# Presentation: 527423

## Pediatric Hematology

-  Dr. Mariana Silva, MD.F.R.C.P.C.
-  March 2008

## FETAL  AND NEONATAL ERYTHROPOIESIS

-  TABLE 1. Globin-chain development and composition

| Developmental
stage | Hemoglobin
 type | Globin-chain
composition |
| --- | --- | --- |
| Embryo
Embryo
Embryo
Embryo to fetus
Fetus to adult
Adult
Adult | Gower 1
Gower 2
Portland
Fetal
A
A2
Fetal |  Zeta2 , epsilon2a
Alpha2, epsilon2
Zeta2, gamma2
Alpha2, gamma2
Alpha2, beta2
Alpha2, delta2
Alpha2,  gamma2b |

- a This tetramer may be an epsilon tetrad.
- b  Fetal hemoglobin produced by adults has a different amino acid heterogeneity of the  gamma chain at the 136 position than fetal hemoglobin

## Site of Erythropoiesis

## Hemoglobin Synthesis inFetus and Newborn

- 	Gower 1 and 2
-  			-  present in yolk sac
-  			-  75% of early Hgb
- 			-  undetectable after week 12
- 	Week 12 to 32   90% Hgb F

## Hemoglobin Synthesis inFetus and Newborn (cont’d)

- “The Switch” is Hgb F to A
- 	Hgb F  after week 32;  by week 40 is 50-75%;
- 		by 6 month is 5-8%;  by 1 year < 1%
- Delayed Switch (? mechanism ? Stress Erythropoiesis)
-      .  	Maternal hypoxia
-      .  	Small for Gestational Age
-      . 	 Infants of diabetic mothers

## Physiological Anemia of Infancy

-   Gradual  in Hgb after birth for 2   months,
-   	  stable 2-4 month, then 
-   Physiologic as no symptoms of hypoxia and
-    	  not nutritional
- Fetus	-  10 weeks Hgb 9 gr/dl
- 		-  22-24 week, Hgb 14 gr/dl
- 		-  32-40 week, Hgb 16 gr/dl

## Physiological Anemia of Infancy (cont’d)

- age:  blood supply to placenta  Epo to  maintain oxygen supply to infant Hemoglobin (Hgb)
- Oxygen delivery to fetus determines Hgb level at birth.
- 	Examples:
- Small for gestational
- Infant of diabetic mother:  metabolic demands on fetus from  glucose  oxygen needs Hemoglobin
-  Infants of smokers:  fetal CO  oxygen
-       available  Hemoglobin to compensate
- Infants gestated at  altitudes:  inspired
-      oxygen by mothers  Hemoglobin in newborn

## Physiological Anemia of Infancy (cont’d)     

- Birth:  Hemoglobin (Hgb) due to placental transfusion
-  RBC production after birth due to  availability
- 	of extrauterine oxygen
- 2 month of age  Hgb due to  RBC production,
- 	shorter life fetal RBC
- Nadir at 7-9 wk of age: Hgb 11 gr./dl

## Physiological Anemia of Infancy (cont’d)

-  placental transfusion in:
- 	 placenta previa or abruptio
- 	 multiple gestation
- 	 cord clamping < 30 seconds
- 	 C-section
- 	 Cord around neck
- 24-32 week retics are 15% of RBC’s, at birth 7%
- Day 7, retics  to 1%

## Postnatal changes in hemoglobin and ared-blood-cell indices in term infants

## Anemia of Prematurity

- Premature Infant: more rapid decline and lower
- 	nadir of Hgb than term
- 	40% infants <33 weeks show symptoms of anemia
- Epo  rapidly, Epo levels 50% < than adults at
- 	same Hgb level
- Epo  slowly as Hgb falls in premature babies
- 	Epo produced in liver

## Anemia of Prematurity (cont’d)

- Decision to transfuse  controversy for last
- 	30 years
- Anemia  risk of apnea and failure to thrive.
- Transfusion at predetermined Hgb level not cost  effective and doesn’t  apnea

##     Sites and Timing of Neonatal 	 Blood Loss

**A  ****	**Fetus
- 		1.  Internal hemorrhage
- 		2.  Fetomaternal Hemorrhage
- 		3.  Fetoplacental hemorrhage:
-                abruption,previa, marginal sinus ,or hematoma
- 		 4.   Twin-twin transfusion: chronic

## Sites and Timing of Neonatal Blood Loss (cont.)

- B	Newborn
- 	1.  Twin-Twin transfusion: acute
- 	2.	  Umbilical-cord rupture or hematoma-normal
-               or abnormal cord
- 	3.  Internal hemorrhage: Intracranial, hepatic or
-              splenic rupture or hematoma, adrenal or
-              retroperitoneal hematoma. Pulmonary bleed
- 	4.  Placental trapping: caesarean section, early
-               cord clamping, precipitous delivery

## Fe Deficiency Anemia

- Most common etiology of anemia
- 						         Lack of dietary iron
- Contributing factors in children              Rapid growth
- 			                                             Insufficient Fe
- Absorption
- Blood loss
- 			Breast milk or formula vs. cow’s milk
- Diet		Cereals
- 			Meat

## Fe Deficiency Anemia (cont’d)

- Lab : Hemoglobin
- 			MCV 
- 			Serum Fe/TIBC
- 		Serum Ferritin
- Platelets frequently 
- “Trial of Fe”
- Treatment: Oral ferrous sulfate  5-6 mg/kg of elemental Fe x day x 3 months
- Side effects of Fe

## THROMBOPOIESIS IN FETUS AND NEWBORN

## Thrombopoiesis

-   I 	   Yolk sac phase:
- 	small megakaryocytes  by 5 week,
- 	platelets large and  hypogranular
-  II    Hepatic phase:
- 	early stage by 6 week
- 	Megakaryoblasts and  promegakaryocytes seen
-   late stage: 9-11 weeks
- 		Megakaryocytes comparable to  adult, but smaller

