{'fraction_non_alphanumeric': 0.022480451781059948, 'fraction_numerical': 0.009339704604691572, 'mean_word_length': 4.999022801302932, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Prophylaxis and hemophilia care in LATAM: Baring it all—Highlights from the CLAHT 2021 symposium

Abstract A large group of countries constitute Latin American (LATAM) countries, where hemophilia care is as varied as the landscape of this region. To better understand the care provided to persons with bleeding disorders, especially hemophilia, a symposium was organized as part of the CLAHT Congress 2021 in Colombia to highlight the issues of hemophilia care and challenges faced by persons with hemophilia in four LATAM countries, Colombia, Peru, Argentina, and Mexico. A summary of the symposium is provided. Four clinicians highlighted the issues in their own country, the status, and the path forward to bring the standard of care to the international level in each of these countries. The geography of the country, the health infrastructure, and the resources available are obstacles in these countries to provide state‐of‐the‐art care to the bleeding disorder community. However, depending on the country, its infrastructure and the resources available, progress is being made to upend the care provided. Indeed, the care of persons with hemophilia has been greatly improved, including personalized prophylaxis. The information summarized here first emphasizes how the geography of a country and the different healthcare infrastructures play a major role in how care is offered. It also provides a path for other countries to evaluate these issues in their own realities. In parallel, these data provide hope to many developing countries; despite obstacles, strides can be made in the care of the bleeding disorder community.

virtual Congress in Colombia with the purpose of looking at the current state for prophylaxis and hemophilia care in these countries.
Given the time available for the symposium, four countries provided an overview from the treater's perspective. This paper summarizes highlights from this symposium, which showcased the current state of care in these four countries. The symposium was chaired by Prof. Giovanni DiMinno from Italy, while the speakers included hemophilia treaters from Colombia, Peru, Argentina, and Mexico.

SYMPOSIUM SUMMARY
The stage was set by the chair, highlighting the availability and improve- where the employer covers 30% and the employee 70% of the cost of healthcare services. Within the public fund, there are also EAPBs; however, these are funded by the Colombian government and provide services to people with low economic resources. There is also a group of people who do not have an EAPB, such as street dwellers. Finally, there are special regimes that include the army and the teachers, who have the advantage of having no access restrictions to special drugs that require approval from a professional board.

Providers
These include special regime providers, service-providing institutions, state social enterprises, and the IPS (Instituciones Prestadores de Salud) or "health provider institutions," which include private clinics, public hospitals, and healthcare centers that provide medical care to all the patients ( Figure 1).

Care for bleeding disorders
Diseases such as hemophilia and VWD are considered orphan diseases and receive special protection from the Colombian government; their healthcare is never denied. However, one of the issues that emerged was the finding that some health-providing institutions tried to obtain financial benefits from patients being falsely reported as hemophiliacs or affected by VWD due to the high reimbursement cost of clotting factors. As a result, the Colombian government ordered a price regulation on these drugs and created a high-cost account to carry out exhaustive surveillance of the number of existing patients with bleeding disorders in the country, who must have a diagnostic confirmation by laboratory tests and be fully verified by said entity.

Patients
Ninety-three percent of patients with hemophilia are cared for by a hematologist. There were 2863 patients with hemophilia A (82%) and B (18%) reported in 2020 ( Figure 2, Table 1

Effect of prophylaxis
Prophylaxis has been associated with a 60% decrease in the risk of inhibitor development compared to on-demand treatment. Personalized prophylaxis in hemophilia depends on several factors, including severity, number of bleeds, presence of inhibitors or arthropathies, adherence to the therapy and treatment costs, as well as selfmanagement capacity. Table 2 shows the demographics and characterization of the treatments provided in 2020, with 56% of PWH receiving some type of prophylaxis. Of these, only 6% developed highresponse inhibitors. Hospitalizations for bleeding decreased from 19% in 2015 to 10% in 2020, and a 9% growth in medical care by the interdisciplinary team was observed, from 39% in 2019 to 48% in 2020.

Prophylaxis recommendations in Colombia
Initiating prophylaxis in hemophilia A and B with plasma-derived products, at least for the first 50 exposure days, to reduce the risk of inhibitor development (from the SIPPET study data) [6]. The choice of the product used should be agreed upon together with the patient and their family after discussion about the benefits and limitations of each product. Continued ongoing education of the patient and family is of key importance. Finally, it is important to understand the difficulties of PWH that limit the use of prophylaxis and to encourage self-infusion.

Limitations in Colombia
There are only a few institutions that are called referral centers where patients can receive integrated care, both outpatient and hospital care. with suspected hemophilia may take 1-2 weeks in low-complexity clinics or hospitals due to a lack of resources. Thus, samples must be sent out to be processed by an external laboratory.

