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ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 4  |  Page : 1363-1368

Inherited bleeding disorders other than hemophilia in pediatrics: single-center experience


1 Depatrement of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
2 Depatrement of Clinical and Chemical Pathology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt

Date of Submission10-Jul-2021
Date of Decision16-Aug-2021
Date of Acceptance28-Aug-2021
Date of Web Publication24-Dec-2021

Correspondence Address:
Yasmen A Mohamed
MD, Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_123_21

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  Abstract 


Objective
The aim was to study the inherited bleeding disorders other than hemophilia with special emphasis on clinical spectrum, diagnosis, and management.
Background
Inherited bleeding disorders are a variable group of disorders that vary in incidence and clinical presentations. They include hemophilia A, hemophilia B, von Willebrand disease (VWD), inherited platelet-function disorders (IPFDs), and rare bleeding disorders (factors I, II, V, combined Vand VIII, VII, X, XI, and XIII deficiencies).
Patients and methods
It is a prospective follow-up study over a period of 5 years, in which patients suffering from bleeding tendency and referred to the hematology clinic were included and prospectively followed up. They were subjected to detailed history, full examination, and laboratory investigations; complete blood count, prothrombin time, and activated partial thromboplastin time; and accordingly other investigations were done, such as factor assay and platelet-function tests.
Results
The authors reported 52 patients with inherited bleeding disorders other than hemophilia. Among them, IPFDs were the most common (38.5%), followed by VWD (26.9%). While 34.6% were diagnosed as rare bleeding disorders (FI, V, VII, X, and XIII deficiencies).
Conclusion
IPFDs were the most common inherited bleeding disorders other than hemophilia followed by VWD. Among the rare bleeding disorders, FI deficiency was the most common, while FXIII and FVII deficiency were the most serious. Also, fresh frozen plasma was the most frequent therapeutic product used to control bleeding episodes in our patients.

Keywords: inherited bleeding disorders, other than hemophilia, prospective follow-up study


How to cite this article:
Mohamed YA, Ezzat DA, Elkareem RM, Adel DM. Inherited bleeding disorders other than hemophilia in pediatrics: single-center experience. Menoufia Med J 2021;34:1363-8

How to cite this URL:
Mohamed YA, Ezzat DA, Elkareem RM, Adel DM. Inherited bleeding disorders other than hemophilia in pediatrics: single-center experience. Menoufia Med J [serial online] 2021 [cited 2024 Mar 29];34:1363-8. Available from: http://www.mmj.eg.net/text.asp?2021/34/4/1363/333225




  Introduction Top


Inherited bleeding disorders are a variable group of disorders that vary in incidence and clinical presentations. They include hemophilia A, hemophilia B, von Willebrand disease (VWD), rare bleeding disorders, and inherited platelet-function disorders (IPFDs). Hemophilia A, hemophilia B, and VWD are the most frequent inherited bleeding disorders [1]. Rare inherited bleeding disorders are usually transmitted in an autosomal-recessive manner and include fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI, and FXIII deficiencies [2]. IPFDs are some of the most frequent heritable bleeding diseases [3]. IPFDs are classified into disorders affecting the platelet adhesion, including Bernard–Soulier syndrome, disorders affecting platelet aggregation, including Glanzmann thrombasthenia, disorders affecting platelet receptors, and a heterogeneous group of disorders known as storage-pool disease that are caused by deficiency of platelet granules or their contents [4]. The inherited bleeding disorders differ in their clinical presentations ranging from asymptomatic or mild conditions to life-threatening bleeding. IPFDs were commonly presented with mucocutaneous bleeding and easy bruising. Whereas coagulopathies showed bleeding in deep internal sites and intracranial hemorrhage [5]. An initial bleeding-disorder workup often includes the following coagulation-screening tests: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio, a fibrinogen level, and a thrombin time [6]. Functional tests are the first-line tests for diagnosis of platelet disorders [7]. Treatment is replacement of the deficient factor and use of adjunctive therapy (antifibrinolytics). In clinically severe cases or specific deficiency states, prophylactic treatment is considered [8]. There are variable options available and the choice between them depends on the type of the disease and the available resources for each country. These options include fresh frozen plasma (FFP), cryoprecipitate, platelet concentrate, factor concentrate, and recombinant products. FFP can be used in all types of coagulation-factor deficiencies. It is the main choice in countries with restricted resources, despite its high risk of blood-borne infection transmission. Cryoprecipitate can be used only in patients with factor I, VIII, abd XIII deficiencies and VWD. Factor concentrate is used in factor I, V, VII, VIII, X, IX, and XIII deficiencies. Recombinant products are not available for all coagulation-factor deficiencies but available only for factor VII, VIII, IX, and XIII deficiencies and VWD [5]. We aimed to study the inherited bleeding disorders other than hemophilia with special emphasis on clinical spectrum, diagnosis, and management.


