i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource. Gain insight and expertise in this presentation on acquired thrombotic thrombocytopenic purpura. Spero Cataland, MD, Professor of Clinical Internal Medicine and Director of Benign Hematology at The Ohio State University, will provide guidance on current treatment standards and will discuss emerging therapies with the potential to improve patient outcomes in aTTP. STATEMENT OF NEED Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening thrombotic microangiopathy with a rapid onset and progression and a mortality rate of 10% to 20% with prompt treatment. Onset of aTTP is characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and a constellation of associated symptoms including hemorrhage, neurologic and renal manifestations, cardiac abnormalities, and mesenteric ischemia (Joly et al, 2017). Survivors of first aTTP events tend to have relapse events which need to be controlled. Rapid recognition and immediate appropriate treatment are critical for achieving optimized outcomes in aTTP. In this activity chaired by Spero Cataland, MD, Professor of Clinical Internal Medicine and Director of Benign Hematology at The Ohio State University, expert faculty will provide insightful guidance on current treatment standards and will discuss emerging therapies with the potential to improve patient outcomes in aTTP. TARGET AUDIENCE Hematology fellows, attending faculty, and other health care professionals involved in the treatment of patients with acquired thrombotic thrombocytopenic purpura (aTTP). LEARNING OBJECTIVES Upon completion of this activity, participants should be able to Evaluate the clinical and laboratory features of aTTP that can inform timely and accurate diagnosis Discuss how ADAMTS13 activity can be used to guide the management of aTTP Assess the mechanism of action, efficacy, and safety of novel anti-von Willebrand factor nanobodies in aTTP as elucidated by recent clinical trials Evaluate novel treatment combinations and sequences with the potential to improve the outcomes of patients with aTTP

1. Current Standards and New Directions in the
Treatment of Acquired Thrombotic
Thrombocytopenic Purpura
Spero R. Cataland, MD
Professor of Internal Medicine
Division of Hematology, Benign Hematology Section Head
Wexner Medical Center at The Ohio State University

2. Disclosures
Consultant: Sanofi and Takeda
i3 Health has mitigated all relevant financial relationships

3. Learning Objectives
aTTP = acquired thrombotic thrombocytopenic purpura; ADAMTS13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
Evaluate the clinical and laboratory features of aTTP that can inform
timely and accurate diagnosis
Discuss how ADAMTS13 activity can be used to guide the
management of aTTP
Assess the mechanism of action, efficacy, and safety of novel anti–
von Willebrand factor nanobodies in aTTP as elucidated by recent
clinical trials
Evaluate novel treatment combinations and sequences with the
potential to improve the outcomes of patients with aTTP

4. DPSKAMATTD
Venous thromboembolism
Hemochromatosis
Heparin-induced thrombocytopenia
Thrombotic thrombocytopenic purpura
Atypical hemolytic uremic syndrome (aHUS)
Slide courtesy of Lawrence Rice, The Methodist Hospital, Weill Cornell Medical College, Houston, TX.

5. TMA
TTP
Infection
HUS
Cancer-
associated
TMA
Drug-
associated
TMA
DIC
Autoimmune
disease/vasculitis
Pregnancy-
associated
TMAs
Malignant
hypertension
Differential Diagnosis of Thrombotic Microangiopathy
TMA = thrombotic microangiopathy; HUS = hemolytic uremic syndrome;
DIC = disseminated intravascular coagulation.
Slide courtesy of Marie Scully, University College London, United Kingdom.

6. Pathophysiology of aTTP/iTTP
iTTP = immune-mediated TTP.
Moschowitz, 1925.
16-year-old female, high school
graduate, business school, now
employed for 8 months
Awoke with “weakness, pallor,
constipation”
Petechiae reported, no platelet count
Progressed to partial paresis of left
arm and leg, coma, irregular
respirations, and death
Immune-Mediated (Acquired) TTP

7. Types of Thrombotic Thrombocytopenic Purpura (TTP)
Arnold et al, 2017; Bae et al, 2022.
Thrombotic microangiopathy caused by severely reduced ADAMTS13
activity
ADAMTS13 protease cleaves ultra-large von Willebrand factor (VWF)
multimers on the endothelial surface
Acquired form of iTTP
Autoantibodies against ADAMTS13 protease
Incidence approximately 3 per million
Congenital form of TTP
<5% of all TTP cases
Biallelic pathogenic variants in ADAMTS13
Incidence approximately 1 per million

