Role of ADAMTS13 in TTP and TMA · Case-1 A 45-AAF (110 Kg) with uncontrolled diabetes, CKD stage...
Transcript of Role of ADAMTS13 in TTP and TMA · Case-1 A 45-AAF (110 Kg) with uncontrolled diabetes, CKD stage...
Role of ADAMTS13 in TTP and TMA
Ravi Sarode, MD
John H Childers Professorship in Pathology
Professor of Pathology and Internal Medicine (Hematology/Oncology),
Chief of Pathology and Medical Director
of Clinical Laboratory Services, UT Southwestern Medical Center
Director, Transfusion Medicine and Hemostasis
UT Southwestern Medical Center, Dallas, TX
AABB October 14th, 2018 Boston
Disclosures
Consultant Octapharma
Advisor Alexion
Chair DSMB, Ablynx
Please don’t confuse me early
in the morning!@#$%
Case-1
A 45-AAF (110 Kg) with uncontrolled diabetes, CKD stage IV and
hypertension (210/120) presents to the ED with altered mental status.
Hb 7 g/dl, Plt 45 x 109/L, LDH 400 (150-230 IU/L), S Cr 3 mg/dL.
Numerous schistocytes on PBS
Although a diagnosis of TTP is suspected further discussion and evaluation
of the patient suggest it could be malignant hypertension associated TMA.
Case-1 ARS
An ideal approach would be:
To obtain a stat ADAMTS13 level because you think this is not TTP
To perform emergent PLEX and send out ADAMTS13 (TAT 3-5 days)
To start and continue PLEX – since ADAMTS13 has no diagnostic value
To call Dr. Kiss for help!
Diagnostic value of ADAMTS13 in TTP vs TMA
Statements from ASFA consensus conference and “International working group for TTP and TMA” :
A severe ADAMTS13 deficiency (<10%) is diagnostic of TTP
Many TMAs present with similar clinical and hematological features
ADAMTS13 generally >20%
TTP must be differentiated from other TMAs because
• Exacerbation and relapses are common
• Requires aggressive immune therapy in ~50%
• Specific therapies: caplacizumab and recombinant ADAMTS13
• Other TMAs do not need PLEX and/or don’t respond
Neil’s study
TTP (n=38) TMA (n=30) P value
Median ADAMTS13 Undetectable (<5%) 51 (33-122%)
ADAMTS13 inhibitor 28 (74%) NA NA
Neurological features 23 (61%) 9(30%) 0.0155
Creatinine 1.2 0.85 2.7 2.2 0.0003
Platelet count (109/L) 23 ± 26 65 41 0.0001
LDH 1062 787 1359 ± 1371 0.27
Hematocrit 26.3 7.3 26.4 4.5
Schistocytes (mod to severe) 47% 30%
Haptoglobin undetectable 94% 61% 0.004
PLEX performed 35/38 (92%) 16/30 (53%)
Median # of PLEX 15 (3-107) 5 (2-10)
Mortality 2(5.7%) 1 (3.3)
In ADAMTS13
Utility of fast TAT - BJH
Patient ADAMTS13 Plt Diagnosis, clinical Management
1 <5% 9 New aTTP PLEX before ADAMTS13
2 <5% 24 New aTTP PLEX before ADAMTS13
3 <5% 9 New aTTP PLEX before ADAMTS13
4 36% 343 Known aTTP – HA during pregnancy 19 wks Re-assured
5 <5% 220 Known aTTP – subclinical relapse Rituximab out-pt
6 <5% 10 Known cTTP, viral illness and TMA Plasma infusion
7 47% 250 Known cTTP – monitoring during pregnancy Plasma infusion and PLEX
Thomas et al
Case ADAMTS13 Plt Final Diagnosis PLEX Clinical Outcome
1 42 5 Malignant HTN 1 then D/C Alive
2 104 9 DIC No Died
3 65 12 DIC No Died
4 38 24 Cancer-TMA No Died
5 36 142 D+ HUS No Alive
6 84 37 DIC No Died
7 92 21 D+ HUS No Alive
8 73 13 Drug – TMA (carfilzomib) 1 then D/C Alive
9 69 54 Pneumo-HUS 2 then D/C Alive
10 36 43 Sepsis/DIC No Alive
11 57 45 Malignant HTN No Alive
12 59 34 Vasculitis and CMV No Alive
13 63 95 Vasculitis No Alive
14 36 53 Post-cardiac Sx-TMA PI Alive
