|Year : 2015 | Volume
| Issue : 2 | Page : 85-89
The frequency of iron deficiency among patients with haemophilia-A in northern Nigeria: correlation with the disease severity and clinical implications
Sagir G Ahmed MBBS, FWACP 1, Modu B Kagu2, Umma A Ibrahim3, Audu A Bukar2
1 Department of Haematology, Aminu Kano Teaching Hospital, Kano, Kano State, Nigeria
2 Department of Haematology, University of Maiduguri Teaching Hospital, Maiduguri, Borno State, Nigeria
3 Department of Paediatrics, Aminu Kano Teaching Hospital, Kano, Kano State, Nigeria
|Date of Submission||13-Jan-2015|
|Date of Acceptance||26-Jan-2015|
|Date of Web Publication||22-Jul-2015|
Sagir G Ahmed
Department of Haematology, Aminu Kano Teaching Hospital, PMB 3452, Kano, Kano State
Source of Support: None, Conflict of Interest: None
Background Haemophilia-A (HA) is an X-linked recessive disorder characterized by the deficiency of functional clotting factor VIII resulting in lifelong bleeding diathesis. We predict that HA would be associated with iron deficiency and the risk will be higher in those with severe disease. If our prediction is correct, the frequency and the relative risk (RR) of iron deficiency will be higher in patients with severe HA in comparison with nonsevere HA.
Materials and methods We evaluated the levels of haemoglobin concentrations, red cell indices and serum ferritin retrospectively with respect to the disease severity among a cohort of treatment-naive patients with HA as seen at the time of diagnosis in some hospitals in northern Nigeria.
Results Out of the 39 patients studied, 19 were iron deficient, yielding an overall frequency of iron deficiency of 48.7%. Out of the 39 patients, 24 (61.5%) had severe HA and 15 (38.5%) had nonsevere HA. Patients with severe HA had a significantly higher frequency of iron deficiency in comparison with nonsevere HA (66.7 vs. 20%, P < 0.004) and the RR of iron deficiency for patients with severe HA was 2.6 (95% confidence interval: 1.9-3.4, P = 0.003).
Conclusion Iron deficiency is very common among patients with HA, the frequency and the RR of which is higher among patients with severe disease. Therefore, patients with HA should be regularly screened and treated for iron deficiency to prevent the adverse impact of iron deficiency on wound healing, the immunity and the mental development of haemophilic patients. However, the possibility of undesirable side effects of iron such as erosive gastritis, which can increase the risk of gastrointestinal haemorrhage in HA patients, calls for caution in the choice of oral pharmaceutical iron preparations vis-à-vis nonpharmaceutical dietary supplementation. Healthcare centres should formulate standard guidelines for the effective and safe treatment of iron deficiency in haemophilia patients.
Keywords: deficiency, haemophilia-A, iron, Nigeria, severity
|How to cite this article:|
Ahmed SG, Kagu MB, Ibrahim UA, Bukar AA. The frequency of iron deficiency among patients with haemophilia-A in northern Nigeria: correlation with the disease severity and clinical implications. Egypt J Haematol 2015;40:85-9
|How to cite this URL:|
Ahmed SG, Kagu MB, Ibrahim UA, Bukar AA. The frequency of iron deficiency among patients with haemophilia-A in northern Nigeria: correlation with the disease severity and clinical implications. Egypt J Haematol [serial online] 2015 [cited 2020 Jan 27];40:85-9. Available from: http://www.ehj.eg.net/text.asp?2015/40/2/85/161294
| Introduction|| |
Haemophilia-A (HA) is an X-linked recessive disorder characterized by a qualitative defect or a quantitative deficiency of clotting factor VIII (FVIII)  . Inadequate FVIII levels result in the insufficient generation of thrombin by the FIXa and FVIIIa complex in the intrinsic pathway  . The severity of the disease is largely determined by the extent to which different mutations abolish functional FVIII production. Severe disease is typically associated with null mutations including inversions, insertions, deletions and nonsense and mis-sense mutations, whereas milder disease is usually caused by non-null mutations such as mis-sense, single-nucleotide deletions and splicing error mutations  . The clinical severity of the disease is correlated with residual FVIII levels, which is classified as severe (FVIII level<1%), moderate (FVIII level 1-5%) or mild (FVIII level 6-40%)  . HA is a lifelong bleeding disorder, the clinical course of which is dominated by both overt and covert blood loss. Frequent external blood loss from orifices, the skin and epithelial injuries would be expected to eventually cause iron deficiency in HA. Patients with HA, especially in severe cases, also suffer from frequent internal blood loss within the joints, resulting in the deposition of iron in the synovium  . The vulnerability of haemophiliac joints to recurrent bleeding is related to the role of synovial cells and chondrocytes as producers of the tissue factor pathway inhibitor, which aggravates the bleeding tendency within the joints  . However, synovial iron deposits are not physiologically functional