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THROMBOEMBOLIC DISEASES OF CHILDHOOD
Need of the well designed prospective trials. Need of appropriate diagnostic strategies
Confirmatory diagnostic test
Need to establish standard drug regimens of different anti-thrombotic agents for
Prevention treatment
Out line for discussion
Inherited thrombotic disorders Anti-thrombin deficiency Neonatal Purpura Fulminans (Homozygous Protein C
& S deficiency) Activated protein C resistance
Acquired thrombotic problems Non catheter related events Catheter related events
Congenital thrombophilia
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
Clinically the most significant inherited prothrombotic disorders are
AT PC PS APCR/FvL Prothrombin G20210 polymorphism Increased levels of factor VIII, IX, XI
And recently Plasma lipoprotein (a) levels
The occurrence of thrombosis in children of families with estiblished AT, PC, PS def. & FvL mutation was found to be low?
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 Single chain GP, synthesized in the liver
Serine protease inhibitor superfamily Direct inhibitor of thrombin Also inhibits Xa, IXa, XIa & XIIa Most important regulator of fibrin production
Type I Quantitative
Type II Functional
II RS (reactive site defect) II HBS (heparin binding site defect) II PE (multiple site defect)
Neonatal period and AT deficiency
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
Clinical features 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
Aortic thrombosis, multiple thrombotic events including MI and cerebral dural sinus thrombosis during the first few days of life have been reported.
Diagnosis 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)
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 Most effective when bound to thrombomodulin on endothelial
surface
Activated protein C has also profibrinolytic acitvity
Clinical feature Homozygous cases presents as life threatening
disorder in neonatal period Microcirculation is affected first (purpura
fulminans), with features of DIC 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 Retinal hemorrhage Partial or complete blindness
Diagnosis DIC screening is positive
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 Replacement of deficient factors
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
In more than 90% APC resistance is due to single point mutation in the gene of FV 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
The peak incidence is at the age of less than 1 year
Can be classified as Catheter related Non catheter related
Systemic venous thromboembolism DVT / PE Renal vein thrombosis
Systemic arterial thrombosis
Non catheter related events
Spontaneous events are uncommon in neonates
Other frequently encountered risk factors in children
Cancer / chemotherapy Cardiac disease Surgery / infection and trauma
Infrequent risk factors Autoimmune disease Nephrotic syndrome Thalassemia
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
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 Perinatal asphyxia Dehydration Polycythemia Sepsis Nephrotic syndrome, maternal diabetes Congenital heart disease
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
Catheter related thrombosis
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 DVT / Arterial thrombosis is venography and
angiography PE with V/Q scan
Management
Remain largely undefined Supportive care Anticoagulant therapy
Heparin LMWH Warfarin
Thrombolytic therapy Surgery
Unfractionated heparin
The optimal dose is different in children due to biological differences 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
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
Predictable pharmacology Lack of interaction with other drugs Reduced risk of HIT and oesteoprosis
Oral anticoagulant
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
Massive pulmonary embolism In children thrombolysis is down regulated
and thrombolytic therapy is impaired due to reduced concentration of plasminogen.