1. General Heme Update Tom DeLoughery, MD FACP FAWM Oregon Health and Sciences University

2. DISCLOSURE Relevant Financial Relationship(s) Speaker Bureau - None Consultant – Amgen Grants - Alexion

3. Topics Thrombotic microangiopathies Bridging therapy Quick hits

4. Thrombotic Microangiopathy Key diagnostic features –Microangiopathic hemolytic anemia Schistocytes Hemolysis –Thrombocytopenia –End organ damage

5. Classification TTP –Classic –Relapsing –Chronic HUS –Typical –Atypical Other thrombotic microangiopathies –Pregnancy HELLP syndrome Post-partum HUS TTP –Chemotherapy related –Transplant related –Cancer related

6. The Pentad of TTP: Dead, Dead, Dead Thrombocytopenia MAHA Mental status changes: only seen in 40-50% Renal insufficiency: most often mild –Proteinuria most common Fevers: 20%

7. Other Abnormalities LDH elevations (>2-3x nl) Myocardial involvement Pulmonary involvement Gastrointestinal involvement –Pancreatitis

8. Pitfalls in Diagnosis Classic pentad most often not present Thrombocytopenia may be mild (20-60,000/ul) Neurological defects vague Diagnosis not thought of

9. TTP: Role of Von Willebrand's Factor VWF synthesized as huge molecules and is cleaved to large molecular Ability of VWF to bind to platelets varies in proportions to size Largest VWF can bind spontaneously to platelets Metaloprotease is responsible for cleaving VWF –ADAMTS13

10. VWF GPIb

11. VWF GPIb

12. VWF ADAMTS13 VWF

13. ADAMTS13 GPIb

14. ADAMTS13 Y Shiga VWF

15. ADAMTS13 in TTP Papers have demonstrated lack of ADAMTS13 activity in TTP patients –IgG inhibitory antibody found in many patients –ADAMTS13 activity increased with exchange Usually decreased in classic TTP Usually normal in classic HUS Mutations seen in hereditary TTP/HUS

16. ADAMTS 13 Levels Levels may guide therapy <5% and inhibitor –More severe disease but lesser risk of death –Strong role for immunosuppression esp if relapses <5% and no inhibitors –Congenital? 5-50% –Many diseases Normal –Still can be TTP –May do worse?

17. Therapy Steroids Plasma exchange Immune globulin (??) Vincristine Rituximab Splenectomy

18. Steroids Seems to play a role in TTP therapy Usually 60-120 mg prednisone Slow taper when patients responds Some patients steroid sensitive

19. Plasma Exchange Key factor in outcome –2 RCT Start with 1.5 plasma volume exchange for at least 5 days Follow LDH Taper when LDH normal Plasma infusion until exchange –1 unit/4-6 hours

20. Other Therapies IVIG: not effective Vincristine: classic drug for resistance disease –2 mg day 1, 4, 7, 10 Splenectomy: very controversial

21. Rituximab Appears to be useful for TTP No great RCT but abundant anecdotes –Faster remissions –Less relapses Give after exchange

22. Phase II Study 40 patients with acute TTP –34 de novo, 6 relapse Rituximab within 3 days Compared to historical controls Blood 118:1746, 2011

23. Results No difference in number of exchanges No difference in hospital days –Was decreased in non-ICU patients Marked decrease in relapses –10% from 57%

25. ADAMTS13 Levels

26. Bottom Line Rituximab useful in preventing relapses in antibody positive patients Acute role is undefined –Refractory cases?

27. If ADAMTS ab + Transfusion 50, 2010,: 2753–2760

28. Problem Patients Getting worse on therapy –Increase pheresis to 1 vol BID –Vincristine –Rituximab –Splenectomy? –Look for infection

29. Problem Patients Slow responders –Patience Slow tapers –Rituximab

30. Relapsing TTP Relapses common 30-60% –Most ADAMTS13 inhibitors Can be fatal Early - inadequate therapy Late – inhibitor, congenital Tx: –+ Inhibitor – rituximab, splenectomy –No inhibitor + ADAMTS13 – aHUS - ADAMTS13 - congenital TTP

31. Oddball Presentations Severe thrombocytopenia but not much else –Platelets <10,000/ul but with mild hemolysis and neuro symptoms –Most with <5% ADAMTS13 Thrombosis w/o TTP –3 cases reported in patients with history of TTP

32. Congenital TTP Common? Appears at any age –Pregnancy, etc –Relapsing TTP –Plasma responsive

33. Congenital TTP Very low ADAMTS 13 but no inhibitor Can do DNA studies now –Wisconsin blood center

34. Congenital TTP Management –Plasma infusions 2 units 2-4 weeks –rADAMTS13 Trial to start soon at OHSU

35. HUS MAHA, thrombocytopenia and renal failure Classic (e coli) –Treat uremia Adults –Plasma exchange may help Reportable disease!!

