NEONATAL THROMBOSIS Panel discussion & case presentation

2. NEONATAL THROMBOSIS Panel discussion &case presentation Peyman Eshghi Prof. of Pediatric Hematology &Oncology Mofid Children Hospital Shahid Beheshti University of Medical Sciences TEHRAN-6-1396

3. CASE-1

4. 3-day old, 39-week infant born by urgent cesarean section due to failure to progress, prolonged rupture of membranes, and chorioamnionitis • G1 mother with no other prenatal abnormalities • Developed tachypnea after birth and placed on nasal cannula • Ampicillin and Gentamicin started but stopped at 48-hours due to negative blood cultures • Currently on room air and taking full PO breast milk feedings • Heel stick specimen CBC ordered for following morning: platelet count of 95 x 103/L otherwise were WNL • PT=14`` & aPTT=39`` • NO petechia or ecchymosis Clinical diagnosis?

5. Last 3 diapers have been dry • Lower limbs is going to be cyanotic and cold • Abdominal mass has been palpated • Stat creatinine obtained and value 1.9 mg/dL

6. •Renal US demonstrates bilateral renal vein thromboses with extension into the IVC Adrenal hemorrhage also observed • more imaging: • Doppler? • Diagnosis in acute phase? • Monitoring the treatment • Monitoring blood flow to affected kidney • CTA? • MRA?

8. Thrombophilia Evaluation

9. Conceptualization of Risk Factors for Neonatal Thrombosis Maternal Factors Fetal/Neonatal Factors Catheters CHD Infection RDS Dehydration Birth Asphyxia Polycythemia Inherited thrombophilias • Infertility • Oligohydramnios • Thrombotic states • Preeclampsia • Autoimmunity • Diabetes • Chorioamnionitis

10. Risks of recurrent thrombosis with Congenital Prothrombotic Risk Factors • Recurrent thrombosis: • OR 4.6 (95% CI 2.3 - 9.0) with single gene defect • OR 24.0 (95% CI 5.3 - 108.7) for combined defect *Nowak-Gottl et al. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood. 2001;97:858-862

11. Complete Laboratory Evaluation • Complete blood count • PT, PTT • Fibrinogen • Antiphospholipidantibody panel • Protein C and S activity levels • Antithrombinactivity assay • Factor V G1691A (Leiden mutation) • ProthrombinG 20210A • MTHFR • Homocysteinelevel • Lipoprotein (a) • Factor VIII Activity • Factor IX Activity • Factor XI Activity • Factor XII Activity • Plasminogen activity • Heparin cofactor II

12. Evaluation For Genetic Thrombophilia • A step-wise approach based on pre/ante/postnatal risk factors • Protein based assays (if initially done) must be repeated within 3-6 months May do initial evaluation at 3-6 months • Lower levels in newborn period make diagnosis of mild deficiency difficult • DNA assays are reliable when done Do not need to repeat • If anticoagulation is being administered, obtain levels 14-30 days after discontinuing medication • If initial NICU evaluation negative or not done Follow-up with hematology warranted at 3-6 months

14. Interpretation of diagnostic laboratory results should be approached with caution • Test results outside the 95% confidence limit are not sufficient to define a disease • Diagnosis of thrombophilia in neonates should be based on the presence of a positive clinical phenotype, family history, and of reproducible abnormal laboratory results • Evaluation with hematologist will be tailored based on severity of thrombosis, type of thrombosis, family history, and clinical risk factors *Shoshana Revel-Vilk. The conundrum of neonatal coagulopathy.. American Society of Hematology

15. Initial Neonatal Evaluation for Treatment/ Thrombophilia Evaluation Done in NICU 1-2 ml blood sampleSaxonhouse MA, Manco-Johnson M. The evaluation and management of neonatal coagulation disorders. SeminPerinatol2009. 52-65. . 2 • Complete blood count • PT, PTT • Fibrinogen • Antiphospholipidantibody panel (mother) • Protein C and S activity levels • Antithrombinactivity assay • Factor V G1691A (Leiden mutation) • ProthrombinG 20210A • MTHFR • Homocysteinelevel • Lipoprotein (a) • Factor VIII Activity • Factor IX Activity • Factor XI Activity • Factor XII Activity • Plasminogen activity • Heparin cofactor II

16. Tier 1 Laboratory Evaluation for Symptomatic Neonatal Thrombosis Perform at 3-6 Months Saxonhouse MA, Manco-Johnson M. The evaluation and management of neonatal coagulation disorders. SeminPerinatol. 2009. 52-65. 2009. 52-65. • Complete blood count • PT, PTT • Fibrinogen • Antiphospholipidantibody panel • Protein C and S activity levels • Antithrombinactivity assay • Factor V G1691A (Leiden mutation) • ProthrombinG 20210A • MTHFR • Homocysteinelevel • Lipoprotein (a) • Factor VIII Activity • Factor IX Activity • Factor XI Activity • Factor XII Activity • Plasminogen activity • Heparin cofactor II

