What’s with HIT?

1. What’s with HIT? Heparin Induced Thrombocytopenia A Perfusion Perspective M. Savelberg June 2010

2. Overview What is HIT? Diagnosis/Testing Management Recent Literature Perfusion Considerations Summary

3. HIT 1 HIT 2 Characteristics of HIT (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

4. 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.)

5. HIT 2 The IgG- PF4-heparin immune complex bind to platelets through the platelet Fc receptor, resulting in platelet activation, degranulation and (releases intracellular protein kinases) causing aggregation. Generation of platelet derived microparticles (procoagulants) = trigger thrombotic complications Activated platelets trigger a host of other systems including inflammatory cells, coagulation pathways and endothelial cells. Thomboxane A2 is synthesized and released into circulation. This leads to generation of thrombin and intravascular coagulation. Image taken from: Gurbuz, A.T., et al.,(2005) European Journal of Cardio-thoracic Surgery 27:138-149

6. HIT: The Big Picture

7. Frequency of HIT Highly variable and influenced by many factors: Patients receiving UFH > 1week ( with incidence ranging from 0.1%-1.0%) Heparin from bovine lung is more likely to produce HIT than the heparin from porcine intestine. (Warkentin, 2000; 2005) Unfractionated heparin (UFH) is more likely to cause HIT-2 than LMWH because heparin chains bind to PF4 in relation to chain length. Females more likely to have HIT than males (Warkentin, 2006) Warkintin, T.E., et al. (2006) Gender imbalance and the risk factor interactions in heparin-induced thrombocytopenia. Blood; 108;2937-2941

8. Suspected HIT? Less Expensive Standard management protocol used in cases of suspected HIT following exposure to UFH resulting in thrombocytopenia. More Expensive Test Gurbuz, et al. (2005) Heparin Induced Thrombocytopenia in the Cardiovascular Patient: Diagnostic and Treatment Guidelines, Eur. J of Card-Thor Surg. 27:138

9. Thromboembolic Complications Electron micrograph of thrombus

10. 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

11. General HIT Management • Suspicion of HIT includes: • Thrombocytopenia (PLT count falls by > 50%) * • Resistance to heparin anticoagulation* • Thrombosis during heparin therapy* • Stop all forms of heparin • Including LMWH, flush solutions, catheters • To avoid a hypercoagulable state • Warfarin should be started once platelet count is > 100 x 109/L, and continued for up to 3 months since the risk of thrombosis remains high up to 6 weeks after discontinuing heparin in HIT patients. (Gurbuz, 2005) • The American College of Chest Physicians suggests (Grade 2C) that vitamin K should be given to minimize the risk of warfarin induced limb gangrene or skin necrosis. • Overlap alternative anticoagulant agents with Warfarin at least 5 days due to protein C deficiency (otherwise could lead to microvascular thrombi and limb gangrene) • Start a rapidly acting, non-heparin anticoagulant • i.e. danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], bilvalrudin [Grade 2C] are recommended over the further use of UFH or LMWH • Prophylactic platelet transfusions may contribute thrombotic risk, and are NOT recommended. (Levy; 2007, Warkentin; 2008) Gurbuz, et al. (2005) Heparin Induced Thrombocytopenia in the Cardiovascular Patient: Diagnostic and Treatment Guidelines, Eur. J of Card-Thor Surg. 27:138-149 Levy, et al., (2007) Reducing Thombotic Complications in the Perioperative Setting: An Update on Heparin Induced Thrombocytopenia. Anes. Analg. 105(3):570582 Warkintin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S

12. Management of HIT

13. Site-Dependent Considerations for the Management of HIT • Availability of drug • Laboratory monitoring • Previous physician experience • Patient dependent factors (renal or hepatic insufficiency). - Alcoholism, diabetic nephropathy?

