Rare inherited coagulation disorders in young children in Oman.

Background: Rare coagulation disorders represent 3-5% of all inherited coagulation deficiencies and are usually inherited as autosomal recessive. Oman has high rate of consanguineous marriages; we aimed to study the prevalence, presentation and management in affected Omani children. Materials and Methods: Retrospective study in pediatric patients with rare coagulation disorders in a tertiary hospital in Oman from 2009 to 2020. Results: Rare coagulation disorders were diagnosed in 79 patients (39 males/40 females), aged 1 day to 13 years, accounting for 24.7% (79/319) of all children with inherited coagulation disorders; remainder included patients with hemophilia and von Willebrand disease. FXI deficiency was most common with prevalence of 39.2%, followed by fibrinogen disorders 32.9%, FVII 18.9%, FV 5%, FXIII 2.5%, and FX deficiencies 1.2%. Manifestations ranged from mild to serious to rare/atypical; presentation at birth, ruptured-hemorrhagic ovarian cyst, splenic laceration-rupture, and sight-threatening retrobulbar-intraocular hemorrhage. Intracranial hemorrhage (ICH) occurred in 9/79 patients, it was initial mode of presentation in seven of them. Global developmental delay as a complication occurred in three. Standardized treatment strategies were used with prophylaxis initiation early in life in severely affected children. Conclusions: This ethnic group demonstrated unique features in terms of: heterogenous/atypical presentations; severe manifestations in moderate phenotype hypofibrinogenemia; clinical severity and laboratory phenotype correlation in FV deficiency; poor association between factor activity level and bleeding severity in FVII deficiency and severe bleeding tendency despite moderate laboratory phenotype in FXIII deficiency. We recommend multicenter collaboration to identify the genotype-phenotype correlation and therapeutic options of such rare, yet serious disorders.

Management of pregnancy in women with factor VII deficiency: A case series.

INTRODUCTION: Inherited factor VII deficiency is the most common autosomal recessive inherited bleeding disorder, with an estimated incidence of one per 500 000 cases in the general population. Bleeding manifestations correlate poorly with circulating FVII levels. During pregnancy, increases in FVII levels can occur in women with mild-moderate FVII deficiencies but not in those with severe deficiency. AIM: We present five pregnant patients with FVII deficiency and describe the management during their pregnancies and peripartum periods. METHODS: Retrospective analysis of six pregnancies in five women with FVII deficiency followed during pregnancy and delivery at an academic medical centre between January 2013 and December 2019. RESULTS: Of the five patients, two had severe, one with moderate and two with mild FVII deficiency. Early postpartum haemorrhage (PPH) occurred in two patients. One of the two severe FVII-deficient patients had PPH with a laceration at delivery despite replacement therapy with recombinant factor VII. The other PPH occurred in a patient with mild FVII deficiency who delivered twins by caesarean section under general anaesthesia. Neuraxial anaesthesia was utilized in only one woman with mild deficiency whose FVII level normalized at the end of the pregnancy. CONCLUSIONS: Management of delivery for women with FVII deficiency should be addressed on a case-by-case basis at centres with expertise in rare bleeding disorders, maternal foetal medicine and obstetric anaesthesiology. These management discussions should factor the patient's bleeding history, third trimester PT, FVII level, multiple gestation and mode of delivery.

The impact of foetal restrictions on mode of delivery in women with inherited bleeding disorders.

OBJECTIVES: Management of pregnancy in women with congenital bleeding disorders (CBD) is challenging and requires understanding of risks conferred to both the mother and the foetus. Some elements of labour management are considered to increase the risk of neonatal bleeding and are not recommended for neonates at risk of a significant bleeding disorder. The impact of these restrictions on obstetric outcomes in women with CBD is unknown. METHODS: We retrospectively reviewed obstetric outcomes in a large cohort of women with CBD attending a specialised obstetric/haematology antenatal clinic over a 6-year period. RESULTS: Ninety-four pregnancies in 76 women with a wide variety of CBDs were assessed. Foetal precautions were recommended in the majority of cases (88%). Twenty (21.2%) were delivered by elective Caesarean section (CS), predominantly for obstetric indications. Of the 63 women who laboured with foetal precautions in place, 6 (10%) had a CS that was performed because of these precautions. There was no neonatal bleeding but primary postpartum haemorrhage (PPH) occurred in 12.2% of women. CONCLUSIONS: These data show that foetal precautions in labour recommended for women with CBDs will influence mode of delivery in approximately 10% of cases. This is important information for counselling these women about labour and delivery.

