Clinical and epidemiological profile of hemophilia in Cuba based on the National Registry of Congenital Coagulopathies. First report

doi:10.21203/rs.3.rs-3322449/v1

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Clinical and epidemiological profile of hemophilia in Cuba based on the National Registry of Congenital Coagulopathies. First report

https://doi.org/10.21203/rs.3.rs-3322449/v1

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Aims

The objective of the study was the description of the hemophilia in Cuba and to observe the relationship between clinical parameters and inhibitors.

Methods

Cross-sectional study of the clinical characterization of hemophilia in Cuba based on the National Registry of Congenital Coagulopathies.The main variables obtained were place of residence, type of hemophilia, levels of functional activity, age and age at diagnosis, skin color, family history, degree of response to inhibitors.

Results

The total number of subjects included was 496; statistically significant differences were founded showing a lower age for moderate patients compared to severe and mild patients. Mean difference for severe vs moderate patients 7.54 (95%CI 3.14–11.95), p < 0.0001. The number of subjects with inhibitors was 35 (8.5%). There was no statistical significance between age range and the presence of inhibitors, but differences were observed when age was analyzed as continuous variable p < 0.05 (inverse relation between age and inhibitors). For severity, statistical significance was observed in relation to the presence of inhibitors p < 0.05.

Conclusions

Our study showed a high percentage of subjects diagnosed in the first year of life, mainly severe cases, which implies the use of management tools adapted to the needs of patients from the very beginning, as well as continuous monitoring with treatment alternatives according to individual aspects.

Hemophilia

Diagnostic

Prevalence

Inhibitors

Hemophilia is a bleeding disorder caused by deficiency of coagulation factor VIII (FVIII) for the hemophilia A and factor IX (FIX) for hemophilia B.¹ Patient care should be oriented to prevent and treat bleeding at comprehensive care centers provide the best care for the hemophilic patient.² Treatment should be initiated early to prevent the joint disease and improving quality of life. ³

Study design

Cross-sectional study of the clinical characterization of hemophilia in Cuba based on the National Registry of Congenital Coagulopathies (RNCC).

Patients

All male patients with HA or HB registered in the country up to June 2022 were included. The following age groups were created: 1–5 years; 6–12; 13–19; 20–35; 36–50; 51–65; >66 years. The diagnostic criterion for the disease was established by a decrease in the procoagulant activity of FVIII or FIX below 40% measured through the one-state coagulation technique recommended by the World Federation of Haemophilia (WFH). ⁴

Data collection

The data were obtained from the RNCC, that registers all the patients attended in the different hematology services of the country. The first version of this registry began in 2006 and each year new variables and patients have been added. Since 2018 it presents a web interface. During the year 2020, it was possible to incorporate it into the national telematic network of medicine in Cuba (Infomed.sld.cu). Both aspects have facilitated better access from the provincial hematology services and more agile incorporation of cases. Both aspects have facilitated better access from provincial treatment centers and more agile incorporation of cases. With all the information obtained, a data extraction form was created for each patient, elaborated with the factors determined for this project. Currently it cannot be accessed outside the national domain.

Variables

Some sociodemographic and clinical variables were included: Place of residence according to municipality and region, type of hemophilia, A or B, severity by levels of functional factor activity, severe < 1%, moderate 1–5% and mild between > 5 and < 40%. Biological age (in years) and by age group; age at diagnosis by age group in 1 year, 1 to 5, 6 to 15 and older than 15 years; skin color, classified into mixed race, white, black, and dichotomized into white vs non-white, family history and degree of response to inhibitors according to high or low responder, as well as transient or not present.

Statistical Analysis

Frequency distributions were constructed using double-entry tables. For qualitative variables, frequencies and percentages were obtained, while for quantitative variables the data were obtained in means (SD) and medians according to whether the distribution of the data was considered normal or not based on an analysis of the Kolmogorov-Smirnov test.

