A cross-sectional study of the clinical manifestations of Sickles Cell Disease in Ghana, Nigeria and Tanzania and its association with foetal haemoglobin parameters

doi:10.21203/rs.3.rs-5328156/v1

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A cross-sectional study of the clinical manifestations of Sickles Cell Disease in Ghana, Nigeria and Tanzania and its association with foetal haemoglobin parameters

https://doi.org/10.21203/rs.3.rs-5328156/v1

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Background: Prevalence of Sickle Cell Disease (SCD) across African countries ranges between 1–3% and contributes up to 7-16% of under-five mortality. Nigeria, Ghana and Tanzania are among the top ten countries globally, with over 11,000 babies born with SCD annually. In order to bridge the gap in management and cognate research, the SickleInAfrica consortium was established in 2017 to facilitate collaboration among African nations in order to establish regionally relevant healthcare standards for SCD patients. This work utilised the SickleInAfrica platform to study haematological, clinical and genetic profiles of participants in the consortium.

Methods: This was a cross-sectional omni-directional study involving three sites in Ghana, Nigeria and Tanzania.This study enrolled 290 individuals with SCD aged five years and above who were confirmed to have SCD at steady state and were hydroxyurea naïve. Clinical history was obtained using an interviewer administered questionnaire. Haematological parameters were determined by automated haematology analyzer while quantification of HbF and F cells was implemented by high performance liquid chromatography and flow cytometry, respectively. Age adjusted logistic regression was employed to assess the association of HbF with the clinical manifestations.

Results: Participants were predominantly less than 18 years (63%) across the three countries. Most of the participants (across sites) had received blood transfusion in their lifetime. The most reported complication of SCD, requiring management in a hospital setting (in-patient or outpatient) was pain crises, ranging from 66-96% with the highest in Tanzania and lowest in Ghana. Overall, participants from Ghana had higher HbF levels(median = 8.20 with IQR= 4.80, 14.68, n = 68) compared with the level of HbF among participants from Tanzania (median = 4.45 with IQR= 2.33, 7.15, n = 92) and Nigeria (median = 4.30 with IQR= 2.60, 7.20, n = 7.20) and such difference was statistically significant, p < 0.001.

Conclusion: This work highlights important differences and similarities across SCD populations in the three countries. This is important especially in development of interventions for patients with SCD in the light of personalised medicine. A larger dataset is required for further analysis and validation of the findings.

Sickle Cell Disease

foetal haemoglobin

clinical manifestation

F cells

HbF per F cells

It is estimated that annually 515,000 babies are born with sickle cell disease (SCD) in Africa, mainly in the sub-Saharan Africa region, with 50–-90% dying before adulthood¹. Prevalence of SCD across African countries ranges between 1–3%; and contributes up to 7–16% of under-five mortality^2–5. Nigeria, Ghana and Tanzania are among the top ten countries globally, with more than 11,000 babies born with SCD annually in each country.

There is a substantial gap between high-income nations like the USA and Europe compared to those in Africa with respect to standards of care for SCD and cognate research. In order to bridge this gap, SickleInAfrica was established in 2017 to facilitate collaboration among African nations in order to establish regionally relevant healthcare standards for SCD patients^6,7. SickleInAfrica involves seven African countries including Ghana (Kwame Nkrumah University of Science and Technology), Nigeria (University of Abuja), Tanzania (MUHAS), Mali (Centre de Recherche et Lutte contre la Drépanocytose), Uganda (Makerere University), Zimbabwe ((University of Zimbabwe) and Zambia (University Teaching Hospital in Zambia), the SPARCo Clinical Coordinating Center (CCC) based at MUHAS in Tanzania, and Data Coordinating Centre (DCC) based at the University of Cape Town in South Africa. The SickleInAfrica network provides a unique platform to study SCD epidemiology and modifiers of the disease in an African context. The work reported in this manuscript utilised the SickleInAfrica platform in the three countries Ghana, Nigeria and Tanzania to study variations in SCD manifestation and disease modifiers.