36. aHUS Disease of uncontrolled complement activation leading to renal failure Difficult to diagnoses Course in past usual terminated in renal failure/death

37. Complement and Atypical HUS ProteinGeneSourceLocation% of aHUS Factor HCFHLivercirculates~ 15-30% Factor ICFILivercirculates~ 5-10% Membrane Cofactor Protein MCPWidespreadMembrane bound ~ 10-15% Factor BCFBLiver, ?circulates<5% C3 Liver, ?circulates~ 5-10% Anti-FH-AbCFHR1/ CFHR3 Lymphocytecirculates~ 10% Unknown~ 40-50% Jozsi et al. Blood 2008, Frémeaux-Bacchi V et al. Blood 2008, Goicoechea de Jorge 2007, Caprioli, et al Blood 2006, Kavanagh Curr Opin Nephrol Hypertens, 2007

38. Sellier-Leclerc, A.-L. et al. J Am Soc Nephrol 2007;18:2392-2400 C3 Levels By Mutation

39. Diagnosis Thrombotic microangiopathy with: –Normal ADAMT13 –Predominant renal involvement –Gradually progressive with therapy Specific diagnosis –Some with low C3 –Genetic testing - Iowa http://www.healthcare.uiowa.edu/labs/ morl/index_CDS.htm –Remember many patients will NOT have defects!

40. Eculizumab Effective in PNH Known to shut down complement after C5 Now approved for aHUS

41. Eculizumab in Plasma Resistant aHUS Greenbaum #193 Phase II trial 26 weeks –Progressive disease despite plasma –13/15 patients with increased platelets –15/17 no need for plasma or plasma exchange –4/5 patients stopped dialysis

42. Eculizumab in Plasma Resistant aHUS Extension study Dosing –900mg wks 1-4 –1200mg biweekly

43. Eculizumab in Plasma Resistant aHUS Patients characteristics –Median age 28 –Time from diagnosis 10 month –Mean plasma tx – 17 –24% with no complement mutations

44. Eculizumab in Plasma Resistant aHUS Results –17/17 patients event free by end of study –65% with improvement in renal function by one CKD state

45. Eculizumab in Plasma Sensitive aHUS Licht #3303 20 patients “controlled” on plasma therapy At 60 weeks –Improved GFR –No need for therapy

46. Eculizumab in aHUS Controlls disease and prevents end organ damage Need to recognized patients before severe renal disease occurs

47. Work-Up of TM Pre-treatment –ADAMTS13 levels and inhibitors –C3 and C4 Consider aHUS –ADAMTS13 normal –Family history of aHUS –Progressive disease

48. Antithrombotics and Surgery When to stop before surgery When to bridge

49. Antiplatelet Agents Aspirin –Stop 5 days before Clopidogrel, Prasugrel –Stop 5-7 days before Ticagrelor –5 days before

50. Ticagrelor Time of Offset of Action http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022433s000lbl.pdf

51. Drug Eluting Stents Drug eluting stents require long term dual antiplatelet therapy Increasing reports of fatal MI long after stent placement if antiplatelet agent stopped Patients should stay on one agent for procedures

52. Cardiac Stents Bare metal –< 4 weeks: need combined therapy –> 4 weeks: aspirin Drug eluting stents –< 12 months: need combined therapy –> 12 months: shortest possible duration of stopping clopidogrel

53. The Future? Cangrelor is intravenous reversal ADP receptor antagonist with short half-life Recent study using it as bridging JAMA online first

55. Cangrelor No increase risk of bleeding Small study but promising May be good option for stents Needs more studies!

56. Approaches to Anticoagulation and Procedures Continue agents Stop drug Bridging therapy

57. Continue Warfarin Recommended approach for low risk procedures –Dental extractions –Cataracts –Simple endoscopy/colonoscopy –Pacemaker/ICD placement –Hip arthroplasty Works best if INR < 3.0

58. Stop all Drugs Approach associated with least risk of bleeding but (in theory) highest risk of thrombosis Warfarin and antiplatelet agents must be stopped 5-7 days before procedure Can take 2-5 days to get INR back up Best approach for patients not at high risk of thrombosis

