Abstract
Background
Inherited bleeding disorders can lead to lifelong bleeding; they are mainly caused by quantitative or qualitative defect of coagulation factors, von Willebrand factor (VWF) or platelets. No published data are available about the different types of inherited bleeding disorders in Iraq.
Objectives
To describe types, severity and presentation of inherited bleeding disorders in pediatric patients in the major referral center in Iraq.
Patients and Methods
This is a cohort prospective descriptive study conducted at the National Center of Hematology, a referral center for bleeding disorders in Baghdad-Iraq, from January 2015 to December 2019. One hundred ninety-one patients, aged 1 day to 14 years, with suspected inherited bleeding disorder are included in this study. Each patient was interviewed, accompanied by a chaperone, mostly parent(s), with revision of personal and familial bleeding history, conducting a brief medical examination, and withdrawing blood for complete blood count, peripheral blood film, bleeding time, PT and APTT. Further investigations including mixing studies, lupus anticoagulant, clotting factor activity, VWF:antigen (VWF:Ag), VWF: Ristocetin cofactor (VWF:RiCof) and platelet function tests using light transmission aggregometry were performed only if indicated.
Results
The mean ± 1SD of age of patients is 5.3 ± 3 years, with a male:female ratio of 1.3:1. Family history of a similar bleeding disorder is recorded in 44.9% patients (P < 0.05). Consanguineous marriage was observed in 70.8% of the families (P < 0.001). The most prevalent inherited bleeding disorder is von Willebrand disease (VWD) (43.9%), of which type 3 is the most common (86.9%). Thrombasthenia is the second most prevalent (39.8%) inherited bleeding disorder; of these, the majority have Glanzmann’s thrombasthenia (82.9%). Hemophilia A is found in 9.4% of patients.
Conclusion
Type 3 VWD, Glanzmann’s thrombasthenia and hemophilia A are the most common inherited bleeding disorders in the central part of Iraq, collectively they constitute >86% of patients. Consanguineous marriage should be discouraged in our society to decrease hereditary bleeding disorders. Also, there is a need to increase awareness and knowledge of bleeding disorders to improve early identification, mitigate the risk of further bleeding and prevent complications.
Keywords: Inherited bleeding disorders, Von willebrand disease, Severity of bleeding, Glanzmann thrombasthenia, Hemophilia A
Introduction
Inherited bleeding disorders (IBD) are heterogeneous group of rare diseases that can lead to lifelong bleeding; they are mainly caused by quantitative or qualitative defect of coagulation factors or platelets.
Hemophilia A, von Willebrand disease (VWD) and platelet function defect comprise the majority of inherited coagulation disorders in Saudi Arabia, Turkey and Iran, the countries neighboring Iraq. The higher degree of consanguineous marriages in these countries may play a crucial role in the higher prevalence of these rare inherited disorders [1–3].
Despite the impact of IBD, there are no published data available about the types and characteristics of these disorders in Iraq.
Therefore, this study was conducted with the aim of describing types, severity and presentation of inherited bleeding disorders in pediatric patients in the National Center of Hematology in Baghdad-Iraq.
Patients and Methods
This is a cohort prospective descriptive study conducted at the National Center of Hematology, a referral center for bleeding disorders in Baghdad-Iraq, from January 2015 to December 2019. One hundred ninety-one patients, aged 1 day to 14 years, with suspected inherited bleeding disorder are included in this study. Each patient was interviewed, accompanied by a chaperone, mostly parent(s), with revision of personal and familial bleeding history and conducting a brief medical examination by the same physician.
First-line hemostatic laboratory investigation included complete blood count with peripheral blood film, blood group, Ivy’s bleeding time, prothrombin time (PT), and activated partial prothrombin time (APTT).
Further investigations were carried out as per the requirements including mixing studies for patients with prolonged PT and/or APTT. Clotting factor activity assay was performed accordingly for suspected clotting factor deficiency using one-stage coagulometric method, and acetic acid clot solubility test performed for suspected FXIII deficiency.
Von Willebrand antigen level (VWF:Ag) was measured by enzyme-linked immunosorbent assay technique, ELISA; and ristocetin cofactor activity, VWF:RiCoF was determined using stabilized platelets aggregated with VWF and ristocetin antibiotic using light trans-illumination aggregometry (LTA) (Platelet Aggregation Profile {PAP-E8}, Bio/DATA Corporation, USA), both tests were performed for patients with suspected hemophilia A and VWD.
Classification of types of VWD was according to the International Society of Thrombosis and Hemostasis [4]. As VWF is an acute-phase reactant protein and is affected by many factors such as stress, exercise, use of corticosteroids, presence of infection and/or inflammation; therefore, evaluation was repeated after proper rest and/or required management when the result of VWF was normal despite clinical suspicion of VWD. Blood group O have a lower than normal value of VWF:Ag and VWF:RiCoF [4], which was taken in consideration during evaluation of the investigations. The diagnosis of Type 3 was made when the activity and/or level of VW Ag is 3% or less, with prolonged bleeding time and low levels of FVIII [5]. Platelet function test was performed by LTA, platelet aggregation was studied with 5 agonists: adenosine diphosphate, epinephrine, collagen, arachidonic acid, and high and low dose ristocetin.
