|Year : 2014 | Volume
| Issue : 4 | Page : 227-231
Correlation between ABO blood group and vaso-occlusive crisis among adult patients with sickle cell anaemia in northern Nigeria
Sagir G Ahmed FWACP 1, Modu B Kagu2, Umma A Ibrahim3
1 Department of Haematology, Aminu Kano Teaching Hospital, Kano, Kano State, Egypt
2 Department of Haematology, University of Maiduguri Teaching Hospital, Maiduguri, Borno State, Egypt
3 Department of Paediatrics, Aminu Kano Teaching Hospital, Kano, Kano State, Egypt
|Date of Submission||10-Nov-2014|
|Date of Acceptance||18-Nov-2014|
|Date of Web Publication||25-Mar-2015|
Sagir G Ahmed
Department of Haematology, Aminu Kano Teaching Hospital, PMB 3452, Kano, Kano State 11399
Source of Support: None, Conflict of Interest: None
Background In sickle cell disease (SCD), the vascular endothelium is in a continuous state of activation by inflammatory cytokines, leading to increased secretion of von Willebrand factor (vWF), which is a potent mediator of cytoadherence. Vaso-occlusive crisis (VOC) involves cytoadherence of sickle red cells, leucocytes and platelets onto vascular endothelium. Non-O blood groups are also associated with the elevation of vWF levels. Thus, SCD and non-O blood groups are independently associated with the elevated levels of vWF, which is an important cofactor in the pathogenesis of VOC.
Objectives We hypothesized that SCD patients with non-O groups would have higher levels of vWF and greater risk of VOC than SCD patients with blood group O. If our hypothesis is correct, SCD patients with non-O groups would have higher frequency of VOC than those with blood group O.
Materials and methods We conducted a retrospective study of frequencies of VOC with respect to ABO blood groups and vWF levels in 352 adult patients with SCD in Nigeria.
Results In comparison with blood group O, patients with non-O blood groups had significantly higher mean levels of vWF (189 vs. 153%, P < 0.05), significantly higher proportion of patients affected by VOC (75.8 vs. 34.2%, P < 0.05) with a significantly higher mean number of VOC episodes per patient (3.2 vs. 1.5, P < 0.05). The relative risk of VOC for patients with non-O blood groups was 1.94 (95% confidence interval 1.5-2.7, P = 0.004).
Conclusion SCD patients with non-O blood groups had higher frequencies and risk of VOC that were attributed to the effect of higher levels of vWF. These data suggest that non-O blood group is a risk factor for frequent VOC and an adverse prognostic index in SCD. This preliminary report calls for further studies to precisely determine the clinical significance of ABO blood groups in SCD within the context of clinical subphenotyping
Keywords: ABO, blood, crisis, group, sickle
|How to cite this article:|
Ahmed SG, Kagu MB, Ibrahim UA. Correlation between ABO blood group and vaso-occlusive crisis among adult patients with sickle cell anaemia in northern Nigeria. Egypt J Haematol 2014;39:227-31
|How to cite this URL:|
Ahmed SG, Kagu MB, Ibrahim UA. Correlation between ABO blood group and vaso-occlusive crisis among adult patients with sickle cell anaemia in northern Nigeria. Egypt J Haematol [serial online] 2014 [cited 2019 Nov 13];39:227-31. Available from: http://www.ehj.eg.net/text.asp?2014/39/4/227/153964
| Introduction|| |
ABO blood groups have significant effect on the incidence of cardiovascular morbidities with individuals having the non-O blood groups being at higher risk for thromboembolism owing to higher levels of von Willebrand factor (vWF) and factor VIII (FVIII) ,,. Moreover, genotype analysis of the non-O blood groups revealed that the thromboembolic risk was comparatively higher in homozygous than in heterozygous individuals because the ABO alleles have a dose-dependent effect on vWF and FVIII levels, which suggested that the risk was inversely related to H antigen expression . The disparity in vWF levels between ABO blood groups is due to intergroup variations in vWF metabolism. Different ABO alleles influence the plasma levels of vWF by affecting the rate of its proteolytic clearance by ADAMTS-13 . This ABO-related disparity in vWF metabolism resulted in the half-life of vWF being shorter in the plasma of blood group O in comparison with the non-O blood groups . Consequently, plasma vWF levels are 25-30% higher in non-O blood groups than in blood group O .