8. Immune-Mediated (Acquired) TTP
Survival now >90% with prompt recognition
Risk of future relapse
High prevalence of PTSD in TTP survivors
35% with positive screen for PTSD
Long-term complications from a prior iTTP diagnosis
Shortened life expectancy
Cardiovascular complications
Neurocognitive deficits
Short-term memory, new memory issues
PTSD = post-traumatic stress disorder.
Adeyemi et al, 2022; Chaturvedi et al, 2017; Deford et al, 2013; Sukumar et al, 2022; Cataland et al, 2011.

9. TTP: Evolution of the Clinical Syndromes
Slide courtesy of Dr. James George.
George, 2021.
1925-1964 1964-1980 1982-1989
Thrombocytopenia 96% 96% 100%
Hemolytic anemia 96% 98% 100%
Neurologic symptom
symptom
92% 84% 63%
Renal disease 88% 76% 59%
Fever 98% 59% 26%
Death 90% 54% 22%

10. Case Study 1: Ms. HB
ITP = immune thrombocytopenia.
22-year-old Caucasian female with a history of ITP as a child,
presenting with 7 days of nausea and headaches. She had epistaxis
that morning prior to her arrival
Past medical history: ITP
Family medical history: Hypertension
Social history: Smoker, social alcohol

11. Case Study 1: Ms. HB (cont.)
LDH = lactate dehydrogenase; Cr = creatinine.
George, 2006.
Laboratory Data at Presentation
10.4
1K
8.5
Serum Cr: 1.3 mg/dL
LDH: 1,200 U/L
ADAMTS13 activity: ?

12. Pathophysiology of TTP
Sadler et al, 2008.

13. Treatment of iTTP
CVA = cerebrovascular accident.
Arnold et al, 2017; Kremer Hovinga Strebel et al, 2022; Upreti et al, 2019.
Serves to confirm the clinical diagnosis of TTP
Defines those patients at greatest risk for exacerbations of iTTP
Predicts the risk of relapse during long-term follow-up
? Predicting the risk for long-term complications
CVA in patients with a history of iTTP in remission
What Is the Utility of ADAMTS13 Activity in Treatment?

14. ADAMTS13 Activity and TTP
Motto et al, 2005; Banno et al, 2006.
Deficient ADAMTS13 alone not sufficient
to lead to an acute TTP episode
ADAMTS13 -/- mice do not spontaneously
develop TMA findings
Shiga toxin, collagen/epinephrine required
to initiate the development of
thrombocytopenia
Congenital TTP
Delayed presentations at the time of
pregnancy
Second Hit Hypothesis

15. ISTH Guidelines for the Diagnosis of TTP
ISTH = International Society on Thrombosis and Hemostasis; IgG = immunoglobulin G.
Zheng et al, 2020b.
Stage 1
Acquire a plasma sample for ADAMTS13 testing (eg, ADAMTS13 activity and inhibitors or anti-ADAMTS13
IgG) before an initiation of therapeutic plasma exchange treatment (PEX) or use of any blood product
Stage 2
Start PEX and corticosteroids without waiting for the results of ADAMTS13 testing (see
Recommendation 1 in Management Guidelines)
Stage 3
Consider early administration of caplacizumab (see Recommendation 5 in Management Guidelines) before
receiving ADAMTS13 activity results
Stage 4
When the result of plasma ADAMTS13 activity is available, continue caplacizumab if ADAMTS13 activity is
<10 IU/dL or <10% of normal (a positive result) or stop caplacizumab and consider other diagnoses if
ADAMTS13 activity is >20 IU/dL or >20% of normal (a negative result)
Stage 5
For patients with a plasma ADAMTS13 activity <10 IU/dL or <10% of normal (a positive result), consider
adding rituximab as early as possible, as a majority of these patients (>95%) have autoantibodies against
ADAMTS13 (see Recommendation 2 in Management Guidelines)
Recommendation 1:
In settings with timely access to plasma ADAMTS13 activity
testing and for patients with a high clinical suspicion of
immune TTP, the panel suggests the following diagnostic
strategies (a conditional recommendation in the context of
low-certainty evidence)

