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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 24  |  Issue : 1  |  Page : 18-22

Frequency of hemophilia and hemostatic evaluation in persons with bleeding symptoms in Southeast, Nigeria


1 Department of Physiology, University of Nigeria, Nsukka, Nigeria
2 Department of Haematology and Immunology, Bleeding and Thrombosis Unit, University of Nigeria Teaching Hospital, Ituku Ozalla, Enugu, Nigeria

Date of Web Publication1-Aug-2019

Correspondence Address:
Dr. Theresa U Nwagha
Department of Haematology and Immunology, University of Nigeria Teaching Hospital, Ituku Ozalla, Enugu
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmh.IJMH_2_19

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  Abstract 

Background: A significant number of people living with hemophilia and other bleeding disorders are reported to be either underdiagnosed or untreated in most developing countries. Objectives: To evaluate the frequency of hemophilia and some hemostatic parameters in persons with bleeding symptoms in Southeast Nigeria. Materials and Methods: This was a cross-sectional, hospital-based pilot study of 50 persons consecutively recruited with bleeding symptoms from four tertiary hospitals in Southeast Nigeria. Full blood count was carried out using Mythic 22 semiautomated analyzer, (Orphee, Geneva, Switzerland). Prothrombin time (PT) and activated partial thromboplastin time (APTT) mixing studies and one-stage factor assays were carried out using tube tilt technique. Bleeding score was assessed using the International Society on Thrombosis and Haemostasis bleeding assessment tool. Data were analyzed using the Graphpad Prisim, version 6.0, San Diego. Results: Only 2% of the subjects had hemophilia A, whereas 68% of the subjects had thrombocytopenic bleeding. Most (32.4%) had bleeding score of four. Analysis of variance of these variables showed a significant relationship with P < 0.0001. Post hoc analysis showed significant P values for platelet count versus bleeding score (P = 0.000, 95% confidence interval [CI]: 95.74–126.4) and APTT versus bleeding score (P = 0.000, 95% CI: 44.34–74.98). Conclusion: Bleeding assessment tools are important in evaluating persons with bleeding symptoms and it may be necessary to screen for hemophilia in these cases. Larger multicenter epidemiological studies are needed to determine the prevalence of hemophilia and other bleeding disorders in our environment.

Keywords: Bleeding assessment tool, bleeding symptoms, hemophilia


How to cite this article:
Okparaoka S, Nwagha TU, Anyaehie B. Frequency of hemophilia and hemostatic evaluation in persons with bleeding symptoms in Southeast, Nigeria. Int J Med Health Dev 2019;24:18-22

How to cite this URL:
Okparaoka S, Nwagha TU, Anyaehie B. Frequency of hemophilia and hemostatic evaluation in persons with bleeding symptoms in Southeast, Nigeria. Int J Med Health Dev [serial online] 2019 [cited 2019 Oct 22];24:18-22. Available from: http://www.ijmhdev.com/text.asp?2019/24/1/18/263544




  Introduction Top


Bleeding disorder affects 1 in 1000 men and women globally,[1] with hemophilia being the most well-known inherited bleeding disorder, although it is relatively rare and affects mostly males. The World Federation of Hemophilia (WFH) estimates that the prevalence of hemophilia worldwide is 105 and 28 per million males of hemophilia A and B, respectively. With a global population of six billion, this would give a prevalence of approximately 315,000 and 84,000 persons living with hemophilia (PLWH) A and B, respectively.[2] Data collected among 84 countries showed that approximately 115,000 persons have hemophilia, which means that approximately 70% of PLWH remain undiagnosed and untreated mostly in developing countries, including Nigeria.[2]

Other types of bleeding disorders present with varying types of bleeding symptoms. To limit the subjectivity of these self-reported symptoms, assessment tools have been developed over the years with the key objective to ensure reproducibility and collection of the bleeding history.[3] They presented an easy, cost-effective alternative from the expensive, complicated diagnostic tests of some bleeding disorders. International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT) was developed in 2010.[4] Its pre-validated diagnostics generates data on the frequency and severity of bleeding symptoms by assigning scores to each bleeding symptom.[4] In 2014, a consensus from combining data from other assessment tool scores and cutoff was set: ≥4 (males), ≥6 (females), and ≥3 (children).[5]

ISTH observed that majority of persons with hemophilia in the world have not been diagnosed because of lack of diagnostic capabilities, no access to proper care, no economic means of managing those persons, and little or no available factor VIII replacement therapy.[6] In Nigeria, there is a paucity of data on the prevalence and characterization of hemophilia; however, on the basis of WFH, it is estimated that there are 9,000–12,000 PLWH in Nigeria.[7]

The research question is what is the prevalence of hemophilia among persons with suspected bleeding disorders in Nigeria? With the resultant increase in disease-related morbidity and mortality in childhood, chronic pain, and crippling disabilities requiring lifelong care[2],[6] in adulthood, the disease burden affects the quality of life, socioeconomic status, and ability to contribute positively to the society. Equally, there is a need to assess the bleeding symptoms with a validated assessment tool that offers a cost-effective diagnostic tool to identify bleeding disorders other than hemophilia. Therefore, this pilot study aims at evaluating the frequency of hemophilia and bleeding parameters of persons with bleeding symptoms using ISTH BAT in Southeast Nigeria.