The clinical intra and inter individual variation in individuals with SCD is due to both genetic and environmental factors ⁸. Foetal haemoglobin (HbF) which is a product of gamma globin gene is a major disease modifier ^9–11. To-date, several studies have shown that SCD patients with high HbF levels are protected from the severe expression of the disease ^12–15. HbF modifies disease severity of SCD by directly inhibiting polymerization of haemoglobin S (HbS)¹¹. The blood of normal adults contains HbF in small amounts ranging from less than 0.03% up to 0.7% of the total haemoglobin present in the whole hemolysate. These trace amounts are not uniformly distributed among erythrocytes, rather they are restricted to a few erythrocytes termed F cells. Although the percentage of F cells within an individual is stable, there is a wide variation between individuals¹⁶. It has been shown that levels of HbF are determined by the number of F cells produced¹⁶. The percentage of F cells in normal individuals ranges between 0.5 to 7%, while in SCD, the range is broader and levels are higher (up to 60%). Consequently, SCD individuals with an increased number of F cells containing high levels of HbF are more protected from the severity of disease.

The relationship between HbF and clinical manifestation is routinely based on absolute levels of HbF, however, there have been reports of SCD individuals with high HbF levels who experience severe disease¹¹. The hypothesis is that the discrete amount of HbF in red blood cells is important, as RBCs with higher levels of HbF (known as F cells) reduce sickling of the RBC¹⁷. However, assessing absolute quantities of HbF in a red cell may not necessarily reflect its concentration per cell in relation to the volume and amount of haemoglobin per cell¹⁴ (ref). Therefore, previous studies had suggested the need for a more stringent measure of HbF concentration per cell¹¹. The concentration of HbF per cell can be estimated by calculating the HbF concentration, a measure which can be obtained by calculating the ratio of HbF to F cells.

There is a paucity of data on HbF and F cell parameters in the African populations with diverse backgrounds - Ghana, Nigeria and Tanzania. To address this gap, this study assessed the levels of HbF, F cells and HbF/ F cells and their relationship with the SCD clinical manifestations. The findings of this study may be pivotal in explaining the few variations in response to SCD interventions such as hydroxyurea and gene therapies. Such studies provide a more robust platform for assessing HbF parameters across African SCD populations while striving towards development of population-specific (tailored) interventions.

Study design

This was a cross-sectional study involving three sites; 1. Muhimbili University of Health and Allied Sciences (MUHAS), Tanzania 2. University of Nigeria Teaching Hospital Enugu, Nigeria and 3. Komfo Anokye Teaching Hospital, Kumasi, Ghana from July 2023 to January 2023. These sites were selected due to their participation in Phase 1 of SickleInAfrica.

Study participants

This study involved a sample of 290 individuals with SCD aged five years and above who were confirmed to have SCD at steady state and were hydroxyurea naïve.

Measurement of clinical parameters

Information on the frequency of pain crisis, presence of any learning difficulties, presence of chronic complications of the disease, number of units of blood transfused in the past, whether or not the patient had been treated for malaria in the past 30 days and number of admissions in the past 30 days, was determined using a questionnaire completed by the investigators.

Laboratory investigations

All laboratory investigations were conducted at the sites following standardised procedures.

Determination of Haematological parameters

Haemoglobin level (g/dl), red blood cell (RBC) counts (x10^6/µl), mean cell volume (MCV) (fl), mean cell haemoglobin (MCH) (pg), reticulocyte count (%), white blood cell (WBC) count (x10^3/µl) and platelet counts (x10^3/µl) was determined by automated haematology analyzer (Sysmex XT 2000i Kobe, Japan).

Determination of HbF and F cell levels

HPLC machine variant II (Bio Rad, Hercules, CA, USA) was used to confirm the sickle cell phenotypes as well as quantifying haemoglobin subtypes including HbF, following manufacturers guidelines. EDTA blood was washed in PBS and fixed with cold 0.05% glutaraldehyde. 0.1% of Triton-X was used for permeabilization. In order to stain for HbF, FITC conjugated mouse anti-human monoclonal antibody to foetal haemoglobin (MoAb-HbF-FITC, BD Pharmingen, USA) was used. A total of 20,000 events were measured. RBCs were gated on the forward scatter against side scatter. F-cells were identified as RBC staining positive for FITC in the FL1-H channel and expressed as percentage of the total red blood cells counted for each sample

Calculation of amount of HbF per F cells (HbF/F cell)

Currently, there is no high throughput technique to measure the amount of HbF in each cell. The amount of HbF per F cell was calculated using the formula: HbF% x MCH pg/ F cell, This formula was used to estimate HbF/F cells which assumes even distribution of HbF within F cells (13).

