|Year : 2023 | Volume
| Issue : 2 | Page : 101-107
Clinicopathological features of rare bleeding disorders in high consanguinity population; A retrospective analysis from two tertiary hospitals in Saudi Arabia
Mansour S Aljabry1, Fahad Alabbas2, Ghaleb Elyamany3, Qanita Sedick3, Omar Alsuhaibani3, Huda Elfaraidi2, Azzah Alzahrani2, Sultan Alotaibi4, Mohammed S Alqahtani1, Ahmad M Alshahrani3, Mohammed Abdulaziz Alharbi1, Hassan S Abusabah1, Lulwa Alremali1, Abdulmohsen Abduaziz Alameen4, Mohammed Almohammadi5
1 Department of Pathology, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
2 Department of Pediatric Hematology/Oncology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
3 Central Military Laboratory and Blood Bank, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
4 Department of Adult Hematology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
5 King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Pathology and Laboratory Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia
|Date of Submission||17-Nov-2022|
|Date of Decision||04-Mar-2023|
|Date of Acceptance||13-Mar-2023|
|Date of Web Publication||27-Jul-2023|
Mansour S Aljabry
Department of Pathology, College of Medicine, King Saud University Medical College, King Saud University, P. O. Box: 2925, Riyadh 11461
Source of Support: None, Conflict of Interest: None
BACKGROUND: Rare bleeding disorder (RBDs) encompasses a deficiency of one or more of FXIII, FXI, FX, FVII, FV, FII, and FI clotting factors, leading to bleeding disorders with variable presentations and outcomes ranging from none or minimal to life-threatening events. RBDs are still underdiagnosed and underreported, especially in Saudi population with a high prevalence of consanguinity.
OBJECTIVES: The study aimed to determine the frequency of RBDs, grading of their bleeding severity, and assessment of clinical manifestations and management of RBDs in tertiary Saudi Arabian hospitals.
DESIGN AND SETTINGS: This retrospective study of RBDs describes the clinicopathological features of refereed cases to both Prince Sultan Military Medical City and King Khaled University Hospital in Riyadh, Saudi Arabia, from September 2018 to September 2021. Any patient who had already been diagnosed or suspected to have RBDs was enrolled in the study.
PATIENTS AND METHODS: Patient's medical records were reviewed for demographic data, clinical presentations, bleeding and family history, consanguinity, treatment outcomes, and molecular testing. Samples were run in specialized coagulation laboratories. Patients with liver dysfunction or acquired factor deficiency were excluded. Patients were categorized into four groups according to the severity of bleeding episodes: asymptomatic, Grade I, Grade II, and Grade III.
RESULTS: A total of 26 cases with RBDs were identified during the study period. Most of the included patients are males and pediatrics (<14 years) representing 15 (57.7%) and 14 (53.8%), respectively. FVII was the most common factor deficiency encountered in 9 (35%) patients, followed by FXIII in 5 (19%), FXI in 4 (15%), FX in 3 (11.5%), FV in 3 (11.5%), and combined factor deficiency in 2 (8%) patients. 17 (65.4%) RBD patients presented with bleeding manifestation either with Grade I (9%), Grade II (39%), or Grade III (15%), whereas 47% were asymptomatic.
CONCLUSION: The study emphasizes on importance of establishing a national registry of RBDs in Saudi Arabia and the need for further genetic studies to clarify the genotype/phenotype relationships.
Keywords: Bleeding, coagulation factor, rare bleeding disorders
|How to cite this article:|
Aljabry MS, Alabbas F, Elyamany G, Sedick Q, Alsuhaibani O, Elfaraidi H, Alzahrani A, Alotaibi S, Alqahtani MS, Alshahrani AM, Alharbi MA, Abusabah HS, Alremali L, Alameen AA, Almohammadi M. Clinicopathological features of rare bleeding disorders in high consanguinity population; A retrospective analysis from two tertiary hospitals in Saudi Arabia. J Appl Hematol 2023;14:101-7
|How to cite this URL:|
Aljabry MS, Alabbas F, Elyamany G, Sedick Q, Alsuhaibani O, Elfaraidi H, Alzahrani A, Alotaibi S, Alqahtani MS, Alshahrani AM, Alharbi MA, Abusabah HS, Alremali L, Alameen AA, Almohammadi M. Clinicopathological features of rare bleeding disorders in high consanguinity population; A retrospective analysis from two tertiary hospitals in Saudi Arabia. J Appl Hematol [serial online] 2023 [cited 2023 Oct 4];14:101-7. Available from: https://www.jahjournal.org/text.asp?2023/14/2/101/382407
| Introduction|| |
Rare bleeding disorders (RBDs) due to rare coagulation factor deficiencies represent 3%–5% of all inherited coagulation deficiencies. These disorders include single coagulation factor (F) deficiency in factor FI, II, V, VII, X, XI, and XIII and combined factors deficiencies such as FV/FVII and FV/FVIII. These inherited bleeding disorders are usually transmitted as autosomal recessive traits and occur in both developing and developed countries and are mainly due to the high rate of consanguineous marriages and the expanding immigrant population, respectively., Thus, RBDs have been gaining attention globally.
