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Case study. 21 year man Presented with pancytopenia

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1 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.

2 Marrow trephine

3 Aplastic Anaemia Maj Gen Dr Muhammad Ayyub
MBBS, PhD (London), MRCPath (London), FRCPath (UK) Prof & HOD AM College

4 Outline Introduction Aetiology Pathogenesis
Clinical features & diagnosis Treatment Paroysmal Nocturnal Haemoglobinuria (PNH) Case Study

5 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.

6 History of Aplastic anaemia.
Paul Ehrlich ( ) 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.

7 Diagnosis of pancytopenia.
Suspect from signs and symptoms Made by check of full blood count, FBC Male Female Hb g/dl g/dl PCV 38-50% 36-45% MCV 80-100fl MCH 27-34pg WBC 4-11x109/l Neut Lymph 1.5-4 Platelet

8 Normal Erythropoiesis.
Red cell life span 120 days. Platelet life span 6 days. Granulocyte life span < 24 hours. Constant marrow activity needed to replace dead cells.

9 Haematopoietic stem cell.

10 Aetiology. ACQUIRED(80%) Idiopathic Drug induced
INHERITED(20%) Fanconi Anaemia Dyskeratosis congenita Shwachman-Diamond syndrome Diamond-Blackfan anaemia. ACQUIRED(80%) Idiopathic Drug induced Viral (hepatitis, EBV) Ionising radiation Toxins (pesticides, benzene, arsenic) Pregnancy leukaemic

11 Inherited marrow failure.
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.

12 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.

13 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)

14 Soil or seed?

15 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.

16 Clinical Features. Anaemia; tiredness & fatigue, palpitations, SOB.
Low white count; recurrent infections, flu-like illness. Low platelets; easy bruising and bleeding.

17 Investigations. FBC Reticulocyte count Blood film. B12/folate.
Liver function tests Virology Bone marrow aspirate & trephine PNH screen.

18 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.

19 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)

20 Haemoglobinuria.

21 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)

22 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.

23 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.

24 Severe Aplastic Anaemia
Peripheral Blood 2 of 3 Granulocytes <0.5 x 109/l Platelets <20 x 109/l Reticulocytes <1% Marrow trephine Markedly hypocellular <25% normal

25 Treatment of aplastic anaemia.
Supportive with blood products. Prophylactic antibiotics. Growth factor support. Androgens. Immunosuppressive therapy with antilymphocyte globulin & cyclosporin. Allogeneic stem cell transplantation.

26 Immunosuppressive therapy
Indicated for patients > 40 years Patients with no HLA matched sibling donors. Anti-Thymocyte Globulin(ATG) or anti-lymphocyte globulin (ALG), cyclosporin, methylprednisolone. Best results are for combination therapy. Response is slow, 4-12 weeks to see early improvement.

27 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.

28 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.

29 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.

30 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.

31 Figure 1. Cumulative survival probability of patients with aplastic anemia
Montane, E. et al. Haematologica 2008;93: Copyright ©2008 Ferrata Storti Foundation

32 Figure 2. A. Effect of the year of diagnosis of aplastic anemia on cumulative survival probability
Montane, E. et al. Haematologica 2008;93: Copyright ©2008 Ferrata Storti Foundation

33 Table 2. Factors associated with death at 2 years after diagnosis
Montane, E. et al. Haematologica 2008;93: Copyright ©2008 Ferrata Storti Foundation

34 New approaches to transplantation.
Fludarabine based regimens. Umbilical cord blood transplants.

35 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.

36 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

37 PNH pathophysiology Acquired stem cell mutation defect
Inability to synthesize the glycosyl-phosphatidylinositol (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.

38 PNH treatment 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.

39 Case study, further results
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.

40 Case study 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%.

41 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.

42 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.

43 Conclusions. Rare condition.
Needs accurate diagnosis to ensure proper treatment. Still devastating outcomes for young adults. New treatments may further improve survival.

44 Further Reading Postgraduate Haematology, by Hoffbrand & Lewis Fifth Edition Making Therapeutic decisions in adults with Aplastic Anaemia; Judith Marsh. ASH education program Book 2006.

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