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Platelet type bleeding disorder-18 (BDPLT18) caused by mutations of Ras guanyl releasing protein 2 ( RASGRP2 ) is a relatively rare, new autosomal recessive disorder. Here, we reported a splice mutation in RASGRP2 gene in the patient with recurrent epistaxis and nasal vascular malformation. The patient, an 8-year-old girl, suffered from anemia due to frequently severe recurrent epistaxis, requiring regular blood transfusions every 2-3 months. Hematological investigations showed moderate anemia (Hb: 89 g/L), normal platelet count, morphology, and platelet glycoproteins. Arachidonic acid and adenosine diphosphate induced platelet aggregation was markedly reduced in the patient. A homozygous splice variant (C.74-1 G>C) in RASGRP2 gene, located within the exon 3, was detected by next-generation sequencing. Interestingly, we identified nasal vascular malformation by percutaneous super-selective angiography during the treatment of an intractable epistaxis. Our case further support that genetic testing should be performed for some unexplained bleeding diseases.

Secretion analysis is a useful tool in forensic genetics, since it establishes the (cellular) origin of the DNA prior in addition to the identification of the DNA donor. This information can be crucial for the construction of the crime sequence or verification of statements of people involved in the crime. For some secretions, rapid/pretests already exist (blood, semen, urine, and saliva) or can be determined via published methylation analyses or expression analyses (blood, saliva vaginal secretions, menstrual blood, and semen). To discriminate nasal secretion/blood from other secretions (like oral mucosa/saliva, blood, vaginal secretion, menstrual blood, and seminal fluid), assays based on specific methylation patterns at several CpGs were set up in this study. Out of an initial 54 different CpG markers tested, two markers showed a specific methylation value for nasal samples: N21 and N27 with a methylation mean value of 64.4% ± 17.6% and 33.2% ± 8.7%, respectively. Although identification or discrimination was not possible for all nasal samples (due to partial overlap in methylation values to other secretions), 63% and 26% of the nasal samples could be unambiguously identified and distinguished from the other secretions using the CpG marker N21 and N27, respectively. In combination with a blood pretest/rapid test, a third marker (N10) was able to detect nasal cells in 53% of samples. Moreover, the employment of this pretest increases the proportion of identifiable or discriminable nasal secretion samples using marker N27 to 68%. In summary, our CpG assays proved to be promising tools in forensic analysis for the detection of nasal cells in samples from a crime scene., (© 2023. The Author(s).)

Background and Aims: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by recurrent epistaxis, telangiectatic lesions in the skin and mucosal membranes, and arteriovenous malformations (AVMs) in various organs. In 3%-5% of patients, HHT is caused by pathogenic germline variants (PVs) in SMAD4 , and these patients often have additional symptoms of juvenile polyposis syndrome and thoracic aneurysms. The phenotypic spectrum of SMAD4 -associated HHT is less known, including the penetrance and severity of HHT. We aimed to investigate the phenotypic spectrum of HHT manifestations in Danish patients with PVs in SMAD4 and compare the findings with current literature., Methods: The study is a retrospective nationwide study with all known Danish patients with PVs in SMAD4 . In total, 35 patients were included. The patients were identified by collecting data from genetic laboratories, various databases and clinical genetic departments across the country. Clinical information was mainly collected from the Danish HHT-Centre at Odense University Hospital., Results: Twenty-nine patients with PVs in SMAD4 (83%) were seen at the HHT-Centre. Seventy-six per cent of these fulfilled the Curaçao criteria, 86% experienced recurrent epistaxis and 83% presented with telangiectatic lesions at different anatomical localisations. Almost 60% had AVMs, mainly pulmonary and hepatic, while none was found to have cerebral AVMs. Fifteen per cent had thoracic aortic abnormalities., Conclusion: We present a nationwide study of one of the largest populations of patients with PVs in SMAD4 that has systematically been examined for HHT manifestations. The patients presented the full spectrum of HHT-related manifestations and the majority fulfilled the Curaçao criteria., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare inherited disorder characterized by development of mucocutaneous telangiectases and visceral organ arteriovenous malformations, which can lead to recurrent, spontaneous bleeding and development of iron deficiency anemia. The primary objective of this study was to ascertain the relationship between epistaxis severity scores (ESS), laboratory values, genotype, and phenotype in HHT. Our secondary objective was to assess efficacy of systemic antifibrinolytic therapy in reducing ESS in HHT., Methodology: We conducted a retrospective review of patients seen at the UNC HHT Center from January 1, 2009 to February 28, 2015. ESS, demographics, and results of genetic testing were abstracted from the medical record. Response to antifibrinolytic therapy was evaluated by comparing pre-post ESS., Results: One hundred and forty nine patients were eligible with 116 having genetic testing and 33 without. Age, hemoglobin and ferritin levels were predictive of ESS. Of the 116 patients that underwent genetic testing: 63 had an ACVRL1 mutation, 40 had an ENG mutation, 2 had a SMAD4 mutation, and 11 patients had no pathologic HHT genetic variation detected. Compared to patients without a detectable HHT-associated genetic variation, patients with a HHT-associated genetic variation had higher ESS scores (p < 0.05). Neither ESS nor genotype was predictive of pulmonary or brain AVMs. Twenty-four HHT patients with ESS > 4 were started on antifibrinolytic therapy (tranexamic acid or aminocaproic acid) and had a post-treatment ESS recorded. All patients had a decrease in ESS of > 0.71 (minimal meaningful difference), but patients taking antifibrinolytics displayed larger decreases. No patients on antifibrinolytics experienced a VTE with median follow up of 13 months., Conclusions: We demonstrate that the ESS correlates with age, hemoglobin and ferritin. Additionally, we demonstrate that HHT patients with genetic mutations have higher ESS scores. Our data demonstrate that antifibrinolytics are effective in decreasing epistaxis severity and safe with long-term use in HHT patients.