Different comparisons were established and, the means of the ages were related through the T-student test for independent samples, as well as the one-factor ANOVA test for the analysis of the different levels of severity of hemophilia. In cases where the result showed statistical significance, paired comparisons between the three classification groups and the disease were performed through a post hoc Scheffé analysis.

Qualitative variables were analyzed according to Pearson's X2 estimator and Yate's correction and Fisher's exact with normal distribution.

The analyses were performed with IBM SPSS V24 software at two tails and an alpha value of 0.05.

Demographics and patient characteristics

The 496 subjects included came from the 15 provinces of the country and the municipality of Isla de la Juventud. Havana had the highest percentage of subjects, with 22% of the total sample, followed by Holguin with 9.5%. By type of hemophilia, the provinces of Mayabeque and Matanzas had more unbalanced ratios than in the rest of the municipalities with proportions of 4.1 and 3.5% respectively for hemophilia type B compared to type A.

The ratio of HA vs HB was 4.76:1 with a predominance of subjects with severe disease, followed by moderate and finally mild disease. Inhibitors were identified in 8.5% of cases and family history was obtained in 54.4% of all subjects included. There was also a predominance of white and mestizo skin color. In both types of hemophilia, the severe form of the disease predominated, while the cases considered as mild were similar in both HA and HB with 20% of the subjects studied, without finding an association between the type of hemophilia and the severity, p > 0.05. Complete characterization according relevant clinical characteristics of the disease in the study population, in Table1.

Table 1

Clinical characteristics of the disease in the study population.
Relevant clinical characteristics in studied patients.
Variable	N				Percentage
Hemophilia type
HA HB	410 86				82.7 17.3
Classification according to the deficient factor
Severe Moderate Mild	217 182 97				43.8 36.7 19.6
Inhibitors
No Yes	461 35				92.9 7.1
Family history
Yes	270				54.4
No	226				45.6
Skin color
White	303				61.1
Mestizo	138				27.8
Black	55				11.1
Distribution of patients according to type of hemophilia and deficiency of factor VIII and IX
Deficiency levels	A		B			Total
Deficiency levels	N	%	N	%		N	%
Severe	173	42.2	44	51.1		217	43.8
Moderate	157	38.3	25	29.1		182	36.7
Mild	80	19.5	17	19.8		97	19.5
Total	410	82.7	86	17.3		496	100
X² = 2.95, p = 0.228
Distribution of patients by age group and type of hemophilia.
Age groups (years)	A		B			Total
Age groups (years)	N	%	N	%		N	%
1–5	18	4.4	8	9.3		26	5.2
6–12	31	7.6	9	10.5		40	8.1
13–19	44	10.7	7	8.1		51	10.3
Pediatric Subtotal	93	22.7	24	27.9		117	23.6
20–35	135	32.9	20	23.3		155	31.3
36–50	93	22.7	21	24.4		114	23
51–65	69	16.8	16	18.6		85	17.1
≥ 66	20	4.9	5	5.8		25	5
Subtotal adults	317	77.3	62	72.1		379	76.4
Total	410	100	86	100		496	100
X² = 6.95, p = 0.325

The minimum age was 1 year, and the maximum age was 85 years. However, the mean age was not statistically significant when comparing by type of hemophilia with 35.90 years for HB and 34.61 years for HA, p > 0.05. Adult patients were 76.4% of the sample studied considering both types of hemophilia and, of these adults, 54.3% were younger than 50 years. Five percent of the subjects included were over 66 years of age. Mean age in severe patients 38.13 (95%CI 35.85–40.42); moderate 30.59 (95%CI 27.85–33.33) and mild 34.54 (95%CI 30.95–38.12) p < 0.001. Likewise, pairwise comparisons showed statistically significant differences between severe and moderate patients: Mean difference for severe vs moderate patients 7.54 (95%CI 3.14–11.95), p < 0.0001 Table 2.

