Pediatric Hematology/Oncology Overview Clinical & Laboratory Based Approach Assist.Prof. Chanchai Traivaree MD. Msc. (Cini Epi) Phramongkutklao College of Medicines

1 A three-year-old boy presents with pallor, irritability, and dark urine. The hemoglobin is 6 g/dL. The peripheral blood film is shown here. What is the most likely diagnosis? A.

Autoimmune hemolytic anemia

B. C.

Hemolytic uremic syndrome Thalassemia disease

D. E.

DIC G6PD deficiency

1 A three-year-old boy presents with pallor, irritability, and dark urine. The hemoglobin is 6 g/dL. The peripheral blood film is shown here. What is the most likely diagnosis? A.

Autoimmune hemolytic anemia

B. C.

Hemolytic uremic syndrome Thalassemia disease

D. E.

DIC G6PD deficiency

1 A three-year-old boy presents with pallor, irritability, and dark urine. The hemoglobin is 6 g/dL. The peripheral blood film is shown here. What is the most likely diagnosis? A.

Autoimmune hemolytic anemia

B. C.

Hemolytic uremic syndrome Thalassemia disease

D. E.

DIC G6PD deficiency

G6PD Deficiency  Most common red cell enzymopathy  X-linked inheritance

 Decreased production of NADPH with inability to maintain reduced glutathione levels  Hemolysis occurs in response to oxidative stresses such as infections, drugs, fava beans (“favism”), naphthalene (moth balls)

 Reticulocytes have 5X higher G6PD, so assay after resolution of hemolytic crisis

Guideline for PRBC Transfusion  Hgb <7 g/dL: transfusion indicated  Hgb <9 g/dL with hemolysis: transfusion indicated  Hgb ≥9 g/dL with hemolysis or between 7 and 9 g/dL without hemolysis: close observation at least 48 hrs

2 A ten-year-old girl previously healthy presents with a three-day history of fever, seizure, dark urine and alteration of consciousness. Hemoglobin is 6.2 g/dL. The peripheral blood smear is shown here. Which of the following tests would be most helpful in determining the correct diagnosis? A. B.

Serum LDH Mixing study

C. D.

Direct antiglobulin test G6PD screening test

E.

Serum creatinine

2 A ten-year-old girl previously healthy presents with a three-day history of fever, seizure, dark urine and alteration of consciousness. Hemoglobin is 6.2 g/dL. The peripheral blood smear is shown here. Which of the following tests would be most helpful in determining the correct diagnosis? A. B.

Serum LDH Mixing study

C. D.

Direct antiglobulin test G6PD screening test

E.

Serum creatinine

2 A ten-year-old girl previously healthy presents with a three-day history of fever, seizure, dark urine and alteration of consciousness. Hemoglobin is 6.2 g/dL. The peripheral blood smear is shown here. Which of the following tests would be most helpful in determining the correct diagnosis? A. B.

Serum LDH Mixing study

C. D.

Direct antiglobulin test G6PD screening test

E.

Serum creatinine

Pathophysiology of TTP

ADAMTS13 = a disintegrin and metalloprotease with eight thrombospondin-1-like domains

Management of TTP 

Aggressive plasma exchange using plasma as replacement therapy*



For relapsed idiopathic cases ( especially those with high levels of inhibitor autoantibodies against ADAMTS13 ) consider simultaneously starting immunosuppressive therapy

* no definitive evidence that cryopoor supernatant is superior to FFP

Hemolytic-Uremic Syndrome • Infants and young children

• Preceding colitis with bloody diarrhea • Usually due to E. coli verotoxin (serotype 0157:H7)

• Renal failure primary manifestation • CNS and other organ involvement in some cases • Normal levels of VWF-cleaving protease • Management – Dialysis and other supportive care – Plasmapheresis usually not required