Data management and Statistical analysis

Data was collected and entered into the REDCap software version. Data was analysed using IBM SPSS Statistics version 26.0, and visualisation was performed using GraphPad Prism version 8.2. Descriptive statistics were deployed to describe the socio-demographic and clinical characteristics of the study participants. This included frequencies for categorical variables and medians (IQR) for the non-Gaussian distributed numerical variables. Chi-square tests were used to compare categorical demographic characteristics as well as proportions of participants who reported experiencing clinical events among the three countries: Tanzania, Ghana, and Nigeria. Red blood cell indexes, platelet count, HbF, F cells, and HbF per F cells were compared between participants from the three countries using the Kruskal-Wallis test, as these variables were not normally distributed. The association between HbF, F cells, and HbF per F cells with the occurrence of clinical events among sickle cell patients was analysed using age and site-adjusted logistic regression. A p-value of < 0.05 was considered statistically significant.

Demographic and clinical characteristics

The study population was predominantly less than 18 years (63%) across the three countries. Ghanaian patients with SCD were the youngest (median = 8 years) and contributed the least number proportion of adults (7%) in contrast to the Nigerian population which had more adults(59%, median = 20 years). With respect to age, the samples from the countries were significantly different from each other (p = < 0.001). Across the sites, males were the most dominant with the largest proportion contributed by Ghana(Table 1).

A large proportion of the participants (across sites) had received blood transfusion in their lifetime. The most common complication of SCD reported as requiring management in a hospital setting (in-patient or outpatient) across the three sites was pain crisis with proportions ranging from 66–96% with the highest in Tanzania and lowest in Ghana. All other complications assessed ranged from 4–24%. Proportion of participants reporting being admitted in their lifetime ranged from 27–52% lowest in Tanzania and highest in Ghana(Table 1).

Table 1

Demographic and clinical characteristics of the study participants
		Total N= 290	Tanzania n = 92	Ghana n = 98	Nigeria n = 100
Variable		n(%)	n (%)	n (%)	n (%)	P - value
Age group (years)
	< 18	185(63.8)	53 (57.6)	91 (92.9)	41 (41.0)	< 0.001
	≥ 18	105(36.2)	39 (42.4)	7 (7.1)	59 (59.0)	< 0.001
Median age (IQR)		13(8,21)	16 (10, 21)	8 (5, 12)	20 (12, 27)	< 0.001
Sex
	Male	155(53.5)	48 (52.2)	60 (61.2)	47 (47.0)*	0.128
	Female	135(46.5)	44 (47.8)	38 (38.8)	53 (53.0)	0.128
Blood transfusion
	Yes	212(73.4)	73 (79.3)	63 (64.3)	76 (76.8)*	0.041
	No	77(26.64)	19 (20.7)	35 (35.7)	23 (23.2)	0.041
Dactylitis
	Yes	78(27.6)	22 (23.9)	16 (16.3)	40 (43.0)*	< 0.001
	No	205(72.4)	70 (76.1)	82 (83.7)	53 (57.0)	< 0.001
Pain crises
	Yes	235(81.6)	89 (96.7)	56 (57.1)	90 (91.8)*	< 0.001
	No	53(18.4)	3 (3.3)	42 (42.9)	8 (8.2)	< 0.001
Acute Chest Syndrome
	Yes	68(23.9)	11 (12.0)	18 (18.6)	39 (40.6)*	< 0.001
	No	217(76.1)	81 (88.0)	79 (81.4)	57 (59.4)	< 0.001
convulsions
	Yes	14(4.9)	5 (5.4)	2 (2.0)	7 (7.5)*	0.210
	No	269(95.1)	87 (94.6)	96 (98.0)	86 (92.5)	0.210
Neurological deficit
	Yes	10(3.7)	7 (7.6)	0 (0.0)	3 (3.8) *	0.009
	No	260(96.3)	85 (92.4)	98 (100.0)	77 (96.3)	0.009
Leg ulcer
	Yes	26(9.1)	6 (6.5)	3 (3.1)	17 (17.5)*	0.001
	No	261(90.9)	86 (93.5)	95 (96.9)	80 (82.5)	0.001
Priapism (Males)
	Yes	12(8.1)	4 (8.3)	4 (6.7)	4 (10.0) *	0.928
	No	136(91.9)	44(91.7)	56(93.3)	36 (90.00)	0.928
Febrile illness
	Yes	205(71.9)	91 (98.9)	46 (47.4)*	68 (70.8) *	< 0.001
	No	80(28.1)	1 (1.1)	51 (52.6)	28 (29.2)	< 0.001
Ever been admitted
	Yes	120(42.0)	25 (27.2)	51 (52.0)	44 (45.8) *	0.002
	No	166(58.0)	67 (72.8)	47 (48.0)	52 (54.2)	0.002

