APLASTIC ANAEMIA Flashcards
(16 cards)
What is Aplastic anaemia?
What is it characterized?
- Aplastic anaemia is a rare bone marrow failure syndrome (BMFS)
- It is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin.
- The presence of pancytopenia in the peripheral blood with hypocellular marrow in which normal haemopoietic marrow is replaced by fat cells.
- It can also be defined as pancytopenia resulting from bone marrow aplasia.
- It could be inherited or acquired.
- The majority of cases are acquired
History of AA
The first known reported case of aplastic anaemia was in 1888 when Dr. Paul Erlich described a young pregnant woman with bleeding, fever and severe anaemia.
Her bone marrow at autopsy was found to be largely devoid of blood-forming elements.
The term aplastic anaemia was introduced by Vaquez and Aubertin in discussions of the Society of the Hospitals of Paris in 1904.
Epidemiology
Incidence of AA is 2 per million per year.
2 – 3 fold higher incidence rate in Asia. In a large prospective study from Thailand, an incidence
3.9 per million Bangkok; 5 per million in Thailand and an incidence of 7.4 per million in China.
The reasons for the differences in incidence are not known, but may include environmental and genetic factors.
There is a biphasic age distribution, with peaks at 10–25 years and over 60 years
It occurs with equal frequency in both genders
What is the AETIOLOGIC CLASSIFICATION OF AA?
ACQUIRED
- Autoimmune
- Drugs
- Toxins e.g. Toxins, Chlorinated Hydrocarbons, Organophosphates
- Viruses e.g. EBV, Hepatitis, HIV
- PNH
- Autoimmune/Connective Tissue disorders e.g. Eosinophilic Fascitis, RA, SLE, Immune Thyroid dxs.
- Thymoma
- Pregnancy
- Iatrogenic e.g. Radiation, Cytotoxic Drug Therapy
HEREDITARY
- Fanconi Anaemia
- Dyskeratosis Congenita
- Shwachman – Diamond Syndrome
- Others
Which DRUGS are IMPLICATED IN AA?
Drugs
Antibiotics: chloramphenicol, sulphonamides, co - trimoxazole, linezolid
Anti - infl ammatory agents: phenylbutazone, indomethacin,
diclofenac, naproxen, piroxicam, gold, penicillamine
Anticonvulsants: phenytoin, carbamazepine
Antithyroid agents: carbimazole, thiouracil
Antidepressants: dothiepin, phenothiazides
Antidiabetic agents: chlorpropamide, tolbutamide
Antimalarial agents: chloroquine
Others: mebendazole, thiazides, allopurinol, ticlopidine
Which Occupational and environmental exposures are risk factors for AA?
Benzene: evidence base includes large industrial studies, case – control study from Thailand
Pesticides (organochlorines such as lindane; organophosphates; pentachlorophenol): evidence base includes literature review of case reports and UK case – control study
Cutting oils and lubricating agents: evidence base includes UK case– control study
Recreational drugs (e.g. methylenedioxymethamphetamine, Ecstasy)
What is the PATHOPHYSIOLOGY OF APLASTIC ANAEMIA?
Remains unclear
The aetiology of aplastic anaemia may be multifactorial but with numerous possible overlapping pathophysiologic mechanisms leading to common final result,i.e failure of normal haemopoiesis
- Most types of congenital aplastic anaemia are linked to DNA repair defects or other types of chromosomal abnormalities
- For acquired aplastic anaemia the primary pathophysiologic mechanism is likely antigen driven, immune mediated T-cell destruction of progenitor cells.
Progenitor/stem cell numbers are substantially reduced in acquired aplastic anaemia patients, the consequence of cytotoxic T-cell production of apoptosis-inducing cytokines.
Such cytokines are IFN-Y, TNF-α .
TNF-α also upregulates Fas antigen expression on CD34+ cells which may explain the reduced survival of aplastic anaemia marrow progenitor cells.
Clinical response to antilymphocyte globulin[ALG] in about two-thirds of patients is the most persuasive evidence for the autoimmune pathogenesis of aplasia - There is evidence of both qualitative and quantitative stem cell defects in aplastic anaemia and increasing apoptosis of the remaining early haemopoietic progenitor cells.