Purpose: Our aim was to evaluate if epistaxis is directly associated with the etiology or pathophysiological mechanism which results in the syndrome itself or arises as a secondary effect., Methods: We performed an extensive literature review of the web-based PubMed database from the National Library of Medicine to ascertain syndromes related to this condition. Etiology, pathophysiological mechanisms, occurrence, clinical features and management were noted for each of these syndromes., Results: Epistaxis is commonly seen in syndromes that are usually directly related to vascular abnormalities or coagulation defects. However, in some cases, it is not., Discussion and Conclusion: Since a number of these syndromes are rare and elaborate tests are not carried out in the absence of a positive family history or until other specific clinical features appear, a risk of underdiagnosis and the dilemma of whether epistaxis is specifically related to the syndrome or a secondary effect still remains.

Aim: The aim of this retrospective single-centre study was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different phenotypes in hereditary haemorrhagic telangiectasia (HHT)., Methods: The case records of 21 HHT patients with verified mutations in ENG, ACVRL1, or SMAD4 genes were reviewed. The numbers of HHT diagnostic criteria fulfilled for the three genotypes were compared, as was the prevalence of complications such as iron deficiency anaemia, gastrointestinal haemorrhage, stroke, and cerebral abscess., Results: Our results indicate that mutations in the ENG (HHT1), ACVRL1 (HHT2), and SMAD4 genes result in different HHT phenotypes. Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2. One patient with mutations in both ENG and ACVRL1 genes was identified, as were two SMAD4-mutated patients suffering from the overlapping juvenile polyposis-HHT syndrome. Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications., Conclusion: Our results showing that ENG and ACVRL1 gene mutations result in different HHT phenotypes confirm the results from other HHT centres worldwide. Cerebral complications of HHT are common, underscoring the importance of regular screening for pulmonary AVMs and early intervention against such AVMs. We have identified an HHT patient with simultaneous mutations in the ENG and ACVRL1 genes. Surprisingly, this patient has had a mild course of the disease.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that can lead to frequent and severe sequelae. Although the condition has no cure, many of its physical symptoms can be managed to improve the quality of life and lower the risk of life-threatening complications. This article discusses HHT presentation, genetic screening, diagnosis, and management. The management of HHT can involve interventional radiology techniques, particularly for patients with pulmonary arteriovenous malformations.

Factor XIII deficiency (FXIIID) is an extremely rare bleeding disorder with the highest global incidence in southeast of Iran. Southwestern Afghanistan (Nimruz Province) is located near the border with Iran in the vicinity of Sistan and Baluchestan Province in southeast Iran, and there seems to be a high prevalence of FXIIID in Nimruz. Thus, this cross-sectional study was designed to assess the prevalence of FXIIID, molecular basis as well as clinical manifestations of FXIIID in Southwestern Afghanistan. During the course of the study, all patients suspected of FXIIID were clinically examined and assessed by routine coagulation tests, including bleeding time, activated partial thromboplastin time, prothrombin time, as well as platelet count and clot solubility test. Patients with normal routine coagulation tests, but abnormal clot solubility test, underwent further investigations by FXIII activity, as well as molecular analysis for FXIII-A gene mutation (Trp187Arg) by PCR-restriction fragment length polymorphism that confirmed by sequencing. Patients with confirmed FXIIID deficiency were registered to receive prophylaxis treatment. All data including demographic information, clinical manifestations, as well as therapeutic response and type and duration of treatment, were recorded, and the data were analyzed by SPSS software. In this cross-sectional study, we found five patients with abnormal clot solubility test, among whom two patients abandoned the study, whereas three patients remained for a more precise study. All the patients were residents of Zaranj city, the capital of Nimruz Province. All these patients had undetectable activity of FXIII, which indicates a severe deficiency. Molecular analysis of patients showed mutation of Trp187Arg in all of them. Hematoma was the most common clinical presentation leading to diagnosis of FXIIID in these patients (100%). Epistaxis (67%), gum bleeding (33%), and hematuria (33%) were other recurrent clinical presentations of the patients. Three cases of death due to FXIIID were detected in the family of these patients. There was a high prevalence of FXIIID in Zaranj city with a population of 50 000, which was appropriately equal to the prevalence of the disorder in southeast of Iran, which seemed to have the highest global prevalence of FXIIID, and underlines that the same mutation (Trp187Arg) in both regions is same.

