1. Thrombophilia A pediatric perspective. Craig Dobson, MD CPT, MC, USAR NCC Pediatrics Residency Program

2. Definitions Unexpected tendency to form clots under inappropriate circumstances. Family history of vascular disease under age 50. Incl. MI, CVA or DVT.

3. Case 9yo male at presents for eval for psych admission to CNMC for acute psychosis. Disorganized behavior, non-communicative except occasional screaming fits. Associated symptoms headache, high fevers, occasional watery stools. Head CT with contrast notes lateral venous sinus thrombosis. But why?

4. Epidemiology Venous thrombosis lifetime prevalence 5- 10% of total population. Highest incidence in neonatal and post- pubertal. Neonates 5/100k. Teens incidence 23/100k.

5. Neonatal Presentation Typically in-utero or within first 48hrs of life. Catheter thrombosis. – Still requires evaluation. Renal vein thrombosis – Flank mass on exam – Thrombocytopenia, HTN, hematuria. Seizures from CVA or lesion on head U/S. Neonatal Purpura Fulminans – Homozygous Protein C or S def.

6. Adolescent Presentation DVT CVA Asymptomatic, suspected through FHx. Important to screen to avoid sudden death early in adulthood.

7. Coagulation Cascade (Robbins)

8. Anti-coagulation (Subar)

9. Virchow’s Triad (Robbins)

10. Work Up PT/PTT, Mixing studies if elev PTT. CBC ATIII, Protein C&S (total and free) Factor V Leiden Homocysteine level or MTHFR gene mutation Prothrombin G20210A gene mutation Anti-phospholipid Abs Lipoprotein a

11. Etiology/Genetic Excessive factor VIII (11/100 whites) Factor V Leiden (8/100 whites) Prothrombin excess (2/100 whites) Antithrombin III def. (1/5000)

12. Etiology/Genetic Sickle cell disease (1/400 blacks) Protein C deficiency (1/500) Protein S deficiency Rare conditions: Def in fibrinolysis, congenital HUS, pro-coagulant platelets.

13. Etiology/Acquired Platelets and RBCs – Polycythemia/thrombocythemia – TTP, HUS Excess Thrombin – Factor V Leiden – Lupus anticoagulant/ anti-cardiolipin – Incr tissue factor (infection/trauma/malignancy)

14. Etiology/Acquired Def thrombin regulation – ATIII deficiency (renal failure) – Hepatic synthetic dysfunction. – Auto-antibodies – DIC Medications – OCPs – Heparin – L-asp (really hepatic synth.)

15. Etiologies/Acquired Homocysteinemia – Smoking – Sedentary lifestyle – Coffee – Diet (low folate, B6 or B12)

16. Therapies/Heparin Mechanism: catalysis of AT. Neonates have lower AT levels. Monitoring: aPTT Problems – aPTT levels based on adult therapeutic studies. – Even in adults, therapeutic aPTT may not suggest clinically sufficient anti-coag.

17. Therapies/Heparin Recommended dose 75U/kg loading. Maintenance drip dose varies: – Infants <1yr of age 28U/kg/hr – Children > 1yr 20U/kg/hr Side effects (besides bleeding): – Heparin induced thrombocytopenia – Osteoporosis

18. Therapies/ LMWH Low Molecular Weight Heparin Less monitoring needed, more predictable blood levels, less osteoporosis. Increase dose needed for age 2mo (0.5mg) Monitor anti-factor Xa levels. – In children you need to monitor, unlike adults. – Peak is 2-6hrs after injection SQ.

19. Therapies/Oral-anticoagulants Increases vitamin-K dependent proteins (II, VII, IX, X) plus Proteins C & S. Newborns have reduced levels of vitamin-K dependent proteins. (Shot at birth helps.) Vitamin K added to formulas. Minimal in breastmilk.

20. Therapies/Oral Anti- coagulants Monitor INR 2-3. Problem: requires stable diet. Impossible in 2yr old. Some recommend INR 1.5-2.5. Large difference in required dose: – Infants 0.32mg/kg/d – Teens 0.09mg/kg/d

21. Case Revised Etiology thought originally to be erosive mastoiditis due to fluid in mastoid near lateral venous sinus. Mastoidectomy performed, culture negative transudate. Further testing by GI, revealed pt with early presentation of Crohn’s disease.

22. References Manco-Johnson, M & Nuss, R. Advances in Pediatrics, Chp 12, Vol 48. 2001.) Monagle, et al. Antithrombotic Therapy in Children. Chest. 119 (1), 2001. Cotran: Robbins Pathologic Basis of Disease, 1999 (all images). Subar M - Clin Geriatr Med - 01-Feb-2001; 17(1): 57-70, vi Van Cott, E. Coagulation disorders and treatment strategies: laboratory evaluation of hypercoagulable states. Hematology/oncology Clinics of North Amer. V12 (6), 1998.