Introduction to Pediatric Hematology
F
Domiline C. Arca, MD, DPPS,
DPSHBT, DPSPH
Head, Section of Hematology
Department of Pediatrics
University of Perpetual Help DALTA Medical Center
Goals:
Learn approach to anemia and RBC disorders
Be able to fully evaluate a complete blood count
Understand the etiology of common hematologic conditions
Know when to refer
Definition: Hematology is the study of the normal and pathologic aspects of blood and blood elements
Hematopoietic Stem Cells (HSC)
 Progenitor cells in the blood
 Derived from hemangioblast in the aorta-mesonephros-gonad (AGM) region
o Give rise to the blood system that seeds the liver and then the bone marrow
The Myeloid System
 From medullary cavity
 Consists of
o RBCs (erythrocytes)
o WBCs (neutrophils, monocyte, eosinophils, basophils)
o Platelets (thrombocytes)
Anemia
 Extremely common
 Worldwide, 1/3 of the population is anemic
 Definition of anemia: Hemoglobin (Hb) concentration more than two standard deviations below the
normal for age and gender
Anemia: Important clues:
 Patient’s history
 Physical examination
 Laboratory study
 Peripheral blood smear
Symptoms:
 Hypotension, Orthostasis, Syncope, Shock → Hypovolemia 2° to acute hemorrhage
 Fatigue, Dyspnea, Light-headedness, Cognitive abnormalities, Ischemic pain→ Tissue hypoxia 2° to
↓ O2-carrying capacity of blood
 Tachycardia, Palpitations , Congestive heart failure→ Cardiovascular manifestations
Note: Chronic anemia of gradual onset is generally well tolerated until the Hb declines to very low levels
(≤8g/dl)
Adaptive physiologic responses to anemia
 ↑ cardiac output due to ↑ heart rate (mild to moderate anemia)
 ↑ ventricular stroke volume (Severe anemia)







Reflex vasoconstriction → Triggered by acute blood loss and hypovolemia
Decrease vascular resistance →In chronic anemia
Cerebral blood flow is preserved
Decreased renal blood flow
Expansion of intravascular volume (Kidneys retain salt & water)
Unloading of O2 in tissues (↑levels of 2,3DPG)
↑ erythropoietin (Leads to ↑ RBC production)
Laboratory Diagnostics
CBC, platelet count
Red cell indices – MCV, MCH, MCHC
Peripheral Blood Smear reading:
 RBC morphology: Hypochromia, microcytosis, anisocytosis, poikilocytosis, target cells,
polychromasia, inclusion bpdies
 WBC – estimated count, differential count including abnormal cells, toxic granulations, septic
picture, ANC
 Platelets – estimated count: singly, in clumps, giant forms
Laboratory Diagnosis of Iron Deficiency Anemia
*increased RDW
 Decreased Hb, Hct, RBC count, retic count
 RBC morphology: hypochromia, microcytosis
 Decreased MCHC
 Decreased Serum Iron
 Increased TIBC
 Decreased serum ferritin
Diagnostic Work-Up of Hemolytic Anemia
 Peripheral smear
 Reticulocyte stain
 Blood typing
 Coombs’ test
 Osmotic Fragility Test - (autohemolysis test)
 Hemoglobin electrophoresis - (Kleihauer method for fetal Hb)
 G6PD assay
Bleeding Profile:
 CBC, platelet count
 Peripheral smear
 Bleeding time
 Prothrombin Time
 Partial Thromboplastin Time