ADAMTS13 – Conflicting Test Results
52 AAF presented with acute cholecystitis and thrombocytopenia
Past history of ITP treated at OSH with steroids
Hb 7.7 g/dL, plt 14K, LDH 647 (IU/L), Hapto 5 mg/dL, 2/HPF schistocytes,
Negative DAT, DIC r/o, no plasma free hemoglobin
Hematologist and TM physician – “clinical judgement did not suggest TTP”
FRET assay (ATS-13, Immucor) under validation = 33%
Supported clinical impression that this is not TTP
Split sample sent to a ref lab = <1% activity (Technozym) + Ab 64 IU (<18)
Supported a diagnosis of TTP
ADAMTS13 Conflicting Test Results- ARS
Based on this conflicting information from in-house FRET assay undergoing validation (33% activity) compared to a reference lab value (<1%), with a clinical history of past ITP, current plt count of 14K, elevated LDH and very low haptoglobin in the absence of DIC or other TMA would you support a diagnosis of TTP?
YES
NO
ADAMTS13 Conflicting Test Results
No intervention based on low clinical suspicion and in-house assay
Next day 2nd specimen was sent to another ref lab as part of their validation process – the same Immucor ATS-13 FRET assay
However, in the mean time started PLEX with CPP
Clinical improvement and Plt normalized with 7 PLEXs (174 x 109/L)
ADAMTS13 23% from 2nd ref lab with a negative inhibitor
ADAMTS13 from the same ref lab was 65% - 3 days post D/C PLEX
“Although clinical suspicion was low and not corroborated by FRET assay, we elected to continue PLEX since plt count rose in apparent response to the treatment!”
Conclusions?
Case - 2
27 y/o HF presents with pelvic pain x 2 d
Altered color perception L- eye x 1d
URI – 1 week prior
Neuro exam – no focal deficits, vision 20/20, CT head unremarkable
CBC: Hb = 12.1 g/dL, Plt = 5 x109/L
Recommends hemolysis and DIC work-up, Ophthalmology consult = B/L chorioretinopathy with serous retinal detachment, no optic neuritis
No schistocytes on PBS
H/O fellow = Dx ITP, IV solumedrol and IVIG
Case-2 ARS
Based on normal Hb, no schistocytes, and severe thrombocytopenia, what is your first diagnosis?
ITP
TTP
Labs Next Day
• Haptoglobin <10, LDH = 709 (<220), Retic 2.5% , PBS – no schistocytes or spherocytes
IVIG + steroids Platelets IVIG
4 Days Later
Despite aggressive ITP treatment no improvement
Headaches developed
Another Hematology attending suspected TTP
PBS = 10-12 schistocytes/HPF
LDH = 709 – 943 – 1255
Emergent PLEX started
ADAMTS-13 <5%; inhibitor 0.9 U/mL
Retrospective study of national database of 423 TTP patients
84 patients (20%) were initially misdiagnosed
Goal was to determine causes for diagnostic errors and consequences to delay in treatment
Causes of Errors in TTP Diagnosis
Evans syndrome = 51%
ITP = 37%
Absence of schistocytes or anemia
Positive DAT
At UTSW:
Stroke as a presenting feature without hematological involvement
Acute renal failure – aHUS first diagnosis
No anemia or schistocytes
ITPvs
TTP
Hematologist
Accuracy and Speed of ADAMTS13 assays
Because of diagnostic cut off of <10%, it is essential that the ADAMTS13 measurement be accurate for clinical decision making to either initiate or continue PLEX
Rapid TAT is also essential for better patient care, to reduce patient harm from unnecessary treatments, and reduce healthcare cost
Current ADAMTS13 Assays
Use rVWF-73 fragment with a cleavage site for ADAMTS13.
