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.