Rare Inherited Bleeding Disorders Research Articles

Surgery in rare bleeding disorders: the prospective MARACHI study

BackgroundDespite the wide use of bleeding scores and the reliability of clotting factor level measurement, bleeding risk stratification before surgery remains challenging in patients with rare inherited bleeding disorders. ObjectivesThis multicenter observational prospective study assessed in patients with rare coagulation factor deficiency, the perioperative hemostatic management choices by hemostasis experts and the bleeding outcomes after surgery. MethodsOne hundred seventy-eight patients with low coagulation activity level (factor [F] II, FV, combined FV-FVIII, FVII, FX, or FXI <50%) underwent 207 surgical procedures. The bleeding outcome, Tosetto’s bleeding score, and perioperative hemostatic protocols were collected. ResultsAmong the 81 procedures performed in patients with severe factor deficiency (level ≤10%), 27 were done without factor replacement (including 6 in patients at high bleeding risk), without any bleeding event. Factor replacement therapy was used mainly for orthopedic procedures. In patients with mild deficiency, 100/126 surgical procedures were carried out without perioperative hemostatic treatment. In patients with FVII or FXI deficiency, factor replacement therapy was in function of the procedure, bleeding risk, and to a lesser extent previous bleeding history. Tranexamic acid was used in almost half of the procedures, particularly in case of surgery in tissues with high fibrinolytic activity (76.8%). ConclusionsThe current perioperative hemostatic management of patients with rare bleeding disorders appears to be adapted. Among the 207 procedures, only 6 were associated with excessive bleeding. Our findings suggest that rather than the bleeding score, factor level and surgery type are the most relevant criteria for perioperative factor replacement therapy.

Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories.

Coagulation factors, anticoagulants, and fibrinolytic proteins are important for hemostasis, and mutations affecting these proteins causes some rare inherited bleeding disorders that are particularly challenging to diagnose. This review provides current information on rare inherited bleeding disorders that are difficult to diagnose. A review of the literature was conducted for up to date information on rare and difficult to diagnose bleeding disorders. Some rare bleeding disorders cause an inherited deficiency of multiple coagulation factors (F), such as combined FV and FVIII deficiency and familial vitamin K-dependent clotting factor deficiency. Additionally, congenital disorders of glycosylation can affect a variety of procoagulant and anticoagulant proteins and also platelets. Some bleeding disorders reflect mutations with unique impairments in the procoagulant/anticoagulant balance, including those caused by F5 mutations that secondarily increase the plasma levels of tissue factor pathway inhibitor as well as THBD mutations that increase functional thrombomodulin in plasma or cause a consumptive coagulopathy due to thrombomodulin deficiency. Some bleeding disorders accelerate fibrinolysis due to loss-of-function mutations in SERPINE1 and SERPINF2 or in the case of Quebec platelet disorder, a duplication mutation that rewires PLAU and selectively increases expression in megakaryocytes, resulting in a unique platelet-dependent gain-of-function defect in fibrinolysis. Current information on rare and difficult to diagnose bleeding disorders indicates they have unique clinical and laboratory features, and pathogenic characteristics to consider for diagnostic evaluation. Laboratories and clinicians should consider rare inherited disorders, and difficult to diagnose conditions, in their strategy for diagnosing bleeding disorders.

Management of rare inherited bleeding disorders: Proposals of the French Reference Centre on Haemophilia and Rare Coagulation Disorders.

The rare coagulation disorders may present significant difficulties in diagnosis and management. In addition, considerable inter-individual variation in bleeding phenotype is observed amongst affected individuals, making the bleeding risk difficult to assess in affected individuals. The last international recommendations on rare inherited bleeding disorders (RIBDs) were published by the United Kingdom Haemophilia Centre Doctors' Organisation in 2014. Since then, new drugs have been marketed, news studies on surgery management in patients with RIBD have been published, and new orphan diseases have been described. Therefore, the two main objectives of this review, based on the recent recommendations published by the French Reference Centre on Haemophilia and Rare Bleeding Disorders, are: (i) to briefly describe RIBD (clinical presentation and diagnostic work-up) to help physicians in patient screening for the early detection of such disorders; and (ii) to focus on the current management of acute haemorrhages and long term prophylaxis, surgical interventions, and pregnancy/delivery in patients with RIBD.