The cleaved fragment measured by
FRET (Fluorescence resonance energy transfer) assay
ELISA
FRET-Assay Principle
TECHNOZYM – ADAMTS13 Chromogenic ELISA
ARS
Which of the following ADAMTS13 assays may be affected by high bilirubin and high free plasma hemoglobin?
VFW-73 FRET assay
VWF-73 ELISA assay
Detection of autoantibody to ADAMTS13
Almost essential to rule out congenital TTP and probably to give rituximab
Inhibitor assay - Bethesda type assay – neutralizing antibody
• Usually detected in ~80% at presentation and later in some others
• No good correlation with response and relapse
Anti-ADAMTS13 antibody – ELISA assay – detects both neutralizing and clearing antibodies
• Very high titer may predict poor response or exacerbation/relapse
Role of ADAMTS13 during Acute Episode
Wu et al measured daily ADAMTS13 in 19 pts
12/19 still had activity <10% by day 7
They required longer treatment to achieve a clinical response when compared to those who had >10% activity (p <0.001)
There was also a trend for more exacerbation
Good candidate for rituximab
Wu et al Transfusion 2015
Case -3
Early July 2015 a 62 AAF was diagnosed with TTP at OSH
7/23/2015 Presented to us with exacerbation
ADAMTS13 was <5%
Daily PLEX x 5 with plt >150K
Tapered
Given two standard doses of rituximab (375 mg/m2)
Case-3 ARS
9/10/2015 ADAMTs 13 = 59% and plt 275K
10/2/2015 ADAMTS <5% and plt 293 K
What would you do:
Admit for PLEX because ADAMTS13<5%
Wait and watch – weekly CBC to monitor plt
Give rituximab
Give steroids
During follow-up her ADAMTS13 and management
Dates ADAMTS13 Platelet counts Rituximab ADAMTS13 post-RTX
9/10/2015 59% 275 Not given ND
10/2/2015 <5% 293 4 Std doses 84%
12/7/2015 55% 336 2 std doses 86%
7/19/2016 31% 293 4 low doses 97%
2/3/2017 46% 383 4 low doses 102%
12/13/2017 34% 337 4 low doses 83%
8/10/2018 27% 347 4 low doses 61%
Std = 375 mg/m2 weekly, low dose = 100 mg fixed dose weekly
Role of ADAMTS13 during Remission
Jin et al – Higher relapse rate in patients with lower ADAMTS13 during remission (24 pts in the study)
Hie et al – 46/109 patients had relapses and severe deficiency was found in 46% as compared to 22% who did not have severe deficiency at relapse.
