TTP-The Treatment Pathway - Microsoft · • The diagnosis of TTP should be treated as a medical emergency • The initial diagnosis of TTP should be made on clinical history, examination

TTP-The Treatment Pathway

Dr Marie Scully

UCLH,

London, UK

What is TTP?What is TTP?• Thrombotic Thrombocytopenia• Purpura

• Acute life-threatening illness

• Mortality: 90% without treatment– Associated morbidity

• Affects females>males

• Median age at presentation: 30-40 years

• A disorder of platelets-VWF resulting in disseminated VWF-platelet microthrombi

Tsai HM Int J Hemat 2010

Tsai Sem Throm Hemostasis 2012

Normal Coagulation

ADAMTS 13 deficiency

Ott et al Am J Clin Pathol. 2010

NP TTP

Moake et al. NEJM 1982

Sadler et al. Ann Rev Med 2005

VWF-Cleaving Protease (ADAMTS 13)VWF-Cleaving Protease (ADAMTS 13)

AA DDisintegrin AAnd MMetalloproteinase with TThromboSSpondin type-1 repeats 1313

• ADAMTS13 is secreted as active enzyme

• No natural inhibitor - long plasma ½-life (~2-3 days)

• Highly specific

• Only cleaves VWF

• Single site - A2 domain (Tyr1605-Met1606)

Regulates VWF multimeric size/function in plasma

TTP HUS

Low platelets, MAHA,

neurological features,

fever, renal impairment

Low platelets, MAHA, AKICongenital

TTP

ADAMTS13 analysis

‘Serum creatinine level >150–200 μmol/l or a platelet count >30,000/mm3

almost eliminates a diagnosis of severe ADAMTS13 deficiency’

Zuber J et al. Nat Rev Nephrol 2012;8:643–57

Differentiating TTP & aHUS

DIAGNOSIS-TTP & HUS

• FBC-Anaemia & Thrombocytopenia-Increased Reticulocytes

• MAHA-red cell fragmentation, polychromasia• Normal coagulation• -ve DAT• Increased bilirubin• Increased LDH• Troponin T• Renal impairment• Virology-HIV, Hepatitis A, B & C• Pregnancy Test

Guidelines on the diagnosis and management ofthrombot ic thrombocytopenic purpura and other thrombot icmicroangiopathies

Marie Scully,1 Beverley J. Hunt,2 Sylvia Benjamin,3 Ri Liesner,4 Peter Rose,5 Flora Peyvandi ,6 Betty Cheung7 and Samuel J.Machin8 on behalf of British Committee for Standards in Haematology

1Department of Haematology, UCLH, London, 2Department of Haematology, King’s College and Guys &St Thomas’ NHS Trust, Lon-don, 3Department of Haematology, NBSBT and Oxford University Hospitals (OUH) Trust, UK, 4Department of Haematology,GOSH, London, 5Department of Haematology, University Hospitals Coventry &Warwickshire NHS trust, Coventry, UK, 6Departmentof Haematology, IRCCS Maggiore Hospital Ca’ Granda Foundation, University of Milan, Milan, Italy, 7Department of Haematology,Queen Elizabeth Hospital, SLHT, London and 8Department of Haematology, UCL, London, UK

guideline

• The diagnosis of TTP should be treated as a medical emergency

• The initial diagnosis of TTP should be made on clinical history, examination

and routine laboratory parameters of the patient, including blood film

review

• In view of the high risk of preventable, early deaths in TTP, treatment with

plasma exchange (PEX) should be initiated as soon as possible, preferably

within 4-8 hours, regardless of the time of day at presentation, if a patient

presents with a MAHA and thrombocytopenia in the absence of any other

identifiable clinical cause

Scully & Goodship, Br J Haematol 2014;164:759–66

Summary of treatment of TMAs

Acute MAHA and

thrombocytopenia

STEC-HUS Acute TMA-TTP, aHUS

PEX

Acute renal

failure

Neurological/cardiological

involvement

ADAMTS13

testing

*Samples taken

preplasma therapy

Plus investigations to

exclude secondary

causes of TMA

HUS

(or congenital TTP)

