This document provides an overview of diseases of the blood, including various types of anemias and disorders of hemostasis. It discusses topics like hematopoiesis, iron deficiency anemia, sickle cell disease, thalassemia, immune thrombocytopenic purpura, and hemophilia. For each condition, it outlines causes, clinical features, laboratory findings, diagnosis, and treatment approaches. The document thus serves as a comprehensive reference for pediatricians on blood disorders commonly encountered in clinical practice.
3. Hematopoiesis
• Hematopoiesis is process by which cellular elements of
blood are formed.
• Divided into 3 anatomic stages.
– Mesoblastic: occurs in extraembryonic structures (yolk sac), btw
10-14 day of gestation. Ceases by 10-12 wk.
– Hepatic: Starts by 6-10 wk, diminishes during 2nd trimester,
placenta also contribute. (liver predominate organ during 20-24
weeks)
– Myeloid: Increases after 2nd trimester.
4. Hemoglobins in Fetus and Neonate
Hemoglobin is a tetramer of globin chains, with an iron containing porphyrin ring
(heme) bound to each chain.
• Embryonic: Predominate upto 6 wk, no longer detectable by 3 months
Gower 1
Gower 2
Hb Portland.
• Fetal: Predominates by 6-8 wk.
90% at 24 wk, 70-80% in 3rd trimester,
Declines rapidly postnataly, reaches adult level <2% by 6-12
months
• Adult: HbA 5-10% at 24 wk, 30% at term, reaches adult level by 6-12 m.
HbA2 <1 % at birth, by 12 month 2-3.4%. (ratio of HbA to HbA2 30:1)
5.
6. Red cell Span
• Highest hematocrit occurs at birth.
• Lowest hematocrit 8-10 wk postnataly.
• Erythrocyte life span in adults is 120.
• Fetal / Neonatal erythrocyte life span previously
considered 60-90 days, newer studies show same as
adult.
• Neocytolysis: removal of young RBC that were formed
during hypoxia, following normoxic or hyperoxic
conditions.
7.
8. Anemias
• Anaemia: Reduction of haemoglobin
concentration or RBC volume below the range
occurring in healthy person.
• Physiologic adjustment to anemia:
– Increased cardiac output
– Augmented O2 extraction
– Shunting of blood flow to vital organs.
– Increase concentration of 2,3 diphosphoglycerate
– Reduced affinity of hemoglobin for oxygen
– Increased EPO.
9.
10. History and Examination
History:
• Age
• Sex
• Diet
• Medication
• Chronic disease
• Infections
• Travel and exposures.
• Family history of anemia and
other difficulties(
splenomegaly, jaundice, gall
stones)
Exam:
• Clinical finding generally
appear when Hb is< 7-8g/dl.
• Pallor( tongue, nail bed,
conjunctiva, palm, palm
creases)
• Sleepiness
• Irritability
• Flow murmur
• Decreased exercise tolerance
• Weakness, tachypnea,
tachycardia, shortness of
breath, heart failure( when
severe)
18. Treatment
• Corticosteroids, prednisone started as 2mg/kg/dose and tapering
the dose when hb concentratin reaches>9g/dl. 0.5mg/kg/daily or
1mg/kg/alternate day.
• Red cell transfusion: Required in pt not responding to steroids.
Given at 3-5 week interval to maintain hb>8 g/dl.
• HSCT: Usually done between 3 to 9 yr. some advocate HSCT at
younger age to avoid iron overload and allosensitization from
chronic transfusion.
Prognosis
• Spontaneous remission occur in 25% by 25 yr of age.
• DBA is cancer pedisposing syndrome( myelodysplastic syndrome,
AML, colon carcinoma, osteogenic sarcoma, female genital cancers)
• Overall survival is 75% at 40 yr of age.
19. Acquired red cell Anemia
• TEC (Transient erythroblastopenia of childhood) is most
common.
• Occurs btw 6 month to 3yr.
• Usually resolves spontaneously.
• TEC follows viral infection.
• Suppression of erythropoesis IgG, IgM and cell mediated
mechanism.
• MCV is normal for age
• HbF levels are normal.
• RBC adenosine deaminase levels are normal.
• All children recover within 1-2 months.
• Transfusion may be necessary in severe anemia.
• Corticosterid therapy is of no value
20. • Parvovirus B19 infection.
• Cytomegalovirus infection
• Epstein barr virus infection.
• Use of chloramphenicol.
21. Physiologic Anemia of infancy
• Progressive decline in hb begins after 1st wk and
persist for 6-8 wk.
• As child breaths hb O2 saturation increases from
50% to 95%.
• Gradual shit f Hb F to adult Hb.
• Down regulation of EPO.
• Removal of aged RBCs.
• Hb continue to decline till 8-12 wks.
• Hb rarely falls below 10g/dl in term infants.
• No therapy is required unless, anemia is
exacerbated by other ongoing process.
22. • In premature infants hb decline is more extreme and
rapid. (Anemia of prematurity)
• Hb level of 7-9g/dl reached by 3-6 wk.
• Hb also declines due to repeated phlebotomies.
• Shortened RBC life span(40-60days).
• Accelerated RBC expansion due to rapid growth.
• Decreased EPO production.
• Vitamin E does nor play any role. (breast milk and
formula provide adequate vitamin E).
• Iron stores are sufficient for 1-2 months.
• Apnea of prematurity always presents with clinical signs
and requires transfusion.
23. Treatment
• Term infant usually don’t require treatment when diet is
adequate.
• Preterm should be transfused with RBC volume of 10-
15ml/kg ( split units from single donor)
• Late transfusion can result NEC and early transfusion
can cause IVH in preterm.
• Delayed cord clamping and umbilical cord milking cause
less need of transfusions.
• Limited phlebotomy can result decreased need of
transfusion.
• Iron therapy for all premature infants from 1 month to 1
yr of age.( 1-2mg/kg/day elemental iron).
