Thrombocytopenia, IsolatedTHC4NCT07026578
Unravelling the Role of Apoptosis in Platelets Biogenesis Through the Study of the Thrombocytopenia THC4
An observational study of Thrombocytopenia, Isolated and Thrombocytopenia 4, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site in Italy.
Trial summary
Inherited thrombocytopenias (ITs) are disorders characterized by a reduced platelet count, caused by variants in at least 40 genes. Mutations in CYCS cause a rare autosomal-dominant IT, named Thrombocytopenia 4 (THC4). The CYCS gene encodes cytochrome C (CytC), a small heme protein localized in mitochondria. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Thrombocytopenia, Isolated, Thrombocytopenia 4, CYCS MUTATION- ASSOCIATED THROMBOCYTOPENIA THC4
- What is being tested?
- Blood draw for the laboratory assessment
- Type of treatment
- Surgery or procedure
- How many people
- 38 participants
- Where
- 1 siteItaly
- Study dates
- 18 Jun 2024to 30 Jun 2026
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: All subjects with suspected Inherited Thrombocytopenia (IT) observed at the SC Medicina generale 1, Fondazione IRCCS Policlinico San Matteo
Who may be able to join
- Molecular diagnosis of THC4, through the identification of a pathogenic variant of the CYCS gene
- Acquisition of written informed consent
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country.
Italy1 site
SC Medicina Generale 1, Fondazione IRCCS Policlinico San Matteo
Pavia, Pavia, 27100
About this study
Official title: Unravelling the Role of Apoptosis in Platelets Biogenesis Through the Study of the CYCS Mut-associated Thrombocytopenia THC4
Inherited thrombocytopenias (ITs) are disorders characterized by a reduced platelet count, caused by variants in at least 40 genes. Mutations in CYCS cause a rare autosomal-dominant IT, named Thrombocytopenia 4 (THC4). The CYCS gene encodes cytochrome C (CytC), a small heme protein localized in mitochondria. It functions as an electron carrier in the respiratory chain as well as one of the main actors of the intrinsic pathway of apoptosis.
Although THC4 is the only disease associated with CYCS mutations, its clinical and molecular features are still poorly characterized. Moreover, pathogenesis of THC4 is still unclear. In vitro studies demonstrated that CYCS mutations exert a proapoptotic activity and enhanced peroxidase activity, as well as affect the mitochondrial respiratory function in yeast.
Read more
The role of apoptosis in platelet biogenesis is a highly controversial issue. Some studies suggested that megakaryocytes must undergo apoptosis to promote platelet release. In fact, mice carrying mutations impairing apoptosis exhibited thrombocytopenia and pharmacological inhibition of caspases blocked platelet production, supporting this hypothesis. Conversely, investigations on mice genetically modified for the BCL-2 family proteins, initiators of apoptosis, concluded that megakaryocytes must restrain apoptosis in order to generate platelets.
Since thrombocytopenia is the only phenotypic manifestation of CYCS mutations, the investigators believe that THC4 represents a unique model for deciphering the role of Cytc and apoptosis in megakaryopoiesis and platelet biogenesis.
Preliminary data:
The applicant unit is a reference center for ITs. The database includes 375 families; among these, 7 presented with mutations in CYCS gene, accounting for 26 THC4 patients.
Patients presented mild thrombocytopenia, normal mean platelet volume and morphology, without hematological or extra-hematological defects.
The investigators isolated platelets and hematopoietic progenitors from peripheral blood of 9 patients. Platelets were analyzed under baseline conditions; a part was treated with an inducer of apoptosis (ABT-737).
Surprisingly, the expression of cytC was found reduced in platelets of all analyzed patients. Platelets showed no signs of early death. Instead, when stimulated with ABT-737, they showed inability to undergo apoptosis, suggesting that CYCS mutations confer resistance to apoptosis.
Hematopoietic progenitors from 3 patients were differentiated in megakaryocytes. Maturation and differentiation were comparable between THC4 and healthy controls. Instead, their capability to form proplatelets was profoundly defective.
