Pediatrics

3B – March 2017 WHAT IS LEUKEMIA?

HEMATOLOGY • Generalized à Disseminated at onset
Dr. Rondilla (from old trans + MRA trans + Lecture) • Irreversible à No reversal to normal
LEUKEMIAS
• Malignant à Can disseminate and kill
LEUKEMIA
• Clonal à Same morphologic and
• Results from unbridled (uncontrolled/continuous)
immunologic and
proliferation of immature hematopoietic precursors
biochemical
derived in some, if not all cases, from damaged
characteristics
hematopoietic progenitors that lack the capacity to • Self-perpetuating à Stem cells/ precursor cells
transfer differentiation program to the precursors to • Purposeless à No use, but can do harm
which they give rise
• Staging is only for SOLID tumors
CLONAL EXPANSION THEORY
• There is NO staging for leukemia.
• Single damaged progenitor capable of expansion by
• Leukemia staging is ”DISSEMINATED”
indefinite self-renewal, gives rise to malignant poorly
• Leukemia can affect ANY organ system.
differentiated precursors
• 3 cell lines from BM: RBC, platelet, WBC
o Eg: G6PD Isoenzymes


DEFINITION
THE CELL CYCLE
• RESULTING IN: PANCYTOPENIA
1. Anemia à pallor
2. Thrombocytopenia à bleeding
3. Neutropenia à infections (ANC
(Absolute Neutrophilic Count) <1500 TO get this,
calculate Total WBC * neutrophil %)
4. DEATH (usually die within 3 – 6 months without
treatment)

1. Bone marrow
2. Lymphadenopathy (1 of the 3 RES)
3. Hepatomegaly (1 of the 3 RES)

4. Splenomegaly (1 of the 3 RES)
We need 1 Tumor suppressor genes & 2 DNA repair genes so 5. RES including extramedullary tissues
cancer won’t manifest o Example: skin, CNS, testicles, etc.
o Testicles as hard as elbow (instead of nose)

ALL AML
Bone Pancytopenia Pancytopenia
marrow with blast cells
RES Yes (lymphadenopathy, No
Hepatomegaly,
splenomegaly)

CLASSIFICATION
• ACUTE (NOT referring to time. It refers to maturity)
o Profusion of immature hematopoietic or
lymphoid precursors
• CHRONIC
o Expansion of mature marrow element
This is for ALL CANCERS, not just leukemia. Normal DNA
repair genes & tumor suppressor genes will prevent this above
• CONGENITAL LEUKEMIA

o Diagnosed during first month of life


DEON 1
 o Lymph, Myeloid, or BOTH (“biphenotypic”) 1ml for immunophenotypin
1ml for cytochemistry and
ACUTE LEUKEMIA chromosomal studies
• 35% of childhood malignancies o Need assistant to prevent clotting.
• Acute lymphoblastic – 80% (more common in child) o Not smearing. It’s squashed because it’s
fatty to distribute it.
• Acute myeloblastic – 15% (more common in adults)

• Acute undifferentiated - 5% (stem cell or 1. MORPHOLOGY
biphenotypic LYMPHOBLAST MYELOBLAST
Bigger nucleus, less Bigger cytoplasm, less
CLINICAL MANIFESTATION cytoplasm nucleus
• Anemia: pallor • Higher N/C ratio • Lower N/C ratio
• Thrombocytopenia: bleeding • Agranular • Granular
• Neutropenia: infections • Small rim of light blue • Abundant dark blue
o Hepatosplenomegaly: 30-40% staining cytoplasm staining cytoplasm with
generally without granules
o Lymphadenopathy: 30-50%
granules • Auer rods (granules)
o Mediastinal Mass: 71% T cell ALL (so CXR
• Smooth homogenous • More firmly developed
seen in “bulky” disease) nuclear chromatin nuclear chromatin (coarse)
o CNS 1-10% (T-cell ALL) • Indistinct nucleoli • More distinct punched
• EXTRAMEDULLARY LEUKEMIA out nucleoli
o CNS: 5% at dx
o SPINAL CORD BONE MARROW MORPHOLOGY
o THYMUS: 10% ALL • Small (lymphoblasts) cells with high N/C ratio
FAB • Scanty, pale blue cytoplasm
o TESTICULAR: 1-6%
L1 • Indistinct nucleoli and nuclear membranes
o RENAL
round or elicited
o OVARIAN ALL • Larger, more heterogenous, lower N/C ratio
o BONES AND JOINTS FAB • Prominent nucleoli with perinuclear chromatin
o GIT L2 condensation
o OCULAR • Irregular nuclear membranes – reniform or
o CARDIAC irreg.
o PULMONARY • Combo of small and large lymphoblasts
o SKIN (Leukemia cutis) ALL • Mature B cells immunophenotypically
FAB • Homogenous groups of cells with deeply