16. Stage 1
Acquire a plasma sample for ADAMTS13 testing (eg, ADAMTS13 activity and inhibitor or anti-
anti-ADAMTS13 IgG) before an initiation of PEX or use of any blood product
Stage 2
Consider starting PEX and corticosteroids, depending on the clinician’s judgement and
assessment of the individual patient
Stage 3
Do not start caplacizumab until the result of plasma ADAMTS13 activity is available
Stage 4
When the result of plasma ADAMTS13 activity testing is available, consider adding
caplacizumab and rituximab (see Recommendation 2 in Management Guidelines) if
ADAMTS13 activity is <10 IU/dL or <10% of normal with an inhibitor or elevated anti-
ADAMTS13 IgG (a positive test result), but do not start caplacizumab and consider other
diagnoses if ADAMTS13 activity is >20 IU/dL or >20% of normal (a negative result)
ISTH Guidelines for the Diagnosis of TTP (cont.)
Recommendation 2:
In settings with timely access to plasma ADAMTS13 activity
testing and for patients with intermediate or low clinical
suspicion of iTTP, the panel suggests the following diagnostic
strategies (a conditional recommendation in the context of
low-certainty evidence)
Zheng et al, 2020b.

17. Prediction of ADAMTS13 Activity
Acquired Thrombotic Microangiopathies
Study
ADAMTS13
Threshold
ADAMTS13 Activity
Severely Deficient Non-Deficient
Platelets
(x 109/L)
Creatinine
(mg/dL)
Platelets
(x 109/L)
Creatinine
(mg/dL)
Raife et al, 2004 15% 13 1.2 44 2.7
Coppo et al, 2010 5% 17 1.3 67 5.1
Kremer Hovinga et al, 2010 10% 11 1.6 22 4.6
Bentley et al, 2010 15% 16 1.1 64 3.5
Cataland et al, 2012 10% 12 1.5 66 5.8
Raife et al, 2004; Coppo et al, 2010; Kremer Hovinga et al, 2010; Bentley et al, 2010; Cataland et al, 2012.

18. Predicting Severely Deficient (<10%) ADAMTS13 Activity
TTP
Derivation
(n=200)
Internal
cohort
(n=150)
External
validation
(n=146)
0-4 0/84 (0%) 0/89 (0%) 2/47 (4%)
5 2/44 (5%) 3/32 (9%) 6/25 (24%)
6 or 7 58/72 (81%) 18/29 (62%) 61/74 (82%)
Data are number of individuals with ADAMTS13 activity of ≤10%/total number of
number of individuals with that score (%)
Validation of PLASMIC score
PLASMIC score for prediction of microangiopathy
associated with severe ADAMTS13 deficiency
POINTS
Platelet count <30 x109/L 1
Hemolysis variable 1
No active cancer 1
No history of solid organ or stem-cell transplant 1
MCV <90 fL (<9.0 x10-14 L) 1
INR <1.5 1
Creatinine <2.0 mg/dL 1
Score of 0-4 denotes low risk for severe ADAMTS13 deficiency; score of 5
of 5 denotes intermediate risk; score of 6 or 7 denotes high risk
7-component score designed by the Harvard TMA Research
Collaborative Registry
PLASMIC
Score
MAT-GLB-2003153
MCV = mean corpuscular value; INR = international normalized ratio.
Bendapudi et al, 2017.

