Thrombocytopenia-Associated Multiple Organ Failure and Pediatric Septic Shock: Is Plasma

Exchange a Promising Therapy?

James D Fortenberry MD, FCCM, FAAPPediatrician in Chief

Children’s Healthcare of AtlantaProfessor, Pediatric Critical Care

Emory University School of MedicineAtlanta, Georgia

2

Disclosures

No financial disclosures I am an intensivist

• Dumber than smartest nephrologist

• Able to intubate dumbest kidney

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Respiratory Failure

Cardiovascular Failure

Renal FailureHematologic Failure

Immunologic Failure

The MODS Patient

HIGH MORTALITY

50-90%

-Courtesy of Matt Paden

4

Thrombotic Thrombocytopenic Purpura (TTP)

A thrombotic microangiopathy syndrome Critical defect: deficiency of ADAMTS-13

(< 10%):

A disintegrin and metalloprotease with thrombospondin motifs-13 (formerly vWf cleaving protease)

Ultra-large vWf multimer-platelet thrombi Microthrombotic multi-organ vascular injury:

MOF and autopsy findings

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Thrombotic Microangiopathy: TTP/TAMOF

IL- 8TNF-IL- 6+R

ADAMTS13 AbIL-6

X

ADAMTS13(vWF-CP)

Endothelium

Endothelium PAI-1

PAI-1

PAI-1

PAI-1

PAI-1 PAI-1

vWF

vWF

PAI-1

TFPI TFPI

PlasminPlasminogen

PAI-1

X

Platelet

Platelet

Platelet

Platelet

Platelet

Platelet

TF TF

Shear stress

Platelet

Platelet

Platelet

ADAMTS13 AbIL-6

ADAMTS13(vWF-CP)

x

IL- 8TNF-

IL- 6+R

6

Thrombocytopenia-Associated Multiple Organ Failure (TAMOF)

A thrombotic microangiopathy described in children (Nguyen, Carcillo 2001)

Similarities to TTP• Deficient ADAMTS-13• Increased ADAMTS-13 inhibitors• Increased vWF antigen• Increased ULvWF multimers• Thrombocytopenia

Primarily secondary to sepsis 3 or greater organ failure High mortality in children

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ADAMTS-13 Deficiency in Adult Sepsis

-Martin et al., Crit Care Med 2007

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Adult Sepsis-Survival by ADAMTS-13 Level

ADAMTS-13 above median

Below median

-Martin et al., Crit Care Med 2007

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ADAMTS-13 Deficiency in Pediatric Sepsis

-Nguyen, Hematologica 2006

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Refractory Sepsis/MOSF: Desperate Times…

Diseases desperate grownBy desperate appliance are relieved, Or not at all.

-Claudius, King of Denmark,Hamlet Act IV Scene 3W. Shakespeare

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Rationale for Plasma Exchange: TTP

80-90% mortality Plasma Exchange

10% mortality:• Replenishes ADAMTS-

13

• Removes ADAMTS-13 inhibitors

• Removes thrombogenic ULvWf multimers

-Rock, NEJM 1991

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Plasma Exchange: Rationale In Sepsis

Subset of patients who demonstrate thrombotic microangiopathy similar to TTP

Similar clinical and coagulation factor profile• Deficiency of vWf cleaving protease (ADAMTS-

13)• Platelet/vWf microthrombi• Thrombocytopenia

13

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CRRT/Plasma Exchange

CRRT/Plasma Exchange

Time

Time

SIRS/CARS

SIRS CARS SIRS CARS

I mmunohomeostasis

I mmunohomeostasis

Pro-inflammatoryMediators

Anti-inflammatoryMediators

IL-1TNF PAF

IL-10

Adapted f rom Ronco et al. Artificial Organs 27(9) 792-801, 2003

Peak Concentration Model of Sepsis

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Plasmapheresis in Severe Sepsis and Septic Shock

PRCT, Russian adult ICU

106 sepsis patients randomized to:• Standard therapy• Addition of

plasmapheresis (1/2 FFP, 1/2 albumin)

Decreased mortality with plasmapheresis

- Busund et al., Intensive Care Medicine 2002;28:1410

53.8

33.3

0

10

20

30

40

50

60

Standard Plasma

*

*P< .05

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TAMOF/Plasma Exchange in Children: CHP Trial

28 children with TAMOF• Decreased ADAMTS-13 vs. non-TAMOF• Correlated with outcome

Small RCT (10 patients) 28-day survival

• No PEx: 1/5• PEx: 5/5 (p < .05)

-Nguyen et al., CCM 2008

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CHP Trial: PELOD Improved with PEx

Pediatric Logistic Organ Dysfunction Score

DAY

0 5 10 15 20 25 30

PE

LOD

0

20

40

60

80

100

Plasma ExchangeNo Plasma Exchange

Figure 3. Pediatric Logistic Organ Dysfunction Score, Mean with standarderror for patients who received plasma exchange therapy (N = 5) and who did not receive plasma exchange therapy (N = 5) for each day x 28 days.