DDAVP and VWD challenges
In Colombia, desmopressin is available for intravenous administration only, and it is easily accessible. It is underutilized due to the difficulty of measuring the antigen levels and the activity of Von Willebrand factor (VWF) and FVIII in laboratories for the evaluation of this drug's effectiveness. Nasal DDAVP is not available in Colombia.

Limitations for the use of DDAVP in VWD
There are challenges for the diagnosis and classification of VWD due to limitations with the laboratories that process the samples. The results may take between 1 and 2 weeks, sometimes due to batching of samples for processing, to save on use of the reagents and reduce the

Conclusions
Colombia has availability and access to factor replacement therapy, and prophylaxis from childhood into adulthood is provided.

Land
The country of Peru has an area of 1,285,220 km 2 with a large territory and a population of 32,971,854 inhabitants, according to the last census. The concentration of the population on the coast is 52.6%; 38% are concentrated in the highlands and 9.4% in the jungle ( Figure 3).
The population is centered mainly in Lima, the capital city, with almost 30% of the overall population; in rural areas and especially in the jungle, the density of the population is very low. The country is divided into 24 regions, and the percentage of health expenses, the GDP (Gross domestic Product), is 3.3%. This is the last data taken in 2018, but it has not changed much in the last few years: it is one of the lowest in the region.

Health system
The health system is a mixed public-private system that generates

Hemophilia treatment centers
There

Laboratory diagnosis
This is also a serious problem since only a few treatment centers perform hemostasis tests routinely, specifically the coagulation profiles. products. Emicizumab has already been included in the registry for 2 years, but no purchase has been made yet. EsSalud has just authorized a special purchase of emicizumab for a patient with inhibitor.

Von Willebrand disease
There is an issue concerning its diagnosis and treatment by the Ministry of Health, since it is not under the national petitioner, while EsSalud has this capacity. Desmopressin is only used as a nasal spray in Peru, and the intravenous form is not available. Therefore, there exists a tremendous challenge in continuing the identification process through the national census. Eighty-five percent of patients had hemophilia A, and 15% had hemophilia B. Regarding the degree of severity, those who had symptoms were those who went to the hospital; 65% were severe patients, and 22% were moderate patients. The mild population who does not present major symptoms are only identified once they attend the hospital for some type of surgery. As many as 53% of patients are over 18 years of age. However, in recent years, we have identified patients earlier; therefore, the number of patients under 18 years old is increasing and is now 47% of the population. Sixty-two percent of the patients came from Lima and Callao, and only 38% were from other provinces. This is because people migrate to Lima and the cities on the coast precisely to receive a diagnosis, and therefore, they access treatment more than anywhere else. That is why we see the population concentrated especially in Lima.

Path forward
Working with the treatment centers in creating a network that will allow to start new lines of action to improve the care of PWH: 1. First, increasing the number of identified patients. This is key, since only 31% of them are presumably identified. A national census has been set up to this end. As a major issue for the state, the Ministry of Health is called to support this enterprise by providing professionals willing to move to the second phase of the project. and emicizumab. We also want to improve access to desmopressin because it is not available for venous use, mainly due to logistical issues. Finally, we also need to consider other treatments based on a cost-benefit analysis.

Conclusions
We have improved during the last few years, but we are still facing big challenges. However, by unifying the professionals who work on this topic, we will further improve the care to our patients, not only for PWH but also, and even more, for those affected by VWD.

Land
Argentina is composed of 23 provinces in a federal district (Figure 4). It is an extremely vast country, measuring more than 3000 km in length and more than 1000 km in width ( Figure 5). It has 45 million inhabitants, 48% men, and the population is mostly living in few areas. Almost

Health care
Access to healthcare is quite complicated. Those who are covered by regular health insurance, which is called union health insurance, represent approximately 30% of national health coverage. Then, there are employees who depend on the provincial states that, depending on the province, cover 30%-50% of the population. Finally, there are those who depend directly on the nation, who are retired or pensioners, and armed forces, who constitute approximately 30% of the population. However, in reality, more than half of the population in Argentina does not have a permanent job, work, or are irregularly employed, and therefore, they do not have health insurance. Thus, having access to healthcare is quite difficult, and it falls onto the shoulders of the provincial states to cover those uninsured.

Hemophilia treatment centers
Currently, there are approximately 41 care centers in Argentina.
Unfortunately, not all of them are treatment centers; most are hospitalbased, which leads to difficulties in many aspects of healthcare management. Fortunately, each province has at least a laboratory center for the assay of clotting factor VIII, a key availability to grant access to both the diagnosis and the possibility of carrying out personalized treatment.

Prophylaxis
Based on the lifestyle and the physical activity of the patient, we have been implementing personalized prophylaxis for several years based on population PK either by the WAPSS-Heme or the myPKFiT platform. The widespread use of prophylaxis began in 2003, and most of our patients were on secondary or tertiary prophylaxis. We already have several patients in primary prophylaxis.

