Dental management of people with complex or rare inherited bleeding disorders.

Advances in haematological therapies for people with complex or rare inherited bleeding disorders (IBD) have resulted in them living longer, retaining their natural teeth with greater expectations of function and aesthetics. Dental management strategies need to evolve to meet these challenges. Utilising low level laser diode therapy to reduce pre-operative inflammation to reduce the intraoperative and postoperative burden on haemostasis is described in a case series of 12 patients. For these individuals who previously required further medical management to support haemostasis or experienced such prolonged haemorrhage sufficient to warrant hospital admission, haemostasis was achieved in the dental surgery such that they were able to return home with no further medical intervention or overnight stays. Global inequities in accessing novel treatments for complex or rare IBD necessitates a comprehensive understanding of the local haemostatic agents available to dentists and the most commonly used agents and techniques are described including the use of single tooth anaesthesia (STA). STA is a computerised delivery mechanism that allows routine dental procedures that would previously have required block injections needing factor replacement therapy to be undertaken safely and effectively with no additional haemostatic intervention. The challenges of inhibitors in oral surgery are explained and discussed although more research and evidence is required to establish new treatment protocols. The importance of establishing good dental health in the quality of life of people with complex or rare IBD is highlighted with respect to the dental specific impact that more novel therapies may have on people with IBD.

Altered platelet-megakaryocyte endocytosis and trafficking of albumin and fibrinogen in RUNX1 haplodeficiency.

ABSTRACT: Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. Germ line RUNX1 haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMMs), is associated with thrombocytopenia, platelet dysfunction, and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen, and immunoglobulin G (IgG) were decreased in a patient with FPDMM. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen, and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, small interfering RNA RUNX1 knockdown (KD) increased uptake of these proteins over 24 hours compared with control cells, with increases in caveolin-1 and flotillin-1 (2 independent regulators of clathrin-independent endocytosis), LAMP2 (a lysosomal marker), RAB11 (a marker of recycling endosomes), and IFITM3. Caveolin-1 downregulation in RUNX1-deficient HEL cells abrogated the increased uptake of albumin, but not fibrinogen. Albumin, but not fibrinogen, partially colocalized with caveolin-1. RUNX1 KD resulted in increased colocalization of albumin with flotillin and fibrinogen with RAB11, suggesting altered trafficking of both proteins. The increased uptake of albumin and fibrinogen, as well as levels of caveolin-1, flotillin-1, LAMP2, and IFITM3, were recapitulated by short hairpin RNA RUNX1 KD in CD34+-derived MK. To our knowledge, these studies provide first evidence that platelet endocytosis of albumin and fibrinogen is impaired in some patients with RUNX1-haplodeficiency and suggest that megakaryocytes have enhanced endocytosis with defective trafficking, leading to loss of these proteins by distinct mechanisms. This study provides new insights into mechanisms governing endocytosis and α-granule deficiencies in RUNX1-haplodeficiency.

Genomic landscape of patients with germline RUNX1 variants and familial platelet disorder with myeloid malignancy.

ABSTRACT: Familial platelet disorder with associated myeloid malignancies (FPDMM) is caused by germline RUNX1 mutations and characterized by thrombocytopenia and increased risk of hematologic malignancies. We recently launched a longitudinal natural history study for patients with FPDMM. Among 27 families with research genomic data by the end of 2021, 26 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 25 of 51 (49%) patients without hematologic malignancy, somatic mutations were detected in at least 1 of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 6 other CHIP- or AML-driver genes (TET2, DNMT3A, KRAS, LRP1B, IDH1, and KMT2C) were also found in ≥2 patients without hematologic malignancy. Moreover, 3 unrelated patients (1 with myeloid malignancy) carried somatic mutations in NFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in older adult patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring changes in somatic mutations and clinical manifestations prospectively may reveal mechanisms for malignant progression and inform clinical management. This trial was registered at www.clinicaltrials.gov as #NCT03854318.

Desmopressin to prevent and treat bleeding in pregnant women with an inherited bleeding disorder: a systematic literature review.