17-Nguyen et al., CCM 2008

PEx

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Plasma Exchange Replenishes ADAMTS-13

-Nguyen et al., CCM 2008

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Children’s TAMOF Network

Broader group of Pediatric ICUs Goals:

• Create a study group to perform prospective, observational studies

• Identify TAMOF and evaluate: Clinical and biochemical course Use of specific therapies Associated outcomes

• Inform development of future prospective trials

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Children’s TAMOF Network

Enrolling centers (site co-I):• Children’s of Atlanta at Egleston: coordinating center

(Fortenberry)• Children’s of Pittsburgh (Raj Aneja/Joe Carcillo)• Cincinnati Children’s (Derek Wheeler)• Nationwide Children’s-Columbus OH (Mark Hall)• Phoenix Children’s Hospital (Sandra Buttram/Heidi

Dalton)• Texas Childrens’ Hospital (Laura Loftis/Trung

Nguyen)• Michigan-Mott Children’s (Yong Han)• Minnesota (Rod Tarrago)• Vanderbilt-Carrell Children’s (Rick Barr/Geoffrey

Fleming)

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Hypotheses

Children with TAMOF demonstrate decreased ADAMTS-13 levels and increased vWf antigen levels.

Children with TAMOF receiving PEx demonstrate associated improvement of organ dysfunction and survival vs. those receiving standard therapy alone.

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Methods

Prospective, observational, nonrandomized cohort study

Enrolled patients 1 month-21 years of age meeting TAMOF criteria:• Sepsis, transplant, chemotherapy• Platelet count < 100,000/mm3

• Organ failure index (OFI) > 2 Data collected via web-based registry

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Methods

Blood obtained for:• ADAMTS-13• vWf antigen levels• Studies performed at Baylor College of Medicine

(Trung Nguyen MD) Therapy, and use of PEx at attending/center

discretion• Typical: centrifugation approach• Suggested protocol:

FFP: 1.5x plasma volume day 1 1x plasma volume daily exchanges x 4 days

• Duration at MD discretion

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Results: Demographics

Overall No PEx (21) PEx (60)

Mean age (yr) 8.6 + 6.2 6.7 + 6.3 9.2 + 6.4

Mean weight (kg)

35.2 + 27.9 29.8 + 27.6 37.2 + 28.5

Race: White (%) 65.4 63.6 66.1

Race: A-A 19.8 22.7 18.6

Diagnosis-Sepsis

79/81 20/21 59/60

Ever on ECMO 30/81 (37%) 4/21 (13) 26/60 (43.3)

Ever on CRRT 46/81 (56.8%) 8/21 (41.1) 38/60 (63.3)

-No differences between groups

- 81 patients enrolled and met criteria

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Results: Severity of Ilness

Overall No PEx (21) PEx (60) P value

Baseline PELOD

20.2 + 12.1 15.8 + 10.1 21.9 + 12.4 .04

Baseline PRISM 18.2 + 6.8 16.9 + 5.5 18.7 + 7.2 0.28

Baseline OFI 4.5 + 1.2 4.2 + 1.0 4.6 + 1.2 0.21

Baseline Platelet Count (x 1000)

62.2 + 42.1 55.9 + 35 64.6 + 44.7 0.42

Baseline ADAMTS-13 (%)

52.9 + 27.8 63.7 + 26 49.9 + 28 0.22

Baseline vWF Ag (%)

161 + 66.3 217 + 73 146 + 56.4 0.005

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Results: Therapies

Treatment:• No PEx: 21 patients• PEx: 60 patients

Use of CVVH: 46 patients (57%)• No PEx 8 (41%)• PEx 38 (63%) p = 0.07

Use of ECMO: 30 patients (37%)• No PEx: 4 (13%)• PEx: 26 (44%) p = 0.07

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TAMOF Network Results: 28 Day Survival

No PEx: 61.9%

PEx: 68.3%

P = 0.5

-PELOD scores decreased more rapidly in patients receiving PEx (p < .05)

*

- PEx associated with increase in ADAMTS-13 in first 4 days

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Multivariable Risk Factors for Death: PELOD and Plasma Exchange