Epidemiology of Congenital Bleeding Disorders: a Nationwide Population-based Korean Study.

BACKGROUND: Except for data in the Korea Hemophilia Foundation Registry, little is known of the epidemiology of congenital bleeding disorders in Korea. METHODS: Data were obtained from the Korean Health Insurance Review and Assessment Service (HIRA) database. RESULTS: From 2010 to 2015, there were 2,029 patients with congenital bleeding disorders in the Korean HIRA database: 38% (n = 775) of these patients had hemophilia A (HA), 25% (n = 517) had von Willebrand disease (vWD), 7% (n = 132) had hemophilia B (HB), and 25% (n = 513) had less common factor deficiencies. The estimated age-standardized incidence rate (ASR) of HA and HB was 1.78-3.15/100,000 and 0.31-0.51/100,000, respectively. That of vWD was 1.38-1.95/100,000. The estimated ASR of HA showed increase over time though the number of new patients did not increase. Most patients with congenital bleeding disorders were younger than 19 years old (47.8%), and most were registered in Gyeonggi (22.1%) and Seoul (19.2%). CONCLUSION: This is the first nationwide population-based study of congenital bleeding disorders in Korea. This study provides data that will enable more accurate estimations of patients with vWD. This information will help advance the comprehensive care of congenital bleeding disorders. We need to continue to obtain more detailed information on patients to improve the management of these diseases.

[Inherited bleeding disorders in adolescents with excessive menstrual bleeding. Should we evaluate the fibrinolytic pathway?] / Trastornos hereditarios de la coagulación en adolescentes con sangrado menstrual excesivo, ¿debemos evaluar la vía fibrinolítica?

INTRODUCTION: Heavy Menstrual Bleeding (EMB) is a frequent problem in adolescence. The prevalence of inherited bleeding disorders (IBD) as a cause of EMB is not well established and the involvement of fibri nolytic pathway defects has been poorly explored. OBJECTIVE: To determine the prevalence of IBD and fibrinolysis defects in adolescents with EMBs. PATIENTS AND METHOD: 93 adolescents (11 to 18 years old) were included. Personal and family history of bleeding were obtained through a standard ized questionnaire. The following lab tests were performed: prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor quantification, and platelet count and function. Those patients who were not diagnosed with IBD were further evaluated with clot lysis time assay. RESULTS: 41 patients (44%) were diagnosed as IBD (Von Willebrand disease n = 28, platelet func tion defects n=8, mild hemophilia n = 5. Decreased clot lysis time was found in 31 patients. 54% of patients diagnosed with IBD had EMB as the first hemorrhagic manifestation. CONCLUSION: These results support the need to evaluate the coagulation process, including the fibrinolytic pathway in the study of adolescents with EMB.

FranceCoag: a 22-year prospective follow-up of the national French cohort of patients with inherited bleeding disorders.