Clinically, RBDs are characterized by a variety of bleeding symptoms ranging from none or minimal to life-threatening events., Excessive bleeding during surgical procedures, such as circumcision or dental extraction, is the most prevalent symptom of RBDs. Mucosal bleeding is also a common feature, especially epistaxis and menorrhagia. Central nervous system (CNS) bleeding is a life-threatening condition that may exhibit in severe cases of FI, FII, FX, and FXIII deficiencies. Gastrointestinal bleeding is also reported with severe FX and FV + FVIII deficiencies. In the perinatal period, RBDs can be detected by cephalohematomas, bleeding after parenteral injections, or venipunctures. Identifying RBDs is a worldwide challenge due to their scarcity, (inadequate) laboratory testing, clinical heterogeneity, and frequent lack of proper family history tracing to identify inherited disorders of bleeding.
Although Saudi Arabia has a high rate of consanguineous marriages, the prevalence of these RBDs in the local population has only been reported in a few studies.,, A recent survey conducted by Owaidah et al. showed that out of 3881 Saudi participants, only 72 (1.9%) were previously diagnosed with any bleeding disorder, including hemophilia. They demonstrated that the most commonly reported symptoms of bleeding disorders were epistaxis 764 (19.7%), bleeding under the skin 624 (16.5%), postsurgery bleeding 410 (10.9%), and digestive bleeding 318 (8.4%). A family history of bleeding disorder was observed in 237 (6.4%) participants. Although this is the largest study that assessed the symptoms of bleeding disorders in Saudi Arabia, they did not report sufficient data about the actual disorder or deficient factors. Therefore, we aimed to determine the frequency of rare factor deficiencies, the related clinical presentations, and the characteristics of bleeding symptoms and treatment outcomes.
| Patients and Methods|| |
This was a retrospective study of RBDs that describes the clinicopathological features of refereed cases to both Prince Sultan Military Medical City and King Khaled University Hospital in Riyadh, Saudi Arabia, from September 2018 to September 2021. Any patient who had already been diagnosed or suspected to have a RBD was enrolled in the study. The samples were collected and run in the specialized coagulation laboratories of both aforementioned tertiary hospitals. All primary and secondary coagulation tests were performed using automated analyzers and reagents procured from Diagnostica Stago, France (all run on STA-R Evolution). The medical records, present in the hospital's patient registry system, were reviewed for epidemiologic and demographic data, laboratory data, clinical presentations, bleeding history, family history of bleeding disorders, consanguinity, treatment outcomes, and molecular testing. Patients with liver dysfunction, acquired factor deficiency, and disseminated intravascular coagulopathy were excluded. The study was approved by the local Institutional Review Board Committee.
[Table 1] summarizes the clinical features, laboratory diagnosis, reference range, as well as the level of severe factor deficiency.
|Table 1: Rare bleeding factors; main clinical features, laboratory diagnosis, the reference ranges, and level of severe factor deficiency|
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Grading of bleeding severity
RBDs patients were categorized into four groups: asymptomatic, Grade I, Grade II, and Grade III according to the severity of clinical bleeding F [Table 2]. For a patient to be classified in a certain category, he needs to have at least one episode matching the described bleeding severity without any episode matching the next severity grade. The scale of clinical bleeding severity was adopted from the European Network of RBDs.,
| Results|| |
Demographic and clinical characteristics
A total of 26 cases were identified retrospectively during the study period from September 2018 to August 2021 [Table 3]. Most of the included cases are male and pediatrics (<14 years) representing 15 (57.7%) and 14 (53.8%) of the 26 cases, respectively. A history of consanguinity was present in 11 patients (42.3%). Bleeding manifestations were reported in 17 patients (65.4%), while 9 cases were asymptomatic. Grade II bleeding features were reported in 11 (35%), followed by Grade III features in 4 (15%) and Grade I feature was present in 2 (9%) patients [Figure 1]. The most common bleeding features were ecchymosis (40%), epistaxis (20%), hematoma (20%), and menorrhagia (15%). Congenital syndromes were reported in four patients (15.9%), while concurrent hematological disorders were present in 2 (0.77%) patients. No fibrinogen or prothrombin deficiencies were encountered during the study period, while FXII deficiency was documented in 2 cases but excluded as not considered a bleeding disorder. The details of the patient's characteristics, frequency of rare factor deficiencies, and grading of bleeding severity are listed in [Table 3] and [Figure 1], [Figure 2].
