Gingival bleeding is a useful clinical feature in the diagnosis of hereditary bleeding disorders in children.

The search for hereditary bleeding disorders (HBD) prior to invasive procedures in children is primarily based on personal and family bleeding history. Although several scores are available, they have only been evaluated in specific situations or in adults. Our monocentric retrospective study aimed to analyze the association between clinical history and four scores (HEMSTOP, PBQ, ISTH-BAT, TOSETTO) and the diagnosis of MHC in children referred to the University Hospital of Montpellier for hemostasis investigations. A total of 117 children were retrospectively included in the study. Of these, 57 (49%) were diagnosed with HBD, with 30 having primary bleeding disorders and 27 having coagulation disorders. The diagnosis of HBD was significantly associated with gingival bleeding, which was present in 30% of HBD patients. In our population, only the HEMSTOP score showed an association with the diagnosis of HBD, but it was positive in only 48% of patients. By including gingival bleeding as a factor, we modified the HEMSTOP score, which increased its sensitivity from 0.45 to 0.53. When examining primary bleeding disorders, the modified HEMSTOP score, with the inclusion of gingival bleeding, enables us to diagnose 63% of patients (see Fig. 1).    Conclusion: Therefore, gingival bleeding should be considered a useful factor in bleeding history for HBD diagnosis. Adding this symptom to a screening score such as HEMSTOP improves its sensitivity. To confirm our findings, a prospective study is required.    Trial registration: Study registration number: NCT05214300. What is Known: • Screening for hereditary bleeding disorder diseases is a necessity and a challenge in children. • Minor disorders of primary hemostasis are the most common, but often escape standard coagulation tests. What is New: • Gingival bleeding is a frequent symptom that is easy to investigate and may point to a primary hemostasis disorder. • Adding the gingival bleeding item to a routine screening score such as HEMSTOP improves sensitivity.

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.

JTH in Clinic - Obstetric bleeding: VWD and other inherited bleeding disorders.

Individuals with inherited bleeding disorders (IBDs) have higher bleeding risk during pregnancy, childbirth, and the postpartum period. Clinical management requires recognition of the IBD as high risk for postpartum hemorrhage and a personalized multidisciplinary approach that includes the patient in decision making. When the fetus is known or at risk to inherit a bleeding disorder, fetal and neonatal bleeding risk also need to be considered. In pregnant IBD patients, it is common for providers to need to make decisions in the absence of high level of certainty evidence. We here present the case of a pregnant von Willebrand disease patient that reached multiple decision points where there is currently clinical ambiguity due to a lack of high level of certainty evidence. For each stage of her care, from diagnosis to the postpartum period, we discuss current literature and describe our approach. This is followed by a brief overview of considerations in other IBDs and pregnancy.

Gastrointestinal Bleeding in Congenital Bleeding Disorders.

Gastrointestinal bleeding (GIB) is serious, intractable, and potentially life-threatening condition. There is considerable heterogeneity in GIB phenotypes among congenital bleeding disorders (CBDs), making GIB difficult to manage. Although GIB is rarely encountered in CBDs, its severity in some patients makes the need for a comprehensive and precise assessment of underlying factors and management approaches imperative. Initial evaluation of GIB begins with assessment of hematological status; GIB should be ruled out in patients with chronic anemia, and in presentations that include hematemesis, hematochezia, or melena. High-risk patients with recurrent GIB require urgent interventions such as replacement therapy for treatment of coagulation factor deficiency (CFD). However, the best management strategy for CFD-related bleeding remains controversial. While several investigations have identified CBDs as potential risk factors for GIB, research has focused on assessing the risks for individual factor deficiencies and other CBDs. This review highlights recent findings on the prevalence, management strategies, and alternative therapies of GIB related to CFDs, and platelet disorders.

Osteonecrosis of the Femoral Head in Patients with Hypercoagulability-From Pathophysiology to Therapeutic Implications.

Osteonecrosis of the femoral head (ONFH) is a debilitating disease with major social and economic impacts. It frequently affects relatively young adults and has a predilection for rapid progression to femoral head collapse and end-stage hip arthritis. If not diagnosed and treated properly in the early stages, ONFH has devastating consequences and leads to mandatory total hip arthroplasty. The pathophysiology of non-traumatic ONFH is very complex and not fully understood. While multiple risk factors have been associated with secondary ONFH, there are still many cases in which a clear etiology cannot be established. Recognition of the prothrombotic state as part of the etiopathogeny of primary ONFH provides an opportunity for early medical intervention, with implications for both prophylaxis and therapy aimed at slowing or stopping the progression of the disease. Hereditary thrombophilia and hypofibrinolysis are associated with thrombotic occlusion of bone vessels. Anticoagulant treatment can change the natural course of the disease and improve patients' quality of life. The present work focused on highlighting the association between hereditary thrombophilia/hypofibrinolysis states and ONFH, emphasizing the importance of identifying this condition. We have also provided strong arguments to support the efficiency and safety of anticoagulant treatment in the early stages of the disease, encouraging etiological diagnosis and prompt therapeutic intervention. In the era of direct oral anticoagulants, new therapeutic options have become available, enabling better long-term compliance.

