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Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura (HERCULES)

Primary Purpose

Acquired Thrombotic Thrombocytopenic Purpura

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Caplacizumab
Placebo
Sponsored by
Ablynx, a Sanofi company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acquired Thrombotic Thrombocytopenic Purpura

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Adult male or female ≥ 18 years of age at the time of signing the informed consent form (ICF).
  2. Clinical diagnosis of acquired thrombotic thrombocytopenic purpura (aTTP) (initial or recurrent), which included thrombocytopenia and microscopic evidence of red blood cell fragmentation (e.g., schistocytes).
  3. Required initiation of daily PE treatment and had received 1 PE treatment prior to randomization
  4. Others as defined in the protocol

Exclusion Criteria:

  1. Platelet count ≥100×10E9/L.
  2. Serum creatinine level >200 µmol/L in case platelet count is > 30×10E9/L
  3. Known other causes of thrombocytopenia
  4. Congenital TTP (known at the time of study entry).
  5. Pregnancy or breast-feeding.
  6. Subjects who were previously enrolled in a clinical study with caplacizumab and received caplacizumab or for whom the assigned treatment arm is unknown
  7. Others as defined in the protocol

Sites / Locations

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Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Caplacizumab

Placebo

Arm Description

Caplacizumab 10 mg once daily

Placebo once daily

Outcomes

Primary Outcome Measures

Time to Platelet Count Response
Platelet count response was defined as initial platelet count ≥ 150,000/μL with subsequent stop of daily PE within 5 days. It refers to the first time both conditions, platelet count ≥ 150,000/μL and the stop of daily PE within 5 days, were met.

Secondary Outcome Measures

Number and Percentage of Subjects With TTP-Related Death, Recurrence of TTP, or a Major Thromboembolic Event During the Study Drug Treatment Period
Number and percentage of subjects with TTP-related death, a recurrence of TTP, or at least one treatment-emergent major thromboembolic event during the study drug treatment period (i.e., first key secondary endpoint).
Number and Percentage of Subjects With a Recurrence of TTP in the Overall Study Period
Number and percentage of subjects with a recurrence of TTP during the Overall Study Period (i.e., including follow-up [FU]) (i.e., second key secondary endpoint).
Number and Percentage of Subjects With Refractory Disease
Number and percentage of subjects with refractory TTP, defined as absence of platelet count doubling after 4 days of standard treatment, and lactate dehydrogenase (LDH) > upper limit of normal (ULN) (i.e., third key secondary endpoint).
Time to Normalization of Organ Damage Marker Levels
Time to first normalization of LDH, cardiac troponin I (cTnI) and serum creatinine was defined as: first time of LDH ≤ ULN and cTnI ≤ ULN and serum creatinine ≤ ULN - time of first i.v. loading dose of study drug after randomization + 1 minute. Subjects in either initial treatment group who switched to open-label caplacizumab before having reached the endpoint were censored at time of switch. Of note, the key secondary endpoints were hierarchically ordered to allow statistical testing for these endpoints at the same nominal significance level of 5% without adjustment, as long as the tests occurred in the pre-defined sequential order, and given that all null hypotheses tested for endpoints with a higher rank (including the primary endpoint) were rejected. No confirmatory testing was done for this fourth key secondary endpoint, as the statistical test was not significant for the proportion of subjects with refractory disease (i.e., the third key secondary endpoint).

Full Information

First Posted
September 14, 2015
Last Updated
March 31, 2023
Sponsor
Ablynx, a Sanofi company
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1. Study Identification

Unique Protocol Identification Number
NCT02553317
Brief Title
Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura
Acronym
HERCULES
Official Title
A Phase III Double-blind, Randomized, Parallel Group, Multicenter Placebo-controlled Trial to Study the Efficacy and Safety of Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
November 2015 (Actual)
Primary Completion Date
August 2017 (Actual)
Study Completion Date
August 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ablynx, a Sanofi company

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The study was a Phase III, double-blind, placebo-controlled, randomized study to evaluate the efficacy of caplacizumab in more rapidly restoring normal platelet counts as measure of prevention of further microvascular thrombosis

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acquired Thrombotic Thrombocytopenic Purpura