Challenges
We do not have official records, so we base cases on presumptions or partial records. Access to health care in general, especially for hemophiliac patients, is very inadequate. It depends on the centers, the resources they have and the provinces where they are located.
Since most centers are hospital based, the time that health professionals devote to hemophilia cases is not a priority. Indeed, each clinician has to solve a variety of hematological pathologies that are often very pressing and demanding. Thus, in many centers, the time devoted to hemophilia is not adequate.

Path forward
In 2015, the process of joining several treatment centers to form a consolidated union was initiated. This process was achieved in 2020 by the creation of AAHDA, the Argentine Association of Hemophilia Treatment Centres, which allowed us to focus on several goals: create a registry to know exactly what is being done countrywide and to coordinate between centers, since there are many centers that do not have the resources and experience necessary, and others that care for only a few patients. The exchange of experiences and the training that have been implemented through this association of centers have helped to achieve several objectives, one of which was the creation of a biochemist network at the country level that could involve all biochemists from different centers. As a result, in each of the provinces, there is at least one laboratory where clotting factor assays can be carried out.

Von Willebrand disease
According to the WFH report, there are only approximately 400 cases diagnosed in Argentina, which is a substantially low number. This is because there are few laboratories that can assay VWF activity and antigen levels. Additionally, rather than by treatment centers, most patients with potentially confirmed diagnoses of VWD are managed by general hematologists. These patients are neither registered nor they have a treatment plan, especially before interventions, which causes a huge diversity of treatment from one center to another.

DDAVP
Currently, we only have access to the intravenous formulation. This makes the use of this drug difficult for us on an outpatient-care basis, either for Von Willebrand or for mild hemophilia, where the outpatient use of DDAVP would be very beneficial. Although the use of DDAVP is included in the treatment guidelines for both VWD and hemophilia, it is mainly used as hormonal treatment in many social projects or social health insurance, and its administration cost is not fully covered. This implies that, at variance with clitting factor use, the patient must pay for a part of this medication. This further complicates its use. Additionally, because of the lack of ad hoc laboratory expertise, the very important use of the desmopressin response test is difficult to perform.

Conclusions
Argentina is fortunate to have many treatment centers with properly trained professionals spread throughout all of Argentina, in relatively close proximity, despite being a very large country. There is adequate availability of clotting factors for all patients, allowing for appropriate treatment. Availability to prophylaxis is variable according to the different circumstances, such as access to healthcare, but there is availability of prophylaxis to all patients. There are several centers that have routinely used personalized prophylaxis for several years, but unfortunately, a lack of records impairs the details on these patients.

Treatment of severe hemophilia
Most of the pediatric population has been treated with prophylaxis using recombinant and plasma-derived products for a few years. Protocol for Haemophilia Care [8], which standardizes the comprehensive management of patients with hemophilia regardless of the institution that treats them. This protocol includes all products to treat hemophilia A and B, as well as bypass agents and emicizumab. Based on this publication, access to factor concentrates is guaranteed for all patients, and the goal of >3 IU per capita is achieved. This will make it possible to standardize patient care for primary and secondary prophylaxis, as well as guarantee the use of desmopressin (DDAVP) and tranexamic acid.

Conclusions
In Mexico, efforts have been made toward a consolidated purchase system and additional services for the benefit of patients due to the efforts of a committee of advisers in hemophilia. This is a huge effort from the federal government and the clinicians who keep working to ensure that all the established agreements are met. The COVID-19 pandemic has delayed the completion of established agreements. However, the work to fulfil them continues through the Special Program for Haemophilia Patient Care across the country, with the endorsement of health authorities. With such agreements and commitments, it is expected that Mexico will improve patient care in the medium term, with a significant improvement in international indicators as well.

OVERALL CONCLUSIONS
The vastness of the geographies of some of the countries and the available resources hampers progress in the care of persons with bleeding disorders in LATAM countries, as illustrated by this symposium. The information summarized emphasizes how the geography of a country and the different healthcare infrastructures play a major role in how care is offered. It also provides a path for other countries to evaluate these issues in their own realities. In parallel, these data provide hope to many developing countries; despite obstacles, strides can be made in the care of the bleeding disorder community.

ACKNOWLEDGMENTS
The authors wish to thank the translation service ERA-ms for helping in translating the Spanish presentations of the presenters to English, which was then summarized here by the authors. The data for the symposium and this article were taken from the high-cost account 2021, the entity in charge of the surveillance and monitoring of patients with bleeding disorders reported in Colombia by healthcare entities, as well as data from the respective countries data system and national organizations. The figures were provided by the presenting authors of the symposium. The symposium was supported through an educational grant to CLAHT from Kedrion de Colombia SAS (a Kedrion Biopharma Group subsidiary, Barga, Italy).