Thrombin Time
Fibrinogen
Fibrin Degradation Products
Fibrin Monomers
Bone marrow aspiration/biopsy
When to do it – when 2 cell lines are down
Helpful in: Very severe aplastic anemia, Acute leukemia, Lymphoma and solid tumors
Bone marrow aspiration/biopsy:
 Very severe aplastic anemia - Pancytopenia , Bone marrow biopsy: empty marrow spaces, many fat
spaces
 Acute leukemia: Bone marrow aspiration: (+) blasts
 Lymphoma and solid tumors: Bone marrow aspiration/biopsy: (+) metastatic cells in the marrow
Etiologic Classification of Anemia
 Impaired Red Cell Formation: Deficiency, Bone marrow failure
 Blood Loss
 Hemolytic Anemia
Nutritional Anemia:
Iron Deficiency Anemia
 Still the most common cause of anemia in infants, children, and adolescents in our country
 Associated with cognitive and psychomotor abnormalities in children
 Most common cause: Inadequate dietary intake
Iron Deficiency Anemia: Recommendations
Source: 7th Edition of Preventive Pediatric Health Care Handbook 2014
 DOH →- Recommends oral iron supplementation for infants, children, adolescents
 PPS and PSHBT; 6th Nat’l Nutrition Survey, Philippines 2003→ Recommends CBC monitoring at least
once between 6-24 months, at least once bet 2-6 years, at least once bet 10-19 years for those at risk
- Philippine Society of Adolescent Medicine Specialists - Recommend CBC at each stage of adolescence
Iron Deficiency Anemia
Diagnosis:
Poor nutritional history
Signs/symptoms of anemia
Laboratory tests
Positive response to oral iron supports the diagnosis
Treatment of IDA
 Oral iron therapy
o Elemental iron (ferrous sulfate, ferrous gluconate, ferrous fumarate)
o Dose: 4.5-6.0 mg/kg/day in divided doses between meals in infants;
100-200 mg/day in older children
 Dietotherapy
- Iron-fortified formulas, cereals; iron-rich foods
Causes of Failure of Iron Therapy
1. Noncompliance
2. Timing of administration
* empty stomach
*Enhancers – low gastric pH, ascorbic acid, iron deficiency state
3. Deterrents – phytates, antacids, gluten diet
4. Iron given in a form poorly absorbed
5. Continuing unrecognized blood loss
6. Insufficient duration of therapy – at least 2 weeks
7. Inhibitors of iron absorption/utilization - lead, aluminum intoxication, chronic inflammation, neoplasms
8. Incorrect diagnosis - therapeutic failure of iron medication
Note: * If causes 1 – 7 are ruled out, and the patient was given oral iron for about a month already and still
NO response, consider another diagnosis like thalassemia.
Refer to the Hematologist.
Other nutritional anemia
 Megaloblastic anemia
 Cobalamin (B12) Deficiency
 Folic Acid deficiency
Differential Diagnoses of Microcytic Anemias
 Iron deficiency
 Thalassemias
 Hemoglobinopathies
 Vitamin B6 deficiency
 Lead poisoning
 Sideroblastic anemias
Hemolytic Anemia
Hemoglobin defects
Membrane defects
Enzymatic defect
Immune
Clinical Triad of Hemolytic Anemia
Pallor or anemia
Jaundice
Splenomegaly (may be absent in the newborn)
Diagnostic Work-up of Hemolytic Anemia
Clinical Triad of HA