19. ADAMTS13 Activity After Starting PEX
PE = plasma exchange.
Wu et al, 2015.
Should I Still Order It?
14/18 (78%)

20. The Guideline Process
GRADE = Grading of Recommendations, Assessment, Development, and Evaluation.
Slide courtesy of Sara Vesely, PhD, University of Oklahoma.
Used the GRADE process (www.gradeworkinggroup.org)
Panel selection
Meeting 1: June 2018
PICO questions: use to frame and answer a clinical or health care
question
Population, Intervention, Comparison, Outcome
McMaster Team literature search and creation of Evidence Tables
Meeting 2: May 2019
Created Evidence to Decision Tables
Decided on a recommendation
Creating a Checklist for Guideline Developers

21. P = Population
I = Intervention
C = Comparison
O = Outcome
Example:
Should PEX plus corticosteroidsvs PEX alone be used for patients
with iTTP experiencing the first acute event?
Outcomes from most to least important, as follows:
1. All-cause mortality
2. All cardiovascular events
3. Stroke/TIA/clinically obvious neurologic deficit
4. Platelet count recovery
5. Relapse
6. Time to relapse
7. Acute kidney injury/dialysis
8. Days in hospital or days of therapeutic plasma exchange
9. Exacerbation
10. Normal ADAMTS13 level
PICO Questions
TIA = transient ischemic attack.
Slide courtesy of Sara Vesely, PhD, University of Oklahoma.

22. Conflict of Interest: During the Meetings
Slide courtesy of Sara Vesely, PhD, University of Oklahoma.
Individuals with major conflicts of interest (COI)
Were required to abstain from:
The formulation of individual PICO questions
Voting for the corresponding recommendations
Were allowed to:
Contribute to the discussion leading up to the final vote

23. Strength of Recommendations: Strong
Slide courtesy of Sara Vesely, PhD, University of Oklahoma.
Expressed as “the guideline panel recommends...”
The panel is confident that the desirable effects of following the
recommendation outweigh the undesirable effects
Most patients would accept the recommended course of action, while only a
small proportion would not
Most clinicians should follow the recommended course of action, and the
recommendation can be adopted as a policy in most situations
Recommendations are usually based on high-quality evidence in which we
have high confidence. However, in some cases, strong recommendations
are issued in the absence of high-certainty evidence

24. Strength of Recommendations: Conditional
Slide courtesy of Sara Vesely, PhD, University of Oklahoma.
Expressed as “the guideline panel suggests…”
Desirable effects of following the recommendation probably outweigh the
undesirable effects
Most patients would accept the suggested course of action, but many patients
would not
Decision aids might be useful in helping patients make this decision in a way that is
consistent with their values and preferences
Clinicians should note: different choices are appropriate for different patients
Policy making/standard setting around conditional recommendations should be
undertaken with caution; it requires substantial debate and engagement of a wide
range of stakeholders (eg, patients, treating physicians, and insurance
companies/payers)

25. Treatment of iTTP: Goals of Therapy
VWF = von Willebrand factor.
Slide courtesy of Spero R. Cataland, MD.
Zwicker et al, 2019.
Clinical response of disease:
PEX and immune suppressive therapy
Normalization of the platelet count
Surrogate for ongoing microvascular injury
End-organ recovery
Short- and long-term
Prevention of exacerbations of TTP
Need to restart PEX within the first 30
days after stopping PEX or anti-VWF
therapy (caplacizumab)
30%-40% of cases
Plasma
Platelet-rich
plasma leukocytes
Erythrocytes
Whole blood in
Component to be
removed out

26. Treatment of TTP: Immune Suppressive Therapy
Cataland et al, 2017; MayoClinic.org, 2022; Scully et al, 2011.
Corticosteroids:
Suppress anti-ADAMTS13
antibody production
Recovery of ADAMTS13
functional activity
Complications:
Mood issues, weight gain,
infection, osteoporosis
Rituximab:
Anti-CD20 antibody
Suppression of the production of
anti-ADAMTS13 antibodies
Responses begin in 1-2 weeks

27. Rituximab and Prevention of Relapse
Page et al, 2016.
Much clearer in the relapsed patient
Relapsing iTTP phenotype
What is the risk of relapse in my newly
diagnosed patient?
When is this risk determined?
Risk likely dynamic more that static
Rituximab and relapse prevention
If only the first episode, is the use of
rituximab potentially over-treating
patients?
Who then is at the greatest risk?