The prevalence of rare bleeding disorders among children in the Russian Federation

Rare bleeding disorders account for about 3–5% of all inherited bleeding disorders. Due to the rarity and complexity of diagnosing these disorders, their prevalence estimates vary greatly. There is currently no national registry of rare inherited bleeding disorders and their prevalence across the country has not been studied yet. Aim: to estimate the prevalence of rare coagulation disorders among Russian children. For this multicenter study, we used retrospective anonymous patient data collected during clinical practice, so the approval of the ethics committee was not required. We analyzed completed questionnaires containing the number of patients with rare bleeding disorders aged from 0 to 18 years from 72 subjects of the Russian Federation. The survey had been conducted from April to June 2022. Our analysis included patients with deficiencies of factor I, II, V, VII, X, XI or XIII, as well as with combined factor deficiencies and unspecified hemorrhagic conditions. According to the reported data, the total number of children with rare bleeding disorders is 398. The most common disorder is deficiency of factor VII (52%, n = 210); it is followed by fibrinogen deficiency (16%, n = 63) and deficiency of factor X (12%, n = 48). Deficiencies of factors XI, V and XIII account for 9% (n = 35), 5% (n = 20), and 4.5% (n = 18) of all cases, respectively. Combined factor deficiency was diagnosed in 1.7% of patients (n = 7) and factor II deficiency was detected in only 1% of patients (n = 4). In order to determine the actual prevalence and incidence of rare coagulation disorders and their clinical manifestations and to identify the need for factor concentrates, it is necessary to establish a national registry of rare bleeding disorders, following the example of the national hemophilia registry.

Comprehensive analysis of clinical spectrum of rare inherited bleeding disorders in a tertiary center in South India

Comprehensive analysis of clinical spectrum of rare inherited bleeding disorders in a tertiary center in South India

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

BackgroundIn 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. MethodsA 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%). ResultsFollowing 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%). ConclusionThis 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.

Results of genetic analysis of 11 341 participants enrolled in the My Life, Our Future hemophilia genotyping initiative in the United States

BackgroundHemophilia A (HA) and hemophilia B (HB) are rare inherited bleeding disorders. Although causative genetic variants are clinically relevant, in 2012 only 20% of US patients had been genotyped. ObjectivesMy Life, Our Future (MLOF) was a multisector cross‐sectional US initiative to improve our understanding of hemophilia through widespread genotyping. MethodsSubjects and potential genetic carriers were enrolled at US hemophilia treatment centers (HTCs). Bloodworks performed genotyping and returned results to providers. Clinical data were abstracted from the American Thrombosis and Hemostasis Network dataset. Community education was provided by the National Hemophilia Foundation. ResultsFrom 2013 to 2017, 107 HTCs enrolled 11 341 subjects (68.8% male, 31.2% female) for testing for HA (n = 8976), HB (n = 2358), HA/HB (n = 3), and hemophilia not otherwise specified (n = 4). Variants were detected in most male patients (98.2%% HA, 98.1% HB). 1914 unique variants were found (1482 F8, 431 F9); 744 were novel (610 F8, 134 F9). Inhibitor data were available for 6986 subjects (5583 HA; 1403 HB). In severe HA, genotypes with the highest inhibitor rates were large deletions (77/80), complex intron 22 inversions (9/17), and no variant found (7/14). In severe HB, the highest rates were large deletions (24/42). Inhibitors were reported in 27.3% of Black versus 16.2% of White patients. ConclusionsThe findings of MLOF are reported, the largest hemophilia genotyping project performed to date. The results support the need for comprehensive genetic approaches in hemophilia. This effort has contributed significantly towards better understanding variation in the F8 and F9 genes in hemophilia and risks of inhibitor formation.

Treatment of patients with rare bleeding disorders in the Netherlands: Real‐life data from the RBiN study

