Pediatric Hematology/Oncology Interhospital Conference 19 December Faculty of Medicine Chiang Mai University
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1 Pediatric Hematology/Oncology Interhospital Conference 19 December 2017 Faculty of Medicine Chiang Mai University
2 Chief Complaint Petechiae and bruises on face and body 7 months prior to admission (PTA)
3 Identification Data A 1-year-old Thai boy from Wiang Pa Pao District, Chiang Rai
4 7 mo PTA (8 months old) Petechiae + bruise Dx. immune thrombocytopenia (ITP) Rx. 1 st intravenous immunoglobulin (IVIg) (not respond) About 4-7 mo PTA Off prednisolone, start dexamethasone 1 MKDay Plt 3,000-6,000/mm 3 1 mo after discontinuing dexamethasone Hb 10 g/dl, WBC 2,800/mm 3 (N 18%, L 70%) PLT 4,000/mm 3, MPV 8.4 fl BMA: blast <5%, megakaryocytes Rx. prednisolone 2 MKDay Plt 7,000/mm 3 Rx. 2 nd IVIg (not respond) Plt 6,000-9,000/mm 3 Wean off dexamethasone Refer to CMU Hospital
5 Past History Singleton, term, male newborn, normal delivery of the first pregnancy, BW 3,053 gm No history of mucosal nor life-threatening bleeding episodes No history of undergoing any surgeries nor procedures Not taking any medications or herbal products
6 Family History He is the only child of this family No family history of bleeding disorders or bleeding issues No history of consanguinity Father: thalassemia trait (unknown type)
7 Pedigree
8 Physical Examination Vital signs: BT 36.7 C, RR 20/min, HR 120/min, BP 68/50 mmhg, SpO 2 98% (room air) GA: a boy, crying during examination, no dysmorphic feature BW 10.6 kg (P50-75), height 72 cm (<P3), head circumference 47 cm (P50) HEENT: mild pallor, no jaundice, no wet purpura Lymph nodes: not palpable Heart: regular rhythm, no murmur, normal S1&S2
9 Physical Examination Lungs: normal chest contour, normal and equal breath sound, no adventitious sound Abdomen: soft, no tenderness, liver and spleen not palpable, no mass Extremities: no deformities Skin: ecchymosis above left eyebrow 2x1.5 cm in diameter and generalized petechiae on face, neck, trunk, perineum and both feet
10 11/5/2017 Hb (g/dl) 9.2 Hematocrit (%) 27.9 WBC (cell/mm 3 ) 2,960 Neutrophil (%) 12 Eosinophil (%) 0 Basophil (%) 0 Lymphocyte (%) 78 Atypical lymphocyte (%) 4 Monocyte (%) 5 Myelocyte (%) 1 Platelet (cell/mm 3 ) 0 MCV (fl) MCH (pg/rbc) 33.3 MCHC (g/dl) 33.0 RDW (%) 16.1 CBC
11 Problems List
12 Problems List A 1-year-old male infant with generalized petechiae Pancytopenia
13 Investigations
14 Peripheral Blood Smear White blood cell (WBC) Decreased number of WBC Lymphocyte predominate No toxic granulation No vacuolization Red blood cell (RBC) Few microcyte Anisopoikilocytosis 1+ Platelet 0-1/oil field No platelet clumping Normal staining and size
15 Reticulocyte Count 11/5/2017 Reticulocyte count (%) 9.46 Absolute reticulocyte count (x10 9 /L) CHr (pg) 35.4
16 Coagulogram Coagulogram 11/5/2017 PT (sec) INR 1.03 APTT (sec) 26.60
17 Urine Analysis Urine exam 11/5/2017 Color Dark yellow Appearance Cloudy ph 5.5 Specific gravity Albumin 2+ Sugar Negative Blood 4+ RBC/HPF Many WBC/HPF 0-1 Epithelial cell/hpf 0-1
18 Chemistry 11/5/2017 BUN (mg/dl) 10 Creatinine (mg/dl) 0.29 Na (mmol/l) 136 K (mmol/l) 4.5 Cl (mmol/l) 92 Total CO2 (mmol/l) 12 Ca (mg/dl) 10.9 P (mg/dl) 5.1 Mg (meq/l) 1.74 Uric acid (mg/dl) /5/2017 Total Protein (g/dl) 7.5 Albumin (g/dl) 4.2 Globulin (g/dl) 3.3 Alkaline phosphatase (U/L) 174 Cholesterol (mg/dl) 115 AST (U/L) 41 ALT (U/L) 21 Total bilirubin (mg/dl) 0.82 Direct bilirubin (mg/dl) 0.33 LDH (U/L) 438
19 10x
20 20x Bone marrow aspiration
21 40x
22 40x