Kasabach-Merritt Syndrome LOCALIZED INTRAVASULAR CONSUMPTION IN HEMANGIOMA(s)  Kaposiform hemangioendothelioma  Tufted angioma  Infantile hemangioma ( rare ) LESION(s)  Cutaneous lesions often dark red/purple  May be multiple / visceral

Hematologic Abnormalities  



Thrombocytopenia  Fibrinogen,  FDP’s / D-dimer Microangiopathic hemolytic anemia Hall G Brit J Haematol 2001 ; 112 : 851-862

CBC : Hb 9.4 g/dl, Hct 28.4 % WBC 11,700 cells/mm3 (N 29%, L 67%, M 1%, E 2%) Platelet 26,000/mm3 Coagulogram PT 18.3 sec (10-13) INR 1.66 APTT 37.5 sec (23-36) TT 17.2 sec (4-10)

Component RBC morphology

Vit.K def. Normal

Liver disease Target cell

DIC Fragmented cells, burr cells, schistocyte

PTT

Prolonged

Prolonged

Prolonged

PT

Prolonged

Prolonged

Prolonged

D-dimer

Normal

Normal

Markedly increased

Platelets

Normal

Normal

Reduced

Factors decreased

II, VII, IX, X

I, II, V, VII, IX, X

VIII

Breakdown of Fibrin(ogen)

Scoring system for overt Disseminated Intravascular Coagulation

3 A two-year-old boy previously healthy presents with a three-day history of increasing pallor and jaundice following viral illness. Hemoglobin is 6.2 g/dL. The peripheral blood smear is shown here. Which of the following laboratory studies would be most helpful in determining the correct diagnosis? A. Osmotic fragility test B. Hemoglobin typing

C. D. E.

Inclusion body Direct antiglobulin test Serum haptoglobin level

3 A two-year-old boy previously healthy presents with a three-day history of increasing pallor and jaundice following viral illness. Hemoglobin is 6.2 g/dL. The peripheral blood smear is shown here. Which of the following laboratory studies would be most helpful in determining the correct diagnosis? A. Osmotic fragility test B. Hemoglobin typing

C. D. E.

Inclusion body Direct antiglobulin test Serum haptoglobin level

3 A two-year-old boy previously healthy presents with a three-day history of increasing pallor and jaundice following viral illness. Hemoglobin is 6.2 g/dL. The peripheral blood smear is shown here. Which of the following laboratory studies would be most helpful in determining the correct diagnosis? A. Osmotic fragility test B. Hemoglobin typing

C. D. E.

Inclusion body Direct antiglobulin test Serum haptoglobin level

Autoimmune hemolytic anemia Warm type

PCH

Cold type

Antibody isotype

IgG

IgG

IgM

DAT

IgG

IgG, C3

C3

PBS

Spherocyte

Schistocyte

Autoagglutination

Hemolysis

Extravascular

Intravascular Intravascular

Common disease associations

Viral Autoimmune disease

Viral

Mycoplasma

Extravascular vs. Intravascular Hemolysis Location of RBC Clearance Antibody Type* Mechanism of Hemolysis Lab Findings

Example

Intravascular

Extravascular

Inside vessels

In spleen and or liver (RES) IgG

IgM Complement mediated Hgbinemia Hgbinuria Haptoglobin PCH

Macrophages digest RBCs  Bilirubin  LDH

Warmed type

4 A 1 year-old boy presents with pallor for several months. Physical examination reveals marked pallor, mild jaundice. The liver and spleen just palpable. Hemoglobin is 7 g/dL. The peripheral blood smear is shown here. Which of the following is the most likely diagnosis? A. Aplastic anemia B. Thalassemia disease C. G6PD deficiency

D. Iron deficiency anemia E. AIHA

4 A 1 year-old boy presents with pallor for several months. Physical examination reveals marked pallor, mild jaundice. The liver and spleen just palpable. Hemoglobin is 7 g/dL. The peripheral blood smear is shown here. Which of the following is the most likely diagnosis? A. Aplastic anemia B. Thalassemia disease C. G6PD deficiency