14. Management of HIT: The Evidence • June 2008, American College of Chest Physicians published Evidence-based Guidelines for the Treatment and Prevention of HIT. Chest;133;340S-380S • Treatment Guidelines look at the two categories of heparin alternatives. Non-thrombin inhibitors: low molecular weight heparin (LMWH), danaproid and ancrod. Direct thrombin inhibitors: hirudin and its recombinant derivative lepirudin as well as the synthetic direct thrombin inhibitors

15. Alternative Anticoagulant Protocols for CPB in HIT Patients Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S

16. Management of HIT for Pts Undergoing Cardiac Surgery • Management depends on if patient undergoing surgery is a previous HIT patient or Acute/Subacute HIT patient : Previous HIT: • If patient is HIT antibody negative and require cardiac surgery it is recommended that UFH is used over a non-heparin alternative [Grade 1B] (Pre and Post-operative anticoagulation should be using non-heparin anticoagulant) • If patient is HIT antibody positive by PF4 dependent enzyme immunoassay (EIA) but antibody negative by washed platelet activation assay (PAA) the use of UFH over non-heparin alternative is again recommended [Grade 2C] Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S

17. Management of HIT for Pts Undergoing Cardiac Surgery Management depends on if patient undergoing surgery is a previous HIT patient or Acute/Subacute HIT patient : Acute HIT: • Acute HIT (thrombocytopenic & HIT antibody positive) • Delay surgery if possible until HIT has resolved and antibodies are negative (or weakly positive) (mean time 50-80 days). [Grade 1B] The time in days (is shown to the right) to a negative test by both the activation and antigen assay. (Warkentin, 2001) The antigen test tended to become negative more slowly. At 100 days, heparin-associated antibodies disappeared, with less than 20% tested positive. Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S Warkentin, T.E., et al. (2001) Heparin-induced thrombocytopenia. Marcel Dekker Inc. NY. Second Edition. pg. 51

18. Management of HIT for Pts Undergoing Cardiac Surgery Management depends on if patient undergoing surgery is a previous HIT patient or Acute/Subacute HIT patient : Acute HIT: • Acute HIT (thrombocytopenic & HIT antibody positive) ii. Use bivalirudin for intraoperative coagulation during CPB or OPCAB (adapting surgical and anesthesia techniques according to bivalrudin pharmacology) [Grade 1B] iii. Using lepirudin for intraoperative anticoagulation (if ECT available, and patient has normal renal function with little risk for post-op renal failure). [Grade 2C] iv. Using UFH + antiplatelet agent epoprostenol (Flolan®) (if ECT not available or renal function precludes lepirudin use) [Grade 2C] Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S

19. Bivalirudin – Angiomax® • Direct thrombin inhibitor (DTI) • Synthetic peptide (20 amino acids) with lower MW that hirudin. • T1/2 = 25 mins via proteolytic cleavage (80%) present in blood when exposed to foreign/wound surfaces. • Minor renal excretion (20%) – can be used in patients with both renal or hepatic impairment (Cheng, D., 2006) • Minimal immunological activity, <1% after 5 day infusion. • ECT (Ecarin clotting time) preferred monitor on CPB Levy, et al., (2007) Reducing Thombotic Complications in the Perioperative Setting: An Update on Heparin Induced Thrombocytopenia. Anes. Analg.105(3):570-582

20. Bivalirudin – Angiomax® CPB Dosage: Initial dose IV bolus = 1.5mg/Kg followed by continuous infusion at the rate of 2.5 mg.Kg/hr during CPB. (Cheng, 2006) In agreement with Toronto General Hospital protocol (2006), Initial IV bolus dose of 1.0mg/Kg used by London Health Sciences Center. • A bolus of 50 mg should be added to the priming solution (by perfusionist) • ECT should be maintained between 400-500 sec or >370 seconds ACT (must not go on before!). • Clots noted in areas of stagnant blood is normal – to be taken back by cell saver. • Infusion can be terminated 15 minutes prior to decannulation. (TGH/LHSC Protocol) • Maintain a core temperature of >34 37 degrees after CPB • A bolus of 25-50mg should be added to pump after CPB. • Followed by a continuous infusion at 50mg/hr into pump after CPB, taken from anesthesia. (Levy; 2007, Cheng; 2006; and TGH protocol 2006) • If there is need to go back on bypass, the full loading dose should be re-administered to patient, and into extracorporeal circuit. IV Line Incompatibilities with Angiomax® Alteplase Diazepam Reteplase Amiodarone HCl Dobutamine HCl (at 12.5 mg/mL) Streptokinase Amphotericin B Prochlorperazine edisylate Vancomycin HCl Cloropromazine HCl