Presence of Hemolysis

Blood typing

Coombs’ Test (Direct & Indirect)
___________________________________


Positive
Negative
AIHA
Osmotic Fragility Test
_____________________________


Positive
Negative
Hereditary Spherocytosis

Hemoglobin Electrophoresis
_______________________________


Positive
Negative
Thalassemias

Hemoglobinopathies
G6PD assay
________________
Positive
Negative
G6PD deficiency
Other causes
(Infection)
Long term care of children/adolescents with hemolytic anemias:
1. Monitor the growth curves, Hb, absolute reticulocyte counts, and size of the spleen.
- Ultrasound of hepatobiliary tree for stones (bilirubin)
2. Transfuse PRBC only for symptomatic anemia to avoid iron overloading and toxicity.
3. Monitor patients for possible crises:
hemolytic, aplastic, megaloblastic.
4. Give folic acid. DO NOT give oral iron.
5. When to do a splenectomy
Hemolytic Anemia: Hemoglobin defects
Thalassemia – a quantitative defect; reduced synthesis of globin chains, alpha or beta
Hemoglobinopathy – a qualitative defect; substitution in amino acid sequence in globin chains
May see combinations Ex. HbE-Beta thalassemia, which behaves like a thal major
Thalassemias
 2nd most common microcytic anemia
 A cause of hemolytic anemia
 A hemoglobin defect
– decreased synthesis of either alpha or beta
globin chains in the Hemoglobin molecule
2 types: Alpha thalassemia & Beta thalassemia
Diagnostic test: Hemoglobin electrophoresis
Pathophysiology:
 Reduced or absent synthesis of globin chains in the Hb molecule, alpha or beta (quantitative defect).
 Caused by mutations in the genes for the alpha and beta globin chains, resulting in severe ineffective
erythropoiesis and extraordinary marrow expansion.
Classification:
Alpha Thalassemia Syndromes
Silent carrier
Thalassemia trait
Hemoglobin H disease (4)
Hydrops fetalis
Beta Thalassemia Syndromes
Silent carrier
Thalassemia trait
Thalassemia intermedia
Thalassemia major
Thalassemia Major
 “Cooley’s anemia” in 1925
 Mode of inheritance:
Usually autosomal recessive
 Usually diagnosed between 6 months and 2 years of age
 Pallor, jaundice, splenomegaly (clinical triad); also with hepatomegaly
 Craniofacial changes (classic thalassemic facies)
 Stunting of growth
 Diagnostic procedure:
Hemoglobin electrophoresis
Hb A1 (2 2) NV 96-98%
Hb F (22) NV 1-2%
Hb A2 (22) NV 2-3%
 Other laboratory tests: RBC morphology, tests for fetal Hb, skull x-ray (“hair-on-end” appearance),
serum iron, serum ferritin
Anticipatory Care:
 Hypertransfusion, supertransfusion to suppress erythropoiesis
 Folic acid supplementation
 Genetic counseling
Hypertransfusion vs Supertransfusion
Hypertransfusion
 hemoglobin level at >10 g/dL, mean of 12 g/dL
 if initiated in the first year of life:
 promotes normal initial growth and development
 limits the development of hepatosplenomegaly
 prevents disfiguring bone abnormalities
 reduces intestinal iron absorption
 decreases cardiac workload
Supertransfusion
 pretransfusion hgb level >12 g/dL, mean of 14 g/dL
 more effectively eliminate chronic tissue hypoxia
 increase the quantity of transfused blood, increase iron loading
 no longer recommended
Hypertransfusion, supertransfusion:
 Transfusion management and the optimal maintenance level of hemoglobin have evolved. Wolman
and associates first recommended a pretransfusion hemoglobin level of 8.5 g/dL. This approach
improved survival, but chronic illness, bone disease, and anemic cardiomyopathy persisted.
 To enhance quality of life, Piomelli and colleagues suggested maintaining the hemoglobin level at
greater than 10 g/dL with a mean of 12 g/dL. Such “hypertransfusion,” if initiated in the first year of
life, promotes normal initial growth and development, limits the development of
hepatosplenomegaly, prevents disfiguring bone abnormalities, reduces intestinal iron absorption,
and decreases cardiac workload.
 In 1980, Propper and colleagues proposed a “supertransfusion” program with a pretransfusion
hemoglobin level greater than 12 g/dL and a mean of 14 g/dL to more effectively eliminate chronic
tissue hypoxia. Initial studies reported that the quantity of blood required to maintain a higher
hemoglobin level was no greater than that required for maintenance of a lower level because of a
decrease in intravascular volume. Further data, however, suggested that increasing the
pretransfusion hemoglobin level may simply increase the quantity of transfused blood and thus
increase iron loading, and this regimen is no longer recommended
Treatment:
 PRBC transfusion for symptomatic anemia
 Iron chelation
 (desferrioxamine,deferasirox, deferiprone), Vitamin C