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
145 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Caplacizumab
Arm Type
Experimental
Arm Description
Caplacizumab 10 mg once daily
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo once daily
Intervention Type
Biological
Intervention Name(s)
Caplacizumab
Other Intervention Name(s)
ALX-0081
Intervention Description
First day of treatment: 10 mg intravenous (i.v.) injection prior to plasma exchange (PE) followed by a 10 mg subcutaneous (s.c.) injection (in the abdominal region) after completion of PE on that day. Subsequent days of treatment during PE: daily 10 mg s.c. injection (in the abdominal region) following PE. Treatment after PE period: daily 10 mg s.c. injections for 30 days. If the underlying immunological disease was not resolved, treatment could be extended for a maximum of 4 additional 1-week periods (i.e., 28 days) and was to be accompanied by optimization of immunosuppression.
Intervention Type
Biological
Intervention Name(s)
Placebo
Other Intervention Name(s)
ALX-0081 Placebo
Intervention Description
First day of treatment: i.v. injection prior to PE followed by a s.c. injection (in the abdominal region) after completion of PE on that day. Subsequent days of treatment during PE: daily s.c. injection (in the abdominal region) following PE. Treatment after PE period: daily s.c. injections for 30 days. If the underlying immunological disease was not resolved, treatment could be extended for a maximum of 4 additional 1-week periods (i.e., 28 days) and was to be accompanied by optimization of immunosuppression.
Primary Outcome Measure Information:
Title
Time to Platelet Count Response
Description
Platelet count response was defined as initial platelet count ≥ 150,000/μL with subsequent stop of daily PE within 5 days. It refers to the first time both conditions, platelet count ≥ 150,000/μL and the stop of daily PE within 5 days, were met.
Time Frame
Only data from the DB daily PE period (median = 5 days) up to the cut-off were used. The cut-off point was defined by whichever occured first: 1) 45 days of daily PE after start of study drug, 2) stop of daily PE, 3) stop of study drug (median = 34 days)
Secondary Outcome Measure Information:
Title
Number and Percentage of Subjects With TTP-Related Death, Recurrence of TTP, or a Major Thromboembolic Event During the Study Drug Treatment Period
Description
Number and percentage of subjects with TTP-related death, a recurrence of TTP, or at least one treatment-emergent major thromboembolic event during the study drug treatment period (i.e., first key secondary endpoint).
Time Frame
The study drug treatment period, a median (min, max) of 36 (2, 82) days. For both treatment groups, only events that occurred prior to a switch to open-label caplacizumab were evaluated for this analysis.
Title
Number and Percentage of Subjects With a Recurrence of TTP in the Overall Study Period
Description
Number and percentage of subjects with a recurrence of TTP during the Overall Study Period (i.e., including follow-up [FU]) (i.e., second key secondary endpoint).
Time Frame
The overall study period (covers both the overall treatment period and the follow-up period), a median (min, max) of 65 (2, 110) days.
Title
Number and Percentage of Subjects With Refractory Disease
Description
Number and percentage of subjects with refractory TTP, defined as absence of platelet count doubling after 4 days of standard treatment, and lactate dehydrogenase (LDH) > upper limit of normal (ULN) (i.e., third key secondary endpoint).
Time Frame
The study drug treatment period, a median (min, max) of 36 (2, 82) days.
Title
Time to Normalization of Organ Damage Marker Levels
Description
Time to first normalization of LDH, cardiac troponin I (cTnI) and serum creatinine was defined as: first time of LDH ≤ ULN and cTnI ≤ ULN and serum creatinine ≤ ULN - time of first i.v. loading dose of study drug after randomization + 1 minute. Subjects in either initial treatment group who switched to open-label caplacizumab before having reached the endpoint were censored at time of switch. Of note, the key secondary endpoints were hierarchically ordered to allow statistical testing for these endpoints at the same nominal significance level of 5% without adjustment, as long as the tests occurred in the pre-defined sequential order, and given that all null hypotheses tested for endpoints with a higher rank (including the primary endpoint) were rejected. No confirmatory testing was done for this fourth key secondary endpoint, as the statistical test was not significant for the proportion of subjects with refractory disease (i.e., the third key secondary endpoint).
Time Frame
Overall study period, a median (min, max) of 65 (2, 110) days. For both treatment groups, normalizations occurring during the open-label period were not evaluated in this analysis.
Other Pre-specified Outcome Measures:
Title
Number of Days of Plasma Exchange
Description
The number of days of PE during the overall study drug treatment period, including the number of days of PE during the open-label study drug treatment period. Data were analyzed according to the initial treatment allocation (both before and after switch to open-label caplacizumab).
Time Frame
Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Title
Total Volume of Plasma Exchange
Description
The total volume of PE during the overall study drug treatment period, including the total volume of PE during the open-label study drug treatment period. Data were analyzed according to the initial treatment allocation (both before and after switch to open-label caplacizumab).
Time Frame
Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Title
Number of Days in Intensive Care Unit
Description
The number of days in intensive care unit (ICU) during the overall study drug treatment period, including the number of days in ICU during the open-label study drug treatment period. Data were analyzed according to the initial treatment allocation (both before and after switch to open-label caplacizumab).
Time Frame
Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Title
Number of Days in Hospital
Description
The number of days in hospital during the overall study drug treatment period, including the number of days in hospital during the open-label study drug treatment period. Data were analyzed according to the initial treatment allocation (both before and after switch to open-label caplacizumab).
Time Frame
Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult male or female ≥ 18 years of age at the time of signing the informed consent form (ICF). Clinical diagnosis of acquired thrombotic thrombocytopenic purpura (aTTP) (initial or recurrent), which included thrombocytopenia and microscopic evidence of red blood cell fragmentation (e.g., schistocytes). Required initiation of daily PE treatment and had received 1 PE treatment prior to randomization Others as defined in the protocol Exclusion Criteria: Platelet count ≥100×10E9/L. Serum creatinine level >200 µmol/L in case platelet count is > 30×10E9/L Known other causes of thrombocytopenia Congenital TTP (known at the time of study entry). Pregnancy or breast-feeding. Subjects who were previously enrolled in a clinical study with caplacizumab and received caplacizumab or for whom the assigned treatment arm is unknown Others as defined in the protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Ablynx NV
Official's Role
Study Director
Facility Information:
Facility Name
Investigator Site
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35249
Country
United States
Facility Name
Investigator Site
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Investigator Site
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Investigator Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Investigator Site
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Investigator Site
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Investigator Site
City
Rochester
State/Province
New York
ZIP/Postal Code
55905
Country
United States
Facility Name
Investigator Site
City
Valhalla
State/Province
New York
ZIP/Postal Code
10595
Country
United States
Facility Name
Investigator Site
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Investigator Site
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Investigator Site
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
Investigator SIte
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Investigator Site
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Investigator Site
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Investigator Site
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Investigator Site
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Investigator Site
City
Greenville
State/Province
South Carolina
ZIP/Postal Code
27834
Country
United States
Facility Name
Investigator Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Investigator Site
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
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Investigator Site
City
Brisbane
Country
Australia
Facility Name
Investigator Site 1
City
Melbourne
Country
Australia
Facility Name
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City
Melbourne
Country
Australia
Facility Name
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City
Melbourne
Country
Australia
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Investigator Site 4
City
Melbourne
Country
Australia
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Investigator Site 5
City
Melbourne
Country
Australia
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City
Perth
Country
Australia
Facility Name
Investigator Site 1
City
Sydney
Country
Australia
Facility Name
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City
Sydney
Country
Australia
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City
Vienna
Country
Austria
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City
Antwerp
Country
Belgium
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City
Brussels
Country
Belgium
Facility Name
Investigator Site
City
Haine-Saint-Paul
Country
Belgium
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City
La Louviere
Country
Belgium
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Investigator Site
City
Leuven
Country
Belgium
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Invesigator Site
City
Montreal
State/Province
Quebec
Country
Canada
Facility Name
Investigator Site
City
London
Country
Canada
Facility Name