24. Megaloblastic Anemias
• Characterized by impaired DNA synthesis.
• RBCs are larger than normal.
• Delayed nuclear development.
• Often associated with thrombocytopenia and
leukopenia.
• Hypersegmented neutrophils, having > 5 lobes.
• Most cases result from folic acid or vitamin B12
deficiency , inborn errors of metabolism.
25. Folic Acid Deficiency
• Folic acid or pteroyglutamic glutamic acid
consists of pteroic acid conjugated with glutamic
acid.
• It is essential for DNA replication and cellular
proliferation.
• Human can not synthesize folic acid.
• Dietary sources( green vegetables, fruits, liver,
kidney)
• Folates are heat labile and water soluble.
• Folate deficiency peak incidence at 4-7 month of
age
26. Causes
• Increased requirement( pregnancy, rapid growth, hemolysis).
• Infant born to folate deficient mothers are not folate deficient.
• Goat milk
• Hemoglobinopathies.
• Infections
• Malabsorption( chronic diarrhea, celiac disease, previous surgery)
• Malnutrition( older child).
• Folate free diet will result aemia in 2-3 months.
• Alcohol overuse
• Anticonvulsants (phenytoin, primidone, Phenobarbital.
• Antifolates ( Methotrexate, pyrimethamine, trimethoprim)
• Hereditary folate malabsorption( 2-6 mo).
27. Clinical Features
• Anemia
• Irritability
• Chronic diarrhea
• Poor weight gain.
• Hemorrhages
• HFM:(Hreditary folate
malabsorption) Severe
infection, FTT, neurologic
abnormalities, cognitive delay
Laboratory Findings
• MCV= >100 fl
• Variation in RBC size
• Megaloblastic RBC
• Neutropenia
• Thrombocytopenia
• Large hypersegmented
neutrophils
• Low retic
• Normal folic acid level 5-
20ng/ml. deficiency <3 ng.
• Iron , LDH raised
• RBC folate( 150-600ng/ml)
good indicator of chronic def:
28. Treatment
• Folic acid orally/ parentrally 0.5 -1 mg/day.
• Continued for 3-4 wk.
• Maintenance with multivitamin( 0.2 mg folate).
• Very high doses required in HFM.
• Transfusion is only required in severe anemia
• When diagnosis in doubt, give <0.1mg/ day (
response seen in 72 hours). If given >0.1 mg
can correct anemia of vit: B12 def: but will
aggravate neurologic abnormalities.
29. Vitamin B12(cobalamin) deficiency
• Vitamin B12 is water soluble, essential for
synthesis of DNA, RNA and protein.
• Synthesized by microorganisms.
• Dietary sources( meat, eggs, fish, milk).
• Older children and adults have sufficient
stores upto 3-5 yr.
• Young infants born to deficient mothers,
present at 6-18 mo of life.
30. Causes
• Nutritional (low levels in breast milk of deficient mothers).
• Strict vegetarian diet.
• Impaired absorption
– Surgery ( gastric/ terminal illiuem)
– Medication( that reduce acid secretion)
– IF deficiency
– Pancreatic enzyme deficiency
– Celiac disease
– IBD,NEC
– Infection with diphylobothrium latum..
• Hereditary IF deficiency.
• Imersland Grasbeck syndrome (selective vit B12 malabsorption, hypotonia,
develop: delay, brain atrophy, movement disorder, dementia)
• Juvenile pernicious anemia ( antibodies against IF and H-K pump).
• Abscense of B12 transport protein.
• Inborn errors of cobalamin metabolism.
32. Treatment
• Treatment regimen in children is not well
studied.
• Daily requirement is 1-3 microgram/day.
• IM/ intranasal vit B12 is given in pernicious
anemia.
33. Iron Deficiency anemia
• Common nutritional disorder in world, 30-50% of
global population.
• Daily requirement of iron is 1mg in childhood,
<10% dietry iron is absorbed so 8-10mg intake
is must
• 1 litre of breast and cow milk contain 1 mg iron
• Iron in breast milk 2-3 times more efficiently
absorbed.
• Breastfed infants need iron fortified foods by 6
mon.
• Iron deficiency anemia usually occurs at 9-24
mo of age.
36. Diagnosis
• CBC
– microcytic anemia
– Increased RDW
– Reduced RBC
– Normal or raised palatelets.
• Reduced Ferritin <30-100
• Reduced serum iron
• Increased total iron binding capacity
• Increase in hb >1g/dl after iron therapy of 1 mon
37. DD:
• alpha or beta thelesemia
• hemoglobinopathies
• Lead poisning
• Anemia of chronic disease.
38. Treatment
• Oral iron therapy (ferrous sulphate) is much effective,
less toxic
• Daily 3-6mg/kg of elemental iron. Max= 150-200mg
• Usually given between meals, with vitamin C containing
juice
• Parentral iron, when malabsorption (low molecular
weight iron dextran).
• Iron therapy may increase virulance of malaria and gram
–ve organisms.
• Dietary counslling along with iron therapy.
• Continued 2-3 months after normal blood values, to
replenish stores.
• Transfusion is rarely necessary, when Heart failure or
acute blood loss
39.
40. Hemolytic Anemias
Hemolysis: Premature destruction of red blood cells.
• Normal RBC survival 110-120 days.
• 0.85% of old RBC are removed and replaced each day.
• During hemolysis RBC survival is shortened.
• As result erythroid hyperplasia occurs, marrow increase
output 2-3 fold acutely, 6-7 fold in chronic hemolysis.
• Chronic hemolysis=> expansion of medullary spaces=>
decreased cortical bone => increased fractures.
• Increased degradation of HB => Increased indirect
hemoglobin =>increased excretion of heme pigment=>
formation of gall stones.
• Free hemoglobin appear in urine.
44. Hereditary spherocytosis
• Common cause of inherited haemolytic anemia.