  Materials and Methods Top


Fifty consecutive consenting persons with bleeding symptoms (epistaxis, menorrhagia, bleeding into cavities, musculoskeletal bleeding, and hematuria) were recruited from the four tertiary hospitals in Southeast Nigeria—University of Nigeria Teaching Hospital, Federal Teaching Hospital Abakaliki, Nnamdi Azikiwe Teaching Hospital Nnewi, and Federal Medical Center Owerri (involving all age groups)—excluding those persons with liver disease (deranged liver function and positive hepatitis screening tests), anticoagulant therapy, and aspirin therapy, between June 2015 and January 2016. This study was reviewed and approved by the institutional review board of University of Nigeria Nsukka, College of Medicine, Research Ethics Committee with protocol number: 004/05/2015.

Sample size calculation

The sample size was determined using formula:



where, N = minimum sample size, Z = coefficient of Z statistics obtained from standard normal distribution, P = Proportion (in %) Q = 1 − P, and D = sample error tolerated (in %).{Inline 1}

Using a prevalence of 2.3%[6] at a confidence limit of 95% (D = 5%) and Z of 1.96, the minimum sample size (N) is calculated as:{Inline 2}



Thus, the calculated minimum sample size (N) was approximately 35 for the study; however, the sample size was increased to 50 persons with bleeding symptoms.

Bleeding assessment tool

ISTH BAT validated questionnaires were administered to all enrolled patients. Demographics (social and disease) and bleeding score data were also collected using case report forms.

Sample collection and preparation

Blood sample was collected by venipuncture using sterile procedure. This was carried out within 1min or less of tourniquet application. A total of 7mL of blood was collected, then 2mL of that blood was added into sodium ethylenediaminetetraacetic acid (EDTA) for full blood count and 4.5mL of the same blood was added into citrate tubes containing 0.5mL of 0.105–0.109 M (3.2%) aqueous trisodium citrate, maintaining the proportion of blood to citrate as 9:1. Prompt and adequate mixing with citrate solution was carried out by gentle inversion. Collected samples were transported to the laboratory within 1h, and plasma was separated by double centrifugation method within 4h of collection. Platelet-poor plasma was drawn in aliquots into 1mL micro-vials, stored at −70°C freezer, and later tested in batches. The blood samples collected were subjected to full blood count, coagulation screening test, prothrombin time (PT), activated partial thromboplastin time (APTT) mixing studies and factors VIII and IX bioassay. Data were analyzed using the Graphpad Prisim, version 6.0, San Diego. Probability of <0.05 was considered as statistically significant.


  Results Top


Sociodemographic characteristics

Of the 50 patients recruited, 56% (28/50) were males and 48% (22/50) were females, the median age of the subjects was 39 years (range: 1–85 years, 95% confidence interval [CI]: 29–41; P, 0.90). [Table 1] further shows their sociodemographic parameters in detail.
Table 1: Demographic characteristics of the subjects

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Hematological parameters

Anemia (hemoglobin [Hb] < 10g/dL) was seen in 54% of the patients, the median Hb was 8.7g/dL (range: 4–16g/dL, 95% CI: 8–10; P = 0.24). Thrombocytopenia (platelet count < 100.0 × 109/L) was seen in 32% (16/50) of the patients, the median platelet count was 102 × 109/L (range:14–212 × 109/L, 95% CI: 101–129; P < 0.0001), platelet indices were not measured. Further details of the hematological parameters of the subjects with bleeding disorders are shown in [Table 2] and [Figure 1].
Table 2: Statistics of hemostasis parameters and ISTH bleeding assessment score of the subjects

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,
Figure 1: Abnormal versus normal hemostatic parameters among subjects

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Coagulation test parameters

Twenty-two percent (11/50) of the subjects had prolonged PT, the median PT was 13s (range: 10–14s), whereas 14% (7/50) had prolonged APTT, the median APTT was 56s (range: 40–240s). Detailed information is shown in [Table 2] and [Figure 2]. Factor VIII assay of subjects with isolated prolonged APTT showed that 2% (1/50) had factor VIII deficient plasma (hemophilia A), factor level was 12.5%. No factor IX deficiency was detected. Detailed information on the coagulation tests is given in [Table 2] and [Figure 1].
Figure 2: Types and frequency of bleeding symptoms seen in subjects