Background: Recurrent epistaxis in hereditary haemorrhagic telangiectasia (HHT) patients significantly decreases their quality of life. Treatment in therapy refractory patients is limited although various options have been tested so far., Case Report: Herein, one patient is described that was treated for HHT for over 20 years with only intermediate benefits. As epistaxis duration and frequency increased continuously, bevacizumab 5 mg/kg was administered every 2 weeks. During the time of treatment (six doses) and up to 3 month afterwards clinical symptoms, blood pressure, cardiac output, pulmonary arterial hypertension (PAH), bleeding duration and frequency were assessed as criteria for treatment benefit., Results: Duration and frequency of epistaxis decreased immediately after the first application resulting in reduced need of blood transfusions. After completion of six cycles, a further decrease in frequency and duration of bleeding was noted. Cardiac output and PAH decreased or remained stable, respectively, during time and after treatment. No increase in blood pressure could be found but a significant increase in heart rate was experienced after completion of all six applications. Unfortunately, the patient died due to a cerebral abscess., Conclusion: Bevacizumab led to an improvement of HHT related epistaxis, refractory to other treatments.

Post exercise epistaxis, the manifestation of a severe form of exercise-induced pulmonary haemorrhage (EIPH), has been observed in many equine racing populations. Although multiple analyses have suggested that non-genetic factors may lead to the development of this condition, relatively little consensus has been reached regarding its genetic aetiology. The objective of this study was to provide insight into both genetic and non-genetic factors that may contribute to the expression of epistaxis in the Australian Thoroughbred racing population. Racing records and reported epistaxis occurrences were acquired for 117,088 horses entered in races and official barrier trials from 1 August 2000 until 22 February 2011. Heritability was estimated using two different logistic generalised linear mixed models (lifetime epistaxis risk h(2) = 0.27 and individual race epistaxis risk h(2) = 0.50). Sex, age, and year of birth were shown to be significant; however, trainer, jockey, race distance, condition of the track (i.e. 'going'), racecourse, track surface, number of race starters, year and month of race were not significant. Evidence suggests genetic and non-genetic links to EIPH expressed as epistaxis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The formation of new blood vessels from existing vasculature, angiogenesis, is facilitated through a host of different signaling processes. Members of the TGF-β superfamily, TGF-β1, TGF-β3, and BMP9, are key propagators of both inhibition and initiation of angiogenesis. HHT, characterized by AVM and capillary bed defects, is caused by germline mutations in the ENG and ACVRL1/ALK1 genes, respectively. Clinical symptoms include epistaxis and GI hemorrhage. The membranous receptors endoglin and ALK1 activate proliferation and migration of endothelial cells during the angiogenic process via the downstream intracellular SMAD signaling pathway. Endothelial cell senescence or activation is dependent on the type of cytokine, ligand concentration, cell-cell interaction, and a multitude of other signaling molecules. Endoglin and ALK1 receptor levels in tumor vasculature correlate inversely with prognosis in humans, whereas in mice, endoglin deficiency decelerates tumor progression. Therefore, endoglin and ALK1 have been identified as potential therapeutic targets for antibody treatment in various cancers. Early phase clinical trials in humans are currently underway to evaluate the efficacy and safety of biological therapy targeting endoglin/ALK1-mediated cells signaling., (© 2013 John Wiley & Sons Ltd.)

Background: Germline mutations in the SMAD4 gene lead to both juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia (HHT)., Case Description: A 23-year-old man underwent colectomy with ileo-anal pouch anastomosis at the age of 12 due to colorectal juvenile polyposis. At follow-up, recurrent juvenile polyps in the pouch were removed. No gastric polyps were found. The family history was negative for intestinal polyposis. In addition, the patient had recurrent epistaxis. DNA testing revealed a pathogenic SMAD4 mutation: c.1558G>T; p.(Glu520*). Further examination confirmed suspected HHT., Conclusion: DNA testing in patients with juvenile polyposis is important for subclassification of this syndrome with implications for the management of patients and family members.