However, not all patients with severe or low ADAMTS13 levels are uniformly associated with relapses
Some remain low without relapses
Others normalize these levels
Therefore, a clinical decision to use preemptive rituximab should be based on risk-benefit discussion or previous history
Jin et al BJH 2008, Hie et al Blood 2014
92 patients with long term f/u had ADAMTS13 measured regularly
All had activity <10% during clinical remission
Given preemptive rituximab (1-4 doses)
“0” clinical or hematological relapse over 31.5 months f/u
Before preemptive regimen
40% (37/92) had a median of 3 (IQR 2-3) relapses
Historically 23 patients with persistent ADAMTS13 <10%
74% (16/23) had relapse over 7 year f/u
Prediction of relapse ADAMTS13 related bio-markers
Biomarker At the time of diagnosis
Measured at Clinical response
Measured in Remission
ADAMTS13 <5% Diagnostic of TTP Predictor of relapse Predictor of relapse
ADAMTS13 Antigen No association Higher levels = sustained remission
Associated with relapse vs no association
ADAMTS13 inhibitor No association No association Associated with relapse
Anti-ADAMTS13 antibody
IgG associated with relapse
- IgG associated with relapse
VWF Ag No association No association No association
Masias and Cataland, Blood 2018
ADAMTS13 in other TMAs
Mild to Moderately decreased in some TMA
Severe sepsis = mean 43% (IQR 32.7-67%)
Organ failure = mean 67% (IQR 57.4-87.9)
Malignancy, vasculitis = median 33.5% (range 16-47%)
Malignant HTN = median 64%
HSCT transplantation – usually TMA is aHUS with ADAMTS13 being not severely deficienct
Masias and Cataland, Blood 2018
Severe ADAMTS13 (<10%) is diagnostic of TTPTMAs do not have severe ADAMTS13 deficiency and do not benefit from PLEXRapid TAT for ADAMTS13 assay is desirableADAMTS13 assay selection should be done judiciously ADAMST13 levels are useful biomarker During acute episode At clinical response including for taperDuring remission to predict exacerbation and relapses.
Summary
Joseph E. Kiss, M. D.
Medical Director
Northeast Division Blood Services
Vitalant
Professor of Medicine
Division of Hematology-Oncology
Department of MedicineUniversity of Pittsburgh
Pittsburgh, PA
Blood Systems and The Institute for Transfusion Medicine are now Vitalant
ADAMTS13 in the Pathogenesis of Sepsis
with Multiple Organ Failure (MOF)
Joseph E. Kiss, MDDisclosures
• Ablynx nv : Medical Advisory Board
Objectives
1. Recognize clinical phenotypes of sepsis and the risk
of developing multiorgan failure (MOF)
2. Consider the relationship between new onset
thrombocytopenia, von willebrand factor excess,
and ADAMTS13 deficiency in critically-ill patients
3. Understand the rationale for considering ADAMTS13
replacement or VWF-directed therapy in
Thrombocytopenia-associated MOF (“TAMOF”)
www.aabb.org
ARS Question 1: In patients admitted to the intensive care unit,
thrombocytopenia (platelet count < 100, 000/ul) either on admission or developing
while in the ICU is an independent risk factor for mortality.
TRUE
FALSE
Microbial
Invasion
SIRSSepsis Severe
Sepsis Septic
Shock
MSOF
[Inflammation]
[Documented
Infection] [Hypotension
Hypoperfusion][Pressors]
ACCP/SCCM 1992
Mortality in Sepsis is Related to Organ Failure
SEPSISMortality 15-30%,Decreasing in recentsurveys
11% for kids <1 year – teens
40% for ages >85 years
Women have lower age-specific incidence and mortality
Up to 70% in patients with >3 failing organs
Vincent CCM 1998
Thrombocytopenia-associated MOF
ICU Patient
and J. Carcillo MD
Both the presence and severity of thrombocytopenia independently
predict mortality in the ICUHui P. CHEST 2011
Thrombocytopenia in the ICU
• 8.3% to 67.6% of patients on admission
• 13.0% to 44.1% of patients during the ICU stay Hui P. CHEST 2011
**
SEPSIS Subtypes
Podd & Carcillo 2017
ARS Question 2: What Causes Platelet Consumption
and Microthrombi in TTP?