BACKGROUND: Although desmopressin (DDAVP) is an accessible and inexpensive hemostatic drug, its use in pregnancy is still debated due to safety uncertainties. OBJECTIVES: We aimed to review the safety and effectiveness of DDAVP in women with an inherited bleeding disorder during pregnancy and delivery. METHODS: Databases were searched for articles up to July 25, 2022, reporting maternal and/or neonatal outcomes. PRISMA methodology for systematic reviews and meta-analyses was followed (PROSPERO CRD42022316490). RESULTS: Fifty-three studies were included, comprising 273 pregnancies. Regarding maternal outcomes, DDAVP was administered in 73 women during pregnancy and in 232 during delivery. Safety outcome was reported in 245 pregnancies, with severe adverse events reported in 2 (1%, hyponatremia with neurologic symptoms). Overall, DDAVP was used as monotherapy in 234 pregnancies, with effectiveness reported in 153 pregnancies (82% effective; 18% ineffective). Regarding neonatal outcomes, out of 60 pregnancies with reported neonatal outcomes after DDAVP use during pregnancy, 2 children (3%) had a severe adverse event (preterm delivery n = 1; fetal growth restriction n = 1). Of the 232 deliveries, 169 neonates were exposed to DDAVP during delivery, and in 114 neonates, safety outcome was reported. Two children (2%) experienced a moderate adverse event (low Apgar score n = 1; transient hyperbilirubinemia not associated with DDAVP n = 1). CONCLUSION: DDAVP use during pregnancy and delivery seems safe for the mother, with special attention to the occurrence of hyponatremia and for the child, especially during delivery. However, due to poor study designs and limited documentation of outcomes, a well-designed prospective study is warranted.

National strategic advocacy to manage patients with inherited bleeding disorders in low and lower-middle income countries.

INTRODUCTION: Inherited bleeding disorders (IBDs) including hemophilia, von Willebrand disease, platelet disorders, mucocutaneous bleeding disorders and coagulation factor deficiencies are rarely found and under-recognized in low and lower-middle-income countries. Some patients succumbed to serious bleeding without diagnosis and treatment during childhood. AREA COVERED: Diagnosis, management, and prevention should be integrated into the existing health care system. Although some countries have not implemented appropriate health care infrastructure, an initiative plan should be set up by cooperation of experienced experts and health care providers. Identification of patients with IBDs should be started in the antenatal setting to search for females at risk of carrier state. The investigations include bleeding assessment, mixing venous clotting time, coagulogram, coagulation factor assay and mutation detection. Genotypic analysis is helpful for confirming the definite diagnosis, carrier detection as well as prenatal diagnosis for females at risk of bearing an offspring with severe bleeding manifestations. Management involves replacement therapy ranging from blood component to virus-inactivated factor concentrate. Appropriate research is an essential backbone for improving patients' care. EXPERT OPINION: Effective national strategic advocacy to manage patients with IBDs requires intensive collaboration among policy makers, health care providers, patients, and family members.

Bombardier Blood (2020): Un documental más allá de la enfermedad / Bombardier Blood (2020): A Documentary beyond the Illness

Si bien la hemofilia era conocida como una enfermedad que perturbaba solo a las familias reales de Europa, actualmente afecta a uno de cada 5.000 y a uno de cada 30.000 varones recién nacidos vivos tanto para la de Tipo A como B, respectivamente. La hemofilia es un trastorno de la coagulación sanguínea que afecta principalmente a varones por su carácter de herencia recesiva ligada al X, siendo su manifestación principal las hemorragias que pueden llegar a ser mortales si no son tratadas correctamente. En Bombardier Blood (2020) de Patrick James Lynch, un documental enfocado al recorrido de Chris Bombardier, una persona hemofílica cuyo sueño es escalar las siete cumbres más altas del mundo, incluyendo en su paso el monte Everest en el Himalaya. El documental además de destacar los aspectos médicos sobre esta enfermedad hace ver los diferentes estilos de vida de acuerdo a su localización, las normativas y sistemas de salud que los rige y como esto incide en el diagnóstico, seguimiento y tratamiento. (AU)

While hemophilia was considered a disease that disturbed only the royal families of Europe, it currently affects one in 5.000 and one in 30.000 live newborn males for both Type A and B, respectively. Hemophilia is a blood clotting disorder that mainly affects men due to its character of recessive inheritance linked to X, its main manifestation hemorrhaging that can become fatal if they are not treated correctly. Bombardier Blood (2020) by Patrick James Lynch is a documentary focused on the journey of Chris Bombardier, a hemophilic person whose dream is to climb the seven highest summits in the world, including Mount Everest in the Himalayas. The documentary, in addition to highlighting the medical aspects of this disease, shows the different lifestyles according to their location, the regulations and health systems that govern them, and how these affect diagnosis, monitoring, and treatment. (AU)

Preoperative diagnosis and management of inherited bleeding disorders in female adolescents and adults.