TTP

ADAMTS13 <10%:

exclude congenital TTP

ADAMTS13 not <10% +/-

no evidence of anti-ADAMTS13

IgG antibodies: HUS

ADAMTS13 <10%

+ IgG antibodies to ADAMTS13

ADAMTS13

replacement

STEC-HUS

Supportive care

Atypical HUS:

eculizumab

Immunosuppressive

therapy eg, rituximab

Rock et al, NEJM 1991

5% 5%7%

2%2%2%

77%

Congenital

Preg/COCP

HIV

Pancreatitis

Other

Ca/Tx

idiopathic

Scully et al BJH 2008

Confirmation of diagnosis of TTP: ADAMTS 13 <10%

0

10

20

30

40

50

60

70

80

90

100

Neurological Temperature Renal impairment Abdominal symptoms

Cardiac symptomatic low platelets

% o

f al

l cas

es


Intramyocardial artery occludedby platelet microthrombusH&E X400

CD 61 confirms microthrombuscomprised of plateletsAlkaline phosphatase andfast red X400

<0. 01n=13

0. 01-0. 09n=11

>0. 1n=14

0

25

50

75

100

125

150

175

200

Box-whisker plots of Anti-ADAMTS 13 IgG levels depending on troponin T in patients with acute TTP. Median IgG levels are documented in each group. Cases with higher Troponin t levels (>0.1 µg/L) had a significantly higher (p=0.028, Mann-Whitney U test) IgG level at presentation.

Ant

i-AD

AM

TS

13

IgG

(%)

Troponin T (µg/L) Normal <0.01 µg/L

Median IgG:35% Median IgG:45% Median IgG:69.5%

Hughes et al JTH 2009

Rock et al, NEJM 1991

0

10

20

30

40

50

60

70

80

90

100

Time (Days)

AD

AM

TS

13

act

ivity

(%

)

0

10

20

30

40

50

60

70

80

90

100

IgG

ant

ibod

y to

AD

AM

TS

13

(%)

0

20

40

60

80

100

120

140

160

1 12 19 25 26 33 49 84 109

TI ME ( da ys)

AD

AM

TS

13

activ

ity

(%)

0

10

20

30

40

50

60

70

80

90Ig

G a

ntib

odi

es t

o

AD

AM

TS 1

3 (%

)

0

20

40

60

80

100

120

1 4 8 22 43 64 85 123 183

Time (Days)

AD

AM

TS 1

3 ac

tivity

(%

)

0

20

40

60

80

100

IgG

an

tibo

die

s to

A

DA

MTS

13

(%)

-

X4X 4

X4

0

20

40

60

80

100

1 32 38 94 122

299

376

495

T ime ( d ays)

AD

AM

TS

13

acti

vity

(%

)

0

20

40

60

80

100

IgG

ant

ibo

dies

to

AD

AM

TS

13

(%)X4


0

20

40

60

80

100

120

1 8 58 77 129 136 303 616 786 848 854 891 949

TIME (days)

AD

AMT

S 1

3 ac

tivity

(%

)

0

20

40

60

80

100

IgG

ant

ibod

ies

to A

DAM

TS

13

(%

)

X 4 X 4

0

10

20

30

40

50

60

70

80

90

1

195

215

231

251

266

341

415

556

Time (Days)

ADAM

TS 1

3 a

ctivity

(%)

0

20

40

60

80

100

IgG

antibod

ies to A

DAM

TS 1

3 (%

)X6

0

20

40

60

80

100

120

1

15

35

261

275

283

289

310

320

347

410

Time (Days)

AD

AM

TS 1

3 ac

tivity

(%)

0

20

40

60

80

100

IgG

ant

ibod

ies

to

AD

AM

TS

13

(%)

X4

0

20

40

60

80

100

120

1

224

359

400

414

443

494

565

732

TIME (days)

ADAM

TS 1

3 ac

tivity

(%)

0

20

40

60

80

100

120

IgG

antib

odie

s to

ADAM

TS 1

3 (%

)

X4

• Acquired idiopathic TTP

– Take longer to a normal Platelet count

– Require more plasma

– Relapse (30-50%)

• 40 acute TTP cases 2006-2009

• Follow up 12 months

• Treated with first dose rituximab within 3 days of admission. Total of 4, up to 8

• Standard local protocol

Scully et al Blood 2011

• Trial– No relapses within 12 months of follow up– Median time: 27 months

• Historical controls: – 21/40 relapsed median 18 months (3-60 months)– 6 relapsed within 12 months

What is the effect of PEX on rituximabclearance?