BackgroundPatients with rare inherited bleeding disorders (RBDs) exhibit hemorrhagic symptoms, varying in type and severity, often requiring only on‐demand treatment. Prolonged bleeding after invasive procedures is common. Adequate peri‐procedural therapy may reduce this bleeding risk. ObjectiveTo describe general treatment plans of RBD patients and evaluate the use of peri‐procedural hemostatic therapy. MethodsIn the Rare Bleeding Disorders in the Netherlands (RBiN) study, RBD patients from all six Dutch Hemophilia Treatment Centers were included. General treatment plans were extracted from patient files. Patients with a dental or surgical procedure in their history were interviewed about use of peri‐procedural treatment and bleeding complications. ResultsTwo‐hundred sixty‐three patients with a rare coagulation factor deficiency or fibrinolytic disorder were included. Eighty‐four percent had a documented general treatment plan. General treatment plans of patients with the same RBD were heterogeneous, particularly in factor XI deficiency.Overall, 308 dental and 408 surgical procedures were reported. Bleeding occurred in 50% of dental and 53% of surgical procedures performed without hemostatic treatment and in 28% of dental and 19% of surgical procedures performed with hemostatic treatment. Not only patients with severe RBDs, but also patients with mild deficiencies, experienced increased bleeding without proper hemostatic treatment. ConclusionLarge heterogeneity in general treatment plans of RBD patients was found. Bleeding after invasive procedures was reported frequently, both before and after RBD diagnosis, irrespective of factor activity levels and particularly when peri‐procedural treatment was omitted. Improved guidelines should include uniform recommendations for most appropriate hemostatic products per RBD and emphasize the relevance of individual bleeding history.

Clinical profile of rare inherited bleeding disorders: Registry data from a tertiary hospital in South India

Clinical profile of rare inherited bleeding disorders: Registry data from a tertiary hospital in South India

Gene Therapy for Inherited Bleeding Disorders.

Decades of preclinical and clinical studies developing gene therapy for hemophilia are poised to bear fruit with current promising pivotal studies likely to lead to regulatory approval. However, this recent success should not obscure the multiple challenges that were overcome to reach this destination. Gene therapy for hemophilia A and B benefited from advancements in the general gene therapy field, such as the development of adeno-associated viral vectors, as well as disease-specific breakthroughs, like the identification of B-domain deleted factor VIII and hyperactive factor IX Padua. The gene therapy field has also benefited from hemophilia B clinical studies, which revealed for the first time critical safety concerns related to immune responses to the vector capsid not anticipated in preclinical models. Preclinical studies have also investigated gene transfer approaches for other rare inherited bleeding disorders, including factor VII deficiency, von Willebrand disease, and Glanzmann thrombasthenia. Here we review the successful gene therapy journey for hemophilia and pose some unanswered questions. We then discuss the current state of gene therapy for these other rare inherited bleeding disorders and how the lessons of hemophilia gene therapy may guide clinical development.

Deficiency of coagulation factor Vll in a 4 years old child with 13q deletion syndrome: a case report

Background: Factor VII deficiency is rare inherited bleeding disorders, have been identified in the Factor VII gene located on chromosome 13 with very few cases reported. Factor VII deficiency was first described by Alexander et al. in 1951.The disorder has also been known as Alexander's disease. It is the rare inherited bleeding disorders’ with an estimated incidence of 1 case per 3,00,000 to 5,00,000 individuals. Objective and method: We did a case report and literature review for deficiency of coagulation factors VII was found in a 4 years patient who had chromosomal aberration 13q deletion syndrome (46, XX, del 13q32-13q33). This loci involved in synthesis or constitution of factor VII. Results: A review of the gene map of chromosome 13 indicated that Factors VII and X are coded on the long arm of chromosome 13, within the deleted region. Conclusion: Congenital Factor VII deficiency is a rare cause of bleeding disorder, which should be suspected in a bleeding child presenting in infancy when platelets and aPTT are normal with abnormal PT. Congenital Factor VII deficiency association with 46, XX, del (13q32– 13q33) syndrome is very rare disorder and further cases should be reported to know the outcome and the risk of complication in such a cases.

Deficiency of coagulation factor Vll in a 4 years old child with 13q deletion syndrome: a case report

Background: Factor VII deficiency is rare inherited bleeding disorders, have been identified in the Factor VII gene located on chromosome 13 with very few cases reported. Factor VII deficiency was first described by Alexander et al. in 1951.The disorder has also been known as Alexander's disease. It is the rare inherited bleeding disorders’ with an estimated incidence of 1 case per 3,00,000 to 5,00,000 individuals. Objective and method: We did a case report and literature review for deficiency of coagulation factors VII was found in a 4 years patient who had chromosomal aberration 13q deletion syndrome (46, XX, del 13q32-13q33). This loci involved in synthesis or constitution of factor VII. Results: A review of the gene map of chromosome 13 indicated that Factors VII and X are coded on the long arm of chromosome 13, within the deleted region. Conclusion: Congenital Factor VII deficiency is a rare cause of bleeding disorder, which should be suspected in a bleeding child presenting in infancy when platelets and aPTT are normal with abnormal PT. Congenital Factor VII deficiency association with 46, XX, del (13q32– 13q33) syndrome is very rare disorder and further cases should be reported to know the outcome and the risk of complication in such a cases.

