Family History Of Bleeding Tendency Research Articles

Determination of von willebrand factor antigen in patients with undiagnosed menorrhagia

This prospective study is about screening of von willbrand antigen in patients with undiagnosed menorrhagia, because the underlying cause may be haematological disorder in 50% of cases. To estimate the incidence of von willbrand disease in patients with undiagnosed menorrhagia. During the period of 2 months from February to april 2005, total of 50 patients were included in this study that were referred to Al-yarmok teaching hospital. The age range of these patients was 18-45 year. Full history and physical examination done, ultrasound examination to exclude local causes of menorrhagia, thyroid function done. 30 healthy volunteer age matched were included as control group. For each patient and control group the following tests were done: Bleeding time, Prothrombin time, Activated partial thromboplastin time, Factor 8 level, Von willbrand factor antigen level.Results1.There was no obvious or statistically significant difference in mean bleeding time and activated partial thromboplastine time observed between healthy controls and patients with menorrhagia.2.The mean Von Willebrand factor antigen (%) was significantly lower in patients with menorrhagia compared with healthy controls.3.The mean Von Willebrand factor antigen was slightly lower at the older age group compared to younger age group.4.The proportion of patients with prolonged activated partial thromboplastine time was obviously higher among those with abnormally low Von Willebrand factor antigen compared to those with acceptable level.5.The relative frequency of cases with abnormally low factor VIII activity was higher among subjects with other bleeding manifestations compared to those with no manifestations. 6.The relative frequency of cases with abnormally low factor VIII activity was higher among subjects with positive family history of bleeding tendency. 7.The relative frequency of cases with abnormally low Von Willebrand factor was obviously higher among subjects with other bleeding manifestations compared to those with no bleeding manifestations, also it was higher among cases with positive family history of bleeding tendency and those with past history of severe bleeding episodes.Conclusions: The prevalence of Von Willebrand disease is increased in women with menorrhagia. So it is reasonable to believe that Von Willebrand disease is the underlying cause for meborrhagia in a small but significant proportion of women. This study revealed that 6% of women with menorrhagia had Von Willebrand disease.

Haemophilia A in a Female Patient with Turner Syndrome

A 28-year-old female presented with occasional swelling of knees and prolonged bleeding after trauma. She also complained of gum bleeding in few occasions. She also gave history of primary amenorrhoea and failure of development of secondary sexual character. There was negative family history of bleeding tendency in both maternal and paternal family. Her investigation profile showed prolonged Partial Thromboplastin Time and reduced factor VIII activity (2.5%). Karyotyping showed (45 XO) Turner syndrome. This is the reported first case of association of Turner syndrome with moderate Haemophilia A in Bangladesh.

Systematic Screening for Familial Leukemia Based on Somatic Genomic Profiling Results

The incidence of familial acute leukemias (AL) and myelodysplastic syndrome (MDS) in the adult population is not well characterized, though recent estimates report that up to 4% of newly diagnosed individuals have a familial syndrome. Recognizing these syndromes is critical to proper clinical management of patients with an inherited susceptibility, and for genetic screening of family members. Within our tertiary care academic institution, less than 1% of AL/MDS cases are referred to genetic counseling, presenting an opportunity for improvement in practice. With the integration of next generation sequencing into standard clinical practice, we recently initiated a bi-monthly meeting to review these sequencing results, with the intent to detect possible familial AL/MDS syndromes and increase appropriate genetic counseling referrals. Here, we describe the potential value of this approach, through a retrospective analysis of somatic genomic profiling results in AL/MDS patients. We performed a retrospective, single-center analysis of all patients who underwent somatic genomic profiling with FoundationOne Heme for AL and MDS between May 2015 and July 2018. Genomic alterations implicated in familial leukemias or familial cancers and included in the FoundationOne Heme panel were as follows: RUNX1, CEBPA, ETV6, GATA2, TERC/TERT, PAX5, CHEK2, and TP53. We recorded baseline characteristics including age, sex, and diagnosis. The presence of the suspected germline variant and up 6 other genomic alterations were recorded. We described whether a comprehensive family history, defined as whether a family history of bleeding tendency, low blood counts, or cancers, was documented for all patients. All patients with a positive family history had the malignancies and blood disorders reported. Finally, we observed if a genetic counseling referral was placed. A total of 108 patients underwent genomic profiling during the study period. Pathogenic variants implicated in familial AL/MDS or familial cancers were detected in 41 of those patients. The number of patients under the age of 50 was 7. Twenty-nine patients had a diagnosis of AML and 12 patients had MDS. Of the reported relevant pathogenic variants, TP53 was seen in 20 patients, RUNX1 in 14 patients, CEBPA in 4 patients, ETV6 in 4 patients, and GATA2 in 3 patients. There were 5 patients that had 2 pathogenic variants noted on their genetic testing. Among the patients with positive pathogenic variant, 22/41 had a comprehensive family history performed. Family history was positive for malignancy in 26/41 patients. Of those 26, 9 patients had a first degree relative with a history of hematologic malignancy including leukemia. Only 2 patients overall were referred to genetic counseling. In AL/MDS patients who underwent somatic genomic profiling at our institution, nearly half of patients with suspected germline variants for familial AML-MDS syndromes had either a family history of malignancy or development of their malignancy at an earlier age, warranting genetic counseling referral. There also is room to improve comprehensive family history collection. Beginning in March 2018, we initiated a bi-monthly meeting to review somatic genomic profiling results in AL/MDS patients with a licensed geneticist. If a suspected germline variant is discovered, we now issue a statement to the primary oncologist to clarify family history if needed, and recommend a referral for formal genetic counseling in the presence of a suggestive family history or on the basis of age. In future investigations, we plan to study how this changes the rate of genetic counseling referrals, and whether this results in an increase in the detection of familial AL/MDS or familial cancer syndromes among this patient group. DisclosuresAtallah:Abbvie: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Jazz: Consultancy; Novartis: Consultancy.

