Transcript Presentation 1 - Oregon Health & Science University

General Heme Update
Tom DeLoughery, MD FACP FAWM
Oregon Health and Sciences University
DISCLOSURE
Relevant Financial Relationship(s)
Speaker Bureau - None
Consultant – Amgen
Grants - Alexion
Topics
• Thrombotic microangiopathies
• Bridging therapy
• Quick hits
Thrombotic Microangiopathy
• Key diagnostic features
– Microangiopathic
hemolytic anemia
• Schistocytes
• Hemolysis
– Thrombocytopenia
– End organ damage
Classification
• TTP
– Classic
– Relapsing
– Chronic
• HUS
– Typical
– Atypical
• Other thrombotic microangiopathies
– Pregnancy
• HELLP syndrome
• Post-partum HUS
• TTP
– Chemotherapy related
– Transplant related
– Cancer related
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%
Other Abnormalities
•
•
•
•
LDH elevations (>2-3x nl)
Myocardial involvement
Pulmonary involvement
Gastrointestinal involvement
– Pancreatitis
Pitfalls in Diagnosis
• Classic pentad most often not
present
• Thrombocytopenia may be mild
(20-60,000/ul)
• Neurological defects vague
• Diagnosis not thought of
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
VWF
GPIb
GPIb
VWF
GPIb
GPIb
GPIb
VWF
VWF
VWF
VWF
VWF
GPIb
GPIb
GPIb
GPIb
GPIb
VWF
ADAMTS13
VWF
VWF
VWF
VWF
VWF
VWF
VWF
VWF
VWF
ADAMTS13
GPIb
GPIb
GPIb
GPIb
GPIb
ADAMTS13
ADAMTS13
Shiga
VWF
ADAMTS13
Y
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
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?
Therapy
•
•
•
•
•
•
Steroids
Plasma exchange
Immune globulin (??)
Vincristine
Rituximab
Splenectomy
Steroids
• Seems to play a role in TTP
therapy
• Usually 60-120 mg prednisone
• Slow taper when patients
responds
• Some patients steroid sensitive
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
Other Therapies
• IVIG: not effective
• Vincristine: classic drug for
resistance disease
– 2 mg day 1, 4, 7, 10
• Splenectomy: very controversial
Rituximab
• Appears to be useful for TTP
• No great RCT but abundant
anecdotes
– Faster remissions
– Less relapses
• Give after exchange
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
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%
ADAMTS13 Levels
Bottom Line
• Rituximab useful in preventing
relapses in antibody positive
patients
• Acute role is undefined
– Refractory cases?
If ADAMTS ab +
Transfusion 50, 2010,: 2753–2760
Problem Patients
• Getting worse on therapy
– Increase pheresis to 1 vol BID
– Vincristine
– Rituximab
– Splenectomy?
– Look for infection
Problem Patients
• Slow responders
– Patience
• Slow tapers
– Rituximab
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
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
Congenital TTP
• Common?
• Appears at any age
– Pregnancy, etc
– Relapsing TTP
– Plasma responsive
Congenital TTP
• Very low ADAMTS 13 but no
inhibitor
• Can do DNA studies now
– Wisconsin blood center
Congenital TTP
• Management
– Plasma infusions 2 units 2-4 weeks
– rADAMTS13
• Trial to start soon at OHSU
HUS
• MAHA, thrombocytopenia and
renal failure
• Classic (e coli)
– Treat uremia
• Adults
– Plasma exchange may help
• Reportable disease!!
aHUS
• Disease of uncontrolled
complement activation leading
to renal failure
• Difficult to diagnoses
• Course in past usual terminated
in renal failure/death
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
Liver, ?
circulates
~ 5-10%
CFHR1/
CFHR3
Lymphocyte
circulates
~ 10%
C3
Anti-FH-Ab
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
C3 Levels By Mutation
Sellier-Leclerc, A.-L. et al. J Am Soc Nephrol 2007;18:2392-2400
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!
