Impact of Haplotypes on the Frequency of Morbid Complications in Homozygous SSFA2 Sickle Cell Disease in Cote D’ivoire

  

    
Evolving Complications
    
Phenotype
    
P-value
    
Total N(%)
  
  

    
Benign N(%)
    
Intermediate N(%)
    
Severe N(%)
  
  

    
Infectious
    
42(20.8)
    
76(37.6)
    
84(41.58)
    
P=0.005
    
202(58.72)
  
  

    
Ischemic
    
3(20%)
    
6(40)
    
6(40)
    
15(4.36)
  
  

    
Anemic
    
23(18.1%)
    
51(40.50)
    
53(41.73)
    
127(36.92)
  
  

    
Total
    
68(19.76)
    
133(38.66)
    
143(41.56)
    
344(100)
  

Table 4: Laboratory values at hospital admission.

The average age of patients with sickle cell disease is increasing with the improvement of management. In our study, it was 11 years, with extremes ranging from 6 months to 42 years, with nearly 37% of patients over 15 years old (Table 1). From a relatively low average of around 11 years in the 1980s [6], then 14.5 (2 to 38 years) between 1990 and 2000 [7]; it is nowadays around 21 years (06 months and 62) [8]. Nevertheless, there is a variability in the average age due to the heterogeneity of the different series in relation to the selection criteria.

The proportion of hemoglobin S ranging from 75 to 98% with a mean of 86% was inversely proportional to the level of hemoglobin F, which ranged from 2 to 15% with a mean of 9.5%. In contrast to hemoglobin S, hemoglobin F does not bind 2-3 DPG, hence its high affinity for O₂, which gives it the property of inhibiting hemoglobin polymerization and therefore sickling of SS red blood cells. The proportion of hemoglobin F in the red blood cell determines the haplotypes of the SSFA2 phenotype [3] in addition to the MCHC, hematocrit, blood viscosity, mechanical properties and surface/ volume ratio of SS-RBC.

Haplotype was said to be severe if HbF <5%; intermediate haplotype if HbF >10% and <5% and benign haplotype if HbF >10%. It has been shown that a level of hemoglobin F >10% prevents the occurrence of chronic organic complications [2]. In addition, according to several authors, the percentage of hemoglobin F is a modulating factor in the clinical expressiveness of sickle cell disease [9]. In our study, 17% of the patients had a benign haplotype, 37% an intermediate haplotype, and 45% a severe haplotype (Table 2).

Most authors estimate the annual number of attacks to be between 1 and 5 [4,9], thus corroborating the results of our series (Table 3), but the haplotypes did not have a statistically significant influence on the number of annual vaso occlusive attacks (P=0.63). Several authors including Bailet [10] state that it is established that the hemoglobin F level modulates the severity and not the number of sickle cell crises. This mechanism is explained by the fact that fetal hemoglobin interrupts the growth of the hemoglobin F polymer, thus blocking the gelification and sickling phenomenon which are responsible for the vaso occlusive crisis of sickle cell disease.

Our result was in contradiction (Table 3) with those of the literature and Akinsheye [11], who showed a statistically significant correlation between the level of hemoglobin F and the number of annual hospitalizations. In the same study [11], on the level of Hb F and the clinical severity of the disease in sickle cell patients, a correlation was found between the level of Hb F and the number of transfusions. This difference could be explained by the fact that our sample included only patients with complications. Furthermore, 35% of the patients had a hemoglobin level below 6 grams per deciliter and there was no statistically significant relationship between the hemoglobin level and the haplotype. Except for intolerance, patients were systematically transfused only below 6g/dl

Concerning the different evolving complications, the analysis of our results showed that there was a statistically significant relationship between the haplotypes and the occurrence of complications in general and infectious complications in particular (p=0.005). This was partly explained by the high endemicity of plasmodial infection in our region. Even if the protection against severe forms of malaria is known in sickle cell disease, the malaria attack through fever and rheological disturbances created by the parasite is at the origin of hemolytic crises which can be severe. Most authors have noted a predominance of pulmonary and bone complications [6,13,14]. This susceptibility to infection in sickle cell patients is explained by functional asplenia and the reduced opsonizing power of the serum towards encapsulated germs. It appears from this analysis that patients with a severe haplotype have more complications than others. Our result is in agreement with that of Kueviakoe [12] who observed in his study on the influence of the hemoglobin F level on the progressive profile of sickle cell disease that the complications are less when the Hb S level is high. However, it has also been shown that a hemoglobin F level >10% prevents the occurrence of chronic organic complications [15]. Indeed, previous studies had already described the protective effect of Hb F against ischemic complications such as osteonecrosis [16], retinopathy [17], and leg ulcers [18]. Similarly, the effect of the β globin gene haplotype has been studied, finding an increasing severity of the following haplotypes: Senegal, Arab-Indian, Benin and Bantu. In the latter case, the baseline HbF level is lower, which would explain more organ damage [19].