Congenital FXI deficiency (hemophilia C) is a rare bleeding disorder that has been documented mostly in Ashkenazi Jews. Unlike other hemophilias, bleeding tendency varies considerably among individuals, and FXI deficiency rarely manifests as spontaneous bleeding. FXI deficiency is caused primarily by mutations in the F11 gene. Herein, we report a case of a 10-year-old boy with recurrent nose bleeding due to FXI deficiency who was confirmed to have a novel mutation in F11. A molecular analysis of DNA extracted from peripheral blood collected from the patient [FXI clotting activity (FXI:C): 11%] revealed compound heterozygous mutations, Q226X and L424F, in F11, consistent with the severe disease phenotype of the patient. Pedigree analysis showed that the patient received L424F from his father (FXI:C = 49%) and Q226X from the mother (FXI:C = 48%). The sister (FXI:C = 47%) of the patient only had L424F, presumably inherited from her father. Multiple sequence alignment demonstrated that L424 is highly conserved across mammals, indicating that it is important for the function of FXI. In-silico analysis indicated that replacement of L424 by phenylalanine had a detrimental influence on FXI, consistent with the severe phenotype of the patient. Compilation of FXI deficiency cases in east Asian populations would be of great value because different populations appear to have different F11 mutation spectra.

Objective: To study the early gene diagnosis of hereditary hemorrhagic telangiectasia (HHT) induced severe nosebleed., Method: Clinical features of 23 family members in two HHT pedigrees were examined. Genomic DNA was extracted from peripheral blood samples. PCR amplification was conducted to screen ENG and ACVRL-1 genes with their specific primers. Direct sequencing was performed to detect the mutation. Mutation analysis was carried out to evaluate its significance., Result: A heterozygous c. 263A > G mutation was identified in exon 3 of ACVRL-1 in 6 out of 11 members in NMG-1 pedigree. In GD-2 pedigree, 5 of 11 members carried c. 199C > G mutation. Mutation detection rate was 100% in subjects with nosebleed history and 25% in family members without epistaxis., Conclusion: Gene diagnosis characterized by high sensitivity and specificity is of great practi-cal significance and early genetic screening should be a clinical routine test for HHT induced severe nosebleed.

The factor VIII gene is located on the X chromosome,making haemophilia A, a sex-linked disorder. Thus on pedigree grounds all daughters of such patients are obligate carriers. One female case of haemophilia A was reported and related literatures were reviewed.

Inherited factor VII (FVII) deficiency is a rare disorder characterized by a bleeding phenotype varying from mild to severe. To date, more than 200 mutations have been described along the F7 gene encoding for FVII. The aim of this study was the identification of genetic defects underlying FVII deficiency in 10 patients belonging to eight unrelated families of the North provinces from Tunisia. Mutation detection was performed by sequencing the whole F7 gene coding region, exon-intron boundaries and about 400 bp of the promoter region. We identified 5 mutations in five unrelated families; the novel p.F328Y mutation and the reported mutations: p.R304Q, p.M298I, IVS1aG > A and p.G-39G. For the remaining 5 patients we didn't identified any mutations using PCR/Sequencing protocol. In conclusion, this study represents the first comprehensive molecular series of FVII deficiency affected patients in Tunisia from the North. We will try in the future to continue the molecular study for Tunisian patients from Center and South provinces in order to have a complete idea about the FVII deficiency mutational profile in our country., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1288044089753085.

Thalidomide was recently reported to reduce the severity and frequency of epistaxes in patients with hereditary haemorrhagic telangiectasia (HHT). We here describe the case of a patient with HHT and severe epistaxes refractory to medical and local surgical treatments who developed an extensive deep vein thrombosis shortly after initiation of treatment with thalidomide. This is the first report of venous thromboembolic complication induced by thalidomide prescribed in this setting. Although thalidomide was recently found to provide an alternative therapeutic strategy in patients with HHT and refractory epistaxes, this agent should be used with great caution in this indication, given its thrombogenicity and difficulties to manage systemic anticoagulation in patients with HHT.

Summary: While the majority of this session will deal with selected inherited vascular abnormalities that may manifest as a haemorrhagic disorder, the initial discussion by Dr Key will focus on the interplay between the vessel wall and components of the coagulation system, with a focus on haemophilia A and B. Although it is generally accepted that physiological haemostasis is triggered by contact of blood with tissue factor (TF), there remains some controversy regarding the cellular origin of TF in vivo. In addition, the initiation and propagation of thrombin generation are highly dependent on the balance of pro- and anticoagulant functions of endothelium, a profile that varies significantly throughout the vasculature. Drs De Paepe and Malfait address heritable collagen disorders such as the Ehlers-Danlos syndromes (EDS), a heterogeneous group of diseases involving the skin, ligaments and joints, blood vessels and internal organs. Most EDS subtypes are caused by mutations in genes encoding fibrillar collagens, or in genes coding for enzymes involved in posttranslational modifications of collagens. Accurate biochemical and molecular testing is now available for most EDS subtypes and can direct genetic counselling and medical management for these disorders. Dr Shovlin reviews recent developments in hereditary haemorrhagic telengiectasia (HHT), a frequently undiagnosed disorder characterized by arteriovenous malformations in multiple organs. These abnormal blood vessels are the result of mutations in one of a number of genes whose protein products influence TGF-beta signalling in vascular endothelial cells. Several HHT management guidelines have been published and are discussed.