*n < N due to missing information

Haematological parameters of the study participants

Assessment of the haematological indices by age categorization across countries reveals a mosaic pattern. The median WBC was lowest for Nigeria in persons < 18 years of age- 12(IQR: 9.0, 17.2) but among persons 18 years and above it was lowest for Ghana- 8.4(IQR:7.4, 10.6). For RBC indices, the highest was Ghana in persons < 18 years and Tanzania in persons ≥ 18 years similar to the haemoglobin levels and MCHC levels. Nigeria had the highest median MCV in persons < 18 years but was second to Ghana in median MCV among persons ≥ 18 years. Median MCH values were highest in Ghana in both age categorizations. Median platelets levels were however highest in Tanzania in persons < 18 years and highest in Nigeria for persons ≥ 18 years. (Fig. 1) The differences among the countries based on the age categorizations were found to be statistically significant for WBC, RBC, MCH and MCHC. The differences in the MCVs both age groups across the countries however, were not statistically significant( p-value: 0.50, 0.12) Among persons 18 years and older, the differences in the haemoglobin differences and platelets across the countries were not statistically significant [p-value: Hgb(0.70) Plt(0.36)]. (Supplementary table 2)

HbF, F cells and HbF per F-cell levels

Overall, participants from Ghana had higher HbF (median = 8.20 with IQR = 4.80, 14.68, n = 68) compared with the level of HbF among participants from Tanzania (median = 4.45 with IQR = 2.33, 7.15, n = 92) and Nigeria (median = 4.30 with IQR = 2.60, 7.20, n = 7.20) and such difference was statistically significant, p < 0.001. F cell levels were highest in Nigeria (median = 30.10 with IQR = 15.05, 44.53, n = 34) followed by Tanzania (median = 21.60 with IQR = 13.20, 32.50, n = 84), and Ghana (median = 19.45 with IQR = 15.65, 31.10, n = 20) Participants from Ghana had higher HbF per F cells (median = 8.66 with IQR = 5.23, 10.87, n = 20) compared with the level of HbF among participants from Tanzania (median = 5.67 with IQR = 4.14, 7.89, n = 84) and Nigeria (median = 4.57 with IQR = 3.80, 6.38, n = 19) and such difference was statistically significant, p = 0.003. (Fig. 2)

Association of HbF, F-cells and HbF per F cell with clinical manifestation

Across the three countries, an increase of 1% in HbF was associated with decreased odds of splenomegaly (aOR = 0.88, 95% CI 0.63–1.21, p = 0.42), leg ulcer( aOR = 0.97, 95% CI 0.88–1.07, p = 0.553), priapism (aOR = 0.97, 95% CI 0.85–1.1, p = 0.603), pain crisis (aOR = 0.98, 95% CI 0.93–1.02, p = 0.307), and decreased odds of blood transfusion (aOR = 0.95, 95% CI 0.91–0.99, p = 0.017) requiring hospital setting management. A unit increase in HbF/F-cell was associated with decreased odds of neurological defects (aOR = 0.97, 95% CI 0.84–1.13, p = 0.734), acute chest syndrome (aOR = 0.98, 95% CI 0.91–1.07, p = 0.689), dactylitis (aOR = 0.99, 95% CI 0.92–1.06, p = 0.754) and priapism (aOR = 0.99, 95% CI 0.93–1.05 p = 0.741). A 1% increase in f-cells was associated with decreased odds of blood transfusion (aOR = 0.98, 95% CI 0.97–1.00, p = 0.076) and acute chest syndrome (aOR = 0.99, 95% CI 0.94–1.05, p = 0.774). (Fig. 3)

This study which includes SCD populations across three countries presents a unique framework to look at similarities and differences across SCD populations in sub-Saharan Africa(SSA). SSA bears more than 70% of the global SCD burden ⁴ and requires targeted interventions to reduce its impact in this low-resource setting.