21. Bilvalirudin – Angiomax® Perfusion Specific Considerations: • Circuit Stagnation: Cardioplegia:must be continually re-circulated during periods without administration. • A plan must be developed regarding cardioplegia delivery; either continuous blood, crystalloid, intermittent blood every 10 minutes or any other method that will prevent stasis • The cardioplegia line from the pump to the table may be flushed with normal saline, if blood cardioplegia is to be used, following administration in order to prevent clot formation in line. The line flush should be placed in a sterile bowl at the table, and sent back to the cell saver. • The line from double spike (where crysalloid cardiplegia is hung to cardioplegia device (Myotherm®) must be re-flushed with high potassium cardioplegia and then cardiplegia delivery line reflushed to table between each administration. Purges: All purges must be flushed every 10 minutes (min) on bypass. • These include: arterial filter bypass line, mannifold (if off for any period of time), recirculation line, one-way de-airing line from oxygenator (if you plan to use again).

22. Bilvalirudin – Angiomax® Perfusion Specific Considerations: • Circuit Stagnation: Suckers: Intracardiac blood can be sent back to the pump, however any and all pericardial blood should be sent to the cell saver. Venting: Technique would need to be procedure and patient dependent: • In the case of a CABG procedure, where much venting is not expected, this blood may be sent back to the cell saver. • In the case of a valve or with a CABG where mod-severe AI may be present, increased venting may require the vent line to be flushed during periods of no venting to prevent fibrin/clot formation in vent line. • The vent can be wye’d and flush diverted to sequestration bag if required. • Cell Salvage: • Shed pericardial blood should not be re-infused, and cell salvage should be used. (Levy; 2007) • Cell salvage must be done with sodium citrate. Contact pharmacy in advance.

23. Bilvalirudin – Angiomax® Perfusion Specific Considerations: • Elimination Considerations: • Drugs: • Lasix with increase the elimination of the drug and therefore should be avoided during CPB. Also should be avoided prior to CPB, so as not to alter anticipated pharmokinetics. • Mannitol: Although an oxygen free radical scavenger, as an osmotic diuretic you may wish to avoid additional doses on bypass unless anuric to prevent excessive elimination. • Hemoconcentration/Dialysis: Will decrease the concentration of Bilvalirudin within circulation rapidly, and therefore should be avoided. If necessary, should monitor ACTs/ECTs consecutively and increase rate of Bilvalirudin infusion during CPB. • MUF:MUF post bypass to decrease Bivalirudin for severe hemorrhage • Emergency: • Emergency pump set-up:Should have an emergency pump set-up and available in the event that massive clot is detectable. • Oxygenator in room: Have an extra oxygenator in the room in the case of poor gas exchange due to clot/fibrin formation on the membrane.

24. Bilvalirudin – Angiomax® Other considerations for Cardiac Surgical Management with Bilvalirudin: • Heparin-free Equipment:including ECC coating free of heparin, as well as PA catheter, Cortis®, heparin coated syringes (see ABG section below). • ABGs: • Should use in-line blood gas monitor if available for early detection of poor gas exchange with may indicate oxygenator failure (due to fibrin/clot formation) • Do ABGs regularly at least every 15 minutes if in-line monitor not available. Sampling Technique: Option #1: Sample with a non-heparinized syringe and transfer to a heparinized syringe for ABG analysis. Option #2: After sampling with heparin coating syringe, pull back another 1-3cc, to flush stopcock and prevent possible contamination of line with heparin. • Blanket warmers should be used so as not to prolong ACT at cooler temperatures yielding more inaccurate ACT interpretation. • Cooler temperatures also decrease drug metabolism worsening problems with eliminating Bilvalirudin post-operatively, and increasing post-operative bleeding and transfusion requirements.

25. Bilvalirudin – Angiomax® Other considerations for Cardiac Surgical Management with Bilvalirudin: • Reservoir Levels: • If possible maintain levels in the reservoir <1000mL in order to prevent stasis. • Cold Cardioplegia: • Is acceptable, as long as systemic temperature >34ºC, in theory should decrease enzymatic activity and therefore decrease Bilvalirudin metabolism in cardioplegia delivery line and within grafts. • Cannulation: • Flush arterial cannula with prime following cannulation • RAP: • May be best to avoid RAP prior to CPB in the event that you may have to wait prior to initiating CPB and stagnation occurs. • Decannulation: • Following termination of CPB a ½” x 3/8” connector should be used to reconnect the arterial and venous lines, as soon as all transfusion forward is complete, so that the circuit can be kept patent.