Although inherited bleeding disorders (IBDs) affect both females and males, this review of the preoperative diagnosis and management of IBDs focuses on genetic and gynecologic screening, diagnosis and management of affected and carrier females. A PubMed literature search was conducted, and the peer-reviewed literature on IBDs was evaluated and summarized. Best-practice considerations for screening, diagnosis and management of IBDs in female adolescents and adults, with GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) evidence level and ranking of recommendation strength, are presented. Health care providers need to increase their recognition of and support for female adolescents and adults with IBDs. Improved access to counselling, screening, testing and hemostatic management is also required. Patients should be educated and encouraged to report abnormal bleeding symptoms to their health care provider when they have a concern. It is hoped that this review of preoperative IBD diagnosis and management will enhance access to women-centred care to increase patients' understanding of IBDs and decrease their risk of IBD-related morbidity and mortality.

Endodontic therapy in patients with inherited bleeding disorders: a scoping review.

This systematic scoping review aimed to map available evidence regarding endodontic therapy in patients with inherited bleeding disorders (IBDs). Studies in medicine or dentistry were selected if they reported on endodontic therapy in individuals with IBDs such as hemophilia A, hemophilia B, or von Willebrand disease. Two independent researchers performed searches and screening in PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library. The search initially yielded 676 potentially relevant studies, 14 of which were included in the final analysis. Of these 14 studies, 3 were classified as consensus statements or guidelines, 3 as observational studies, 2 as reviews, 5 as case reports, and 1 as an editorial. Most of the evidence regarding prophylactic treatment (eg, blood transfusion, replacement therapy, or medication administration) prior to endodontic therapy was derived from observational studies. The most frequently reported procedure was endodontic therapy, while 1 case report described a surgical endodontic procedure. Most studies included in the analysis reported that these procedures could be performed under local anesthesia. Two case reports and 1 observational study described complications after endodontic therapy in patients with IBDs. This scoping review revealed a lack of well-designed studies related to the topic of endodontic therapy in patients with IBDs. The available evidence suggests that endodontic therapy in patients with IBDs can be considered a low-risk procedure; local anesthesia should be used in most cases when patients with IBDs are treated, but the use of prophylactic measures is preferred when nerve block anesthesia is required; endodontic therapy can be conducted in a clinical setting without the need for hospital admittance; and, although the number of reported complications is small, the risk should not be ignored.

Prevalence of hemorrhagic ovarian cysts in patients with rare inherited bleeding disorders.

BACKGROUND: In comparison with the general population, women with bleeding disorders are more prone to develop obstetrical and gynecological problems. However, no comprehensive evaluation has investigated the prevalence of hemorrhagic ovarian cysts (HOCs) in rare bleeding disorders (RBDs). In this study, we sought to determine the prevalence of HOCs in a large cohort of Iranian patients with RBDs. METHODS: A total of 210 symptomatic patients suspected of HOCs with RBD were included. The median age of the study population was 24 years. Patients were diagnosed with fibrinogen disorders (n = 7, 3%), factor (F) II (n = 4, 2%), FV (n = 28, 13%), FVII (n = 4, 2%), FX (n = 6, 3%), FXIII (n = 122, 58%), combined FV and FVIII (n = 8, 4%), Glanzmann's thrombasthenia (n = 10, 5%), and von Willebrand disease (VWD) type 3 (n = 21, 10%). RESULTS: Following further clinical and ultrasound examinations of these 210 patients, 68 (32.4%) were confirmed with a diagnosis of HOCs. Of which, FXIII deficiency with 46 cases (67.6%), followed by VWD type 3 (6 cases, 8.8%) showed the highest number. Other coagulation defects associated with HOCs were including fibrinogen deficiency (n = 2, 3%), FII (n = 2, 3%), FV (n = 4, 6%), FVII (n = 2, 3%), FX (n = 1, 1.5%), combined FV and FVIII (n = 2, 3%), and Glanzmann's thrombasthenia (n = 3, 4.5%). CONCLUSION: This study found a high prevalence of HOCs in patients with RBDs, indicating the importance of early diagnosis and optimal management of obstetric and gynecological complications in these patients.

Molecular basis of rare congenital bleeding disorders.

Rare bleeding disorders (RBDs), including factor (F) I, FII, FV, FVII, combined FV and FVIII (CF5F8), FXI, FXIII and vitamin-K dependent coagulation factors (VKCF) deficiencies, are a heterogeneous group of hemorrhagic disorder with a variable bleeding tendency. RBDs are due to mutation in underlying coagulation factors genes, except for CF5F8 and VKCF deficiencies. FVII deficiency is the most common RBD with >330 variants in the F7 gene, while only 63 variants have been identified in the F2 gene. Most detected variants in the affected genes are missense (>50% of all RBDs), while large deletions are the rarest, having been reported in FVII, FX, FXI and FXIII deficiencies. Most were located in the catalytic and activated domains of FXI, FX, FXIII and prothrombin deficiencies. Understanding the proper molecular basis of RBDs not only can help achieve a timely and cost-effective diagnosis, but also can help to phenotype properties of the disorders.