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Bleeding parameters

The bleeding symptoms of the subjects showed that the most common bleeding symptom was gastrointestinal bleeding (24%, n = 12/50) and the least common presenting symptom was intracranial bleeding (1.4%, n = 3/50). Detailed information is given in [Figure 2]. Total bleeding scores (TBSs) of the study subjects showed that majority of the cumulative frequency (32.4%) had a TBS of 4, whereas 1.0% had a bleeding score of 1. Detailed information is present in [Table 3]. Post hoc analysis showed significant P values for platelet count versus bleeding score (P = 0.000, 95% CI: 95.74–126.4) and APTT versus bleeding score (P = 0.000, 95% CI: 44.34–74.98).
Table 3: TBSs of the subjects

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  Discussion Top


Results obtained from this pilot study showed that of the 50 subjects with bleeding disorders, 2% were deficient for factor VIII (hemophilia A) and their clinical severity was within mild range. This supports the work done on male infants undergoing circumcision in Southwest Nigeria; about 1.64% was diagnosed of having hemophilia A and studies done on prevalence of hemophilia around the world[5] and in West Africa[9] showed that about 2.69 and 2.3 per 100,000 male birth respectively has hemophilia. A study carried out in India stated that 78.7% of those with bleeding disorders had hemophilia,[6] which was not in agreement with this study where 2% of those with bleeding symptoms had hemophilia, this could be traced to the fact that the study performed in India excluded persons with bleeding disorder due to acquired causes, which may be the possible reason for a higher percentage of persons with hemophilia, whereas this study included both subjects with bleeding disorders arising from acquired or inherited causes.

Significant number of studies[9],[10],[11],[12] reported that hemophilia A (factor VIII deficiency) was more common than hemophilia B (factor IX deficiency), which supports the results obtained from this study as all subjects diagnosed with hemophilia had factor VIII deficiency (hemophilia A). A study carried out in Korea[10] on clinical severity of hemophilia cases stated that the severe form was the most common presenting form of hemophilia due to the severity of their bleeding episodes resulting in seeking medical care early; however, the report was not in agreement with this study where the subjects with hemophilia were of mild form, this could be because this study was a pilot study with a small size in a heterogeneous population with bleeding symptoms.

Results from this study also showed that thrombocytopenia was found in 32% of the subjects with bleeding symptoms, this supports the statement by the American Society of Hematology on bleeding disorder, which states that platelet disorder is the most common cause of bleeding disorder and is usually acquired rather than inherited,[13] this implies that platelet count abnormality is a major cause of bleeding disorder also in Southeast Nigeria as platelet plays a significant role in hemostasis (blood clotting). Abnormal coagulation screening test was also observed in this study and it supported the fact that although clotting factor abnormality is also a major cause of bleeding disorders, it is not as common as the platelet abnormality.[13] Prolonged APTT was found in approximately 14% of subjects with bleeding symptoms, this agreed with the study carried out in Korea on hemophilia where APTT was prolonged in cases of patients with hemophilia,[10] this further supported the fact that prolonged APTT with normal PT may be a possible indication of either factor VIII (hemophilia A) or factor IX (hemophilia B) deficiency or the presence of an inhibitor.[14] In this study, only factors VIII and IX bioassays were performed.

The most common bleeding symptom observed in this study was gastrointestinal bleeding (23.8%), whereas bleeding from central nervous system (1.4%) was the least observed symptom. This result supported the work carried out in Korea on bleeding symptoms, which showed that gastrointestinal bleeding was observed as the most common bleeding complication.[9] Online-based questionnaire study of 500 healthy adults showed that 47% of the subjects reported heavy menstrual bleeding and 25% of the subjects reported epistaxis.[15] These findings were not in agreement with the result of this study, again the small sample size was contributory. Another reason could be that healthy adults were used instead of subjects with bleeding symptoms that were used in this study. Also, studies performed in Northern and Southwestern Nigeria suggested that post-circumcision bleeding was the most common presenting symptoms of hemophilia,[9],[16] which did not agree with this study where gastrointestinal bleeding was the most common presenting symptoms, possibly because this study involved all age groups with bleeding symptoms when compared to a study carried out only on infants undergoing circumcision.

More than 80% had TBS >3 meaning approximately 80% of this study population had abnormal bleeding history as stated by the Vicenza group.[17] Also, more than 32% of the study population had a TBS = 4.