26. Bivalirudin – Angiomax® • Has been systematically investigated in a number of studies. • 3 RCTs have examined Bivalrudin vs. UFH (with protamine reversal) 1) Utilizing fixed dose Bivalirudin protocols using routine intraoperative coagulation studies (ACT) to ensure a minimal threshold level of anticoagulation is feasible. Case Report: Pappalardo, et al., 2007 reported use of Bivalrudin for anticoagulation during CPB - Initial dose 75 mg (1mg/Kg) prior to aortic cannulation - Put 50 mg bilvalrudin in the priming solution (1500 LR, 100mL (18%) mannitol) - The bolus was followed by an infusion of 2.5 mg/Kg per hour during bypass which was discontinued during cross-clamp removal or graft completion. - ACTs were maintained perio-operatively (422-557 seconds) - Post-operative blood loss = 390mL. - ACTs are satisfactory method of monitoring anticoagulation with bilvalirudin (however this statement is based on a single case report) (Zucker et al., 2005) 2) Special surgical, anesthesiology and perfusion techniques must be used due to the unique pharmacology of bivalirudin, in particular its progressive, nonenzymatic degradation in areas of stagnant blood flow. (Guidelines available). If not followed, intraoperative clot formation in the bypass grafts and stagnant areas have been found. 3) Compared in both on-pump and off-pump cases, the efficacy and safety results of bivalirudin in comparison to UFH/protamine are comparable in both transfusion requirements and post-operative bleeding. Pappalardo, F., Franco, A., Crescenzi, G., Zangrillo, A., Zoster, A., (2007) Successful use of bilvalirudin for cardiopulmonary bypass in a patient with heparin allergy. Perfusion: 2267-69

27. Bivalirudin – Angiomax® • Surgical Considerations: • Stasis Management: • Ensure there is no stasis in the surgical field. • Graft Patency: • Flush coronary grafts with crystalloid solution to keep them patent • Considerations for flushing IMA • Sucker Blood Management: • Send intra-cardiac blood back to the pump, and pericardial blood to the cell saver. • Plan for Cardioplegia Delivery: • A plan must be developed regarding cardioplegia delivery; either continuous blood, crystalloid or intermittent blood cardioplegia every 10 minutes. • Any method that will prevent stasis.

28. Bivalirudin – Angiomax®Current Research

29. CABG HIT/TS On- and Off-pump Safety and Efficacy: on pump (CHOOSE-ON) was a Phase III multicenter, open-label trial designed to assess the safety and efficacy of bivalirudin in 50 patients compared to a historical control group of 50 patients with or at risk of HIT/HITTS undergoing on-pump cardiac surgery. • 49 patients treated with Bivalirudin: 43 had acute HIT and thrombosis syndrome with antibodies at the time of surgery. • Mean intra-operative blood loss = 575 ± 524 mL • 24 hr post-operative blood loss = 998 ± 595 mL Blood Product Usage 5.6 ± 3.8 units RBCs 8.6 ± 7.2 units platelets 6.0 ± 4.7 units FFP Koster et al., (2007) Bivalirudin During Cardiopulmonary Bypass in Patients With Previous or Acute Heparin-Induced Thrombocytopenia and Heparin Antibodies: Results of CHOOSE-ON Trial The Societ y of Thoracic Surgeons 83:572-577

30. Randomized, open-label, multicenter trial.Published March 2006 in the Journal of Thoracic and Cardiovascular Surgery. • 21 institutions enrolled 150 patients in the United States and Germany. • 101 were randomized to Bivalirudin arm • 49 to Heparin-Protamine reversal arm. • Clinical Outcomes: • Procedural success rates at 7 days/discharge were: • Major bleeding events at day 7/discharge occurred in: • Transfusion rate was: The EValuation of patients during coronary Artery Bypass Graft Operation: Linking UTilization of Bilvalirudin to Improved Outcomes and New Anticoagulation Strategies. 94.9%(Bivalirudin grp) vs. 96.2% (Heparin grp). 6.1%(Bivalirudin grp) vs. 1.9% (Heparin grp). 58.2%(Bivalirudin grp) vs. 59.6% (Heparin grp). Dyke, et al., (2006) A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: The EVOLUTION-ON study. The Journal of Thoracic and Cardiovascular Surgery. 131:533-9

