Antithrombotic Therapy in Pediatric Cardiology: Clinical Insights

1. Antithrombotic therapy in children Dr.K.Mahesh

2. Introduction • Rising use of Anticoagulant / Antithrombotic drugs among pediatric patients • Thromboembolic Disease – “The new Epidemic of Pediatric Tertiary Care Hospitals”. • Nowhere more evident than in pediatric cardiac/cardiac surgery patients. • In the last decade – vast improvements in surgical techniques,new drugs, new applications,critical and supportive care- resulted in improved survivals. • TE Disease is one the most frequent complications in these ‘survivors’.

3. Majority of children on primary anticoagulant prophylaxis have underlying CHD/acquired heart disease • Venous thromboembolic disease in children has a mortality of 7% • Morbidity in the form of post-phlebitic syndrome and recurrent venous thrombosis occurs in 20%

5. Arterial Thromboembolic Disease

8. Points of discussion • Antithrombotic / Anticoagulant therapy in context of Pediatric Cardiac morbidities. • Biochemical basis of coagulation and factors that influence / modify it. • Specific drugs that regulate coagulation • Recommendations for anticoagulant therapy in specific clinical situations

9. Indications for Anticoagulant / Antithrombotic therapy in Pediatric Cardiology • Native structural cardiovascular disease • Vavular heart disease • Cardiomyopathies • Surgically altered cardiovascular architecture • BT Shunt, Glenn, Fontan, Norwood • Valve replacements • Post-op / intensive care related issues • Central line, sepsis • Cardiac catheterization and interventions • Prophylaxis • Interventional procedures

10. How are things different in children compared to adults?

11. Epidemiolgical differences • High proportion of secondary thrombosis in children with major underlying HD • Role of central venous access devices • Biphasic age difference – highest risk in neonates and Adolescents • Age distribution of major illnesses that require CVA. • Small physical size of blood vessels related to CVA in neonates • Maturation of coagulation system in adolescents

12. Frequency and type of intercurrent illnesses – makes administration and regulation of oral anticoagulant therapy difficult • Vascular access impacts ability to deliver and monitor AC • GA used in procedures more commonly in children, affecting ability to confirm and monitor thromboembolic disease and therefore therapeutic decisions

13. The coagulation cascade

14. Thrombogenesis • Vasospasm • Platelet adhesion • Platelet aggregation • Viscous metamorphosis • Platelet plug • Fibrin reinforcement • Local production of thrombin • Platelet ADP • Thromboxane A2, Prostacyclin (PGI2). • Serotonin • White thrombus, Red thrombus

16. Drugs that affect coagulation

17. Indirect Thrombin Inhbitors Heparin Fondaparinux Vitamin K Antagonists Warfarin Coumarinsl Antithrombotics Direct Thrombin inhibitors Hirudin, Bivaluridin Argatroban, Melagatran Ximelagatran Antiplatelet agents Aspirin Dipyridamole , Clopidogrel Ticlopidine

18. Indirect Thrombin Inhbitors Act on ANTITHROMBIN Vitamin K Antagonists Act via Vit K dependent factors – II, VII, IX, X Direct Thrombin inhibitors Directly bind to Thrombin

19. Adults Vs Children / Infants

20. Developmental Haemostasis • Affects frequency, natural history, and response to agents • Global functioning of the haemostatic system is different from adults • Plasma values of many coagulation proteins are different • Qualitative differences in many of the coagulation proteins, especially in neonates • Significant differences in the antithrombotic properties of the vessel wall

21. Developmental Haemostasis • Antithrombin (AT) levels are physiologically low at birth (0.50 U/ml) • Adult values are reached only after 3 months • Sick preterms have levels less than 0.30 U/ml • Fetal range 0.20-0.37 at 19-38 weeks • Significance : Profound effect on the action of Heparin • Following infancy, thrombin generating capacity increases but remains 25% less than adult capacity throughout childhood • In-vitro tests show both increased sensitivity and resistance to Unfractionated Heparin (UFH) in neonates