The haemoglobin S (HbS), which is a structural variant of the normal haemoglobin (HbA), arose because of a genetic mutation in the b-globin gene where thymidine replaced adenine, resulting in the substitution of glutamic acid by valine in position 6 of the b-globin chain . This substitution conferred upon HbS a significant alteration in physicochemical properties with reduced solubility in the deoxygenated state . Sickle cell anaemia (SCA) is the homozygous state for the HbS gene (HbSS), and it is the commonest and severest type of sickle cell disease (SCD) . However, less common and milder types of SCD can arise owing to the coinheritance of a-thalassaemia in HbSS patients or as a result of double heterozygosity between HbS gene and other mutant b-globin genes such as C (HbSC), D (HbSD), O (HbSO), E (HbSE) or b-thalassaemia (HbSbthal), all of which share a similar basic pathophysiology dominated by red cell sickling, haemolysis and vasculopathies . The haematological feature of SCD is characterized by red cell sickling, haemolytic anaemia, leucocytosis and thrombocytosis . The clinical course of SCD is typically characterized by variable periods of painless steady state that is periodically interrupted by painful vaso-occlusive crisis (VOC) resulting from deoxygenation of HbS, red cell sickling, vaso-occlusion and tissue necrosis ,. Red cell sickling and haemolysis are also associated with the development of other acute vaso-occlusive morbidities such as acute chest syndrome, priapism and stroke ,. However, the painful VOC is by far the commonest form of acute vaso-occlusive morbidity in SCD .
The pathophysiology of VOC has been shown to be intimately related to adhesions of the blood cells, including sickled red cells, leucocytes and platelets to the vascular endothelium ,. In SCD, the vascular endothelium is in a continuous state of activation by inflammatory cytokines leading to increased production and secretion of vWF . The high levels of vWF in the plasma of SCD patients is also associated with increased amounts of large vWF multimers resulting from moderate deficiency of the metalloprotease ADAMTS-13 in the plasma of such patients . Moreover, the large vWF multimers are stabilized by extracellular Hb, which makes them hyperadhesive and resistant to ADAMTS-13 cleavage . The clinical significance of the elevated levels of vWF in SCD is related to the facilitation of adherence of the sickle red cells, leucocytes and platelets to the vascular endothelium, thereby playing an important role in the pathogenesis of VOC and a myriad of thrombotic complications, which adversely affect the severity of SCD ,.
We deduced that SCD patients with non-O blood groups would have greater elevations of vWF because of the dual effect of SCD and non-O blood group, both of which are independently associated with the elevations of vWF ,,,,,,. Therefore, we hypothesized that SCD patients with non-O groups would have higher levels of vWF and greater risk of VOC than those with blood group O. If our hypothesis is correct, SCD patients with non-O groups would have higher frequency of VOC than those with blood group O. To the best of our knowledge, the relationship between ABO blood groups and sickle cell VOC has not been previously studied. Hence, in this paper we performed a retrospective analysis of the frequencies of VOC with respect to ABO blood group and vWF levels in patients with SCA in northern Nigeria.
| Materials and methods|| |
This is a retrospective cross-sectional cohort study conducted in the University of Maiduguri Teaching Hospital, Maiduguri, Borno State, northeast Nigeria, 2006-2007 (2 years) and in Aminu Kano Teaching Hospital, Kano, northwest Nigeria, 2009-2010 (2 years).
Patients studied were diagnosed with SCA (HbSS) based on haemoglobin electrophoresis at a pH of 8.6 on cellulose acetate paper, positive sickling test and haemoglobin quantitation . Consecutive SCA patients who presented for routine follow-up at the adult haematology clinics and were clinically proven to be in steady state devoid of any form of crisis or infection were recruited at the two centres . Each patient was entered into the study only once.
Patients with SCA complicated by chronic infections including hepatitis, HIV infection and tuberculosis were excluded from this study. Patients who were on long-term transfusion regime as well as those taking hydroxyurea and those with chronic renal failure were also excluded. Patients with less common and milder types of SCD such as HbSS with a-thalassaemia, HbSC and HbS/b-thalassaemia were excluded from this study. Female patients who were pregnant or taking oral contraceptives were also excluded.
Ethics, procedures and data collection
All procedures were performed with the approval of local institutional ethics committees and in accordance with the ethical standards of human experimentation as enshrined in the Helsinki Declaration of 1975 as amended. All patients were recruited with informed consents. At the point of recruitment, the demographic profile (age and sex), haematological parameters (haematocrit, red cell indices, white blood cell (WBC) and platelet counts, and haemoglobin F levels), ABO blood group and vWF level of each patient were determined. Thereafter, the case note of each patient was retrospectively analysed for the enumeration of VOC that occurred in the past 1 year of 12 calendar months.