Table 2

Current mean age according to the levels of activity of the deficient factor
Mean current age of patients according to disease classification
Classification	N	Mean age	SD	SE	CI 95%
Classification	N	Mean age	SD	SE	Lower bound	Upper bound
Severe	217	38.13	17.073	1.159	35.85	40.42
Moderate	182	30.59	18.737	1.389	27.85	33.33
Mild	97	34.54	17.807	1.808	30.95	38.12
Total	496	34.66	18.123	0.814	33.06	36.26
F = 8.85, p < 0.0001
Multiple comparisons of the means of the ages according to classification by levels of the deficient factor (Scheffé test)
I	(J)	Mean difference	SE	P	CI 95%
I	(J)	Mean difference	SE	P	Lower bound	Upper bound
Severe	Moderate	7.546* 3.598	1.793 2.179	< 0.0001 0.257	3.14 -1.75	11.95 8.95
Severe	Mild	7.546* 3.598	1.793 2.179	< 0.0001 0.257	3.14 -1.75	11.95 8.95
Moderate	Severe	-7.546* -3.948	1.793 2.243	< 00001 0.213	-11.95 -9.46	-3.14 1.56
Moderate	Mild	-7.546* -3.948	1.793 2.243	< 00001 0.213	-11.95 -9.46	-3.14 1.56
Mild	Severe	-3.598 3.948	2.179 2.243	0.257 0.213	-8.95 -1.56	1.75 9.46
Mild	Moderate	-3.598 3.948	2.179 2.243	0.257 0.213	-8.95 -1.56	1.75 9.46
*Statistically significant at the 0.05 level
Legend: SD: Standard deviation, SE: Standard error, CI: Confidence interval, P = p-value

When analyzing the distribution of patients by regions of residence, it was observed that in HA the proportion by levels of impairment was very homogeneous in Havana and West, while it was unequal in the regions of Center and East, with severe and moderate patients predominating, respectively.

In general, more severe patients were observed in HB and the proportions were not very homogeneous according to levels of the deficient factor when compared to patients with HA.

Age of initial diagnosis

For the initial diagnosis of the disease, 52.8% were diagnosed in the first year of life, with a decrease in the number of diagnoses with increasing age: 37.7% from 1 to 5 years and 8.1% from 6 to 15 years. According to the type of hemophilia and age at diagnosis, no statistical significance was observed, although the percentage of patients with HB (61.6%) diagnosed before one year of age was considerably higher than those diagnosed between 1 to 5 years (32.5) and 6 to 15 years (4.7%). In relation to the severity of the disease, statistical significance was obtained according to age at diagnosis p < 0.0001, with earlier diagnosis in patients with severe disease. Thus, 68.7% of patients under 1 year of age were classified as severe, 50.5% as moderate and 52.8% as mild compared to the rest of the age groups.

Inhibitors

The occurrence of inhibitors was identified only in patients with HA, so the analyses were performed based on this subgroup. The number of subjects were predominantly in the age range of 20 to 35 years (53.8%), followed by the range between 13 and 19 years (26.9%). There was no statistical significance between age range and the presence of inhibitors, but differences were observed when age was analyzed as continuous variable p < 0.05 (inverse relation between age and inhibitors). For severity, statistical significance was observed in relation to the presence of inhibitors p < 0.05. Thus, patients classified as moderate had the highest percentage within the subjects with presence of inhibitors (60%) compared to severe (34.3%) and mild (5.7%) patients. Table 3. No differences were found in relation to inhibitors for skin color, p > 0.05.On the other hand, multivariate analysis for the dependent variable inhibitors showed how disease intensity remained a statistically significant variable increasing risk of inhibitors among subjects with moderate disease compared to mild disease.

