Hypoplastic Anaemia

Hypoplastic AnaemiaRoll No. 406 Win Yu SweRoll No. 407 Win Yupar LwinRoll No. 408 Win Shwe Sin OoRoll No. 409 Win Lei Khine Roll No. 410 Win Lai YinRoll No. 411 Win Lei Lei NaingRoll No. 412 Wyne Myat NoeSeminar on Paediatric Hematology & Oncology19th August, 2015

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DefinitionIt is a condition resulting from marked reduction in precursor cells.

Disturbances in these precursor cells lead to aplasia of single line of cells in the marrow, or all cell lines.

Low growth of blood-forming stem cells HypoplasticNo growth of blood-forming stem cells Aplastic

Discovery of Aplastic Anaemia

Dr. Paul Ehrlich, a famous German pathologist, first identified the condition in 1888after studying the case of a pregnant woman who died of bone marrow failure. In 1904, the disorder was termed aplastic anemia.Marrow failure, early in its history, was linked to environmental exposures, 1st among Swedish bicycle makers, followed many workers exposed to benzene.It has been associated with pharmaceutical drug use, most infamously with chloramphenicol.During World War II, of many more cases of aplastic anemia among American soldiers in the Far East than in other theaters of war, which was suggested to be due to malarial prophylactic drug exposure.

IncidenceOne of the very rare hematological diseases Age all age groups incidence in childhood due to inherited syndromesSex 1 : 1

Geographical distribution Asia >> US & EuropeEurope 2 cases /million populationThailand 6 cases /million population(China 7.4 cases /million)

International Aplastic Anemia and Agranulocytosis Study in Europe and Israel in the 1980s, Thailand in 20064

Classification of Aplastic anemia according to severity SEVERE aplastic anaemia (SAA)Neutrophil count < 500 /L (N=1500-8000)Platelet count < 20,000 /L (N=150,000-400,000)Retic count< 1 % or < 20,000 /L(Adult N=0.5-1.5 %, infants N=3-6 %)Hypocellular marrow(2 out of 3 criteria required for diagnosis)

VERY SEVERE aplastic anaemia (VSAA)Neutrophil count < 200 /L (N=1500-8000)

CausesIdiopathic (80 %)

Acquired/secondary ChloramphenicolDipyronesSulphonamidesQuinacrinePhenytoinCarbamazepine

3.ChemicalsDDTBenzeneAromatic hydrocarbonHeavy metals gold, arsenicalsExposure to ionizing radiation

4. InfectionsParvo virusHepatitis virusEB virus

5.Paroxysmal nocturnal haemoglobinuria (PNH) 25 % of cases are associated with aplastic anaemia

Congenital pancytopeniaFanconi anaemiaDiamond-Blackfan anaemia (congenital pure red cell aplasia)Shwachman-Diamond syndromeDyskeratosis congenitaAmegakaryocytic thrombocytopenia

EtiopathogenesisHematopoietic stem cells are damaged by various mechanismsAcquired stem cell injury from viruses, toxins or chemicalsAbnormal cellular control of hematopoiesisAbnormal marrow microenvironment Immunologic suppression of hematopoiesis, mediated by antibodies & cytotoxic T cellsMutations in genes, resulting in inherited bone marrow failure syndromes

Pathophysiology

Damaged stem cells can produce progeny expressing neoantigens that evoke an autoimmune reaction, or give rise to a clonal population with reduced proliferative capacity. Either pathway can lead to marrow aplasia.

Johns Hopkins medicine: Aplastic anemia

Clinical Presentation

Clinical Features1) Anaemia

Progressive and persistent anaemiaInsidious onsetAssociated with progressive weakness and fatigue

Clinical features2) Bleeding

Cutaneous bleedingPetechiae, purpura and ecchymoses are commonMucosal bleedingGut bleedingHaematuriaHaemorrhage into tissues and viscera less commonLife threatening bleeding episodes are not uncommonIntracranial bleeding HeadacheIrritability Excessive drowsiness Neurological deficit

Clinical features3)Infection

Common as a result of leucopenia and neutropeniaRecurrent respiratory tract infections and GI tract infections which may be fatal

Venn diagram of the clinical and pathophysiologic relationshipsamong the bone marrow failure syndromes, leukemia, and autoimmunediseases. Overlapping circles indicate difficulties in diagnostic discrimination andshared underlying mechanisms.

InvestigationsFull blood count (Blood for CP)

Anemia - normocytic /macrocytic normocyticLeukopenia- granulocytopeniaThrombocytopeniaReticulocytopenia (despite of anemia)PANCYTOPENIABlood film examination no abnormal cells

Investigations to confirm diagnosisBone marrow aspiration & trephine biopsy

Hypocellular cell trail (< 25 %)Replaced by fatty tissueContaining reticulum cells, lymphocytes, plasma cells, and usually tissue mast cellsMegaloblastic changes & other features indicative of dyserythropoiesis

Bone marrow in aplastic anemia

Other investigationsHam test - to exclude PNH (10-25 % association)Flow cytometry for CD 55 & CD 59 (most sensitive test for PNH)(deficiency of CD 55/59 markers is hallmark of PNH)

Hb F % - for Fanconi anaemia (diagnosis is by lymphocyte chromosomal breakage using DEB)

Viral studies- Hepatitis B, C and HIVClotting profile (BT-prolonged, CT-normal)Blood G&M