Determination of haematological parameters
Blood samples were collected in EDTA containers and the haemoglobin concentration, haematocrit, WBC and platelet counts were determined using automatic blood analysers (Celltac Alpha MEK 6400 (Nihon Kohden Corporation, Tokyo, Japan) or Cell-Dyn 3700CS (Abbott Laboratories, Abbott Park, Illinois, USA)). Automated WBC count errors owing to the presence of circulating nucleated red cells were manually corrected. HbF levels were determined by quantitation using 24-VISU densitometer (Helena, Paris, France).
Determination of ABO blood groups
ABO blood groups were determined manually by using monoclonal anti-A and anti-B against the patients' red cells suspended in saline tubes at room temperature and ready for agglutinations after 15 min incubation in accordance with standard procedures and manufacturer's guidelines .
Determination of von Willebrand factor levels
Plasma levels of vWF of patients and equal number of age-matched and sex-matched healthy control subjects, with electrophoretically confirmed normal Hb genotype AA, were determined by sandwich enzyme-linked immunosorbent assay techniques using test kits (Helena Laboratories, Beaumont, Texas, USA or Asserachrom Diagnostica, Stago, France) in accordance with manufacturer's instructions.
Retrospective analysis of vaso-occlusive crisis and case definition of vaso-occlusive crisis
The medical case note of each patient was scrutinized to determine and enumerate the number of documented episodes of VOC in the past 1 year. An episode of VOC was diagnosed if the patient presented at the clinic or emergency room with acute onset of pain in the extremities, back, chest, abdomen or head region that lasted at least 2 h and could not be explained by conditions other than SCD; however, pain episodes that occurred within a 2-week time span were counted as a single episode .
Data collation and calculation
The data accrued from the two centres were merged and collated. Mean values of demographic and steady-state haematological parameters, and vWF levels of patients studied, were calculated for each ABO blood group.
The proportion (%) of patients who had VOC during the period of study in each ABO group was calculated as: (number of patients that had VOC for a particular ABO group)χ(number of patients in that particular ABO group)´100.
The mean number of VOC per patient during the period of study for each ABO group was calculated as: (number of VOC recorded among patients of a particular ABO group)χ(number of patients that had VOC in that particular ABO group).
The mean values and proportions of the parameters studied were compared between O and non-O blood groups using the t-test for mean values and the c2 -test for proportions, with a P-value of less than 0.05 taken as significant. In addition, the relative risk of VOC among patients with the non-O blood group was determined based on Poisson regression analysis model. Value of relative risk was considered statistically significant if its range of 95% confidence interval did not include 1.0 with a P-value of less than 0.05. Statistical analyses were executed using SPSS software (version 19.0; IBM, SPSS Statistics, Chicago, Illinois, USA).
| Results|| |
A total of 352 patients with SCA were studied in this report. The proportions of patients in each ABO blood group are shown in [Table 1]. The SCA patients had significantly higher mean steady-state vWF level (165 ± 30%) in comparison with the mean vWF level found in normal control subjects (98 ± 21%) (P < 0.05) (figures not shown in table). [Table 2] compared the values of demographic indices, steady-state haematological parameters, steady-state vWF levels and frequencies of VOC as found in SCA patients with the blood group O and non-O blood groups; there were no significant differences between patients with blood group O and those with non-O blood groups in terms of mean age, sex ratio as well as mean values of haemoglobin concentrations, haematocrit, red cell indices, WBC count, platelet count and HbF levels (P > 0.05). However, in comparison with blood group O, patients with non-O blood groups had significantly higher mean value of vWF level (189 vs. 153%, P < 0.05), higher proportion of patients affected by VOC (75.8 vs. 34.2%, P < 0.05) and higher mean number of VOC episodes per patient (3.2 vs. 1.5, P < 0.05). In a regression model adjusting for age, sex and HbF levels as covariables, the relative risk of VOC for patients with the non-O blood groups was 1.94 (95% confidence interval 1.5-2.7, P = 0.004).
|Table 1: Frequency distribution of ABO blood groups among sickle cell anaemia patients|
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|Table 2: Demographic profiles, steady-state values of haematological parameters and von Willebrand factor, and frequencies of vaso-occlusive crisis among sickle cell anaemia patients with respect to ABO blood groups|
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| Discussion|| |
The proportions of patients in each ABO blood were consistent with the frequencies of ABO blood groups in northern Nigeria ,. The demographic profiles and steady haematological parameters did not differ significantly between patients with blood group O and those with non-O blood groups in this study. The haematological parameters revealed the presence of anaemia, leucocytosis, thrombocytosis and a modest elevation of HbF levels, all of which are consistent with the haematological profiles of SCD in Nigeria .
