Thrombotic Thrombocytopenic Purpura A Disorder of VWF Proteolysis

1
Thrombotic Thrombocytopenic PurpuraA Disorder of
VWF Proteolysis?
Inreasing incidence? Often strikes young adults,
mainly females
Untreated, mortality gt90 Treated with
plasmapheresis, mortality lt20
2
VWF Multimers in TTP
Endothelial Cell
Normal Plasma
Active
Remission
Unusually large Multimers
Moake et al, NEJM 3071432, 1982
3
Shear and VWF Proteolysis

• Proteolysis increased by
• Shear stress (aortic stenosis)
• VWD type 2A mutations
• Denaturants (urea, guanidine)

4
VWF Cleaving Protease in Plasma

• Discovered in 1996 by Tsai and by Furlan
• Requires Ca2 and Zn2 ions
• Cleaves VWF between Tyr1605 - Met1606
• Activated by shear stress, mild denaturants

• Absent in children with congenital TTP

• Absent in most adults with idiopathic TTP
• (acquired IgG autoantibody inhibitor)

5
VWF Cleaving Protease(ADAMTS13)
Metalloprotease
Thrombospondin 1
Disintegrin
A Disintegrin-like And Metalloprotease with
ThromboSpondin-1 repeats
6
Attempted Passive Transfer of Thrombotic
Thrombocytopenic Purpura
T. E. Brittingham III and Hugh Chaplin, Jr. Blood
1957 12 480-482
It has been shown that idiopathic
thrombo-cytopenic purpura can be passively
transferred by the infusion of plasma (Harrington
et al, 1951). It seemed desirable to attempt a
similar demon-stration for thrombotic
thrombocytopenic purpura. We are reporting such
an experiment.
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Attempted Passive Transfer of Thrombotic
Thrombocytopenic Purpura
35 year old male with 1 week of purpura,
platelets lt 20K, Hgb 7.2 g/dl, Coombs neg, retic
34. Treated with cortisone, splenectomy on day
27. Died on day 42. Postmortem demonstrated
lesions of TTP diffusely. 500 ml blood
withdrawn prior to any therapy into 120 ml
standard ACD preservation solution. 300 ml plasma
was infused rapidly into a normal group AB Rh 32
year old male volunteer. No change in CBC,
reticulocyte count, or differential count over 16
days. No illness after 10 months.
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ADAMTS13 Deficiency in Idiopathic TTP

• Idiopathic, acquired TTP in adults
• Tsai 1998 37/37 with undetectable ADAMTS13
• Furlan 1998 20/24 with undetectable ADAMTS13
• Veyradier 2001 22/22 with undetectable
  ADAMTS13
• Mori 2002 12/18 with undetectable ADAMTS13
• Plus many case reports
• Severe ADAMTS13 deficiency correlates with
  idiopathic, acquired TTP

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Idiopathic versus Non-Idiopathic TTP

• Severe ADAMTS13 Deficiency
• Veyradier 2001 22/22 idiopathic, 16/35
  non-idiopathic
• Studt 2003 33/59 idiopathic, 6/239
  non-idiopathic
• Vesely 2003 16/48 idiopathic, 2/94
  non-idiopathic
• Variable discrimination
• Case definitions?
• Referral patterns?

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ADAMTS13 Assays in TTP

• Vesely 2003 Only study with mortality data
• 15/48 (31) idiopathic, 68/94 (72)
  non-idiopathic
• 3/18 (17) ADAMTS13 lt5, 68/94 (72) gt5
• What about response to plasma exchange?
• 38/48 (79) idiopathic, 48/94 (51)
  non-idiopathic
• 16/18 (89) ADAMTS13lt5, 70/94 (74) gt5

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ADAMTS13 Assays in TTP

• Vesely 2003 Idiopathic TTP only
• Response to PE in 14/16 (88) for ADAMTS13 lt5,
  24/32 (75) for ADAMTS13 gt5 (P 0.46)
• Death in 3/16 (19) for ADAMTS13 lt5, 12/32 (38)
  for ADAMTS13 gt5 (P 0.123)
• ADAMTS13 level does not seem to predict response
  to PE or death in idiopathic TTP.
• But idiopathic and absent ADAMTS13 arent
  independent, and prior transfusion may confound
  ADAMTS13 assays

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TTP and ADAMTS13 Response to Plasma Exchange

• Prospectively enroll adults with TTP
• Plasma samples on admission and every 2-3 days
  during therapy
• Assay for VWF cleaving protease and inhibitor