Generally most of the participants were children. This may be reflecting the low survival rates of individuals with SCD on the continent ⁴. The high proportion of paediatric participants in the Ghana sample highlights the success of the country’s longstanding newborn screening program, which is the longest-running in Africa. This goes a long way reflecting in the statistically significant differences in all the complications assessed, except for priapism and convulsions. The proportion of males in the various countries is comparable to reported registry numbers alluding to a representative sample of the population in these countries based on sex^18–20. Blood transfusion, pain crises and febrile illnesses continue to be the biggest bane of patients with SCD as several studies have shown. This calls for more efforts to improve availability and accessibility of blood products in many health facilities and pain management across the continent.

This study uniquely involved a systematic comparison of haematological parameters focusing on HbF levels and HbF/F cells in relation to SCD clinical manifestation in three SSA countries. The haematological differences among the countries based on the age categorizations were found to be statistically significant for WBC, RBC, MCH and MCHC. Such differences may reflect underlying differences in the genetic background across the three populations including those influencing HbF parameters.

In Ghana where the highest levels of HbF were recorded, self-reported occurrence of complications was also lowest across all the complications assessed, except Acute Chest syndrome which was unexpected.The paediatric dominance in the Ghanaian participants could also have been a factor as children would have lived shorter lives with SCD compared to older cohorts. This phenomenon could be largely due to the protective tendencies of the foetal haemoglobin in persons with SCD as described by some studies ^{13–15,21–23}, even in this sample who are hydroxyurea naive. The levels of HbF are known to decrease by about 5% per week from birth until 6 months ²⁴. There is also a variation in HbF levels in children compared with adults living with sickle cell disease ^13,16.

The Nigerian cohort had higher HbF and a lower F cells compared to the Tanzanian cohort, irrespective of their similarities in terms of ratio of children to adults. This indicates that high HbF does not imply high F cells and that the discrete quantity of HbF per cell may be a more important laboratory variable in assessing the overall impact of foetal haemoglobin in ameliorating features of sickle cell disease. Consequently, an increase in both parameters was found to lead to a reduction in febrile illnesses and transfusion needs. These are events that increase the financial burden as well as mortality of people living with sickle cell. This will imply that use of interventions like HU which has been found in several studies to improve HbF levels will definitely improve disease outcome and reduce the burden of care as has been proposed by previous studies ^23,25–30.

The observation made here indicates that the HbF and F cell parameters had significant association with some disease features of importance like transfusion rates,frequency of painful crises and episodes of febrile illness. However the HbF/F cell ratio seemed to discriminate more and showed significant association with only frequency of painful crisis and febrile illness. This may explain the variation in clinical response seen in HU therapy whose mode of action includes increasing HbF and F cell levels, among others. This observation may indicate the use of personalised treatment strategies or HU-based combination in some individuals who show sub-optimal responses to HU alone.

The importance of monitoring of HbF levels which has been known to play a major role as a disease modifier and in deciphering disease severity, cannot be overemphasised. The findings of this study presents an opportunity for the targeting of interventions which are not only aimed at modifying the HbF levels but also increasing the F cell percentage. These interventions must also consider the statistically significant differences in the samples across the three sampled countries which could be evident in other countries. The statistically significant differences in the countries could also be due to healthcare seeking behaviours and accessibility to care differences in the countries.

In SSA, HbF modulating therapies such as hydroxyurea might be of greater importance as they have been found to be cheaper and several studies have found it feasible in sub-Saharan Africa across all age groups ^31–33. This is further strengthened by the findings of this study in hydroxyurea-naive individuals, where higher HbF and F cells were associated with fewer incidence of transfusions and episodes of febrile illness irrespective of haemoglobin concentration. A study by Willen et al reported that initiating hydroxyurea at younger ages when HbF levels of > 20% ensures persistence of HbF production, improvement in haematological efficacy³⁴ and by extension better quality of life. This provides a great opportunity and challenge in the assessed countries where the median HbF levels are below 10%. Sub-Saharan countries could therefore identify this threshold in their patients and initiate hydroxyurea, overcoming the age barrier. Though several reports have indicated low uptake of HU in Nigeria ^35–37, overcoming the barriers would provide the most benefit as their HbF levels were lowest and spur on the perception of impact. In Ghana where a fairly higher proportion have been initiated on hydroxyurea and HbF levels were found to be high, focus should be shifted towards initiating when HbF level is > 20% at younger ages for optimal benefit. On the other hand, the higher HbF levels in Ghana might be due to their predominant paediatric sample population and not necessarily a marked variation from what was observed in the other countries.