L3 basophilic cytoplasm (easy differentiation) with
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
CLASSIFICATION OF ALL cytoplasmic vacuolation
• MORPHOLOGY • Rare in children. Much less common then L1/2
• IMMUNOPHENOTYPE
2. BONE MARROW IMMUNOPHENOTYPE
• HISTOCHEMISTRY
• B CELL CD 19, CD 22, HLA-DR
• BIOCHEMICAL
• EARLY PRE-B CD 19, CD 20, CD 10, HLA-DR
• MOLECULAR
• PRE-B CD 19, CD 22, CD 10, HLA-DR
Initial test: CBC • MATURE B-CELL CD 19,CD22,HLA-
• Pancytopenia and sometimes BLASTS in peripheral DR,KAPPA,LAMDA
• For eg: bulky disease • T-CELL CD 3, CD 5, CD 7, HLA-DR
• Pancytopenia without organomegaly? Differential is: • MYELOID CD 13, CD 33, HLA-DR
o aplastic anemia • MIXED LINEAGE Lymphoid and myeloid markers
o aleukemic leukemia (pancytopenia but no • AUL CD 34, CD 38, CD 7, HLA-DR
blasts in peripheral blood; so to diagnose,
you MUST do BM aspiration) *All cells in body have cell markers. Leukemics are CD
• BM aspiration locations (with LOCAL anesthesia): (“Cluster of Designation” in surface of blast cells)
o Infant: Tibial bone *“AKR”
o Child <10yo: ASIS *CD 10 = “CALLA” (Common Acute Lymphocytic Leukemia
o Child >10yo: Lateral decubitus à PSIS Antigen) indicates GOOD PROGNOSIS = “PRE” cell
o Obese: Sternum *Acute undifferentiated = stem cell
• Aspiration = 0.5ml for BM morphology
DEON 2
*To be MIXED lineage, you need TWO markers from each AML UNFAVORABLE PROGNOSIS: (PR) POOR RISK ALL
and ALL 35% cure rate
*Basic leukemia panel tests for both lymph and myeloid • Two Most Important Factors
*Mature B-Cell has poor prognosis o Age < 1 or ≥ 10 years*
o Initial WBC ≥ 50, 000/mm3*
3. BONE MARROW CYTOCHEMISTRY • Male
When patient can’t afford immunotyping above, then do this • Lymphomatous or bulky disease
PERIODIC • Cytoplasmic glycogen à red • Platelet count < 100
ACID SCHIFF • 80% lymphoblasts; fine staining in • Morphology FAB L2 or L3
(PAS) myeloid • Immunophenotype Sig(+), CD10(-), CD20(-)
• (+) in ALL • Cytogenetics- pseudodiploid
MYELO- • Cytoplasmic granular enzymesà brown- • DNA Index <1.16
PEROXIDASE black • Response to Induction d14 > 25% blasts
• 75% myeloblasts
SUDAN • Cytoplasmic lipids àblack POOR RISK FACTORS IN LEUKEMIA
BLACK • Myeloblasts • Age below 1 year, older than 10 years
NON • Stain granules and Auer rods; monocytes • Initial WBC > 100,000
SPECIFIC and monoblasts (differentiates • Bulky disease
ESTERASE monoblasts from myeloblasts) • Biphenotypic
(NSE) • Extramedullary disease
*So if you want to differentiate lymphoblasts from • AML
myeloblasts, send it for PAS, myeloperoxidase, and NSE. • Ph+ ALL
• High count T-ALL
4. BONE MARROW BIOCHEMICAL MARKERS (not done in the • Late remissions
Philippines)
• TDT Patient first has pallor, petechiae, huge organs, anemia,
• HEXOSAMINIDASE thrombocytopenia, neutropenia, bone marrow > 25%.
• PURINE NUCLEOSIDE PHOSPHORYLASE
• 5’ NUCLEOTIDASE COMPLETE REMISSION should be in 3 parameters:
• ADENOSINE DEAMINASE 1. Anemia (no anemia, thrombocytopenia, infection)
2. Peripheral blood (Hgb, platelet count, WBC)
5. BONE MARROW MOLECULAR STUDIES 3. Bone marrow blasts < 5%
• HYPERDIPLOID: “GR” = good risk. BEST prognosis Complete remission as early as 14 weeks of induction therapy
• PSEUDODIPLOID: “GR”
• HYPODIPLOID: “GR”. GOOD prognosis OVERRIDING OBJECTIVE OF TREATMENT IN LEUKEMIA
• Translocations = PR (poor risk) • Maximum cell kill as early as possible
o t (9:22) - Philadelphia (Poor prognosis) • ↓ leukemia cell mass before drug resistance
o t (1:19) emerges
o t (4:11) (q21:q23) • SEVERAL treatment regimens in ONE SITTING to
o t(8:14), t(2:8), t(8:22) prevent resistance. (not once each week)
• Double-edged sword
FAVORABLE PROGNOSIS: (GR) GOOD RISK ALL (95% cure o Don’t treat à die
rate) o Treat à destroy all blast cells in BM, but
• Two Most Important Factors kills normal cells also. So with treatment,
o Age 1-10y you must be ready to treat infections,
o Initial WBC <50,000/mm3 anemia, etc.
• Female
• Absent lymphomatous disease (no “bulky dse”)
• Platelet count ≥ 100
• Morphology FAB L1
• Immunophenotype CD 10, CD 20
• Cytogenetics- hyperdiploid
• DNA Index ≥ 1.16
• Ig at Diagnosis Normal IgM, IgA, IgG
• Response to Induction D14 BMA <5% blasts