• Prevalence 1 in 2000 to 5000 persons.
• 75% Autosomal dominant, 25% has no family history
• Abnormalities in ankyrin and spectrin( cell mem proteins).
Clinical Manifestations:
• Presents in neonatal period, anemia, hyperbilirubinemia( requiring
phototherapy, transfusion).
• Mild cases( 20-30%) are asymptomatic in adulthood.
• Moderate / Typical HS (60-70%), present as fatigue, pallor, intermittent ,
jaundice.
• Severe HS(3-5%), life threatening anemia, transfusion dependent.
• Spllenomegaly after infancy.
• Gallstones
• Aplastic crises( parvovirus infection).
• Megaloblastic crises( folate def).
• Rare: splenic sequestration, gout, cardiomyopathy, priapism, leg ulcers
45. Diagnosis
• Anemia
• Reticulocytosis
• Indirect hyperbilirubinemia
• Normal/low MCV
• MCHC increased> 35g/dl
• MCHC >35.4 g/dl with RDW< 14% (sceering test for HS).
• Spherocytes ( increased no in severe disease)
• Increased LDH.
• Decreaed binding of EMA to mem proteins.
• Increased osmotic fragility (poor sensitivity and specificity), may miss mild
HS
• Genetic diagnosis
• Coombs negative
DD: Isoimmune ( haemolytic disease of newborn)= direct coombs positive
autoimmune hemolytic anemia. Rare: Thermal injury, hemolytic transfusion
reaction, Wilson disease, snake, bee or wasp envenomation.
46. Treatment
• Transfusion
• Phototherapy
• Exchange transfusion
• Annual visit to haematologist
• Spleen size on each follow-up.
• Growth monitoring
• Screen for gallbladder stone at 4 yr then every 3-5 yr.
• Vaccination up to date
• Folate suppl: in moderate to severe HS.
• Counselling about aplastic, hypo plastic crisis.
• Spleenectomy.
47. Guidelines for splenectomy
• Done in moderate and severe HS.
• Frequent hypo plastic /aplastic crises, poor growth, cadiomegaly
• Should be performed after 6 yr of age.
• Subtotal spleenectomy(85-95%) removal.
• Increased risk of atherosclerosis, thrombosis, cardiovascular
disease, pulmonary hypertension postspleenectomy.
• Prophylactic antibiotic untill pt is 5 yr old or 2 yr after surgery.
• UP to date vaccination of pt and contacts.
48. Sickle cell disease
• HbS is the result of single base pair change thymine for adenine
in B globin gene.
• Presence of HbS results in change in Hb, which causes
formation of rigid polymers ( sickled) of RBC in deoxygenated
state.
• Sickle cell anemia( Hb SS) (HbS>90%): both B allels have sickle
cell mutation.
• Sickle cell disease (Hb S>50%): 1 B allele has sickle cell
mutation, other allele has some other mutation (hbC, HBD, B-
thalessemia)
49. Clinical Manifestations
• Fever and Bacteraemia (Streptococcus pneumonia,
haemophilus influenzae, neisseria meningitidis).
– Occurs due to functional asplenia
– Increased risk of death.
– Hospital admission, iv antibiotics(3rd gen:
cephalosporin
– OPD management, who are at low risk of
bacteremeia, after getting culture and iv cetriaxone.
– If inf with salmonella/ staph: aureus, osteomyelitis
should be evaluated with bone scan.
50.
51. • Aplastic crisis: Infection with parvovirus B19, asso: with pain, ACS, AGN,
arthropathy, splenic sequestration
• Splenic sequestration:
– Usually occur btw 6mo – 2 yr, triggered by fever, bact /viral inf
– Rapid spleen enlargement, left sided pain
– Fall of hb 2 g/dl below baseline, total hb falling< 3g/dl
– Hypovolemia
– Deceased WBC and platelets count
– Treatment with isotonic fluids or RBC transfusion(5m/kg), target Hb 8
g/dl.
– Hb>10g/dl can cause hyperviscosity syndrome
– Prophylactic spleenectomy.
• Sickle cell pain:
– Dactylitis, often 1st manifestation, occuring in 50% by 2nd yr.
– Acute vasoocclusive pain: occurs in chest, abdomen, extrimities.
– Treatment is done with acetaminophen, NSIADS, Opiods, IV morphine,
may require admission
52. • Avascular necrosis:
– Femoral head (commonly), can cause limp and leg length disrepancy.
– Humeral head, mandible.
– Risk factors, vasooclusive episodes, inc hematocrit, hbS disaese
– Transfusion has no role.
– Treatment is pain med: physical therapy, reduced weight baering,referal
to orthopedic.
• Priapism:
• Neurological complications:
– Acute ischemic stroke
– Silent stroke
– Transient ischemic attacks
– Posterior reversible encephalopathy syndrome (PRES)
– Seizures
– Cerebral vein thrombosis
– Screening, trancranial doppler ultrasonography (TCD), >200cm/sec at
increased risk of stoke.
– CT Scan, MRI, MR venography, MR angiography
– Treatment O2 supply: target sat >96%, blood transfusion/ exchange
transfusion, target Hb of 10 g/dl, Hb S < 30%.
53. • Acute chest syndrome:
– Life threatning pulmonary complication
– New radiodensity on CXR plus any 2 of these, cough,
fever, hypoxia, resp: distress, chest pain.
– CXR finding, left lower lobe involvment usually, both
lower lobes, pleural effusion.
– Common etiology is infection (s-pneumoniae, M-
pneumonia, Chlamydia spp), Fat emboli.
54.