59. Bridging Covering the patient with LMWH while off warfarin Increasing data –Increases risk of bleeding –No substantial decrease in thrombosis Shift away from aggressive bridging

60. Mechanical Heart Valve Patients Author Aortic Mitral Both Clot Douketis (04) 215 143 46 26 0.9% n n Pengo (09) 190 114 76 ? ? 1.6% Kovacs (04) 112 ? ? ? ? ? ? 4.5% Hammerstingl (07) 116 76 31 9 9 0% Bleed 0.5% 1.2% 7.1% 0.9% Mayo (2007) 556 372 136 48 0.7% 3.6% Total 1189 1.2% 2.7% Courtesy Robert D. McBane, M.D

61. Bridging - Canada Skieth #546 Venous thrombosis reviewed –Excluded if Other indications for bridging VTE < 90 days 613 procedures/413 patients

62. Results 4 DVTs (0.63%) 1.58% incidence bleeding –13.6 patients with bleeding and 30% with major bleeding developed DVT Conservative approach is best

63. Factors Which Increase Risk for Bleeding Pre-procedure –Trough LMWH level too high Need to stop q12 LMWH 24 hours before and q24 maybe 36-48% Too aggressive LMWH in patients with renal disease Post-procedure –Starting therapeutic LMWH too soon!! Need 48 hours or more

64. -5-4-3-20123 Stop Warfarin Start LMWH Stop LMWH ~24 hour before Restart Warfarin Restarting LMWH Simple procedure – after procedure Complex – Prophylactic 24-48 hrs - Therapeutic 48 hrs or more

65. Who We Bridge Valves –Mitral valve replacement –Multiple valves –Non-bileaflet aortic valve – Bileaflet AVR with other risk factors

66. Who We Bridge Atrial fibrillation –History of stroke –CHADS2 > 4 –Cardiac thrombus

67. Who We Bridge Venous Thrombosis –Thrombus within 3 months One month IVC filter? –Cancer and thrombosis –Virulent thrombophilia

68. ITP Some new data on TPO agonists No major trials

69. Eltrombopag and Fibrosis Brynes #528 Fibrosis concern with TPO agents Long term study of eltrombopag with annual bone marrows performed N = 156

71. Results No pattern of increasing reticulin with long use of agent 2.6% with increase reticulin Increase reticulin is rare and associated with TPO is uncertain

72. Safety of TPO agonists May be thrombotic risk with very high platelets counts –Don’t be greedy! >50,000 goal Reticulin risk is low In MDS will increase blasts so contraindicated

73. My Current Approach Dexamethasone 40mg x 4 repeat q14 x 4 –Only dexamethasone exposure –Saves other agents for later Uncertainties –Some data adding rituximab upfront may increase remission –Not clear if dex is better than standard prednisone – RCT planned

74. Multicenter Study: Response to High- Dose Dexamethasone At 15 mos of follow-up, 5 relapses each among subjects who achieved CR or PR/MR 65% 87% CR: n = 58 PR/MR: n = 19 0510 2025 Mos Relapse-Free Survival 25 75 100 50 15 P =.05 NR: n = 13 0 This research was originally published in Blood. Mazzucconi M, et al. Blood. 2007;109:1401-1407. © the American Society of Hematology. CR: n = 58 (64%) PR or MR: n =19 (21%) NR: n =13 (14%)

75. 2 nd Line Splenectomy –Oldest and most effective therapy Rituximab –60-70% response –Only 20% “cure” rate TPO agonist –90% response –Need for chronic therapy

76. Eltrombopag in Marrow Failure MPL signaling can influence expansion and growth of stem cells and progenitor cells Is this clinical relevant?

77. Eltrombopag in Marrow Failure Olnes #54 Phase II severe aplastic anemia Median age = 45 Dose escalation –50mg -> 150mg –N = 25 (22 evaluable)

78. Eltrombopag in Marrow Failure 41% with some response 32% platelet transfusion independent 6 with red cell improve – 4 transfusion independent 5 patients with neutrophil response Marrows show improvement

79. Eltrombopag in Marrow Failure Promising results Needs long term follow-up Option for severe aplastic anemia?

80. Aspirin for Venous Disease! Becattini #543 First idiopathic DVT N = 403 Randomized after 6-18 months –Most ~ 1 year Aspirin 100mg daily vs placebo

83. One patient in each group had major bleeding

85. Aspirin Provocative trial! Need to replicate and compare to warfarin An options for patients who refuse/ineligible for warfarin?