General Heme Update Tom DeLoughery, MD FACP FAWM Oregon Health and Sciences University.
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Transcript of General Heme Update Tom DeLoughery, MD FACP FAWM Oregon Health and Sciences University.
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General Heme Update
Tom DeLoughery, MD FACP FAWMOregon Health and Sciences University
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DISCLOSURE
Relevant Financial Relationship(s)
Speaker Bureau - None
Consultant – Amgen
Grants - Alexion
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Topics
• Thrombotic microangiopathies
• Bridging therapy
• Quick hits
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Thrombotic Microangiopathy• Key diagnostic features
– Microangiopathic hemolytic anemia• Schistocytes• Hemolysis
– Thrombocytopenia– End organ damage
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Classification• TTP
– Classic– Relapsing– Chronic
• HUS– Typical– Atypical
• Other thrombotic microangiopathies– Pregnancy
• HELLP syndrome• Post-partum HUS• TTP
– Chemotherapy related– Transplant related– Cancer related
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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%
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Other Abnormalities
• LDH elevations (>2-3x nl)
• Myocardial involvement
• Pulmonary involvement
• Gastrointestinal involvement– Pancreatitis
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Pitfalls in Diagnosis
• Classic pentad most often not present
• Thrombocytopenia may be mild (20-60,000/ul)
• Neurological defects vague
• Diagnosis not thought of
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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
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VW
F
VW
F
VW
F
VW
F
VW
F
GPIb
GPIb
GPIb
GPIb
GPIb
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VWF
VWF
VWF
VWF
VWF
GPIb
GPIb
GPIb
GPIb
GPIb
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VWF
ADAMTS13
VWF
VWF
VWF
VWF
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VWF
VWF
VWF
VWF
VWF
ADAMTS13
GPIb
GPIb
GPIb
GPIb
GPIb
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ADAMTS13
ADAMTS13
ADAMTS13
Y
Shiga
VWF
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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
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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?
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Therapy
• Steroids
• Plasma exchange
• Immune globulin (??)
• Vincristine
• Rituximab
• Splenectomy
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Steroids• Seems to play a role in TTP
therapy
• Usually 60-120 mg prednisone
• Slow taper when patients responds
• Some patients steroid sensitive
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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
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Other Therapies• IVIG: not effective
• Vincristine: classic drug for resistance disease– 2 mg day 1, 4, 7, 10
• Splenectomy: very controversial
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Rituximab• Appears to be useful for TTP
• No great RCT but abundant anecdotes– Faster remissions
– Less relapses
• Give after exchange
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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
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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%
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ADAMTS13 Levels
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Bottom Line
• Rituximab useful in preventing relapses in antibody positive patients
• Acute role is undefined– Refractory cases?
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If ADAMTS ab +
Transfusion 50, 2010,: 2753–2760
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Problem Patients• Getting worse on therapy
– Increase pheresis to 1 vol BID– Vincristine– Rituximab– Splenectomy?– Look for infection
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Problem Patients
• Slow responders– Patience
• Slow tapers– Rituximab
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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
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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
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Congenital TTP• Common?
• Appears at any age– Pregnancy, etc
– Relapsing TTP
– Plasma responsive
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Congenital TTP
• Very low ADAMTS 13 but no inhibitor
• Can do DNA studies now– Wisconsin blood center
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Congenital TTP
• Management– Plasma infusions 2 units 2-4 weeks
– rADAMTS13• Trial to start soon at OHSU
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HUS• MAHA, thrombocytopenia and
renal failure• Classic (e coli)
– Treat uremia
• Adults – Plasma exchange may help
• Reportable disease!!
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aHUS• Disease of uncontrolled
complement activation leading to renal failure
• Difficult to diagnoses
• Course in past usual terminated in renal failure/death
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Complement and Atypical HUS
Protein Gene Source Location % of aHUS
Factor H CFH Liver circulates ~ 15-30%
Factor I CFI Liver circulates ~ 5-10%
Membrane Cofactor Protein
MCP Widespread Membrane bound
~ 10-15%
Factor B CFB Liver, ? circulates <5%
C3 C3 Liver, ? circulates ~ 5-10%
Anti-FH-Ab CFHR1/CFHR3
Lymphocyte circulates ~ 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
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Sellier-Leclerc, A.-L. et al. J Am Soc Nephrol 2007;18:2392-2400
C3 Levels By Mutation
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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!