A. Severe ADAMTS13 deficiency (< 10%
Activity)
B. Platelet Activating Factor (PAF)
C. Ultralarge VWF multimers (ULWWF)
D. Unknown
Platelet Aggregation is Increased in Proportion to VWF Multimer Size
Moake J. JCI 1986
3
1 2 3
1
2
Severe Sepsis is associated with an Intense Endotheliopathy +/- Coagulopathy
• Increased cytokines & inflammatory mediators
• Endothelial activation & apoptosis, loss of vascular integrity
• Enhanced pro-thrombotic milieu
– Tissue factor expression– Decreased natural
anticoagulants– Decreased thrombomodulin– Release of PAI-1 (decreased
fibrinolysis)– Decreased ADAMTS13;
increased vWF (ULvWF)
• Microvascular thrombosis, impaired tissue perfusion, organ failure
PAI-1
I-CAM
IL-1IL-6
TMIIa
PC APC
TMIIa
IIa Tissue
Factor
ATIII
PS
PSATIII
ADAMTS13
ADAMTS13
VWF
VWF
Day in MOF 1 3 5 Control
%ADAMTS13
Activity 23 12 21 100
%vWf
Antigen 238 338 320 100
Platelet Ct 52 29 37
INR 1.4 3.5 2
PAI-1
activity 12.7 105 105 <23
ADAMTS13 activity remained lowPresence of Ultra large vWf multimersElevated vWf Antigen, INR, and PAI-1 activity
Day 1 Control 3 5
3 year old boy, Gram negative sepsisPersistent Multi-organ Failure and Death
Nguyen TC. Crit Care Med 2008 Vol. 36, No. 10
Anti-vwf ab stain of brain and
kidney at autopsy
“ULVWF”
Decreased ADAMTS13 Activity in Inflammation - Mechanisms
• Consumption - Significant inverse relationship between ADAMTS13 & VWF
Dong J Biol Chem 2003;278:29633
Majerus J Biol Chem 2005;280:21773
Nguyen Haematologica 2007;92:121
• Proteolysis – Thrombin, plasmin, neutrophil elastaseCrawley Blood 2005;105:1085
Ono Blood 2006;107:528
• Inhibition – IL6, hemoglobin, thrombospondinBernardo Blood 2004;104:100
Studt Blood 2005;105:542
Novelli haematologica 2013; 98;e132
Alternative Mechanisms can also make VWF Resistant to ADAMTS13
• Oxidation of VWF met1606 (cleavage site in A2 domain)
De Filippis Biochem J 2012; 442:423
Lancellotti Free Rad Bio Med 2009; 48: 446
Ono T. Blood 2006;107:528
Secondary Deficiency of ADAMTS13
May Play a Role in Renal Injury in Sepsis
Ono T. Blood 2006;107:528
Ono T. Blood 2006;107:528
Decreased ADAMTS13 and Appearance of ULVWF in Critically Ill Patients
Relationship between ADAMTS13 activity and Cleavage of Endothelial Cell-ULVWF
Dong J-F. 2004
www.aabb.org
ARS Question 3: In your institution, have you been requested to
perform plasma exchange in a patient with sepsis multiorgan-failure?
Yes
No
I. PLEX is first line therapy
II. PLEX is second line therapy
III. PLEX is is not established. Decision
making should be individualized.
IV.PLEX is ineffective or harmful. Go to the
IRB!
ARS Question 4: According to Current ASFA (American
Association for Apheresis) Guidelines, the role of plasma exchange (PLEX) in sepsis
multiorgan failure is classified as category:
There have been numerous failures of monotherapy
directed at signaling molecules, inflammatory and coagulation
mediators in sepsis…“…the exact targets for blood
purification in sepsis are unknown.”
F. Zhou & J. KellumCrit Care Med 2013; 41:2209–2220
Targeted Therapies in Sepsis have Failed to Improve Outcome
• IL-1ra (1994)
• Endotoxin (1995)
• TNF-alpha (1996)
• Activated Protein C (2001)
• TFPI (2003)
• ATIII (1985-2013)
• Others
Early Rationale for TPE
EH-1
EH-3
EH-2
Metchnikoff: “Blood poisoning”EH: Early (EVIL) Humour
PLASMAEXCHANGE
MAN
Courtesy of J. Carcillo MD
Hypothesis: How Might Plasma Exchange Therapy Work in
Sepsis-Multiple Organ Failure (MOF)?
