Thrombocytopenia-Associated Multiple Organ Failure and Pediatric Septic Shock: Is Plasma Exchange a Promising Therapy?

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Thrombocytopenia-Associated Multiple Organ
Failure and Pediatric Septic Shock Is Plasma
Exchange a Promising Therapy?

• James D Fortenberry MD, FCCM, FAAP
• Pediatrician in Chief
• Childrens Healthcare of Atlanta
• Professor, Pediatric Critical Care
• Emory University School of Medicine
• Atlanta, Georgia

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Disclosures

• No financial disclosures
• I am an intensivist
• Dumber than smartest nephrologist
• Able to intubate dumbest kidney

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The MODS Patient
HIGH MORTALITY 50-90
-Courtesy of Matt Paden
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Thrombotic Thrombocytopenic Purpura (TTP)

• A thrombotic microangiopathy syndrome
• Critical defect deficiency of ADAMTS-13
• (lt 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
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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 grown By desperate appliance
are relieved, Or not at all. -Claudius, King of
Denmark, Hamlet Act IV Scene 3 W. 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

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(No Transcript)
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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

Plt .05
- Busund et al., Intensive Care Medicine
2002281410
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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 lt .05)

-Nguyen et al., CCM 2008
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CHP Trial PELOD Improved with PEx
PEx
-Nguyen et al., CCM 2008
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Plasma Exchange Replenishes ADAMTS-13
-Nguyen et al., CCM 2008
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Childrens 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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Childrens TAMOF Network

• Enrolling centers (site co-I)
• Childrens of Atlanta at Egleston coordinating
  center (Fortenberry)
• Childrens of Pittsburgh (Raj Aneja/Joe Carcillo)
• Cincinnati Childrens (Derek Wheeler)
• Nationwide Childrens-Columbus OH (Mark Hall)
• Phoenix Childrens Hospital (Sandra Buttram/Heidi
  Dalton)
• Texas Childrens Hospital (Laura Loftis/Trung
  Nguyen)
• Michigan-Mott Childrens (Yong Han)
• Minnesota (Rod Tarrago)
• Vanderbilt-Carrell Childrens (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 lt 100,000/mm3
• Organ failure index (OFI) gt 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
- 81 patients enrolled and met criteria
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
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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
PEx 68.3
No PEx 61.9
P 0.5
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-PELOD scores decreased more rapidly in patients
receiving PEx (p lt .05)
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- 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 Statistics No. () / 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 (p0.0006)
• 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 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

• Plasma Infusion
• Restores procoagulant factors
• Restores anticoagulant factors (protein C, AT
  III, TFP-I)
• Restores prostacyclin
• Restores tPA
• Restores ADAMTS-13

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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
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Days of Plasma Exchange
Non-survivors(n  19) Survivors(n  40)
No. / Total () 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 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 Childrens 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 gt 21 (47)
• No PEx 50
• PEx 56.4
• Survival PELOD lt 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