55. Treatment
Blood transfusion (simple or exchange), depending on
clinical features;
consider maintaining an active type and crossmatch
Supplemental O2 for drop in pulse oximetry by 4%
over baseline, or values <90%
Empirical antibiotics (third-generation cephalosporin
and macrolide)
Continued respiratory therapy (incentive spirometry
and chest physiotherapy as necessary)
Bronchodilators and corticosteroids for patients with
asthma
Optimum pain control and fluid management
Overall Strategies for the Management of Acute Chest Syndrome
• Prevention
Incentive spirometry and periodic ambulation in patients
admitted for sickle cell pain, surgery, or febrile episodes
Watchful waiting in any hospitalized child or adult with sickle cell
disease
(pulse oximetry monitoring and frequent respiratory
assessments)
Cautious use of intravenous fluids
Intense education and optimum care of patients who have sickle
cell anemia and asthma
Diagnostic Testing and Laboratory Monitoring
Blood cultures, if febrile
Nasopharyngeal samples for viral culture (respiratory syncytial
virus,
influenza), depending on clinical setting
Complete blood counts every day and appropriate chemistries
Continuous pulse oximetry
Chest radiographs, for persistent or progressive illness
56.
57. Treatment
• Hydroxyurea, : Beginning at 9 mo of age, decreases acute pain, ACS,
Dactylitis, need for blood transfusion. Dose= 15-20mg/kg once daily
incraesing 5mg/kg every 8 wk upto 3mg/kg.
• Stem cell transplantation: HLA matched sibling or unrelated doner,
done when recurrent ACS, stroke and abnormal TCD.
• RBC transfusion: ACS, aplastic crisis, splenic sequestration, stroke.
– 100ml/kg or > 10 transfusions can cause iron overload.
– Chelation , Deferoxamine 5 days/ wk SC over 10 hours
– Deferasirox( oral) can cause neutropenia, Deferiprone (oral).
• Penicillin prophylaxis: oral penicillin until at least 5 yr, 125mg bd upto
3yr, then 250mg bd.
• Immunization: All routine immunizations, annual influenza vaccine, if
functional asplenia additional pneumococcal and meningcoccal vaccine
58. Thalassemia
• Group of genetic disorders of globin chain production.
• B-thal syndromes result from decrease in B globin chains, with result in
excess of A- chains.
• B-Thalessemia major: absence of B- globin
• B+ Thalessemia: Decreased amount of normal B globin.
• B Thalessemia intermedia: are less severe, non transfusion
dependent..
• A0-Thalessemia: Indicate no A chain production
• A+-Thalessemia: Decreased amount of a- globin chain.
59.
60. Thalassemia Major(cooley Anemia)
• Transfusions are necessary, beginning from 2nd mo- 2nd yr.
• Transfusion is needed because of
– Ineffective erythropoisis
– Growth failure
– Hepatospleenomegally
– Bone deformities.
• Thalassemic facies( maxilla hyperplasia, flat nasal bridge, frontal bossing)
• Pathologic bone fractures
• Marked hepatospleenomegally, hypersplenism
• Cachexia
• Increased iron absorption (resulting hemosiderosis).
• Transfusion induced hemosiderosis
1. Liver
2. Endocrine (hypothyroidism, growth hormone deff:, hypoparathyroidsm,
hypogonadotrophic gonadism, diabetes)
3. Heart ( cardiac failure, arrhythamias leading cause of death)
63. Management
• Transfusion
– Transfusion required every 3-4 wk
– Goal is to maintain pretransfusion hb 9.5- 10.5g/dl.
• Iron overload monitoring
– Serial serum ferritin levels
– R2 MRI of liver( best indicator of body iron).
– T2 Cardiac MRI ( usually starting at 10 yr old).
• Chelation therapy
– Usually started after 1 yr of transfusion, serum ferritin > 1000ng/ml/ liver iron
>5000ug/g dry weigh, not done <2 yr age
– Deferoxamine (desferal) SC/IV 25mg/kg- 60 mg/kg 5 days/wk in infusion of 8
hours, adverse effects local skin reaction, ototoxicity, retinal changes, bone
dysplasia.
– Deferasirox (oral) Dispersible tab 20-40mg/kg/day
Film coated tab 14-28mg/kg/day
– Deferiprone (Ferriprox) oral 75- 99mg/ kg/day in 3 divided doses neutropenia
64. Management
• Hydroxyurea (increases HbF production)
– 10-20mg/kg/day.
– Usually given in thalessemia intermediae
• Hematopoitic stem cell transplantation:
– Most succesful when done before 14 yr, without excessive iron
stores and hepatomegally
• Spleenectomy (who develop hypersplenism)
65. Preventive monitoring
• Serial Echocardiography (to evaluate cardiac function
and pulmonary hypertension)
• T2 cardiac MRI> 8 yr of transfusion
• Monitoring of endocrine function( wt, ht, pubertal
assesment, sitting ht) after 5 yr of age/ 3 yr of chronic
transfusion.
• Bone scan after 2nd decade (for osteopenia)
• Nutritional assesment (vit D,C zinc)
• Psychosocial support
66. A- Thalassemia syndromes
• New-borns are identified by increased production of bart hemoglobin
• Silent trait (Deletion of 1 A- globin gene )
– not identifiable hematologicaly.
– Normal MCV, MCH.
– Hb bart < 3%
• A-thal: trait:(2 missing a-globin genes).
– Microcytic anemia ( commonly mistaken as iron def)
– Hb analysis, Hb bart> 3%, <8%
– If both parents are carrier( cis conformation) future risk of hydrops fetalis
• HBH: ( deletion of 3 a-globin genes)
– Nondeletional mutation is more severe form
– Hb bart>25%
– Marked microcytic anemia ( hb range7-11g/dl)
– Mild splenomegaly, cholilithiasis, icterus
– Not transfusion dependent, intermittent transfusion may be required.
• Hydrops fetalis: ( deletion of all 4 a-globin genes)
– Profound anemia during fetal life
– NO normal hb present at birth.
– Intrauterine transfusion may rescue fetus.
– LIife long transfusion dependence.