This study was approved by the Ethical Committee of the institution and was conducted in accordance with Helsinki’s declaration [6]. Informed consent was obtained from caregivers.
Inclusion criteria included neonates and children aged up to 14 years old with repeated/prolonged bleeding episodes and clinical suspicion to have hereditary bleeding disorders, including those with family history of similar bleeding.
Patients with clinical and laboratory features suggesting acquired bleeding disorders were excluded from the study.
A thorough bleeding history and brief medical examination were recorded, with number, site and duration of bleeding episodes, bleeding after circumcision or surgical interventions, admissions to hospital, blood and blood product administration, family history of bleeding and parental consanguinity.
Severity of bleeding was assessed according to the European Network of Rare Bleeding Disorders, 2012, in which patients are divided into three categories (grade I, bleeding after trauma; grade II, spontaneous minor bleeding; and III, spontaneous major bleeding) according to the severity of their bleeding episodes, the location of the bleeding and its clinical impact and whether it was spontaneous or induced [7].
Statistical analysis of all data was performed using statistical program SPSS version 23 (Chicago: SPSS Inc.). The mean of the variables is determined, while a comparison of the variables was estimated by applying Chi-square. A P value ≤ 0.05 is considered statistically significant.
Results
One hundred ninety-one patients of pediatric age group with IBD are included in this study. The mean age is 5.3 ± 3 years, with a range of 1 month to 14 years. Patients aged 1–5 years comprised 45.5% of all patients. Male patients are 108 (56.5%), male: female ratio is 1.3:1. A family history is reported in 86 (44.9%) patients; (P = 0.05). The parents of 135 (70.8%) patients had consanguineous marriage (P < 0.0001). The majority of patients are from Baghdad (75; 39.3%), and the south governorates (76; 39.9%) including Babylon, Karbala, Najaf, Dewania, Muthana and Basra (Table 1). In Table 2, the types of deficiencies in patients with IBD are presented. Spectrum of bleeding episodes in IBD patients are shown in Table 3.
Table 1.
The demographic characteristics of patients with IBD
| Parameter (n = 191) | No. (%) | |
|---|---|---|
| Gender | Male | 108 (56.5%) |
| Females | 83 (43.5%) | |
| Age group (years) | Birth-1 | 21(10.9%) |
| 1–5 | 87(45.5%) | |
| 6–10 | 60(31.4%) | |
| 11–14 | 23(12, 1%) | |
| Family history of similar bleeding | Yes | (44.9%) |
| No | (55.1%) | |
| Consanguinity | Yes | (70.8%) |
| No | (29.2%) | |
| Residency | Baghdad | 75 (39.3%) |
| South | 76 (39.9%) | |
| East | 19 (10.1%) | |
| North | 12 (6.2%) | |
| West | 9 (4.5%) | |
Table 2.
Types of bleeding disorder
| Bleeding disorders (n = 191) | No | |
|---|---|---|
|
VWD n = 84(43.9%) |
Type 3 | 73 |
| Type 2A or 2M | 5 | |
| Type 2B | 2 | |
| Type 1 | 2 | |
| Pseudo (Platelet-type) | 2 | |
|
Thrombasthenia n = 76 (39.8%) |
GT | 63 |
| BSS | 5 | |
| Other PFD | 8 | |
|
Hemophilia A n = 16 (8.4%) |
Severe | 12 |
| Moderate | 2 | |
| Mild | 2 | |
|
Hemophilia B n = 2 (1.0%) |
Severe | 1 |
| Moderate | 1 | |
|
RBD n = 13(6.8%) |
FVII | 6 |
| FXI | 2 | |
| FV | 1 | |
| FX | 1 | |
| Afibrinogenemia | 1 | |
| FXIII | 2 | |
VWD von Willbrand disease, GT Glanzmann’s thrombasthenia, BSS Bernard Solier syndrome, PFD platelet function defect, RBD rare bleeding disorders
Table 3.
Spectrum of bleeding episodes in IBD patients
| Type of Bleeding | No. (%) |
|---|---|
| Ecchymosis | 124 (64.9%) |
| Epistaxis | 86 (49%) |
| Bleeding from minor wound | 68 (35.6%) |
| Oral bleeding | 39 (20.4%) |
| Menorrhagia/ no. of girls after menarche | 8/9 (88.9%) |
| GI bleeding | 22 (11.5%) |
| Hemarthrosis | 10 (5.2%) |
| Hematoma | 6 (3.1%) |
| Umbilical bleeding | 3 (1.6%) |
| Hematuria | 3 (1.6%) |
| CNS bleeding | 2 (1%) |
In this study, 84 (43.9%) are diagnosed with VWD, the majority of patients have type 3 VWD (73 patients; 86.9%). The second most common IBD observed is thrombasthenia (76 patients; 39.8%), among them, 63 patients (82.9%) have Glanzmann’s thrombasthenia (GT) (Table 2). With respect to the type of bleeding episodes and their severity, the most common type of bleeding is ecchymosis (64.9%), followed by epistaxis (49%) and bleeding following minor wounds (35.6%) (Table 3). In Table 4 the severity of bleeding in patients with IBD is demonstrated.