Although most cases of prekallikrein deficiency are asymptomatic, a few reports link severe prekallikrein deficiency with thrombotic phenomena and recurrent pregnancy loss. Here, we present a case of a Jamaican female patient with prekallikrein deficiency, associated with a severe bleeding diathesis. A low level of plasma prekallikrein activity, along with the presence of C529Y mutation, confirmed the diagnosis in our patient. Some animals with prekallikrein deficiency were shown to have moderate bleeding tendencies. Furthermore, the first patient with prekallikrein deficiency from the African continent was a young child who presented with severe, hemophilia-like bleeding, featuring recurrent hemarthrosis and subcutaneous hematomas. We find it intriguing that our patient is of African heritage and presented with a moderate nasal bleeding tendency in her youth, followed by severe recurrent mucosal bleeding later in life.

The aim of this study was to characterize the variability of bleeding phenotype and its association with plasma factor IX coagulant activity (FIX:C) in haemophilia B carriers in a large Amish pedigree with a unifying genetic mutation, C-to-T transition at base 31008 of the factor IX gene (Xq27.1-27.2). A cross-sectional survey of haemophilia B carriers included a multiple choice questionnaire evaluating symptoms of mucocutaneous bleeding, joint bleeding and bleeding after haemostatic stress [menstruation, postpartum haemorrhage (PPH), dental extractions and invasive surgeries]. Severity of bleeding was graded as 0 to 4, 0 being no bleeding whereas 4 being severe bleeding. Association between total bleeding scores and the FIX:C was evaluated. Sixty-four haemophilia B carriers participated in this study. Median age: 18 years (range 1-70 years); median bleeding score: 1 (range 0-8). Besides PPH, isolated symptoms of bruising, epistaxis, menorrhagia and postsurgical bleeding including dental extraction were not associated with lower FIX:C. Bleeding score >/=3 was associated with involvement of at least two bleeding sites and a lower mean FIX:C of 42 +/- 10.3% (95% CI 36.4-47.7) while a score >3 had involvement of /=3. Phenotypic variability existed among the carriers of haemophilia B who belonged to a single pedigree carrying a single unifying mutation. The utility of bleeding scores to define bleeding phenotype precisely in haemophilia B carriers needs further evaluation.

Background: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by epistaxis, mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs), particularly in the brain (CAVMs), lungs (PAVMs), liver (HAVMs) and gastrointestinal tract (GI). The identification of a mutated ENG (HHT1) or ALK-1 (HHT2) gene now enables a genotype-phenotype correlation., Objective: To determine the incidence of visceral localizations and evaluate phenotypic differences between ENG and ALK1 mutation carriers., Methods: A total of 135 consecutive adult patients were subjected to mutational screening in ENG and ALK1 genes and instrumental tests to detect AVMs, such as chest-abdomen multislice computed tomography (MDCT), brain magnetic resonance imaging and magnetic resonance angiography (MRI/MRA), upper endoscopy, were offered to all patients, independent of presence of clinical symptoms. The 122 patients with identified mutations were enrolled in the study and genotype-phenotype correlations were established., Results: PAVMs and CAVMs were significantly more frequent in HHT1 (75% vs. 44%, P < 0.0005; 20% vs. 0%, P < 0.002, respectively) and HAVMs in HHT2 (60% vs. 84%, P < 0.01). No age difference was found for PAVMs whereas HAVMs were significantly higher in older patients in both HHT1 and HHT2. Neurological manifestations secondary to CAVMs/PAVMs were found only in HHT1 patients, whereas severe liver involvement was detected only in HHT2. Respiratory symptoms were mainly detected in HHT1., Conclusions: Our study evidences a higher visceral involvement in HHT1 and HHT2 compared with previous reports. HHT1 is more frequently associated with congenital AVM malformations, such as CAVMs and PAVMs whereas HHT2 predominantly involves the liver. The ENG gene should be first targeted for mutational screening in the presence of large PAVM in patients < 45 years.