Conclusion

The prospective transversal study, which took place in the clinical hematology department of the University Hospital of Yopougon on 150 patients had the general objective of evaluating the impact of haplotypes on the frequency of morbid complications in homozygous sickle cell disease (SSFA2).

Analysis of the results showed no statistically significant relationship between the haplotypes and the number of annual infectious episodes; the number of annual vaso-occlusive crises; the number of annual hospitalizations; and the number of transfusions, hemoglobin levels and white blood cell counts. (p=0.05). However, there was a statistically significant relationship between the haplotypes and the occurrence of complications in general and infectious complications in particular.

The clinical expression of the SSFA2 homozygous form and the occurrence of complications is closely related to the haplotype.

Limitation

The main limits of this study were related to its retrospective nature.

Declarations

Consent to participate: The informed consent obtained from study participants was written.

Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors.

Data availability: The data sets used and/or analyzed during the current study are available from the corresponding author on request.

Authors’ contributions: Silue and Koffi collected data from files of patients. K-KG: Designed the study. S-D: A wrote the manuscript. KKG: Supervised this work. All authors reviewed the final manuscript and agreed for submission.

References

1. Cabanne R, Bonhomme J, Sendrail A. La Drépanocytose, problème de santé publique. Ann Univ ABJ Série B. 1970; 4: 141-147.
2. Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood. 1984; 63: 921-926.
3. Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991; 325: 11-16.
4. Sekongo YM. Prévalence des complications et facteurs de risque dans les drépanocytoses majeures. Thèse Médc Abidjan, UFR Sc Med. 2002; 3051.
5. Kueviakoe MD, Padaro E, Magnang H, Mawussi K, Womey KMC, Layibo Y, et al. Complications Chroniques de la Drépanocytose dans une Population de 893 Patients, Adultes Suivis au CHU Campus de Lomé. European Scientific Journal. 2019; 15: 12.
6. Cabannes R, Sangare A, Kple-faget P, Bassimbie J. Prise en charge de la drépanocytose: Expérience ivoirienne. Ann Univ Abidjan Série B (Méd.) Tome. 2021; XXI: 176-185.
7. Tolo A, Touré A, N’dhatz , Nanho D C, Kouakou B, Sanogo I. et al. Profil évolutif de la drépanocytose homozygote suivie: expérience du service d’hématologie clinique du CHU de Yopougon. Med Afr Noire. 2006; 53: 5-10.
8. Konate BI, Sangare A. Profil hématologique de la drépanocytose homozygote en Côte d’Ivoire expérience du service d hématologie clinique du chu de Yopougon. Thèse Méd. Abidjan, UFR Sc. Med. 2006; 4305.
9. Kouehion P. Influence de l’hémoglobine F dans la drépanocytose Homozygote Thèse Méd. Abidjan. 1994: N°1543.
10. Bailey K, Morris JS, Thomas P, Serjeant GR. Fetal haemoglobin and early manifestations of homozygous sickle cell disease. Arch Dis Child. 1992; 67: 517-520.
11. Akinsheye I, Alsultan A, Solovieff N, Nadia Solovieff, Ngo D, Baldwin TC, et al. Fetal hemoglobin in sickle cell anemia. Blood. 2011; 118: 19-27.
12. Kueviakoe N’zouonta V, Agbetiafa K, Padaro E, VovorA, SegbenaA Y. Influence du taux d’hémoglobine F sur le profil évolutif de la drépanocytose homozygote au Togo. J. Rech. Sci. Univ. Lom (Togo). 2010; 12: 243-248.
13. Elira-dokekias A. Etude analytique des facteurs d’aggravation de la maladie drépanocytaire au Congo Pub. Méd. Afr. 1994; 131: 12-16.
14. Pegelow CH, Colangelo L, Steinberg M, Wright EC, Smith J, Phillips G. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med. 1997; 102: 171-177.
15. Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood. 1984; 63: 921-926.
16. Hawker H, Neilson H, Hayes RJ, Serjeant GR. Haematological factors associated with avascular necrosis of the femoral head in homozygous sickle cell disease. Br J Haematol. 1982; 50: 29-34.
17. Fox PD, Dunn DT, Morris JS, Serjeant GR. Risk factors for proliferative sickle retinopathy. Br J Ophtalmol. 1990; 74: 172-176.
18. Koshy M, Entsuah R, Koranda A, Kraus AP, Johnson R, Bellvue R, et al. Leg ulcers in patients with sickle cell disease. Blood. 1989; 74: 1403-1408.
19. Nagel RL, Rao SK, Dunda-belkhodja O, Connolly MM, Fabry ME, Georgesand A, et al. The hematologic characteristics of sickle cell anemia bearing the Bantu haplotype: the relationship between Gγ and hemoglobine F level. Blood. 1987; 69: 1026-1030.