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Year : 2019  |  Volume : 22  |  Issue : 3  |  Page : 416-421

Inhibitors among patients with hemophilia in Basra, Iraq – A single center experience

1 Department of Pediatrics, Al-Muthana Maternity and Children's Hospital, Al-Muthana, Iraq
2 Department of Pediatrics, College of Medicine, University of Basra; Center for Hereditary Blood Disease/Basra Health Directorate, Basra, Iraq

Date of Acceptance13-Dec-2018
Date of Web Publication6-Mar-2019

Correspondence Address:
Prof. M K Hassan
Department of Pediatrics, College of Medicine, University of Basra, Basra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njcp.njcp_388_18

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Introduction: Inhibitor formation is a major complication of hemophilia treatment because it interferes with the clinical response to factor replacement and causes significant morbidity. This cross-sectional study was conducted to assess the presence and frequency of inhibitors among registered person with hemophilia and to identify risk factors associated with inhibitor development. Patients and Methods: A total of 143 hemophilics, 118 with hemophilia A (HA) and 25 with hemophilia B (HB), were enrolled for the study. Participant's clinical data were obtained through patient's medical records. Factor VIII and IX levels and the presence of inhibitors were assessed using a fully automated coagulometer. From the results of a Bethesda assay, patients were divided into those with high titers (≥5 BU) and those with low titers (<5 BU). Results: The patient's age ranged from 1 to 67 years with median of 13.8 years. Inhibitors were detected in 18.6% and none of HA and HB patients, respectively. Of the 22 patients with HA and inhibitors, 18 (82%) had high titer inhibitors. The frequency of inhibitors was significantly higher among patients with severe hemophilia, a history of early exposure (≤3 months) to factor VIII concentrate, and family histories of autoimmune disease and immune system challenges (P < 0.05). The independent risk factors associated with inhibitor development were severe hemophilia (95% CIs = 1.02–55.6, OR = 7.5) and immune system challenges (95% CIs = 1.14–5.99, OR = 2.6). Conclusion: Inhibitors were common among HA patients, and both severe HA and immune system challenges (surgery and trauma) are independent risk factors for inhibitor development.

Keywords: Basra, hemophilia, inhibitors

How to cite this article:
Taresh A K, Hassan M K. Inhibitors among patients with hemophilia in Basra, Iraq – A single center experience. Niger J Clin Pract 2019;22:416-21

How to cite this URL:
Taresh A K, Hassan M K. Inhibitors among patients with hemophilia in Basra, Iraq – A single center experience. Niger J Clin Pract [serial online] 2019 [cited 2019 May 21];22:416-21. Available from:

   Introduction Top

Persons with hemophilia (PWH) are at risk of recurrent musculoskeletal bleeding and, less frequently, life-threatening hemorrhage. Hemophilic arthropathy resulting from recurrent bleeding into the joints is the most common form of morbidity.[1]

The introduction of prophylactic treatment for PWH has led to an improved joint health and a high level of health-related quality of life. However, therapy by the infusion of deficient factors is associated with the development of inhibitors directed against the factors.[2] Inhibitor development is a major complication of hemophilia treatment because it makes managing bleeding episodes difficult, hinders prophylaxis, and leads to significant socio-economic burden on the patient.[3],[4]

Inhibitor formation is a multifactorial and results from the complex interactions between the patient's immune system, genetic, and environmental factors.[3],[5]

The rate of F VIII inhibitor development is high in patients younger than 5 years. Older age groups exhibit a decrease in the relative incidence until the age of 60, at which point the trend is reversed, and a second peak in relative incidence is observed.[5]

Risk factors in inhibitor development include genetic factors (risk is higher for null mutations, non-sense mutations, and intrachromosomal aberrations),[5],[6],[7] race,[8],[9] type of hemophilia, and disease severity. Patients with severe hemophilia are at higher risk for inhibitor formation. Among those with hemophilia A (HA), approximately 25%–30% with severe disease will develop an inhibitor, whereas only 3%–5% of those with moderate disease and less than 0.3% of those with mild hemophilia will do the same.[8],[10],[11]

Of those with severe hemophilia B (HB), inhibitors develop in up to 5%; however, this figure is lower among those with mild and moderate deficiencies.[11]

Studies have suggested the presence of an inverse relationship between age at the commencement of treatment and the risk of developing antibodies against F VIII, without considering other potential confounders.[12],[13]

The use of prophylactic therapy is associated with a lower frequency of inhibitors, even after adjusting for confounders.[9],[14],[15] In countries such as Sweden, where primary prophylaxis has been extensively used for several decades, the inhibitor incidence is similar to that of other cohorts treated with factors on demand.[16]

Inhibitor formation is associated with the inflammatory response (e.g., severe infections and immunizations) has the potential to modulate the immune response and increase the risk of inhibitor formation during replacement therapy.[17],[18]

This study was conducted to assess the frequency of inhibitors in patients with HA and HB who were registered at the Center for Hereditary Blood Diseases (CHBD) in Basra, and to evaluate the potential risk factors for inhibitor development among patients with hemophilia.