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Eculizumab• Effective in PNH
• Known to shut down complement after C5
• Now approved for aHUS
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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
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Eculizumab in Plasma Resistant aHUS
• Extension study
• Dosing– 900mg wks 1-4
– 1200mg biweekly
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Eculizumab in Plasma Resistant aHUS
• Patients characteristics– Median age 28
– Time from diagnosis 10 month
– Mean plasma tx – 17
– 24% with no complement mutations
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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
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Eculizumab in Plasma Sensitive aHUS
• Licht #3303
• 20 patients “controlled” on plasma therapy
• At 60 weeks– Improved GFR
– No need for therapy
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Eculizumab in aHUS
• Controlls disease and prevents end organ damage
• Need to recognized patients before severe renal disease occurs
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Work-Up of TM• Pre-treatment
– ADAMTS13 levels and inhibitors
– C3 and C4
• Consider aHUS– ADAMTS13 normal
– Family history of aHUS
– Progressive disease
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Antithrombotics and Surgery
• When to stop before surgery
• When to bridge
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Antiplatelet Agents
• Aspirin– Stop 5 days before
• Clopidogrel, Prasugrel– Stop 5-7 days before
• Ticagrelor– 5 days before
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TicagrelorTime of Offset of Action
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022433s000lbl.pdf
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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
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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
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The Future?
• Cangrelor is intravenous reversal ADP receptor antagonist with short half-life
• Recent study using it as bridging
• JAMA online first
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Cangrelor
• No increase risk of bleeding
• Small study but promising
• May be good option for stents
• Needs more studies!
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Approaches to Anticoagulation and Procedures
• Continue agents
• Stop drug
• Bridging therapy
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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
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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
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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
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Mechanical Heart Valve PatientsMechanical Heart Valve Patients
AuthorAuthor AorticAortic MitralMitral BothBoth ClotClot
Douketis (04)Douketis (04) 215215 143143 4646 2626 0.9%0.9%
nn
Pengo (09)Pengo (09) 190190 114114 7676 ?? 1.6%1.6%
Kovacs (04)Kovacs (04) 112112 ?? ?? ?? 4.5%4.5%
Hammerstingl (07)Hammerstingl (07) 116116 7676 3131 99 0%0%
BleedBleed
0.5%0.5%
1.2%1.2%
7.1%7.1%
0.9%0.9%
Mayo (2007)Mayo (2007) 556556 372372 136136 4848 0.7%0.7% 3.6%3.6%
TotalTotal 11891189 1.2%1.2% 2.7%2.7%
Courtesy Robert D. McBane, M.D
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Bridging - Canada
• Skieth #546
• Venous thrombosis reviewed– Excluded if
• Other indications for bridging• VTE < 90 days
• 613 procedures/413 patients
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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
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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
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-5 -4 -3 -2 -1 0 1 2 3
Stop Warfarin
Start LMWH
Stop LMWH ~24 hour before
Restart Warfarin
Restarting LMWHSimple procedure – after procedureComplex – Prophylactic 24-48 hrs
- Therapeutic 48 hrs or more
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Who We Bridge
• Valves– Mitral valve replacement
– Multiple valves
– Non-bileaflet aortic valve
– Bileaflet AVR with other risk factors
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Who We Bridge
• Atrial fibrillation– History of stroke
– CHADS2 > 4
– Cardiac thrombus
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Who We Bridge
• Venous Thrombosis– Thrombus within 3 months
• One month IVC filter?
– Cancer and thrombosis
– Virulent thrombophilia
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ITP
• Some new data on TPO agonists
• No major trials
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Eltrombopag and Fibrosis
• Brynes #528
• Fibrosis concern with TPO agents
• Long term study of eltrombopag with annual bone marrows performed
• N = 156
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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
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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
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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
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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
0 5 10 20 25Mos
Rel
apse
-Fre
e S
urv
ival
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%)
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2nd Line• Splenectomy
– Oldest and most effective therapy
• Rituximab– 60-70% response
– Only 20% “cure” rate
• TPO agonist
– 90% response
– Need for chronic therapy
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Eltrombopag in Marrow Failure
• MPL signaling can influence expansion and growth of stem cells and progenitor cells
• Is this clinical relevant?
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Eltrombopag in Marrow Failure
• Olnes #54
• Phase II severe aplastic anemia
• Median age = 45
• Dose escalation – 50mg -> 150mg
– N = 25 (22 evaluable)
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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
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Eltrombopag in Marrow Failure
• Promising results
• Needs long term follow-up
• Option for severe aplastic anemia?
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Aspirin for Venous Disease!
• Becattini #543
• First idiopathic DVT N = 403
• Randomized after 6-18 months– Most ~ 1 year
• Aspirin 100mg daily vs placebo
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One patient in each group had major bleeding
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Aspirin
• Provocative trial!
• Need to replicate and compare to warfarin
• An options for patients who refuse/ineligible for warfarin?