 Splenectomy – hypersplenism,
 transfusion requirement(>250 ml/kg per year)
 Allogeneic bone marrow transplantation
 Gene therapy
Other Causes of Hemolytic Anemia:
G6PD deficiency
Other Causes of Hemolytic Anemia
Hereditary Spherocytosis
- A red cell membrane defect - spectrin, ankyrin
- Autosomal dominant in inheritance
- Generally mild, well-compensated hemolysis
- Splenectomy is curative
Cause: RBC membrane defects
Pathophysiology:
- Osmotically fragile, spherical cells selectively trapped in the spleen.
- Splenic sequestration and conditioning  metabolic depletion, spheroidicity, hastened demise.
Hereditary Spherocytosis
Mode of inheritance:
75 % autosomal dominant w/ variable penetrance;
(+) family history
25 % de novo mutation or recessive
Hemolysis can be further triggered by infections
– viral, bacterial
Hereditary Spherocytosis Symptoms:
 Pallor, jaundice, splenomegaly → clinical triad of HA
 Formation of pigment gallstones
 Due to high turnover of heme
 Leg ulcers → In severe anemia
 Clinical classification:
silent carrier
mild
moderate
moderately severe
severe
* May be a cause of neonatal jaundice
Hereditary Spherocytosis Diagnostic procedure:
 (+) Osmotic Fragility Test: incubated and unincubated phases
 Others: (+) spherocytes on peripheral smear, MCHC
 (+) autohemolysis test
Hereditary Spherocytosis Anticipatory Guidance:
 Increase host resistance to prevent viral infections
 oral folic acid
 genetic counseling
Other Causes of Hemolytic Anemia
G6PD deficiency- A red cell enzyme defect
Mode of inheritance: X-linked; random inactivation of the X chromosome
Pathophysiology:
 Deficiency of the G6PD enzyme causes oxidant damage to the red cell, resulting in hemolysis
 Several mutants or variants of the G6PD enzyme
G6PD Deficiency
Symptomatology:
Pallor, jaundice, splenomegaly
 Splenomegaly may be absent in the newborn
 Prolonged jaundice in the newborn period should make one suspect G6PD deficiency
– exposure to naphthalene balls
G6PD Deficiency Diagnostic procedure:
G6PD assay, included in the Newborn Screening Tests
Heinz bodies on reticulocyte stain
Prevention: Avoidance of agents/conditions, Genetic counseling
Agents/conditions commonly associated with hemolysis in G6PD-deficient individuals
Drugs – Sulfonamides
Antibacterials – Chloramphenicol
Antimalarials
Chemicals – Benzene, Naphthalene, Phyenylhydrazine, toluidine blue, TNT
Infections – Viral hepatitis, pneumococcus
Diabetic acidosis
G6PD Deficiency Treatment:
 Removal of causative agent
 In the newborn period, naphthalene balls.
 Exchange transfusion in severe cases in the newborn.
 Transfusion of PRBC for symptomatic anemia
 Vitamin E?
G6PD Deficiency
Rare complication: Acute renal failure
Prognosis: Good
→ compatible with a long life
→ avoidance of agents/conditions is very important
long term care of children/adolescents with hemolytic anemias:
1. Monitor the growth curves, Hb, absolute reticulocyte counts, and size of the spleen.
- Ultrasound of hepatobiliary tree for stones (bilirubin)
2. Transfuse PRBC only for symptomatic anemia to avoid iron overloading and toxicity.
3. Monitor patients for possible crises:
hemolytic, aplastic, megaloblastic.
4. Give folic acid. DO NOT give oral iron.
5. When to do a splenectomy
Approach to Bleeding
BLEEDING DISORDERS
• Factor deficiency
• Von Willebrand Disease
• Disorders of Fibrinogen
• Congenital
• Acquired
•
•
•
•
•
Anti-coagulation defects
Disseminated Intravascular Coagulation
Liver disease
Vitamin K deficiency
Massive transfusion
Clinical Evaluation of a Bleeding patient
 Get a detailed History
 What is abnormal bleeding?
 Epistaxis
 unrelieved by 15 minutes of pressure
 Menstrual periods
 > 7 days
 associated with clots, saturation of pads or frequently stained clothing
 Detailed History
 What is abnormal bleeding?
 Bleeding from dental procedures
 Lasting beyond day of procedure
 Requiring a blood transfusion
 Ecchymoses
 size or character inconsistent with trauma
 What is abnormal bleeding?
CLUE: + previous surgery or dental procedure without bleeding complications
 unlikely to have congenital bleeding disorder
 Family History - Important because most children have not encountered severe hemostatic
challenges
 Ask about:
 Previous surgical procedures/dental extractions
 Transfusions
 Menstrual and obstetric histories
 20% of girls with menorrhagia from menarche have congenital bleeding disorder
 Type of Bleeding
 Time of onset
TIME OF ONSET
TYPE OF BLEEDING
Coagulation factor
deficiencies
(e.g. hemophilia)
Platelet Disorder
(or VWD)
Mucosal membrane
bleeding
 Gingival
hemorrhage
 Epistaxis
 Menorrhagia
 Petechiae
 Bruising