   Patients and Methods Top

This cross-sectional study included patients with HA and HB who have been registered at the CHBD. The study was conducted from August 1, 2014 to March 2015.

In total, 156 patients were registered cases of Hemophilia at CHBD. Only 143 patients who had complete records were recruited.

Information was taken from the patients, their parents and from a review of their medical records. These data included date of birth, place of residence, type of feeding during infancy, type of hemophilia, family history of autoimmune disease (vitiligo, diabetes, and thyroid diseases), family history of inhibitors, a history of surgery (e.g., circumcision and herniorrhaphy), trauma, and vaccination during the administration of factor concentrate.

Factor level at diagnosis, age at first exposure to factor replacement, type of treatment (on demand or prophylactic therapy), and blood and blood product exposure were also recorded.

The severity of hemophilia was classified according to the patients' factor VIII or IX levels, where severe was <1%, moderate was 1–5%, and mild was >5% factor level.[10],[19]

Patients were also assessed for history of intensive treatment exposure and early replacement therapy. Intensive treatment is defined as a treatment with rFVIII or F IX for bleeding or surgery for at least 5 consecutive days, whereas early replacement therapy is defined as therapy before 3 months of age.[20]

The inhibitor assay was according to the analysis of the mixing study of activated partial thromboplastin time (aPTT) test. When an inhibitor is present the prolonged aPTT is not corrected by the addition of normal plasma. Inhibitors were quantified using the Bethesda assay method. Normal control plasma, assumed to contain 100% factor VIII activity, was incubated with patient plasma containing the inhibitor. The amount of residual F VIII was then measured. A Bethesda unit is the amount of inhibitor required to neutralize 50% of F VIII in normal control plasma after incubating at 37°C for 2 h.[19] A high titer or high-responding inhibitor was defined as an inhibitor titer of ≥5 Bethesda units.[20],[21],[22] Patients with a positive inhibitor screening test were followed up every 6months using the Bethesda test.

Previously untreated patients (PUPs) are those without prior exposure to F VIII concentrates. Patients with a previous exposure to blood components other than plasma derivatives (i.e., red blood cells or platelets) or with <5 exposure days to fresh frozen plasma were also considered as PUPs.[19]

An informed consent was obtained from patients and/their families before enrollment in the study after approval by the Ethical Committee of the College of Medicine, Basra University.

Statistical analyses

All statistical analyses were conducted using the Statistical Packages for Social Sciences (SPSS) version 17.0, Chicago, IL, USA. Data were expressed as means ± standard deviations; however, the standard error was used when there was significant variation from the mean or extreme values in the sample data were present. Comparisons of proportions were performed using the crosstab module using Chi square test when each cell had an expected frequency of five or more, and Fisher's exact test was used when one or more of cells had an expected frequency of less than five in a 2×2 table.

A binary logistic regression analysis was also conducted to analyze different variables, and an odds ratio and 95% confidence intervals were assessed. For all tests, a P value of < 0.05 was considered as significant.

   Results Top

A total of 143 patients with hemophilia were enrolled for this study: HA (118) and HB (25). Approximately, 39.8% of registered patients with HA had a severe form of the disease, and more than one-third were older than 15 years old, whereas 56% of the patients with HB had a mild form of the disease, and nearly half were younger than 5 years old. Of the 143 patients, only 6 (8.2%) were regarded as PUPs [Table 1].
Table 1: Selected characteristics of the studied patients by type of hemophilia

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This study found that 18.6% of patients with HA presented with inhibitors, whereas none of patients with HB presented with inhibitors.

Among patients with HA, most inhibitors were of high titer; 18 (82%) had a mean titer of 25.33 ± 3.37, whereas only 4 (18%) were of low titer with a mean of 3.75 ± 0.51. The overall frequency of inhibitors among those with severe disease was 11.9%, compared with 5.9% and 0.8% among patients with the moderate and mild disease types, respectively.

A significantly higher percentage of patients with inhibitors had a history of early exposure (≤3 months) to F VIII than those without inhibitors. In addition, among those 3 months old or younger with inhibitors, 3 (37.5%) were less than 1 month old at first exposure. There was no significant differences were observed with regard to age distribution or type of feeding among patients with and without inhibitors [Table 2].
Table 2: The distribution of inhibitors among patients with hemophilia A by selected patient variables

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Only 28 (19.6%) of patients were on prophylactic regimen. A significantly higher percentage of patients with inhibitors received early intensive treatment by rF VIII, P < 0.05, whereas no significant differences were found with regard to the frequency of inhibitors between patients on demand therapy and those on prophylaxis [Table 2].