- There is some association of HLA DR2 especially DR15 split with acquired aplastic anaemia.
- Increased telomere length shortening is also implicated in the pathophysiology of both acquired and inherited aplastic anaemia.
- Defects in macrophage function which further compromises haemopoiesis have also been described in patients with acquired aplastic anaemia.
- The accelerated terminal restriction fragment loss in aplastic anaemia provides the background for increased risk of transformation to MDS.
8.CD4+, CD25+, FOXP3+ regulatory T cells are impaired.
What are the CLINICAL FEATURES of AA?
- Anaemia which presents with easy fatiguability,weakness headache,shortness of breath,angina.
- Thrombocytopenia which presents with easy bruising, petechiae, bleeding gums, epistaxis and menorrhagia [in women].
- Neutropenia which presents with sore throat, recurrent fever, skin infection, etc
- In chronic cases of PNH dark red urine is reported.
- GI and genitourinary bleeding is rare.
- Young children may present with poor feeding, lack of interest in playing and excessive sleeping
Most patients, however, appear clinically well on initial presentation.
A careful history must be obtained regarding exposure to drugs,chemicals or any preceding infection.
Any family history of blood diseases, early onset cancers or congenital anomalies should be ascertained to assess for a potential inherited bone marrow failure syndrome.
The physical examination is generally unremarkable except for bruising and petechiae.
Hepatomegally and lymphadenopathy are usually absent.
The presence of short stature and congenital anomalies such as abnormal thumb or forearm, cafe’au lait spots and rashes suggest a possible underlying inherited bone marrow failure disorder such as fanconi anaemia.
Laboratory Investigations
To diagnose AA with certainty, it is important to consider other possible causes of pancytopenia with a hypocellular bone marrow and to exclude an inherited form of AA.
This will have important implications for treatment options, the choice of conditioning regimen and donor for HSCT, genetic screening and counselling of family members.
- FBC - Pancytopenia with reticulocytopenia. Single cytopenia especially thrombocytopenia may precede pancytopenia. Raised MCV common.
- Blood film examination - Toxic granulation of neutrophils, anisopoikilocytosis, macrocytosis. Exclude blasts, dysplastic neutrophils and hairy cells.
- Liver function tests, vitamin B12 and folate - To detect preceding hepatitis; exclude and correct vitamin B12 or folate deficiency.
- Virology - Post-hepatitic AA occurs in 5–10% cases, serology usually negative for known hepatitis viruses; HIV and parvovirus are very rare causes of AA; check CMV exposure for potential BMT candidates.
- Antinuclear antibody and dsDNA - SLE is very rare cause of AA, and other autoimmune syndromes associated with pancytopenia.
- Radiology - Chest X-ray to exclude infection; HRCT scan of chest to exclude pulmonary fibrosis if DC or RUNX1 familial BMF suspected. Abdominal ultrasound or CT scan: splenomegaly or lymphadenothy indicate alternative diagnosis; abnormal or misplaced kidneys may occur in Fanconi anaemia.
- BM examination - Aspirate fragments easily obtained, hypocellular fragments and trails. Reduced/absence of haemopoietic lineages. Dyserythropiesis common. Absence of dysplasia in granulocytic and megakaryocytic lineages. Lymphocytes, plasma cells, macrophages and mast cells often prominent.
- Iron stain to exclude ringed sideroblasts.
- CD34+ immunostain negative.
Trephine - Good length (at least 1–2 cm) essential. Hypocellular. May be patchy cellularity.
- Absence of blasts. Lymphoid aggregates (reactive) common.
- Reticulin stain negative.
- CD34 immunocytochemistry negative.
- CD61 useful to exclude dysplastic megakaryocytes
The diagnosis of AA usually requires the presence of pancytopenia with what?
neutrophil count <1.5 x 109/L,
platelet count< 50 x 109/L,
hemoglobin concentration <10 g/dL
absolute reticulocyte count <20 x 109/L,
A hypocellular marrow without abnormal or malignant cells or fibrosis.