|Table 3: Patient characteristics, frequency of rare factor deficiencies, and grading of bleeding severity in the cohort|
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Five patients – 3 adult males, one adult female, and one pediatric female – were reported with severe FXIII deficiency that ranged between <0.04 and 0.09 IU/ml. An umbilical stump bleeding was reported in 3 patients, while hematoma was present in 2 cases. One patient had a family history of FXIII deficiency. Plasma-derived FXIII was applied in all patients. Cryoprecipitate was the treatment option before the availability of plasma-derived FXIII in our centers.
Three pediatric male patients were diagnosed with FXI deficiency. No bleeding manifestations were observed except the history of mild bruises in a 13-year-old patient who presented with B-acute lymphoblastic leukemia. Perioperative fresh frozen plasma (FFP) was administrated in two patients with no postoperative complications. One of our patients has sickle cell beta-thalassemia disease with a history of venous occlusive disease discovered to have FXI deficiency without any bleeding manifestations.
The level of FX ranged between 0.04 and 0.09 IU/ml in three patients. One male patient with a frequent episode of epistaxis and one adult female had menorrhagia with a positive family history of FXD whereas no clinical manifestation in the third patient who had been admitted for an elective urology procedure. All patients were subjected to FFP with no reported complications.
The most common deficiency in our study was found in 9 (34.6%) patients: 6 pediatric males and 3 adult females. Six patients had Grade II bleeding manifestation, one had Grade I and two had no bleeding features. Epistaxis was the most common symptom in male pediatrics while menorrhagia had been reported in all female patients. Five patients had a history of consanguineous parents. The level of FVII ranged between 0.02 and 0.21 IU/mL. Two patients had no bleeding features despite severely low factor activity (<0.08), in contrast to another two patients who had Grade II bleeding features with higher FVII levels (0.13 U/mL with menorrhagia and 0.21 U/mL with frequent episodes of epistaxis). FVII level was 0.02 U/mL in one adult female who presented with severe postpartum hemorrhage and managed with recombinant FVII with good response. Four patients were administered recombinant FVII, and the rest of the bleeding patients received either tranexamic acid or hormonal therapy.
Three females were diagnosed with FV deficiency: two children and one adult. The level of FV ranged between 0.08 and 0.25 IU/ml. Regarding the bleeding manifestations, only gum bleeding was reported in one adult female. FFP was applied in the two pediatrics with no reported complications. Subcutaneous anti-FXa was applied in the adult female and associated with lower gum bleeding episodes.
FV/FVII deficiency was observed in a patient with mitochondrial DNA depletion syndromes who presented with scalp hematoma. This patient was subjected to FFP with no reported complications. Combined FIX/FXI deficiency was diagnosed in a pediatric male patient with neurodegenerative disorder on antiepileptic medication with no history of bleeding manifestations.
| Discussion|| |
The majority of RBD patients in our study, 17 patients (65.4% %), presented with bleeding manifestations, which can be attributed to the severity of coagulation factor deficiency level as 22 (84.6%) of our patients experienced severely low factor activity. Previous reports have shown a higher occurrence of major bleeding episodes in patients with severely low factor activity despite the remarkable variability in clinical outcomes between different RBDs. Moreover, clinical bleeding severity correlated strongly with the level of factor activity in fibrinogen, FX, and FXIII deficiencies, while other factors revealed either poor or even no correlation., In the current study, severe FXIII deficiency was associated with clinically significant bleeding in almost all cases (Grade III in 3 cases and Grade II in 2 cases). A weaker correlation with phenotype was present for FX and FVII deficiencies, while no clear association was found between levels of FV and FXI and bleeding severity.
Since the prevalence of consanguinity in Saudi Arabia remains high, especially in rural areas, RBDs are more prevalent as they are inherited in an autosomal recessive pattern with a minor exception in FXI and dysfibrinogenemia in which an autosomal dominant manner has been reported.,, The rate of consanguinity in our study is 42.3% in keeping with previous national and regional reports from Iraq, Turkey, and Iran.,,,
A comprehensive analysis of each RBD is described below.
FXIII deficiency was the most serious bleeding disorder in our cohort. All patients with FXIII deficiency had a very low factor level (<0.04–0.09 U/ml) with a severe bleeding manifestation.