Table 3

Presence of inhibitors according to disease classification
Classification	Inhibitors				Total
	Yes		No		Total
	N	%	N	%	N	%
Severe	12	34.3	161	42.2	173	42.2
Moderate	21	60.0	136	36.3	157	38.3
Mild	2	5.7	78	20.8	80	19.5
Total	35	100,0	375	100.0	410	100.0
X² = 9.010, p = 0.011

Hemophilia affect about 400,000 people worldwide,⁵ and comprehensive care centers offer the best approach to the disease by promoting psychosocial health and quality of life.⁶ It is a complex disorder in terms of both diagnosis and treatment that requires, in addition to the prevention of bleeding; the management of complications such as joint and muscle damage, development of inhibitors and possible viral infections through transmission. ⁷

There were more subjects with severe disease in HB than in HA, which does not coincide with other studies, where similar figures are observed in HA and HB or predominance of persons with severe hemophilia for HA. ^8,9 Subjects with mild disease in each type of hemophilia in this study were similars.

A review of the 2009 study of hemophilia in Spain ⁹ reported many persons with mild disease (51.3%), as did other countries that for many years have achieved optimization of hemophilia registries.¹⁰ On the other hand, in registries such as that of South Korea, 2/3 of the cases had severe disease, which reflects that they still have many undiagnosed persons with mild and moderate hemophilia.¹¹ The information obtained in Cuba shows that a greater number of PWH with moderate and mild symptomatology could be registered, which was contributed by the optimization in the control of people living with this condition in the country. ¹² The work carried out by the Comprehensive National Program for Patients with Hemophilia (PNAIH) improved hemophilia care by bringing specialized health services closer to this group of people. The registry of cases analyzed in this study included 2.8 times more patients with moderate and mild phenotype than the previous study ¹³. It is still suspected that there are individuals with mild symptomatology who are not diagnosed in a timely manner, probably because they present infrequent clinical manifestations that may go unnoticed and therefore some of them are still not adequately identified in the national registry of this condition.

Another reason that could influence the results is due to the laboratory method used to evaluate the coagulant activity of FVIII and FIX in the country. It has been demonstrated that two-stage coagulation and chromogenic methods are more accurate, which have been incorporated for some time in several developed countries.¹⁴ In the hemostasis laboratory of the IHI, the one-stage coagulometric study is performed, which is considered valid and sensitive, but people with coagulant FVIII values between 30 and 40% may be diagnosed with parameters within normality when in fact they could be classified as mild. ¹⁰

In Cuba, the mean age of the persons studied was high with a wide range and the life expectancy was 77.70 years in the period of 2018–2020; in this study there are subjects living with hemophilia who are more than 80 years old. We were able to identify an increase in this variable by 2.9 years of life when compared to our previous study, ¹³ probably related to the advances of the implementation of a more organized comprehensive care program. These results are similar some developed countries that have been attributed to the use of effective therapeutics, early prophylaxis, and comprehensive hemophilia care ¹⁵ aspects that are not part of the routine work in hemophilia in Cuba due to budgetary point. Therefore, it is worth noting that the fact of improving the organization, the training of professionals, family members and PWH, strengthening the network and the Cuban Health System has allowed these people to have a good life expectancy.

When comparing the mean age of the patients of the current research with the observed in studies of Indiana, USA (29.7 years) and Spain (26 years). ^16,8 It is possible to identify differences and ages lower than those reported in Cuba, these results are probably related to the high mortality of PWH infected with HIV since the 1980s, a phenomenon that occurred largely in developed countries that had access to clotting factor concentrates, at that time, not subjected to viral inactivation processes, coming from infected donors. ^17,18 This adverse reason for those countries and favorable for Cuba, is one of the possible causes of the difference in the mean ages. Cuba did not receive concentrates from other countries; only blood components from Cuban donors were consumed. At that time, the prevalence of HIV infection in Cuba was very low and even lower in blood donors. ¹⁹

Others studies in Arab countries and some Latin-Americans regions show even lower mean age. ^{20, 21}

In our study, PWH-B presented older mean age than those with HA, results that coincide with others reports. ⁸ The finding in HB could agree with the statement that HB is a less severe disease phenotypically than HA. ¹ However, one aspect to highlight is that in our work more severe patients were observed in HB than in HA.

