xtra - Medicine - Aplastic Anemia

Medicine - Aplastic Anemia 
​Pancytopenia caused by hypocellular bone marrow without infiltrates or fibrosis is classified as acquired (much more common) and congenital. Acquired aplastic anaemia has an insidious onset and is caused by an exogenous insult that sets off an autoimmune reaction. It is usually responsive to immunosuppression. Congenital forms are rare and are typically present in childhood, with the exception of an atypical presentation of Fanconi syndrome in adults in their 30 The line separating the congenital and acquired types of aplastic anaemia has become more hazy due to the prevalence of particular mutations in telomere complex genes in patients with acquired aplastic anaemia.
Heme/lymphatic/immunologic system(s) impacted Synonym(s): toxic paralytic anaemia, aleukia hemorrhagica, hypoplastic anaemia, panmyelophthisis, refractory anaemia

Hematopoietic growth factors must be closely monitored in newly diagnosed patients; early intervention for aplastic anaemia considerably increases the likelihood of successful treatment.

Aspects of Geriatrics
The elderly are frequently exposed to several medicines, making them potentially more prone to developing acquired aplastic anaemia.

Child Safety Considerations
Treatment plans for acquired aplastic anaemia, which affects children exposed to ionising radiation or receiving cytotoxic chemotherapeutic medicines, differ from those for congenital forms of the condition.

Pregnant women's issues
Aplastic anaemia can indeed, though rarely, be caused by pregnancy.
Low platelet counts and paroxysmal nocturnal hemoglobinuria-associated aplastic anaemia are two pregnancy complications that might develop. Symptoms may go away after delivery or after termination.

EPIDEMIOLOGY
​Predominant sex: male = female Predominant age: biphasic 15 to 25 years (more prevalent) and >60 years
The incidence is three times higher in Thailand and China than it is in Europe and North America, where there are 2 to 3 new cases per million people per year.

PATHOPHYSIOLOGY AND AETIOLOGY
Idiopathic (around 70% of cases) Drugs: antiepileptics (felbamate, carbamazepine, valproic acid, phenytoin), phenylbutazone, chloramphenicol, sulfonamides, gold HIV, Epstein-Barr virus (EBV), nontypeable postinfectious hepatitis (not A, B, or C), parvovirus B19 (most commonly in immunocompromised individuals), and atypical mycobacterium are examples of viruses.  Exposure to toxins (benzene, insecticides, arsenic); Exposure to radiation
Immune conditions (graft against host disease, eosinophilic fasciitis, systemic lupus erythematosus)  Pregnancy (infrequent)
Congenital immunological conditions include Fanconi anaemia, dyskeratosis congenita, Shwachman-Diamond syndrome, and amegakaryocytic thrombocytopenia. T cell activation and cytokine release cause harm to the death of hematopoietic stem cells. As a result, the bone marrow becomes hypocellular and marrow fibrosis is avoided.
T cell activation most likely results from a combination of genetic and environmental factors. Variations in its clinical manifestations and patterns of responsiveness to treatment are probably due to individual variances in the features of the immune response, exposure to different environmental precipitants, various hosts, genetic risk factors, and immune response characteristics.
Short telomeres result from telomerase deficiency. This results in decreased marrow progenitors and a qualitative deficit in the ability of hematopoietic tissue to repair itself. Reduction of natural killer cells in the bone marrow. A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal hemoglobinuria. There is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosy

Genetics: A limited number of patients with acquired and congenital variants have telomerase mutations. Carriers of these mutations are more vulnerable to environmental irritants.
 Adults with acquired aplastic anaemia who lacked the physical abnormalities or a family history typical of inherited forms of bone marrow failure had mutations in the TERC and TERT genes detected in their pedigrees. These genes produce the RNA necessary for telomerase.
HLA-DR2 is twice as common in those with aplastic anaemia as it is in the general population.