The result of this study had shown that SCD patients had significantly higher vWF levels than healthy control individuals. This finding reaffirms the fact that the vascular endothelium of patients with SCD is in a continuous state of activation by inflammatory cytokines, leading to increased production and secretion of vWF . Our finding of elevated vWF in patients with SCD is also consistent with the results of previous studies ,,. This study also revealed that in comparison with the blood group O, the non-O blood groups had significantly higher levels of vWF with corresponding higher frequencies of VOC as suggested by higher proportion of patients affected by VOC and higher mean number of VOC episodes per patient. Furthermore, the finding of a relative risk of 1.94 suggests that patients with non-O blood groups were about two times more likely to develop VOC than patients with blood group O. These findings have confirmed our earlier hypothesis, which is consistent with the role of vWF as a mediator of cytoadherence of sickle red cells, leucocytes and platelets to the vascular endothelium in the pathogenesis of VOC ,,. Although we did not measure FVIII levels in this study, it has already been established from previous studies that the high levels of plasma vWF seen in individuals with the non-O blood groups was always associated with a concomitant elevation of FVIII because of the role of vWF as the carrier of FVIII and its protector from proteolysis in the plasma . This scenario makes the non-O blood groups to be rated as the commonest genetic risk factors for venous thromboembolism . It can therefore be inferred that SCD patients with non-O blood groups would be particularly predisposed to frequent and severe VOC as a result of the combined effects of elevated levels vWF and FVIII, leading to endothelial cytoadherence (vWF effect) and thrombosis (FVIII effect) within the microvasculature ,,,,.
VOC can be triggered by psychological, physical or infective factors . Patients with SCD have impaired immune response and are prone to develop recurrent infections in general . However, malaria infection deserves special consideration within the context of this study for three reasons. First, the majority of SCD patients live in malaria-endemic countries of the world . Second, malaria infection is a potent trigger of VOC among patients with SCD . Third, the non-O blood groups are associated with higher risk of developing severe malaria . The mechanisms underlying variations in the susceptibility of different ABO blood groups to severe malaria are fairly well investigated. Individuals with blood group O exhibit reduced red cell rosetting with greater humoral and phagocytic antimalarial immune response resulting in clinically nonsevere malaria ,,,,. In contradistinction, individuals with non-O blood groups exhibit enhanced red cell rosetting with relatively lower humoral and phagocytic antimalarial immune response, leading to the development of clinically severe malaria ,,,,. The malaria parasites can trigger VOC through a number of mechanisms, which include alteration of red cell metabolism leading to sickling and the formation of histidine rich protein knobs on red cell membrane that mediate cytoadherence of sickle red cells to vascular endothelium ,. Moreover, a recent study had shown that severe malaria infection was also associated with decreased ADAMTS-13 activity, which would further aggravate vWF concentrations and increase the risk of VOC in SCD patients . Thus, we speculate that any episode of severe malaria infection among SCD patients with non-O blood groups would further escalate their pre-existing high risk of VOC owing to elevated levels of steady-state vWF, as found in this study. It can therefore be surmised that although antimalarial prophylaxis is beneficial to SCD patients in general, the need for such prophylaxis would be more compelling for patients with non-O blood groups in whom the risk of severe infection is considerably higher ,,,,,.
The importance of our finding rests upon the fact that the frequency of VOC is of prognostic significance in SCD ,. Increased frequency of VOC is associated with severe disease characterized by multiple organ damage, poor overall prognosis and early mortality in patients with SCD ,. Hence, the findings of our study, though preliminary, would suggest that the non-O blood groups are associated with frequent VOC, which is an adverse prognostic factor in SCD.
| Conclusion|| |
In comparison with blood group O, the non-O blood groups were associated with higher levels of vWF and more frequent sickle cell VOC. Therefore, inheritance of the non-O blood groups should be considered a genetically determined nonmodifiable risk factor for frequent VOC and an adverse prognostic index in SCD patients. This preliminary report calls for further and larger studies to precisely determine the impact of ABO blood groups on the overall clinical course of SCD within the context of clinical phenotyping of patients with SCD.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]