Table 4.
Severity of bleeding in patients with IBD
| Type of deficiency n = 191 | No | Grade I | Grade II | Grade III | |
|---|---|---|---|---|---|
|
VWD n = 84 (43.9%) |
Type 3 | 73 | 0 | 41 (56.2%) | 32 (43.8%) |
| Type 2A or 2M | 5 | 0 | 4 (80%) | 1(20%) | |
| Type 2B | 2 | 0 | 2 (100%) | 0 | |
| Type 1 | 2 | 0 | 2 (100%) | 0 | |
| Pseudo | 2 | 0 | 2 (100%) | 0 | |
|
Thrombasthenia n = 76 (39.8%) |
GT | 63 | 0 | 51 (80.9%) | 12 (19.1%) |
| BSS | 5 | 0 | 5(100%) | 0 | |
| Other PFD | 8 | 3 (37.5%) | 3 (37.5%) | 2 (25%) | |
|
Hemophilia A n = 16 (8.4%) |
Severe | 12 | 0 | 8 (66.7%) | 4 (33.3%) |
| Moderate | 2 | 0 | 1 (50%) | 1 (50%) | |
| Mild | 2 | 0 | 2 (100%) | 0 | |
|
Hemophilia B n = 2 (1.0%) |
severe | 1 | 0 | 1 (100%) | 0 |
| Moderate | 1 | 0 | 1 (100%) | 0 | |
|
RBD n = 13 (6.8%) |
FVII | 6 | 1 (16.7%) | 3 (50%) | 2 (33.3%) |
| FXI | 2 | 0 | 2 (100%) | 0 | |
| FV | 1 | 0 | 1 (100%) | 0 | |
| FX | 1 | 0 | 1 (100%) | 0 | |
| Afibrinogenemia | 1 | 0 | 0 | 1 (100%) | |
| F XIII | 2 | 0 | 0 | 2 (100%) | |
IBD inherited bleeding disorders, VWD von Willbrand disease, GT Glanzmann thrombasthenia, BSS Bernard Solier syndrome, PFD platelet function defect, RBD rare bleeding disorders
Discussion
IBDs are rare, usually difficult to manage and expensive to treat. Because consanguineous marriages are common in Iraq, 70.8% in the current study, the prevalence of IBDs is likely to be higher; however, insufficient data are published.
VWD is the most common IBDs, with a prevalence of 1–2% [8]. In theory, patients with VWD should be diagnosed with Type 1 VWD in the majority of patients, followed by type 2 VWD, with all its subdivisions, 2A, 2M, 2B and 2N, followed by the rarest Type 3 VWD, which is caused by the absence of VWF. However, in Iraq, Type 3 VWD, which is the most severe and debilitating type of VWD, is the most commonly (86.9%) diagnosed type. This finding can be explained by 1st, the high rate of consanguineous marriages in the country, thereby leading to higher incidence of this rare recessive disorder, and 2nd, the bleeding in this type of VWD is severe, thereby resulting in patient being referred earlier to specialized center. In a large-scale study in India (N = 1576), hemophilia A was found to be to be the most common (52.31%) IBD, followed by PFDs (27.77%), which is lower than that observed in our study, while type 1 VWD was less frequent in comparison with western countries [9]. Worldwide, hemophilia A is the most common IBDs, and it is an X-linked recessive disease. In contrast, in the current study, hemophilia A and hemophilia B were only found to be the third most common disorder. The difference between this study and the study conducted in India [10] can be explained by the fact that in Iraq the NCH is a referral center where mostly undiagnosed patients with bleeding are usually referred to, i.e., usually excluding patients with more straight forward diagnosis like hemophilia A, resulting in some biased results.
Most patients with type 3 VWD (56.2%) in this study have grade II bleeding, and the rest of patients with type 3 VWD (43.8%) have grade III bleeding; of these, menorrhagia was observed in 8 out of 9 girls (88.9%) who already had menarche, aged 11–14 years, and type 3 VWD.
Thrombasthenia or platelet function defects (PFD), are transmitted as autosomal recessive, and are more frequent in developing countries with high consanguinity [11]. The high frequency of GT, reported in India as well as in Iraq is likely because of high consanguinity [9].
Other PFDs are diagnosed provisionally using clinical presentation, personal and family history of bleeding and lab findings including platelet LTA; however, although sometimes it is obvious that the patient has some sort of PFD, it may not be always possible to name the exact defect [12].
Conclusion
Type 3 VWD, Glanzmann’s thrombasthenia and hemophilia A are the most common inherited bleeding disorders in the central part of Iraq, collectively they constitute >86% of patients. Consanguineous marriage should be discouraged in Iraqi society to decrease inherited diseases. Also, there is a need to increase awareness and knowledge of bleeding disorders to improve early identification, mitigate the risk of further bleeding and prevent complications.
Compliance with ethical standards
Conflict of interest
The authors have no conflicts of interest to declare.
Footnotes
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