Investigator Site
City
Toronto
Country
Canada
Facility Name
Investigator Site
City
Brno
Country
Czechia
Facility Name
Investigator Site
City
Hradec Kralove
Country
Czechia
Facility Name
Investigator Site
City
Olomouc
Country
Czechia
Facility Name
Investigator Site
City
Ostrava-Poruba
Country
Czechia
Facility Name
Investigator Site
City
Caen
Country
France
Facility Name
Investigator Site
City
Lille
Country
France
Facility Name
Investigator Site
City
Marseille
Country
France
Facility Name
Investigator Site
City
Nantes
Country
France
Facility Name
Investigator Site 1
City
Paris
Country
France
Facility Name
Investigator Site 2
City
Paris
Country
France
Facility Name
Investigator Site 3
City
Paris
Country
France
Facility Name
Investigator Site 4
City
Paris
Country
France
Facility Name
Investigator site 5
City
Paris
Country
France
Facility Name
Investigator Site
City
Rouen
Country
France
Facility Name
Investigator Site
City
Salouel
Country
France
Facility Name
Investigator site 1
City
Dresden
Country
Germany
Facility Name
Investigator site 2
City
Dresden
Country
Germany
Facility Name
Investigator site
City
Erlangen
Country
Germany
Facility Name
Investigator site
City
Goppingen
Country
Germany
Facility Name
Investigator site
City
Kiel
Country
Germany
Facility Name
Investigator site
City
Köln
Country
Germany
Facility Name
Investigator site
City
Leipzig
Country
Germany
Facility Name
Investigator site
City
Würzburg
Country
Germany
Facility Name
Investigator Site 1
City
Budapest
Country
Hungary
Facility Name
Investigator Site 2
City
Budapest
Country
Hungary
Facility Name
Investigator Site
City
Debrecen
Country
Hungary
Facility Name
Investigator Site 1
City
Be'er Ya'aqov
Country
Israel
Facility Name
Investigator Site 2
City
Be'er Ya'aqov
Country
Israel
Facility Name
Investigator Site
City
Haifa
Country
Israel
Facility Name
Investigator Site 1
City
Jerusalem
Country
Israel
Facility Name
Investigator Site 2
City
Jerusalem
Country
Israel
Facility Name
Investigator Site
City
Nahariya
Country
Israel
Facility Name
Investigator Site
City
Petah Tiqva
Country
Israel
Facility Name
Investigator Site
City
Tel Aviv
Country
Israel
Facility Name
Investigator Site
City
Catania
Country
Italy
Facility Name
Investigator Site 1
City
Milan
Country
Italy
Facility Name
Investigator Site 2
City
Milan
Country
Italy
Facility Name
Investigator Site
City
Pesaro
Country
Italy
Facility Name
Investigator Site
City
Rome
Country
Italy
Facility Name
Investigator Site
City
Vicenza
Country
Italy
Facility Name
Investigator Site
City
Amersfoort
Country
Netherlands
Facility Name
Investigator Site
City
Leiden
Country
Netherlands
Facility Name
Investigator Site
City
Rotterdam
Country
Netherlands
Facility Name
Investigator Site
City
Veldhoven
Country
Netherlands
Facility Name
Investigator Site 1
City
Barcelona
Country
Spain
Facility Name
Investigator Site 2
City
Barcelona
Country
Spain
Facility Name
Investigator Site
City
Madrid
Country
Spain
Facility Name
Investigator Site
City
Sevilla
Country
Spain
Facility Name
Investigator Site 1
City
Valencia
Country
Spain
Facility Name
Investigator Site 2
City
Valencia
Country
Spain
Facility Name
Investigator site 3
City
Valencia
Country
Spain
Facility Name
Investigator Site
City
Bern
Country
Switzerland
Facility Name
Investigator Site
City
Zurich
Country
Switzerland
Facility Name
Investigator Site
City
Ankara
Country
Turkey
Facility Name
Investigator Site 1
City
Denizli
Country
Turkey
Facility Name
Investigator Site 2
City
Denizli
Country
Turkey
Facility Name
Investigator site 3
City
Denizli
Country
Turkey
Facility Name
Investigator Site
City
Istanbul
Country
Turkey
Facility Name
Investigator Site
City
Kayseri
Country
Turkey
Facility Name
Investigator Site
City
Trabzon
Country
Turkey
Facility Name
Investigator Site
City
Bristol
Country
United Kingdom
Facility Name
Investigator Site
City
Liverpool
Country
United Kingdom
Facility Name
Investigator Site 1
City
London
Country
United Kingdom
Facility Name
Investigator Site 2
City
London
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
Citations:
PubMed Identifier
33881463
Citation
Peyvandi F, Cataland S, Scully M, Coppo P, Knoebl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Minkue Mi Edou J, De Winter H, Callewaert F. Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis. Blood Adv. 2021 Apr 27;5(8):2137-2141. doi: 10.1182/bloodadvances.2020001834.
Results Reference
derived
PubMed Identifier
31691462
Citation
Knoebl P, Cataland S, Peyvandi F, Coppo P, Scully M, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Minkue Mi Edou J, De Winter H, Callewaert F. Efficacy and safety of open-label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES study. J Thromb Haemost. 2020 Feb;18(2):479-484. doi: 10.1111/jth.14679. Epub 2019 Dec 9.
Results Reference
derived
PubMed Identifier
30625070
Citation
Scully M, Cataland SR, Peyvandi F, Coppo P, Knobl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Callewaert F, Biswas D, De Winter H, Zeldin RK; HERCULES Investigators. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019 Jan 24;380(4):335-346. doi: 10.1056/NEJMoa1806311. Epub 2019 Jan 9.
Results Reference
derived

Learn more about this trial

Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura

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