THROMBOEMBOLIC DISEASES OF CHILDHOOD

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THROMBOEMBOLIC DISEASES OF CHILDHOOD

• Dr. Tariq Roshan

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• 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

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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

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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

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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
• And recently
• 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?
• 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

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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)

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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

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• 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

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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

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• 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

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• 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 gt0.25 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

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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

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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

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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

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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
• 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

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• Non catheter related systemic arterial
  thromboembolic disease are rare
• Takayasus 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

• 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

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Management

• Remain largely undefined
• Supportive care
• Anticoagulant therapy
• Heparin
• LMWH
• Warfarin
• Thrombolytic therapy
• Surgery

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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

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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

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LMWH

• Predictable pharmacology
• Lack of interaction with other drugs
• Reduced risk of HIT and oesteoprosis

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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

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Thrombolytic therapy

• Massive pulmonary embolism
• In children thrombolysis is down regulated and
  thrombolytic therapy is impaired due to reduced
  concentration of plasminogen.