Download Acute Lymphoblastic Leukemia in Infancy

Pain Management (2 phase approach)
Neonatal Screening for Hemoglobinopathy
Epistaxis: The Hematological Angle
Thrombophilia Investigation: When and How
Hadi Sawaf MD
A new BOXED WARNING, FDA’s strongest
warning, will be added to the drug label
Health care professionals should prescribe an alternate analgesic for post-operative pain
control in children who are undergoing tonsillectomy and/or adenoidectomy. Codeine should
not be used for pain in children following these procedures
Codeine
• Codeine effect is dependent upon its conversion to morphine by the hepatic
cytochrome P450 2D6 (CYP2D6).
•
Some people have DNA variations that make this enzyme more active, causing codeine
to be converted to morphine faster and more completely than in other people
• High levels of morphine can result in breathing difficulty, which may be fatal.
• Taking codeine after tonsillectomy and/or adenoidectomy may increase the risk for
breathing problems and death in children who are “ultra-rapid metabolizers.”
• For other types of pain in children, codeine should be used if the benefits are
anticipated to outweigh the risk
Codeine


Eliminate the use of codeine in pediatric
patients <18 years of age in inpatient and
outpatient settings throughout Ascension
Health
Will undertake a codeine phase-out over an
approximate 90-day period
W.H.O. ANALGESIC LADDER
3
By the
Strong opioid
+/- adjuvant
2
Clock
1
Non-opioid
+/- adjuvant
Weak opioid
+/- adjuvant
ANALGESIC LADDER
By the
Clock
1
Non-opioid
+/- adjuvant
2
opioid
+/- adjuvant
Oral Dose
Medicine
Neonate: 0
to 29 days
Infants: 30 d
to 3 mos
Infant 3-12 mos
or child 1-12 yrs
Maximum
Daily dose
Acetaminophen
5–10 mg/kg
every 6–8 hr
10 mg/kg
every 4–6 hr
10–15 mg/kg
every 4–6 hrs
4 doses/day
5–10 mg/kg every
6–8 hrs
Child: 40
mg/kg/day
Ibuprofen
Intravenous Acetaminophen
• Approved by FDA for the use in children 2
years of age and older
• Maximum serum concentration after IV
acetaminophen was 70% higher than the same
dose given orally
• Does not appear to increase the risk for
hepatotoxicity
• Dose: 12.5 mg/kg IV every 4 hours or 15
mg/kg IV every 6 hours, with a maximum
dose of 75 mg/kg every 24 hours.
Opioid Brand Names
Generic Name
fentanyl
hydrocodone
hydromorphone
Brand Name
Duragesic
Norco, Vicodin
Dilaudid, Exalgo
morphine
oxycodone
Astramorph, Avinza
OxyContin, Percocet
Medicine
Route of
administration
Starting dose
Morphine
Oral (immediate release)
1–2 years: 200–400 mcg/kg Q 4 hrs
2–12 years: 200–500 mcg/kg Q 4 hrs
(max 5 mg)
IV injection
1–2 years: 100 mcg/kg Q 4 hrs
2–12 years: 100–200 mcg/kg Q 4 hrs
Oral (immediate release)
30–80 mcg/kg Q 3–4 hrs (max 2
mg/dose)
Oral (prolonged release)
15 mcg/kg Q 3–6 hrs
Hydromorphone
*opioid-naive children
OPIOID ANALGESIA
PRN PO morphine
Q 4 hrs PO morphine
Q 12 hrs PO Slow Release
(50%)
IV Morphine (1:3 ratio)
Escalate dose by 25% until
pain relieved or adverse
effects unacceptable
+ Break Through Q 4 hrs
(10%)
Convert to a new opioid
(50%)
OPIOID CONVERSION
Opioid
Most Potent
Fentanyl
100:1
Methadone
10:1
Hydromorphone
5:1
Oxycodone
1.3:1
Hydrocodone
1.2:1
Morphine 1:1
NSAIDS
Ibuprophen
1:40
Naproxen
1:50
ASA
Least Potent
1:130
Acetamenophen 1:130
Amino Acid Disorders:
X 14
- April 2014-CCHD
- October-2011 SCIDCCHD
- October 2007 CF and Hearing
Fatty Acid Oxidation Disorders:
X 12
Organic Acid Disorders:
X13
Hemoglobinopathies:
• S/Beta thalassemia
• S/C disease
• Sickle cell anemia
• Variant hemoglobinopathies
• Hemoglobin H disease
- October 2004-HCY, CIT, ASA
- April 2005-31 MS/MS Disorders
- April 2003-MCAD
- July 1993-CAH
- October 1987-Niotinidase Deficiency,
- MSUD and Hemoglobinopathy
- Spring 1985-Galactosemia
- June 1977-CH
Endocrine Disorders:
X2
Other Disorders:
X7
- August 1865-Phenyketonia
In 2011:
1 in 364 screened African American newborns and 1
in 1,907 screened newborns were diagnosed with
SCD.
• An additional 2,817 newborns were identified as
having sickle cell trait based on initial screening
results.
• 61 newborns were diagnosed with SCD
Incidence:
In 2011: 1 in 364 screened African American newborns and 1 in 1,907
screened newborns were diagnosed with SCD. 61 newborns were
diagnosed with SCD
SCD Subtype, Confirmed Cases, 2011
Subtype
N
%
Hemoglobin SS (HbSS)
33
54
Hemoglobin SC (HbSC)
20
33
Sickle Beta Thal Plus
8
13