What is the staging system of AA?
Discuss the severe and very severe AA
Called the Cammitta system
There are three stages :
Non severe Aplastic Anaemia,
Severe Aplastic Anaemia
Very severe Aplastic Anaemia
Severe Aplastic Anaemia :
Neutrophils is < 0.5 × 10⁹/L
Platelets count is < 20 × 10⁹/L
Reticulocytes is < 20 × 10⁹/L
hypocellularity of <30%
Very Severe Aplastic anaemia:
neutrophil < 0.2 × 10⁹/L
Platelets count is < 20 × 10⁹/L
Reticulocytes is < 20 × 10⁹/L
hypocellularity of <30%
What is the diagnostic algorithm
Discuss the treatment therapy for AA and SAA
What is the conditionining regimen for BMT?
What is One of the major problems of BMT and why?
What is a complication of BMT? And what treatment has been proven to reduce the risk of it?
When can unrelated BMT be justified?
The choices of therapy are:
i. Supportive replacement therapy plus
ii. Immunosuppression or
iii. Bone marrow transplant
The choice of treatment depends on :
Age of patient
Severity of the disease
Availability of HLA – identical sibling donor
i. Supportive Replacement therapy:
* Avoiding unnecessary transfusions
* Avoid transfusions from family members due to of possible sensitization against non-HLA tissue antigens of the donors (for potential bone marrow donors)
* The blood products should undergo leukoreduction (removal of wbc) and irradiation (to prevent graft-versus-host disease (GVHD))
ii. Bone marrow transplant (BMT) with an HLA-matched sibling donor is curative and is the treatment of choice for a young patient with SAA.
One of the major problems of BMT in aplastic anemia is the high rate of rejection (10%), and this is positively correlated with the number of transfusions and duration of diseasebefore undergoing transplantation.
The conditioning regimen most often used is
1. a combination of antithymocyte globulin (ATG), cyclosporine (CSA), and cyclophosphamide.
- Reduced intensity conditioning: Fludarabine- and cyclophosphamide-based reduced intensity conditioning (RIC) regimens +/– ATG.
GVHD is a complication of BMT.
It is positively correlated with increasing age of the patient.
Grafts depleted of T cells reduce the risk of GVHD but increase the risk of graft failure.
The addition of CSA along with methotrexate has substantially reduced the incidence of GVHD.
Unrelated-donor BMT is probably justified only if the donor is a full match
In unrelated-donor transplantation, radiation along with cyclophosphamide may be used to reduce graft rejection. Fludarabine-based conditioning regimens have been tried along with ATG and cyclophosphamide.
Unrelated-donor BMT using high resolution allelic matching has improved outcome especially in younger patients.
Immune suppression is especially useful if a matched sibling donor for BMT is not available or if the patient is older than 60 years.
Options include ATG, CSA, and methylprednisolone, with or without cytokine support.
ATG and CSA alone may also produce a response in aplastic anemia, but the combination improves the likelihood of a response.
At least 4-12 weeks is usually needed to observe improvement.
About 50% patients respond by 3 months after ATG administration, and about 75% respond by 6 months.
Relapses are common, and continued immune suppression is often needed.
Furthermore, the risk of some form of clonal disease such as Leukaemia is 15-30%
Discuss Stem Cell Stimulation Therapy?
Growth factors have had limited utility in aplastic anaemia
Anaemia does not respond to Erythropoietin, nor Neutropenia to GCSF (levels are already high in patients)
Supportive treatment
Management of infections in the Neutropaenic patients, administration of antifungals, antibacterials, and antiviral agents.
Platelet support if less than 10,000mm3.
Marked improvement in survival.
Granulocyte transfusion at times might be life saving
Management of Refractory Aplastic Anaemia Patient
Refractory AA – is defined as a lack of response to first-line immune-suppressive therapy with ATG and cyclosporine with persistence of severe cytopaenias at 6 months after IST.
Supportive care is paramount in view of the overwhelming life-threatening infections. Improvement in supportive care has improved survival.
A second course of Anti-thymocyte globulin plus cyclosporine can be offered. (response is only 30 – 35%).