– Only cure (HSCT)
67. G6PD Deficiency
G6PD deficiency, involving enzymes of monophosphate
pathway.
1. Episodic acute hemolytic anemia
(triggered by infections, dugs)
2. Chronic nonspherocytic hemolytic anemia.
• It is X-linked deficiency
• About 140 mutations in genes.
• Normal enzyme found in most population is G6PD B+( enzyme
activity <5% normal)
• Normal variant is G6PD A+( common in africans)(5-15%)
• Occurs more frequently in males than females.
69. Clinical Manifestations
• Most are asymptomatic, unless trigerred by infection, drugs or ingestion of
fava beans.
• Typically haemolysis occurs 24-48 hour after exposure.
• Ingestion of fava beans can produce acute severe hemolytic anemia
(favism)
• Degree of hemolysis depends on inciting agent, amount, severity of of
enzyme deficiency.
• Severe cases present as hemoglobinuria and jaundice.
• G6PD def: can produce hemolytic anemia in newborn.
• G6PD B- can present as kenicterus.
• Neonates with G6PD and co-inheritance of Gillbert syndrome can have
more severe jaundice.
76. Treatment
• For mild disease observation is sufficient
• When hb>23g/dl, hct > 65-70, phlebotomy is
done.
• Iron status should be assesed and treated if iron
deficiency.
77. Fanconi Anemia
Fanconi anemia is a rare multisystem hereditory disorder
resulting in marrow failure, inherited as autosomal
recessive.
1. Typical physical features and hemotologic findings(
majority of pts).
2. Normal physical features, abnormal hematologic
findings( 1/3rd of pts)
3. Physical anomalies and normal hematologic findings(
unknown percentage)
78.
79. Clinical manifestations
• Skeletal anomalies( most common)
– Absent radi/ thumb
– Hypoplastic, supernumerary/ bifid thumb
– Short stature
– Conginital hip dislocation
– Leg and feet anomalies
• Skin (common )
– Hyperpigmention ( café –au-lait spots)/ vitiligo
• Undesceded testes, underdeveloped penis
• Malformations of vagina, uterus, ovary, infertility
• Facial dysmorphism
– Microcephaly, small eyes, epicanthal folds, abnormal size or position of ears.
• Kidney anomalies( hypoplastic, dysplastic/ absent, ectopic, horseshoe)
• Cardiovascular anomalies
• GI anomalies
• Bone marrow failure ( usually in 1st decade)
– Thromocytopenia
– Macrocytes, increased Hb F
– Neutropenia
– Anemia
80. Complications
• Higher risk of developing cancers
• Most frequent squamous cell carcinoma( head
and neck)
• Carcinoma of upper esophagus, lower
esophagus, vulva, cervix, anus.
• Benign and malignant liver tumors.
• Myelodysplastic syndrome
• AML
82. Diagnosis
• Lymphocyte chromosomal
breakage study
• Genetic diagnosis
• Next generation sequencing
• U/S
• Echocardiography
• Endrocrine evaluation
• Evaluation of renal, liver,
thyroid, metabolic and immune
system
Treatment
• Blood counts every 3 mo
• Bone marrow aspirate every yr
• Glucose count annually /
biannually
• Screen for hypothyroid
annually
• Solid tumors annually
• Androgens( oral
oxymetholone, danazol)
• HSCT ( only curative
therapy), survival rate higher
when done < 10 yr
83. RBC Transfusion
• Fresh RBC ( <7 day storage)
• Stored RBC( 42 day storage)
• Usuall dose 10-15 ml/kg over 2-4 hours.
• RBC should be leucoreduced, if wt < 1500g also irradiated ( to reduce
graft vs host disease)
84. Platelets Transfusion
• PLT products generally expire in 5 days.
• Usuall dose 10-15 ml/kg, given within 2 hr.
• Plt should be identical to ABO group.
85. FFP Transfusion
• FFP, plasma frozen within 8 hours.
• F24 , plasma frozen within 24 hours ( decreased levels
of factor v and viii)
• Starting dose is 15 ml/kg.
• Efficacious in treatment of factor ii, v, x, xi.
• Cryoprecipitate/ special factor products for factor xiii, viii,
von willebrand and fibrinogen, vii, ix.
Indication in neonates:
• Haemorrhage 2ndry to vit K def:
• DIC with bleeding
• Bleeding in congenital clotting factor def:
See next Table
86.
87. Evaluation of Hemostasis
History
• Site of bleeding
• Severity and duration of bleeding
• Age of onset
• Was bleeding spontaneous/ with trauma.
• Does bruising occur spontaneously
• Any previous personal/ family history.
• Any history of bleeding/ mucocutaneous bleeding after surgery.
• Menstrual history in postpubertal females.
• Reduction of symptoms during pregnancy/ oral contraceptive.
• Bleeding after using aspirin/ NSAIDS.
Physical examination:
• Bleeding from mucous membrane or skin ( mucocutaneous)
• Muscle and joint ( deep bleeding).
• Presence of petechia, ecchymoses, hematomas, hemarthroses
• Bruising, loose joints, lax skin ( Ehlers-danlos-syndrome)
• Swollen, warm , tender extrimities ( venous thrombosis)
• Unexplained dyspnea/ persistent pneumonia ( pulmonary embolism)
• Acute stroke, MI, Painful, white, cold extremity ( Arterial thrombi)
88. • Petechiae= pinpoint non blanching spots.
• Purpura= Larger non blanching
spots>2mm.
• Ecchymosis= Larger purpura >1cm
89. Laboratory Test
• Platelet count, bleeding is rare, > 50, 000/L
• Prothrombin time (PT) , 10-13 sec.
– (factor i, ii, v, vii, x)
• Activated partial throbmoplastin time aPTT 40 sec
– (factor i, ii, v, viii, ix, xi, xii)
• Thrombin time, 11-15 sec ( hypo/afibrinogenemia ,heparin
contamination).