The purpose of newborn hemoglobinopathy
screening is to detect sickle cell disease (HGB SS,
SC, Sβ° and Sβ⁺)

Most common, abnormal (non sickle) HGBs: C, D,
E and Bart’s hemoglobin

Methodology : high performance liquid
chromatography (HPLC) and isoelectric focusing.

A confirmatory hemoglobin electrophoresis is
required before age 3 months
Neonatal Screening for Hemoglobinopathy

Other hemoglobins are reported as “V”. They
invariably have no or minimal clinical or genetic
significance and are not report to parents

Hemoglobins are generally reported in decreasing
order of concentration (F>A>S)

Newborn hemoglobinopathy screening will not
identify beta thalassemia trait
DIAGNOSIS
CONFIRMATORY
FAMILY STUDIES
Sickle Cell Anemia (SS)
FS
Both parents AS
Sickle Beta
Thalassemia
Zero (Sβ°)
FS
One parent AS
One parent AA with
elevated HB A2
Sickle Cell with HPFH F
FS
One Parent AS
One parent AF with
Hb F approx. 20‐30%
Education Session
Completion
Sep 2011- Oct 2012
•
•
•
•
Session 1
SCD overview
Early health problems
Sickle cell trait vs disease
Session 2
• Transmission of SCD
• Types of SCD
• Late health problems
50%
40%
30%
20%
10%
0
2 sessions
completed
1 session
completed
Previously
educated
Refuse or
unable
Unknown
Sickle Cell Disease in Michigan
Percent of Children with SCD with
TCD Screen by Year and Gender
Percent of Children with SCD
Receiving Antibiotic Prophylaxis
100%
25%
80%
20%
60%
15%
Within 120 days
40%
Female
10%
Before 5 mos
Male
20%
5%
0
0
2007
2008
2009
Birth Year
2010
2011
2008
2009
Birth Year
2010
2011
Sickle Cell Disease




Confirm diagnosis
Penicillin prophylaxis
Disease Education
Referral to Pediatric Hematology/Oncology
RESULT
DIAGNOSIS
ACTION REQUIRED
FAS
Sickle cell trait
Clinically benign but
genetically significant
No confirmatory testing
Genetic counseling
FAC
Hemoglobin C trait
Clinically benign but
genetically significant
No confirmatory testing
Genetic counseling
FAD
Hemoglobin D trait
Clinically benign but
genetically significant
No confirmatory testing
Genetic counseling
FAE
Hemoglobin E trait
Clinically benign but
genetically significant
No confirmatory testing
Genetic counseling
RESULT
DIAGNOSIS
ACTION REQUIRED
FAV
Fetal hemoglobin,
normal adult and an
unidentified hemoglobin
variant
Most likely clinically
Physician of record
insignificant hemoglobin responsible for reassuring
variant
the parent that this is
clinically insignificant. No
confirmatory testing
required.
FA-Bart’s
Fetal Hemoglobin,
Hemoglobin A
and Bart’s Hemoglobin
Hemoglobin H disease
Alpha Thalassemia Trait
MDCH will send specimen
to reference lab for further
analysis. SCDAA will
provide information to
parents and physician of
record for clinically
significant findings
Thrombophilia Testing
Who and How
Definition:
Thrombophilia an inherited or acquired abnormality of hemostasis
predisposing to thrombosis

Some form of Thrombophilia can be identified in approximately half of patients
presenting with VTE

Thrombophilia factors may enhance the risk of recurrent thrombosis.