FranceCoag is an ongoing open prospective multicentre cohort project aimed at improving epidemiological knowledge about inherited bleeding disorders in France. The main objective of this article was to evaluate the project's progress as of the 30th December 2016. Between 1994 and this date, of the 10,047 patients included in the study, 384 (3.8%) were reported by clinicians to have died and 159 (1.6%) to be lost to follow-up. Among the remaining 9504 patients still being followed up, 5748 (60.5%) had haemophilia A, 1300 (13.7%) haemophilia B, 1980 (20.8%) von Willebrand Disease while 476 (5.0%) had another clotting factor deficiency (Factor I, II, V, combined V and VIII, VII, X, XI and XIII). The median age of the population was 32 years (Inter-quartile range (IQR) 18-50 years) at data extraction on December 30th, 2016. The subgroup of children (i.e., < 18 years old) with severe haemophilia and comprehensive information available since the first exposure to treatment was identified as the PUPs (Previously Untreated Patients) cohort. Data for the 643 children included in the PUPs' cohort had been collected since their birth. Follow-up data were collected by the clinicians in haemophilia treatment centres (HTC) every 12.9 months on median (IQR 11.4-21.3). In the PUPS cohort, data were updated every 6.2 months on median (IQR 3.7-11.7). A unique patient number assigned at study inclusion was kept at individual HTC by participating clinicians. The data collected included demographic, clinical, therapeutic and biological items on standard electronic forms. As of December 30th 2016, a plasma and serum samples was available for 2581 patients (27.1%).

Intracranial Hemorrhage in Children With Inherited Bleeding Disorders: A Single Center Study in China.

BACKGROUND: Intracranial hemorrhage (ICH) is a life-threatening condition in children. Inherited bleeding disorders (IBD) have high risk of ICH. AIM: This single center study aims to identify the incidence, risk factors, and neurological outcome of ICH in children who suffer from IBD. METHODS: From 2005 to 2017, 241 children with IBDs from Nanfang hospital, Department of Pediatrics, were evaluated. The ICH episodes were identified by medical history, general physical examination, detailed neurological examination, and computed tomographic or magnetic resonance imaging examination. The risk factors, location of ICH, management strategies, and outcome were noted. RESULTS: ICH was confirmed in 54/241 (22.4%) children with IBD among them 52/54 (96.2%) (95% confidence interval [CI], 91.1%-99.9%) were hemophilia A and hemophilia B patients. The overall risk of ICH among children with IBD was 22.4% (95% CI, 17.2%-27.8%). The median age of ICH was 30 months (0 to 204) and 18/54 (33.3%) (95% CI, 20.3%-46.3%) children had an ICH in the first year of life. Twenty-eight of 52 (53.8%) hemophilic children with ICH were assessed for inhibitor of FVIII and FIX. Nine of 28 (32%) hemophilic children with inhibitor developed the ICH. Six of 52 (11.5%) (95% CI, 2.6%-20.5%) hemophilic children had multiple episodes of ICH in which 4 were inhibitor positive. Thirteen of 54 (24%) (95% CI, 12.3%-35.9%) had positive family history of IBD. Twenty-two (36%) (95% CI, 23.7%-48.5%) of 61 ICH episodes were caused by trauma and 39 (63.9%) (95% CI, 51.5%-76.3%) were nontrauma related. Subdural hematoma was most frequently observed. Mortality risk from ICH in children with IBD was 5/54 (9.2%) (95% CI, 1.3%-17.2%). Eleven (22.4%) (95% CI, 10.3%-34.6%) of 49 survivors had known neurological squeal, whereas 38 (77.5%) (95% CI, 65.4%-89.7%) had no documented evidence of neurological impairment. CONCLUSIONS: Hemophilia is the most common IBD and most frequently associated with ICH. Risk and consequences of ICH in IBD were high during the first year of life while in older children better outcome may be expected. The optimal management of ICH depends on immediate recognition and prompt replacement therapy.

Intracranial Hemorrhage: A Devastating Outcome of Congenital Bleeding Disorders-Prevalence, Diagnosis, and Management, with a Special Focus on Congenital Factor XIII Deficiency.

