A first version of the RITI was initially created in 2007, collecting data on thrombotic events. The RITI was designed and created thanks to the joint effort of a multidisciplinary team based in Padova, Italy, with expertise in thrombosis and coagulation disorders, pediatrics, neonatology, neurology, hematology, oncology, cardiology, nephrology, and intensive care. Beside health care providers, a team of informatics and statisticians has played an essential role in all stages of the registry creation, maintenance and updates. The study received Ethical Committee approval on May 12th, 2008 (Protocol #1653P), and the RITI was soon opened to all physicians on the Italian territory, who were invited to participate and enroll patients on a voluntary basis. Periodic national in-person meetings were initially held to discuss registry-related issues and promote the awareness of neonatal and pediatric thrombosis.

On 30th June 2017, a new version of the RITI was officially launched, prospectively collecting data on patients with thrombosis rather than on thrombotic events. This change was deemed strongly necessary in order to allow for a more accurate collection of follow-up data and to conform to the main international and national registries (Table 3).

In view of the different ages involved (neonatal and pediatric), and the inclusion of both cerebral and systemic thrombosis, both in the arterial and venous compartments, the RITI scope is broad, and include: i)

to improve the understanding on neonatal and pediatric thrombosis in Italy, their clinical features, diagnosis, management and outcome, including efficacy and safety of treatments used;

The RITI is a non-interventional retrospective and prospective registry, collecting anonymized data on neonatal and pediatric patients (age 0–18 years) who experienced a systemic or cerebral thrombotic event in the arterial or venous compartment, in Italy [in particular, arterial ischemic stroke (AIS), cerebral sinovenous thrombosis (CSVT); systemic venous, arterial and intracardiac thrombosis]. No additional diagnostic or therapeutic procedures are required after inclusion in the RITI besides those relative to the standards of good clinical practice. Internationally agreed definitions are used for the diagnosis of thrombotic events (cerebral or systemic, venous or arterial), and patient treatment occurs according to available international and local guidelines, also likely partly influenced by the treating physician's experience and assessment of a patient's risk of bleeding.

Participation to the RITI is open to all physicians on the Italian territory, on a voluntary basis. Inclusion in the RITI registry is subject to written informed consent by the patient's family; the consent form can be found online (https://www.trombosiinfantili.info/). Enrolling physicians are requested to insert both data on the acute phase of the thrombotic event and follow-up data.

Data is directly entered into the RITI platform by the treating physicians, after physician's registration in the RITI (https://www.trombosiinfantili.info/) and identity verification. Data collection system is based on two separate web-based platforms to store personal and clinical data separately, in compliance with the General Data Protection Regulation. Site personnel access a secure web-based platform used for patients’ registration and pseudonymization. Access is protected by a personal username and password.

The patient's personal data are entered into the system and a unique alphanumeric code is generated for each patient. The alphanumeric code serves as the subject's identifier on the web-based platform used for the collection of clinical data.

Study data are collected and managed using REDCap, (Research Electronic Data Capture) (34, 35) a tool hosted at the Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, a secure web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture, (2) audit trails for tracking data manipulation and export procedures, (3) automated export procedures for seamless data downloads to common statistical packages, and (4) procedures for data integration and interoperability with external sources.

This section comprises standardized questions for all patients, regardless of the type of thrombotic event and the age at onset.

This is the core section of the registry, where the most important and detailed data are collected. Due to the diversity of features between different types of thrombosis events (neonatal/pediatric, cerebral/systemic, arterial/venous), this section contains thrombosis type-specific questions that are not applicable or relevant in other types of thrombosis. Below we provide a general overview of the data collected.

At present, 48 Italian primary, secondary and tertiary pediatric and intensive care units have joined the RITI with 85 medical doctors from 16 out of 20 Italian regions being actively involved in data collection (Figure 2), and a total of 160 medical doctors registered in the RITI (see Appendix). These latter medical doctors are mostly afferent to pediatric units (69%), followed by neonatal units (21%), and other departments (10%); subspecialties include pediatrics (43%), child neuropsychiatry (25%), neonatology (21%), internal medicine (5%), neurology (3%), hematology (2%), emergency medicine (1%).

Data presented below are subject to heterogenous availability, therefore denominators may vary. Since 2007, 1,001 neonatal and pediatric patients affected by thrombosis have been retrospectively and prospectively identified (thrombotic events occurred between 1996 and 2022): 579/1,001 (57.8%) were male and the remaining 422/1,001 (42.2%) were female; age at first thrombotic event was median 0.9 years (interquartile range 0.02–6.6 years) (data on age at thrombotic event available in 960/1,001 patients). Data on age at onset and thrombosis type were simultaneously available in 909/1,001 patients: 225/909 (24.8%) had neonatal cerebral thrombosis, 79/909 (8.7%) had neonatal systemic thrombosis, 377/909 (41.5%) had pediatric cerebral thrombosis and 228/909 (25.1%) had pediatric systemic thrombosis. Data on treatment were available in 910/1,001 of the total population: 647/910 of these received antithrombotic treatment (71.1%). Follow-up data were available in 480/1,001 patients: in these, length of follow-up was median 16 months (interquartile range 6–37.8 months) (≥12 months in 290/480). Outcome data were available in 840/1,001 patients, and death was reported in 20/840 (2.4%) of these. Thrombosis recurrence was reported in 61/1,001 patients (6.1%). Stratification of thrombotic events is displayed in Figure 3.

Publications on RITI data so far have covered the areas of pediatric cerebral thrombosis (25), neonatal systemic thrombosis (36), pediatric venous thromboembolism (37), and pediatric systemic catheter-related venous thromboembolism (24). The main data derived from these publications are provided in Table 4.