D. Iron deficiency anemia E. AIHA

4 A 1 year-old boy presents with pallor for several months. Physical examination reveals marked pallor, mild jaundice. The liver and spleen just palpable. Hemoglobin is 7 g/dL. The peripheral blood smear is shown here. Which of the following is the most likely diagnosis? A. Aplastic anemia B. Thalassemia disease C. G6PD deficiency

D. Iron deficiency anemia E. AIHA

HB TYPING

β-Thalassemia Hb E

5 •

A 9-year-old boy presents with high grade fever and hepatosplenomegaly. CBC showed Hb 7.1 g/dL, WBC 2,500/cu.mm, platelets 70,000/cu.mm The peripheral blood smear is shown here.

Which of the following is the most likely diagnosis?

A. B. C. D. E.

ALL ( L1) ALL (L2) ALL (L3) AML (M3) AML (M5)

5 •

A 9-year-old boy presents with high grade fever and hepatosplenomegaly. CBC showed Hb 7.1 g/dL, WBC 2,500/cu.mm, platelets 70,000/cu.mm The peripheral blood smear is shown here.

Which of the following is the most likely diagnosis?

A. B. C. D. E.

ALL ( L1) ALL (L2) ALL (L3) AML (M3) AML (M5)

5 •

A 9-year-old boy presents with high grade fever and hepatosplenomegaly. CBC showed Hb 7.1 g/dL, WBC 2,500/cu.mm, platelets 70,000/cu.mm The peripheral blood smear is shown here.

Which of the following is the most likely diagnosis?

A. B. C. D. E.

ALL ( L1) ALL (L2) ALL (L3) AML (M3) AML (M5)

Burkitt’s Leukemia/Lymphoma

• • • • • • • •

40% of NHL in children/adolescents Mature B-cell (TdT-), CD10(+/-), CD19(+), CD20(+), sIg (+) C-MYC (+) - t(8;14), t(2;8), t(8;22) Burkitt leukemia (B-ALL) (10% of cases) – treated same as lymphoma Abdominal disease most common presentation Head & neck second most common site Extranodal disease very common Very rapidly growing (doubling time 18-24 hr)

L1

L2

Obstruction

phlegmon

thickened cecal wall (curved arrow) in a patient with typhlitis

small-bowel intussusception

Children who had Clostridium difficile infection within 8 weeks before developing typhlitis were more likely to develop typhlitis compared with controls (odds ratio 7.99, 95% confidence interval 1.46-43.7, P=0.01) El-Matary, W. J Pediatr Hematol Oncol,2011

6 •

A 15-year-old girl presents with gum hypertrophy. CBC showed Hb 7.1 g/dL, WBC 55,000/cu.mm, platelets 60,000/cu.mm The peripheral blood smear is shown here. Which of the following is the most likely diagnosis?

A. B. C. D. E.

CML Lymphoma ALL (L3) AML (M7) AML (M5)

6 •

A 15-year-old girl presents with gum hypertrophy. CBC showed Hb 7.1 g/dL, WBC 55,000/cu.mm, platelets 60,000/cu.mm The peripheral blood smear is shown here. Which of the following is the most likely diagnosis?

A. B. C. D. E.

CML Lymphoma ALL (L3) AML (M7) AML (M5)

6 •

A 15-year-old girl presents with gum hypertrophy. CBC showed Hb 7.1 g/dL, WBC 55,000/cu.mm, platelets 60,000/cu.mm The peripheral blood smear is shown here. Which of the following is the most likely diagnosis?

A. B. C. D. E.

CML Lymphoma ALL (L3) AML (M 7) AML (M5)

AML(M5) in Children Feature

Infancy

Childhood

M5 WBC CNS Disease Leukemic cutis Chloromas Hepatosplenomegaly Relapse site

Common Higher Common Common Common Common Extramedullary

Lower Variable Low Rare Low Variable BM

Leukemia Cutis in an Infant

Arceci, R. and Weinstein, H., Neoplasia in the neonate and young infant. In: Neonatology: pathophysiology and management of the newborn. Avery, G.B., ed. J.B. Lippincott Company, 2005.