28. ISTH Guidelines for the Treatment of TTP (cont.)
Zheng et al, 2020b.
Rituximab has a beneficial effect in preventing relapse
Data are of low certainty (historical controls)
Risk of relapse may be higher in those with previous relapse
Conditional recommendation of rituximab in addition to PEX and
corticosteroids
More strongly consider if underlying autoimmune disorders
Recommendation 2/4: For patients with iTTP experiencing a first event/relapse,
the panel suggests the addition of rituximab to corticosteroids and PEX over
corticosteroids and PEX alone (a conditional recommendation in the context of
moderate-certainty evidence)

29. Clinical Issues in TTP: Exacerbations
Zwicker et al, 2019.
Definition:
Recurrent thrombocytopenia <30 days after last PEX or anti-VWF therapy
Differentiate continuation of prior event from “new” event
Need to restart PEX therapy
Occurs in 30%-40% of cases
Most common in first 2 weeks
Significant clinical issue
Readmission to hospital, line placement, PEX
Longer courses of PEX

30. Important TTP Clinical End Points
Med = median; BU = bethesda units; conc = concentration; AA = African American.
Cataland et al, 2009.
Exacerbation Rates and Risk Factors
Acute
(n=44)
Presenting Laboratory Data
(Median) Med.
Exchanges
Response
(Range)
Med. Days
Exacerbation
Platelet count
(150-
400x109/L)
LDH
(100-190)
Exacerbation 13 (30%)
16
(3-38)
900
(340-2,583)
7
(5-12)
7
(2-20)
Non-
exacerbation
31 (70%)
16
(5-93)
684
(370-3,077)
5
(3-23)
N/A
Samples Biomarkers (Median)
Comparison Groups
Exacerbation Non-Exacerbation
Pretreatment
ADAMTS13 activity
0.8%a
(<0.5-7.2)
1.4%a
(<0.5-57.5)
BU
2.2
(0.6-16.0)
4.0
(0.5-60.8)
Inhibitor conc. (µg/mL)
(µg/mL)
406
(94-4,040)
574
(59-3,397)
Response
ADAMTS13 activity %
1.2%
(<0.5-71.4)
22.5%
(<0.5-132.1)
BU
1.6
(0.5-89.6)
0.5
(0.5-44.8)
Inhibitor conc. (µg/mL)
(µg/mL)
534
(107-8,195)
259
(95-1,549)
aP=0.011; no longer statistically significant after
accounting for race, as covariate AA race
associated with an increased risk for
exacerbations P=0.014

31. Caplacizumab
Scully et al, 2019; Hanlon & Metjian, 2020.
A1 domain binding nanobody
Derived from heavy chain only
antibodies
Subcutaneous administration
Given concurrently with PEX
No significant clearance by PEX
Blocks microthrombotic disease
Does not alter/improve the
ADAMTS13 activity

32. Platelet string
formation inhibited by
anti-VWF nanobody
Anti-VWF
TITAN: Caplacizumab in iTTP
IV = intravenous; SC = subcutaneous.
Scully et al, 2019.
Phase 2 Study
Primary end point
• Time to a response, defined as confirmed
normalization of the platelet count
Key secondary end points
• Exacerbations
• Relapses
• Complete remission after PEX
• Safety

33. TITAN: Caplacizumab in iTTP (cont.)
Peyvandi et al, 2016.
Exacerbation, Relapse Status, and ADAMTS13 Activity

34. TITAN: Caplacizumab in iTTP
Peyvandi et al, 2016.
Adverse event Caplacizumab (n=35) Placebo (n=37)
Event related to study drug 57% 14%
Event leading to discontinuation
discontinuation
11% 5%
Bleeding-related event 54% 38%
Immune-related event 49% 32%
Drug-induced antidrug-antibody responses occurred in 3 (9%)
No neutralizing activity was detected
One patient treated with caplacizumab had moderate allergic dermatitis
Safety

35. HERCULES: Caplacizumab
Randomized, double-
blind, placebo-controlled, multi-
national study
Scully et al, 2019.
Phase 3 Study Design Recurrence
Daily PE & open-label caplacizumab
Key Eligibility Criteria:
• TTP episode
• First PEX
• Adults ≥18 (at some
sites, adults and
children 2-18 years)
1:1
PEX
Placebo n=73
PEX
Caplacizumab n=72 (10 mg IV, then 10 mg SC daily)
Treatment period Extension
Variable 30 days 4 x 7 days maximum 28 days
F
o
l
l
o
w
U
p
Extension based on
ADAMTS13 <10%
Primary end point
• Time to a response, defined as confirmed normalization of the platelet count (with
discontinuation of PEX within 5 days thereafter)
Secondary end points
• TTP-related death, recurrence of TTP, major thromboembolic event
• Recurrence of TTP
• Refractoriness to treatment
• Time to normalization of organ damage markers