• Plasma exchange removes – Inflammatory mediators (endotoxin, cytokines)
– Other toxic mediators (hemoglobin)
– Fibrinolytic pathway inhibitors (PAI-1)
– Thrombogenic high molecular weight vWF
• Plasma exchange replenishes – ADAMTS 13
– Physiologic anticoagulants (Protein C, ATIII, TFPI, etc.), inhibitors (haptoglobin)
These changes may restore vascular homeostasis (anticoagulant/profibrinolytic), diminish microvascular thrombosis, improve tissue perfusion and reverse organ failure in “ischemic microangiopathy”
TPE in Sepsis/Septic Shock: Results of Meta-analyses
RR, 0.63 [95%CI, 0.42-0.96]; p=0.03, 2 trials, n=128
RR, 0.83 [95%CI, 0.45-1.52]; p=0.53, 3 trials, n=194
(Plasma-JK)
1
2
3
Therapeutic Rationale: Early intensive removal of sepsis mediators
Plasmapheresis in Severe Sepsis & Septic Shock: A Prospective, Randomized, Controlled Trial
Busund R, et al 2002
• RCT 106 consecutive ICU patients
• 28-day mortality
PEX(n=54) Control(n=52) p
18 (33.3%) 28 (53.8%) 0.05*ARDS 2 4
CV 7 10
MOF 6 13
Cerebral 0 1
edema
DIC 1 0
Bleeding 2 0
*p= 0.07(NS) after adjusting for correcting for baseline imbalance
Cau
se o
f D
eat
h
• Design: single center RCT in a pediatric ICU
• Inclusion criteria: children with platelet count < 100K and 3 failed organs for 24 h (a condition associated with 80% mortality in CHP PICU regardless of diagnostic category)
• Protocol: treatment within 30h of meeting criteria with plasma exchange for two 7-day cycles of 1.5 volume x 1 d followed by 1 volume x 6d, or until the resolution to < 3 organ failure for 48h
RCT of Plasma Exchange in Pediatric Patients with Thrombocytopenia Associated MOF
Nguyen TC. Crit Care Med 2008 Vol. 36, No. 10
Therapeutic Rationale: Restore vascular homeostasis
(antithrombotic/profibrinolytic)in “ischemic microangiopathy”
Pediatric Logistic Organ Dysfunction Score
DAY
0 5 10 15 20 25 30
PE
LO
D
0
20
40
60
80
100
Plasma Exchange
No 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
PELOD decreased from 25.0 2.0 to 0.8 0.6 with plasma exchangeat 28 d
PELOD increased from 25.4 2.3 to 73.6 18.4 without plasma exchange at 28 dp < 0.05
Plasma exchange: 5/5 patients survived
No plasma exchange: 1/5 patients survived
Pediatric Logistic Organ Dysfunction Score
Nguyen TC. Crit Care Med 2008 Vol. 36, No. 10
Plasma Exchange Replenishes ADAMTS13
Activity in TAMOF
ADAMTS13 Activity and PEx vs No PEx
Day
0 1 2 3 4 5 6 7 8
AD
AM
TS
13
Activity (
% r
ela
tive
to
co
ntr
ols
)
-20
0
20
40
60
80
100
day vs pe cp
day vs nope cp
Plasma Exchangen = 4
No Plasma Exchangen = 4
2F ANOVA p<0.05
Nguyen TC. Crit Care Med 2008 Vol. 36, No. 10
Qu et al.
Effect of sustained treatment on organ function
Conclusions• The pathophysiologic features of sepsis induced-
MSOF provide a rational basis for consideration of ADAMTS13 replacement and/or VWF-directed therapy
• Some studies and clinical trials suggest that plasma exchange improves organ failure & outcome, however, they also have important design and/or methodologic issues that limit interpretation of efficacy (and safety).
