Transcript Aplastic-Anaemia-31.10.11

Case study.
• 21 year man
• Presented with pancytopenia
• Hb 5.0 WBC 2.6,neutrophils 1.1, platelets
45, MCV 104.
• B12/folate/ferritin were normal.
• Main symptom tiredness
• Examination was unremarkable.
Marrow trephine
Aplastic Anaemia
Maj Gen Dr Muhammad Ayyub
MBBS, PhD (London), MRCPath
(London), FRCPath (UK)
Prof & HOD AM College
Outline
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Introduction
Aetiology
Pathogenesis
Clinical features & diagnosis
Treatment
Paroysmal Nocturnal Haemoglobinuria
(PNH)
• Case Study
Definition of aplastic anaemia.
• Peripheral blood pancytopenia and a
hypocellular marrow in which normal
marrow is replaced by fat cells.
• Abnormal cells are not found.
History of Aplastic anaemia.
• Paul Ehrlich (1854-1915) described the
first case of aplastic anaemia in a
pregnant woman who died of marrow
failure in1888.
• The term “aplastic anaemia” first used by
Anatole Chauffard in 1904.
Diagnosis of pancytopenia.
• Suspect from signs
and symptoms
• Made by check of full
blood count, FBC
Male
Female
Hb
13.517.5g/dl
11.5-16g/dl
PCV
38-50%
36-45%
MCV
80-100fl
80-100fl
MCH
27-34pg
27-34pg
WBC
4-11x109/l
4-11x109/l
Neut
2.0-7.5
2.0-7.5
Lymph
1.5-4
1.5-4
Platelet 135-450
135-450
Normal Erythropoiesis.
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Red cell life span 120 days.
Platelet life span 6 days.
Granulocyte life span < 24 hours.
Constant marrow activity needed to
replace dead cells.
Haematopoietic stem cell.
Aetiology.
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INHERITED(20%)
Fanconi Anaemia
Dyskeratosis congenita
Shwachman-Diamond
syndrome
o Diamond-Blackfan
anaemia.
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ACQUIRED(80%)
Idiopathic
Drug induced
Viral (hepatitis, EBV)
Ionising radiation
Toxins (pesticides,
benzene, arsenic)
o Pregnancy
o leukaemic
Inherited marrow failure.
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Important diagnosis to make.
Implications for treatment.
Detailed history and examination.
Nail dystrophy, skin pigmentation and
leukoplakia may suggest dyskeratosis.
• Short stature, metaphyseal dysarthrosis,
pancreatic exocrine deficiency or family history
of cytopenia in Shwachman-Diamond syndrome.
• Check for gene mutations can help.
Incidence of Acquired Aplastic
Anaemia.
• Rare condition; 2-5/million per year
• <1 in Ipswich catchment per year.
• Incidence is higher in East, environmental
as migrants have incidence of local
population.
• male to female incidence = equal
• Disease of young adults, 2nd peak in 4th 5th decade of life.
Pathogenesis.
• Primary defect or damage to
haematopoietic stem cell.
• possible Immunological attack on stem
cells.
• HLA-D2 is overrepresented in patients,
suggests a role for antigen recognition.
• Defective microenvironment (i.e. marrow
stromal defect)
Soil or seed?
Pathogenesis 2
• Evidence shows marrow stromal cells
have normal function.
• Normal growth factor production.
• Adequate marrow stromal function also
evidenced by success of stem cell
transplantation.
Clinical Features.
• Anaemia; tiredness & fatigue, palpitations,
SOB.
• Low white count; recurrent infections, flulike illness.
• Low platelets; easy bruising and bleeding.
Investigations.
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FBC
Reticulocyte count
Blood film.
B12/folate.
Liver function tests
Virology
Bone marrow aspirate & trephine
PNH screen.
Bone marrow aspirate in aplastic
anaemia
• Hypocellular
• Abnormal cytogenetics in 12% patients
• Trisomy 6, 8, or 15 most common, similar
outcome to no clone.
• Monosomy 7 may have poor outcome,
suggests possible hypoplastic MDS.
PNH screening.
• Paroxysmal nocturnal haemoglobinuria.
• Historically test was Ham’s test; showed
red cell lysis by complement activation in
acidified serum.
• Currently test for absent proteins on cell
surface. CD55(DAF) and CD59(MIRL)
Haemoglobinuria.
Clinical course 1
• Stable AA
• Pancytopenia remains stable over months
to years.
• Greater the degree of pancytopenia the
worse the prognosis. (see severe aplastic
anaemia)
Clinical course 2.
• Progressive or fluctuating aplasia.
• Initially small degrees of pancytopenia or
single lineage cytopenia.
• Progressive sometimes following viral
infections.
• Occasionally single cytopenia e.g.
thrombocytopenia becomes true aplastic
anaemia.
Clinical course 3.
• Unstable Aplasia.
• Improvement in counts may be associated
with abnormal clones.
• PNH clone in up to 20% of long term
aplastic anaemia.
