THROMBOEMBOLIC DISEASES OF CHILDHOOD

1. THROMBOEMBOLIC DISEASES OF CHILDHOOD

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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)

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

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

20. 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

21. 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

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

23. 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

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