Intracranial hemorrhage (ICH) is a medical emergency. In congenital bleeding disorders, ICH is a devastating presentation accompanied with a high rate of morbidity and mortality. The prevalence of ICH is highly variable among congenital bleeding disorders, with the highest incidence observed in factor (F) XIII deficiency (FXIIID) (∼30%). This life-threatening presentation is less common in afibrinogenemia, FVIII, FIX, FVII, and FX deficiencies, and is rare in severe FV and FII deficiencies, type 3 von Willebrand disease and inherited platelet function disorders (IPFDs). In FXIIID, this diathesis most often occurs after trauma in children, whereas spontaneous ICH is more frequent in adults. About 15% of patients with FXIIID and ICH die; the bleeding causes 80% of deaths in this coagulopathy. Although in FXIIID, the bleed most commonly is intraparenchymal (> 90%), epidural, subdural, and subarachnoid hemorrhages also have been reported, albeit rarely. As this life-threatening bleeding causes neurological complications, early diagnosis can prevent further expansion of the hematoma and secondary damage. Neuroimaging plays a crucial role in the diagnosis of ICH, but signs and symptoms in patients with severe FXIIID should trigger replacement therapy even before establishment of the diagnosis. Although a high dose of FXIII concentrate can reduce the rate of morbidity and mortality of ICH in FXIIID, it may occasionally trigger inhibitor development, thus complicating ICH management and future prophylaxis. Nevertheless, replacement therapy is the mainstay of treatment for ICH in FXIIID. Neurosurgery is performed in patients with FXIIID and epidural hematoma and a hemorrhage diameter exceeding 2 cm or a volume of ICH is more than 30 cm3. Contact sports are not recommended in people with FXIIID as they can elicit ICH. However, a considerable number of safe sports and activities have been suggested to have more benefits than dangers for patients with congenital bleeding disorders, and are hence suitable for these patients.

Application of whole-exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia.

Rare inherited bleeding disorders (IBD) are a common cause of bleeding tendency. To ensure a correct diagnosis, specialized laboratory analyses are necessary. This study reports the results of an upfront diagnostic strategy using targeted whole exome sequencing. In total, 156 patients with a significant bleeding assessment tool score participated in the study, of which a third had thrombocytopenia. Eighty-seven genes specifically associated with genetic predisposition to bleeding were analysed by whole exome sequencing. Variants were classified according to the five-tier scheme. We identified 353 germline variants. Eight patients (5%) harboured a known pathogenic variant. Of the 345 previously unknown variants, computational analyses predicted 99 to be significant. Further filtration according to the Mendelian inheritance pattern, resulted in 59 variants being predicted to be clinically significant. Moreover, 34% (20/59) were assigned as novel class 4 or 5 variants upon targeted functional testing. A class 4 or 5 variant was identified in 30% of patients with thrombocytopenia (14/47) versus 11% of patients with a normal platelet count (12/109) (P < 0·01). An IBD diagnosis has a major clinical impact. The genetic investigations detailed here extricated our patients from a diagnostic conundrum, thus demonstrating that continuous optimization of the diagnostic work-up of IBD is of great benefit.

The haemtrack home therapy reporting system: Design, implementation, strengths and weaknesses: A report from UK Haemophilia Centre Doctors Organisation.

INTRODUCTION: Haemtrack is an electronic home treatment diary for patients with inherited bleeding disorders, introduced in 2008. It aimed to improve the timeliness and completeness of patient-reported treatment records, to facilitate analysis of treatment and outcome trends. The system is easy to use, responsive and accessible. METHODS: The software uses Microsoft technologies with a SQL Server database and an ASP.net website front-end, running on personal computers, android and I-phones. Haemtrack interfaces with the UK Haemophilia Centre Information System and the National Haemophilia Database (NHD). Data are validated locally by Haemophilia Centres and centrally by NHD. Data collected include as follows: treatment brand, dose and batch number, time/date of bleed onset and drug administration, reasons for treatment (prophylaxis, bleed, follow-up), bleed site, severity, pain-score and outcome. RESULTS: Haemtrack was used by 90% of haemophilia treatment centres (HTCs) in 2015, registering 2683 patients using home therapy of whom 1923 used Haemtrack, entering >17 000 treatments per month. This included 68% of all UK patients with severe haemophilia A. Reporting compliance varied and 55% of patients reported ≥75% of potential usage. Centres had a median 78% compliance overall. A strategy for progressively improving compliance is in place. Age distribution and treatment intensity were similar in Haemtrack users/non-users with severe haemophilia treated prophylactically. CONCLUSION: The Haemtrack system is a valuable tool that may improve treatment compliance and optimize treatment regimen. Analysis of national treatment trends and large-scale longitudinal, within-patient analysis of changes in regimen and/or product will provide valuable insights that will guide future clinical practice.