Outcome of Surgical Interventions and Deliveries in Patients with Bleeding of Unknown Cause: An Observational Study.

BACKGROUND: The most optimal management for patients with bleeding of unknown cause (BUC) is unknown, as limited data are available. OBJECTIVE: Evaluate management and outcome of surgical procedures and deliveries in patients with BUC. MATERIALS AND METHODS: All patients ≥12 years of age, referred to a tertiary center for a bleeding tendency, were included. Bleeding phenotype was assessed and hemostatic laboratory work-up was performed. Patients were diagnosed with BUC or an established bleeding disorder (BD). Data on bleeding and treatment during surgical procedures and delivery following diagnosis were collected. RESULTS: Of 380 included patients, 228 (60%) were diagnosed with BUC and 152 (40%) with an established BD. In 14/72 (19%) surgical procedures major bleeding occurred and 14/41 (34%) deliveries were complicated by major postpartum hemorrhage (PPH). More specifically, 29/53 (55%) of the BUC patients who underwent surgery received prophylactic treatment to support hemostasis. Despite these precautions, 4/29 (14%) experienced major bleeding. Of BUC patients not treated prophylactically, bleeding occurred in 6/24 (25%). Of pregnant women with BUC, 2/26 (8%) received prophylactic treatment during delivery, one women with and 11 (46%) women without treatment developed major PPH. CONCLUSION: Bleeding complications are frequent in BUC patients, irrespective of pre- or perioperative hemostatic treatment. We recommend a low-threshold approach toward administration of hemostatic treatment in BUC patients, especially during delivery.

Main Factors Predicting Nonresponders to Autologous Cell Therapy for Critical Limb Ischemia in Patients With Diabetic Foot.

Autologous cell therapy (ACT) is a new treatment for patients with no-option critical limb ischemia (NO-CLI). We evaluated the factors involved in the nonresponse to ACT in patients with CLI and diabetic foot. Diabetic patients (n = 72) with NO-CLI treated using ACT in our foot clinic over a period of 8 years were divided into responders (n = 57) and nonresponders (n = 15). Nonresponder was defined as an insufficient increase in transcutaneous oxygen pressure by <5 mm Hg, 3 months after ACT. Patient demographics, diabetes duration and treatment, and comorbidities as well as a cellular response to ACT, limb-related factors, and the presence of inherited thrombotic disorders were compared between the 2 groups. The main independent predictors for an impaired response to ACT were heterozygote Leiden mutation (OR 10.5; 95% CI, 1.72-4) and homozygote methylenetetrahydrofolate reductase (MTHFR 677) mutation (OR 3.36; 95% CI, 1.0-14.3) in stepwise logistic regression. Univariate analysis showed that lower mean protein C levels (P = .041) were present in nonresponders compared with responders. In conclusion, the significant predictors of an impaired response to ACT in diabetic patients with NO-CLI were inherited thrombotic disorders.

Challenges and concerns of patients with congenital bleeding disorders affected by coronavirus disease 2019.

Coronavirus disease 2019 (COVID-19) is a new medical challenge for all individuals, especially for those with underlying disorders, such as congenital bleeding disorders (CBDs). Therefore, the pandemic might significantly change the behaviour of patients with CBDs and results in some challenges. In the present study, we assessed the main challenges of COVID-19 infection to patients with CBDs. Data were collected from medical files and interviews of patients with CBDs who had COVID-19 infection. Follow-ups were performed on patients who had active severe acute respiratory syndrome coronavirus 2 infection between April and October 2020. All patients were interviewed by an expert in order to collect the pertinent data. Some questions were about patients' preventive behaviors and feelings prior to infection, and some were about the consequences of infection on patients' replacement therapy and bleeding management. Among 25 patients, infection and death of loved ones (n: 7, 28%), and their own (n: 5, 20%) or family members' (n: 1, 4%) infection, and the resulting economic burden (n: 2, 8%) were main concerns. Six patients experienced depression during the pandemic. The pandemic caused all severely affected patients but one (n: 11, 92%) to abandon replacement therapy. However, two received on-demand therapy after exacerbation of their bleeding. Only one (25%) of four patients on prophylaxis received in-home therapy, whereas the others (75%) abandoned prophylaxis. It seems that COVID-19 infection has great consequences on the lives of patients with CBDs, causing some to take dangerous actions, such as abandonment of their treatment. Healthcare systems, and healthcare providers, should have an appropriate strategy for management of patients with CBDs that prevents infection and provides timely replacement therapy.

