Pediatric Venous Thromboembolism 2012

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Author: Danielle Cassidy, PharmD, BCPS …

Author: Danielle Cassidy, PharmD, BCPS
Audience: Third year pharmacy students at University of Colorado School of Pharmacy & Oregon State University College of Pharmacy.
Background: Provides overview of common causes of pediatric venous thromboembolism & treatment management.

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  • American Heart Association estimates that ~2 million cases of VTE will be diagnosed annually.Neonates- postulated to be due to immature coagulation pathway, Adolescents-postulated to be due to hormonal changes highest among teenage boys
  • The pathogenesis of VTE (Virchow triad) consist of venous stasis, endothelial damage, and the hypercoagulable state. risk factors often from more than one component of the triad.most common clinical prothrombotic risk factors in childhood is an indwelling central venous catheter. More than 50% of cases of DVT in children and more than 80% of cases in newborns
  • First choice due shorter half-life than LMWH {Half-life of UFH is dose dependent (~90 minutes),longer half-life is usually seen at high doses.}UFH can only prevent clot propagation and growth.Rate of elimination is reduced in patients with hepatic or renal dysfunction; dose adjustments may be necessary.
  • Studies suggests clearance is faster in newborns due to a larger volume of distribution than older children. Also, it is thought that heparin protein binding in newborns also different from that in older children and adults.
  • UFH requires frequent monitoring due to intra- and inter-patient variability. ApTT not good indicator as this extrapolated from adults
  • Preferred agent d/t ease of administration, the decreased need for monitoring, decreased risk for the development of HIT.LMWH-AT complex can not inactivate clot-bound factor Xa and can only prevent clot propagation and growth.{Factor Xa and thrombin inhibition ratio 4:1 (UFH ratio 1:1), LMWH’s contain a lesser quantity of 18-unit chain lengths as compared to UFH and therefore cannot bind simultaneously to AT and thrombin}.
  • Preferred agent d/t greatest amount of clinical data in kids
  • Therapeutic range of anti-Xa activity for LMWH is higher than that for UH because UH inhibits antithrombin as well as anti-Xa activity.Peak anticoagulant effect: 3-5 hours
  • Dosing, safety, and efficacy have not been established in the pediatric population.
  • A short term hypercoaguable state is produced due to rapid depletion of protein C and S and delayed depletion of factors II and X; response to warfarin is dependent upon degradation half-life of VK dependent clotting factors; complete depletion of factors II (~120 hrs) and X (~70 hrs)
  • Maximum starting dose=discuss
  • Drug interactions: Increase: bactrim, marijuana, amiodarone, azole antifungals Decrease: Rifampin,
  • Duration is derived from adult data
  • Most common antiplatelet used in kidsLow dose well tolerated as compared with higher doses used for inflammation.Reye syndrome appears to dose dependent effect and usually associated with doses >40 mg/kg. Usually recommend child stop med when febrile.

Transcript

  • 1. Pediatric Venous Thromboembolism & Anticoagulation Danielle Cassidy, Pharm.D. May 2012
  • 2. Objectives Define common risk factors and adverse outcomes of venous thromboembolism (VTE). Identify appropriate anticoagulation therapy for VTE. Recommend appropriate dosing and monitoring parameters for anticoagulation therapy. Appropriately counsel families on LMWH and warfarin therapies.
  • 3. Background
  • 4. VTE Pathophysiology Thrombi form in venous valve pockets and/or other areas of stasis within the venous vasculature. Clots can embolize and travel through the vasculature to the heart or lungs. Clots that originate proximal to the knee are at higher risk for emobolizing. Image available at: www.childrenshospital.org/az/Site2850/mainpageS2850P0.html
  • 5. Coagulation CascadeFrom Ferri F [ed]: Practical Guide to the Care of the Medical Patient, 7th ed. St. Louis, Mosby, 2007
  • 6. Incidence of VTE in Children ~2 million cases annually. Estimated incidence of VTE  Adults: 1 per 1000 patients per year  Pediatrics (per 10,000 patients per year)  Overall=0.49  Neonates=14.5  Adolescents=1.1 (15-17 years) Mortality rate due to VTE  Adults: 18%  Pediatrics: 0-2%
  • 7. Clinical Risk Factors ~90% of pediatric VTE is risk associated as compared to ~60% in adults. Risk factors  Transient: indwelling catheter, oral contraceptives, cast/splint, surgery, trauma, surgically correctable congenital heart disease.  Chronic: genetic/acquired thrombophilia, cancer, infection, chemotherapy, inflammatory diseases, prosthetic cardiac valves, sickle cell anemia, hyperhomocysteinemia.