Myeloid Chloroma of Spine MRI of the Spine: An extradural soft tissue mass extending from T2 to T6 is present and which compresses the postero-lateral as of the cord resulting in increased cord signal compatible with myelopathy.

7 A 12-year-old boy presents with epistaxis and high grade fever. CBC: showed pancytopenia. Coagulogram was prolonged in PT,PTT and TT Which of the following is the most likely diagnosis? A. B.

Antiphospholipid syndrome DIC

C. D. E.

ALL (L3) APML CML

7 A 12-year-old boy presents with epistaxis and high grade fever. CBC: showed pancytopenia. Coagulogram was prolonged in PT,PTT and TT Which of the following is the most likely diagnosis? A. B.

Antiphospholipid syndrome DIC

C. D. E.

ALL (L3) APML CML

7 A 12-year-old boy presents with epistaxis and high grade fever. CBC: showed pancytopenia. Coagulogram was prolonged in PT,PTT and TT Which of the following is the most likely diagnosis? A. B.

Antiphospholipid syndrome DIC

C. D. E.

ALL (L3) APML CML

Acute Promyelocytic Leukemia Distinctive Features – Morphologic Variants APML

APML - Microgranular

Acute Promyelocytic Leukemia Distinctive Features

Poor Prognostic Factors - High WBC (>20,000/mm3)

- Microgranular Variant (increased in children and particularly in Italy and Latin America) - Persistence of Minimal Residual Disease

Acute Promyelocytic Leukemia Distinctive Features – Molecular Variants t(15;17) (q22;q21)

(PML/RAR-alpha)

Most common

ATRA Responsive t(11;17)(q23;q21)

(PLZF/RAR-alpha)

Rare ATRA Poor Response

Finer granules/CD56 t(11;17)(q13;q21)

(NuMa/RAR-alpha)

Rare

t(5;17)(q34;q21)

(NPM/RAR-alpha)

Rare

t(17;17)(q21;q21)

(Statb5/RAR-alpha)

Rare More microgranular ATRA Poor Response

Acute Promyelocytic Leukemia Treatment -Hyperleukocytosis - Leukopheresis contraindicated - Start treatment with chemotherapy plus ATRA and possibly hydroxyurea and consider dexamethasone - Do not use ATRA alone which may result in further differentiation and often an increase in WBC

8 A 14-year-old boy presents with fatigue and hepatosplenomegaly. CBC shows WBC of 400,000 cells/cu.mm, Hgb of 7 g/dL and platelet count of 700,000/cu.mm. Peripheral smear as shown here. Which of the following is the most likely diagnosis? A. B. C.

CML AML ALL

D. E.

JMML APML

8 A 14-year-old boy presents with fatigue and hepatosplenomegaly. CBC shows WBC of 400,000 cells/cu.mm, Hgb of 7 g/dL and platelet count of 700,000/cu.mm. Peripheral smear as shown here. Which of the following is the most likely diagnosis? A. B. C.

CML AML ALL

D. E.

JMML APML

8 A 14-year-old boy presents with fatigue and hepatosplenomegaly. CBC shows WBC of 400,000 cells/cu.mm, Hgb of 7 g/dL and platelet count of 700,000/cu.mm. Peripheral smear as shown here. Which of the following is the most likely diagnosis? A. B. C.

