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Heparin Pathologies

Presented by: Maggie Savelberg, Group Members: Desiree Bonadonna and Britt McIlwain University of Nebraska Medical Center Omaha, Nebraska. Heparin Pathologies. Overview. 1. Introduction. 2. Coagulation & Anticoagulation. 3. Heparin . 4. Resistance & Rebound. 5.

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Heparin Pathologies

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  1. Presented by: Maggie Savelberg, Group Members: Desiree Bonadonna and Britt McIlwain University of Nebraska Medical Center Omaha, Nebraska Heparin Pathologies

  2. Overview 1 Introduction 2 Coagulation & Anticoagulation 3 Heparin 4 Resistance & Rebound 5 Allergic Rxn’s & HIT 6 SOP 7 World Knowledge

  3. Introduction Cardiac surgery requiring cardiopulmonary bypass (CPB) places a large burden of activation of the hemostatic coagulation system Caused by.. Re-infusion of pericardial blood exposed to thrombogenic surfaces Blood –foreign circuitry interface & Blood-air interface Effects of microemboli on endothelial cells Decrease in circulating protein buffers (Speiss et al., 2008)

  4. Introduction

  5. Introduction

  6. Anticoagulation Elevated hemostatic activity without anticoagulation is associated with CPB may induce a systemic inflammatory reaction and lead to: Therefore, adequate anticoagulation is a critical component of successful management of hemostatic and inflammatory responses associated with CPB. (Parekh, 2008)

  7. Coagulation • Understanding current concepts of coagulation is important in determining the preoperative bleeding risk of patients and in managing hemostatic therapy perioperatively. (Tanaka KA., 2009)

  8. Coagulation

  9. Anticoagulation • Although the immature systems of neonates needs further study, according to Gruenwald et al., 2010 (Sick Kids Hospital Toronto) She can conclude definitively that individualized heparin and protamine management in pediatrics has been shown to reduce platelet activation and coagulopathies.

  10. So how should anticoagulation during CPB be managed and what other pathologies associated with heparinization for anticoagulation, be understood and accounted for?

  11. Anticoagulation 1. 2. 3. (Hirsh, 2001)

  12. Heparin (Hirsh, 2001)

  13. Heparin

  14. Heparin

  15. Heparin (Hirsh, 2001)

  16. Heparin (Hirsh, 2001)

  17. Heparin Venous thromboembolism Prophylaxis of DVT and PE Treatment of DVT Coronary heart disease UA and Acute MI (Hirsh, 2001)

  18. Heparin Dosing

  19. Anticoagulation Management (Lobato, 2010)

  20. Anticoagulation Monitoring

  21. Anticoagulation Monitoring

  22. Anticoagulation Monitoring (Dunning, 2008)

  23. Anticoagulation Monitoring

  24. Anticoagulation Monitoring

  25. Anticoagulation Management

  26. Anticoagulation Management

  27. Heparin Resistance

  28. Heparin Resistance Heparin Resistance (Speiss et al., 2008)

  29. Heparin Resistance Heparin Resistance (Leong, et al. 1998)

  30. Heparin Resistance Heparin Resistance (Leong, et al. 1998)

  31. Heparin Resistance Heparin Resistance (Leong, et al. 1998)

  32. Heparin Resistance Heparin Resistance • SOP Recommendations for AT III dosing are: • 100 x (weight in kgs) to increase AT III levels from 0% to 100%. • (Gravlee, 1993) • (Speiss et al., 2008)

  33. Heparin Rebound • Heparin rebound phenomenon has been in existence for more than 45 years. • Kolff (1956) described heparin rebound as: • "a treacherous hemorrhagic phenomenon” • Sise and colleagues (1961), Wright (1961); • "rebound hypercoagulable state” • Ferarris (2007) “Heparin rebound is the reappearance of anticoagulant activity after adequate neutralization with protamine” • History

  34. Heparin Rebound • Why is there rebound? • Heparin is bound in equilibrium to nonspecific • to plasma proteins, vascular wall • matrix proteins and endothelial cells. • Protamine is administered = binding to unbound heparin and heparin dissociated from tissue and protein binding sites • Heparin/protamine complexes are then cleared from the circulation 43% of CPB Patients (Teoh, 2004) (Subramaniam, 2008)

  35. Heparin Rebound • Why is there rebound? • Heparin rebound occurs because not all heparin is bound to and cleared by protamine. • proportion remains bound nonspecifically to plasma proteins and vascular cells, which provides a reservoir of heparin. • Dissociates over time and produces an anticoagulant effect when it binds to AT “Heparin Rebound Effect” (Teoh, 2004)

  36. Heparin Rebound Heparin Rebound 1. (Teoh , 2004)

  37. Heparin Rebound (Ferraris , 2007)

  38. Heparin Rebound Heparin Allergy (Subramaniam, 2008)

  39. Heparin Rebound (Subramaniam, 2008)

  40. Heparin Allergy

  41. Heparin Allergy Type III Reactions (Jappe, 2008)

  42. Heparin Allergy (Jappe, 2008)

  43. Heparin Allergy Type I Reactions

  44. Heparin Allergy: HIT HIT 1 HIT 2 (1) Cheng, D.., (2006) Perioperative Care in Cardiac Anesthesia and Surgery. Chp 19: HIT and Alternatives to Heparin Table taken from pg.174, (2) (Gurbuz, A.T., et al., 2005) European Journal of Cardio-thoracic Surgery 27:138-149

  45. Heparin Allergy: HIT 2 Caused by heparin-dependent immunoglobin G (IgG) antibodies (HIT-IgG) binding to a conformationally modified epitope on platelet factor 4 (PF4) antibodies present in 18% of patients exposed to UFH (Gurbuz, 2004) The binding of heparin and other glycosaminoglycans to PF4 = heparin-PF4 complex, alters its shape rendering it immunogenic. Against which IgG antibodies are formed. (Antigenicity of the heparin-PF4 complex depends on the molecular weight and degree of sulfation of the heparin molecule.)

  46. Heparin/PF4 Complex PF4 Complex IgG antibody

  47. HIT: The big picture

  48. HIT: Diagnosis 1. Thrombocytopenia during heparin therapy. Note: Thrombocytopenia during first 4 post-operative days of cardiac surgery due to hemodilution and platelet consumption is rarely HIT related. 2. Exclusion of other causes of thrombocytopenia i.e. septicemia, MOF (multi-organ failure),post-transfusion purpura. 3. Diagnosis confirmed by: a) Detection of HIT-IgG antibodies by ELISA, for heparin-PF4 complexes using goat anti-human antibody (antigen assay) b) Or by a heparin-induced platelet aggregation study (HIPAA) 4. Resolution of thrombocytopenia after cessation of heparin. ELISA Plate Gurbuz, et al. (2005) Heparin Induced Thrombocytopenia in the Cardiovascular Patient: Diagnostic and Treatment Guidelines, Eur. J of Card-Thor Surg. 27:138

  49. Heparin Allergy

  50. World Knowledge

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