• Reptilase time, not sensitive to heparin, prolongd in reduced
fibrinogen.
• Mixing studies: 1: 1 mixing of patient and normal plasma, correction
of PT, PTT.
• Platelet aggregation, (ADP, epinephrine, collagen, thrombin,
ristocetin).
• Testing for thrombotic predisposition
– Factor V Leiden( resistant to protein C), Protein C,S ,AT111
90. Hemopihilia
1. Hemophilia A ( factor viii deficiency)
2. Hemophilia B ( factor ix deficiency)
3. Hemophilia C ( factor xi deficiency)
HemophilIa A or B:
• Most common inherited disorder.
• X- linked recessive disorder.
• Occurs in 1: 5000 males, 85% having hemophilia A, 10-15% having
hemophilia B.
• Hemostatic level of factor viii> 30-40 %, factor ix >25-30%. Lower limit of
normal is 50%.
– Severe hemophilia <1% activity= spontaneous bleeding
– Moderate hemophilia 1-5% activity= bleeding after mild trauma
– Mild hemophila >5% activity= bleeding after significant trauma
91. Clinical Manifestations
• May go undiagnosed in newborn period.
• 90% with severe hemophilia present by 1 yr of age.
• 2% present with IVH.
• 30% males bleed after circumcision.
• 30% have no +ve family history( new mutation).
• Easy bruising, intramuscular hematomas, hemarthroses, begin when child
starts cruising.
• Hallmark of hemophila, hemarthroses (bleeding in joint), repeated bleeding
in same joint ( target joint).
• Bleeding in illiopsoas muscle( vague pain in groin, inability to extend hip),
hypovolemic shock.
• Life threatning bleeding in vital structures( CNS, Upper airway)
92. Diagnosis
• Prolonged aPTT, usually 2-3 times upper limit of normal.
• Platelet count, bleeding time, PT, thrombin time normal.
• Reduced levels of Factor VIII or IX.
• Correction of aPTT after mixing normal plasma.
• U/S or CT to see iliopsoas hematoma.
• Quantitative bethedsa assay for inhibitors
93. Treatment
• When mild to moderate bleed, factor must be raised to
35-50% range.
• When severe bleed, factor activity be raised to 100%.
• For mild hemophilia A, desmopressin acetate can be
used, ( no role in hemophilia B)
– 1 intranasal spray (150ug) for < 50kg
– 2 intranasal sprays (300ug) for> 50kg.
• Once weekly S/C inj of monoclonal antibody emicizumab
can increase factor viii activity.
Dose of FVIII(IU)= % desired of Fviii x body wt x 0.5
Dose of FIX(IU) = % desired of FIX x body wt x 1.3
95. Prophylaxis:
• Life long prophylaxis in severe hemophilia to prevent
joint bleeding
• Usually started after 1st / 2nd joint hemorrhage.
• Target factor trough level are 1-2% activity.
Supportive care:
• Counselling about avoiding trauma
• Use of car seats, seatbelts, helmets, avoidance of high
risk behaviour.
• Hep B vaccination.
• Screening for hep B, C, HIV.
• Avoid aspirin and NSAIDS.
96. Chronic complications:
• Chronic arthropathy
• Transfusion transmitted infections
• Development of inhibitor to Factor viii/ ix (25-
30% with hemophilia A, 2-3% with hemophilia B)
– Desensitization ( high doses of factor viii /ix)
– If desensitization fails, active factor vii / prothrombin
complex
– Emicizumab
97. Von Willebrand Disease
Most common inherited bleeding disorder, prevalence 1:100 to
1:10000.
1. VWF serves to tether platelets at injured endothelium.
2. Act as a carrier protein for factor viii.
Clinical presentation:
• Mucosal bleeding (epistaxis, bruising, menorrhagia)
• Surgical bleeding (dental extraction, adenotonsilectomy)
• Joint bleeds
• Men and women are equally affected.
• Women are more likely to be diagnosed
98. Classification VWD
VWD may be caused by qualitative and quantitative defects in VWF.
Type 1 VWD:
• Most common type, 60- 80 %
• Symptoms are mucosal bleed (epistaxis, menorrhagia), easy
bruising, surgical bleed.
• Diagnosed by VWF:Ag assay of <30IU/dl
Type 1C VWD:
• Low level of VWF due to increased clearance.
99. Classification VWD
Type 3 VWD:
• Most severe form.
• VWF protein completely absent.
• Can present like mild hemophilia.
• Mucosal bleed, joint bleed, CNS hemorrhage.
• Very low FVIII <10 IU/dl
Type 2A VWD:
• Decreased VWF activity ( platelet binding)
• Mutations , that affect multimer assembly and processing
• Mutation that cause increased proteolyses of secreted VWF.
Type 2B VWD:
• Mutation, that increase VWF activity to bind platelets.
• Increased clearance of both platelets and VWF.
• Thrombocytopenia may be present during stress ( surgery, pregnancy)
• Desmopressin treatment is contraindicated. ( may increase platelet, VWF
binding and clearance)
100. Classification VWD
Platelet-type-pseudo VWD:
• Defect in GP1b, spontaneous binding to VWF, Decreased VWF
activity.
• Loss of HMW multimers, thrombocytopenia
• Treatment require platelet transfusion.
Type 2M VWD:
• Decreased VWF activity
• Normal multimer distribution.
• Defect in ability of VWF to bind platelet GP1b.
Type 2N VWD:
• Defect in ability of VWF TO BINF FVIII
• May be misdiagnosed as mild hemophilia.
• Low FVIII level, absent family history of FVIII deficiency.
101. Diagnosis
• No reliable screening test for VWD.
• VWF:Ag ratio, measure total amount of VWF.
• VWF activity test, VWF:RCo provide amount of
functional VWF.
• Multimer distribution
• VWF binding to GP1b , VWF: GP1bM.