RISK FACTORS
include high-dose radiation or chemotherapy, harmful chemical exposure, using specific drugs, being pregnant, autoimmune disorders, major infections, and thymus tumours (red cell aplasia).

GENERAL PREVENTION
Use safety precautions when working with radiation. Avoid potentially harmful industrial substances.


DIAGNOSIS/HISTORY: Patients frequently exhibit no symptoms, but they may experience frequent infections, exhaustion, shortness of breath, headaches, or bleeding or bruises. They may also have a history of exposure to radiation, solvents, and infectious diseases.
Physical examination findings include: mucosal haemorrhage, petechiae; pallor; fever; haemorrhage, menorrhagia, occult stool blood, melena, and epistaxis; dyspnea; palpitations; progressive weakening; retinal flame haemorrhages; systolic ejection murmur; weight loss; and indications of congenital aplastic anaemia. - Oral leukoplakia - Nail dystrophy - Short height - Microcephaly - Nail dystrophy - Abnormal thumbs - Hyperpigmentation (café au lait patches) or Hypopigmentation


DIFFERENTIAL  DIAGNOSIS
includes additional causes of pancytopenia and bone marrow failure Acute lymphoblastic leukaemia, lymphoma, hairy cell leukaemia (increased reticulin and infiltration of hairy cells), large granular lymphocyte leukaemia, fibrosis, hypoplastic myelodysplastic syndrome (MDS), marrow replacement, folate deficiency, vitamin B12 deficiency, paroxysmal nocturnal hemoglobinuria, hemolytic anaemia (dark urine), pancytopenia, 
Prolonged fasting or anorexia nervosa (Bone marrow is fluid with loss of fat cells and increased ground substance) Systemic lupus erythematosus  
Childhood erythroblastopenia that is transient, medication-induced agranulocytosis that may improve with drug withdrawal, and an intense HIV infection with myelodysplasia and viral hemophagocytic syndrome.

DETECTION & INTERPRETATION OF DIAGNOSIS
Initial tests (lab, imaging) for anti-DNA and antinuclear antibody (ANA)
CBC: leukopenia, neutropenia, thrombocytopenia, pancytopenia, anaemia (typically normocytic), and 
Increased serum iron from transfusions; normal total iron-binding capacity; high mean corpuscular volume (MCV) >104; decreased CD34+ cells in blood and marrow; hematuria on urine analysis; viral serology including hepatitis A, B, C; EBV; cytomegalovirus (CMV); and HIV; vitamin B12 and folate levels; increased serum iron from transfusions; normal total iron-binding capacity; and high mean corpuscular volume
Increased foetal haemoglobin (Fanconi), abnormal liver function tests (hepatitis), more chromosomal breaks under specific circumstances (Fanconi), and more. 
Human leukocyte antigen (HLA) testing on patients and their close relatives, a CT scan of the thymus region if thymoma-associated RBC aplasia is suspected, and radiographs of the radius and thumbs (if congenital anaemia is suspected) are only a few of the procedures that can be used to identify faulty genes (Fanconi). 
Renal ultrasonography (to screen out malignant hematologic disorders or congenital anaemia) 
A chest x-ray to rule out infections like mycobacterial infections Diagnostic Techniques/Other Biopsy and aspiration of the bone marrow
Interpretation of Tests
Bone marrow: Normochromic RBC; decreased cellularity (10%); no fibrosis; no malignant or dysplastic cells seen; decreased megakaryocytes; decreased myeloid precursors; decreased erythroid precursors; prominent fat gaps and marrow stroma; and polyclonal plasma cells

​TREATMENT
Immunosuppressive therapy along with growth factor therapy and hematopoietic stem cell transplantation are the two main choices.
Age, illness severity, and the availability of an HLA-matched sibling donor for transplantation all factor into treatment considerations.