Rare bleeding disorders: spectrum of disease and clinical manifestations in the Pakistani population.

BackgroundRare inherited coagulation factor deficiencies constitute an important group of bleeding disorders. A higher frequency of these disorders is seen in areas of high consanguinity. Our aim was to study the prevalence and spectrum of rare inherited bleeding disorders, characterize the severity of the deficiencies, identify different clinical manifestations, and evaluate different treatments provided.MethodsThis cross-sectional study was conducted in the Department of Haematology, Armed Forces Institute of Pathology Rawalpindi, between January 2014 and December 2018. A detailed history was taken, and an examination was performed. The signs and symptoms were noted, and the patients were diagnosed on the basis of a coagulation profile. The disease severity was assessed using factor assays.ResultsAmong 2,516 patients with suspected coagulation disorders, 774 (30.8%) had an inherited bleeding disorder. Of the 774 patients, 165 (21.3%) had a rare bleeding disorder; 91 (55.2%) of them were males, and 74 (44.9%) were females, with a male-to-female ratio of 1.21. The median patient age was 9 years 3 months. The most common disorder was factor VII deficiency (46 patients, 27.9%). The most common clinical presentation was bruising in 102 (61.8%) and gum bleeding in 91 (55.2%) patients.ConclusionThe most common rare bleeding disorder in our population is factor VII deficiency. The prevalence of these bleeding disorders is high in our population due to a high number of consanguineous marriages.

Proteomic prediction of embryo viability and pregnancy outcome in assisted reproductive technology (ART) thought determination of an embryo “finger print”

The area of women and inherited bleeding disorders has undergone quick expansion in recent years. More patients are being identified and expertise to diagnose and manage these patients is now essential for practising physicians. Programs to help educate and empower patients and caregivers are now in place. Common inherited bleeding disorders affecting women include von Willebrand disease (VWD), inherited platelet disorders, and rare inherited bleeding disorders such as factor VII (FVII) deficiency and factor XI (FXI) deficiency. Specific clinical tools have been developed to help clinicians and patients screen for the presence of these bleeding disorders in both adult and pediatric populations. Affected women can experience heavy menstrual bleeding and resulting iron deficiency anemia, postpartum hemorrhage, and hemorrhagic ovarian cysts which need to be properly managed. Excessive bleeding can adversely affect quality of life in these women. Front line therapy for bleeding in mild cases focuses on the use of non-specific hemostatic agents such as DDAVP ®, tranexamic acid and hormonal agents but specific factor replacement and/or blood products may be required in more severe cases, in severe bleeding or as second line treatment when bleeding is not responsive to first line agents. Iron status should be optimised in these women especially in pregnancy and use of an electronic app can now help clinicians achieve this. These patients should ideally be managed by a multidisciplinary team whenever possible even remotely. Although clinical research has closed some knowledge gaps regarding the diagnosis and management of these women, there remains significant variation in practise and lack of evidence-based guidelines still exists in many spheres of clinical care in which caregivers must rely on expert opinion. Ongoing efforts in education and research will continue to improve care for these women and restore quality of life for them.

Clinical utility of viscoelastic testing (TEG and ROTEM analyzers) in the management of old and new therapies for hemophilia.

Hemophilia A and B are rare inherited bleeding disorders resulting from deficiency of coagulation factors VIII and IX respectively. In the past few decades, the field of hemophilia has witnessed pivotal management challenges and therapeutic advances. Routine coagulation and factor assays, while useful in the classification of severity and treatment monitoring in hemophilia patients, have been shown to be of limited use in managing clinical presentations and outcomes. This prompted the investigation of viscoelastic studies in hemophilia care, which have established their utility in various bleeding and thrombotic states. In this review, we will discuss and critically assess the current literature highlighting the use of viscoelastic studies in various aspects of hemophilia including the determination of clinical phenotype, management of patients with inhibitors, perioperative management, and monitoring of novel agents.

Phenotypical variability in congenital FVII deficiency follows the ISTH-SSC severity classification guidelines: a review with illustrative examples from the clinic.