as they are not readily available for haemoglobin synthesis, but rather they are pathological mediators of inflammatory changes leading to crippling synovitis and arthropathy  . Therefore, increased synovial iron stores in haemophiliac patients cannot possibly compensate for the iron deficiency resulting from external blood loss and the depletion of normal storage compartments such as the liver and the bone marrow. It can thus be reasonably predicted that HA would be causally related to iron deficiency, a condition that could potentially have an adverse impact on the clinical status of the haemophilic patient. Nonetheless, iron deficiency has not been studied adequately in haemophilia, and there is a dearth of information on this subject matter in the literature. A solitary study on the iron status of haemophiliac patients conducted on a cohort of only seven patients revealed that marrow iron stores were decreased in all and absent in four patients despite increased iron deposits in the synovium  . There is therefore the need for more studies on iron deficiency in haemophilia. We predict that HA would be strongly associated with iron deficiency, and that there will be a clear correlation between the frequency of iron deficiency and the disease severity among patients with HA. If our prediction is correct, the frequency and the relative risk (RR) of iron deficiency will be higher in patients with severe HA in comparison with those having nonsevere HA. To test our prediction, we retrospectively evaluated the levels of haemoglobin concentrations, red cell indices and serum ferritin with respect to the disease severity among a cohort of treatment-naive patients with HA as seen at the time of diagnosis in northern Nigeria; the clinical and therapeutic implications of iron deficiency in patients with HA were also discussed.
| Materials and methods|| |
This is a retrospective cohort study of patients with HA diagnosed in the haematology laboratories of four Nigerian tertiary health institutions including the University of Maiduguri Teaching Hospital, Maiduguri, northeast Nigeria (1995-2007), the Federal Medical Centre Birnin Kudu, northwest Nigeria (2004-2005), the Murtala Muhammad Specialist Hospital, Kano, northwest Nigeria (2008-2009) and the Aminu Kano Teaching Hospital, Kano, northwest Nigeria (2007-2009). The retrospective data collected from the four centres were collated and analysed.
All patients who presented with bleeding diathesis and were diagnosed with HA at the four centres were included in this study. Only treatment-naive patients were included in this study; hence, patients who received any form of blood product transfusions in the last 3 months were excluded. In view of the fact that serum ferritin is an acute-phase reactant that can be elevated in the context of infection and inflammations, data accrued from patients with fever or any other evidence of infection at the time of diagnosis were excluded  .
Ethics, procedures and data collection
The research procedures were conducted with informed consents obtained from parents or guardians of young patients with supplementary assent from older patients and the approval of local institutional ethics committees in accordance with the ethical standards of human experimentation as enshrined in the Helsinki Declaration of 1975 as amended. The demographic profile (age and sex), haematological parameters (haemoglobin concentration and red cell indices), and serum ferritin and FVIII levels of each patient as determined at the point of diagnosis were retrieved from medical records and analysed.
The diagnosis of HA and the determination of FVIII levels
All of the patients studied presented with bleeding diathesis, and provisional diagnoses of HA were made if the clotting profiles revealed a normal platelet count and bleeding time and normal prothrombin and thrombin times with a prolonged activated partial thromboplastin time corrected by mixing patient plasma with fresh normal plasma, but not with aged plasma or serum  . The diagnoses were confirmed by FVIII assays. Assays were performed by automated coagulometers or by the one-stage manual assay technique based on the ability of serial dilutions of patients' plasma and standard plasma to correct the prolonged activated partial thromboplastin time of a plasma known to be severely deficient in FVIII as described by Laffan and Manning  . On the basis of the FVIII levels, patients were categorized as having severe (FVIII level <1%), moderate (FVIII level 1-5%) or mild (FVIII level 6-40%) haemophilia  . In this study, moderate and mild diseases are merged and categorized as 'nonsevere disease' (FVIII level 1-40%).
The determination of haematological parameters
Haemoglobin concentration and red cell indices were determined using automatic blood analysers (Celltac Alpha MEK 6400; Nihon Kohden Corporation, Tokyo, Japan; Cell-Dyn 3700CS; Abbott Laboratories, Abbott Park, Illinois, USA; Beckman Coulter AcT diff; Beckman Diagnostics, Brea, California, USA; or Beckman Coulter AcT-8; Beckman Diagnostics).