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Patient Characteristics
14
Patient Characteristics
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TTP and ADAMTS13 Response to Plasma Exchange
Clinical Characteristics of 37 Patients
Sex 30 female/7 male Age 47 (16-79) LDH
(IU/dl) 939 (263-28,000) Hematocrit () 28
(16-33) Platelets (K/µl) 18 (2-147) Creatinine
(mg/dl) 2.0 (0.6-3.4)
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TTP and ADAMTS13 Response to Plasma Exchange
Clinical Characteristics of 37 Patients
Single event 25 Multiple events 12 Fever 13 CNS
involvement 21 Creatinine gt1.5 17 Dialysis 7
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TTP and ADAMTS13 Response to Plasma Exchange
ADAMTS13 Deficient Category Number
Deficient Inhibitor Idiopathic 20 16 7 BMT 8
0 0 Cancer/Chemo 4 0 0 Peripartum 2 0 0 Other
3 0 0 Total 37 16 7
18
ADAMTS13 Deficient, No Inhibitor
19
ADAMTS13 Deficient, No Inhibitor
20
ADAMTS13 Deficient, No Inhibitor

• 9 patients
• Recurrences in 3 and 1 death
• Good response to plasma exchange
• Improvement correlates with increased ADAMTS13

• Why protease deficient?
• Insensitive inhibitor assay
• Clearance antibodies
• Other mechanism?

21
ADAMTS13 Deficient, With Inhibitor
22
ADAMTS13 Deficient, With Inhibitor

• 7 patients
• Multiple relapses in 4 and 2 deaths
• Good response to plasma exchange
• No consistent change in ADAMTS13
• Persistent inhibitor

Why is plasma exchange effective?
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TTP and ADAMTS13Why Does PE Work for Inhibitors?

• Stress precipitates TTP in congenital ADAMTS13
  deficiency
• Childhood triggers vaginal delivery, URI,
  pneumonia, otitis media
• Adult triggers any infection, alcohol abuse,
  pregnancy
• Resolution of stress may end an attack

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Non-Idiopathic TTP - Stem Cell Transplants
25
Non-Idiopathic TTP
FK506
Cancer
Clopidogrel
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TTP and ADAMTS13
Yes
No
Yes
No
Idiopathic
Idiopathic
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Mortality and Category
Dead
Alive
Totals
Idiopathic
18 (26)
50
68
Non-Idiopathic
33
78 (70)
111
Totals
96 (54)
83
179
OR 6.6 (3.2-13.7)
Vesely 2003 and our data P lt 0.00000003
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Mortality and ADAMTS13
Dead
Alive
Totals
ADAMTS13 lt5
6 (18)
28
34
ADAMTS13 gt5
55
90 (62)
145
Totals
96 (54)
83
179
OR 5.4 (2.0-15.6)
Vesely 2003 and our data P lt 0.0005
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Relapses and ADAMTS13 Inhibitors
Relapse
No Relapse
Totals
Inhibitor
15 (43)
20
35
No Inhibitor
18
1 (5)
19
Totals
16 (30)
38
54
OR 13.5 (1.6-300)
Veyradier 2001, Vesely 2003 and our data P lt 0.01
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TTP and ADAMTS13Implications for Future Studies

• PE is relatively ineffective for non-idiopathic
  TTP, and inhibitors predict relapse
• ADAMTS13 and inhibitor assays may be useful to
  guide therapy
• Plasma exchange could be reevaluated for TTP not
  caused by ADAMTS13 deficiency

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TTP and ADAMTS13Refractory Disease

• Plasma exchange does not address the underlying
  autoimmune disorder
• Refractory disease may benefit from
  immunosuppression

32
Immunosuppressive Therapy in TTP
33
Immunosuppressive Therapy in TTP
34
Clinical Correlations
Character
Odds Ratio

• ADAMTS13 lt5
• Survival 5
• Idiopathic TTP 8
• Female sex 4
• African ancestry 8
• Obesity (high)
• ADAMTS13 Inhibitor
• Relapse 13

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Conclusions

• Clinical value of ADAMTS13 assays deserves study
• Immediate immunosuppression for persistent
  inhibitors?
• Stratification for intensity of plasma exchange?

36
TTP at BJC
Xinglong Zheng (Univ Pennsylvania) Elaine
Majerus Patricia Anderson Kenji Nishio (Nara
Medical Univ) Agnès Veyradier Elodee Tuley Tim
Goodnough Morey Blinder