More than half of subjects were diagnosed in the first year of life, which reflects that in this disease the clinical manifestations are evident months after birth. Diagnoses are made in the first months of life, especially in infants with severe hemophilia, where early diagnosis is mandatory due to the characteristics of the disease, to achieve favorable survival.²²

The Centers for Disease Control and Prevention (CDC) implemented a surveillance system for early diagnosis reporting identification of the disease in the first days of life. ^{23, 24} In the Cuban national context, although there is a National Hemophilia and Genetic Counselling Networks with advances in the integration of services, full coverage in genetic counseling of female carriers of the disease is still not achieved to identify people in the first two months. The carrier´s attendance to planned consultations and treatment centers is still insufficient. In general, they are identified late in pregnancy or when the disease is suspected in a newborn. In those cases, in which hematologists had access to this information prior to pregnancy or delivery, the diagnosis could be made early (unpublished personal communication). This is an aspect to improve in the coming years.

Infants whose hemophilia was confirmed in the first year of life had a family history of the disease predominated. However, there were still a considerable number of cases that had family members with the condition and were diagnosed after the age of one year and even in adolescence. These individuals did not have the diagnosis confirmed early and waited for some hemorrhagic manifestation to appear, a fact that has also been reported in other studies.²⁵ The phenotypic heterogeneity of the entity and the inadequate perception of the severity of the disease by family members and health professionals could be conditioning factors in the delay of hemophilia diagnosis in our country.

Inhibitors constitute the main secondary complication to treatment in PWH. ²⁶ In our study the results show values below 10% and if high responders are considered, which are the patients who demand differentiated therapy, it would be close to 5%. Spanish reports showed similar results, ⁸ but differ from what was reported by a study that recruited PWH from Indian hemophilia Centers that found that 19.5% of patients presented inhibitors, of which 35.6% were high responders.²⁷ In this report, moderate disease was associated with inhibitors, followed by severe hemophilia. We observed that these moderate PWH mainly had factor levels between 1–2%.

Severity is one of the factors related with the incidence of inhibitors being associated with earlier initiation of replacement therapy, but there are studies where it has not been observed in this way.²⁸ In individuals with mild disease, the likelihood of the appearance is maintained throughout life, as they generally do not require as many early factor exposures as those with severe hemophilia. Other risk factors are associated with inhibitors occurrence, like type of mutation and therapeutic regimen. ²⁶

A study including more than 1000 PWH found an incidence of inhibitors between 6.7% at 50 days of exposure and 13.3% at 100 days. ²⁹ Other researches report similar incidences between 3 and 13%. ³⁰ A study in Slovakia estimated the incidence of inhibitor occurrence during three different periods of therapeutic evolution offered to PWH. ³¹ In the first period pdFVIII was used sporadically, 10.3% of patients developed the complication, similar to ours results. After that, the incidence rose when they introduced other treatment protocols. ³¹ Iorio A et al.³² reported 13% incidence of inhibitors associated with pdFVIII (9.8% high responders) and 28% in relation to rFVIII (17.9% high responders).

Over the years, PWH in Cuba have episodically used fresh frozen plasma and cryoprecipitate as replacement therapy for more than three decades. Starting in 2006, they began to receive treatment with pdFVIII, alternating with hemocomponents. Until now there has been only one type of replacement product and this could be the reason for the low number of patients with inhibitors. The data offered by Santagostino E et al.³³ confirm what was found in the Cuban sample by demonstrating the non-association between the presence of inhibitors and the change of replacement product, although this was not a variable explored, it is assumed as a conjecture since there was no increase in PWH over time.