## Thrombopoiesis (cont’d)

- III  Bone Marrow phase: after 11 weeks
- 	from 11 to 22 stable number megakaryocytes, then  22 to
-             40 week.
-      	Size still small, adult size by one year of age.
- 	Newborns easily develop thrombocytopenia due to
-             sepsis. Little is known of newborn
- 		megakaryocytopoietic-thrombopoietic capacity

## WELL

- Small Platelets
- Congenital anomalies
-  Mean corpuscular volume

- Consumption

-   Synthesis

- Immune

- Congenital

- ITP                                       2° to SLE, HIV               Drug Induced

- TAR                                             Wiskott-Aldrich Syndrome                    X-linked                        Amegakaryocytic                          Fanconi anemia

- Non-immune                                        2B or platelet-type vWd                Hereditary macrothrombocytopenia

- Acquired: Medications,Toxins,Radiation

- Large platelets                Normal hemoglobin                       and WBC

- Maternal ITP        NATP

## ILL

- Fibrinogen                   Fibrin degradation       products                         Large platelets

- Small platelets           HSM

**Consumption**

** ****Synthesis**

- Mass

- Microangiopathy              Hemolytic-uremic syndrome                TTP

- Malignancy             Storage disease

- Disseminated intravascular coagulation                        Necrotizing enterocolitis     Respiratory distress            Thrombosis                           UAC                                         Sepsis                                          Viral infection

- Sequestration

- Hemangioma

- Hypersplenism

## Thrombocytopenia 

- _Infant Factors_
-         Platelet < 100,000/mm3 in 80% sick infants 60%
-         known etiology
- 22% infants in NICU have  platelets
-            Approximately 25% have significant bleeding
-  platelets associated with: sepsis, respiratory distress,  bilirubin,  ventilation,
-             asphyxia, meconium, hypothermia, pulmonary
-             hypertension, polycythemia
- Sepsis  52-77% have  platelets,
-       may be 1st manifestation.  Mean
-       duration 5 days.

## CLINICAL CASES

- I	Tyler is an 11- month- old boy brought to your office by his mother who thinks he is pale and a bit irritable.
- 	He has not had any recent illnesses and is on no medications.
- History of presenting complaint
- Past medical history
- Diet
- Family History
- Physical Exam

## LAB

- Hb 82 g/L
- MVC  65
- WBC  6.9 x 109/L
- Platelets    540,000 x 109/L
- Possible diagnosis
- Treatment

## CLINICAL CASES (cont’d)

- II	Amanda is a 2-month-old girl you are seeing today for her lst immunization. Her 	mother reports that Amanda sleeps a lot and looks pale. She is growing well and breastfeeds vigorously.
- 		She is on no medications.
- History of presenting complaint
- Past medical history
- diet
- Family history
- Physical exam

## LAB

- Hb	102 g/L
- MCV	84
- WBC	8.3 x 109/L
- Platelets 	240,000 x 109/L
- Possible diagnosis
- How would you manage this patient?

**0**

## Pancytopenia

-  Reduction below normal values of 3 blood lines:
- *Leukocytes  * Platelets  * Erythrocytes
-  Hypocellular Marrow Seen in:
- Constitiutional (Inherited) marrow failure syndromes
- Acquired Aplastic Anemia
- Hypoplastic Variant of Myelodysplastic Syndromes

## Pancytopenia  (con’t)

- Cellular marrow seen in:
- Primary bone marrow disease as Acute Leukemia, MDS, Myelofibrosis
- Secondary to systemic disease: autoimmune disease (SLE), Vitamin B12 or folate deficiency, storage disease, metastatic solid tumors, etc.

## Constitutional (Inherited) Pancytopenia Syndromes

- Fanconi Anemia
- Shwachman-Diamond Syndrome
- Dyskeratosis Congenita
- Amegakaryocytic Thrombocytopenia
- Other Genetic Syndromes
- 	Down Syndrome
- 	Dubowitz Syndrome
- 	Seckel Syndrome
- 	Reticular Dysgenesis
- 	Schimke Immuno-Osseous Dysplasia
- 	Familial Aplastic Anemia (non-Fanconi)
- 	Pearson Syndrome
- 	Reticular Dysgenesis
- 	Noonan Syndrome

## Fanconi (Aplastic) Anemia

- Autosomal recessive syndrome
- Hematological findings
- Typical physical anomalies
- Abnormal chromosomal fragility

## Characteristic Physical Anomalies in Fanconi Anemia

- Anomaly
- Skin Pigment Changes
- Short Stature
- Upper Limb Abnormalities (thumbs,hands,radi,ulnas)
- Hypogonadal and Genital Changes (mostly males)
- Other Skeletal Findings (head/face,neck,spine)
- Eye/lid/epicanthal fold anomalies
- Renal Malformations
- Ear Anomalies (external & internal), deafness
- Hip, leg, foot, toe abnormalities
- Gastrointestional/cardiopulmonary malformations

- Approximate Frequency
- (% of Patients)
- 65
- 60
- 50
- 40
- 30
- 25
- 25
- 10
- 10
- 10

## Marrow Failure Before Age 10 Years

- Thrombocytopenia often first
- Granulocytopenia
- Macrocytic Anemia
- Severe Aplastic Anemia in Most Cases
- Increased Propensity for Cancer: Carcinomas of Head, Neck, Carcinoma of Vulva and Anus

## Treatment

- Transfusions
- Hematolpoietic Stem Cell Transplant is only Curative Treatment
- Androgens – Prednisone
- Prognosis: Median Survival is >30 years of 			Age