The RITI working group is also involved in an educational activity with the final scope of improving the knowledge on neonatal and pediatric thrombosis in Italy, and supporting enrolment of patients in the registry.

In particular, the RITI steering group organizes monthly online educational meetings, open to all RITI collaborators, to ensure constant update on thrombotic diseases, discuss clinical cases, and to monitor newly enrolled cases in the RITI. Members of the RITI working group throughout Italy are encouraged to take an active role in these meetings, by taking turns in giving the presentations.

As previously mentioned, a radical change in the registry structure initially created in 2007 was undertaken in 2017, to transition from enrolment of thrombotic events to enrolment of patients with thrombotic events. This was felt strongly necessary in order to allow for a more accurate collection of follow-up data and to conform to the main international and national registries (Table 3). The change involved an enormous effort from the whole team, due to the necessity of creating a new informatic platform and manual data reinsertion in the new platform, therefore it represented a tremendous halt in the progression of patient enrolment and in the scientific production. Although, it was also felt as an opportunity for improvement, and the chance was taken to carry out a thorough critical revision of the registry structure and questions in order to update it, improve it and ameliorate its user-friendliness. With new literature evidence becoming available, modified disease classifications put forward and adopted, new diagnostic techniques and treatments used, it is in the possible natural history of certain registry features to become obsolete. While a periodic registry update to accommodate for these changes may be somewhat necessary and relatively feasible for prospectively enrolled patients, this is hardly possible for patients already enrolled.

Among the main current challenges related to the RITI registry is promoting patient enrolment among a wider pool of Italian physicians, with the aim for the RITI to be representative of the whole Italian territory rather than the expression of a few larger centers only. Indeed, while the current number of involved physicians and Italian centers and regions is considerable, in several cases only a few patients have been enrolled, less than expected for the single centers, even after taking into account the likely different incidence of thrombotic events between smaller and larger centers, and the centralization of more severe patients to centers with higher expertise. Multiple factors likely contribute to this, including the possible heterogeneous vocation for research among different centers, and most importantly the lack of resources dedicated to research and the time-consuming nature of data insertion in the registry platform. Regarding this latter point, it should be noticed that the RITI platform is characterized by a high level of detail, making it a valid source of accurate and precise information but also making patient enrolment a lengthy process (i.e., about 40–60 min per patient), which cannot easily be afforded in resource-constrained environments.

Despite the large amount of data collected in the RITI, only an extremely limited set of information is mandatory for the enrolment of a specific patient, in order to maximize patient inclusion even in the cases when not all data are available. This inevitably results in incomplete data availability for different subsets of information. Data may be missing due to permanent unavailability (i.e., information not collected or not retrievable at the time of the clinical interview, or in case a certain investigation was not carried out, or was performed at a different center and the result could not be retrieved), or temporary unavailability (i.e., outstanding test results at the time of patient enrolment, or follow-up information).

A subset of RITI data particularly prone to incompleteness is that of follow-up. Indeed, enrolment of a patient in the RITI ideally requires a multi-step commitment by the enrolling physician extending beyond the acute phase, that is to update the follow-up data over time. This is a critical step to provide long-term follow-up information on outcome and thrombosis recurrence, which is often lacking in the literature. Although, this also represents a time-consuming activity often going neglected and is a strong limitation in the RITI.

Data inconsistency between different data fields is also possible, due to errors filling in the registry fields, or potentially inaccurate diagnosis.

Creation and maintenance of a registry are expensive, mostly due to the costs of the informatic platform and website. As regards the RITI registry, funds derived from non-profit organization dedicated to thrombosis (ALT, Associazione per la Lotta alla Trombosi e alle malattie cerebrovascolari: https://www.trombosi.org/, and GIRTI, Gruppo Italiano per il Registro della Trombosi Infantile, https://www.girti.it/) and research resources made it possible, beside the voluntary work of several clinical and non-clinical researchers.

Due to the heterogenous patient enrolment on the Italian territory and the voluntary nature of participation to the registry, differently to other models such as the Swiss Neuro-Paediatric Stroke Registry (27) (Table 3), data derived from the RITI registry cannot be used for epidemiological information. Besides, hospital discharge codes do not seem to be completely adequate to retrieve patients with thrombosis in our experience (although this may not apply to other countries).

Moreover, RITI data is subject to selection bias: many of the centers involved are tertiary care hospitals caring for very specific subsets of patients, such as children with congenital heart disease who can be more easily prone to develop incident and relapsing thrombotic events. Furthermore, most of the patients included in the RITI are children who experienced cerebral thrombosis, due to the relatively high participation of pediatric neurologists to the registry.

Therefore, the retrospective observational nature of the registry and the limitations described above, among others, should be kept in mind when handling data derived from the registry, and its results should be interpreted with caution.

Overall, and despite these limitations and challenges, the RITI registry represents a model for multicenter collaboration on a nation-wide scale and the study of rare disorders. The registry may also serve as a tool to support the growth of individual centers through a collaborative discussion on case management, pursuing the final aim of improving the clinical care and outcome of neonatal and pediatric patients with thrombosis through the creation of a network of dedicated professionals and increasing knowledge and awareness on this disorder.

The RITI is currently one of the largest national registries of pediatric thrombosis in Europe, and includes the multidisciplinary expertise of its contributors among its main strengths. Aiming for a growing participation both in patient enrolment and data analysis, increasing scientific production and reaching greater information completeness and quality and are among the main short-term RITI goals. Potential future implementations, such as those to reflect evolving literature definitions and evidence, and to include original patient data for central review, such as radiology imaging, would be welcome future ambitious goals of the registry.