ThrombophiliaThrombophilia

A pediatric perspective.Craig Dobson, MD

CPT, MC, USAR

NCC Pediatrics Residency Program

DefinitionsDefinitions

Unexpected tendency to form clots under inappropriate circumstances.

Family history of vascular disease under age 50. Incl. MI, CVA or DVT.

CaseCase

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?

EpidemiologyEpidemiology

Venous thrombosis lifetime prevalence 5-10% of total population.

Highest incidence in neonatal and post-pubertal.

Neonates 5/100k.Teens incidence 23/100k.

Neonatal PresentationNeonatal 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.

Adolescent PresentationAdolescent Presentation

DVTCVAAsymptomatic, suspected through FHx.Important to screen to avoid sudden death

early in adulthood.

Coagulation Cascade Coagulation Cascade (Robbins)(Robbins)

Anti-coagulation Anti-coagulation (Subar)(Subar)

Virchow’s Triad Virchow’s Triad (Robbins)(Robbins)

Work UpWork 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

Etiology/GeneticEtiology/Genetic

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

Etiology/GeneticEtiology/Genetic

Sickle cell disease (1/400 blacks)Protein C deficiency (1/500)Protein S deficiencyRare conditions: Def in fibrinolysis,

congenital HUS, pro-coagulant platelets.

Etiology/AcquiredEtiology/Acquired

Platelets and RBCs– Polycythemia/thrombocythemia– TTP, HUS

Excess Thrombin– Factor V Leiden– Lupus anticoagulant/ anti-cardiolipin– Incr tissue factor (infection/trauma/malignancy)

Etiology/AcquiredEtiology/Acquired

Def thrombin regulation– ATIII deficiency (renal failure)– Hepatic synthetic dysfunction.– Auto-antibodies– DIC

Medications– OCPs– Heparin– L-asp (really hepatic synth.)

Etiologies/AcquiredEtiologies/Acquired

Homocysteinemia– Smoking– Sedentary lifestyle– Coffee– Diet (low folate, B6 or B12)

Therapies/HeparinTherapies/Heparin

Mechanism: catalysis of AT.Neonates have lower AT levels.Monitoring: aPTTProblems

– aPTT levels based on adult therapeutic studies.– Even in adults, therapeutic aPTT may not

suggest clinically sufficient anti-coag.

Therapies/HeparinTherapies/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

Therapies/ LMWHTherapies/ LMWH

Low Molecular Weight HeparinLess monitoring needed, more predictable

blood levels, less osteoporosis.Increase dose needed for age <2mo (0.75mg

Q12). >2mo (0.5mg)Monitor anti-factor Xa levels.

– In children you need to monitor , unlike adults.– Peak is 2-6hrs after injection SQ.

Therapies/Oral-anticoagulantsTherapies/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.

Therapies/Oral Anti-Therapies/Oral Anti-coagulantscoagulants

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

Case RevisedCase 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.

ReferencesReferences

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.