Diagnosis of Aplastic AnemiaPancytopeniaPersistent, unexplained marrow aplasiaHematopoiesis replaced by fat cellsNo specific markerDiagnosis by exclusion

Management

General Management1)Supportive careAvoid exposure to hazardous drugs and toxins

2)Care for bleeding IM injections should be given carefully, followed by ice pack application to injection sitesUnnecessary skin testing for antibiotics, ear lobe pricking (testing for bleeding time) should be avoided for children already with bleeding manifestationsTeeth should be brushed with a cloth or soft toothbrush

General managementCorrect anaemia maintain Hb 7-8 g/dlPlatelet for bleeding episodes (1 unit of platelet increases platelet count by 10,000 /10 kg)Antifibrinolytic agent can be used to reduce mucosal bleeding in thrombocytopenic patients with good hepatic and renal function (contraindicated if haematuria +)

General management3) Care for infection

Avoid infection by keeping patients out of the hospital as much as possible.If a patient is febrileCulture possible sourcesNeutropenia (+) broad spectrum antibiotics IV Ceftriaxone 50-80 mg/kg/dose BDIV Amikacin 7 mg/kg/dose BDIf remain febrile 4-7 days despite of broad antibacterial coverage, antifungal therapy should be startedAmphotericin B 250 g 1 mg/kg OD 1hr infusion x 4-7 daysKetoconazole 200 mg ODIf perianal infection (+) IV clindamycin or IV metronidazoleNo antibiotic prophylaxis is needed for afebrile, neutropenic patients

Available bone marrow stimulantsAnabolic steroids

Danazol 300 mg daily x 12 weeks 2 yearsOxymetholone 100 mg daily x 6 months - 1 year

Prednisolone should be used with caution because it can encourage bacterial and fungal infection, efficacy is controversialMethyl prednisolone 10-20 mg/kg/day x 10-15 days

Available bone marrow stimulantsTransfusion support

Platelet count is < 10 x109/L prophylactic platelet transfusions Active bleeding & symptomatic anemiapacked red cell transfusion 10 ml/kg over 4 hrs platelet rich plasma platelet concentratesFresh whole blood 15-20 ml/kg over 4 hrs

Specific managementImmunosuppressive therapyCombination of Anti-thymocyte globulin (ATG)Cyclosporine+/- Haemopoietic growth factors (GCSF) Conventional schedule of ATG: 15-40 mg/kg/day on each of 4 or 5 consecutive days x 4-5 cycles

Modify the T cell suppression & restore bone marrow stem cell functionPrimary treatment of choice is Bone marrow transplant

Specific managementMarrow transplant

Allogenic HLA-matched sibling donor (only 20-30 % of cases)60-80 % survival rate

HLA-matched unrelated donorMortality is twice, compared to matched sibling donor5 year survival rate 39 %Graft vs. host disease

Classification of remission statusSevere Aplastic Anaemia (SAA)Non-remission still severePartial remission transfusion independence, no longer meets the definition of severe aplastic anemiaComplete remission Hb normal for age & genderNeutrophil count > 1500 /LPlatelet count > 150,000 /L

Classification of remission statusNon-Severe Aplastic Anaemia (NSAA)Non-remission worse or not meeting the criteria belowPartial remissiontransfusion independence (if required before)doubling or normalization of 1 cell lineIncrease in 1 blood values by Hb - 3 g/dlNeutrophil - 500 /L Platelet - 20,000 /LComplete remission Hb normal for age & genderNeutrophil count > 1500 /LPlatelet count > 150,000 /L

PrognosisIf untreated, severe aplastic anemia has a high risk of death. If treated by drugs or stem cell transplant five-year survival rate about 70% (younger age higher survival)Survival rates for stem cell transplant vary depending on age and availability of a well-matched donor. Five-year survival rates for patients who receive transplants 82 % for patients underneath age 2072 % for those 2040 years old50 % for patients over age 40Success rates are better for patients who have donors that are HLA-matched siblings and worse for patients who receive their marrow from unrelated donors.

Updates on Aplastic anemia24th July, 2015 Eltrombopag (Revolade, Promacta in US) is recently approved once-daily use in patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy & are not eligible to receive a hematopoietic stem cell transplant.Eltrombopag is an oral thrombopoietin receptor agonist , works by helping to induce proliferation and differentiation of bone marrow stem cells to increase production of blood cells.

ReferencesPediatrics for undergraduates, 2nd edition, page 228-230Pediatric management guidelines, 2nd edition, page 179-182Nelsons textbook of pediatrics, 19th edition, chapter 463, 462, 442O. P. Ghai Textbook of Paediatrics, page 312, 313www.bloodjournal.org - Current concepts in pathophysiology & treatment of aplastic anemia, Neal S. Young, Rodrigo T. Calado, and Phillip Scheinberg, Blood Journal, October, 2006www.hematologica.org - Epidemiology of acquired aplastic anemia, Neal S. Young & David W. Kaufman, Haematologica, April, 2008www.aamds.org.us Aplastic anemia & MDS International Foundationwww.theaat.org.uk The Aplastic Anaemia Trustwww.wikipedia.org - Aplastic anemia, Dr. Paul Ehrlichwww.medscape.comwww.youtube.com Johns Hopkins Medicine channelwww.news-medical.net

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