Variable

Descriptive StatisticsNo. (%) / Mean (SD)

Estimate Standard Error

Odds Ratio

95% CI P-value

ECMO 30/81 (37.0%)0.4676

0.6167 1.596 0.48-5.4 0.45

CVVH 45/81 (55.6%)0.7484

0.6215 2.114 0.63-7.2 0.23

Baseline PELOD(per 5 pt increase)

21.2 (11.4)0.1100

0.0321 1.734

1.27-2.4

0.0006

MRSA Infection

12/81 (14.8%)0.8618

1.2200 2.367

0.51-10.9

0.27

Plasma Exchange

60/81 (74.1%) -1.3213 0.6801 0.267 0.07-1.01

0.05

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Risk Factors

For every 5 unit increase in PELOD score at baseline (day 1 on study) mortality risk increases 1.73 times (p=0.0006)

PEx reduced risk of death by 73.3% = odds of survival 3.75 times higher with PEx (p = 0.05)

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Conclusions

TAMOF patients demonstrated:• Decreased ADAMTS-13, increased vWf

antigen, consistent with TTP profile Use of PEx vs. standard therapy was

associated with: Greater improvement in organ dysfunction Better survival (adjusted for severity, risk

factors) Cannot conclude outcome benefit

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Next Steps

These results could inform a randomized trial to determine contribution of PEx to TAMOF outcome

Need to better define subgroups; use biomarkers• ADAMTS-13 real-time

Submitted a U34 Planning Grant: Rare Thrombotic and Hemostatic Disorders

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Alexis- A Success Story

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Why Not Plasma Infusion Alone?

Plasma Infusion• Restores procoagulant

factors• Restores anticoagulant

factors (protein C, AT III, TFP-I)

• Restores prostacyclin• Restores tPA• Restores ADAMTS-13

Plasma Exchange• Restores factor

homeostasis like plasma infusion

In addition:• Removes ADAMTS-13

inhibitors• Removes ultra-large

vWF multimers• Removes tissue factor• Removes excess PAI-1• Maintains fluid balance

during procedure vs. infusion

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Course of Organ Dysfunction and TMA: Plasma Infusion vs. Plasma Exchange

36 adult TMA patients Decreased mortality with

plasma exchange Plasma infusion group

• received larger volumes

• had larger weight gain

- Darmon et al., Crit Care Med, 2006

31.8

0

0

5

10

15

20

25

30

35

Plasma

Infusion

Plasma

Exchange

*

37

Days of Plasma Exchange

Non-survivors(n = 19)

Survivors(n = 40)

No. / Total (%)

Total Days on PEx Therapy 1 6/19 (31.6%) 0/40 (0%)

2 4/19 (21.1%) 1/40 (2.5%)

3 1/19 (5.3%) 7/40 (17.5%)

4 1/19 (5.3%) 1/40 (2.5%)

5 2/19 (10.5%) 14/40 (35.0%)

6 1/19 (5.3%) 6/40 (15.0%)

7 1/19 (5.3%) 9/40 (22.5%)

8 2/19 (10.5%) 0/40 (0%)

10 0/19 (0%) 2/40 (5.0%)

14 1/19 (5.3%) 0/40 (0%)

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Results: Site Enrollment

Non-Plasma Exchange Group(n = 21)

Plasma Exchange Group(n = 60)

Deaths by Site

CHOA-Egleston 0/1 (0%) 10/22 (45.5%)

Pittsburgh - 0/6 (0%)

Columbus 3/5 (60.0%) -

Cincinnati 0/2 (0%) -

Texas Children’s 3/5 (60.0%) 1/2 (50.0%)

Minnesota 0/1 (0%) 3/13 (23.1%)

Vanderbilt 1/6 (16.7%) 2/4 (50.0%)

Michigan - 1/9 (11.1%)

Phoenix 1/2 (50.0%) 2/3 (66.7%)

All sites 8/21 (36.4%) 19/60 (32.2%)

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Results: TAMOF Patients

Overall survival 54/81 (67%) • No PEx: 13/21 (61.9%)• PEx: 41/60 (68.3%) NS

Survival: PELOD > 21 (47)• No PEx 50 %• PEx 56.4 %

Survival: PELOD < 21 (34)• No PEx 77.8 %• PEx 90.5 %

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Everything will be all right in the end. So if it is not all right, then it is not yet the end.

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Desperate but Reasonable?

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Plasma Therapies in Sepsis-Why Use Them?

General: exchange “transfer factors” Specific: control thrombotic microangiopathy

(TMA) Slow progression of TMA-induced organ

failure Treat coagulation abnormalities