BackgroundOne of the most common rare inherited bleeding disorders, congenital factor VII (FVII) deficiency typically has a milder bleeding phenotype than other rare bleeding disorders. Categorizing severity in terms of factor activity associated with hemophilia (severe <1%, moderate 1%–5%, mild 6%–40%) has led to the observation that bleeding phenotype does not follow closely with FVII activity. Over the past decade, large-scale global registries have investigated bleeding phenotype more thoroughly. The International Society on Thrombosis and Haemostasis has reclassified FVII deficiency as follows: severe, FVII <10%, risk of spontaneous major bleeding; moderate, FVII 10%–20%, risk of mild spontaneous or triggered bleeding; mild, FVII 20%–50%, mostly asymptomatic disease.Case reportsEleven illustrative cases of congenital FVII deficiency adapted from clinical practice are described to demonstrate the variability in presentation and in relation to FVII activity levels. Severe FVII deficiency usually presents at a young age and carries the risk of intracranial hemorrhage, hemarthrosis, and other major bleeds. Moderate FVII deficiency tends to present later, often in adolescence and particularly in girls as they reach menarche. Milder disease may not be apparent until found incidentally on preoperative testing, during pregnancy/childbirth, or following unexplained bleeding when faced with hemostatic challenges.ConclusionIt is important for health care professionals to be aware of the new definitions of severity and typical presentations of congenital FVII deficiency. Failure to appreciate the risks of major bleeding, including intracerebral hemorrhage in those with FVII activity <10%, may put particularly young children at risk.

Targeted Whole Exome Sequencing of 87 Predisposition Genes in 156 Patients from the Oresund Region with Bleeding Disorders

Introduction Rare inherited bleeding disorders are a common cause of bleeding tendency. To ensure a correct diagnosis, specialized laboratory analyses are required, and the mere complexity of these investigations renders a significant part of patients without proper diagnosis. Several inherited platelet disorders are part of a syndrome, and thus a correct diagnosis may have clinical consequences, beyond genetic counseling. The aim was to report the results of up front targeted whole exome sequencing (WES).Methods Patients from the Öresund Region referred for an inherited bleeding disorder, were screened for plasma coagulation factor deficiencies and scored by ISTH Bleeding assessment tool (BAT) score. Patients with a significant BAT score and/or chronic thrombocytopenia and without evidence of a coagulation factor deficiency were included. After informed consent, blood samples for genetic screening were obtained. When genetic analysis revealed a mutation or variant of uncertain significance (VUS), further evaluation with specific functional testing and transmission electron microscopy were done, followed by a concluding multidisciplinary conference.WES and variant filtering WES was selected to identify germline mutations, as well as enabling extending the number of genes analyzed. Genomic DNA was purified from whole blood. Illumina‘s HiSeq 2500 platform was used for sequencing. The exome was covered with an average of 84x, where 97 % was covered with at least 9 x. Based on literature search, 87 genes related to bleeding, thrombocytopathia, and thrombocytopenia were analyzed. Common single-nucleotide polymorphisms were subtracted. Variant Classification:The integrated Alamut Visual software (v.2.6.1) (http://www.interactive-biosoftware.com) was used to predict the pathogenicity of specific protein variants. To designate the clinical significance, a clinical score was developed, the Öresund score, combining inheritance pattern of known diseases within the Silico based prediction. Following classification of each variant according to the five-tier scheme, patients were individually evaluated for genetic predisposition.Results 156 patients were included in the study, age 38.6±15 years (mean +/- 1SD), whereof 25 were male (16%) and 131 (84%) were female. The majority of patients had a family history of increased bleeding tendency (111 patients, 71%) and 47 patients (30%) had thrombocytopenia (a value below the normal range). The majority of patients were of European ethnicity (90%). Mean BAT score was 8 +/- 6 (1SD). A total of 421 germline mutations/variants (2.7 variant pr. patient) were found. In 28 patients (18%) a class 4-5 mutation (previously published and/or confirmed by specific functional testing) were found. In 21 patients (13%), a possible contributing class 3 VUS was found. In 21/47 patients (45%) with thrombocytopenia and 27/119 patients (23%) with normal platelet counts (p < 0.0001), a pathogenic or possibly pathogenic class 3 VUS was detected. Incidental findings occured i 3 patients (2%).Discussion and conclusion We implemented targeted WES of 87 genes up front to diagnose rare inherited bleeding disorders. In 156 patients we report the finding of 4 previously published gene mutations and 42 previously non reported mutations or class 3 VUS in 25 genes. The success rate of finding a diagnostic or possible pathogenic VUS was significantly higher in patients with thrombocytopenia. The substantial finding of additional 368 variants required clinical designation and extensive functional testing, before final classification could be made. Our finding of multiple deleterious class 3 variants in COL3A1, COL5A2 and COL5A1 warrant further investigations into the role of collagen deficiency. Only 1 patient had a (tolerated) variant in protein disulfide isomerase (P4HB), a newly discovered gene described to play a key role in initiation of clot formation. In our hands, WES was an efficient tool in defining the underlying cause of bleeding disorders. However, the large number of previously non described variants required substantial efforts to sort out. In patients with rare inherited bleeding disorders, targeted WES is a feasible method to discover possible pathogenic mutations or VUS to direct the specific functional testing. DisclosuresNo relevant conflicts of interest to declare.