Eculizumab
• Effective in PNH
• Known to shut down complement
after C5
• Now approved for aHUS
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
Eculizumab in Plasma
Resistant aHUS
• Extension study
• Dosing
– 900mg wks 1-4
– 1200mg biweekly
Eculizumab in Plasma
Resistant aHUS
• Patients characteristics
– Median age 28
– Time from diagnosis 10 month
– Mean plasma tx – 17
– 24% with no complement
mutations
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
Eculizumab in Plasma
Sensitive aHUS
• Licht #3303
• 20 patients “controlled” on
plasma therapy
• At 60 weeks
– Improved GFR
– No need for therapy
Eculizumab in aHUS
• Controlls disease and prevents
end organ damage
• Need to recognized patients
before severe renal disease
occurs
Work-Up of TM
• Pre-treatment
– ADAMTS13 levels and inhibitors
– C3 and C4
• Consider aHUS
– ADAMTS13 normal
– Family history of aHUS
– Progressive disease
Antithrombotics and Surgery
• When to stop before surgery
• When to bridge
Antiplatelet Agents
• Aspirin
– Stop 5 days before
• Clopidogrel, Prasugrel
– Stop 5-7 days before
• Ticagrelor
– 5 days before
Ticagrelor
Time of Offset of Action
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022433s000lbl.pdf
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
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
The Future?
• Cangrelor is intravenous
reversal ADP receptor antagonist
with short half-life
• Recent study using it as bridging
• JAMA online first
Cangrelor
•
•
•
•
No increase risk of bleeding
Small study but promising
May be good option for stents
Needs more studies!
Approaches to Anticoagulation
and Procedures
• Continue agents
• Stop drug
• Bridging therapy
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
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
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
Mechanical Heart Valve Patients
Author
n
Aortic Mitral Both Clot
Bleed
Douketis (04)
215
143
46
26
0.9%
0.5%
Pengo (09)
190
114
76
?
1.6%
1.2%
Kovacs (04)
112
?
?
?
4.5%
7.1%
Hammerstingl (07) 116
76
31
9
0%
0.9%
Mayo (2007)
372
136
48
0.7%
3.6%
Total
556
1189
Courtesy Robert D. McBane, M.D
1.2% 2.7%
Bridging - Canada
• Skieth #546
• Venous thrombosis reviewed
– Excluded if
• Other indications for bridging
• VTE < 90 days
• 613 procedures/413 patients
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
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
Start LMWH
Stop LMWH ~24 hour
before
Stop Warfarin
-5
-4
-3
-2
-1
0
1
2
3
Restart Warfarin
Restarting LMWH
Simple procedure – after procedure
Complex – Prophylactic 24-48 hrs
- Therapeutic 48 hrs or more
Who We Bridge
• Valves
– Mitral valve replacement
– Multiple valves
– Non-bileaflet aortic valve
– Bileaflet AVR with other risk
factors
Who We Bridge
• Atrial fibrillation
– History of stroke
– CHADS2 > 4
– Cardiac thrombus
Who We Bridge
• Venous Thrombosis
– Thrombus within 3 months
• One month IVC filter?
– Cancer and thrombosis
– Virulent thrombophilia
ITP
• Some new data on TPO agonists
• No major trials
Eltrombopag and Fibrosis
• Brynes #528
• Fibrosis concern with TPO
agents
• Long term study of eltrombopag
with annual bone marrows
performed
• N = 156
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
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
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
Multicenter Study: Response to HighDose Dexamethasone
100
CR: n = 58
Relapse-Free Survival
87%
75
PR/MR: n = 19
65%
NR: n = 13
50
25
CR: n = 58 (64%)
PR or MR: n =19 (21%)
NR: n =13 (14%)
P =.05
0
0
5
10
15
20
25
Mos
• At 15 mos of follow-up, 5 relapses each among subjects
who achieved CR or PR/MR
This research was originally published in Blood. Mazzucconi M, et al. Blood. 2007;109:1401-1407.
© the American Society of Hematology.
nd
2
Line
• Splenectomy
– Oldest and most effective therapy
• Rituximab
– 60-70% response
– Only 20% “cure” rate
• TPO agonist
– 90% response
– Need for chronic therapy
Eltrombopag in Marrow
Failure
• MPL signaling can influence
expansion and growth of stem
cells and progenitor cells
• Is this clinical relevant?
Eltrombopag in Marrow
Failure
•
•
•
•
Olnes #54
Phase II severe aplastic anemia
Median age = 45
Dose escalation
– 50mg -> 150mg
– N = 25 (22 evaluable)
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
Eltrombopag in Marrow
Failure
• Promising results
• Needs long term follow-up
• Option for severe aplastic
anemia?
Aspirin for Venous Disease!
• Becattini #543
• First idiopathic DVT N = 403
• Randomized after 6-18 months
– Most ~ 1 year
• Aspirin 100mg daily vs placebo
One patient in each group had major bleeding
Aspirin
• Provocative trial!
• Need to replicate and compare to
warfarin
• An options for patients who
refuse/ineligible for warfarin?