102. Treatment
• Type 1 patients may be treated with desmopressin. ( except type 1 C).
• Type 2 and 3 require VWF concentrates.
• Antifibrinolytics ( aminocaproic acid, tranexamic acid)
• Hormonal treatment for menorrhagia.
• Local treatment of epistaxis ( cautery, nasal packing).
103. Disseminated Intravascular
Coagulation
DIC: Thrombotic microangiopathy, that result in consumption of clotting
factors, platelets and anticoagulant proteins.
Etiology
• Any life threatening severe systemic disease, with hypoxia, acidosis,
tissue necrosis, shock, endothelial damage.
• Activation and release of cytokines and chemokines. Prothrombotic
state.
• Consumption of pro and anticoagulants
• Hemorrhage
• Thrombosis ( skin, kidney, other organ).
Clinical Manifestation:
• Bleeding from venipuncture sites/ surgical incision.
• Petechiae and ecchymoses
• Infarction of large areas of skin, subcutaneous tissue, kidney.
• Microangiopathic hemolytic anemia
105. Diagnosis:
• Prolongation of PT, APTT, TT.
• Decreased platelet count.
• Blood film contain schistiocytes.
• Fibrinogen degradation product ( D-dimers).
Treatment
• Treatment of cause
• Correction of shock, acidosis, hypoxia.
• Platelet infusion ( thrombocytopenia)
• Cryoprecipitate (hypofibrinoginemia)
• FFP ( for replacement of other coagulation factors and
inhibitor).
• Heparin ( vascular thrombosis)
106. Liver disease
• All clotting factors except factor viii are formed in liver
• Severity of bleeding is directly proportional to liver damage.
• Treatment of coagulopathy of liver disease should be reserved for
patients with clinical bleeding.
Treatment
• Vitamin K ( I/V, S/C, Oral, not I/M)
– 1mg/ 24 hour in infants
– 2-5mg/24 hr in children
– 5-10mg/24 hr in adolescents and adults.
• FFP ( 10-15ml/kg) contains all clotting factors
• Cryoprecipitate (hypofibrinogenemia) 1 unit /5-10kg .
• Desmopressin ( 0.3ug/kg i/v) some role ( used before liver biopsy)
• Recombinant factor VIIa
107. Platelete Disorders
• Platelete life span 10-14 days.
• Normal count 150-450x 10/ L
• Thrombocytopenia refers to < 150 x10/ L
• Significant bleeding is not seen untill count falls below
50, 000.
Causes of thrombocytopenia:
1. Decreased production ( conginital / aquired)
2. Sequestration in enlarged spleen
3. Increased destruction of normal platelets ( immune/
non immune)
111. Idiopathic Thrombocytopenic
purpura
The most common cause of acute thrombocytopenia in a
well child is autoimmune ITP.
Epidemiology
• Occurs in 1: 20,000 children 1-4 wk after common viral
infection (EBV, HIV)
• Can rarely occur after vaccination.
• Autoantibody is directed against platelet surface.
• Recent history of viral infection in 50-65 %.
• Peak age is 1-4 yr, can present in early infancy and
elderly.
• Usually occur in spring and late winter.
112.
113. Clinical Manifestations
• Generalarized petechia and purpura.
• May be bleeding from gum and mucous membrane, (plt count <
10x 10L).
• History of preceding viral infection (1-4wk back)
• Splenomegaly, lymphadenopathy, bone pain, pallor are rare.
(leukaemia)
United kingdom classification on bases of symptoms.
1. No symptoms
2. Mild symptoms, bruising, petechiae. Occasional minor epistaxis,
very little interference with daily activity.
3. Moderate symptoms, more severe skin and mucosal lesions,
more troublesome epistaxis and menorrhagea
4. Severe symptoms, menorrhagea, epistaxis, melena requiring
transfusion/hospitalization, seriously interfere with quality of life
114. Outcome
• Severe bleeding is rare < 3% cases
• In 70-80% spontaneous resolution occur in 6 months.
• Fewer than 1 % develop ICH (intracranial hemorrhage).
• Objective of early therapy is to raise plt >20x10/L ( to prevent serious
bleeding)
• 20% children with acute ITP develop chronic ITP.
• ITP in younger children more likely o resolve.
• ITP in adolescents, 50% develop chronic ITP.
Laboratory findings
• Severe thrombocytopenia (<20x10/L) is common).
• Platelets are of normal/ increased size.
• HB and WBC are normal, HB may be low if massive nose bleed or
menorrhagia
• Bone marrow biopsy, if abnormal WBC count or unexplained anemia,
abnormal physical findings.
• Direct COOMBS test, if unexplained anemia ( to rule out EVAN syndrome=
autoimmune anemia and thrombocytopenia).
• ANA if suspecting SLE
115. Differential Diagnoses
• Drug induced antibodies (Valproic acid, phenytoin,
carbamazepine, sulfonamides, trimethoprim-
sulfamethoxazole)
• Splenic sequestration (portal hypertension)
• Early aplastic process (Fanconi anemia).
• TAR
• Serious systemic illness( HUS, DIC)
• Heparin induced thrombocytopenia
• Autoimmune thrombocytopenia may be initial
manifestation of SLE, HIV, CVID, Lymphoma.
• Wiskott-Aldrich syndrome= thrombocytopenia, small
platelets, eczema, recurrent infections.
116. Treatment
1. No therapy:
• Minimal, mild and moderate disease.
• Education and counseling.
2. Treatment with IVIG/ Corticosteroids.
• Those who present with mucocutaneous bleeding.
• Single dose of IVIG 0.8-1 g/kg/(aseptic meningitis) OR
• Short course of corticosteroids 1-4 mg/kg/24 hr untill plt count >20x10/L ( to
avoid side effects).
3. Treatment of ICH
– Transfusion of plt, IVIG, High dose steroids
– Consultation to neurosurgery and surgery.