17. Tier 2 Laboratory Evaluation for Symptomatic Neonatal Thrombosis Perform at 3-6 Months Saxonhouse MA, Manco-Johnson M. The evaluation and management of neonatal coagulation disorders. SeminPerinatol. 2009. 52-65. 2009. 52-65. • Complete blood count • PT, PTT • Fibrinogen • Antiphospholipidantibody panel • Protein C and S activity levels • Antithrombinactivity assay • Factor V G1691A (Leiden mutation) • ProthrombinG 20210A • MTHFR • Homocysteinelevel • Lipoprotein (a) • Factor VIII Activity • Factor IX Activity • Factor XI Activity • Factor XII Activity • Plasminogen activity • Heparin cofactor II

18. Management

19. Management of Renal Vein Thrombosis : • supportive care • UH • LMWH • rTPA • surgery /nephrectomy • Treatment should only occur at tertiary center that has proper neonatal, pediatric hematology, transfusion medicine, and pediatric surgical support • Pediatric hematologists with experience in thrombosis manage pediatric patients with thrombosis (Grade 2C) *Monagle et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest. 2012;141(2)(Suppl):e737s-e801s

20. Unilateral (Grade 2C) • Absence of renal impairment AND extension into the IVC • Supportive care with radiologic monitoring for extension • Anticoagulation (6 weeks to 3 months) ? • Extends into the IVC OR extension into the IVC • Anticoagulation for 6 weeks to 3 months • Bilateral (Grade 2C) • Evidence of renal impairment • Anticoagulation • Evidence of renal impairment • initial rTPA followed by anticoagulation • *Monagle et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest. 2012;141(2)(Suppl):e737s-e801s

21. UFH • Monitoring : • 6 h after commencing a heparin infusion and • 4 h after any change in infusion rate, • every 24 h once therapeutic levels are achieved

22. LMWH

23. The recommended therapeutic target range : • 0.5–1.0 IU/ml in a sample taken 4–6 h after s.c.injection • 0.5–0.8 IU/ml in a sample taken 2–6 h after s.c.injection • MONITORING: • after every change in dose • at least once weekly in hospital • Once monthly outpatient • Decrease in significant renal impairment, i.e. glomerular filtration rate <30 ml/min

24. Systemic Thrombolysis • rt-PA is administered at a dose of 0.5 mg/kg/h as a continuous infusion for 6 h. • A low-dose UFH infusion is administered concurrently at 10 U/kg/h • UFH rate must be reduced 30 min prior to starting thrombolytic therapy and increased to full dose 30 min after completion of a 6-hour infusion of rt-PA • Assessment after 6 h using appropriate imaging • The course may be repeated if indicated.

25. Catheter-Directed Thrombolysis • placement of a catheter adjacent to the site of a vascular thrombus. • The dose of rt-PA for local thrombolysis varies betweenrangefrom 0.01 mg/kg/h to 0.05 mg/kg/h.

26. Case 2

27. 7 days old neonate;term;G1P1A0;vaginal delivary;BF • Reffered due to lethargy and poor feeding • Made a seizure and focal seizure and apnea in ER • No cardiac murmur • No family HX of VTE , AIS ,MI • CBC, platelet,PT,PTT and INR were WNL • Biochemistry and electrolytes were NL • Brain Sonography and CT scan during the first 6 Hr were normal

28. Do you ask for more imaging ? • Which more investigation is recommended? • Do you recommend to obtain a complete profile of hypercoaguability?

30. Which more investigation is recommended?

31. The stroke work up should include an echocardiogram, to evaluate for a cardiac source of thrombus including cardiac malformations and other right to left shunt lesions, e.g. PFO. • a caseby- case basis: • conventional angiogram, • vasculitis work up • Cerebrospinal fluid tests for vasculitis or infection • Metabolic work up • Hb electrophoresis • TORCH or virological tests

32. Do you recommend to obtain a complete profile of hypercoaguability?

33. It is reasonable and common practice to obtain a complete profile of studies for hypercoagulable states in all cases of confirmed acute AIS, regardless of a known risk factor such as heart disease or cervical arterial dissection. • SICKKIDS Handbook of Pediatric Thrombosis & Hemostasis 2013 • Raffini L. Thrombophilia in children: who to test, how, when, and why? ASH Education Program Book. 2008;2008(1):228-35.

34. No cardiogenic ethiology has been found. • No hypercoaguability state was shown. • How do you manage him? • Starting with UFH • Starting with LMWH • Satarting with ASA • UFH+ASA • LMWH+ASA

35. 2.18. For neonates with a first arterial ischemic stroke (AIS), in the absence of a documented,ongoingcardioembolic source, we suggest supportivecareover anticoagulation or aspirintherapy(Grade 2C) . • 2.19. For neonates with a first AIS and a documentedcardioembolicsource, we suggest anticoagulationwithUFH or LMWH (Grade 2C) . • 2.20. For neonates with recurrent AIS, we suggest anticoagulant or aspirin therapy (Grade 2C) . Antithrombotic Therapy in Neonates and Children, CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT