General Heme Update

Tom DeLoughery, MD FACP FAWMOregon 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

VW

F

VW

F

VW

F

VW

F

VW

F

GPIb

GPIb

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

ADAMTS13

Y

Shiga

VWF

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 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

Sellier-Leclerc, A.-L. et al. J Am Soc Nephrol 2007;18:2392-2400

C3 Levels By Mutation

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

TicagrelorTime 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 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

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

-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

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 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%)

2nd 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?