Inhibitors were also significantly higher among patients with family histories of inhibitors and autoimmune diseases, especially thyroid diseases, immune system challenges prior to surgery, and trauma than those without family histories of inhibitors [Table 3].
Table 3: The distribution of inhibitors by family history of inhibitors and autoimmune diseases

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The independent risk factors for inhibitor development demonstrated in this study included severe hemophilia and immune system challenges [Table 4].
Table 4: Independent risk factors for inhibitor development

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   Discussion Top

Inhibitor formation is a major complication of hemophilia treatment that interferes with the clinical response to factor infusion and results in significant morbidity.[5]

In Iraq, there is one Hereditary Blood Diseases Center in every governorate that provides care for such patients, except in Baghdad where three centers are present.

The frequency of inhibitors among patients with HA was 18.6% in the current study, and no inhibitors were detected among those with HB.

In comparison with other Iraqi governorates, Albeldawi DH reported that the frequency of inhibitors in patients with HA registered at the main Hemophilia Center in Baghdad was 12.8%, and among those with HB was 9%.[23] In Diyala governorate in central Iraq, Lateef IA reported that 5.3% of patients with HA had inhibitors, and none in those with HB;[24] the frequency of inhibitors among those with severe hemophilia is 11%.[25]

Owaidah TM reported that the rates of inhibitors in patients with HA and HB are 22% and 0%, respectively, in Saudi Arabia,[26] whereas Borhany et al. reported that the prevalence of F VIII inhibitors is 15% in Pakistan.[27]

Although the prevalence of inhibitors reported in the current study is comparable to that of other parts of Iraq and neighboring countries, the explanations for the relatively low frequency of inhibitors are the high percentage of previously treated patients (95.8%) in the studied sample, where inhibitor development, is on average, a milder event than in PUPs.[28] Other explanations are the high percentage of patients with mild and moderate disease severity (60%) and low frequency of early intensive treatment by rFVIII (9.8%).

The majority of the patients in the current study with severe HA presented with inhibitors, and disease severity was an independent risk factor for inhibitor development, a finding similar to that of other studies.[15],[29]

Most patients with inhibitors have high titer inhibitors. The risk for high titer inhibitors development might be related to underlying gene mutations, FVIII dose, age at first FVIII administration, type and sensitivity of the test used to detect the inhibitor, and the frequency of inhibitor testing.[30]

Inhibitors were found in a significantly higher percentage of patients who initiated treatment with F VIII at <3 months of age. This result is consistent with the studies conducted in Spain by Lorenzo et al.,[12] and those by van der Bom et al. conducted in the Netherlands [13] who observed a relationship between age at first F VIII exposure and subsequent inhibitor development; those treated at a younger age showed a higher incidence of inhibitor development. However, Chalmers et al. did not observe a significant difference among children treated at different time points during the first year of life in the UK.[31] These differences might be attributed to genetic risk type of F VIII mutation, concomitant immune system defects, and the type and regimen of treatment used, which might modulate the ability of the body to produce antibodies.[15]

Only 2% of patients had a positive family history of inhibitors; this rate is lower than that reported by Gouw et al. in the Netherlands, where 15% of patients had a positive family history of inhibitors.[15] Similarly, Payandeh et al. found a rate of 4.9% in Iran.[32] This finding might reflect the influence of a gene mutation, despite the small number of patients with inhibitors in the current study.

Although one-third of patients with inhibitors had a history of early intensive treatment, this variable was not an independent risk factor for inhibitor formation. This result conflicts those of other studies that reported a significant association between inhibitor development and early intensive treatment with F VIII.[33],[34]

Inhibitors were reported in a significantly higher frequency among patients with hemophilia who had surgery or major trauma, and these immune challenges were independent risk factors for inhibitor formation in the current study.

The increased risk of inhibitors after intensive treatment can be attributed to the significant concentrations of circulating F VIII protein with extensive tissue damage and associated inflammation during intensive treatment for bleeding and surgery. These effects might cause the release of interferon, IL-1, and CD 40 as well as the breakdown products of damaged vessels that might enhance the antibody response against F VIII.[15],[35]

Despite the low percentage of patients on prophylactic therapy in the current study, this type of treatment was not an independent risk factor for inhibitor development. In Sweden, Knobe et al. found that the inhibitor incidence seemed to be similar in cases of prophylactic versus on-demand therapy.[16] However, Shirahata et al.,[29] and Santagostino et al.[14] in Japan and Italy, respectively, have shown that before inhibitors development, the dosing in prophylaxis will, in many cases, be similar to that of low-dose immune tolerance therapy. Furthermore, the use of prophylaxis is associated with a reduced percentage of inhibitors.

Limitations of the study

The relatively small number of studied patients and the unavailability of genetic testing as the type of mutation is a strong determinant of inhibitor development in these patients.

   Conclusion Top

This study found that inhibitors are detected primarily among patients with HA. Furthermore, severe HA and immune system challenges (i.e., surgery and trauma) are independent risk factors for inhibitors development.

Financial support and sponsorship


Conflict of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 4]


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