DEON 3
 CTX, Ara-C, 6MP,
IT MTX
CNS PROPHYL. IT MTX
MAINTENANCE 26 months (girls)
32months (boys) (check testicles)
Vincristine, 6MP, MTX,Prednisone
Intrathecal = lumbar and inject medicine into the back

ACUTE MYELOGENOUS LEUKEMIA (AML)
• 15-20% of childhood
• 80% of adult leukemias
Picture that indicates ALL survival has greatly improved from
20% in 1972 (treatment was just prednisone) à oral, • Incidence stable from birth to 10 y/o, increases in
parenteral, à VERY high survival now, maybe 90+% teenage years, stable, progressive at 55y/o
• Equal sex predilection
• Induction for 1 month • Downs syndrome
• Goal = complete remission, but even when they feel
10
better, they have 10 leukemia, so need CONDITIONS
maintenance chemotherapy for THREE YEARS with • Down’s syndrome
checking up
• Fanconi
o Chemotherapy every 3 months
o BM aspiration every 3 months • Blooms Syndrome
o Every day drinking chemotherapeutic • Kostmann’s syndrome
agents. • Diamond Blackfan Syndrome
• After 3 years, do immunophenotyping. If back to • Alkylating agents
normal, TREATMENT IS DONE, but for next 2 years, • Epipodophyllotoxins
th
(for year 4 and 5), because HIGH RELAPSE, During 4
th • Ionizing radiation
and 5 year, it’s “maintained remission”. DO:
o CBC every month • Myelodysplastic syndromes (preleukemic)
o BM every 3 months • Myeloproliferative disorders (preleukemic)
th
• At end of 5 year o These 2 pre-leukemic are “killing me softly”.
o “CURED” after 5 years, not after 3 years Eventually you’ll develop AML and it’s the
140 DAY PVDA difficult one to treat
PROTOCOL: PROTOCOL:

GOOD RISK ALL POOR RISK ALL
BIOLOGY of AML
(Note 7 below.
• Clonal hemopathy lacking homeostatic coupling of
MORE
INTENSIVE proliferation and differentiation
PROTOCOL) • AML clone rises from leukemic transformation of an
INDUCTION 28 D Vincristine, Vincristine, early hematopoietic progenitor cell
Prednisone, L- Doxorubicin, • The concept of leukemic stem cell with extensive
ASP, IT Prednisone, L- self-renewal capacity and considerable
methotrexate ASP, IT,
differentiation potential
Methotrexate

CONSOLIDATION 70D: Vincristine, 28D: 6MP, Ara-
SYMPTOMATOLOGY
Dexamethasone, C. CTX, IT MTX
(same, 2° to anemia, neutropenia, thrombocytopenia)
IT and Oral MTX,
• Progressive malaise
6MP
INTERIM 6 MP, Oral MTX • Infections
MAINTENANCE 42 • Bleeding diathesis (thrombocytopenia. Most
D common)
RECONSOLIDATION 6 MP, Ara-C, o Some may develop thrombocytopenia from
28D CTX, IT MTX DIC. AUER rods have procoagulants à DIC
DELAYED 42D: Vincristine, 28D: Vincristine,

INTENSIFICATION Dexamethasone, Dexamethasone,

ASP, ASP,

Doxorubicin, Doxorubicin


DEON 4
CLINICAL FINDINGS • For molecular we look for “RARA” gene (important
• Pallor for monitoring treatment)
• Bleeding – skin, mucosa, GIT, GUT, CNS • Because t(15:17) and RARA gene treatment is all-
• Signs of infection trans-retinoic acid
• Gum hyperplasia (foul smelling, grayish)
PHASES OF TREATMENT
DIAGNOSIS o Initial Anthra is given BEFORE to prevent
• BMA MORPHOLOGY later chemotherapy that may burst all
• BMA CYTOCHEMISTRY promyelocytes à ?
• BMA IMMUNOPHENOTYPING • REMISSION INDUCTION
• BMA CYTOGENICS o cytosine, arabinoside, anthracycline
• You have to admit them 7 days, with main treatment
Deals with 4 lines: GEMM every 28 days? Until end of treatment after 3 years.
• Granulocyte Additional costs for common infections of 3
rd

