A Practical Approach to
Coagulopathy in the Pediatric
Patient
August 30, 2012
L. Kate Gowans,
Gowans, M.D.
Pediatric Hematology/Oncology
Objectives
• Review the presentation and
management of pediatric patients with
- Platelet disorders
- Coagulopathy
- Thrombophilia
A
A 33 year
year old
old child
child was
was noted
noted at
at bathtime
bathtime to
to have
have
several
several bruises
bruises on
on her
her back.
back. The
The following
following morning,
morning,
she
she had
had numerous
numerous tiny
tiny red
red spots
spots on
on the
the trunk
trunk and
and
abdomen.
abdomen. Exam
Exam reveals
reveals multiple
multiple petechiae
petechiae on
on the
the
skin
skin and
and several
several on
on the
the soft
soft palate;
palate; exam
exam is
is
otherwise
otherwise unremarkable.
unremarkable. What
What is
is the
the most
most likely
likely
diagnosis?
diagnosis?
A.
B.
C.
D.
Acute Lymphoblastic Leukemia (ALL)
Child abuse
Meningococcemia
Immune thrombocytopenic purpura
(ITP)
1
A
A 33 year
year old
old child
child was
was noted
noted at
at bathtime
bathtime to
to have
have
several
several bruises
bruises on
on her
her back.
back. The
The following
following morning,
morning,
she
she had
had numerous
numerous tiny
tiny red
red spots
spots on
on the
the trunk
trunk and
and
abdomen.
abdomen. Exam
Exam reveals
reveals multiple
multiple petechiae
petechiae on
on the
the
skin
skin and
and several
several on
on the
the soft
soft palate;
palate; exam
exam is
is
otherwise
otherwise unremarkable.
unremarkable. What
What is
is the
the most
most likely
likely
diagnosis?
diagnosis?
A.
B.
C.
D.
Acute Lymphoblastic Leukemia (ALL)
Child abuse
Meningococcemia
Immune thrombocytopenic purpura
(ITP)
ITP – Clinical Features
• Definition: isolated immuneimmune-mediated
thrombocytopenia
• Peak age 22-5 yrs of age (50%), approx
3,000 cases/yr
• Often preceded by a viral illness
• Acute onset usually with skin only, but
may involve mucous membranes (wet
purpura)
purpura)
ITP – Clinical Features
• Microscopic hematuria may be present
• Hepatosplenomegaly or
lymphadenopathy should lead to
exploration of other diagnosis (ALL)
• SelfSelf-limited, 80% resolve within 6
months
• If other cell lines are affected, ITP does
not fit
2
ITP – Diagnostic Evaluation
• CBC with differential: verify only
platelets affected, differential normal;
other abnormalities (anemia,
leuko/neutropenia)
leuko/neutropenia) may suggest
alternate diagnosis (ALL, AA, Evans)
• ABO/Rh
ABO/Rh – therapeutic choices, urgent
need for platelet transfusion
ITP – Diagnostic Evaluation
• Peripheral smear – verifies automated
number, and very large, young platelets
c/w peripheral destructive process
• Bone marrow not necessary unless
diagnosis in question
Acute ITP - Therapy
• Not all children need to be treated
- Treat <10k, <20k with nonnon-life
threatening bleeding, or unfavorable
trend if monitoring
• Goal is not to normalize the count, but
to prevent life threatening hemorrhage
(bleeding may be spontaneous)
3
Acute ITP - Therapy
• Rh+
Rh+ patient: WinRho (anti(anti-D):
75mcg/kg IV; watch for hemolysis
• RhRh- patient: IVIG 800mg/kg IV
• Steroids (alone or in combination w/
above)
• Platelets are NOT used, unless pt is
experiencing life threatening bleeding
(ICH)
Chronic ITP
• Immune mediated thrombocytopenia
for >6 months
• 20% of acute ITP will persist, but
spontaneous resolution is still possible
• ♀ > ♂; adolescents & infants > children
• Platelet counts tend to run not as low;
goal of intervention is to maintain
activity and QOL (>50,000)
Chronic ITP
• Consider screening for autoimmune
disease
• Treatment
- May not be necessary at all
- Intermittent WinRho,
WinRho, IVIG, steroid
pulses, rituximab,
rituximab, splenectomy
4
““Other”
Other” thrombocytopenia
• Acute ITP more often falls into the
severe category; you may at times
uncover more mild (100(100-150) or
moderate (50(50-100) numbers
• ↓ production vs ↑ destruction
• Differential: drug related, congenital,
postpost-viral, autoimmune disease, DIC,
splenomegaly/portal
splenomegaly/portal hypertension
You
You are
are called
called to
to the
the newborn
newborn nursery
nursery to
to evaluate
evaluate aa
term
term newborn,
newborn, product
product of
of uncomplicated
uncomplicated pregnancy
pregnancy
to
to aa G3P2
G3P2 healthy
healthy mother.