• Protocols that adopt (and registries that study) daily, sustained TPE with plasma replacement are needed!
• Children’s Hospital of Pittsburgh
• Drs. Trung C. Nguyen, Joseph A. Carcillo, & the dedicated Pediatric ICU Nursing Staff
• The Institute for Transfusion Medicine, now Vitalant
• Joan Sevcik, RN and our talented and highly skilled Therapeutic Apheresis Staff
ACKNOWLEDGEMENTS
Thank you!
ADAMTS13 Testing: More Questions Than Answers?
Yara Park, MD
University of North Carolina
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ADAMTS13 and…Trauma?!?
Jay S. Raval, MD
Associate Professor
Pathology and Laboratory Medicine
Disclosures
• Speaker / Advisory Board Member
– TerumoBCT, Inc.
• Apheresis applications consultant/speaker
– Alexion, Inc.
• Myasthenia gravis advisory board
– Ablynx, Inc.
• Investigator in Phase III trial for caplacizumab in TTP
• No relevant conflicts of interest
Lethal Triad
Hypothermia
CoagulopathyAcidosis
Kashuk JL et al. J Trauma 1982
Acute Traumatic
Coagulopathy
TRAUMA
• Independent of the
“Lethal Triad”
• Attributed to
– hypoperfusion
– increased circulating thrombomodulin
– abnormal protein C activation
• Deranged hemostasis and suprafibrinolytic state
Hess JR et al. J Trauma 2008Brohi K et al. Ann Surg 2007Kushimoto S et al. J Intens Care 2017
Acute Traumatic
Coagulopathy(ATC)
Trauma
• Leading cause of morbidity and mortality worldwide– 1 in 10 deaths
– Expected to increase
• ATC develops in approximately 1/3rd of patients– Predictive of mortality, organ dysfunction, death
• ATC pathophysiology and mechanisms incompletely understood
Soreide K. Br J Surg 2009Alberdi F et al. Med Intensiva 2014Mathers CD et al. PLoS Med 2006Rhee P et al. Ann Surg 2014Kushimoto S et al. J Intens Care 2017
Gonzalez E et al. Semin Thromb Hemost 2010
ADAMTS13 Domain Structure
N-Terminus C-Terminus
Plautz W et al. Transfusion 2018
Image courtesy of Dr. Matthew D. Neal
2015
• Post-hoc analysis of patient samples from a prospective, double-blind, randomized, parallel-group, controlled trial assessing vasopressin efficacy in resuscitation of those with hemorrhagic shock
• University Hospital, San Antonio, TX
• 17 patients w/ severe hemorrhagic shock and serum samples at time of arrival (time 0 hrs)
– 20 control patients
Furmaga W et al. Clinica Chimica Acta 2015
Biomarker Investigation
• Assessment of various molecules to determine which may help predict– Mortality (24 hours)
• 5 patients
– Multi-Organ Dysfunction Syndrome (MODS)• 1 patient
• ADAMTS13 was chosen because it is involved in both coagulation and systemic inflammation cascades– Both activated during hemorrhagic shock
Furmaga W et al. Clinica Chimica Acta 2015
Furmaga W et al. Clinica Chimica Acta 2015
259 x
✔
✔
Furmaga W et al. Clinica Chimica Acta 2015
Early 2018
• Prospective study assessing a variety of biomarkers associated with ADAMTS13 and vWF in pediatric trauma patients
• University of Alabama, Birmingham, AL
• Correlate findings with mortality and coagulation abnormalities
• 106 patients with severe trauma and citrated plasma samples at time 0 and 24 hrs– 52 controls
Russell RT et al. Thromb Haemost 2018
Russell RT et al. Thromb Haemost 2018
Russell RT et al. Thromb Haemost 2018
Russell RT et al. Thromb Haemost 2018
Russell RT et al. Thromb Haemost 2018
Our Collaborative Group’s Work:Late 2016-current
• Hypothesized that an ‘ultra-large vWF burst’ occurs after severe trauma
• Released into the bloodstream by activated, damaged endothelium