Our study also revealed that majority of the paediatric patients had higher HbF levels especially in the Ghanaian cohort.This might necessitate the need to further explore the criteria for use of HU especially in children with a high baseline HbF level as they may be inadvertently omitted from several clinical trials as well as delay initiation of HUT. There may be a need for an expanded study to obtain baselines HbF reference values from a wider group of people living with sickle cell with varying haplotypes. This will further standardise practice and help to predict outcomes across all populations.

It is recommended that community screening programs should target newborns and younger ages and inculcate measurement of HbF levels and F cell count, where possible, to help determine the disease severity and serve as guide to the timing of the initiation of hydroxyurea.The screening programs should also encompass education on prophylactic therapies and disease modifying therapies like hydroxyurea. It also recommended that access to therapies which modulate HbF levels of SCD patients is increased as well as the diagnostic capacities for HbF levels. This will ensure that severity of SCD in affected patients can be reduced to the barest minimum.

The levels of HbF, F cells and HbF/F cell ratio were found to vary between adults and children in our study cohort. These parameters were found to correlate significantly with frequency of pain crisis, transfusion rate and episodes of febrile illness. The HbF/F cell ratio was found to be only significantly associated with transfusion rates and frequency of febrile illness. Levels of HbF, F cells and HbF/ F cells were fairly low in our sample alluding to a higher severity of disease. The low levels however provide some significant protection from SCD clinical manifestations which provides opportunity and challenge to use HbF modifying therapies to reduce severity of SCD.

Limitations

Sample sizes for the various countries were small compared to the burden in those countries. This was mediated by funding available for this pilot study. The findings therefore might not be largely generalizable but provide indication for further studies.

Self-reported occurrences of clinical manifestations could also have recall bias as participants had to recall any of the events in their lifetime. Further studies using comprehensive medical records could ameliorate this potential bias.

HbF- Foetal Haemoglobin

Hgb- Haemoglobin

MCH- Mean Corpuscular Haemoglobin

MCHC- Mean Corpuscular Haemoglobin Concentration

MCV- Mean Corpuscular Volume

RBC- Red Blood Cell

SCD- Sickle Cell Disease

WBC- White Blood Cell

Ethics approval and consent to participate

Institutional ethical clearance with reference numbers: DA.282/298/01.C/, KATH_IRB/AP/025/21 and NHREC/05/01/2008B-FWA00002458-1RB00002323) was obtained from Muhimbili University of Health, Allied Sciences-Tanzania, Komfo Anokye Teaching Hospital Institutional Review Board-Ghana and University of Nigeria Teaching Hospital, respectively. Written informed consent and assent if applicable, was obtained from individuals and/or guardians who agreed to participate in the study. All participant information was handled confidentially, and the subjects incurred no harm or additional financial burden due to the study.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

The study was funded by the International Centre for Genetic Engineering and Biotechnology (ICGEB), project No CRP/TZA19-01 .The funder had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript

Authors' contributions

SN & FU conceptualised the study and led in funding acquisition. SN, FU, EXA, DA, SYA, CO & MA participated in data curation. EXA & PP analysed and interpreted the data. SN and EXA drafted the manuscript. EED, BOO, PO, conducted laboratory analysis. AOA, VP, ON, EB, JM supervised various aspects of the study. All authors read and approved the final manuscript.

Acknowledgements

We acknowledge all the staff of the various clinics in which the study was contacted for their support.

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No competing interests reported.

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A cross-sectional study of the clinical manifestations of Sickles Cell Disease in Ghana, Nigeria and Tanzania and its association with foetal haemoglobin parameters

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Abstract

Figures

Background

Methodology

Laboratory investigations

Determination of Haematological parameters

Determination of HbF and F cell levels

Calculation of amount of HbF per F cells (HbF/F cell)

Data management and Statistical analysis

Results

Demographic and clinical characteristics

*n < N due to missing information

Haematological parameters of the study participants

HbF, F cells and HbF per F-cell levels

Association of HbF, F-cells and HbF per F cell with clinical manifestation

Discussion

Conclusion

Limitations

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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