mother. Exam
Exam is
is positive
positive for
for facial
facial
bruising
bruising and
and petechiae
petechiae scattered
scattered about
about the
the face,
face,
trunk
trunk and
and legs.
legs. The
The platelet
platelet count
count is
is 8K,
8K, Hgb
Hgb is
is
13g/dl
13g/dl and
and WBC
WBC is
is 12K
12K with
with normal
normal differential.
differential. The
The
mother’
’s CBC
mother
mother’s
CBC is
is normal.
normal. What
What is
is the
the most
most likely
likely
diagnosis?
diagnosis?
A. Neonatal leukemia
B. ThrombocytopeniaThrombocytopenia-Absent Radius
syndrome
C. Sepsis
D. vonWillebrand’
vonWillebrand’s disease
E. Neonatal Alloimmune
Thrombocytopenia
You
You are
are called
called to
to the
the newborn
newborn nursery
nursery to
to evaluate
evaluate aa
term
term newborn,
newborn, product
product of
of uncomplicated
uncomplicated pregnancy
pregnancy
to
to aa G3P2
G3P2 healthy
healthy mother.
mother. Exam
Exam is
is positive
positive for
for facial
facial
bruising
bruising and
and petechiae
petechiae scattered
scattered about
about the
the face,
face,
trunk
trunk and
and legs.
legs. The
The platelet
platelet count
count is
is 8K,
8K, Hgb
Hgb is
is
13g/dl
13g/dl and
and WBC
WBC is
is 12K
12K with
with normal
normal differential.
differential. The
The
mother’
’s CBC
mother
mother’s
CBC is
is normal.
normal. What
What is
is the
the most
most likely
likely
diagnosis?
diagnosis?
A. Neonatal leukemia
B. ThrombocytopeniaThrombocytopenia-Absent Radius
syndrome
C. Sepsis
D. vonWillebrand’
vonWillebrand’s disease
E. Neonatal Alloimmune
Thrombocytopenia
5
Neonatal Thrombocytopenia
• Unusual in healthy babies, more
common in ill babies (20(20-25%)
• Causes: sepsis +/DIC,
hemangioma
+/
(KasabachKasabach-Merritt syndrome), birth
asphyxia, meconium aspiration,
thrombosis, leukemia
Neonatal Thrombocytopenia
• NAIT: platelet equivalent of ABO
incompatibility; usually due to IgG
antibodies directed against HPAHPA-1a
(mother expresses only HPAHPA-1b on her
plts)
plts)
- 1-1,0001,000-5,000 births
- First pregnancy can be affected, and
subsequent may be more severe
Neonatal Thrombocytopenia
• NAIT
- ICH (10(10-20% of cases, ¼ - ½ of which
may be in utero)
utero)
- Management: maternal platelet
transfusion, IVIG, random platelets if
critically low and mother’
mother’s
unavailable
- Keep plts >30k (term) or >50k
(preterm); serial head u/s
6
Congenital Thrombocytopenia
• Very unusual, but in appropriate
context, consider
- Infant leukemia, WiskottWiskott-Aldrich,
Fanconi anemia, TAR, congenital
amegakaryocytic thrombocytopenia
(CAMT)
Qualitative Platelet Defects
• Congenital
- BernardBernard-Soulier (gp Ib)
Ib)
- Glanzmann’
Glanzmann’s (gp IIb/IIIa)
IIb/IIIa)
- Storage pool disorders
• Acquired
- Medication
- Uremia
A
A fifteen
fifteen month
month old
old previously
previously healthy
healthy boy
boy who
who has
has
been
been walking
walking for
for four
four months
months began
began limping
limping this
this
morning,
morning, two
two hours
hours after
after learning
learning how
how to
to jump
jump off
off
the
the couch.