Acute *
Deep muscle bleeding
o Joint bleeding

Acquired disorder
Chronic

Congenital disorder

ITP


Vitamin K deficiency

VWD
Coagulation factor
deficiencies
* over days to weeks
 Time of Onset
 Congenital Coagulation disorders
 At birth
 Birth process
 During circumcision
 In the first months of life
 With immunizations
 When they become mobile
 Experience mild trauma
* Factor XIII deficiency
Good initial hemostasis  followed by persistent oozing (failure to form a firm clot)
DETAILED HISTORY
Liver disease


Decreased production
of coagulation factors
Thrombocytopenia 2
splenic sequestration
Malabsorption

Renal disease

Abnormal platelet
function
Impaired Vit K
absorption
Otherwise well


ITP
Congenital bleeding
disorders
PHYSICAL EXAMINATION
Petechiae < 2mm
Ecchymoses > 1 cm
Purpura 2mm – 1 cm
PHYSICAL EXAMINATION
HEMARTHROSIS
Hematoma
PHYSICAL EXAMINATION
HEMARTHROSIS
PHYSICAL EXAMINATION
INTRAMUSCULAR BLEED, PSOAS
Laboratory Evaluation
 Initial lab tests
 CBC with platelet
 PTT (intrinsic)
 PT (extrinsic)
 PT
 Prothrombin time
7.5,10.2,1
 Tests Extrinsic pathway: Factors VII, V, X, II, I
 aPTT
 activated Partial Thromboplastin Time
 Measures intrinsic pathway: Factors XII, XI, IX, VIII, X, V, II, I
Bleeding Profile
 CBC, platelet count
 Thrombin Time
 Peripheral smear
 Fibrinogen
 Bleeding time
 Fibrin Degradation Products
 Prothrombin Time
 Fibrin Monomers
 Partial Thromboplastin Time
DIFFERENTIAL DIAGNOSIS
BASED ON INITIAL SCREEN
↑PT
Normal plt,
PTT
↑ PTT
Normal plt,
PT
↑ PT,PTT
Normal plt
Early Liver Dx
Vit K Def
F VIII def
Vit K Def
Liver Disease
F VII Def
Warfarin
PT inhibitor
(hemophilia or
VWD)
F IX, XI
F XII def
PTT inhibitor
Massive Transfusion
Oral anticoagulant
(F II, V, X or
fibrinogen def)
DIFFERENTIAL DIAGNOSIS
BASED ON INITIAL SCREEN
↑ PTT, PT
All normal
Platelet dec
VWD
ITP
Platelet fxn d/o
Mild factor def (VIII,
IX, XI, XIII )
Fibrinolytic defect
Collagen Disorder
Vitamin C def
Infection
CVD
Early BM failure
and low plt
DIC
Liver Dysfxn
Inherited platelet
disorder (CAMT,
TAR,BSS
WAS, GPS)
CAMT = Congenital Amegakaryocytic Thrombocytopenia
TAR – Thrombocytopenia with Absent Radius
WAS = Wiskott Aldrich Syndrome
GPS = Gray Platelet Syndrome
Von Willebrand Disease
 Most common inherited bleeding disorder
 Prevalence: 1% - by lab def’n
 only 10% symptomatic
 Quantitative or Qualitative deficiency of vWF
 Symptoms:
 Easy bruising
 Epistaxis from childhood
 Menorrhagia
The Von Willebrand Factor
 Protein in plasma
 Function
- Glues platelets to damaged endothelium
- Binds and protects Factor VIII
 vWD- Classification
 Type 1
 Classic ; 80% of patients
 Partial quantitative deficiency
 Type 2
 Dysfunctional VWF
 Type 3
 Nearly COMPLETE deficiency
 vWD-Inheritance
 Mostly Autosomal Dominant; can be Autosomal Recessive
 Theoretically, equal males and females
 But more females diagnosed (menorrhagia)
 Can be acquired
 rare
 Hypothyroidism, Wilms tumor, Cardiac disease, Renal disease or SLE / Valproic acid
 Most often caused by Ab to VWF
 vWD- S/Sx
 Increased bruising and excessive epistaxis
 Prolonged bleeding with trauma or surgery
 Menorrhagia
 Significant menorrhagia from menarche should prompt investigation for congenital
bleeding disorders (commonly VWD)
 vWD-Labs
 Initial screen:
- PT normal
- PTT sometimes prolonged
> in type 3 (factor VIII dec)
- Platelet sometimes dec
> in types 2 and 3
 Most of the time: PT, PTT, platelet --- all NORMAL
 Blood type ‘O’ – normally lower vWF
 Bleeding time – prolonged
 Platelet function analyzer – prolonged closure time
 vWF assay - Definitive test
TREATMENT
 Intermediate purity F VIII concentrates
 Cryoprecipitate
 Adjunctive
 Antifibrinolytic agents (Tranexamic acid / E-aminocaproic acid )
 Prevents plasminogen  plasmin
 For mucosal bleeding
 Topical thrombin and fibrin glue
 Estrogen containing contraceptive tx
 For menorrhagia
HEMOPHILIA
 Essentials
 Factor VIII (or IX ) deficiency
 X-linked or spontaneous mutation (1/3)
 Bruising, soft tissue bleeding, hemarthrosis
 Prolonged PTT + dec factor VIII (or IX) levels
 Most common severe congenital bleeding disorder
 Prevalence
 Hemophilia A (Factor VIII)
 1 / 10,000 males
 Hemophilia B (Factor IX)
 1 / 50,000 males
 HEMOPHILIA – severity classification
 Factor VIII
– reported in units / ml ( 1 unit/ml = 100% factor activity)
- Normal range: 0.5 – 1.5 U/ml (50 – 150%)
 Classification
- Severe (60% of cases) : < 1% factor VIII
(spontaneous bleeding)
- Moderate : 1 - < 5%
- Mild : 5 – 40 % ( bleeding only with trauma and surgery)
HEMOPHILIA- S/Sx
 Severe Hemophiliacs
 Usually initial presentation in 1st 2 years of life ( severe bruising and joint bleeds)
 40 – 50% present in the 1st month of life
 1-4% present in the neonatal period (birth trauma)
 Mild or Moderate hemophiliacs
 Boys
 Trauma related bruising or bleeding
 Excessive bleeding following surgery or dental extraction
 Girls ( carriers )
~ Often with Factor VIII < normal
 Mild bruising or bleeding
 Heavy menstrual periods
HEMOPHILIA complications
 Hemarthroses
 If recurrent  joint destruction
 Intracranial hemorrhage
 Leading cause of death among hemophilliacs
 Intramuscular hematomas
 Compartment syndrome  muscle and nerve death
Acquired bleeding disorders
 Vitamin K deficiency/warfarin overdose
 Liver disease
 DIC
 ITP
Bone Marrow Failure