Purpose: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations (AVM), mostly cutaneous and mucous (telangiectases), but also involving the lungs (PAVM), liver (HAVM) and brain (CAVM). We studied the relationship between the phenotype and genotype in patients with a proven mutation in either ENG (HHT1) or ACVRL1 (HHT2)., Methods: Clinical features and their age of onset were compared between HHT1 and HHT2. The type of mutation was also analyzed. Clinical manifestations were distinguished from lesions found by screening., Results: Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P<0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P<0.001), as were cerebral abscesses (7.5 vs. 0.8%, P=0.002). Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P=0.017). Symptomatic hepatic involvement was only seen in HHT2 patients. PAVMs were more frequently detected in asymptomatic HHT1 patients (54 vs. 12.8%, P<0.0001). PAVMs and HAVMs were often family clustered in HHT1 and HHT2, respectively. Truncating mutations were associated with a higher frequency of epistaxis and telangiectasis, in HHT2., Conclusion: This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies.

Inherited factor X deficiency (FXD) is a rare (1:1,000,000) recessive bleeding disorder. The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known. To understand the association between clinical manifestations and causative genotype, detailed evaluation of bleeding pattern in a high number of patients is needed. This international study analysed the phenotype and genotype of 102 subjects from Central Europe (Germany, Poland and Slovakia) and Latin America (Costa Rica and Venezuela) with causative mutations in the F10 gene, via sequencing. Twenty-eight homozygous, seven compound-heterozygous and 67 heterozygous FXD subjects were characterized. Twenty-nine different causative mutations, including 15 novel mutations, were analysed. Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%). The manifestation of bleeding symptoms in 9 of 67 (13%) symptomatic heterozygous subjects is described. The bleeding patterns of the enrolled patients showed differences that are associated with the types of F10 mutation, and the corresponding genotypes. The homozygous patients were evaluated for genotype-phenotype correlation. The results suggested that ICH seems to be associated with the F10 mutation Gly380Arg, and possibly with the mutations IVS7-1G>A and Tyr163delAT. A tentative association of other mutations to severe symptoms such as haemarthrosis and GI haemorrhage is reported. The severity of FXD, the genotype-phenotype association, and the results of regional studies are discussed.

Background: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease, characterized by a wide variety of clinical manifestations, including epistaxis, gastrointestinal (GI) bleeding, pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. HHT is a genetically heterogeneous disorder involving at least two loci; HHT 1 mapping to chromosome 9 q 34.1 (ENG) and HHT 2 mapping to chromosome 12 q 31 (ALK-1)., Objective: To evaluate and describe the diversity of clinical manifestations in a Danish population of HHT patients with known HHT 1 or HHT 2 subtype., Design: Prospective clinical examination with genetic evaluation and follow-up., Setting: Investigation centre was Odense University Hospital. All HHT patients in the County of Fyn were included., Methods: HHT family members were invited to a clinical examination including registration of HHT manifestations, screening for PAVM and neurological evaluation. Blood tests were performed for analysis of disease-causing mutation, and clinical manifestations in the HHT subtypes were compared. The survival of the patients was studied in the follow-up period., Results: Included in the study were 73 HHT patients representing 18 families. In 14 of the families we identified a disease-causing mutation. Thirty-nine patients (from 10 families) had HHT1 and 16 HHT patients from four families had HHT2., Conclusion: Amongst patients with HHT1 genotype the prevalence of PAVM was higher than amongst HHT patients with HHT2 genotype. HHT1 patients had experienced more severe GI bleeding than HHT2 patients. There was no significant difference in severity of epistaxis or age at debut. Finally the mortality over a 90-month observation period was not significantly increased.

This study was carried out to estimate the heritability of liability to epistaxis in the southern African Thoroughbred population. Data of all horses that suffered epistaxis while racing in southern Africa and Mauritius from 1986 to 2002 and involving 1252 bleeders were analysed. Pedigree data covering the period 1960-1986 was used as required to calculate the incidence of bleeding amongst ancestors of the post-1986 era. Only pedigrees of horses that raced were included in this study as it was not possible to predict whether non-runners would have bled had they raced. Consequently all non-runners and also those that raced overseas in countries where bleeding occurrence was not recorded, were excluded. The heritability of liability method as described by Falconer (1989) was used to estimate the relative importance of heredity and environment. For the period investigated, the population incidence for epistaxis in southern African horses was 2.1%. The estimation of heritability of liability showed that 1st-degree relatives had a figure of 55.4%. Second-degree relatives had a heritability of 41.3% and 3rd-degree relatives came in at 30.4%. The heritability of liability shown in this study could be regarded as being at the lower end of the range but could be appreciably higher. The data depict horses that bled almost exclusively on race days, as only a small percentage (approximately 5%) was reported as having bled during exercise. Accordingly, the full extent of epistaxis amongst racing Thoroughbreds in southern Africa is difficult to gauge. It is clear that epistaxis in the racing Thoroughbred has a strong genetic basis. It is suggested that horses showing frankbleeding from the nostrils after racing or exercise be suspended, and not used for breeding purposes. This should result in relatively fast progress being made towards eradicating this costly scourge of the modern Thoroughbred racehorse.