couch. He
He now
now completely
completely refuses
refuses to
to bear
bear
weight.
afebrile
weight. Exam
Exam shows
shows aa fussy
fussy infant,
infant, afebrile,
afebrile,, with
with
warmth
warmth and
and swelling
swelling of
of the
the left
left knee.
knee. Which
Which
statement
statement about
about aa patient
patient with
with hemophilia
hemophilia is
is false?
false?
A. PT is normal
B. aPTT is prolonged and does not correct with
addition of control plasma
C. Inheritance is XX-linked
D. Family history may be negative for bleeding
disorders
E. Plasma is the preferred treatment
F. None of the above
G. B and E
7
A
A fifteen
fifteen month
month old
old previously
previously healthy
healthy boy
boy who
who has
has
been
been walking
walking for
for four
four months
months began
began limping
limping this
this
morning,
morning, two
two hours
hours after
after learning
learning how
how to
to jump
jump off
off
the
the couch.
couch. He
He now
now completely
completely refuses
refuses to
to bear
bear
weight.
afebrile
weight. Exam
Exam shows
shows aa fussy
fussy infant,
infant, afebrile,
afebrile,, with
with
warmth
warmth and
and swelling
swelling of
of the
the left
left knee.
knee. Which
Which
statement
statement about
about aa patient
patient with
with hemophilia
hemophilia is
is false?
false?
A. PT is normal
B. aPTT is prolonged and does not correct with
addition of control plasma
C. Inheritance is XX-linked
D. Family history may be negative for bleeding
disorders
E. Plasma is the preferred treatment
F. None of the above
G. B and E
Hemophilia A and B
• Combined incidence 1/5,000 live births
• A more common, ⅔ are severe; >50% of
B are mild/moderate
• Categorized as mild, moderate, severe;
mild pts with >5% factor activity may go
many years before diagnosis
• Long arm of X chromosome; genetic
testing possible, and ⅓ of patients
represent spontaneous mutations
Hemophilia - Clinical
Presentation
• Depends on severity; even severe
patients often not diagnosed until
crawling/walking
- Excessive bruising, hemarthrosis,
hemarthrosis,
oral bleeding, postsurgical bleeding
- Immediate newborn bleeding –
circumcision (30(30-50%), ICH (5%)
8
Hemophilia - Diagnosis
• Lab results are rather straightforward
- Prolonged aPTT,
aPTT, normal PT
- aPTT corrects with addition of
control plasma (“
(“mixing study”
study”)
- Low plasma FVIII or FIX
Hemophilia - Management
• Mild – may do well with just DDAVP and
in selective situations
• Moderate – may require treatment only
with trauma or prophylactically before
certain activities
• Severe – prophylaxis is indicated very
early in life before bleeding and a target
joint have developed
Hemophilia - Management
• For all replacement, recombinant
products are the standard of care (NOT
plasma, or any plasma derived product)
• Replacement guidelines are specific to
the clinical situation; most children do
selfself-infused prophylaxis at home
• Comprehensive lifelong care is
necessary
9
A
Hb 7.5)
((Hb
A teenage
teenage girl
girl has
has severe
severe anemia
anemia (Hb
7.5) and
and has
has
had
had menorrhagia
menorrhagia for
for several
several years.
years. She
She has
has aa
lifelong
lifelong history
history of
of easy
easy bruising,
bruising, and
and frequent
frequent
epistaxis.
epistaxis
epistaxis.. Her
Her father
father and
and paternal
paternal uncle
uncle have
have aa
history
history of
of easy
easy bruising.
bruising. The
The platelet
platelet count
count and
and
PT/INR
PT/INR are
are normal
normal but
but aPTT
aPTT is
is prolonged.
prolonged. Which
Which of
of
the
the following
following is
is true?
true?
A. She is probably a carrier of hemophilia.
B. She shouldn’
shouldn’t worry, because menorrhagia
in teenagers is common.