MCV inc because of production of stress rbc’s
Examples of bone marrow failure
o Aplastic Anemia
o Fanconi’s Anemia
o
o
Diamond-Blackfan anemia (Congenital hypoplastic anemia)
Transient Erythroblastopenia of Childhood (TEC)
Bone Marrow Failure
 Acquired or congenital
 Characterized by a reduction in the effective production of mature erythrocytes, granulocytes, and
platelets by the bone marrow
 Bone marrow failure leads to various peripheral blood cytopenias
o In some conditions, only one or two cell lines may be affected
o In others such as aplastic anemia the result is pancytopenia
Acquired Aplastic Anemia
Pathogenesis:
- Defects in hematopoietic stem cells
- Failure of stromal microenvironment of the marrow
- Presence of stem cell antibodies
**Signs/symptoms due to pancytopenia
Classification of Aplastic Anemia
Very severe aplastic anemia
Moderately severe aplastic anemia
Mild aplastic anemia
Treatment of Aplastic Anemia
Supportive therapy
- Blood component therapy
- PRBC, platelets
- Antibiotic therapy
Definitive treatment
- Stem cell transplantation - expensive
- Antithymocyte globulin, antilymphocyte globulin - expensive
- Ciclosporin – oral, may have good results
- 25 mg, 100 mg caps
- Corticosteroids, testosterone – least effective
Reminders…
When to Transfuse Red Cells
We transfuse patients for severely symptomatic or pathologic anemia, not the numerical value of the
Hemoglobin.
Aim: to restore or maintain the oxygen-carrying capacity of the blood with minimal expansion of the blood volume.
Patients with Hemolytic Anemia usually tolerate very low levels of Hemoglobin.
Ex. Beta thalassemia major
Slow transfusion of RBC’s for very severe anemia to avoid pulmonary congestion.
< 10 ml/kg/transfusion
Thank You!
dlca
2019
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