  Patients and methods Top


The study was a prospective follow-up study conducted over a period of 5 years from July 2015 to July 2020. All patients below 18-years old referred to the hematology clinic with bleeding tendency or abnormal coagulation profile were involved (1200 patients). Then, we excluded patients with hemophilia A, hemophilia B, patients with acquired bleeding disorders, and patients on anticoagulant therapy.

Sample collection

Venous blood samples were withdrawn from patients by clean venepuncture without venous stasis and precautions were taken to prevent frothing. Each sample was divided into two tubes. About 1 ml blood was delivered in EDTA tube to perform complete blood count. About 1.8 ml of blood sample was delivered to 0.2 ml of Na citrate tube for PT, APTT, D dimer, and thrombin time. The baseline-screening tests included

  1. Complete blood count (using CELL DYN RUBY; Abbott, Illinois, U.S.A).
  2. Coagulation profile (PT, APTT) and bleeding time (using Thrombostat BE, Nordersted, Germany).
  3. Further investigations were carried out according to the initial screening tests:


    1. In cases of isolated thrombocytopenia with normal PT and APTT, blood film, bone marrow examination, antiplatelet antibodies, antinuclear antibodies, anti-DNA antibodies, erythrocyte sedimentation rate, lactate dehydrogenase, renal function and liver function tests, d-dimer, and viral markers (hepatitis C virus antibody, hepatitis B surface antigen, human immunodeficiency virus antibody, and PCR for positive cases) were done to exclude acquired cases of thrombocytopenia.
    2. Thrombocytopenia with prolonged APTT and strong family history of bleeding were highly suggestive of type-2B VWD.
    3. FVIII, IX, VWF, V, X, and II fibrinogen were done by ACL9000 Analyzer (Instrumentation Laboratory, Spa, Milan, Italy) in the following orders:


      1. Cases with isolated prolonged APTT with normal PT were tested for factors VIII, IX, and VWF assay. Cases with FVIII and FIX deficiency were excluded.
      2. Cases with isolated prolonged PT with normal APTT were tested for FVII assay.
      3. Factors II, V, X, and fibrinogen were tested in patients with simultaneous prolongation of PT and APTT.
      4. Factor-XIII screening was suspected where all coagulation tests were normal and confirmed by urea clot solubility test using 5 mol/l urea.
      5. Cases with early onset of bleeding, positive family history of bleeding, absence of hemarthrosis, normal or reduced platelet count, and normal or prolonged PTT were tested for VWF assays that include VWF antigen, VWF activity, and FVIII assay.
      6. Cases with suspected IPFDs were tested for platelet aggregation using Impact R (Matis Medical, Belgium), which uses ristocetin, ADP, and collagen as aggregating agents.


Treatment details

Treatment details were recorded by reviewing the past medical history of the patients and recording any treatment (antifibrinolytics, FFP, cryoprecipitate, platelet, packed red blood cells, and factor concentrate) that the patients had received.

Statistical analysis

The SPSS software (Statistical Package for the Social Sciences, version 22.0; SPSS Inc., Chicago, IL) was used for analysis. Comparison between qualitative data was carried out using the χ2 test and the values were expressed as numbers and percentages. P value less than 0.05 was considered statistically significant.

Ethical approval

This study was approved by Ethics Committee of Beni-Suef University, Faculty of medicine and the ethics code was FWA00015574 FMBSUREC/07072019. Informed consent was obtained from the caregivers of the participating children.


  Results Top


We reported 52 patients with inherited bleeding disorders other than hemophilia out of 1200 patients presented with bleeding tendency or abnormal coagulation profile over a period of 5 years from July 2015 to July 2020. Among the 52 patients, IPFDs were the most common (38.5%), followed by VWD (26.9%). While 34.6% were diagnosed as rare bleeding disorders (factors I, V, VII, X, and XIII deficiencies), FI deficiency was the commonest among them (13.5%). While FXIII deficiency was the rarest (1.9%), FV deficiency (7.7%), FVII deficiency (7.7%), and FX deficiency (3.8%).