23 Bone Marrow Aspiration Adequate specimen Hypocellularity grade 1+ Erythroid and myeloid series Normal number and maturation M:E ratio 3:1 Megakarocyte series Not seen Blast <5% No abnormal cell Cytogenetics: 46,XY Impression: Hypocellular marrow Incompatible with malignancy
24 Bone Marrow Biopsy
25 Bone Marrow Biopsy
26 Bone Marrow Biopsy AFB stain GMS stain
27 Bone Marrow Biopsy Markedly hypocellular bone marrow (20%) No granuloma No lymphoma Special stains reveal AFB (-) and GMS (-)
28 Approach to Bi/Pancytopenia Bi/Pancytopenia Decreased production Peripheral destruction Hypersplenism Splenomegaly Normal spleen Immune Non immune Malignancy Infection Storage disease Inherited bone marrow failure syndrome X Metabolic disease Acquired aplastic anemia X X Acute leukemia Evan syndrome ITP + blood loss TTP/HUS Hematologic Solid tumor Acute leukemia Lymphoma Neuroblas toma Ewing sarcoma/p NET
29 Progression
30 The 1 st Admission Platelet transfusion LD-PRC transfusion BMA, BMBx
31 11/5/ /5/ /5/ /5/ /5/2017 Hb (g/dl) Hematocrit (%) WBC/ANC (/mm 3 ) 2,960/355 3,010/458 3,230/581 5,820/1,513 3,880/1,008 Neutrophil (%) Eosinophil (%) Basophil (%) Lymphocyte (%) Atypical lymphocyte (%) Monocyte (%) Myelocyte (%) Platelet (cell/mm 3 ) 0 56,000 29,000 14, ,000 MCV (fl) (P97 at 1 year old = 85 fl) MCH (pg/rbc) MCHC (g/dl) RDW (%) MPV (fl) 7
32 The 1 st Admission The 2 nd Admission: 31 th May Generalized petechiae No active bleeding Platelet transfusion BMA, BMBx Platelet transfusion
33 17/5/ /5/2017 1/6/2017 Hb (g/dl) Hematocrit (%) WBC (/mm 3 ) 3,880 6,270 4,870 Neutrophil (%) Eosinophil (%) Basophil (%) Lymphocyte (%) Atypical lymphocyte (%) 3 0 Monocyte (%) Platelet (/mm 3 ) 102,000 2,000 84,000 MCV (fl) Plt conc. 2U 93.5 MCH (pg/rbc) 31.2 MCHC (g/dl) 33.3 RDW (%) CCI > 5,000 Not immune process
34 17/5/ /5/2017 1/6/2017 5/6/2017 6/6/2017 Hb (g/dl) Hematocrit (%) WBC (/mm 3 ) 3,880 6,270 4,870 6,530 5,100 Neutrophil (%) Eosinophil (%) Basophil (%) Lymphocyte (%) Atypical lymphocyte (%) Monocyte (%) Platelet (/mm 3 ) 102,000 2,000 84,000 22,000 77,000 MCV (fl) MCH (pg/rbc) MCHC (g/dl) RDW (%)
35 The 1 st Admission: 11 th May The 2 nd admission: 31 th May The 3 rd admission: 16 th June generalized petechiae Platelet transfusion BMA, BMBx Platelet transfusion Platelet transfusion Work up for inherited bone marrow failure syndromes
36 6/6/ /6/ /6/ /6/ /6/2017 Hb (g/dl) Hematocrit (%) WBC (cell/mm 3 ) 5,100 5,990 5,760 5,450 6,000 Neutrophil (%) Eosinophil (%) Basophil (%) Lymphocyte (%) Atypical lymphocyte (%) Monocyte (%) Platelet (cell/mm 3 ) 77,000 13, ,000 55,000 6,000 MCV (fl) MCH (pg/rbc) MCHC (g/dl) RDW (%)
37 Management 11/5/ /6/2017 Reticulocyte count (%) Absolute reticulocyte count (x10 9 /L) CHr (pg) 35.4 Platelet transfusion Work up DNA analysis for c-mpl gene
38 c-mpl Gene Analysis DNA analysis
39 Last Follow Up (28/11/2017) 26/6/ /11/2017 Hb (g/dl) Hematocrit (%) WBC (cell/mm 3 ) 6,000 6,650 Neutrophil (%) Eosinophil (%) Basophil (%) Lymphocyte (%) Monocyte (%) Platelet (cell/mm 3 ) 6,000 21,000 MCV (fl) MCH (pg/rbc) MCHC (g/dl) RDW (%) Hb typing (HPLC) 28/11/2017 Hb F (%) (normal < 1%) 4.7 Hb A (%) 84.3 Hb A2 (%) 2.6 Comment : AA Physical examination: Generalized petechiae Bruise on the left side of forehead No wet purpura Liver and spleen - not palpable Rx: Advice for hematopoietic stem cell transplantation
40 Congenital Amegakaryocytic Thrombocytopenia (CAMT)
41 CAMT A bone marrow failure syndrome presents with isolated thrombocytopenia in the neonatal period Autosomal recessive inheritance Petechiae and other bleeding symptoms Compound heterozygous/homozygous Mutation in the TPO receptor c-mpl gene Matthias B and Manuela G. Semin Thromb Hemost 2011.