22. Developmental Haemostasis • Infants have physiologically low levels of Vit K –dependent factors and contact factors which gradually rise to adult values nearing 6 months • Levels of Protein C and Protein S are very low at birth • Interaction of Protein C with Protein S in newborn plasma may be regulated by increased concentration of alpha-2 macroglobulin • Plasma concentration of thrombomodulin is increased in early childhood, decreasing to adult values by teenage • Free tissue factor pathway inhibitor (TFPI) concentrations are significantly lower in neonates

23. Pharmacokinetic differences • Distribution, binding and clearance of AC agents is age-dependent • Larger volume of distribution, faster clearance of UFH, LMWH in newborns • Altered heparin binding (unproved) • Low levels AT • Result : Higher initial dose of Heparin needed to attain therapeutic levels • Maintenance doses required are highest in infants < 2 months • Higher patient-patient variability • Warfarin doses are also age dependent – reasons not known

24. Drug formulations • No specific pediatric formulations available Dietary differences • Vit K concentrations in breast milk and infant formulae differ • Breast fed babies are very sensitive to VKA • Formula-fed babies need high doses, increasing the risk of bleeding in case of intercurrent illnesses etc

25. There are numerous studies defining appropriate strategies in adults with a range of TEs • Anticoagulation strategies are controversial and unproven in children • Attempt to formulate a consensus – 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence based Guidelines

26. Specific DrugsHeparins

27. Heparin • A heterogenous mixture of glycosaminoglycans ranging from 3000 to 30000 daltons in MW • Non-branching, negatively charged pentasachharide chain • Pentasachharide sub-unit structure is instrumental in its ability to bind to Antithrombin

29. Heparin – Mechanism of Action • Indirect thrombin inhibitor • Catalysis the action of Antithrombin by over 1000-fold. • (AT inhibits Thrombin i.e IIa, IXa,and Xa) • Active Heparin molecules bind tightly to AT, causing conformational changes, exposure of its active site for more rapid interaction with the activated clotting factors). • Once AT-protease complex is formed, Heparin is released intact for binding to more AT. • Prevents additional thrombus accretion • Does not lyse a thrombus already formed

30. HMW fraction of Heparin inhibits all three – thrombin (Factor IIa), IXa and Xa, esplly thrombin and Xa. • LMWH inhibits activated factor X but has less effect on thrombin than HMW species. • Commercial heparin consists of a family of molecules of different MW. • Commercial heparin is extracted from porcine intestinal mucosa and bovine lung. • Usually sodium or calcium salts. Lithium salt for in-vitro anticoagulation. • UFH dosing in in USP units/mg

31. Therapeutic range of UFH • That reflects a heparin level by protamine titration of 0.2 – 0.4 U/ml or an Anti Factor Xa level of 0.35 – 0.7 U/ml • aPTT therapeutic ranges are universally calculated using adult plasma and are extrapolated onto the pediatric population as well. Validity yet unknown. • In pediatric patients, aPTT values correctly predict therapeutic concentrations approx 70% of the time

32. Pharmacokinetics and Dose • Volume of distribution is more and clearance rapid in neonates and young infants + heparin binding may also be different. • So higher dose required to achieve adult therapeutic range • Bolus dose of 75 – 100 U/Kg results in therapeutic aPTT value in nearly 90%. • Maintenance is age-dependent • Infants < 2 mo 28U/kg/Hr • Children > 1 yr 20U/kg/Hr • Older children 18U/kg/Hr

33. Heparin Dosing Nomogram

34. Adverse effects of Heparin • Bleeding – Andrew M et al reported 1.5% incidence in their prospective cohort study in children treated for DVT/pulmonary embolism • Thrombocytopenia • Non-immune HAT (HIT Type I) • Immune mediated (HIT Type II) • Osteoporosis and spontaneous fractures • Allergic reactions • Reversible alopecia • Long-term usage : mineralocorticoid deficiency