Background: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterised by mucocutaneous telangiectasis, epistaxis, gastrointestinal haemorrhage, and arteriovenous malformations in the lung and brain. Causative mutations for HHT have been identified in two genes, endoglin and ALK1, which encode proteins involved in serine-threonine kinase signalling in the endothelial cell., Methods: A number of people affected with HHT had completed a postal questionnaire as part of an international study to delineate the HHT phenotype. We identified questionnaires completed by subjects in whom we had identified a mutation in endoglin or ALK1. Further questionnaires were sent to families with known mutations. Data were only included from questionnaires returned by people known to carry disease causing mutations., Results: Questionnaires were completed by 83 subjects with known mutations. Of these, 49 had endoglin mutations (HHT1) and 34 had ALK1 mutations (HHT2). Subjects with HHT1 reported an earlier onset of epistaxis (p=0.01) and telangiectasis (p=0.0001) than those with HHT2. Pulmonary arteriovenous malformations were only reported in the endoglin mutation group in our study (p<0.001)., Conclusions: Our questionnaire based study provides evidence that the HHT phenotype caused by mutations in endoglin (HHT1) is distinct from, and more severe than, HHT caused by mutations in ALK1 (HHT2). This has significant implications for diagnosis, screening, and treatment in the two different forms of HHT, as well as for understanding the pathogenesis of the disease.

Background and Objective: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant fibrovascular dysplasia with the main symptom of recurrent epistaxis. At present, only limited data are available on long-term results in the treatment of epistaxis. A part from the surgical treatment of the bleeding telangiectasia with argon plasma, an additional postoperative long-term treatment with estriol nose-ointment was performed and the results were analysed., Patients and Methods: 69 patients with HHT were treated with APC and estriol nose ointment. 43 patients could be examined over a follow-up period of more than 20 months. The bleeding frequency and intensity as well as the patient's satisfaction with the treatment result were evaluated and the serum estriol level determined., Results: After more than 20 months, the bleeding frequency and intensity were reduced in 95% of the patients compared to their preoperative findings. Under the influence of estriol, former berry-like telangiectasias became flatter and more even. Neither systemic side effects under topically applied estriol nor a relevant increase of serum estriol levels were observed., Conclusion: The combined treatment regimen with APC and topically applied estriol provides a new treatment concept of epistaxis in HHT.

The aim of this study was to assess the value of topically applied estrogens in patients with hereditary hemorrhagic telangiectasia. Twenty-six patients with this disorder were treated with argon plasma coagulation and randomized into 2 groups: group A, which had postoperative application of estriol ointment (n = 14), and group B, which had postoperative application of dexpanthenol ointment (n = 12). Over a period of 12 months, the frequency and intensity of bleeding, the patient's satisfaction, and the success of the treatment were evaluated with a questionnaire. Before the operation, more than 90% of the patients in both groups complained of daily episodes of epistaxis. Twelve months after treatment, the frequency and intensity of bleeding had significantly decreased in group A as compared to group B. Of the patients in group A, 93% were satisfied with the treatment. Of the patients in group B, only 42% were satisfied with the treatment. In both groups, more than 90% of the patients were willing to undergo the same treatment again. The combined treatment approach with argon plasma coagulation and topical estriol enables us to significantly prolong the hemorrhage-free interval.

Background: It has been found that >90% of patients suffering from recurrent epistaxis from Kiesselbach area syndrome (REKAS) simultaneously suffered from hemorrhoids. To clarify this, the authors decided to investigate in the opposite direction, i.e., to find out whether or not REKAS occurs in patients suffering primarily from hemorrhoids., Methods: The study group included 53 randomly selected hospitalized patients with hemorrhoidal disorder (31 males and 22 females: age range 18-57 years). A search for essential clinical signs of REKAS was performed in each patient., Results: Incidence was not high, although all clinical parameters were nearly the same: dilated vessels in Kiesselbach venous plexus (83.01%) and a positive hereditary factor (92.7%). The only missing factor in patients with hemorrhoids was anterior septal deformity, so frequent in REKAS patients. CONCLUSIONS; The authors conclude that REKAS and hemorrhoidal syndrome are separate clinical entities that are characterized by dilated vessels of similar venous plexus and simultaneous appearance in the same patient or close relatives.