42 c-mpl Gene Cellular myeloproliferative leukemia Proto-oncogene on chromosome 1 Consist of 12 exons Ihara K, et al. Proc Natl Acad Sci USA 1999.
43 c-mpl Gene Express on the hematopoietic stem cells, megakaryocytes and platelets 90% reduction of megakaryocytic precursor cells 60-80% decrease of both erythroid and myeloid progenitors Mutations impair c-mpl function Not only thrombocytopenia but also result in the development of trilineage bone marrow failure c-mpl bound by thrombopoietin (TPO) Megakaryocyte development Geddis AE. Int J Lab Hematol 2013.
44 Zhang B and Zehnder JL. Blood 2016.
45 Dasouki M, et al. Hematol Oncol Stem Cell Ther 2015.
46 Diagnosis of CAMT Bone marrow study Plasma TPO levels Analysis of the c-mpl gene
47 Bone Marrow Study If a bone marrow study is performed early Mild-to-moderate paucity of megakaryocytes Reduction or absence of megakaryocytes in an otherwise normocellular marrow If a bone marrow study is performed late Pancytopenia Severe depletion of megakaryocytes and hypocellularity in BMA Decreased progenitors in all lineages difficult to distinguish from aplastic anemia Stoddart MT, et al. Pediatr Blood Cancer 2013.
48 Plasma TPO Level TPO is produced by the liver and removed from the circulation by receptor-mediated uptake and destruction. When megakaryocyte and platelet production are low, plasma TPO levels rise. In CAMT, the megakaryocytes and platelets do not express functional c-mpl, plasma TPO levels are very high. In thrombocytopenia is due to platelet destruction such as TPO levels are normal or only modestly elevated. Stoddart MT, et al. Pediatr Blood Cancer 2013.
49 Types of CAMT Type I Complete loss of functional c-mpl Nonsense mutation: premature stop codon or frame shift Eliminate receptor signaling through ablation of all or most of the intracellular domain Median platelet count 21,000 /mm 3 Onset of bone marrow failure Early onset: < 2 years old Type II Some residual functional c-mpl Missense and splicing mutations Residual receptor function Transient increases of platelet counts up to nearly normal values Median platelet count 35, ,000/mm 3 Onset of bone marrow failure 3-6 years old The most common location for mutations is within exons 2 and 3, encoding the first cytokine receptor homology domain
50 c.235_236del [p.l79efs*] of MPL gene Report of compound heterozygous mutation Frameshift in exon 3 resulting in premature polypeptide termination and a lack of cell surface expression of the receptor The second mutation (c.393+5g>c) disrupts a conserved exon 3- intron 3 splice donor site causing diminished MPL expression Keel SB, et al. Haematologica 2016.
51 MDS type Keel SB, et al. Haematologica 2016.
52 Management Supportive management: transfusion of blood components Curative treatment: HSC transplantation (matched sibling donor) Future curative treatment: gene therapy Nathan and Oski s hematology and oncology of infancy and childhood 8 th ed, 2015.
53 Thank You for Your Attention
54 Thrombocytopenia
55 Pathophysiologic classification Increase platelet destruction - Normal or increased megakaryocytes in the marrow Decreased platelet production - Deficient thrombopoiesis - Decreased or absent megakaryocytes in the marrow Disorder of platelet distribution and pooling - Hypersplenism - Hypothermia Pseudothrombocytopenia
56
57 Suspect hereditary thrombocytopenia Familial history of thrombocytopenia Lack of platelet response to autoimmune thrombocytopenia therapies. Diagnostic features on smear abnormal size platelets, absence of platelet alpha granules, Dohle-like bodies or microcytosis Bleeding out of proportion to the platelet count. Onset at birth. Associated features absent radii, mental retardation, renal failure, high tone hearing loss, cataracts or the development of leukemia. Persistence of a stable level of thrombocytopenia for years. Congenital Amegakaryocytic Thrombocytopenia: A Brief Review of the Literature. Clinical Medicine Insights: Pathology 2010:3
58 Classification of inherited thrombocytopenia A. E. Geddis, Inherited thrombocytopenia. Int. Jnl. Lab. Hem. 2013, 35, 14 25
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