Postpartum bleeding in women with inherited bleeding disorders: a matched cohort study.

: Women with inherited bleeding disorders (IBDs) are reported to have higher rates of primary and secondary postpartum haemorrhage (PPH), even with optimal haemostatic management. We evaluated whether women with IBD have higher odds of PPH compared with those without, when controlled for mode of delivery with a control group of women without IBDs. The obstetric experiences and outcomes of all women with IBD delivering at a tertiary centre between 2008 and 2017, were compared with matched controls (1 : 1). Obstetric care was provided according to national guidelines to both women with IBD and controls. Primary PPH was defined as estimated blood loss at least 500 ml. There were 46 completed pregnancies in women with IBD: 16 haemophilia A carriers, eight haemophilia B carriers, eight factor XI deficiency patients and 14 von Willebrand disease patients (type 1 = 6; type 2 = 8). No peripartum haemostatic treatment was received by carriers of haemophilia A or B. There were 74 control pregnancies. Women with IBD had higher odds of primary PPH, in a model controlling for mode of anaesthesia (adjusted odds ratio 5.30, 95% confidence interval 1.02-27.59, P = 0.048). Carriers of haemophilia A had a higher, statistically nonsignificant, odds for primary PPH than controls (adjusted odds ratio 6.85, confidence interval 0.77-60.73, P = 0.084). An increase in primary PPH was observed in women with IBD, particularly in haemophilia A, despite management according to guidelines. These results warrant further investigation and consideration should be given as to which factor levels to target.

[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.

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

Resumen: Introducción: El Sangrado Menstrual Excesivo (SME) es un problema frecuente en la adolescencia. La prevalencia de trastornos hereditarios de la coagulación (THC) como causa del SME no está bien establecida y la participación de defectos de la vía fibrinolítica ha sido poco explorada. Objetivo: Determinar la prevalencia de THC y defectos de la fibrinólisis en adolescentes con SME. Pacientes y Método: Se incluyeron 93 adolescentes, edad 11 a 18 años. Los antecedentes personales y familiares de sangra do se obtuvieron con un cuestionario estandarizado. Se controló exámenes: tiempo de protrom- bina (TP), tiempo de tromboplastina parcial activada (TTPa), estudio del factor Von Willebrand, recuento y función plaquetaria. Los pacientes que no fueron diagnosticados como THC, se evaluaron adicionalmente con el tiempo de lisis del coágulo. Resultados: 41 pacientes (44%) fueron diagnos ticados como THC: Enfermedad de Von Willebrand n = 28, defectos de la función plaquetaria n = 8, hemofilia leve n = 5. Se confirmó disminución del tiempo de lisis del coágulo en 31 pacientes. El 54% de pacientes diagnosticado como THC, tuvo SME como la primera manifestación hemorrágica. Conclusión: Estos resultados apoyan la necesidad de evaluación de la coagulación, incluyendo la vía fibrinolítica, en el estudio de adolescentes con SME.

Abstract: 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.

Targeting protease nexin-1, a natural anticoagulant serpin, to control bleeding and improve hemostasis in hemophilia.

Hemophilia A and B, diseases caused by the lack of factor VIII (FVIII) and factor IX (FIX) respectively, lead to insufficient thrombin production, and therefore to bleeding. New therapeutic strategies for hemophilia treatment that do not rely on clotting factor replacement, but imply the neutralization of natural anticoagulant proteins, have recently emerged. We propose an innovative approach consisting of targeting a natural and potent thrombin inhibitor, expressed by platelets, called protease nexin-1 (PN-1). By using the calibrated automated thrombin generation assay, we showed that a PN-1-neutralizing antibody could significantly shorten the thrombin burst in response to tissue factor in platelet-rich plasma (PRP) from patients with mild or moderate hemophilia. In contrast, in PRP from patients with severe hemophilia, PN-1 neutralization did not improve thrombin generation. However, after collagen-induced platelet activation, PN-1 deficiency in F8-/-mice or PN-1 blocking in patients with severe disease led to a significantly improved thrombin production in PRP, underlining the regulatory role of PN-1 released from platelet granules. In various bleeding models, F8-/-/PN-1-/- mice displayed significantly reduced blood loss and bleeding time compared with F8-/-mice. Moreover, platelet recruitment and fibrin(ogen) accumulation were significantly higher in F8-/-/PN-1-/- mice than in F8-/-mice in the ferric chloride-induced mesenteric vessel injury model. Thromboelastometry studies showed enhanced clot stability and lengthened clot lysis time in blood from F8-/-/PN-1-/- and from patients with hemophilia A incubated with a PN-1-neutralizing antibody compared with their respective controls. Our study thus provides proof of concept that PN-1 neutralization can be a novel approach for future clinical care in hemophilia.