The genetic basis of fluctuating asymmetry (FA), or nondirectional variation in the subtle differences between left and right sides of bilateral characters, continues to be of considerable theoretical interest. FA generally has been thought to arise from random noise during development and therefore to have a largely or entirely environmental origin. Whereas additive genetic variation for FA generally has been small and often insignificant, a number of investigators have hypothesized that interactions between loci, or epistasis, significantly influence FA. We tested this hypothesis by conducting a whole-genome scan to detect any epistasis in FA of centroid size in the mandibles of more than 400 mice from an F2 intercross population formed from crossing the Large (LG/J) and Small (SM/J) inbred strains. Genotypic deviations were imputed at each site 2 cM apart on all 19 autosomes, and these and centroid size asymmetry values were used in canonical correlation analyses for each of the 171 possible pairs of 19 autosomes to identify the most probable sites for epistasis. Epistasis for centroid size asymmetry was abundant, occurring far more often than was expected by chance alone (there were 30 separate instances of epistasis at the 0.001 significance level, when only two were expected by chance alone). The contributions of epistasis from 30 pairwise combinations of loci tended to suppress the additive and dominance genetic variance, but greatly increased the epistatic genetic variance for FA in centroid size given the intermediate allele frequencies of an F2 intercross population.

Patients with hereditary hemorrhagic telangiectasia (M. Osler-Rendu-Weber disease) often suffer from recurrent epistaxis that poses considerable therapeutic problems. Dermoplasty, electrocoagulation, laser coagulation, iridium brachytherapy and systemic administration of estrogens have been proposed for treatment. Until recently argon plasma coagulation (APC) was not used in ENT surgery, but theoretical considerations render APC a promising therapeutic method for controlling nasal bleeding. Coagulation of tissue is limited to 1-2 mm of penetration and therefore risk of damage to adjacent tissue is low. Effects are best in tissues with high electric conductivity, especially for coagulating bleeding lesions and blood vessels. We have now treated four patients with telangiectasias in the nasal mucosa who had long histories of treatment for epistaxis. The patients were satisfied with the postoperative results and the frequency and intensity of bleeding were significantly reduced. Initial clinical experiences show that APC is a useful alternative for the treatment of bleeding telangiectasias in the nasal mucosa.

Rendu-Osler-Weber disease is an autosomally dominant inherited disease which affects the connective tissue of blood vessels. The major symptom is recurrent epistaxis for which still exists no generally recommended treatment. Treatment modalities discussed in the literature include bilateral closure of the nostrils, brachytherapy, vessel embolization, hormone therapy, dermoplasties, as well as different kinds of laser therapies. Advantages and disadvantages of single treatment modalities are discussed. Dermoplasty and laser therapy seem to be the most suitable treatment procedures currently available for recurrent epistaxis in affected patients. Treatment carried out with the argon, KTP or ND:YAG laser has proven to be suitable as initial therapy. In most cases the additional use of long-term applications of a soft nasal ointment allows a lasting successful treatment. Our experiences show that dermoplasty should be reserved for cases with continued bleeding despite laser treatment but only rarely offers a long-term cure in the sense of a total recovery from epistaxis.

We performed a DNA analysis on a patient with severe type I factor VII deficiency by the polymerase chain reaction amplification and a direct DNA sequencing method. The proband was a 66-year-old Japanese woman who had recurrent episodes of excessive bleeding after dental extraction. The functional and antigenic levels of plasma factor VII markedly reduced to 1.6% and 2% of normal, respectively. However, she had no serious symptoms such as intracranial or intraarticular hemorrhage. The analysis revealed that the patient was homozygous for a missense mutation, Thr (ACG) to Met (ATG) at codon 359 in the catalytic domain. Her deceased parents were first cousins, and their consanguineous marriage presumably resulted in the homozygosity in her. This patient was the first case of homozygote for the Thr359Met mutation, though heterozygotes for the mutation were previously found in an Italian family.

Pulmonary arteriovenous malformations (PAVMs) occur in up to 27% of patients with hereditary haemorrhagic telangiectasia (HHT) and are associated with a rate of paradoxical cerebral embolism at presentation of up to 36%. At least two different loci have been shown for HHT. Mutations in endoglin have been found in some families and the locus designated ORW1. In other families this locus has been excluded. In this paper we confirm that in families linked to ORW1 there is a prevalence of PAVMs among affected members of 29.2%, compared to a prevalence of 2.9% in families in which this locus has been excluded (chi 2 = 19.2, p < 0.001). This information can be used to decide how to screen HHT patients for PAVMs.

A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is characterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(ogen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor XIII deficiency, alpha 2-antiplasmin deficiency, or dysfibrinogenemia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half normal antigen and normal activity of platelet PAI-1. The low concentration of plasma PAI-1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAI-1 deficiency. Studies on this patient emphasize a clear correlation between decreased plasma PAI-1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAI-1 in the balance between the coagulation and fibrinolytic mechanisms.