36. HERCULES: Caplacizumab (cont.)
aPercentages are based on 71 subjects entering the study drug treatment period and 66 subjects in the follow-up period.
bRecurrence = recurrent thrombocytopenia after initial recovery of platelet count, requiring reinitiation of daily PEX.
cADAMTS13 activity levels were <10% at the end of the study drug treatment period in all of these patients.
dRefractory TTP = absence of platelet count doubling after 4 days of standard treatment and LDH >ULN.
Scully et al, 2019.
Key Secondary End Points
Number of subjects (%)
Placebo
n=73
Caplacizumab
n=72a
iTTP recurrenceb 28 (38.4%) 9 (12.7%)
During the study drug treatment period (exacerbations) 28 (38.4%) 3 (4.2%)
During the follow-up period (relapses) 0 6 (9.1%)c
P value <0.001
Percentage of Subjects With Refractory iTTP
Subjects With TTP Recurrence During Overall Study Period
Number of subjects (%)
Placebo
n=73
Caplacizumab
n=72
Refractory iTTPd 3 (4.2%) 0
P value 0.057

37. HERCULES: Caplacizumab (cont.)
aTreatment-emergent adverse events occurring in at least 2 subjects in either group.
bStandardized MedDRA Query “Hemorrhage.”
Slide adapted from Scully et al, 2019.
Safety: Bleeding-Related TEAEsa
Placebo
n (%)
Caplacizumab
n (%)
Bleeding-related TEAEs (by SMQ)b 17 (23.3%) 33 (45.6%)
Epistaxis 1 (1.4%) 17 (23.9%)
Gingival bleeding 0 8 (11.3%)
Bruising 3 (4.1%) 5 (7.0%)
Hematuria 1 (1.4%) 4 (5.6%)
Vaginal hemorrhage 1 (1.4%) 3 (4.2%)
Menorrhagia 1 (1.4%) 2 (2.8%)
Catheter site hemorrhage 3 (4.1%) 2 (2.8%)
Injection site bruising 2 (2.7%) 2 (2.8%)
Hematochezia 0 2 (2.8%)
Hematoma 0 2 (2.8%)

38. Caplacizumab and aTTP
Zheng et al, 2020b.
Based on data of moderate certainty
2 randomized, placebo-controlled studies
Data not available to differentiate newly diagnosed from relapsed TTP
Low mortality rates on both arms of studies (possible selection bias)
Caplacizumab-treated patients:
Significant reduction in exacerbations
Greater benefit if started early in an acute TTP event
Important caveats
FDA-approved drug not yet available worldwide
Only given under the guidance of an experienced clinician
Caplacizumab does not alter the underlying disease (ADAMTS13 deficiency)
Recommendation 5: For patients with iTTP experiencing an acute event
(first event or relapse) the panel suggests using caplacizumab over not
using caplacizumab (a conditional recommendation in the context of
moderate-certainty evidence)

39. ADAMTS13 in Remission and Relapse Risk
Peyvandi et al, 2008; Jin et al, 2008.
Peyvandi et al studied 109
patients with samples studied in
remission
>30 days after PEX
Prior to relapse
Majority with 1 sample
Risk of relapse (odds ratio):
ADAMTS13 <10%: 2.9
ADAMTS13 <10% +
antibody: 3.6

40. ADAMTS13 Activity and TTP
Motto et al, 2005; Banno et al, 2006.
Deficient ADAMTS13 alone not sufficient
to lead to an acute TTP episode
ADAMTS13 -/- mice do not spontaneously
develop TMA findings
Shiga toxin, collagen/epinephrine required
to initiate the development of
thrombocytopenia
Congenital TTP
Delayed presentations at the time of
pregnancy
Second Hit Hypothesis