The determination of serum ferritin levels and cutoff values for iron deficiency
Iron stores of the studied patients were assessed by a serum ferritin analysis using ELISA techniques  . Enzyme immunoassay kits (Genway Biotech, San Diego, California, USA; Clinotech, Richmond, Canada; BioCheck Inc., Foster City, California, USA; Cortez Diagnostics Inc., Calabasas, California, USA; or BioVision Inc., Milpitas, California, USA) were used in accordance with the kit manufacturer's methodology. In this study, cutoff points for the diagnosis of iron deficiency were serum ferritin levels less than 12 μg/l for patients younger than 5 years and less than 15 μg/l for patients older than 5 years in accordance with WHO guidelines  .
Mean values and proportions of the parameters studied were compared between patient categories using the t-test for mean values and the χ2 -test for proportions, with P-values of less than 0.05 taken as significant. The RR of iron deficiency among patients with severe HA was determined on the basis of the Poisson regression analysis model. The value of RR was considered to be statistically significant if its range of 95% confidence interval was greater than 1.0 with a P-value of less than 0.05. Statistical analyses were performed with SPSS software (version 19.0; IBM SPSS Statistics, Chicago, Illinois, USA).
| Results|| |
A total of 39 male patients with HA were studied, out of whom 19 were iron deficient, yielding an overall frequency of iron deficiency of 48.7%. The results of this study with respect to the disease severity and the iron status are shown in [Table 1]. Out of the total of 39 patients studied, 24 (61.5%) had severe HA and 15 (38.5%) had nonsevere HA. The mean age at diagnosis was significantly lower in patients with severe disease than in patients with nonsevere disease irrespective of the iron status: 2.2 years compared with 8.3 years (P < 0.002) for iron-deficient patients, and 2.1 years compared with 9.2 years (P < 0.05) for iron-replete patients, respectively. Patients with severe HA had a significantly higher frequency of iron deficiency in comparison with patients with nonsevere HA (66.7 vs. 20%, P < 0.004). In a regression model adjusting for age, the RR of iron deficiency for patients with the severe haemophilia was 2.6 (95% confidence interval: 1.9-3.4, P = 0.003). Irrespective of the disease severity, patients with iron deficiency had significantly lower mean haemoglobin levels and red cell indices in comparison with iron-replete patients.
|Table 1 Age, the frequency of iron deficiency and haematological parameters of patients with severe and nonsevere haemophilia-A at diagnosis |
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| Discussion|| |
The amount of data captured in this study was low despite the multicentre approach and a fairly extended period of data collection, which may suggest a very low prevalence of HA in Nigeria. The actual prevalence of HA in Nigeria has not yet been determined by a standardized national survey. However, an authoritative review of variations in the reported HA prevalence around the world (based on the world federation of haemophilia global survey and the literature) revealed gross under-reporting from developing nations, including Nigeria, where the estimated prevalence rate of 0.05/100 000 men may be unrealistic  . Therefore, the small amount of data captured in this study may simply be a reflection of the failure of Nigerian haemophilia patients to access tertiary healthcare services for proper diagnosis, management and documentation. In Nigeria, like in other developing nations, maternal and child healthcare are inadequate and it is highly likely that many haemophiliac patients die in the hands of traditional healers, quacks or even qualified but lower-level healthcare personnel who lack the special skills and facilities for the diagnosis and the management of haemophilia. It suffices to say that haemophilia patients in rural areas, where the vast majority of the Nigerians live, virtually have little or no chance of surviving to go through the chain of referral commands from primary to secondary and eventually to tertiary health facilities that are capable of tackling the disease. It can therefore be reasonably presumed that many haemophilia patients in Nigeria die before accessing tertiary healthcare and hence could not have been diagnosed and documented. This situation is largely responsible for the dearth of haemophilia research in Nigeria, notwithstanding the fact that it is the most populous nation in Africa. Consequently, the genetics and frequencies of the various types of haemophilia mutations have not yet been determined in Nigerian patients. However, our HA cohort in this study revealed a higher relative frequency of severe disease, which is probably due to high frequencies of F8 null mutations among Nigerian HA patients. The younger age at diagnosis of patients with severe HA in our cohort is thought to be related to early clinical presentation due to the disease severity and is consistent with a previous report  .