A retrospective study on 17 Saudi patients with FXIII deficiency showed that 71% of the patients had ecchymosis and recurrent hematomas, 55% had bleeding after circumcision, and 41% had umbilical stump bleeding. Poor wound healing and keloids were observed in 18%, which may reflect the poor quality of clotting in such deficiency. Similarly, a recent Sudanese study conducted by Elhadi et al. found that the third common deficient factor was FXIII, with a prevalence of 21.3%. Moreover, they reported that all patients with FXIII deficiency had bleeding manifestations such as cutaneous ecchymosis, postoperative bleeding, epistaxis, umbilical bleeding, bleeding gums, and muscle hematoma. According to Naz et al., the prevalence of FXIII deficiency among the Pakistani population was 4.6%, with a high incidence of gum bleeding (11/13), umbilical cord bleeding (11/13), epistaxis (9/13), and hematoma (6/13). In addition, intracranial hemorrhage was observed in one patient. Between 1978 and 1998, another study was performed in Riyadh Saudi Arabia and detected 17 cases of FXIII deficiency. These patients were followed up over 20 years, and it was found that they were prone to keloid formation, which reflected the poor quality of tensile strength of fibrin polymers leading to abnormal scar formation.
Furthermore, FXIII deficiency was the second most common disorder in our study representing 19%. In a study performed at a tertiary hospital in Riyadh between 2005 and 2014, RBDs were found in 39 pediatric patients, of which FXIII was found to be the most common RBDs occurring with a frequency of 38.59%.
Some epidemiological data have shown that FXI has a role in thrombosis as patients with congenital FXI deficiency are protected from venous thrombosis and ischemic stroke.,, Girolami and his team suggested that FXI deficiency shows no protection from arterial thrombosis but appears to guarantee protection from venous thrombosis. However, in our study, young male patients with sickle cell beta-thalassemia disease and FXI deficiency were presented with venous occlusive disease. The venous occlusive disease is related to his sickle cell vase-occlusive crises, and his low FXI was not protective in this instance.
In 1988, Al-Adhadh reported the first case of a 5-year-old Saudi male with FXI deficiency. After a careful investigation of the patient's family, Al-Adhadh found that the parents of this child were first cousins and had mild FXI deficiency with no bleeding symptoms; however, his sister had a severe FXI deficiency with menorrhagia and post-dental extraction bleeding while another brother had a mild FXI deficiency. The findings of this report highlighted the correlation between consanguineous marriages and RBDs. Bleeding diathesis with FXI deficiency is variable and usually mild., In the current study, only one patient (out of three) had a history of mild ecchymosis Out of 168 patients, two Saudi male patients were reported with FXI deficiency, with a mild degree of disease severity. In the Pakistani study, only one patient was diagnosed with FXI deficiency; however, many bleeding manifestations were reported that included gum bleeding, hematoma, epistaxis, traumatic bleeding, and bruises.
Severe FX <0.01 U/mL is a life-threatening condition and mild FX deficiency between 0.05 and 0.1 U/mL presents usually with variable degrees of bleeding. Residual FX activity >0.1 U/mL is sufficient to preserve coagulation and will rarely present with bleeding.
In our study, a 7-year-old male patient presented with frequent episodes of epistaxis and a history of mild bleeding postdental extraction. The level of FX activity was 0.04 U/mL, and hence, he received prophylactic FFP pre- and post-adenotonsillectomy without any complications. On the other hand, patients with higher FX level (0.09 U/mL) had no bleeding manifestations. Elhadi et al. demonstrated that out of six patients with FX deficiency, 5 (83.3%) had cutaneous ecchymosis, 3 (50%) had epistaxis, and one patient with gum bleeding. In agreement, Naz et al. detected the FX deficiency in two patients with gum bleeding, hematoma, and menorrhagia.
FVII is secreted by endothelial cells of the liver and is involved in the initiation phase of blood coagulation by binding to tissue factor with the subsequent formation of the FVII-TF complex. This complex activates FX and FIX, leading to thrombin generation. Previous studies have shown that bleeding manifestations of FVII are independent of genotype-phenotype relations and FVII levels and can be affected by environmental factors.
Our patients had significantly low factor VII levels and had a high rate of parental consanguinity (56%). Two patients had no bleeding symptoms despite very low levels of FVII. On contrary, two patients had Grade II bleeding features despite relatively higher FVII level reflecting the poor correlation between factor level and the severity of bleeding manifestations. However, Grade II bleeding manifestations were present in six patients. One patient with a hemangioma of the liver presented with menorrhagia and a very low residual FVII level (0.02 U/mL). She was treated with recombinant FVIIa (Novoseven) pre and postoperative emergency cesarean section for breech delivery. Postsurgery, she continued every 3 h Novoseven intravenously for 1 day. She was weaned from Novo seven gradually by spacing the frequency until the medication stopped by day four postoperative. There were no postoperative complications.