CML AML ALL

D. E.

JMML APML

Chronic Myelogenous Leukemia  Accounts for about 5% of all childhood leukemia  80% of pediatric cases occur after age 4 years but CML as been reported in the younger patients

Fu & Altman, Chapter 21, Pizzo and Poplack, Principles and Practice of Pediatric Oncology, 2006

Chronic Myelogenous Leukemia Chronic Phase - Clinical Presentation - As a result of hyperleukocytosis: weakness, fever, night sweats, bone pain, respiratory distress, visual disturbances, priapism, LUQ pain (splenomegaly)

-Lasts approximately three years

Chronic Myelogenous Leukemia Chronic Phase Laboratory – Peripheral Blood Counts - Marked leukocytosis with “shift to left” with increased basophils and eosinophils - Thrombocytosis common - Decreased hemoglobin

Chronic Myelogenous Leukemia Imatinib Dosing in Children - 260 to 340 mg/m2 provides drug exposures similar to the 400 or 600 mg adult dosage levels

Imatinib Resistance - Mutations in bcr-abl - Amplification of bcr-abl - Increased expression of alternative survival pathways - Noncompliance - Alternative bcl-abl inhibitors (e.g., Dasantinib)

Tyrosine kinase inhibitor

9 A 10-month-old boy presents with pallor for 2 weeks. Physical examination reveals mild pallor, no jaundice. The rest of examination are normal. Hemoglobin is 8 g/dL and reticulocytes is 1%. The peripheral blood smear is shown here. Which of the following is the most likely diagnosis? A. Aplastic anemia B. Thalassemia disease C. G6PD deficiency

D. Iron deficiency anemia E. AIHA

9 A 10-month-old boy presents with pallor for 2 weeks. Physical examination reveals mild pallor, no jaundice. The rest of examination are normal. Hemoglobin is 8 g/dL and reticulocytes is 1%. The peripheral blood smear is shown here. Which of the following is the most likely diagnosis? A. Aplastic anemia B. Thalassemia disease C. G6PD deficiency

D. Iron deficiency anemia E. AIHA

9 A 10-month-old boy presents with pallor for 2 weeks. Physical examination reveals mild pallor, no jaundice. The rest of examination are normal. Hemoglobin is 8 g/dL and reticulocytes is 1%. The peripheral blood smear is shown here. Which of the following is the most likely diagnosis? A. Aplastic anemia B. Thalassemia disease C. G6PD deficiency

D. Iron deficiency anemia E. AIHA

10 A 5-year-old boy presents with poor appetite. Physical examination reveals pallor, moderate icteric sclera and splenomegaly. Hb is 8.5 g/dL .His dad has the same symptoms and was cured with splenectomy. Which of the following is the most appropriate investigation for this Patient? A. Direct Coomb’s test B. Hemoglobin electrophoresis C. Osmotic fragility test D. Flow cytometry for CD59 E. G6PD quantitative assay

10 A 5-year-old boy presents with poor appetite. Physical examination reveals pallor, moderate icteric sclera and splenomegaly. Hb is 8.5 g/dL .His dad has the same symptoms and was cured with splenectomy. Which of the following is the most appropriate investigation for this Patient? A. Direct Coomb’s test B. Hemoglobin electrophoresis C. Osmotic fragility test D. Flow cytometry for CD59 E. G6PD quantitative assay

10 A 5-year-old boy presents with poor appetite. Physical examination reveals pallor, moderate icteric sclera and splenomegaly. Hb is 8.5 g/dL .His dad has the same symptoms and was cured with splenectomy. Which of the following is the most appropriate investigation for this Patient? A. Direct Coomb’s test B. Hemoglobin electrophoresis C. Osmotic fragility test D. Flow cytometry for CD59 E. G6PD quantitative assay

Laboratory Manifestations of HS • Spherocytes on peripheral blood smear • Reticulocytosis • Increased incubated osmotic fragility • Negative DAT • Increased MCHC > 36% due to relative cellular dehydration • Increased bilirubin, LDH

Incubated Osmotic Fragility Testing • Red cells are incubated in varying concentrations of saline (0 – 0.9%) for up to 48 hours • As concentration of saline decreases, cells take on water and are hemolyzed

Normal Osmotic Fragility

– Normal cells around 0.5% – HS cells at higher NaCl concentrations

• Degree of hemolysis is detected by spectrophotometry • Not reliable < 6-12 months of age

Increased Sensitivity to Lysis

11 An eleven-month-old boy with pallor and splenomegaly since 4 months of age has been referred with the diagnosis of hereditary spherocytosis. Family history is negative. Physical examination shows marked splenomegaly. Hemoglobin is 6.2 gm/dl. Which of the following tests will most facilitate arriving at the correct diagnosis? A. B. C. D. E.