Hypoprothrombinemia-lupus anticoagulant syndrome secondary to Sjogren's syndrome: A case report. / å¹²ç‡¥ç»¼åˆå¾ç»§å‘ä½Žå‡è¡€é ¶åŽŸè¡€ç—‡-狼疮抗凝物综合征1例.

Hypoprothrombinemia-lupus anticoagulant syndrome (HLAS) is a rare disease in which patients present with varying degrees of bleeding and positive lupus anticoagulant with reduced prothrombin on laboratory tests. This article reports a case of HLAS in a middle-aged woman with recurrent gingival bleeding and epistaxis as the first presentation. After admission, tests revealed prolonged prothrombin time (PT), activated partial thromboplastin time (APTT), and reduced coagulation factor II activity, and positive lupus anticoagulant (LA). Meanwhile, the patient had symptoms of dry mouth and dry eyes for a long time, and the examination of autoantibodies, tear secretion test and salivary gland emission computed tomography (ECT) were consistent with the diagnosis of Sjogren's syndrome. The final diagnosis was HLAS secondary to Sjogren's syndrome. After treatment with methylprednisolone and cyclophosphamide, the coagulation disorder gradually improved, and no recurrent bleeding occurred. HLAS is a rare clinical case, which reminds medical staff to be alert to the possibility of HLAS when encountering patients with unexplained prolonged APTT and PT and positive lupus anticoagulant.

[Young girls and women with congenital bleeding disorders - The challenges of early diagnosis]. / Jeunes filles et femmes avec une maladie hémorragique constitutionnelle - Les enjeux du diagnostic précoce.

Diagnosis of young girls and women with congenital bleeding disorders (CBD) is often delayed. The lack of knowledge of the challenges faced during menstrual cycles and childbirth contribute to this situation. Therefore, a better understanding and identification of the barriers to diagnosis become a useful tool for implementing the steps that promote equitable access and appropriate care. As such, the role of front-line healthcare professionals is crucial in detecting the relevant bleeding symptoms, initiating the first stages of the work-up needed, organizing early access to a specialized clinics and starting non-specific treatments, such as antifibrinolytics for abnormal uterine bleeding, even in the absence of a specific diagnosis of the type of CBD.

Les jeunes filles et femmes avec une maladie hémorragique constitutionnelle (MHC) sont souvent diagnostiquées avec retard. La méconnaissance des défis auxquels elles font face lors des cycles menstruels et des accouchements contribue à cette errance. Mieux comprendre et identifier les freins au diagnostic devient donc un levier utile pour mettre en œuvre les étapes favorisant un accès équitable à un parcours de soins et de suivi adapté. À ce titre, le rôle des acteurs de santé de première ligne est crucial pour dépister les symptômes hémorragiques pertinents, initier les premières étapes du bilan, organiser l'accès précoce à une consultation spécialisée et débuter un traitement non spécifique, tels que les antifibrinolytiques pour les saignements utérins anormaux (SUA), même en absence d'un diagnostic précis du type de MHC.

[Partial research progress of GGCX pathogenic variation associated phenotypes].

γ-glutamyl carboxylase (GGCX), also known as vitamin K-dependent glutamyl carboxylase, catalyzes the posttranslational modification of specific glutamate residues in vitamin K-dependent proteins (VKDPs), and participates multiple biological functions including blood coagulation, bone metabolism, vascular calcification, and cell proliferation. It has been reported originally that GGCX pathogenic variation causes blood coagulation deficiency, which is called as vitamin K-dependent coagulation factor deficiency 1 (VKCFD1). Recently, it has been found that GGCX gene variation results in multiple clinical phenotypes, including dermatological, ophthalmological, skeletal or cardiac abnormalities. Among them, dermatological phenotype is the most common, which is known as pseudoxanthoma elasticum-like syndrome. This paper has reviewed the GGCX pathogenic variation associated phenotypes, in order to increase the recognition of GGCX-related genetic diseases and to help its diagnosis and treatment.

Cerebral sinus venous thrombosis in children with inherited bleeding disorders: A case series.