Similar to our findings, Al-Rahal reported that the most common RBDs among the Iraqi population with a high rate of consanguineous marriage was FVII. Patients with FVII deficiency had Grade III bleeding severity with hemarthrosis, hematuria, and CNS bleeding. These manifestations were also reported by Naz et al. and Elhadi et al. In the Eastern province of Saudi Arabia, Ahmed et al. reported only one case of mild FVII deficiency (6.6%). And hence, he was not subjected to FFP. Another Saudi study that was conducted in Riyadh reported one male with mild FVII deficiency.
FV is a labile coagulation factor of which 80% is produced in liver endothelial cells, and 20% is produced from alpha granules of platelets and megakaryocytes. Therefore, FV levels are primarily affected by reduced liver synthetic function. FV is a cofactor for the prothrombinase complex, which converts prothrombin to thrombin in the final common pathway of the coagulation cascade. FV deficiency has been reported in 8.3% of all inherited bleeding disorders. Its bleeding manifestations include mucosal and soft tissue bleeds, including life-threatening hemorrhages.
Only one of our patients had bleeding manifestations. This patient was a 23-year-old female patient with Budd–Chiari Syndrome who reported gum bleeds with 0.25 U/mL of residual factor V activity and normal levels of all other liver synthesized factors. In contrast to a 15-year-old dysmorphic female and a 9-year-old female with 0.08% of residual factor V activity with absent bleeding manifestations.
Factor V Leiden, which confers a prothrombotic state, has been commonly reported in the literature in association with Budd–Chiari Syndrome but an association between FV deficiency and Budd–Chiari Syndrome has not been reported in the literature to the best of our knowledge., This anomaly suggests an overall compromised liver synthetic function, as occurs in Budd–Chiari Syndrome, leading to reduced synthesis of FV from liver endothelial cells. Al-Fawaz et al. reported 4 (2.38%) cases with moderate FV deficiency. FV deficiency was the most common deficient factor (36.2%) among Sudanese children, according to Elhadi et al. and the third common deficient factor among the Pakistanian population, according to Naz et al. Gum bleeding, epistaxis, and umbilical cord bleeding are the most common associated symptoms.,
Combined factors deficiency
Combined Factor V and VII deficiency is extremely rare, with an incidence of 1 case per one million in the general population. The incidence increases in populations where consanguineous marriages are popular. Patients present with mild-to-moderate bleeding diathesis and have low levels of residual factor activity of both FV and FVII. The disorder is caused by mutations in genes encoding intracellular transport proteins (LMAN1 and MCD2) for FV and FVII.
Alshareef et.al. reported a case of combined FV and FVII deficiency in a child known to have beta thalassemia trait with hemarthrosis post minor trauma. He had a history of prolonged bleeding postcircumcision and subgaleal hematoma postminor trauma. He was managed with FFP and blood transfusion. Our patient had a similar presentation (hematoma) and showed a homozygous mutation for GATT (nucleotides 763–766) duplication in keeping with a mitochondrial depletion syndrome. There are no reported cases of combined FV and FVII deficiency in association with mitochondrial depletion syndrome. It is unclear whether this finding is incidental.
Combined FIX/FXI deficiency is an extraordinarily rare condition reported only in handful of case reports. Soff et.al. reported an autosomal dominant pattern in an affected family composed of 2 sisters, who had sever deficiency of both factors and their brother who had a mild deficiency. In the same study, he reported a down syndrome patient with combined FIX/FXI deficiency. Our patient had no bleeding history, and he underwent minor dental surgery, receiving FFP, without any complications.
| Conclusion|| |
Although our study is based mainly on referred cases to our tertiary hospitals and limited by size and duration, we have noted that a significant proportion of patients with rare factor deficiencies had severe bleeding manifestation, especially with FXIII, FX, FVII, and combined FV and FVII. Moreover, we have noted that rare factor deficiencies in our population are heterogeneous with regard to clinical manifestations, bleeding symptoms, and residual factor activity. FVII deficiency was the most common RBDs in this study, followed by FXIII and FXI. Our study highlights the importance of establishing a national database of rare factor deficiencies in Saudi Arabia. With a high rate of consanguinity in RBDs patients, our study also emphasizes on the need for further genetic studies in factor deficiencies to understand the genotype/phenotype relationships.
The authors thank Diagnostica Stago Inc., Riyadh, Saudi Arabia, for their support of the research in our laboratory and help in this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]