Prior to 2nd dose: ritux undetectable

(except pts who had every 3 days)

No PEX after 3rd /4th dose: Ritux detected,

Levels <10 if received PEX



• Median reduction in serum rituximab: 65%

– NS difference if 1.0 Vol V s 1.5 vol PEX

• Rituximab levels over time/time to undetectable rituximab

– Median 5 months (0-12 months)

– 94% had no detectable rituximab at 9 months

– Comparable if < /> 10 PEX to remission

Rituximab naïve group: timing of first infusion and outcome

≤3 days from admission

(n=52)

>3 days from admission

(n=30)

Median No. of PEX to CR (range)

16 (4-36) 24 (6-40) p=0.03

Median Length of admission (range)

16 (4-86) 23 (7-52) p=0.01

Median Time to CR from admission (range)

12 (4-52) 20 (4-42) P<0.001

Median Time to CR from first infusion (range)

10 (2-50) 9 (0-30) P=0.67

Westwood et al JTH 2013

Rituximab PEX Steroids

Rituximab PEX steroids

Rituximab prophylaxis

I79M/L

V88M

A95P

H96D

R102C/H

S119F

I143T

S150P

I178T

R193W/Q

T196I

S203P

D217H

G227R

L232Q

H234Q/R

D235H/Y

G236C

A250V

S263C/F

R268P

T304C

C311Y

R312C

C347S

R349C

P353L

G385E

W390*

W390C

R398H/C

R409W

Q436H

C438Y

Q448E

Q449*

Q456H

P457L

P475S

R507Q

C508Y

G525D

R528G

G550R

A596V

A606P

P618A

A631V

Y658C

P671L

I673F

A690T

R692C

Q723K

A732V

E735*

C754R

C758R

G761S

E812*

A900V

S903L

C908Y/S/W

G909R

R910*

R916C

Q929*

C946R

C951G

W1016*

C1024G/R

R1034*

S1036*

R1060W

W1081*

C1084Y

R1095Q/W

Q1105*

R1123C

R1206*

C1213Y

I1217T

R1219W

G1239V

W1245*

Q1302*

R1336W

D1362V

Congenital TTP-ADAMTS13 mutationsCongenital TTP-ADAMTS13 mutations

C977F

Loirat et al, Sem Thromb Haemostasis, 2006

Rare Diseases –Collaboration-The UK TTP RegistryRare Diseases –Collaboration-The UK TTP Registry

Harrison et al BJH 1996

Yarranton et al, Transfusion Med 2004

MB-FFPN=38

FFPN=25

No of PEX (P=0.004) 16 +/-13 9+/-7

Volume of plasma to remission (mls/Kg)

(P=0.02)

763+/-678 413+/-326

Recurrences on treatment (p=0.02)

21/38 6/25

Alvarez-Larrán BJ Haem 2008

•MB-FFP •reduced remission rates by day 8 (OR 5.1 95% CI 1.6-15.9)•Increased recurrence rate (OR 4.2 95% CI 1.3-13.5)

Yarranton et al, BJHaem 2003

Features Patient 1 Patient 2 Patient 3

Patient 4 Patient 5a

Patient 5b

Patient 6 Patient 7

VTE PE DVT DVT DVT PE & arterial thrombosis

PE & DVT

DVT DVT

Position of VTE

Both lungs-multiple

External iliac

iliac Brachiocephalic

Multiple PE’s & pulmartery

Multiple PE’s. Common femoral vein

Subclavian

femoral

Day of VTE

14 21 161 106 23 25 24 50

Plt count at VTE

202 12 232 56 193 225 188 181

Risk factors for VTE

Immobileobesity

Immobileobesitypregn

immobile immobile immobile Immobile obesity

immobile immobile

Thrombophiliascreen

Normal Normal Normal FVL Normal Normal Normal Normal

Yarranton et al, BJHaem 2003

Scully et al Vox Sanguinis 2007

PRE-VIAREA

POST-VIAREA

STERILE AREA

Fast thawing of the high quality FFP

Cell and debris removal by filtration [1.0 µm]

S/D treatment [1% TNBP/1% Octoxynol-9, 30°C/4-4.5 h ]

Liquid phase extraction of TNBP

Clear filtration [1.0 µm →→→→ 0.45 µm]