Therapeutic and prophylactic measures are not necessarily different for children
with or without thrombophilic risk factors

Individualized approach is warranted

Incidence: 5 cases per 10,000 children per year

Mortality rate for major vessel thrombosis is 1% - 4%

Thrombus recurrence: 6.5% to 21% of children with VTE

Many cases of DVT and pulmonary embolism (PE) go
unrecognized in part due to a low index of suspicion for young
patients
50
Venous Thrombosis in Children
45
40
Number of Children
35
30
25
20
15
10
5
0
<1 1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18
Age (years)
From Canadian Registry
Venous Thromboembolism in Children
Site
Extremity
Superior vena cava
Splenic vein
Hepatic vein
Renal vein
Portal vein
Pulmonary artery
Cerebral sinus
Presentation
Dx
D-Dimer
Pain
Swelling
Discoloration
Tissue damage
Doppler ultrasound
MR venography (MRV)
CT angiography (CTA)
Venography
Echocardiography
XII
XI
IX
VIII
VII
TFPI
AT
X
PC/PS
PAI
V
t-PA
AT
II
I
Plasminogen
FDP
Fibrin clot
D-Dimer
Risk factors for venous thrombosis
Procoagulant
Anticoagulant
Other
High levels of factor VIII
Antithrombin deficiency
Factor V Leiden (FVL)
High levels of factor IX
Protein C deficiency
Antiphospholipid syndrome
High levels of factor XI
Protein S deficiency
Hyperhomocysteinemia
High levels of fibrinogen
Prothrombin 20210A
Dysfibrinogenemia
Prevalence of Major Hypercoagulable States
Hypercoagulable
State
General
Inheritance Risk for 1st Patient
Population
VTE %
with
%
single
VTE %
Thrombophilic
Families
Factor V Leiden
3-7
AD
3-5
20
50
Prothrombin
G20210A
1-3
AD
2-3
6
18
Anti-thrombin
deficiency
0.02
AD
5-10
1
4-8
Protein C deficiency
0.2-0.4
AD
4-6.5
3
6-8
Protein S deficiency
0.02-0.04
AD
1-10
1-2
3-13
Homocysteinemia
5-10
AR
2-3
10-25
N/A
Antiphospholipid
antibodies
0-7
Acquired
1-8
5-15
N/A
Some numbers
for U.S. population; approximation)
A. Hemophilia
 28,000 have hemophilia A
 5,000 have hemophilia B
B. Thrombophilia
 13 million are heterozygous for factor V Leiden
 170,000 are homozygous for factor V Leiden
 5,6 million are heterozygous for prothrombin 20210 mutation
 28,000 are homozygous for prothrombin 20210 mutation
 70,000 are heterozygous for factor V Leiden plus heterozygous for
prothrombin 20210 mutation
Number of Children
Who should be tested?
VTE at a young age with
 Spontaneous
 Recurrent
 Unusual site
 Positive family history
Testing is probably not helpful
 Catheter related thrombosis
 Before initiation of contraceptive
 Asypmtomatic child with positive family history
Incidence: 4-21.3%
 Multitrait thrombophilia
 Spontaneous VTE
 Homozygous factor V Leiden
 Prothrombin gene mutation
 Antiphospholipid Abs
 Elevated D-dimer at the end of anticoagulant therapy
*The recurrence risk did not decrease with increased duration of anticoagulation
Thrombophilia
Diagnostic Laboratory Studies
Level (I )Testing
Level (II) Testing
Level (III)Testing
Thrombophilia
Laboratory Tests
Factor V Leiden
PCR or clotting assay (APC res.)
Prothrombine G20210A
PCR
Antithrombin deficiency
Chromogenic or clotting assay
Protein C deficiency
Chromogenic or clotting assay
Protein S deficiency
Clotting assay or immunologic
Homocysteinemia
Fasting homocysteine
Antiphospholipid antibodies
Clotting or chromogenic assay
Elevated factor VIII
Clotting assay
Dysfibrinogenemia
Clotting or immunologic assay
Elevated factor IX, XI
Clotting assay
Case History:
A 5- year-old boy presents to clinic
with his parents who are concerned
about his 3-month history or
recurrent nosebleeds On 2 occasions
he was send home from school
because of the nose bleed
His physical examination was entirely
normal with no petechia or bruises
noted.
When in your office he developed
epistaxis that lasts about 15 minutes.
His platelet count is 178,00,000. His
complete blood count and smear
review were normal
▸ Inflammation
– URI
– Allergic rhinitis
– Foreign body
– Vasculitis
▸ Trauma
– Nose picking
– External trauma
▸ Anatomic
– Septal deviation
▸ Medications
– Topical steroid spray
– Nasal decongestants
– Anticoagulants
▸ Hematologic
– Idiopathic thrombocytopenic purpura
– Von Willebrand disease
– Hemophilia
▸ Neoplasms
– Benign
∘ Nasopharyngeal angiofibroma
∘ Pyogenic granuloma
∘ Inverted papilloma
– Malignant
∘ Rhabdomyosarcoma
∘ Lymphoma
▸ Vascular abnormalities
– Hereditary hemorrhagic telangiectasia
– Hemangioma
▸ Idiopathic
Epistaxis unrelieved by 10 minutes
Epistaxis requiring ER visit, or blood transfusion
 History other bleeding manifestations
 Bleeding from trivial wounds >15 mints
 Bleeding from dental procedures > 1 day or requiring
a blood transfusion
 Heavy, prolonged or recurrent bleed after surgical
procedure
 Heavy menses
 Family history of a bleeding disorder