  • 8. Adverse Outcomes Clot progression Recurrent VTE Pulmonary embolism (PE) Cerebral sinovenous thrombosis (CSVT) Post-thrombotic syndrome (PTS) Death
  • 9. PTS A condition of chronic venous insufficiency following DVT. Occurrence rate: 33-70% of children vs. ~29% of adults. Signs & symptoms  pain, chronic edema, visible superficial collateral vein formation.  skin abnormalities: hyperpigmentation, dermatitis, or skin ulceration.
  • 10. Examples of PTS(A) Dilated collaterals in a 14-year- (B) stasis dermatitis in a 13-year- old boy who had ileofemoral old boy who had iliofemoral to DVT. IVC DVT. Goldenberg N and Bernard T. Venous Thromboembolism in Children. Pediatr Clin N Am 2008;55:317.
  • 11. Quiz Question #1Which of the following is not a clinical riskfactor for VTE? a) indwelling catheter b) oral contraceptives c) smoking d) chemotherapy
  • 12. VTE Treatment Options: Anticoagulants
  • 13. Unfractionated Heparin (UFH) First line agent in clinically unstable patients or patients with significant/liable renal function. MOA: UFH binds to anti-thrombin (AT) resulting in inhibition of thrombin (factor IIa), factors IXa, Xa, XIa, XIIa. Elimination: Heaptic and renal
  • 14. UFH: Contraindications Pork allergy or history of heparin induced thrombocytopenia (HIT). Loading doses are contraindicated in:  Cerebrovascular accident  Active bleeding  Severe thrombocytopenia  Mechanical cardiac prosthesis  Patient’s at high risk for bleeding  DVT prophylaxis
  • 15. UFH: Dosing Loading dose: 50-100 units/kg IV over 10 minutes Initial maintenance dosing:  preterm infants: 15 units/kg/hour  term infants: 25 units/kg/hour  greater than 1 month: 15-20 units/kg/hour Dose adjustment: dependent upon anti-Xa levels.
  • 16. UFH: Goals and Monitoring Standard treatment anti-Xa goals: 0.35-0.7 units/mL Monitoring:  6 hours after initiating the infusion, 6 hours with every infusion rate change, and every 24 hours once a stable infusion rate is obtained.  Exception: 8 hours if no bolus was given.  More frequent with significant renal (CrCl <30 mL/min) or hepatic impairment.
  • 17. Low-Molecular Weight Heparin (LMWH) Enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep) First line agent in clinically stable patients for acute or long-term treatment. MOA: binds to AT resulting in inhibition of factor Xa. Contraindications: HIT, invasive procedures in previous 24 hours, allergy to UFH/LMWH.
  • 18. Enoxaparin Dosing Based on actual body weight. Initiating therapy  Route: subcutaneous  Frequency: q12 hours  Initial dosing  Preterm infant: 1.375-1.625 units/kg/dose  0 to <1 month: 1.625 units/kg/dose  1 month to <1 year: 1.5 units/kg/dose  1 year to < 6 years: 1.375 units/kg/dose  6 years to <21 years: 1.25 units/kg/dose
  • 19. Dalteparin Dosing Based on actual body weight. Initiating therapy:  Route: subcutaneous  Frequency: q 24 or 12 hours  Initial dosing: 100–150 international units/kg Further studies are needed to better define dosing parameters.
  • 20. Tinzaparin Dosing Based on actual body weight. Initiating therapy  Route: subcutaneously  Frequency: q12 hours  Dosing  Preterm infant: no information available  0-2 months: 275 units/kg/dose  2-12 months: 250 units/kg/dose  1-5 years: 240 units/kg/dose  5-10 years: 200 units/kg/dose  Greater than 10 years: 175 units/kg/dose Further studies are needed to better define dosing parameters.
  • 21. LMWH: Goals & Monitoring Standard treatment anti-Xa goal: 0.5-1 units/mL. Dose adjustments are dependent upon anti-Xa levels. Monitoring  Level ~4 hours after the 1st or 2nd dose and with every dose change.  Once therapeutic, levels necessary only if there are significant changes in weight (>10%), renal function, or serious bleeding side effects.  Levels usually obtained weekly in infants.