• Erythroid th
generation and 4 generation antibiotics are usually
• Monocyte needed, plus PRBC, platelets, growth factors, on top
• Megakaryocyte of these medications
• POSTREMISSION THERAPY
1. BMA MORPHOLOGY FAB o Consolidation
CLASSIFICATION of AML
o Intensification
FAB MORPHOLOGY CYTOGENETICS OTHER
o CNS prophylaxis
FEATURES
o Supralethal radiochemotherapy à BMT
M0 Undifferentiated Myeloid
(BM transplant)
immune
§ Poor outcome if BMT needed
markers
o Maintenance
M1 Myeloblastic, t (8;21)

undifferentiated Febrile neutropenia requires these 3 criteria:
M2 Myeloblastic, Auer rods 1. 2 episodes of 38C in 24 hours
differentiated 2. ANC < 500
M3 Hypergranular t (15;17) Auer rods 3. Post-chemotherapy
promyelocytic (this is (coalesce
the one prone to DIC) to form PROGNOSTIC FACTORS
“fallot”? • Ability to survive intensive therapy
cells) o Age
M4 Myelomonocytic Inversion 16 o Performance status
leukemia; t (9;11) o Abnormal hepatic function
M4 Myelomonocytic with Abnormal o Abnormal renal function
Eo eosinophilia eosinophils o Presence of DIC
M5 Monoblastic/monocytic Gingival • Ability to enter and maintain complete remission
hyperplasia o Cytogenetics
M6 Erythroblastic leukemia § Best response t (8;21), inv16
M7 Megakaryoblastic Platelet § Intermediate t (15;17)
leukemia specific o In vitro studies: Worst – autonomous
immune growth in clonogenic
markers assay, low labelling index,
M0-M5 = GR low ara-c triphosphate
• Best AML to get is M3, since it’s best one treatable retention
with alltrans-retinoid acid (Vit A). • Clinical response – better prognosis
M6-M7 = PR o Rapid cytoreduction
o One course to complete remission
2. Cytogenetics
• Look for t(15:17)
DEON 5
 • Immunophenotyping Mixed • Mixture of lymphocytes, plasma cells,
o Worst prognosis – CD 13, 14, 34; Cellularity eosinophils, histiocytes,
biphenotypic; CD 11b, CD 11c 40-50% • reticular cells, RS cells
o Better prognosis – low levels of CD 13, 14, Lymphocyte • Bizarre malignant reticular cells, RS
34; lack of HLA-DR reactivity Depletion cells and few lymphocytes
• MDR expression <10% • Poorest prognosis
o Worst prognosis – M0, M5, M6, M7
o Better – M3, M4Eo, Auer rods HISTOLOGY of HD: NEW WHO/REAL Classification (another
• Prior disease classification than the one above)
o Poor – antecedent hematologic disorder, • Nodular Lymphocyte Predominance
therapy related leukemia • Classical Hodgkin Lymphoma
• Age – older age is independent poor prognostic • Lymphocyte rich
factor • Mixed cellularity
• Clinical features at presentation • Nodular Sclerosis
o Poor – WBC >100,000, marrow fibrosis, CNS • Lymphocyte depletion
leukemia, extramedullary leukemia • Anaplastic large cell

HODGKIN LYMPHOMA: HODGKINS DSE STAGING: Ann Arbor
• Rare before 5 y/o • A = absence
• Peaks at 15-34 and after 55 y/o (adults) • B = 10% weight loss, fever, night sweats
• Male > female • Eg: “Hodgkins IIB”
• Associated with EBV I Single node region or single extranodal site
• More in adults, rare in children II 2 ≥ nodes/ sites on same side of the diaphragm
III localized nodes/ sites both sides of the diaphragm
Clinical Manifestations IV diffuse spread (bone marrow)
• Enlarged nodes: firm, non-tender <supraclavicular>
• Chronic cough: mediastinal <anterior> TREATMENT
• Night sweats, fever, weight loss, lethargy, • Chemo & Radio COMBO
fatigability, anorexia, pruritus • Determined by
• Assoc. with Immune disorders o Disease stage
o Patient’s age
DIAGNOSIS o Presence of “B” symptoms
• Lymph node biopsy o Presence of hilar lymphadenopathy
• CXR • CHEMOTHERAPY
• CT scan For Staging o Hybrid protocols – MOPP, COPP, ABV/COPP,
• Bone marrow biopsy ABVD (can cause sterility, so they’re
• Laparotomy recommended to first undergo sperm bank)
• CBC o Outpatient, every 21 days, for 6 courses. If
• ESR, Ferritin, Copper still residual tumor, extend another 6-12
• Liver function test months before radiation.
• Gallium scan • RADIATION
o Involved field irradiation
HISTOLOGY of HD: RYE Classification o M- Mustargen
Lymphocyte • Occasional RS cells (pathognomonic), o O- Oncovin <Vincristine>
predominance mostly mature lymphocytes o P- Procarbazine
10-20% • Best prognosis o P-Prednisone
Nodular • Collagen bands in lymph nodes o A- Adriamycin <Doxorubicin>
sclerosis • RS cells appear as lacunar cells o B- Bleomycin
50-70% o V-Vinblastine
o D-Dacarbazine

DEON 6
 • PROGNOSIS of HD • Follicular, Small • Diffuse small • Small non-
o Stage I and II >90% complete remission cleaved cell cleaved cell cleaved cell-
o Stage III 75% CR • Mixed small • Diffuse small burkitts,
o Stage IV 50% CR cleaved and cleaved and follicular (non-
large cell large cell burkitts)
If you had to have NHL or HL, HL is BETTER because it behaves • Diffuse large cell
like leukemia


MAJOR PATHOLOGICAL SUBTYPES (skimmed, except the %)
NON-HODGKIN LYMPHOMA (NHL)
Burkitt • Sporadic type – Abdominal 40%
• More common than HD in younger children
Lymphoma (BL) • Endemic type – head, neck,
• WORSE. It behaves like leukemia. Choose HL over
BM, CNS
NHL
Lymphoblastic • Intrathoracic, mediastinal 30%
• 60% of all lymphomas in children and adolescents
Lymphoma (LL) supradiaphragmatic mass,
• 8-10% of all malignancies 1-19 y/o
BM, CNS
• M:F is 3:1
Diffuse Large B • Abdominal, mediastinal 20%
• >70 % advanced disease (↑BM involvement)
Cell Lymphoma
• Immunodeficiencies (DLBCL)
• Usually lymphoblastic, aggressive type Anaplastic Large • Primary cutaneous 10% or 10%
Cell Lymphoma systemic disease (fever, wt
CLINICAL MANIFESTATIONS (ALCL) loss)
• Painless, unexplained LN swelling, non-tender, firm
• Spread: liver, spleen, lung,
• Anterior mediastinal mass – cough, dyspnea, pleural
mediastinum or skin, BM,
effusion, SVC syndrome
CNS
o For BOTH NHL and HL, before we send them

for LN biopsy, we give therapeutic trial of STAGING OF NHL – St. Jude
antibiotics for 2 weeks first, to see if they I Single tumor or node anywhere except
are exempted of having cancer of the LN. If mediastinum or abdomen
EBV is ruled out (from EBV titer) and no II Single tumor or node plus regional LN or two
response, then do LN biopsy. nodes/ sites on same side of diaphragm, primary
o Unless they have SVC syndrome, and it’s abdominal
compressing the heart, then that’s already III Both sides of the diaphragm, primary intrathoracic,
diagnostic of it, so we need to shrink mass or extensive primary intraabdominal
first by radiation or steroids. IV plus bone marrow, CNS (most patients)
• Abdominal: mass, obstruction, intussusceptions
• BM: bone pains; >25% blasts TREATMENT
• Meningeal: increase ICP • SURGERY – diagnostic (biopsy)
• Fever, weight loss • CHEMOTHERAPY
o Systemic (CHOP (cyclophosphamide,
DIAGNOSIS of NHL atramycin, vincristin, prednisone) given
• Lymph node biopsy (for diagnosis) EVERY DAY for NHL unlike in HL, every 21d)
• CXR (for staging) o And CNS prophylaxis
• CT scan (for staging) • RADIATION
• Bone marrow biopsy (for staging)
PROGNOSIS
HISTOLOGY of NHL • Stage I and II 90-100% SR (survival)
LOW GRADE INTERMEDIATE HIGH GRADE • Stage III, IV 60-95% SR
GRADE (70% at • Lymphoma-leukemia worst prognosis
diagnosis) o If >25%lymphoma cells
• Small • Follicular • Large cell o Differentiate from NHL by BM problems:
Lymphocytic predominantly immunoblastic § NHL has tumor CLUSTERS
large cell • Lymphoblastic

DEON 7
 § Lymphoma-leukemia is DIFFUSE • When to suspect clotting disorder
• BMT for relapsed disease o Too many bruises for the degree of trauma
• One of the differentials for SMALL-ROUND-BLUE cell o New Bruises keep on appearing
o Multiple bruises of different stages
tumors (pancytopenia with huge LN)
CLINICAL FEATURES OF BLEEDING DISORDERS

PLATELET COAGULATION
PLATELET & COAGULATION DISORDERS
DISORDERS FACTOR
HEMOSTASIS
DISORDERS

Site of Bleeding Skin Deep in soft

Mucous tissues (muscles,
membranes joints)
(epistaxis, gum,
vaginal, GIT)
Petechiae Yes No
Ecchymoses Small, superficial Large, deep
(bruises)
Hemarthroses Rare Common
muscle bleeding
Bleeding after Yes No
cuts, scratches
Bleeding after Immediate Delayed (1-2 d)
surgery/ trauma Usually mil Often severe
(+) 2° bleeding
Abnormal 2°
bleeding time
ASSESSMENT OF BLEEDING PROBLEMS
• LABORATORY DIAGNOSIS
o Standard Coagulation Testing
§ Platelet count
§ PT, APTT
• EXTRINSIC: Vascular injury à Factor 7 stimulated § Fibrinogen Levels
• Anti-thrombin 3, protein C, and Protein S are o Additional Options
NATURAL anticoagulants that lyse fibrin clots, I think § Platelet function testing - BT, CRT
§ Specific factor assay (Factors VIII,
ASSESSMENT OF BLEEDING PROBLEMS IX, XI)
• Normal Coagulation Function § Fibrin degradation products
o Vasculature (Patients with DIC)
§ microcirculation
§ endothelium SCREENING TESTS (APTT, PT, Platelet Ct)
o Platelets
§ Quantity and Quality
o Coagulation Factors
§ Extrinsic Factors
§ Intrinsic Factors
• BLEEDING HISTORY
o Personal History
§ location of bleeding
§ surgical procedures
§ menstruation/childbirth
§ transfusion requirement
o Family History
o Medication History
• Petechiae
o Typical of platelet disorder
o Do not blanch with pressure ALLERGIC VASCULAR PURPURA
o Not palpable • Non thrombocytopenic purpura
• Ecchymoses Purpura • Allergic symptoms (Allergic Rhinitis, Conjunctivitis,
o Typical of coagulation factor disorder Bronchial asthma)
DEON 8
 • Normal PT, PTT, BT, CRT Platelet count <20,000/uL 30,000-
• Acute or chronic inflammation of the blood vessels 80,000/uL
of joints, kidney, GIT (Acute abdomen, hematuria, Eosinophilia and Common rare
petechiae) à HENOCH SCHONLEIN PURPURA Lymphocytosis
Duration 2-6 weeks (short) Months or years
IMMUNE THROMBOCYTOPENIC PURPURA (ITP) (insidious)
• “Morbus Maculosus Hemorrhagicus”,Werthof in Spontaneous Occur in 80% of Uncommon (2%)
1735 remissions cases
• Other names
o Autoimmune Thrombocytopenic Purpura FEATURES OF CHILDHOOD AND ADULT ITP
(ATP) FEATURE CHILDREN ADULT
o Immune Thrombocytopenic Purpura Occurrence
o Idiopathic Thrombocytopenic Purpura Peak age (yrs) 2-4 15-20
ITP
Sex (F:M) Equal 2.6:1
• Most common autoimmune disorder affecting
Prevalence/million 10-40 65
blood element
Presentation
• Most frequent cause of thrombolytic
Onset Acute Insidious
thrombocytopenia in immune platelet destruction
Most with Most with
• Diseases known to cause secondary
symptoms in symptoms in
thrombocytopenia have been excluded
<1wk >2mos
• Accelerated destruction of sensitized platelets by
Symptoms Purpura Purpura
phagocytic cells in the reticuloendothelial system
<10% with Typical bleeding
leads to thrombocytopena
severe bleeding not severe
• Function of the BM is normal. Platelet count Most <20,000 Most >20,000
• PATHOPHYSIOLOGY OF ITP Course
o Triggers like infection, immunization and
Spontaneous 83% 2%
toxin induces format’n of antibody against
remission
platelets
Chronic disease 24% 43%
o Ab attached to the platelets cause
Response to 71% 66%
sensitization of the platelets
splenectomy
o Sensitized platelets are then destroyed by
Eventual complete 89% 64%
phagocytic cells in the RES
recovery
• INFECTIONS PRECEDING ITP
Morbidity/Mortality
o Rubeola and Rubella
o Viral respiratory disease Cerebral <1% 3%
o Varicella zoster virus hemorrhage
o EBV Hemorrhagic death <1% 4%
o Non-specific viral infections Mortality of chronic 2% 5%
refractory disease
CLASSIFICATION
• Primary vs secondary BLEEDING MANIFESTATIONS
• Acute vs chronic 1. Skin and mucous membrane
o Chronic ITP defined as platelet count of o “Dry purpura”: Ecchymoses and petechiae
9
o <150 x 10 / L for > 6 months o “Wet purpura”: Skin + mucus membranes
§ (Epistaxis, gingival <30%)
• Childhood versus Adult
2. Hematuria and GI bleeding: <10%
FEATURES OF CHRONIC AND ACUTE ITP 3. CNS
o Usually subarachnoid hemorrhage
FEATURE ACUTE CHRONIC
o Often multiple
Peak age Children, 2-5 y/o Adults, 20-40 y/o
o Retinal/subconjunctival hemorrhage
Sex predilection None F:M 3:1
4. Bleeding after trauma/surgery
(10yo female)