Epistaxis Scoring system
Component
Score
Frequency
5-15/yr
16-25/yr
>25/yr
0
1
2
Duration
< 5 min
5-10 min
>10 min
0
1
2
Amount
< 15 ml
15-30 ml
>30 ml
0
1
2
Epistaxis history/age
< 33%
33-67%
>67%
0
1
2
Site
Unilateral
Bilateral
0
2
Mild:
0-6
Severe: 7-10
Likelihood Ratio for VWD
10000
1000
100
0.10
1
0.1
0.01
0.001
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
20
Bleeding Score
Likelihood ratio for VWD based on Vicenza bleeding assessment tool
Elsevier 2007
CBC, PT, PTT.
Fibrinogen or TT
(optional)
If bleeding history is
strong consider
performing initial
VWD assays
Prolonged PTT
1:1 mixing
Corrected
Initial VWD assay
Not corrected
Antiphospholipid
antibody
Other cause identified. eg.
thrombocytopenia, Prolonged
PT or TT
Possible referral for
appropriate evaluation
FVIIF, IX and FXI
Referral for
appropriate evaluation
 VWF:Ag
 VWF:Rco
 FVIII
Referral for specialized
VWD studies
Repeat VWD panel
VWF:Rco/VWF:Ag
Multimer analysis
Collagen binding
RIPA binding
Plat VWF studies
DNA sequencing
Case Discussion
Coagulation testing: PTT 42 sec (22.5-35 sec). Normal PT, and platelet count.
Mixing studies: - PTT corrected with 1:1 mixing with Plasma
Test
F XI
F IX:C
F VIII:C
vWF R:Co
vWF:Ag
Result
59%
78%
32%
35%
30%
Normal
50-150%
60-150%
50-150%
45-200%
36-157%
von Willebrand Disease
ä
Most common hereditary coagulation abnormality in human
ä
Estimated to occur in 1% to 0.1% of the population
ä
Female /Male ratio is 2:1
ä
Borderline or modestly low VWF levels are unlikely to run in
families, and usually symptomatic
ä
VWD subtype I and II are dominant. Type III is recessive
ä
Type II and III can be diagnosed by molecular genetic testing
ä
rVWF (BAX 111) has recently been introduced
platelet
F-VIII
vWF
endothelial cell
Adherence of platelet to damaged endothelium is vWF dependent
platelet plug
fibrin clot
Personal history of excessive bleeding
Low VWF levels
Known mutation consistent with VWD (type II)
In absence of all three criteria, modestly low VWF
levels should be treated as a risk factor for bleeding
rather than a bleeding disorder
GP Ib
GP IIb& IIIa
Decreased
Increased binding
binding to
to
platelet
platelet
VWD type 2A
VWDtype
type2M
2B
VWD
Complete deficiency
Adhesion
of VWF
Impaired binding of
site
VWD
type 3
VWF
to collagen
Reduced production
GP Ia
Decreased binding of
vWF to factor VIII
Aggregation
VWD type 1site
VWD type 2N
VWD type 1C
Collagen binding site
F VIII
N
D1
D2
D3
GPIb
GPIIb/IIIa
Collagen
A1 A2 A3
D4
C1 C2 C3
C
Mutations
2A
2N
2B 2A 2M
2A
Type 1
>100 different mutations throughout the gene, missense predominate
Type 2A
Mutation in proteolysis site at A2 region (most common)
Type 2A
Loss of propeptide, required for multimer formation from dimers
Type 2A
Mutation in C-terminus, required for dimer formation from monomers
Type 2B
Mutation in GPIb binding site, causing increased binding of vWF to GPIb
Type 2M
Mutation in GPIb binding site, causing decreased binding of vWF to GPIb
Type 2N
Mutation in N-terminis (FVIII binding) with decreased binding of vWF to factor VIII
Type 3
Large null mutations
Analysis of von
Willebrand factor
(VWF) multimers:
The distribution of
VWF multimers is
analysed using sodium
dodecyl sulphate
(SDS)–agarose
electrophoresis followed
by immunostaining





Local measure, pinching
Topical antiseptic cream
Nasal cauterization
Topical hemostatic agents such as tranexamic acid
Correcting underlying clotting problems (i.e. DDAVP)