These preliminary data suggest that CytC deficit could be associated with inability to form proplatelets in THC4 megakaryocytes, and that this defect underlies thrombocytopenia, supporting the crucial role of cytC in platelet production.
- Conditions
- Thrombocytopenia, Isolated, Thrombocytopenia 4, CYCS MUTATION- ASSOCIATED THROMBOCYTOPENIA THC4
- Being tested
- Blood draw for the laboratory assessment
- Keywords
- Apoptosis, Platelet biogenesis, Thrombocytopenia 4
- Medical subject headings
- Thrombocytopenia, Thrombocytopenia 4
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood draw for the laboratory assessmentProcedure or surgery
This is an observational study . The procedures will be carried out in according to clinical practice
| Study group | Role | What they receive |
|---|---|---|
| CYCS mutated | Not described Receives: Procedure: Blood draw for the laboratory assessment | |
| healthy controls | Not described Receives: Procedure: Blood draw for the laboratory assessment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pathogenetic CYCS variants result in defective Cytc expression
The primary outcome of the study is to demonstrate that mutations in CYCS results in reduction of the expression of Cytochrome C in THC4 platelets. The primary endpoint will compare Cytochrome C expression in platelets between THC4 patients and healthy controls. This will be assessed by measuring Cytochrome C protein levels in platelet lysates collected from both groups. Western blotting will be used to quantify the amount of Cytochrome C protein.
Measured: The primary endpoint measurement will be performed immediately after the enrollment (baseline).
Secondary outcomes (1)
The impact of Cytochrome C (CytC) deficiency on apoptotic mechanisms evaluated as the comparison of the apoptotic markers between CYCS-silenced cells and cells transduced with the vector alone
Once CytC deficiency has been confirmed, in vitro models will be created to study the effects on the apoptotic machinery. Parameters will be analyzed in CYCS-silenced cells and baseline cells in the presence or absence of apoptosis inducers: phosphatidylserine exposure, cell viability, depolarization of mitochondrial membranes. Extrinsic and intrinsic apoptotic pathways will be analyzed as the activation of initiator and executioner caspases with different techniques such as flow cytometry, immunofluorescence staining, and immunoblotting. All these results will be expressed as the percentage of positive cells after treatment with an apoptotic inducer relative to treated baseline cells. The data will be aggregated to determine if CytC deficiency results in an increased or decreased apoptotic rate in THC4, expressed as a higher or lower percentage of apoptotic cells in the absence of CytC.
Measured: The production of in vitro models and execution of tests to evaluate the apoptotic profile will take 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2025
- Study start18 Jun 2024
- Primary completion30 Jun 2026 (estimated)
- Study completion30 Jun 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Thrombocytopenia, IsolatedStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Policlinico San Matteo di PaviaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 38 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di Pavia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Serena Barozzi, Fondazione IRCCS Policlinico San Matteo di Pavia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07026578
- Sponsor's protocol ID
- THC4
- Acronym
- THC4
- Status last verified
- Apr 2025
- First submitted
- 13 Mar 2025
- Last updated
- 18 Jun 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Unravelling the Role of Apoptosis in Platelets Biogenesis Through the Study of the CYCS Mut-associated Thrombocytopenia THC4
- ClinicalTrials.gov ID
- NCT07026578
- Acronym / sponsor ID
- THC4 / THC4
- Conditions
- Thrombocytopenia, Isolated, Thrombocytopenia 4, CYCS MUTATION- ASSOCIATED THROMBOCYTOPENIA THC4
- Keywords
- Apoptosis, Platelet biogenesis, Thrombocytopenia 4
- Study type
- Observational
- Recruitment status
- Active, not recruiting
- Enrolment
- 38 participants (estimated)
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di PaviaUniversity, hospital or other
- Study start
- 18 Jun 2024 (actual)
- Primary completion
- 30 Jun 2026 (estimated)
- Study completion
- 30 Jun 2026 (estimated)
- First posted
- 18 Jun 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Inherited thrombocytopenias (ITs) are disorders characterized by a reduced platelet count, caused by variants in at least 40 genes. Mutations in CYCS cause a rare autosomal-dominant IT, named Thrombocytopenia 4 (THC4). The CYCS gene encodes cytochrome C (CytC), a small heme protein localized in mitochondria. It functions as an electron carrier in the respiratory chain as well as one of the main actors of the intrinsic pathway of apoptosis.