C. She may have vonWillebrand’
vonWillebrand’s disease.
D. Type 2 vWD is the most likely diagnosis.
E. She probably has an autosomal recessive
disorder.
A
Hb 7.5)
((Hb
A teenage
teenage girl
girl has
has severe
severe anemia
anemia (Hb
7.5) and
and has
has
had
had menorrhagia
menorrhagia for
for several
several years.
years. She
She has
has aa
lifelong
lifelong history
history of
of easy
easy bruising,
bruising, and
and frequent
frequent
epistaxis.
epistaxis
epistaxis.. Her
Her father
father and
and paternal
paternal uncle
uncle have
have aa
history
history of
of easy
easy bruising.
bruising. The
The platelet
platelet count
count and
and
PT/INR
PT/INR are
are normal
normal but
but aPTT
aPTT is
is prolonged.
prolonged. Which
Which of
of
the
the following
following is
is true?
true?
A. She is probably a carrier of hemophilia.
B. She shouldn’
shouldn’t worry, because menorrhagia
in teenagers is common.
C. She may have vonWillebrand’
vonWillebrand’s disease.
D. Type 2 vWD is the most likely diagnosis.
E. She probably has an autosomal recessive
disorder.
vonWillebrand
’s Disease
vonWillebrand’s
• Very common (1(1-2% of population);
likely that many mild cases are
undiagnosed
• Many responsible mutations, with great
variability between patients and even
within families
• Usually an autosomal dominant pattern
(except type 3)
10
vonWillebrand
’s Disease
vonWillebrand’s
• Presentation: bruising, epistaxis,
epistaxis, oral
bleeding, menorrhagia,
menorrhagia, petechiae
• Diagnosis: fraught with difficulty!
- Regular fluctuations in vWF
- vWF is an acute phase reactant, and
sensitive to hormone levels
vonWillebrand
’s Disease
vonWillebrand’s
• Diagnosis: “vWD”
vWD” versus “low vWF Ag
levels”
levels”
- vWF Ag, ristocetin cofactor activity,
FVIII, platelet function screen
- <40% vWF Ag or activity is
diagnostic, but not seen often
- Type 1 (70(70-80% of pts), 2, 3
vonWillebrand
’s Disease
vonWillebrand’s
• Treatment – depends on type of
disease, type/severity of bleeding
- Type 1: DDAVP, OCPs,
OCPs, Amicar
- Type 2: ?DDAVP, cryo,
cryo, plasma
derived FVIII product with vWF Ag
present, Amicar
- Type 3: plasma derived FVIII/vWF
FVIII/vWF,,
OCPs;
OCPs; often require prophylaxis
11
Rare Coagulopathies
• Deficiency of factor II, V, VII, X or XI
• Factor XIII deficiency – CLASSIC
presentation of bleeding from umbilical
stump
• HypoHypo-/dysdys-/afibrinogenemia
• NOTE that factor XII deficiency causes
prolonged aPTT but is not associated
with clinical bleeding; may be a
thrombosis risk
A
A 55 yr
yr old
old boy
boy has
has acute
acute onset
onset of
of fever
fever to
to 105
105 F,
F,
hypotension,
hypotension, and
and severe
severe headache
headache and
and neck
neck
stiffness.
stiffness. He
He develops
develops oozing
oozing from
from his
his IV
IV site
site and
and
has
has dusky
dusky discoloration
discoloration of
of both
both lower
lower extremities.
extremities.
Which
Which lab
lab result
result is
is NOT
NOT consistent
consistent with
with
disseminated
disseminated intravascular
intravascular coagulation
coagulation (DIC)?
(DIC)?
A.
B.
C.
D.
E.
Prolonged PT and aPTT
Thrombocytopenia
Elevated DD-dimer
Elevated fibrinogen
Leukocytosis in CSF
A
A 55 yr
yr old
old boy
boy has
has acute
acute onset
onset of
of fever
fever to
to 105
105 F,
F,
hypotension,
hypotension, and
and severe
severe headache
headache and
and neck
neck
stiffness.
stiffness. He
He develops
develops oozing
oozing from
from his
his IV
IV site
site and
and
has
has dusky
dusky discoloration
discoloration of
of both
both lower
lower extremities.
extremities.