The demographic distribution of our test subjects supported the studies conducted by Mauer et al.[15] and Bruno et al.,[18] which showed the mean ages were 40 years, males (50%) and females (40%). A study performed in sub-Saharan Africa was not in agreement with this study as their mean age was approximately 15 years,[12] which could be because their study was based on PLWH and those cases presented at a younger age, whereas this study was on a wide range of age distribution with bleeding symptoms. Full blood count results of the subjects showed that anemia was found in 54% of them with bleeding disorder, this was because most of the persons with bleeding symptoms presented with blood loss (internal or external) and may also be prolonged or heavy, leading to anemia. This was in accordance with the study by Bruno et al.[18] as they detected anemia in more than 50% of patients with bleeding symptoms.


  Conclusion and Recommendation Top


This pilot study was able to provide an insight on the frequency of hemophilia and bleeding parameters of the persons with bleeding symptoms in Southeast Nigeria. ISTH BAT offers an easy, cost-effective diagnostic tool to assess subjective bleeding symptoms and history. Results could either imply that hemophilia, though rare, probably has a high disease burden or is underdiagnosed as earlier suggested by other authors.

We recommend the routine application of ISTH BAT and screening for hemophilia (APTT, if prolonged mixing experiments, factors VIII, and IX) in cases with bleeding symptoms when indicated. This could translate to high index of clinical suspicion with resultant better health care, improved quality of life, increased life expectancy, and reduction of complications.

Furthermore, large multicenter studies may be needed to determine the national prevalence of hemophilia and etiology of platelet disorders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Skinner MW WFH: Closing the global gap-achieving optimal care. Haemophilia 2012;18:1-12.  Back to cited text no. 1
    
2.
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Fasulo MR, Biguzzi E, Abbattista M, Stufano F, Pagliari MT, Mancini I, et al. The ISTH Bleeding Assessment Tool and the risk of future bleeding. J Thromb Haemost 2018;16:125-30.  Back to cited text no. 3
    
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Elbatarny M, Mollah S, Grabell J, Bae S, Deforest M, Tuttle A, et al. Normal range of bleeding scores from the ISTH-BAT: Adult and pediatric data from the merging project. Haemophilia 2014;20:831-5.  Back to cited text no. 4
    
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Cochran WG Sampling Techniques. 2nd ed. New York: John Wiley; 1977.  Back to cited text no. 7
    
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Diop S, Seck M, Sy-Bah D, Faye BF, Sow-Ndoye A, Gueye YB, et al. Implementing haemophilia care in Senegal, West Africa. Haemophilia 2014;20:73-7.  Back to cited text no. 8
    
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Fakunle EE, Shokunbi WA, Shittu OB Incidence of factor VIII C deficiency in live male infants undergoing circumcision. Haemophilia 2007;13:567-9.  Back to cited text no. 9
    
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Kir-Young K, Chang HY, Myong JC, Munho L Comprehensive clinical and statistical analysis of haemophilia in Korea. J Korean Med Sci 1988;3:107-15.  Back to cited text no. 10
    
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Lucia JF, Aznar JA, Abad-Franch L, Escuin RR, Jimenez-Yuste V, Perez R Prophylaxis therapy in haemophilia A: Current situation in Spain. Haemophilia 2011;17:75-80.  Back to cited text no. 11
    
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Tagny C, Moudourou S, Mbanya D Haemophilia in developing countries: An analysis of first data in Cameroon, Africa. J Blood Lymph 2014;4:1-4.  Back to cited text no. 12
    
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American Society of Hematology. Helping haematologists conquer blood diseases worldwide. 2013. Available from: http://www.haematology.org/patients/ bleeding.aspx. [Last accessed on 2016 Oct 14].  Back to cited text no. 13
    
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Kitchen S, McCraw A, Echenagucia E Diagnosis of Haemophilia and Other Bleeding Disorders: A Laboratory Manual. 2nd ed. Montreal Quebec, Canada: WFH Publications; 2010. pp. 40-67.  Back to cited text no. 14
    
15.
Mauer AC, Khazanov NA, Levenkova N, Tian S, Barbour EM, Khalida C, et al. Impact of sex, age, race, ethnicity and aspirin use on bleeding symptoms in healthy adults. J Thromb Haemost 2011;9:100-8.  Back to cited text no. 15
    
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Mba EC, Kulkarni AG, Fleming AF, Emembolu J Haemophilia in northern Nigeria. Acta Haematology 1995;41:59-62.  Back to cited text no. 16
    
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Bowman M, Mundell G, Grabell J, Hopman WM, Rapson D, Liticrap D Generation and validation of the condensed MCMDM-1 VWD bleeding questionnaire for von Willebrand disease. J Thromb Haemost 2008;6:2062-6.  Back to cited text no. 17
    
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Bruno A, Gabriele C, Antonio C, Giancarlo D, Emilio D, Bruno M, et al. Gastrointestinal causes of refractory iron deficiency anaemia in patients without gastrointestinal symptoms. Am J Med 2001;111:439-45.  Back to cited text no. 18
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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