4. Splenectomy
• If child is >4 yr, with severe ITP that lasted >1 yr, and symptoms not easily
controlled with therapy.
• When life threatening hemorrhage (ICH) in acute ITP, when plt count can not
be corrected by transfusion, IVIG or steroids.
5. Rituximab (off label)
• Chronic ITP ( 30-40%) partial / complete remission.
6. Thrombopoitin receptor antagonist
117.
118. Chronic ITP
• Persistent thrombocytopenia >12 month is chronic ITP.
• Reevalution should be done for SLE, HIV, H-Pylori, x-
linked thrombocytopenis, wiskott-aldrich syndrome, Von
willebrand disease, CVID.
Treatment:
• Splenectomy is succecful in 64-88%.
• Rituximab
• Romiplostin and eltrombopag ( stimulate
thrombopoiesis)
119. Thrombotic Thrombocytopenic
purpura
TTP is rare thrombotic disorder charecterized by pentad:
fever, microangiopathic hemolytic anemia,
thrombocytopenia, abnormal renal function, and CNS
changes.
• Majority of cases are caused by autoantibody mediated
deficiency of ADAMTS13 ( Metalloproteinase ,responsible
for cleaving high molecular weight multimers of VWF).
• Congenital deficiency (ADAMTS13) cause rare familial
cases.
• Usually presents in adults, occasionally in adolescents
120. Clinical Manifestations:
• Microvascular thrombi in CNS, Changes in orientation, aphasia,
blindness, seizures, initially nonspecific (weakness, pain, emesis).
Diagnosis:
• Microangiopathic hemolytic anemia
• Shistocytes, spherocytes, helmet cells
• Increased retic count
• Thrombocytopenia
• Urea creatinine raised
• Coagulation studies nondiagnostic.
Treatment:
• Plasmapheresis ( effective in 80-95% cases). Should be done on
basis of thrombocytopenia, microangiopathic hemolytic anemia
• Rituximab, corticosteroids, splenectomy for refractory cases.
• Caplacizumab (anti VWF humanized immunoglobulin).
121. Congenital Thrombocytopenic
syndrome
Congenital amegakaryocytic thrombocytopenia (CAMT)
• Rare defect in haematopoiesis due to mutation in stem
cell TPO receptor.
• Usually presents within 1st few days to weeks of life.
• Physical exam is normal except skin and mucous
membrane abnormalities.
• Bone marrow show absence of megakaryocyte.
• Patient often progress to marrow failure with time)
aplasia)
• Hematopoietic stem cell transplantation (HSCT) is
curative
122. Thrombocytopenia-absent radius
(TAR) syndrome
TAR consist of thrombocytopenia (absence or hypoplasia
of megakaryocytes), with bilaterall radial anomalies.
• Linked to RBM8A.
• Presents in early infancy.
• Mild changes to marked limb shortening
• Other skeletal abnormalities of ulna, radius, lower
extremities.
• Thumbs are present
• Intolerance to cow milk formula ( 50%)
• Thrombocytopenia, anemia, esinophilia, leukemoid
reaction
124. Neonatal alloimmune thrombocytopenic purpura
(NATP): Development of maternal antibodies against
antigens present on fetal platelets that are shared with
father.
• This is platelet equivalent of rh disease.
• Incidence is 1 in 4000- 5000 births
• Apparently well child, with petechiae and purpura within
first few days after birth.
• Maternal platelets are normal, moderate to severe
thrombocytopenia in newborn
• 30% present with prenatal/ perinatal ICH
• First pregnancy may be severely affected, subsequent
pregnancies are more severely affected
125. Diagnosis:
• Presence of maternal antibodies against father’s platelets.
• DNA sequence polymorphism (antenatal testing)
• Common cause is incompatibility for platelet alloantigen (HPA-1a).
Treatment
• IVIG prenatally to mother (started in 2nd trimester and continued
throughout).
• Monitoring of fetal platelets by percutaneous umbilical sampling.
• Delivery by C-SEC
• After delivery if severe thrombocytopenia, transfusion of maternal
washed platelets
• Thrombocytopenia usually resolve in 2-4 months.
• Genetic Counselling ( high risk in subsequent pregnancies)
126. Maternal ITP
• Lower risk of serious hemmorhage than NATP.
• Maternal thrombocytopenia can predict severity of
disease in newborn.
• Mother platelete count may be normal in case of
splenectomy.
Treatment
• Prenatal steroids/ IVIG to mother.
• Corticosteroids in infant.
• Thrombocytopenia resolve within 2-4 months.
128. Congenital Abnormalities
Bernard Soulier Syndrome:
Severe congenital (autosomal recessive) platelet
function disorder, caused by deficiency of VWF receptor
on platelet membrane.
• Mutations identified in gene forming GP1b complex
• Thrombocytopenia
• Giant platelets
• Patient present with significant mucocutaneous and GI
bleeding.
• Prolonged bleeding time> 20 min or PFA-100
• Absent ristocetin induced platelet aggregation.
• Normal aggregation to all other factors.
129. Glanzman thrombasthenia:
Congenital autosomal recessive disorder, caused by
deficiency of platelet fibrinogen receptor a11b-B.
• Platelets are of normal size and count.
• Significantly increased bleeding time and PFA closure
time.
• Aggregation studies show abnormal aggregation to all
agents except ristocetin.
• Present with severe mucocutaneous bleed , epistaxis, GI
bleed, gingival bleed.
• Diagnosis confirmed by flow cytometric analysis of
patient’s platelet glycoproteins.
130. Treatment
• Desmopressin 0.3ug/kg I/V can be used in mild to
moderate bleeding (Increases levels of VWF, Factor viii,
corrects bleeding time).
• Antifbrinolytic therapy for mucosal bleed.
• Platelet transfusion (antibodies can develop to deficient
platelet proteins)
• Off label Factor VIIa (in patients with antibodies)
• HSCT is curative.