An Unexpectedly High Rate of Thrombophilia Disorders in Patients with Superficial Vein Thrombosis of the Lower Extremities.

BACKGROUND: Superficial vein thrombosis (SVT) is a common venous condition. Recent studies have shown that SVT is associated with high frequency of thromboembolic complications: from 22-37% for deep venous thrombosis and up to 33% for pulmonary embolism. Our goal was to assess the prevalence of major hereditary and acquired thrombophilic factors in patients with SVT. METHODS: Sixty-six patients presenting with primary SVT underwent evaluation for thrombophilia: molecular testing for the factor V Leiden and factor II G20210 A (prothrombin) mutations, protein C, protein S, antithrombin deficiency, presence of lupus anticoagulant, as well as anticardiolipin antibody titers. Patients aged less than 18 years, with confirmed deep vein thrombosis, and pregnant women were excluded. RESULTS: 95.5% were Caucasian, and 62.1% were female gender. Age ranged from 21-88 years. Molecular testing showed that 34.2% of patients were heterozygous for factor V Leiden, 23.6% were heterozygous for the factor II mutation, 7.8% had antithrombin deficiency, 2.6% had protein S deficiency, and 2.1% had protein C deficiency. CONCLUSIONS: Our study showed that hereditary and acquired thrombophilias are higher than previously expected and reported.

Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.

Maternal rare inherited bleeding disorders and neonatal complications.

AIM: The aim of this study was to examine the association between maternal inherited bleeding disorders and neonatal complications. MATERIAL AND METHODS: This was a historical cohort study. The rare inherited bleeding disorders (RIBD) group consisted of a total of 100 women suffering from inherited bleeding disorders, aged 20-45 years who experienced pregnancy. In the healthy control group, 200 age- and body mass index-matched women were selected. Details of demographic and obstetric characteristics of the samples in both groups were collected using their medical records. RESULTS: The mean ages of the women in the RIBD and healthy control groups were 32.6 (7.07) and 32.4 (7.3) years, respectively. No statistically significant differences were found in terms of age and other demographic characteristics of the women between the groups. The mean neonatal birthweight in the RIBD group was statistically lower than that in the healthy control group, 3018.2 (546.9) g vs. 3299.4 (456.8) g, respectively (P = 0.021). The prevalence of low birthweight in the RIBD group was statistically higher in comparison to that in the healthy control group (P = 0.041). After adjustment for potential confounders, it was found that maternal bleeding disorder had significant negative effects on birthweight in newborns (odds ratio, 1.05; 95% confidence interval, 1.01-3.43, P = 0.001). Those infants were statistically more likely to experience head bleeding, early hyperbilirubinemia and hospitalization than the healthy group (P = 0.001). CONCLUSIONS: Maternal rare inherited bleeding disorders may have a devastating consequence for neonates.

Medical co-morbidities and practice.

All-oral treatments of hepatitis C (HCV) have been trialled in patients with hereditary bleeding disorders and found to be effective. Further refinements of dosing and duration are being established. Importantly for patient acceptability these regimens are interferon-free. Cohort studies in older patients with haemophilia direct the need for attention to weight control, exercice, assessment of cardiovascular risk, especially hypertension and detection of osteoporosis. Where patients live a long way from a comprehensive care centre, telemedicine connections can engage centre experts with the patient and his/her local practitioners in devising and monitoring care plans.

Enhancing haemophilia care through registries.

Clinical registries or databases have an increasing role in the management of inherited bleeding disorders. Initially, research-based registries provided valuable data and now national databases are increasingly being developed with multiple stakeholders, including persons with haemophilia (PWH) and payers, to enable improvements and efficiencies in care. Registries are extending to international collaborations to collect adverse event data and comparisons of national approaches to the management of haemophilia to improve the availability of product to PWH.