Haemoglobin levels of our patients showed that all patients had moderate to severe anaemia due to active haemorrhage at the time of diagnosis. Moreover, patients with iron deficiency, irrespective of the disease severity, had lower haemoglobin levels with reduced red cell indices due to the additional effect of iron deficiency. Results of this study revealed that about one half of our patients with HA had iron deficiency. In comparison with nonsevere HA, patients with severe HA had a significantly higher frequency of iron deficiency with an RR of 2.6. These data suggest that patients with severe HA were about two and a half times more likely to develop iron deficiency than their counterparts with nonsevere HA. This correlation between severe HA and iron deficiency confirmed our earlier prediction, which is consistent with more frequent and greater blood loss as a result of severe disease. However, it needs to be appreciated that precarious iron stores due to socioeconomic and environmental factors such as poverty, parasitic infections and malnutrition will undoubtedly increase the risk of iron deficiency in African haemophiliac patients in whom the additional effect of recurrent haemorrhage can easily result in iron deficiency.
Clinical implications of iron deficiency in HA go beyond anaemia. Iron deficiency has several adverse implications on wound healing, immunity and mental development that may affect the well-being of patients with HA. Experimental models have demonstrated that a number of bleeding disorders including FXIII deficiency, FIX deficiency and dysfibrinogenaemias adversely affect wound healing, suggesting that efficient haemostasis and adequate fibrin deposition are essential for initiating the healing process  . Although there was no specific study on the effect of wound healing on HA, an experimental study on haemophilia-B (which is clinicopathologically closely related to HA), revealed evidence of impaired wound healing  . Therefore, by implication, HA would also be associated with poor wound healing. Iron deficiency impairs wound healing through a number of mechanisms, which include deregulation of hypoxia-inducible factor expression, decreased lactoferrin-mediated cell proliferation and attenuation of collagen synthesis  . It can therefore be inferred that wound healing in iron-deficient HA patients would be doubly jeopardized by the concurrence of ineffective haemostasis and iron deficiency, both of which are associated with impaired wound healing ,, . Impaired wound healing is highly deleterious in HA patients as it would lead to recurrent and prolonged bleeding from wounds, resulting in more blood loss and iron deficiency, which will further impair wound healing in a vicious cycle. In addition, iron deficiency had been shown to significantly impair the immune response , . It can thus be deduced that iron deficiency would predispose one to wound infection that can further jeopardize wound-healing processes , . Thus, the dual adverse effects of iron deficiency with respect to impaired wound healing and the increased risk of wound infection are obviously undesirable in HA patients in whom prompt wound healing is required to prevent wound dehiscence and recurrence of bleeding from skin injuries. A special concern with regard to iron-deficient haemophiliac children is the fact than iron deficiency is associated with adverse cognitive and psychological effects, which can lead to attention deficit, social withdrawal and poor intellectual attainment in school  . It is therefore imperative that patients with HA should be screened regularly for iron deficiency so that affected patients can be identified promptly and treated.
Despite its beneficial effects, iron therapy in haemophiliac patients must be undertaken with caution. One of the side effects of iron therapy is erosive gastritis, which is commonly associated with iron pills, but not with liquid iron preparations  . Erosive gastritis can increase the risk of gastric haemorrhage, which is not uncommon in haemophiliac patients, especially in those infected by Helicobacter pylori , . The risk of iron-induced erosive gastritis would be higher in iron-deficient older children and adult haemophiliac patients as these age groups are more likely to be treated with iron pills rather than liquid iron preparations. Therefore, HA patients taking iron pills must be closely monitored for clinical features of upper gastrointestinal haemorrhage such as passage of melena stool  . However, the dilemma in this perspective is the fact that iron preparations are generally associated with blackish discoloration of the stool that may be physically and chemically indistinguishable from true melena stool  . In view of these eventualities, we recommend that iron-deficient HA patients, irrespective of their ages, should preferably be treated with liquid iron preparations as they are less toxic to the gastrointestinal tract  . Nonetheless, we believe that the safest and the most convenient way of treating iron deficiency in HA patients is by optimal dietary supplementation with iron-rich food items such as liver and red meat in conjunction with iron-fortified cereal-based meals, all of which are devoid of the side effects of pharmaceutical iron preparations  . It is therefore the responsibility of healthcare givers to apply effective and safe modalities for treating iron deficiency in haemophilia patients.
| Conclusion|| |
Iron deficiency is very common among patients with HA in northern Nigeria. The frequency of iron deficiency was higher among patients with severe HA. Therefore, the disease severity is a risk factor for iron deficiency in HA. Patients with HA should be screened regularly for iron deficiency to initiate early treatment and prevent the adverse impact of iron deficiency on wound healing, the immunity and the mental development of haemophilia patients. However, the possibility of undesirable side effects of iron such as erosive gastritis, which can potentially increase the risk of gastrointestinal haemorrhage in patients with HA, calls for caution in the choice of oral pharmaceutical iron preparations vis-à-vis nonpharmaceutical dietary supplementation.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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