UNSPECIFED MEASURES
RBC and platelet transfusions are examples of supportive measures. Especially if the patient is a candidate for hematopoietic stem cell transplantation, only use blood that has been irradiated, leukocyte-reduced, or CMV-negative.
When necessary, antibiotics, antifungals, and antivirals, especially if the absolute neutrophil count (ANC) is below 100 cells per litre; Oxygen therapy for severe anaemia 
Maintaining good oral hygiene and controlling menorrhagia with oral contraceptives or norethisterone.

Transfusion assistance (judiciously recommended RBCs for severe anaemia; platelets for severe thrombocytopenia) – Transfuse when Hb 7 g/dL or if Hb 8 g/dL and symptomatic CHF – Platelet count is 10 109 or if 20 109 with fever/bleeding


First Line: MEDICATION
methylprednisolone) are frequently administered along with immunosuppressive regimens.
Cyclosporine combined with antithymocyte globulin (ATG) is an immunosuppressive treatment. ATG destroys lymphocytes, and cyclosporine inhibits T-cell activity.

ATG, a horse serum with polyclonal antibodies against human T cells, is the first-choice therapy for patients over 40 and for those under 40 who do not have a suitable donor. Think about patients between the ages of 30 and 40.
– Despite having a stronger response when combined with cyclosporine, it can be administered alone. 
Cyclosporine after initial ATG therapy for at least 6 months, with blood levels being tracked. Assay normal values can differ.
– If cyclosporine is stopped too soon after the first response to immunosuppressive medication, relapses may happen. Up to 25% of patients may respond after restarting their cyclosporine treatment.
Eltrombopag day 1 to 6 months in addition to immunosuppression with ATG and cyclosporine 
Granulocyte-colony stimulating factor (G-CSF): Shows faster neutrophil recovery but has no effect on survival when combined with cyclosporine and ATG.
- Two randomised trials question the expense and efficacy of the treatment.

Stem cell transplant: matched sibling allogeneic transplant for patients under 20 years of age with an ANC of 500 or between 20 and 40 years of age with an ANC of 200 Second Line
Cyclosporine and rabbit ATG
Anaemia is a common trait in a subset of patients who can benefit from the usage of androgens like danazol or campath.
Eltrombopag as monotherapy in relapsed refractory AA and matched unrelated donor stem cell transplant 
For refractory disease, cytoxan 50 mg/kg daily for four days may be utilised.

SURGICAL AND OTHER PROCEDURE
Patients with severe aplastic anaemia who have an HLA-identical donor and are under 20 years old or between 20 and 40 years old and have an ANC of less than 200 are advised to undergo first-line hematopoietic stem cell transplantation. Think about patients between the ages of 40 and 50 who are in good general health.
The incidence of graft versus host illness and graft rejection is higher in patients above the age of 40. People with potentially fatal mutations, such as those in ASXL1 or DNMT3A, typically respond poorly to IST, and we may be more inclined to recommend HCT in these cases.
When first-line immunosuppressive medication fails in patients under the age of 40 who do not have a sibling donor who matches their HLA, unrelated donor transplants should be considered.

CONSIDERATIONS FOR ADMISSION, THE INPATIENT, AND NURSING
Use chlorhexidine mouthwash if you have neutropenia, and stay away from raw or undercooked foods that can expose the patient to microorganisms.

ONGOING CARE PATIENT EDUCATION
​Avoid sick people and crowded places; wash your hands frequently; brush and floss your teeth; and receive regular dental care. 
Hematopoietic stem cell transplantation with a sibling who is HLA-matched:

PROGNOSIS: Age 16 years, 91% at 5 years; Age >16 years, 70–80% at 5 years
ATG with cyclosporine immunosuppressive therapy: overall survival of 75%; responders' 5-year survival of 90%.

COMPLICATIONS 
Graft versus host illness in recipients of bone marrow transplants (acute 18%; chronic 26%). Infection (fungal, sepsis). 
Heart failure, haemorrhage, transfusion-associated hemosiderosis, and transfusion-associated hepatitis
Secondary cancer development, such as leukaemia or myelodysplasia (15–19% risk at 6–10 years)