In patients with inherited bleeding disorders, thrombus development poses a challenge in balancing the management of thrombosis and bleeding. Pediatric antithrombotic therapy guidelines do not address the treatment of a thrombus in the setting of a bleeding disorder. We present a case series of four children with inherited bleeding disorders presenting with cerebral sinus venous thrombosis and bleeding, in order to summarize the different therapeutic approaches and outcomes of these patients.

Aetiological Profile and Short-Term Neurological Outcome of Haemorrhagic Stroke in Children.

BACKGROUND: Haemorrhagic stroke (HS) accounts for nearly half of the paediatric strokes. The aetiology of HS in childhood is not well defined in the Indian context. OBJECTIVES: To study the aetiological profile and short-term neurological outcome of children with HS from North India. METHODS: In a prospective observational study, consecutive patients >28 days to <12 years of age admitted with a diagnosis of HS were enrolled. Demography, clinical, radiological details and investigations were recorded. Short-term outcomes were assessed at three months follow-up with the Paediatric Cerebral Performance Category scale and Paediatric Stroke Outcome Measure (PSOM). RESULTS: A total of 48 children with HS were enrolled. The median age was 6 months (1-58 months), and 33 (69%) were <2 years old. Vitamin K deficiency-related bleeding disorder (VKDB, 44%), central nervous system infections (19%), arteriovenous malformations (13%) and inherited coagulation disorders (8%) were the most common risk factors for HS. VKDB and inherited coagulation disorders were more frequent in children <2 years of age, and arteriovenous malformations were more frequent in children >2 years of age (p = 0.001). During hospitalization, 21 (44%) children died. Older age, low Glasgow coma score (<8) at admission and paediatric intracerebral haemorrhage score ≥2 were associated with mortality at discharge (p = <0.05). Among survivors, 15 (56%) children had neurological deficits (PSOM >0.5) at three month follow-up. CONCLUSION: VKDB, inherited coagulation disorders, central nervous system infections and arteriovenous malformations were the most common risk factors for HS. VKDB is the single most important preventable risk factor for HS in infants.

Congenital Bleeding Disorders and COVID-19 - An Emphasis on the Role of Thrombosis as One of the Main Causes of Morbidity and Mortality in COVID-19.

A turbulent coagulation system is a prominent feature of Coronavirus Disease 2019 (COVID-19), with venous thromboembolism (VTE) a leading cause of death. Our hypothesis is that patients with inherited hypocoagulability, like congenital bleeding disorders (CBD), enjoy a protective effect against COVID-19-induced hypercoagulability and related fatal consequences. Our primary and follow-up observations revealed this effect, at least among patients with moderate to severe congenital bleeding disorders, particularly coagulation factor deficiencies. Theoretically, patients with inherited hypocoagulobility have only a potential protective effect against COVID-19-related hypercoagulability. Yet the lower rate of morbidity and mortality in patients with CBDs suggests that hypercoagulability and thrombotic events are the main cause of death in COVID-19. Therefore, appropriate and timely administration of anticoagulants could significantly decrease the rate of morbidity and mortality in COVID-19.

Determining the incidence of postpartum haemorrhage among Ontario women with and without inherited bleeding disorders: A population-based cohort study.

INTRODUCTION: At a population level, there is a poor understanding of the incidence and pre-disposing risk factors of postpartum haemorrhage (PPH) among women with inherited bleeding disorders (IBD). AIM: To determine the incidence of PPH, and identify maternal factors associated with risk of PPH among women with IBD. METHODS: We conducted a retrospective cohort study using data housed within ICES (formerly known as the Institute for Clinical Evaluative Sciences). The cohort included women with an in-hospital, live or stillborn delivery, between January 2014 and December 2019. The primary outcome was PPH (identified by ICD-10 code O72). PPH incidence and risk factors were compared between women with and without IBD. Temporal trends were assessed using the Cochrane-Armitage test. Between group differences were assessed using standardised differences (std. difference). RESULTS: Total 601,773 women were included; 2002 (.33%) had an IBD diagnosis. PPH incidence was 1.5 times higher (7.3 vs. 4.9 cases/100 deliveries, std. difference .1) among women with IBD compared to women without. Women with IBD were slightly older (31.7 vs. 30.7 years), had higher rates of hypertension, previous PPH, and induction of labour. Women with IBD were more frequently diagnosed with anaemia (4.8% vs. 1.8%; std difference .17) and had lower haemoglobin levels at admission for delivery compared to women without IBD. CONCLUSIONS: This study contributes to the literature regarding obstetric bleeding among women with IBD, showing that anaemia at delivery may be an important risk factor for PPH. Given their predisposition to anaemia, clarifying this relationship will optimise management and outcomes.