Bone marrow aspirate Osmotic fragility test Complete blood counts on both parents G6PD assay Serum haptoglobin level

11 An eleven-month-old boy with pallor and splenomegaly since 4 months of age has been referred with the diagnosis of hereditary spherocytosis. Family history is negative. Physical examination shows marked splenomegaly. Hemoglobin is 6.2 gm/dl. Which of the following tests will most facilitate arriving at the correct diagnosis? A. B. C. D. E.

Bone marrow aspirate Osmotic fragility test Complete blood counts on both parents G6PD assay Serum haptoglobin level

11 An eleven-month-old boy with pallor and splenomegaly since 4 months of age has been referred with the diagnosis of hereditary spherocytosis. Family history is negative. Physical examination shows marked splenomegaly. Hemoglobin is 6.2 gm/dl. Which of the following tests will most facilitate arriving at the correct diagnosis? A. B. C. D. E.

Bone marrow aspirate Osmotic fragility test Complete blood counts on both parents G6PD assay Serum haptoglobin level

12 A 4-year-old boy presents with high grade fever, bilateral cervical lymphadenopathy, tonsillar patch and splenomegaly for 2 weeks. On day 6 of fever, he has petechiae at both arms, pallor and mild jaundice. CBC showed Hb 7.1 g/dL, WBC 1,500/cu.mm, platelets 80,000/cu.mm .The bone marrow aspiration is shown here. Which of the following is expected? A. B. C. D. E.

Hyperfibrinogenemia Hypertriglyceridemia Hyperuricemia Reticulocytosis Increased haptoglobin

12 A 4-year-old boy presents with high grade fever, bilateral cervical lymphadenopathy, tonsillar patch and splenomegaly for 2 weeks. On day 6 of fever, he has petechiae at both arms, pallor and mild jaundice. CBC showed Hb 7.1 g/dL, WBC 1,500/cu.mm, platelets 80,000/cu.mm .The bone marrow aspiration is shown here. Which of the following is expected? A. B. C. D. E.

Hyperfibrinogenemia Hypertriglyceridemia Hyperuricemia Reticulocytosis Increased haptoglobin

12 A 4-year-old boy presents with high grade fever, bilateral cervical lymphadenopathy, tonsillar patch and splenomegaly for 2 weeks. On day 6 of fever, he has petechiae at both arms, pallor and mild jaundice. CBC showed Hb 7.1 g/dL, WBC 1,500/cu.mm, platelets 80,000/cu.mm .The bone marrow aspiration is shown here. Which of the following is expected? A. B. C. D. E.

Hyperfibrinogenemia Hypertriglyceridemia Hyperuricemia Reticulocytosis Increased haptoglobin

Histiocytosis Syndromes  Langerhans cell  Macrophage proliferations Hemophagocytic lymphohistiocytosis Familial and “Secondary” to many etiologies

Macrophage activation syndrome Rosai-Dorfman Syndrome Juvenile Xanthogranuloma  Malignancies of macrophages or dendritic cells

Diagnostic Criteria for HLH • Familial disease/known genetic defect • 5 of the following : – Fever ≥ 7 days – Splenomegaly

– Cytopenia ≥ 2 cell lines – Hypertriglyceridemia and/or hypofibrinogenemia – Ferritin ≥ 4000 μg/L – sCD25 ≥ 2,400 U/mL – Decreased or absent NK activity – Hemophagocytosis (Absent 20% of time-treatment may be indicated if other criteria fulfilled)