Antecedent Common 1-3 wks Unusual
OTHER CLINICAL FEATURES
infection (preceded by
• Pallor - 15% (depends on the degree of bleeding)
infxn)
• Palpable spleen – 12%
Before

Onset of bleeding Abrupt Insidious

Hgic bullae in (+) in severe Usually absent

mouth cases
DEON 9

LABORATORY FINDINGS PRACTICE GUIDELINES FOR CHILDHOOD ITP
Blood Platelet Symptoms Therapy
• Megathrombocytes <↑ platelet turnover> count
• Small platelets and platelet fragments <10, 000 Minor purpura IVIg, steroid ± hospital
• Anemia proportional to extent of blood loss /mm3
• Normal WBC and Differential count Wet purpura IVIg, high dose steroid
• Atypical lymphocytes Life threatening hospitalization
• Prolonged bleeding time bleed
• Absent/deficient CRT 10,000- Minor purpura ± IVIg, steroid, hospital
20,000
BONE MARROW ASPIRATION /mm3 Wet purpura IVIg, high dose steroid
• Indications Lifethreatening hospitalization
1. Unusual cases of Refractory to treatment bleed
2. Abnormalities in PE or in the peripheral 20,000 – Minor purpura ± IVIg, oral steroid
blood (young lymphocytes) 50,000
3. The initial treatment will be corticosteroids /mm3 Wet purpura ± IVIg, steroid, Hospital

Bone marrow Life threatening IVIg, high dose steroid
• Increase in number and size of megakaryocytes bleed hospitalization
• Normoblastic hyperplasia
• Normal granulocytes Recommendations for Childhood ITP
• Occasional eosinophilia • Steroids
o High dose Prednisolone 4mg/kg/day, max
1. PIFT - Direct Platelet Immunofluorescence Test 4d
• Used to detect the presence of platelet associated o Methylprednisolone 30mg/kg/day
Immunoglobulin (PAIg) o Low dose: 1-2mg/kg/day not >14 days
2. Assays for specific antibodies for specific platelet o 10-20mg/kg/day
membrane glycoproteins IIb/Iia and Ib/IX
3. TPO Assay PREDNISOLONE or PREDNISONE
4. Reticulated platelets • Mechanism of action:
• Thiazole orange staining to assess platelet maturity 1. ↑ vascular stability and ameliorates
endothelial abnormality
PATHOPHYSIOLOGY: PLATELET SURVIVAL 2. ↓ consumption of antibody – coated
• Shortened in ITP platelet by the spleen or bone marrow
• Measured using 3. ↓ production of anti-platelet antibodies by
o 51-chromium or the spleen and bone marrow
o 111-Iridium – labeled platelets 4. ↑ marrow platelet production by
• Sequestration occurs in undetermined mechanism
o Spleen • 2/3 respond at 1-2mg/kg X 2-4 weeks with tapering
o Liver • Response rate: 30-50%
o RES of the bone marrow • Should be rapidly tapered and stopped in patients
DIFFERENTIAL DIAGNOSIS who fail to respond after 4 weeks
• Basis
o isolated thrombocytopenia INTRAVENOUS GAMMAGLOBULIN (IVIg)
o no evidence of other disease • Mechanism of action:
• Other diseases: sepsis, HUS, HIV, drug induced, 1. Blockade of Fc receptors of RES
congenital 2. Suppression of Ab production and binding
• Dose:
ITP: To treat or not to treat? o 400mg/kg/day for 5 days versus
• Initial treatment of ITP aimed at o 1g/kg/day for 2 days
o Preventing CNS bleeding • 50% will achieve normal platelet count
o Reducing risk of blood loss • APC returns to pre-treatment levels after 3-4 weeks
§ Prolonged epistaxis • Little evidence of a lasting effect
§ Menorrhagia
§ Hematuria Recommendations for Childhood ITP
§ GIT bleeding • Intravenous Gamma Globulin (IVIg)
• Regardless of platelet count
DEON 10
 o Reserve for Emergency treatment of serious
bleeding or when undergoing procedures Follow-Up
likely to induce blood loss • CBC within 10-14 days from diagnosis
o Can raise platelet count rapidly • Monthly platelet counts for the next 6 months
• Platelet transfusion • No immunizations for the next 6 months
o Should be given for ICH or life-threatening • ANA screening every 6 months in patients with
hemorrhage Chronic ITP
o Immunomodulatory drugs should be given • Can be sent home if they have 20,000. Then take
at the same time (IVIg and IV steroids) prednisone for two weeks, and see if it can be
• Splenectomy dropped a bit
o Rarely indicated • Can progress to Lupus
o Indications:
1. Life-threatening hemorrhage OTHER TREATMENT MODALITIES
2. Chronic unremitting ITP • Non-urgent or semiurgent situations
3. Severe ITP present with o Anti-Rh (D)
demonstrable impairment of o Azathioprine
quality of life for 12-24 months o Danazol
o Vinca Alkaloids
GUIDELINES FOR SPLENECTOMY o Cyclophosphamide
• Vaccines should be given at least 2 weeks prior to o Cyclosporine
splenectomy o Dapsone
• Revaccination with pneumococcal every 5 years
• Hib revaccination may not be given Thrombocytopenia Due to Infection
• Annual influenza vaccine • Acute ITP
• Phenoxymethylpenicillin 250-500mg BID possible for 1. Direct effect by the organism or its toxic
life or products on the blood platelet
• Erythromycin 500mgB BID (prophylactic) 2. Immune mediated injury
3. Adhesion of platelets to the subendothelial
Recommendations for Childhood ITP layer of injured blood vessls
Splenectomy • DIC
• Complete remission 70-90%
• MOA: eradicates HEMOPHILIA
o Bulk of anti-platelet antibodies synthesized • Sex linked
in the spleen • Afflicts males (“h” = Carrier)
o Splenic clearance of antibody coated
platelets