• Often only detected by lab tests and not
clinically significant.
Severe Aplastic Anaemia
• Peripheral Blood 2 of 3
o Granulocytes <0.5 x 109/l
o Platelets <20 x 109/l
o Reticulocytes <1%
• Marrow trephine
• Markedly hypocellular <25% normal
Treatment of aplastic anaemia.
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Supportive with blood products.
Prophylactic antibiotics.
Growth factor support.
Androgens.
Immunosuppressive therapy with
antilymphocyte globulin & cyclosporin.
• Allogeneic stem cell transplantation.
Immunosuppressive therapy
• Indicated for patients > 40 years
• Patients with no HLA matched sibling
donors.
• Anti-Thymocyte Globulin(ATG) or antilymphocyte globulin (ALG), cyclosporin,
methylprednisolone.
• Best results are for combination therapy.
• Response is slow, 4-12 weeks to see early
improvement.
Immunosuppressive therapy 2
• Response rates 60-70%
• Relapses are common and continued
supportive care needed.
• Up to 50% of relapsed patients will
respond to 2nd course of
immunosuppressive therapy.
Treatment for adults with acquired severe aplastic anaemia.
Marsh, J. Hematology 2006;2006:78-85
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Treatment for adults with acquired non severe aplastic anaemia.
Marsh, J. Hematology 2006;2006:78-85
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
HLA identical sibling BMT
• Age <40 years.
• Conditioning with Cyclophosphamide &
antithymocyte globulin, with cyclosporin
and methotrexate.
• Long term overall survival = 80-90%
• Chronic graft versus host disease (GVHD)
remains a problem for 25-40% of patients.
Figure 1. Cumulative survival probability of patients with aplastic anemia
Montane, E. et al. Haematologica 2008;93:518-523
Copyright ©2008 Ferrata Storti Foundation
Figure 2. A. Effect of the year of diagnosis of aplastic anemia on cumulative survival probability
Montane, E. et al. Haematologica 2008;93:518-523
Copyright ©2008 Ferrata Storti Foundation
Table 2. Factors associated with death at 2 years after diagnosis
Montane, E. et al. Haematologica 2008;93:518-523
Copyright ©2008 Ferrata Storti Foundation
New approaches to transplantation.
• Fludarabine based regimens.
• Umbilical cord blood transplants.
PNH
• An acquired haematopoietic stem cell
defect with predominant haemolytic
anaemia.
• A descriptive term for the clinical
manifestation of haemolysis and
haemoglobinuria manifest by dark
coloured urine in the morning.
PNH presentation
• Acquired haemolytic anaemia
• Thrombosis in large vessels e.g. hepatic
abdominal, cerebral.
• Pancytopenia or aplastic anaemia.
• This triad makes PNH a unique syndrome
PNH pathophysiology
• Acquired stem cell mutation defect
• Inability to synthesize the glycosylphosphatidylinositol (GPI) anchor that binds
certain proteins to cell membranes.
• Gene (PIG A) located on X-chromosome.
• Complement regulating proteins DAF, MIRL are
lacking on all haemopoietic cells
• Consequent intravascular red cell destruction.
• Pathophysiology of thrombosis is not fully
understood.
PNH treatment
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Treat symptoms
Folic acid for increased erythropoeisis
May need iron if deficient
Transfusions
Anticoagulation
Eculizumab (antibody against complement C5)
Complement inhibition = risk of infection esp
meningococcal. Vaccination required.
Case study, further results
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Marrow aspirate cellular
Trephine biopsy hypocellular
PNH clone of 8-10% detected.
Referred to London for 2nd opinion and
treatment plan.
• Sibling not an HLA match.
• Given not requiring blood or platelet
transfusion then no specific treatment was
indicated.
Case study
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Stable for 18 months
Presented with headache & neck stiffness.
Clinical impression of meningitis made.
Initial CT scan no abnormality
CSF, no organisms
MRI scan confirmed thrombosis.
Started on anticoagulation.
PNH clone had increased to 82%.
Case study
• 4 weeks later admitted with further febrile
episode.
• On antibiotics and anticoagulation.
• Developed left sided weakness and
sensory loss.
• CT brain scan showed massive
intracranial bleed.
• Transferred to neurosurgical centre at
Addenbrooke’s hospital.
New therapy for PNH
• Eculizumab anti complement therapy.
• Used in haemolytic disease with > 50%
PNH clone.
• High cost £250k per year
• National commissioning Group (NCG)
funded 2 centres nationally, Leeds and
London.
• Equal access to treatment irrespective of
address.
Conclusions.
• Rare condition.
• Needs accurate diagnosis to ensure
proper treatment.
• Still devastating outcomes for young
adults.
• New treatments may further improve
survival.
Further Reading
• Postgraduate Haematology, by Hoffbrand
& Lewis Fifth Edition
• Making Therapeutic decisions in adults
with Aplastic Anaemia; Judith Marsh. ASH
education program Book 2006.