  • 22. Reducing pain with injections
  • 23. Commonly Used Direct Thrombin Inhibitors IV: bivalirudin and argatroban Common uses: HIT diagnosis or continued progression on therapeutic UFH. MOA: reversibly binding to the active site of thrombin
  • 24. IV Direct Thrombin Inhibitors Dosing and Monitoring  Argatroban  Initial: 0.75 mcg/kg/min continuous IV infusion  Adjustment: increments of 0.1 to 0.25 mcg/kg/min to achieve aPTT of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds).  Bivalirudin  Bolus dose: 0.125 mg/kg  Initial infusion rate: 0.125 mg/kg/hour  Adjustments: as needed to achieve aPTT 1.2 to 2.5 times the initial baseline value.
  • 25. Alternative Thrombin Inhibitors Not established in pediatrics:  Antithrombin dependent factor Xa inhibitor: fondaparinux (Arixtra)  Direct thrombin inhibitor: dabigatran (Pradaxa)  Direct factor Xa inhibitor: rivaroxaban (Xarelto), apixaban (Eliquis)
  • 26. Warfarin Treatment in patients requiring long-term therapy. MOA:  Inhibits Vitamin K epoxide reductase, blocking the oxidation of vitamin K and depleting vitamin K stores, thus reducing the production of clotting factors II, VII, IX, and X, and proteins C and S.  Does not inhibit the activity of existing clotting factors; depletion occurs via normal catabolism .
  • 27. Warfarin: Pharmacology LMWH or UFH bridge for a minimum of 5 days and/or two INR’s at/or above goal. Steady state: ~5-7 days Hepatic CYP450 metabolism:  Primary: 2C9  Minor: 2C8, 2C18, 2C19, 1A2, and 3A4
  • 28. Warfarin: Dosing, INR Goals, & Monitoring Initial dose: 0.1-0.2mg/kg once daily; dosing based on actual body weight. Standard INR goals: 2.0-3.0 or 2.5-3.0 Monitoring:  INR should be ordered 5-7 days after initiation or dose change.  More frequent monitoring should be considered in patients with significant hepatic impairment or serious bleeding side effects. Dose adjustments: INR, compliance, diet, interactions.
  • 29. Warfarin: What Can Affect INR Levels?  Factors that can  Factors that can increase the INR decrease the INR  Drug interactions  Drug interactions  Acute alcohol  Increased vitamin K ingestion intake  Reduced oral intake  Poor compliance  Fever  Chronic alcohol intake  Vomiting or diarrhea  Growth  Increased activity
  • 30. Anticoagulation Duration Duration of Etiology anticoagulation therapy by episode Resolved risk factors First: 3-6 months Recurrent: 6-12 months Idopathic First: 6-12 months Recurrent: 12 months Chronic risk factors First and recurrent: life long Congenital First and recurrent: life long thrombophilia
  • 31. VTE Treatment Options: Antiplatelet Agents
  • 32. Aspirin MOA: irreversible inhibition of platelet cyclooxygenase 2. Uses: thrombophilia, addition to warfarin therapy in high risk patients, CSVT, or cardiac anomalies. Dose: 1-5 mg/kg po qd (max dose 325mg; round to the nearest ¼, ½, or whole tab). Side effects: low dose well tolerated (alone). Treatment duration: determined by risk factors; standard duration is 1-2 years.
  • 33. Clopidogrel (Plavix) MOA: irreversible inhibition of adenosine diphosphate. Uses: aspirin allergy, thrombophilia, addition to warfarin therapy in high risk patients, CSVT, or cardiac anomalies. Dose: 1 mg/kg qd (max dose 75 mg; round to the nearest ¼, ½, or whole tab). Side effects: well tolerated (alone). Treatment Duration: determined by risk factors; standard duration is 1-2 years.
  • 34. Quiz Question #2Which of the following is considered first linetherapy for a clinically unstable patient withVTE? a) dalteparin b) warfarin c) heparin d) bivalirudin
  • 35. LMWH & Warfarin: Patient Counseling Points
  • 36. Common/Minor Side Effects Irritation at the injection site Hematomas under skin or around injections sites Bruising more easily or around injection sites Gum bleeding Epistaxis Bleeding after a minor cut Women: heavier menstrual bleeding
  • 37. Serious Side Effects Excessive/unusual  Chest pain bleeding  Weakness on one side of Dark brown/red urine the body Red/black (tar-colored)  Sudden difficulty stools speaking Hematemesis  Sudden changes in Excessive bruising vision Severe stomach pain  Unusually severe or Painful swelling of an prolonged headache arm or leg  Yellowing of the skin or Dizziness eyes
  • 38. LMWH Apply 5 minutes of pressure to minimize/prevent bruises and hematomas. Prior to injection can apply ice or numbing topical (e.g. Emla) to minimize injection pain. Injections should be given at the same time every day. Rotate injection sites to prevent scaring and minimize bruising/bleeding.