Which
Which lab
lab result
result is
is NOT
NOT consistent
consistent with
with
disseminated
disseminated intravascular
intravascular coagulation
coagulation (DIC)?
(DIC)?
A.
B.
C.
D.
E.
Prolonged PT and aPTT
Thrombocytopenia
Elevated DD-dimer
Elevated fibrinogen
Leukocytosis in CSF
12
Disseminated Intravascular
Coagulation (DIC)
• Clinical diagnosis of bleeding,
thrombosis and (if untreated)
progressive organ dysfunction
• Underlying tissue destructive process
caused by consumption of coag factors
and platelets
• Typical labs show ↑ PT/aPTT
PT/aPTT,,
thrombocytopenia, ↓ fibrinogen, ↑ Ddimer
Disseminated Intravascular
Coagulation (DIC)
• Causes
- Infection
- Hypoperfusion/reperfusion
Hypoperfusion/reperfusion injury
(cardiac arrest, near drowning)
- Trauma
- Cancer (APML)
- Obstetric complications
Disseminated Intravascular
Coagulation (DIC)
• Treatment
- Treat underlying cause
- Aggressive BP support
- Plasma to replace consumed clotting
factors (goal is PT/aPTT
PT/aPTT <1.5X ULN)
- Cryoprecipitate to keep fibrinogen
near or above 100mg/dL
- Treat underlying cause
13
An
An 11
11 yo
yo boy
boy with
with ALL
ALL has
has been
been admitted
admitted with
with fever
fever
and
and positive
positive blood
blood culture.
culture. He
He develops
develops swelling
swelling of
of
his
his arm
arm (same
(same side
side as
as his
his central
central line).
line). Doppler
Doppler u/s
u/s
confirms
confirms occlusive
occlusive thrombus
thrombus in
in LL axillary
axillary vein.
vein.
Which
Which of
of the
the following
following may
may have
have contributed
contributed to
to the
the
thrombosis?
thrombosis?
A.
B.
C.
D.
E.
Acute inflammation
Factor V Leiden mutation
Central line
Recent asparaginase therapy
All of the above
An
An 11
11 yo
yo boy
boy with
with ALL
ALL has
has been
been admitted
admitted with
with fever
fever
and
and positive
positive blood
blood culture.
culture. He
He develops
develops swelling
swelling of
of
his
his arm
arm (same
(same side
side as
as his
his central
central line).
line). Doppler
Doppler u/s
u/s
confirms
confirms occlusive
occlusive thrombus
thrombus in
in LL axillary
axillary vein.
vein.
Which
Which of
of the
the following
following may
may have
have contributed
contributed to
to the
the
thrombosis?
thrombosis?
A.
B.
C.
D.
E.
Acute inflammation
Factor V Leiden mutation
Central line
Recent asparaginase therapy
All of the above
Thrombophilia
• Susceptibility to thrombosis, either
congenital or acquired
• Genetic susceptibility
- Factor V Leiden mutation
- Prothrombin mutation
- Homozygosity for MTHFR mutation
(?significance w/ normal
homocysteine levels)
14
Thrombophilia
• Genetic susceptibility (less common)
- Protein S deficiency
- Protein C deficiency
- Antithrombin III deficiency
Thrombophilia
• Acquired susceptibility (more common)
- Central line
- OCP use
- Prolonged immobility
- Asparaginase therapy
- Antiphospholipid antibodies (not
transient)
- Chronic inflammation
Thrombosis Management
• Situation dependent
- Thrombolysis rarely indicated for
venous thrombosis
- Immediate anticoagulation, duration
of 33-6 months depending on clinical
situation
- Central line should be removed
15
Thrombosis Management
• Hypercoagulable workup is not
indicated for all (most?) patients
• The acute phase is not the time to do it,
due to consumption of products within
the clot; the results will not change
your acute management
Screening for thrombosis risk
• Hot topic is screening for risk factors in
adolescents prior to OCP use
- Suggested only if pertinent FH
- What to do with the results?
• Depends on FH
• Discuss lifestyle choices,
approach to select situations
16