41. ADAMTS13 Activity Monitoring in Remission
GPS = good practice statements.
Zheng et al, 2020a.
ADAMTS13 activity monitoring in remission:
Patients should be assessed regularly during follow-up
Literature on ADAMTS13 monitoring in remission not reviewed
Patients usually assessed:
Monthly for the first 3 months, every 3 months for the first year, then every 6-12
months if stable
More frequent measurements if declining ADAMTS13 activity
ADAMTS13 activity interpretation
Stable and durable ADAMTS13 activity near lower level of normal is
reassuring
Persistently low levels may be at risk for relapse
Supportive Care GPS: Statement 13

42. Zheng et al, 2020b.
Recommendation 6: For patients with iTTP who are in
remission but still have low plasma ADAMTS13 activity with
no clinical signs/symptoms, the panel suggests the use of
rituximab over non-use of rituximab for prophylaxis (a
conditional recommendation in the context of very low–
certainty evidence)
Preemptive Rituximab in iTTP in Remission

43. Preemptive Rituximab in iTTP in Remission
Jestin et al, 2018.
Data suggest that preemptive rituximab
has fewer relapses and requires longer
time for iTTP relapse
Non-randomized data
No clear effect on survival
Potential issue of expense
Patient commitment necessary:
Serial ADAMTS13 monitoring
Rituximab prophylaxis without
ADAMTS13 monitoring not an evidence-
based strategy

44. Chronic End-Organ Complications in aTTP
Figure 1. Sclerotic glomeruli and atrophic
tubules with petechial hemorrhage
Figure 2. Hypertrophic myocytes
Images courtesy of Spero R. Cataland, MD.

45. SLE = systemic lupus
erythematosus.
Deford et al, 2013.
70 enrolled patients with TTP and
ADAMTS13 activity <10%
57 survivors as of 2012 evaluated
Comparison to US norms
Mood disorders/depression
Hypertension
19% died
Greater than US and Oklahoma
norms (P<0.05)
Major Morbidities in Long-Term Follow-Up of iTTP Patients

46. iTTP Survivors Have Increased Mortality Rates
Sukumar et al, 2022.
47

47. Risk Factors For Early Mortality in iTTP Survivorsa
aAdjusted for AA race, HTN, CKD, and treatment site.
HTN = hypertension; CKD = chronic kidney disease; HR = hazard ratio; CI = confidence interval.
Sukumar et al, 2021.
Characteristic HR 95% CI P
Male sex 3.74 1.65-8.48 0.002
Increasing age 1.04 1.01-1.07 0.011
No. of iTTP episodes 1.10 1.01-1.20 0.022
48
Lack of association of mortality with traditional cardiovascular risk factors (HTN, CKD)
Possibly due to limited sample size, but raises question of iTTP specific factors which
may contribute to mortality  ADAMTS13 activity??

48. Stroke Risk in aTTP Survivors
Upreti et al, 2019.
49

49. -2.6
-2.4
-2.2
-2
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
DET IDN OBK OCL
magnitude
of
impairment
relative
.
to
matched
controls
(z)
.
Depression
in 35-55yrs
Dementia (AD)
in 65-75yrs
0.08%BAC
in 40-50yrs
TMA
DT: Detection Task
IDN: Identification Task
OBK: One Back Memory
OCL: One Card Learning
Neurocognitive Deficits in TTP
BAC = blood alcohol content; AD = Alzheimer disease.
Slide courtesy of Spero R. Cataland, MD.
Cataland et al, 2011.
Detection task:
“Has the card turned over?”
Identification task:
“Is the card red?”
One back memory:
“Does the face-up card exactly
match the one before?”
One card learning:
“Have you seen this card before in
this task?”
Comparison to Differing Disease States

50. Key Takeaways
iTTP is a rare, but very serious, hematologic disorder that requires
prompt recognition and treatment
Novel therapies including immune suppressive therapy (rituximab) and
caplacizumab have dramatic improved treatment outcomes for iTTP
patients
Challenges remain, however:
Greater number of survivors/patients at risk for complications
Shortened life expectancy from cardiovascular complications
Impact on quality of life
Mood disorders, neurocognitive complications, PTSD

51. Thank You

52. References
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