31. Post-op chest tube output was higher for the Bivalirudin treatment group at 2 hrs (p=0.009) However was NOT statistically significant between groups at 24 hrs (p =0.13) • Dosing for Bivalirudin with an intial bolus dose of 1.0 mg/Kg followed by 2.5 mg/Kg/hr during cardiopulmonary bypass, and 50 mg added to the pump by the perfusionist. • Additional doses of 0.1-0.5 mg/Kg to maintain ACT > 2.5x baseline (routine institutional values. • No incident of thrombosis in oxygenator, arterial line, or cardioplegia line. • In 6 cases clot was observed in the cell salvage device (separate from CPB circuit) • Atrial fibrillation was reported in 9.6% of patients receiving heparin and 9.2% of patients receiving Bivalirudin. • Acute renal failure occurred in 2 patients in the heparin and bivalirudin groups, respectively (3.8% vs 2.0%)

32. Bilvalirudin – ECT or ACT? • How the Ecarin Clotting Time Test works: The TIM- ECT test uses a flat test card containing dried agents and thrombolytic assessment system (TAS) (Bayer Diagnostics, Rapid Point) Test card is inserted into instrument, a drop of blood is placed on the reaction chamber on the card.Reagents are rehydrated (including ecarin, and paramagnetic iron oxide particles). • Iron particles are subjected to oscillating magnetic field under the card. • Formation of fibrin clot restricts the movement of these particles (detected by the analyzer’s infared optical system) allowing calculation of clotting time. • Ecarin activates prothrombin producing meizothrombin : with excessive hemodilution resulting in prolonged ECT times, due to diluted prothrombin levels. • Fabrizio, and colleagues in 2001, successfully used ECT and lepirudin during CPB for a patient undergoing coronary artery bypass grafting.

33. Bilvalirudin – ECT or ACT? • ECT (Ecarin clotting time) vs. ACT (Activated clotting time) significant correlation differences with bilvalirudin concentration (Casserly, 2004) • Thrombin inhibitor management (TIM) has been suggested to be more accurate with ECT rather than ACT anticoagulation management. • Multi-center study, 170 patients undergoing PCI, blood samples were taken at 6 different time points measuring ECT, and ACT (using Hemochron Jr.) • For each sample, ECT, ACT and bilvalirudin concentration were determined. • Correlations were 0.96 for ECT citrated, 0.93 for ECT non citrated, 0.90 with ACT • At therapeutic levels of bilvalirudin, correlation coefficients were 0.75, 0.59, and 0.37 respectively. • Therefore ECT would be a much better indicator of bilvalirudin concentration during CPB.

34. Lepirudin- Refludan® • Direct thrombin inhibitor (DTI) • Is a recombinant form of hirudin aka. r-hirudin (which comes from the cloning and expression of yeast cells) is a 65 amino acid peptide. • Elimination half life = 0.8-2.0 hours in patients with normal renal function (exclusively renal elimination) in patients with renal impairment you have prolonged lepirudin concentrations in the plasma which result in prolonged leeding post-operatively. • Dependent on creatinine clearance. • Has stable pharmacokinetics. • Requires ECT monitoring = ecarin clotting time is required which is not a point of care testing coagulation assay available in the cardiac operating room (In Canada can be requested on humanitarian grounds for acute HIT for CPB– Bayer® Diagnostics) • Shows linear correlation with plasma r-hirudin levels. • No antidote • Anaphylaxis with repeat administration • Antibodies to r-hibrudin are reported in 56-74% after 10 days, but do not appear to cause an allergic reaction