Regarding IPFDs, Glanzmann thrombasthenia was the commonest (85%) followed by Bernard–Solier syndrome (15%). While VWD classified into three types: type 1 (64.3%), type 2 (21.4%), and type 3 (14.3%).

Male-to-female ratio of our patients was 1:1, with more prevalent female sex in VWD (71.4%), and more prevalent male sex in rare bleeding disorders (66.7%). Whereas IPFDs showed equal distribution in both sexes. The median age of patients in the study group was 8.35 years. Also, 46.2% of patients had positive family history and 75% had consanguineous marriage.

As regards the age of diagnosis, 50% of IPFDs were diagnosed at the age group 1 month–1 year, and 42.9% of VWD cases were diagnosed at the age group 1–3 years. Also, it is noted that the majority of patients with FI deficiency were diagnosed at the age group below 1 month (85.7%).

The most common bleeding symptom was bruises (86.5), the most serious was intracranial hemorrhage (9.6%). While hemarthrosis was in 7.7%. The frequency of bleeding symptoms in the study group is demonstrated in [Table 1].
Table 1: Frequency of bleeding symptoms in the study group

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As regards the frequency of bleeding episodes per year in the studied group, it was 4–12 times per year in IPFD patients and 8–17 times per year in coagulopathy patients. The frequency of bleeding symptoms in different bleeding disorders is demonstrated in [Table 2].
Table 2: Frequency of bleeding symptoms in different bleeding disorders

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Comparison between platelet disorders and coagulopathy groups showed that IPFDs were commonly presented with mucocutaneous bleeding and easy bruising. Whereas coagulopathies showed bleeding in deep internal sites such as muscle hematoma, umbilical stump bleeding, and intracranial hemorrhage. This means that IPFDs were less severe than coagulopathies. The mean age of onset and sex distribution were almost the same in both. Also, there were no significant differences in family history and consanguinity between them. Comparison between platelet disorders and coagulopathy groups as regards clinical bleeding manifestations is demonstrated in [Table 3].
Table 3: Comparison between platelets disorders and coagulopathies groups as regard clinical bleeding manifestations

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Hemoglobin level and red-cell indices of the studied group revealed hypochromic microcytic anemia in 60% of patients and 30% of patients were on iron-replacement therapy (the range of hemoglobin was 3.30–12.50 g/dl), WBCs was 3.80–23.40 (×106/mm3), platelet was 129–676 (×106/mm3), bleeding time was 1–35 (min), PT was 10.4–50 (s), PC was 12.5–1129 (%), PTT was 30–172 (s), and international normalized ratio was 0.95–7.6.

Inherited coagulation disorders and IPFD, including number, percentage, and level of deficiency, are demonstrated in [Table 4].
Table 4: Inherited coagulation disorders and IPFD including number, percentage and level of deficiency

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About 88.46% of patients received only blood components for treatment of any bleeding episode, which were sufficient to control the bleeding. While the remaining 11.53% were treated with blood components in combination with factor concentrates to control the bleeding. Treatment products used in different inherited bleeding disorders other than hemophilia in our study are demonstrated in [Table 5].
Table 5: Treatment products used in different inherited bleeding disorders other than haemophilia

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The most common therapeutic product used was FFP (61.5%), followed by packed red blood cells (51.9%), antifibrinolytics (44.2%), cryoprecipitate (28.8%), platelet (19.2%), factor VII (9.6%), and koate (3.8%). Also, 94.2% were on demand therapy. While 5.8% were under prophylactic therapy as the following: one patient with FVII deficiency takes rFVII every week, one patient with afibrinogenemia takes cryoprecipitate every week, and one patient with FXIII deficiency takes cryoprecipitate or FFP every week.

We reported one case with FVII deficiency who developed immunoglobulin (Ig) A nephropathy and brain tumor, the patient first presented with intracranial hemorrhage at the age of 6 months and diagnosed to have FVII deficiency and was on prophylactic therapy with recombinant FVII every week, then at the age of 4 years, he presented with hematuria and hypertention, laboratory data revealed impaired renal function and renal biobsy revealed IgA nephropathy. At the age of 6 years, he presented with headache and persistent vomiting, brain imaging showed brain tumor (astrocytoma) for which surgical removal of the tumor was done followed by chemotherapy (temozolomide). Now, the patient was on supportive treatment. We could not find if there is a relation between FVII deficiency, IgA nephropathy, and brain tumor or this had occurred accidentally.