  • 39. Warfarin Take doses at the same time every day. All tablets (brand or generic) are color coded by strength. Double check the dose prior to administration (i.e. check the number and strength of tablets). Double check the bottle before leaving the pharmacy.
  • 40. LMWH and Warfarin Avoid medications that contain aspirin (if not medically necessary), ibuprofen, or naproxen. Never double or take extra doses to make up for a missed dose. Inform all health care providers about any anticoagulation medications you are taking.
  • 41. Real Life Case Studies
  • 42. Case Study #1 RM is a 16 year old obese male (120kg) with type 2 diabetes who was diagnosed with a right femoral DVT three months prior to admission. RM presents today with severe leg pain and swelling making it difficult to walk. RM reports that his insurance lapsed and he stopped using Lovenox two months prior to admission due to cost. Ultrasound was positive and CT showed clot progression in the R femoral vein.
  • 43. Case Study #1 The doctors would like to restart Lovenox therapy for RM. Is this an appropriate choice for first line therapy? Why? Yes first line therapy for all clinically stable patients and RM has no direct contraindications.
  • 44. Case Study #1 The doctors start Lovenox therapy at your recommendation. They would like to know what anti-Xa goal to achieve and when they should check a level. What would you recommend? • Goal anti-Xa: 0.5-1 units/mL •Check level ~4 hours after the 1st or 2nd dose and with every dose change.
  • 45. Case#2 EB is a 6 year old female (32 kg) with a distal left lower extremity DVT. The doctor would like to transition EB from Lovenox to warfarin therapy (INR goal 2.0-3.0). What starting dose would you recommend? 0.1-0.2 mg/kg once daily (3-6mg) What are some common bleeding side effects the family should be counseled about? Bruising more easily, gum bleeding, epistaxis, bleeding after a minor cut.
  • 46. Case#2 EB is started on warfarin 3mg po qd as recommended by pharmacy. Upon filling the prescription at an outside pharmacy the family notices the tablets are green. The family would like to know if the if the prescription was filled with the correct warfarin strength. No  green = 2.5mg tablet. Brown=3mg tablet.
  • 47. References Monagle P, Chan A, Goldenberg N, et al. Antithrombotic therapy in neonates and children: College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest 2012;133;737-801. Manco-Jonson, MJ. How I treat venous thrombosis in children. Blood. 2006:107;21-29. Ronghe MD, Halsey C, Goulden NJ. Anticoagulation Therapy in Children. Pediatr Drugs 2003;5(12):803-820. Goldenberg NA, Bernard TJ. Venous Thromboembolism in Children. Pediatr Clin N Am 2008;55;305-322. Jilma B, Kamath S, Lip GYH. ABC of antithrombotic therapy: Antithrombotic therapy in special circumstance. II-In children, thrombophilia, and miscellaneous conditions. Br J Haematol 2001;114:512-528. Albisetti M, Chan AKC, Mahoney DH, Kim MS. Diagnosis and treatment of venous thromboembolism in infants and children. UptoDate® Accessed September 17, 2008. Last updated October 29, 2007. Coutre S. Heparin Induced Thrombocytopenia. UptoDate® Accessed September 17, 2008. Last updated May29, 2008. Hirsh J, Hoak J. Management of deep vein thrombosis and pulmonary embolism.Circulation 1996; 93:2212-45.
  • 48. References Tapson VF. Acute pulmonary embolism. N Engl J Med 2008; 358:1037-52. Nohe N, Flemmer A, Rumler R, et al. The low molecular weight heparin dalteparin for prophylaxis and therapy of thrombosis in childhood: a report on 48 cases. Eur J Pediatr 1999;158:S134–9. Phillips, KW, Dobesh P, Haines ST. Considerations in using anticoagulant therapy in special patient populations. Am J Health- Syst Pharm August 1, 2008 Vol.65; Suppl. 7. pS14-S21. Valentine KA, Hull RD. Therapeutic use of heparin and low molecular weight heparin. UptoDate® Accessed September 9, 2008. Last updated June 3, 2008. Spandorfer J. The management of anticoagulation before and after procedures. Med Clin North AM 2001;85(5):1109-16,v. American Heart Association. AHA Statistical update: 2012. Accessed May 1, 2012. Available at: http://circ.ahajournals.org/content/125/1/e2.full Kerlin BA. Current and future management of pediatric venous thromboembolism. Am J Hematol 2012;87:S68–S74.