13 A 2 year old patient presents with anemia, fever, bone pain for 2 weeks. CBC showed Hb 7.5 g/dL, WBC 6,500/cu.mm, platelets 75,000/cu.mm . A bone marrow aspirate is shown here. Which of the following statements is true? A. No further information is needed to make the diagnosis of neuroblastoma B. This child most likely has Wilms ‘tumor C. A bone scan is needed to confirm the diagnosis of highrisk neuroblastoma in this patient D. CT scan is sufficient to confirm the diagnosis of neuroblastoma E. Diagnosis of neuroblastoma can not be confirmed

13 A 2 year old patient presents with anemia, fever, bone pain for 2 weeks. CBC showed Hb 7.5 g/dL, WBC 6,500/cu.mm, platelets 75,000/cu.mm . A bone marrow aspirate is shown here. Which of the following statements is true? A. No further information is needed to make the diagnosis of neuroblastoma B. This child most likely has Wilms ‘tumor C. A bone scan is needed to confirm the diagnosis of highrisk neuroblastoma in this patient D. CT scan is sufficient to confirm the diagnosis of neuroblastoma E. Diagnosis of neuroblastoma can not be confirmed

13 A 2 year old patient presents with anemia, fever, bone pain for 2 weeks. CBC showed Hb 7.5 g/dL, WBC 6,500/cu.mm, platelets 75,000/cu.mm . A bone marrow aspirate is shown here. Which of the following statements is true? A. No further information is needed to make the diagnosis of neuroblastoma B. This child most likely has Wilms ‘tumor C. A bone scan is needed to confirm the diagnosis of highrisk neuroblastoma in this patient D. CT scan is sufficient to confirm the diagnosis of neuroblastoma E. Diagnosis of neuroblastoma can not be confirmed

Neuroblastoma ◈ Most common extracranial solid tumor in children

◈ 7% of childhood cancer ◈ High risk group: overall survival rate < 40%

Diagnosis of Neuroblastoma • Unequivocal pathologic examination of tumor tissue or • Unequivocal tumor cells in the bone marrow combined with the detection of elevated urinary catecholamine excretion

Neuroblastoma

Wilms’ tumor

Beckwith-Wiedemann syndrome • Hypoglycemia • Respiratory tract obstruction due to macroglossia • Polycythemia • Tumor 6.5% • Renal ultrasound –Wilms tumor • Alpha fetoprotein –hepatoblastoma

14 Which of the following diets might be expected to result in this peripheral blood film from a two-year-old girl? A.

Unpasteurized cow milk

B.

Unpasteurized goat milk

C.

Unpasteurized camel milk

D.

Fat free diet

E.

Atkins diet

14 Which of the following diets might be expected to result in this peripheral blood film from a two-year-old girl? A.

Unpasteurized cow milk

B.

Unpasteurized goat milk

C.

Unpasteurized camel milk

D.

Fat free diet

E.

Atkins diet

15 A six-year-old girl has a longstanding history of easy bruising. Initial coagulogram and CBC is normal except platelet is 75,000/cu.mm . Peripheral blood smear and platelet aggregation studies is shown here. Which of the following is the most likely diagnosis? A. B. C. D. E.

Chronic ITP MYH-9 Gray platelet syndrome Wiskott-Aldrich syndrome Bernard-Soulier syndrome

Clinical Evaluation Primary Hemostatic Disorder Prototypic disorders

thrombocytopenia

Secondary Hemostatic Disorder hemophilia

platelet function defect

von Willebrand disease Bleeding

immediate

delayed

Petechiae

yes

no

Hemarthrosis

no

yes

Intramuscular

uncommon

common

Epistaxis

common

uncommon

Menorrhagia

common

uncommon

hematoma

Wet purpura

Hematoma

Ecchymosis

Hemathrosis

ADP

Collagen

Epineprine

Thrombin ristocetin

15 A six-year-old girl has a longstanding history of easy bruising. Initial coagulogram and CBC is normal except platelet is 75,000/cu.mm . Peripheral blood smear and platelet aggregation studies is shown here. Which of the following is the most likely diagnosis? A. B. C. D. E.