35. Frequency of HIT

37. Treatment of adverse affects • Bleeding: Cessation of heparin and IV Protamine if needed

38. Treatment of thrombocytopenia • Non-Immune HAT : Promptly discontinue Heparin • Suspected HIT : • Discontinue all Heparin • Confirm diagnosis with alternate tests • Alternative anticoagulants • Monitor for thrombosis and platelet counts • Avoid prophylactic platelet transfusion

39. Treatment of HIT • Stop Heparin • Alternative anticoagulants • Warfarin: disadvantage- takes 4-5 days for full therapeutic effect ; associated with venous limb gangrene when used alone • LMWH • Recombinant Hirudin, • Danaparoid sodium • Ancrod (isolated from Malayan Viper) • Prostacyclin analogues • IVIG • Plasmapharesis

40. Low Molecular Weight Heparins(LMWH) • Principally inhibit Factor X, less effect on Thrombin • Enoxaparin: same source as regular heparin, but doses specified in mg • Dalteparin , Tinzaparin, Danaparoid (a mixture of heparan sulfate, dermatan sulfate and chondroitin sufate):doses specified in Anti Factor Xa units

41. Low Molecular Weight Heparins • Have rapidly become AC of choice in many pediatric patients both for primary prophylaxis, and treatment of TE, despite unproven efficacy • Advantages • Need for minimal monitoring • Lack of interference by other drugs or diet (as for VKAs) • Reduced risk of HIT • Reduced risk of Osteoprosis • Disadvantages • High in-vitro cross-reactivity with Heparin dependent antibodies • Significant risk of recurrent or progressive thrombocytopenia and/or thrombosis • Reduced predictability of anticoagulant effect compared to adults

42. LMWH – Therapeutic range and dosage • Extrapolated from adult data, based on Anti Factor Xa levels – 0.50 – 1.0 U/ml in a sample taken 4-6 hours following a subcutaneous inj • Peak occurs 2-6 hours after s/c inj • < 2-3 months or <5 Kg have higher requirement due to increased volume of distribution, lower levels of AT and or altered heparin pharmacokinetics

43. L M W H D O S A G E

44. Adverse effects of LMWH • Dix D et al reported 10.8% major bleeding complication in infants in a prospective cohort study • Same authors reported bleeding complication in 4.8% patients with enoxaparin • Massicotte P et al reported major bleeding complications in 8.1% patients in a randomized trial, with Reviparin • No data on frequency of osteoporosis, HIT, hypersensitivity reactions in children • TREATMENT: Protamine Sulfate

45. Contra-indications to Heparin • Hypersensitivity • Active bleeding • Hemophillia • Significant thrombocytopenia/purpura • Severe hypertension • ICH • IE • Active TB • Ulcerations of GI tract • Threatened abortion • Visceral Ca • Advanced hepatic or renal disease • AVOID IN : Recent neuro/ophthalmic surgery, or undergoing lumbar puncture / regional anaesthetic block, pregnancy

46. Vitamin K Antagonists

47. Vitamin K Antagonists – Warfarin and coumarin anticoagulants • Discovery of an anticoagulant substance ( bishydroxycoumarin ) formed in spoiled sweet clover silage which resulted in hemorrhagic disease in cattle. • Warfarin is the most reliable member of this group, which also comprises Dicumarol,Phenprocoumon,Phenindione, Diphenindione

48. Warfarin generally administered as a Sodium salt • 100% bio-availability • 99% bound to albumin, small volume of distribution • Long plasma half life – 36 hours • Racemic mixture of levorotatory S-warfarin (4 times more potent) and dextrorotatory R-warfarin

49. MOA of Warfarin • Blocks gamma carboxylation of several glutamate residues in Prothrombin and factors VII, IX, X and endogenous anticoagulant proteins C and S : results in biologically inactive molecules • Oxidative deactivation of Vit K. Prevents reductive metabolism of inactive Vit K epoxide back to its active hydroxyquinolone form