Although THC4 is the only disease associated with CYCS mutations, its clinical and molecular features are still poorly characterized. Moreover, pathogenesis of THC4 is still unclear. In vitro studies demonstrated that CYCS mutations exert a proapoptotic activity and enhanced peroxidase activity, as well as affect the mitochondrial respiratory function in yeast.
The role of apoptosis in platelet biogenesis is a highly controversial issue. Some studies suggested that megakaryocytes must undergo apoptosis to promote platelet release. In fact, mice carrying mutations impairing apoptosis exhibited thrombocytopenia and pharmacological inhibition of caspases blocked platelet production, supporting this hypothesis. Conversely, investigations on mice genetically modified for the BCL-2 family proteins, initiators of apoptosis, concluded that megakaryocytes must restrain apoptosis in order to generate platelets.
Since thrombocytopenia is the only phenotypic manifestation of CYCS mutations, the investigators believe that THC4 represents a unique model for deciphering the role of Cytc and apoptosis in megakaryopoiesis and platelet biogenesis.
Preliminary data:
The applicant unit is a reference center for ITs. The database includes 375 families; among these, 7 presented with mutations in CYCS gene, accounting for 26 THC4 patients.
Patients presented mild thrombocytopenia, normal mean platelet volume and morphology, without hematological or extra-hematological defects.
The investigators isolated platelets and hematopoietic progenitors from peripheral blood of 9 patients. Platelets were analyzed under baseline conditions; a part was treated with an inducer of apoptosis (ABT-737).
Surprisingly, the expression of cytC was found reduced in platelets of all analyzed patients. Platelets showed no signs of early death. Instead, when stimulated with ABT-737, they showed inability to undergo apoptosis, suggesting that CYCS mutations confer resistance to apoptosis.
Hematopoietic progenitors from 3 patients were differentiated in megakaryocytes. Maturation and differentiation were comparable between THC4 and healthy controls. Instead, their capability to form proplatelets was profoundly defective.
These preliminary data suggest that CytC deficit could be associated with inability to form proplatelets in THC4 megakaryocytes, and that this defect underlies thrombocytopenia, supporting the crucial role of cytC in platelet production.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| CYCS mutated | – | Procedure: Blood draw for the laboratory assessment |
| healthy controls | – | Procedure: Blood draw for the laboratory assessment |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- All subjects with suspected Inherited Thrombocytopenia (IT) observed at the SC Medicina generale 1, Fondazione IRCCS Policlinico San Matteo
Key inclusion criteria (2 listed)
- Molecular diagnosis of THC4, through the identification of a pathogenic variant of the CYCS gene
- Acquisition of written informed consent
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Blood draw for the laboratory assessmentThis is an observational study . The procedures will be carried out in according to clinical practice | Procedure or surgery | CYCS mutated, healthy controls |
Primary outcome
Pathogenetic CYCS variants result in defective Cytc expression
Time frame: The primary endpoint measurement will be performed immediately after the enrollment (baseline).
The primary outcome of the study is to demonstrate that mutations in CYCS results in reduction of the expression of Cytochrome C in THC4 platelets. The primary endpoint will compare Cytochrome C expression in platelets between THC4 patients and healthy controls. This will be assessed by measuring Cytochrome C protein levels in platelet lysates collected from both groups. Western blotting will be used to quantify the amount of Cytochrome C protein.
1 secondary outcome
The impact of Cytochrome C (CytC) deficiency on apoptotic mechanisms evaluated as the comparison of the apoptotic markers between CYCS-silenced cells and cells transduced with the vector alone
Time frame: The production of in vitro models and execution of tests to evaluate the apoptotic profile will take 2 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Thrombocytopenia, Isolated and Thrombocytopenia 4, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 18 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pathogenetic CYCS variants result in defective Cytc expression (time frame: The primary endpoint measurement will be performed immediately after the enrollment (baseline).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2025.