Ischemic stroke in a patient with moderate to severe inherited factor VII deficiency

Thrombosis is known to occur in patients with rare inherited bleeding disorders, usually in the presence of a thrombotic risk factor such as surgery and/or factor replacement therapy, but sometimes spontaneously. We present the case of a 72-year-old African American male diagnosed with congenital factor VII (FVII) deficiency after presenting with ischemic stroke, presumably embolic, in the setting of atherosclerotic carotid artery stenosis. The patient had an international normalized ratio (INR) of 2.0 at presentation, with FVII activity of 6% and normal Extem clotting time in rotational thromboelastometry. He was treated with aspirin (325 mg daily) and clopidogrel (75 mg daily) with no additional bleeding or thrombotic complications throughout his admission. This case provides further evidence that moderate to severe FVII deficiency does not protect against thrombosis.

The European Haemophilia Network (EUHANET).

Haemophilia A and B are rare inherited bleeding disorders due to reduced factor VIII (FVIII) or factor IX (FIX) activity, occurring in 1 in 10,000 and 1 in 50,000 of the population respectively1,2. Several other bleeding disorders such as deficiencies of factors I, II, V, VII, X, XI and XIII are even rarer. When the deficiency is severe these disorders present with spontaneous bleeding whilst for milder disorders traumatic bleeding is observed3. When bleeding occurs patients are treated with clotting factor concentrates which can be plasma derived or recombinant. Individuals with inherited bleeding disorders are cared for in Haemophilia Centres. There is major disparity in patient access to Haemophilia Centres throughout Europe4, although it must be appreciated that this publication was based on data from the individual country patient organisations and was not based on national registries. There is a need for harmonisation of the data available in care centres, national data sources and patient organisations and these activities are planned to be improved by the European Haemophilia Network (EUHANET) project. There is also variation in the number of Haemophilia Centres within European countries and whilst in some there are over 80 Haemophilia Centres in others there is only a single centre. The use of clotting factor concentrates has been associated with major adverse effects. Patients treated with plasma derived clotting concentrates prior to 1985 had an almost 100% risk of being infected with hepatitis C (HCV) and a 30–60% risk of Human Immunodeficiency Virus (HIV) infection5. Although the HCV/HIV viruses were eliminated following the introduction of viral inactivation, improvements in diagnostic tools used for the biological qualification of blood donations and the use of recombinant concentrates, other adverse events such as alloantibodies to FVIII or FIX remain6. The rarity of these disorders makes it difficult to determine the precise frequency of the adverse events because large numbers of patients are required which are not available in single centres. To overcome this problem, the European Haemophilia Safety Surveillance (EUHASS) system was set up in 20087. This was a collaboration of over 70 European Haemophilia Centres in 26 countries which agreed to prospectively report adverse events occurring in their patients. The project was funded by the European Commission with pharmaceutical industry support. The EUHASS project demonstrated the willingness of these Haemophilia Centres to work together so the EUHANET was set up. This is a collaboration in four separate areas, the certification of Haemophilia Centres, the set up of a haemophilia website, the expansion of the EUHASS system and the establishment of a prospective project on afibrinogenemia and FXIII deficiency.

Maternal rare inherited bleeding disorders and neonatal complications.

The aim of this study was to examine the association between maternal inherited bleeding disorders and neonatal complications. 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. 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). Maternal rare inherited bleeding disorders may have a devastating consequence for neonates.