  Discussion Top


We reported 52 patients with inherited bleeding disorders other than hemophilia. Among them, IPFDs were the most common (38.5%), followed by VWD (26.9%).While 34.6% were diagnosed as rare inherited bleeding disorders (FI, V, VII, X, and XIII deficiencies), FI deficiency was the commonest among them (13.5%), and FXIII deficiency was the rarest (1.9%).

Ahmad et al. [9] and Gupta et al. [10] reported that IPFDs are the most common after hemophilia. While Al-Rahal [11] reported that VWD is the most common.

As regards Abdelwahab and Khaddah [12] and Naz et al. [13], afibrinogenemia was the most common rare bleeding disorder, which is similar to our study. While World Federation of Hemophilia [14] and Al-Rahal [11] reported that FVII deficiency is the most common rare bleeding disorder and Dorgalaleh et al. [15] reported that FXIII deficiency was the commonest rare bleeding disorder. This is contrary to our study.

Our study illustrated that VWD is significantly more common in females (71%) compared with other bleeding disorders. Mokhtar et al. [16] and Sadler et al. [17] reported similar results.

Also, we found that the rare bleeding disorders are more common in males (66.7). Islam and Quadri [18] and Abdelwahab and Khaddah [12] reported similar results. About 75% of our studied group had a history of positive consanguinity, this explains why we had a significant number of inherited bleeding disorders. Also, 46.2% of patients had a positive family history, so screening of family members is important. Similar results were reported by Al-Rahal [11].

In our study, most cases of rare bleeding disorders were diagnosed during the first year of life. Mokhtar et al. [16] reported the same.

IPFDs in our patients were commonly presented with mucocutaneous bleeding, easy bruising, epistaxis, and gum bleeding. Whereas inherited coagulation disorders were commonly presented with deep bleeding, commonly muscle hematoma. Mokhtar et al. [16] reported the same.

The most frequent bleeding symptom seen in afibrinogenemic patients was the muscle hematoma that was seen in almost 100% of patients. While intracranial hemorrhage was a relatively rare finding being seen in only 1 patient (14.3%). Lak et al. [19] reported similar results. Also, we reported that one afibrinogemic patient presented with splenic rupture. Ehmann and Al-Mondhiry [20] reported six cases.

In our study, 50% of FVII-deficient patients presented with CNS bleeding. Siboni et al. [21] reported similar results. Also, we reported one patient with FVII deficiency with no bleeding symptoms. Similarly, a study by Peyvandi et al. [22] reported 2 asymptomatic patients.

In addition, we reported one patient with FV deficiency with no bleeding symptoms. Similarly, Park et al. [23] reported one case.

We reported only one patient with FXIII deficiency, who presented with umbilical stump bleeding, CNS bleeding, and muscle hematoma. Also, Lak et al. [24] mentioned that factor XIII-deficient patients commonly presented with umbilical stump bleeding and CNS bleeding.

The most common therapeutic product used in our study was FFP being used in 61.5% of cases. Sajid et al. [25] and Hussain et al. [26] reported the same results.

About 94.2% of our patients were on demand therapy. While 5.8% were under prophylactic therapy as the following: one patient with FVII deficiency takes recombinant FVII every week, one patient with afibrinogenemia takes cryoprecipitate every week, and one patient with FXIII deficiency takes cryoprecipitate or FFP every week.


  Conclusion Top


IPFDs were the most common inherited bleeding disorders other than hemophilia followed by VWD. Among the rare bleeding disorders, FI deficiency was the most common, while FXIII and FVII deficiency were the most serious. Also, FFP was the most frequent therapeutic product used to control bleeding episodes in our patients.

Recommendations

We recommend to establish a centrally organized web-based registry for inherited bleeding- disorder data in all hemophilia centers in Egypt with yearly registry update in order to recognize their actual incidence and to evaluate the amount of resources required.

Financial support and sponsorship

Nil.

Conflicts of interest

All authors of the article declare any and all conflicts of interest they may have with publication of the paper or an institution or product that is mentioned in the paper and/or is important to the outcome of the study presented. The authors also declare conflict of interest with products that compete with those mentioned in their paper.

Concept: Y.A. Design: Y.A. Data analysis: Y.A. Data acquisition: R.M. Statistical analysis: D.M. Paper preparation: Y.A. and R.M. Paper editing: Y.A. Paper review: D.A., Y.A., R.M., and D.M.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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