Chronic ITP MYH-9 Gray platelet syndrome Wiskott-Aldrich syndrome Bernard-Soulier syndrome

15 A six-year-old girl has a longstanding history of easy bruising. Initial coagulogram and CBC is normal except platelet is 75,000/cu.mm . Peripheral blood smear and platelet aggregation studies is shown here. Which of the following is the most likely diagnosis? A. B. C. D. E.

Chronic ITP MYH-9 Gray platelet syndrome Wiskott-Aldrich syndrome Bernard-Soulier syndrome

Bernard-Soulier Syndrome • Autosomal recessive inheritance (consanguinity frequent) • Deficiency or abnormality of GPIb, GPIb, GPIX • Prolonged bleeding time • Normal platelet aggregation in response to ADP, epinephrine, and collagen • Abnormal or absent agglutination in response to ristocetin

Wiskott-Aldrich Syndrome / X-Linked Thrombocytopenia ( XLT ) - Sex linked inheritance - Classic features include 

thrombocytopenia with small platelets



eczema



immune deficiency ( T cell defects, early  in

IgM levels )

- Defect in WAS gene ( gene product WASP ) Ochs HD Clin Rev Allergy Immunol 2001 ; 20 : 61-86

MYH9-related disease

May-Hegglin anomaly

Sebastian syndrome N. Pujol-Moix et al., Haematologica 2004;89:330-337

MYH9-related disease • Autosomal dominant • Chromosome 22q11-13 • Nonmuscle heavy chain gene 9 (MYH9) • Nonmuscle myosin heavy chain IIA 4 light chains

2 heavy chains

Criteria diagnosis of MYH-9 related disease Macro-

hearing

thrombocytopenia

cataract

loss

renal

leukocyte

defect

inclusions

MHA

+

--

--

--

+

SBS

+

--

--

--

+

FTNS

+

+

+

+

+

EPTS

+

+

--

+

--

(Balduini C.L. et.al. haomatololiga 2002; 87(8): 860-880)

16 A 5 years old Thai boy with recurrent epitaxis since 3 years of age Hb 8 g/dL, MCV 50 fL, RDW 21%, WBC 6.0 x109/L, PMN 70%, L 25%, M 5%, Platelet 350 x 109/L Bleeding time > 20 min

A. B. C. D. E.

Hermansky Pudlak syndrome Glanzmann thrombasthenia Bernard Soulier syndrome Von Willebrand disease Storage pool disease

Platelet aggregation test

Collagen

Epinephrine

ADP

Ristocentin

A.A.

Glanzmann Thrombasthenia • Autosomal recessive inheritance ( high rate of consanguinity ) • Severe mucocutaneous bleeding starting in infancy • Deficiency or abnormality of GPIIb/IIIa ( platelet IIb3 integrin ) • Normal platelet count and morphology • Absent platelet aggregation in response to ADP, epinephrine, collagen • Normal ristocetin-induced platelet agglutination • Treatment: local measures, DDAVP, fibrinolytic inhibitors, platelet transfusion, FVIIa Poon MC J Thromb Haemost 2004 ; 2 : 1096-1103

(Shapiro A.D. Haemophilia 2000;6 (suppl.1): 120-7)

Acquired Platelet Dysfunction with Eosinophilia (APDE) • • • •

Acquired Normal Platelet count Eosinophilia Absent platelet aggregation in response to ADP, epinephrine, collagen • Normal ristocetin-induced platelet agglutination • Treatment: local measures, platelet transfusion • Resolve in 6-12 mo.

THE END