The current research did not show that Cuban people of African descent are more likely to present inhibitors, and no association was found between these variables (Afro-descendant origin - non-white skin color and inhibitors). Other studies have found similar results to those described in this investigation of absence of association between the presence of inhibitors and the Afro-descendant origin of the PWH. ³⁴ No genetic ancestry study was performed, only skin color was considered. It is valid to point out that it has been demonstrated that the self-assessment of skin color can be a valuable approximation and very close to results obtained through specific tests regarding the ethnic group to which one belongs.³⁵

This is the first study that provides an informative health profile from PWH in Cuba. Data show a high percentage of subjects are diagnosed in the first months of life and have a following through the time in the different centers of treatments. It implies the use of management tools adapted to the needs of patients from the very beginning age. The establishment of a national registry in Cuba allowed us to identify the actual situation in all Cuban PWH. These results will be useful for implementing strategies that improve the quality of care of hemophilia in Cuba. In next papers we will deepen in others clinical aspects, like health joint and inhibitors.

Funding sources: Two projects supported this research, Optimisation of the Haemophilia Programm in Cuba and the National Haemophilia Registry, backed by the Institute of Haematology and Immunology (IHI), the World Federation of Haemophilia (WHF) and the NovoNordisk Haemophilia Foundation. Roche-La Hoffmann supported the medical writer and translation.

IRB approval status: Does not apply

Conflicts of Interest: The authors have not competing interests.

Reprint requests:

Dr Dunia de la Caridad Castillo González

19 st, between 8 & 10. Vedado, Havana, Cuba.

[email protected]

Authorship

Dunia de la Caridad Castillo González: Performed the research, designed the research study, data collection, analysed the data and wrote the paper

Roberto Lardoeyt Ferrer: Designed the research study, analysed the data

César Valdés Sojo, Isabel María Osorio Caballero, Martha Beatriz García Caraballoso , Tamara Cedré Hernández, Lidia Clara Suárez Beyries, Haron Fernández Álvarez, Anmisadays Galarraga Zulueta, Belkis Lázara Rodríguez Jorge, Julio Dámaso Fernández Águila, Ariel Raúl Aragón Abrantes, Ana Margarita Palmero Zubiaurre, Gloritza Rodríguez Matos, María Josefa Plá del Toro, Orlando Olivera Morán, Osvaldo Nuñez Morales, Yicenia Díaz Cabrera, Rogelio Pérez Rivero, Yenilet Escalona Vives, Gertrudis Rodríguez Rodríguez, Alina Pando Durand, Nodalis Querol Betancourt, Coralia Cristina Leblanch Fernández, Ángel Miguel Almirall Chávez: Contributed data collection

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Scientific and ethics committee from Institute of Hematology and Immunology, Havana approved the research in June 2018.

Consent for publication: Not applicable.
Availability of data and materials: All the data mentioned in this paper are available in http://rncc.sld.cu, Registro Nacional de Coagulopatías Congénitas (RNCC), this is a cuban national register that is only affordable from the domain sld.cu

Funding: This research was developed as part of an approved research project at the Institute of Hematology and Immunology.

COMPETING INTERESTS

The authors declare that they have no competing interests.

AUTHORS' CONTRIBUTIONS

DCG: Performed the research, designed the research study, contributed essential reagents or tools, analysed the data and wrote the paper

RLF: Analysed the data, designed the research study

CVS, IMOC, MBGC, TCH, APD, LCSB, HFA, AGZ, BLRJ, JDFA, ARAA, AMPZ, GRM, MJPT, OOM, ONM, YDC, RPR, YEV, GRR, NQB, CCLF, AMAC: Contributed essential reagents or tools

ACKNOWLEDGMENTS

To the medical writer Dr. José Luis R. Martin, Ph.D; on behalf of Biopress.

To Dr. Rosa María Lam from Institute of Hematology and Immunology, Havana, for some statistical considerations.

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Clinical and epidemiological profile of hemophilia in Cuba based on the National Registry of Congenital Coagulopathies. First report

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Abstract

Aims

Methods

Results

Conclusions

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INTRODUCTION

METHODS

Study design

Patients

Data collection

Variables

Statistical Analysis

RESULTS

Demographics and patient characteristics

Age of initial diagnosis

Inhibitors

DISCUSSION

Conclusions

Declarations

References

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