COURSE AND PROGNOSIS
• Good Prognostic Features
o Short duration of disease
o Abrupt onset of symptoms Hemophilia A Hemophilia B Hemophilia C
o Mild symptoms (Classic) (Christmas) (Autosomal)
• Complete remission • Deficiency of • Deficiency of • Deficiency of
o in 60% (1st month) factor VIII factor IX factor XI
o 80-90% (6th month)
• 85% • 15% • Autosomal
o without steroids and splenectomy
• Most common • Use FRESH • Mild form
• Therefore, it can be concluded that treatment does
not alter the natural course of the disease sex-linked frozenplasma
• In most patients coagulopathy
o No new lesions after the first week • Use
o Platelet count normal in 2-8 weeks cryoprecpititate
• Predictors of chronic ITP
o Purpura 2-4 wks before diagnosis CLINICAL MANIFESTATIONS
o Female • Soft tissue – ecchymoses and hematomas
o Age >10 years old
• Joints – hemarthoses
o Higher platelet count
• Intracranial hemorrhage 1% • Nose bleeding
• Mortality rate <1% • Urinary

DEON 11
 • GIT • Prolonged PT, PTT
• Brain • Treatment: Vit. K, FFP (loaded 100%)

CLINICAL SEVERITY DIC
Mild Moderate Severe • Thrombotic microangiopathy
• 5-25% • 2-5% • <1% • Consumption of clotting factors, platelets and
• Bleeding • Hemorrhage • Frequent episodes anticoagulation proteins
after with mild of bleeding into • Widespread deposition of fibrin tissue ischemia,
severe trauma at muscles, joints, necrosis, generalized hemorrhagic state, hemolytic
trauma or intervals ranging skin anemia
surgery from weekly to • with minimal or no • Triggers: Hypoxia, Acidosis, Tissue necrosis, Shock,
monthly recognized trauma Endothelial damage
• Accompanies severe systemic disease
LABORATORY DIAGNOSIS • Clinical manifestations:
Patient Carrier o Bleeding, petechiae, ecchymoses, tissue
• Normal- Bleeding time • Normal clotting screen necrosis, anemia (microangiopathic HA)
• Normal PT, TT • Factor assay • Laboratory findings:
• Prolonged PTT moderately reduced o Low fibrinogen, prothrombin, Factors V and
• Factor assay greatly VIII
prolonged o Prolonged PT, PTT, TT, low platelets
o Elevated FDP, D-dimer assay
TREATMENT • Treatment
(-) inhibitor Cryoprecipitate/FFP/Purified Factor o Treat underlying disorder/ trigger
home therapy for minor bleeds o Restore normal hemostasis by correcting
DDAVP shock, acidosis and hypoxia
(+) inhibitor • Blood components
Stable Replacement at doses to overcome st
o Platelets (1 given), cryoprecipitate, FFP
inhibitors • Activated Protein C Concentrate (for DIC due to
Inducible Low level standard dose PFVIII sepsis)
High level activated CF or very high
PFVIII
Hemarthoses no replacement, immobilization, local
measures

DESIRED % FACTOR CORRECTION (Normal PT and PTT if
factor activity is 30%)
• Mucocutaneous 30-50%
• Epistaxis 30-50%
• Oral Mucosa 30-50%
• Hematuria 50-70%
• GIT 50-70%
• CNS 70-100%

APCD
• Post neonatal Vit. K deficiency
• Breastfed
• lack of oral intake of Vit. K, alterations in the GUT
flora due to prolonged intake of broad spectrum
antibiotics, malabsorption of Vit. K
• fresh frozen plasma until patient wakes
• Change in sensorium, seizures

DEON 12