35. Lepirudin- Refludan® • CPB Dosage: • Initial bolus of 0.25 mg/Kg given 10 mins prior to CPB • A bolus of 0.20 mg/Kg should be added to the pump prime. • A continuous infusion of 0.5 mg/min should be maintained until 15-30 mins before CPB is terminated. • Supplemental dosages (5-20 mg) to maintain plasma levels > 3.5ug/mL (as determined by ECT) • After CPB 5mg of lepirudin is added to the pump circuit volume to prevent clotting. (Cheng, D. et al., 2006) • Literature: 1)Largest study involving the use of Lepirudin in patients with previous acute or HIT reported surgery without thrombosis in 95% of patients. 2)Reports of excessive bleeding post-operatively. 3

36. UFH + Prostacyclin Analogue or Tirofiban • Prostacyclin Analogue: Epoprostenol (Arixtra®) or Iloprost - Two reports using UFH + epoprostenol, one including 9 patients, had favorable outcome in 100% of patients. • Tirofiban (Aggrastat®): Antiplatelet Agent - platelet glycoprotein IIb/IIIa antagonist - In a report using Tirofiban there was successful outcome in 44 of 47 patients. However the manufacturer does not recommend use in cardiac surgical patients as there have been reports of fatal bleeding in two patients with anuria. - 10ug/Kg bolus and then continuous infusion (0.15ug/Kg) + full dose UFH has provided effective anticoagulation during CPB without any TEC (Koster, 2001) - hemofiltration decreases Tirofiban concentration during CPB Koster, et al., (2001) One-year experience with the platelet glycoprotein IIb/IIIa antagonist tirofiban and heparin during cardiopulmonary bypass in patients with heparin induced thrombocytopenia type II. J Thorac Cardiovascular Surgery 122:1254-1255

37. Danaparoid Sodium – Orgaran® • Low molecular weight heparinoid (6,000 Da) derived from porcine intestine mucosa • Is a mixture of polysulfated glycosaminoglycans (84% heparan sulfate, 12% dermatan sulfate, and 4% chondroitin sulfate) derived from porcine intestinal mucosa. • Mechanism: accelerates the activity of ATIII against factor Xa and factor IIa, which is similar to that of heparin but which greater effect on anti-Xa. It is a potent thrombin inhibitor that binds to PF4 and in high doses inhibits platelet activation by the HIT-IgG. • Cross-reactivity of HIT-IgG for Danaparoid leading to exacerbation of HIT has occurred in up to 10-20% (Gurbuz, 2004), therefore screening test should be done prior to use. • Long t1/2 = 25 hrs (anti-Xa activity) with no effect on PTT and INR. • Half life = 7-8 hrs for the inhibition of thrombin formation. • Major route of excretion is through the kidney, and it is not metabolized by the liver. • No specific antidote. • No longer available in USA (2002), but still available in Canada and Europe. • ACTs are unsuitable for monitoring.

38. Danaparoid Sodium – Orgaran® • CPB dosage: • IV bolus = 125U/Kg after sternotomy • Priming dose = 3 U/L • Maintain continuous infusion of 7U/Kg which should be stopped 30 mins prior to the end of CPB. • IF clots are seen an additional bolus of 1,250 U should be given. • Literature: • Largest clinical trial = 666 HIT patients with high clinical response rate. • Has been used in CPB • Associated with 33% of patients having intraoperative clots, and post- operative severe bleeding when used in cardiac surgery. • Reinfusion of pump blood post-operatively with cell saver is discouraged. • Should be “…used only when other anti-thrombin agents are not available” (Gurbuz, 2004)

39. Agatroban – Novastan® • Relatively new direct thrombin inhibitor: Binds competitively and reversibly inhibiting thrombin INDEPENDENT of ATIII • Small synthetic peptide (MW 527 Da) derived from L-arginine. • Primarily hepatic metabolism (may be used in patients with renal dysfunction). However in patients with hepatic dysfunction dosage should be decreased (0.5ug/kg per min) (Gurbuz, et al., 2005) • No cross-reaction with heparin antibodies • T1/2 = 40-50 mins