Solid phase extraction of Octoxynol-9

Sterile filtration [0.45 µm + 0.2 µm]

Aseptic filling

Labelling and vacuum sealing

Optimised integration of 630 to 1,520 single units of FFP

Freezing [ ≤≤≤≤-60°C] and storage [ ≤≤≤≤-30°C]

Full quality control and release

Removal of cells/debris that mightharbour pathogens

Affinity ligandchromatography

for specificPrPSc capture

Lawrie et al, Vox Sang 2010

Gender Male Female

Number 47 108

Mean age (yrs) 49.2 43.9

Range (yrs) 19-87 13-85

McGuckin et al Vox Sang 2014

Summary of findings: Octaplas in TTP 2006-2012

VTE cases

Allergic reactions to plasma

Central venous access: infections

Dichtelmuller et al Transfusion 2009

A single centre prospective study on the safety of Plasma Exchange (PEX) procedures using a double viral inactivated and prion-reduced solvent-detergent fresh frozen plasma as the

replacement fluid in the treatment of Thrombotic Microangiopathies (TMA).

• 90 consecutive acute TMA in-patient episodes over a 36-month period (January 1st 2013 –December 31st 2015)

• Female: 72% (n=65)

• TTP: 69% (n=62), HUS: 19% HUS (n=17) and 12% other TMAs (n=11)

• Total of 981 PEX procedures

Vendramin et al, Transfusion 2017



Demographics and admission characteristics of patients treated with plasma exchange (PEX) for thrombotic microangiopathic anaemias

Octaplas LG N=90

Female: Male 65:25 (2.6:1)

Age: years Female 45 (15-89)

Male 47.6 (21-79)

Ethnicity: WhiteAfro/CaribbeanOther

51%21%18%

Presenting Hb (g/l) 82 (36-145)

Presenting platelets (x109/L) 20 (2-144)

Presenting LDH (IU) 1115 (176-5868)

Length of stay (days) 14 (1-67)

Red cell transfusions 3 (1-23)



Incidence of adverse events associated with plasma exchange procedures



location and platelet count related to venous thrombosis

5/11 Events: Platelet count in the normal range

A recent TTP case

• 45 year old Caucasian female-attended ED• P/C: L sided weakness & numbness

– Facial droop– Slurred speech– Resolved in 15 mins– ? TIA, Px 300mg Aspirin and CT head

• L visual field aura & headache– ?Hemiplegic migraine

• Tonic Clonic epileptic fit: 1 min, self resolved

A recent TTP case

• Hb: 83g/L, Plts 20 x 109/L, ldh:1579IU/L, CRP:6

• Diagnosed: ?TTP

• GCS: 15/15, BP 135/81, sats: 95%

• During transfer: confused, agitated, unable to speak

• GCS: 8/15 on arrival

• Intubated

A recent TTP case• Admission bloods: Hb: 80g/L Plts: 7 x109/L

LDH: 1141, Creatinine: 78 µmol/l, TroponinT: 56ng/L (0-14)Autoimmune screen: negativeCD19: 10.62 %EF: 59%ADAMTS 13 activity <5%, Anti ADAMTS 13 IgG:96%

• Management: CV access• 1.5 Vol PEX• 1g Methylprednisolone• Following day: 1.5 volume PEX X 2 & 1g MP• Within <48 hours: rituximab started

– Extubated

Rituximab

PO Prednisolone

Ambulatory care

Points from the case: role of plasma

• Severe TTP: All poor prognostic factors!

• Total PEX: 11 plasma volumes

• Benefits of Octaplas:– AB plasma can be defrosted while awaiting a blood group

– No reactions!

– No need for pre medications

• Dr Mari Thomas

• Dr JP Westwood

• Dr C Vendramin

• Dr F Alwan

• Dr Alice Taylor

• Ms Siobhan McGuckin: CNS TTP

• Apheresis Team-UCLH

• Ms Debra Ellis: Clinical Trial coordinator

• Mrs Ingrid Obu: Clinical Trial Coordinator

• Mrs Houda Webster: Events Manager

• Collaborators & Investigators of the UK TTP registry

Acknowledgements

Documents

TTP-The Treatment Pathway - Microsoft · • The diagnosis of TTP should be treated as a medical emergency • The initial diagnosis of TTP should be made on clinical history, examination