• vWF burst results in a dysregulation of the circulating vWF multimer composition
• ADAMTS13 activity would be decreased and insufficient to cleave the ultra-large vWF burst, leading to organ injury
Methods
• Obtained patient data and samples enrolled in a pragmatic, multicenter, cluster-randomized, phase 3 superiority trial (PAMPer) that compared the administration of thawed plasma with standard-care resuscitation during air medical transport
• 37 trauma patients with citrated plasma samples at time 0 and 24 hours– Clinical data abstracted from the RCT database and
electronic medical records
Sperry JL et al. N Engl J Med 2018
Time 0 Hrs
Time 24 Hrs
Circulating vWF Multimer Distribution
TOP of Gel
(LARGEST Multimers)
BOTTOM of Gel
(smallest Multimers)
Circulating vWF Multimer Distribution:Time 0 Hrs
TOP of Gel
(LARGEST Multimers)
BOTTOM of Gel
(smallest Multimers)
Circulating vWF Multimer Distribution:Time 24 Hrs
TOP of Gel
(LARGEST Multimers)
BOTTOM of Gel
(smallest Multimers)
Multivariate Analysis:Correlations w/ Time 0 Hrs ADAMTS13 Activity
• Laboratory Markers of Coagulopathy– Presentation INR (=-0.63, p<0.0001)– TEG activated clotting time (=-0.36, p=0.044)– TEG maximum amplitude (=0.36, p=0.047)
• Clinical Markers of Coagulopathy– Overall blood product transfusion requirement in the
first 24 hours (=-45, p=0.008) – PRBC requirements (=-0.43, p=0.011)– Platelet transfusion (=-0.34, p=0.049)– Plasma requirements (=-0.45, p=0.007)
• Injury Severity Score (=-0.34, p=0.043)
Conclusions
• ADAMTS13 activity and antigen acutely decrease in trauma
– Sustained depressions for 24 hrs (or longer)
• Acute dysregulation of physiologic distribution of circulating vWF multimers
• More severely injured patients have larger ADAMTS13 decreases
• Association between decreased ADAMTS13 and coagulopathy / poorer survival
ARS Question
• What accurately summarizes your medical opinion about ADAMTS13 and Trauma?– A) I didn’t believe there was a reasonable
association before, but now I do
– B) I didn’t believe there was a reasonable association before, and I still don’t
– C) I’d support further investigations into this important clinical area
– D) A and C
– E) I’m just going to hope for a TTP patient instead
Thank you
• Neal Lab (UPMC)
– Dr. Matthew D. Neal
– Dr. Mitch Dyer
– Mr. William Plautz
• NIH/DOD/TACTIC
• PAMPer Investigators
• Special Coagulation Lab (UNC)
– Dr. Marian A. Rollins-Raval
– Mr. Preston Parker
– Ms. Cathy Sohier
ADAMTS13 Testing: More Questions
Than Answers?
10/14/2018
Faculty Disclosures
The following faculty have no relevant financial relationships to disclose:
– Yara Park MD
The following faculty have a relevant financial relationship:
– Jay Raval MD
Terumo BCT, Inc.: Consultant
– Joseph Kiss MD
Ablynx NB: Consultant
– Ravi Sarode MD
Octapharma: Consultant
Siemens: Grant/Research Support
Alexion: Honoraria
Ablynx: Honoraria
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Learning Objectives
• Recognize the utility of ADAMTS13 testing in patients with thrombotic thrombocytopenic purpura and other thrombotic microangiopathies
• Identify the different non-thrombotic microangiopathy patient populations that may have deficiencies of ADAMTS13 activity and discuss the significance of these deficits
• Explain the rationale for therapeutic plasma exchange in thrombocytopenia-associated multiple organ failure patients with decreased ADAMTS13 activities
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