40. Agatroban – Novastan® • Monitored by aPTT to 1.5-3.0x baseline • ACT = 300-400 seconds OPCAB (repeat every 15 mins) has been recommended, and 400-600 with CPB. • In pediatric patients ACT>999 sec was associated with major bleeding. (Hursting, 2006) • ACT as a monitoring tool – does not appear to be reliable. • Reports of ACT >600 sec result in excessive bleeding post op (Martin; 2007), however in other reports ACT > 800 sec have shown to have thrombosis in CPB circuit (Nielsen, 2006). • CPB Dosage: • Initial dose of 0.1mg/Kg should be administered prior to CPB (Cheng, D. et al., 2006) • No requirement for additional drug in prime. • Continuous infusion of 5-10ug/Kg/min during CPB (or adjusted) to maintain ACT of 400-600 secs. (Cheng, D. et al., 2006) • 40mcg/kg/min in healthy subjects produces anticoagulant effect Cheng, et al., (2006) Hursting, et al., (2006) Argatroban anticoagulationin pediatric patients: a literature analysis. J Pediatric Hematol. Oncol.28:4-10 Martin, et al., (2007) Argatroban for anticoagulation in cardiovascular surgery. Eur J. Hematol, 76;161-166 Neilsen, et al., (2006) Agatroban, bilvalirudin, and lepirudin to not decrease clot propagation and strength as effectively as heparin activated antithrombin in vitro. J. Heart Lung Transplant. 25;653-663

41. Ancrod – Arvin® • Direct thrombin inhibitor • Mechanism: Reduced fibrinogen levels and blood viscosity. • Hepatic metabolism (may be used in patients with renal dysfunction). However in patients with hepatic dysfunction dosage should be decreased. • T1/2 = 40-50 mins • Monitored by aPTT to 1.5-3.0x baseline, as well as fibrinogen levels. • ACT = 300-400 seconds • 40mcg/kg/min in healthy subjects produces anticoagulant effect • No cross reactivity with heparin induced antibodies • Literature:

42. Management of HIT for Pts Undergoing Cardiac Surgery Management depends on if patient undergoing surgery is a previous HIT patient or Acute/Subacute HIT patient : Acute HIT: • Thrombocytopenic + HIT antibody positive • Using UFH + antiplatelet agent tirofiban (Aggrastat®) [Grade 2C] • Use danaproid for off-pump CAB vs UFH with on-pump CABG with postive PF4-heparin antibodies in pts with acute or sub-acute HIT. Subacute HIT: • Platelet count recovery + continuing HIT antibody positive: i.Recommendation is to delay surgery if possible until HIT antibodies are negative, then use heparin rather than a non-heparin anticoagulant. [Grade 1C] ii.If surgery cannot be delayed until that point, then it is suggested that a non-heparin alternative be used over an UFH. [Grade 2C] Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S

43. Summary of Alternative Anticoagulants for Cardiac Surgery Table 4, taken from: Gurbuz, et al. (2005) Heparin Induced Thrombocytopenia in the Cardiovascular Patient: Diagnostic and Treatment Guidelines, Eur. J of Card-Thor Surg. 27:138-149

44. Misnomers Re: HIT & Heparin • One is usually reluctant to expose a patient with known, or strongly suggested, hypersensitivity to the drug in question. • There are several reasons why this should not be the case with regards to heparin re-administration in patients with HIT. • There is no trend to earlier onset of HIT with secondary exposure to heparin in patients with a history of heparin exposure previously. • Among patients with rapid onset HIT – pre-existing HIT antibodies can be tested for in advance of subsequent exposure to heparin. • There is a stronger association to HIT with recent (<100 days) rather than remote (>100 days) prior heparin exposure. • HIT antibodies are transient with a median time to disappearance being 50-80 days. • Re-administering heparin in patients with previous HIT antibodies which no longer were present, reoccurrence of HIT antibodies did not occur. • In instances where HIT antibodies were regenerated, they did not occur sooner nor at higher levels than the previous HIT event.

45. Heparin Re-challenge? • Repeat heparin exposure is an option for patients with previous acute or subacute HIT, especially if >100 days prior. • At this point HIT antibodies are usually undetectable or weak, and are not regenerated by the brief exposure required during cardiac surgery. • Ideally clinicians should ensure that HIT antibodies are no longer detectable serologically prior to heparin re-exposure. • Patients with recent HIT whose platelet count has recovered, but who still have detectable HIT antibodies (“subacute HIT”), are at risk of developing rapid-onset HIT on heparin reexposure, unless a washed platelet activation assay (eg, SRA, HIPA test) is negative and the antigen assay is only weakly positive or strongly positive because of nonplatelet-activating (IgM, IgA) antibodies.