THROMBOEMBOLIC
DISEASES OF CHILDHOOD
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Need of the well designed prospective
trials.
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Need of appropriate diagnostic strategies
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Confirmatory diagnostic test
Need to establish standard drug regimens of
different anti-thrombotic agents for
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Prevention
treatment
Out line for discussion
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Inherited thrombotic disorders
Anti-thrombin deficiency
 Neonatal Purpura Fulminans (Homozygous Protein C
& S deficiency)
 Activated protein C resistance
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Acquired thrombotic problems
Non catheter related events
 Catheter related events
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Congenital thrombophilia
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Defined as having a positive family history
Early age of onset of TE &
Frequent recurrence
It is suggested that the children with
spontaneous TEs should be investigated
History is important and carefully taken
history will help in ordering investigations
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Clinically the most significant inherited
prothrombotic disorders are
AT
 PC
 PS
 APCR/FvL
 Prothrombin G20210 polymorphism
 Increased levels of factor VIII, IX, XI
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And recently
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Plasma lipoprotein (a) levels
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The occurrence of thrombosis in children of
families with estiblished AT, PC, PS def. & FvL
mutation was found to be low?
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Acquired risk factors were major contributors to the
occurrence of TE
The mean age at first TE was between 30 and
40 years but in females it is 20 years earlier
than male in these families
There is paucity of information on risk and
benefits of long-term prophylaxis versus careful
monitoring with intermittent prophylaxis
Anti-thrombin deficiency
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Single chain GP, synthesized in the liver
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Type I
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Serine protease inhibitor superfamily
Direct inhibitor of thrombin
Also inhibits Xa, IXa, XIa & XIIa
Most important regulator of fibrin production
Quantitative
Type II
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Functional
 II RS (reactive site defect)
 II HBS (heparin binding site defect)
 II PE (multiple site defect)
Neonatal period and AT
deficiency
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There is some protection against the effect
of AT deficiency during the neonatal
period
Differences in the relative proportions of direct
thrombin inhibitors (ATIII, HCII & 2 M)
 Proportionately more thrombin is inhibited by 2 M
than in adult plasma and
 Small but significant increase in the relative
amount of thrombin bound to HC II
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Clinical features
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Homozygous AT type II deficiency has veen recorde only very
rarely
Type I defects are probably incompatible with life
Type IIHBS is rare but homozygous type tend to present early
with severe thrombotic disorder
Heterozygous AT def. tend to present in 2nd decade
Both venous and arterial events can occur
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Aortic thrombosis, multiple thrombotic events including MI and
cerebral dural sinus thrombosis during the first few days of life
have been reported.
Diagnosis
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At birth the levels are 50% and still lower in premature
The level further decreases in the event of thrombosis and n
sick children
The levels of heterozygous overlap with physiologic while
homozygous are easy to diagnose
Sequential levels and family studies are crucial
Neonatal Purpura Fulminans
(Homozygous Protein C & S deficiency)
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Reported in homozygous or compound
heterozygous
Homozygous protein S is even rarer and the
history shows consanguineous parents
Activated protein C has anti FVa & FVIIIa activity
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Most effective when bound to thrombomodulin on endothelial
surface
Activated protein C has also profibrinolytic
acitvity
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Clinical feature
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Homozygous cases presents as life threatening
disorder in neonatal period
Microcirculation is affected first (purpura
fulminans), with features of DIC
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Due to capillary lesions
Initially small mainly at extremities and pressure points or
at site of previous trauma
Cerebral and renal vein thrombosis are also
seen
Ocular manifestations
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Retinal hemorrhage
Partial or complete blindness
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Diagnosis
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DIC screening is positive
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PT, APTT, TCT prolong
Low platelet and fibrinogen
MAHA
Definitive diagnosis difficult; levels of PC & PS are low at
birth
Undetectable Proteins activity and heterozygous levels in
parents help in diagnosis
Management
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Replacement of deficient factors
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Initially FFP
Now specific protein C concentrates are available
 Starting dose 40u/Kg (adjusted after acute phase)
 Levels >0.25 units/ml considered normal
No protein S concentrate available so FFP is the choice
Long term therapy needs to be establish and later therapy is
replaced by oral anticoagulant
Activated protein C resistance
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In more than 90% APC resistance is due
to single point mutation in the gene of FV
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The mutation renders the mutant FVa less
sensitive to inactivation
Diagnosis is based o the detection of
abnormal resistant APC
Confirmation by molecular studies which is
even more important in neonates
Acquired thrombotic problems
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The peak incidence is at the age of less
than 1 year
Can be classified as
Catheter related
 Non catheter related
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Systemic venous thromboembolism
 DVT / PE
 Renal vein thrombosis
Systemic arterial thrombosis
Non catheter related events
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Spontaneous events are uncommon in
neonates
Other frequently encountered risk factors
in children
Cancer / chemotherapy
 Cardiac disease
 Surgery / infection and trauma
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Infrequent risk factors
Autoimmune disease
 Nephrotic syndrome
 Thalassemia
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In adults 40% of DVT / PE idiopathic
In children only 5% are idiopathic
Renal vein thrombosis though rare can
occur during the neonatal period and
present during the first few days of life
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Flank mass with hematuria
Proteinuria and non functioning kidneys
Thrombocytopenia
In quarter of cases thrombosis is bilateral and may
involve inferior vena cava
Pathogenesis poorly understood
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Perinatal asphyxia
Dehydration
Polycythemia
Sepsis
Nephrotic syndrome, maternal diabetes
Congenital heart disease
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Non catheter related systemic arterial
thromboembolic disease are rare
Takayasu’s arteritis
 Arteries of transplant organs
 Giant coronary aneurysms
 TEs occurs at the rate up to 23% in mechanical
valves
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Catheter related thrombosis
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Catheter related events are upto 90% in
the first year of all thrombotic events
Diagnosis is missed in 80% of cases if only
ultrasound is used
Gold standard test for diagnosis
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DVT / Arterial thrombosis is venography and
angiography
PE with V/Q scan
Management
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Remain largely undefined
Supportive care
 Anticoagulant therapy
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Heparin
LMWH
Warfarin
Thrombolytic therapy
 Surgery
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Unfractionated heparin
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The optimal dose is different in children
due to biological differences
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50units/kg loading dose
Followed by continuous infusion of 20
units/kg/h
The levels of antithrombin in children are
low as compare to adults
Thus there is relative heparin resistance
Quicker heparin clearance due to increase
volume disturbance
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Aptt results do not always predict a
therapeutic heparin concentration
On the other hand heparin assay result in
an underestimate due to the reduced
concentration of antithrombin
Bleeding is the major problem
HIT is rare in children
LMWH
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Predictable pharmacology
Lack of interaction with other drugs
Reduced risk of HIT and oesteoprosis
Oral anticoagulant
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OAs should be avoided in the first month
of life
Use is restricted for prophylaxis of
mechanical heart valve
Bleeding is the main complication
Long term use also results into decrease
bone density
Thrombolytic therapy
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Massive pulmonary embolism
In children thrombolysis is down regulated
and thrombolytic therapy is impaired due
to reduced concentration of plasminogen.