Severe hemophilia in a girl infant with mosaic Turner syndrome and persistent hyperplastic primary vitreous

A 6-month-old girl was referred by an ophthalmologist because of postoperative bleeding. She was scheduled for operation because of persistent hyperplastic primary vitreous. Workups were done and prolonged partial thromboplastin time with normal platelet count, normal bleeding time, and prothrombin time were detected. There was negative family history of bleeding tendency in both maternal and paternal family, so at the first step, Factor XI assay was requested which was normal. Then, von Willebrand factor and factor VIII were assayed which was 127% and less than 1%, respectively. Severe factor VIII deficiency was not suspected in a girl unless in siblings of a hemophilic patient who gets married with her carrier cousin. Chromosomal study and genetic testing were requested and mosaic Turner syndrome (45 XO) with ring X (p22, 2q13) along with inversion 22 (hemizygote) was detected. Abdominal and pelvic sonography showed absence of both ovaries with presence of infantile uterus. Maternal genetic study was in favor of carrier of hemophilia (heterozygote inversion 22). To the best of our knowledge, this is the first case of association of Turner syndrome with severe hemophilia A and persistent hyperplastic primary vitreous.

Clinical studies of 162 patients with von Willebrand disease

To analyse the epidemiological feature, clinical characters and therapeutic regimens for von Willebrand disease(VWD). The clinical data and laboratory tests results of 162 VWD patients in our center were analyzed. There were 76 males and 86 female among these patients with the mean age of 7.2(2.0-41.0) and 20.7(5.0-48.0) years, respectively. 86 patients (53.1%) were identified to be type 1 VWD, 34 patients (21.0%) type 3 VWD and 42 patients (25.9%) type 2 VWD. Among type 2 VWD patients, 33 patients were type 2A, 4 patients type 2M, 5 patients type 2B. Eighty-seven patients (53.7%) had a definite family history of bleeding tendency. The most common and specific bleeding symptoms were easy bruising (61.7%), epistaxis (53.7%), prolonged bleeding after surgery or minor injury (53.1%). Menorrhagia (66.3%) was common in female patients. The analysis of Vicenza bleeding scores in all patients showed that only 56(34.6%) patients had abnormal bleeding scores. FVIII/VWF concentrates and cryoprecipitate were applied to 45 patients (27.8% ), Desmopressin (DDAVP) to 8 patients. Eight female patients need oral contraceptives jointly to control menorrhagia. Hysterectomy had to be performed in 2 female patients with VWD. VWD was a common congenital bleeding disorder with heterogeneous characters, it was necessary to screen, identify, classify accurately this disease in order to supply to effectively individualized treatment.

Acquired Von Willebrand Disease – To Treat Or Not To Treat The Inhibitor?

Introduction Acquired von Willebrand disease is a relatively rare but possibly under diagnosed bleeding disorder. The etiology is multifactorial, including underlying malignancy, drugs, valvular heart disease, mechanical cardiac assist devices, autoimmune diseases and infections. The disorder is characterized by mucocutaneous bleeding presenting in adulthood with no prior history or family history of bleeding tendency. Materials and Methods A retrospective chart review was performed on patients with a diagnosis of acquired von Willebrand disease over a period of 15 years. We identified 10 patients with this diagnosis in the absence of valvular heart disease or the presence of a mechanical cardiac assist device. The initial presentation along with demographic features, co-morbidities, laboratory values at the time of initial presentation and subsequent follow up, treatment of bleeding episodes and cause of death were noted. Results The mean age at diagnosis was 56.5 years with range of 39-75 years. Males and females were equally affected. One patient each had aortic valve stenosis and hypothyroidism, both of which were treated and not felt to be responsible for the diagnosis of acquired von Willebrand disease. Six of ten patients had an underlying myelo / lymphoproliferative disorder while two had a remote history of cured high grade colon cancer. Most of the patients presented with mucocutneous bleeding including easy bruising, epistaxis, gingival bleeding, and GI bleeding. Post procedural urinary tract bleeding was the presenting sign in two patients and one patient presented with spontaneous intracranial hemorrhage. All but two patients presented with ristocetin cofactor activity of <10% and factor VIII and von Willebrand antigen levels in the range of 4-31% and 10-23% respectively. Multimer patterns were either severely reduced high molecular weight multimers or decreased multimers with normal distribution. For all patients, the presenting lab values remained unchanged at follow up even over several years (up to 12 in our series), including in those who received treatment for the underlying myelo / lyphoproliferative disorder. Treatment to control bleeding included DDAVP, IVIg, factor VIII/VWF concentrates, rituximab, plasma exchange, and recombinant factor VIIa, all with varying degrees of success. Six of ten patients did experience recurrent bleeding episodes and two ultimately died of uncontrolled GI bleeding. Discussion Acquired von Willebrand disease is a rare entity, typically presenting with severely decreased factor levels, and often associated with significant morbidity and potential mortality. Although some patients experience recurrent and refractory bleeding, others may survive for more than 10 years without major complications with this condition. As reported previously in literature, most of the cases in our series were also associated with underlying myelo / lymphoproliferative disorders. In two of our patients the development of acquired von Willebrand disease preceded the diagnosis of a lymphoproliferative disorder by 3-4 years, suggesting that close monitoring for future development of these disorders is warranted. In contrast to previous reports, treatment of the underlying myelo / lymphoprolifertive disorder did not lead to improvement in the bleeding episodes or lab values in any of our patients that were treated (5/6). In acquired hemophilia, approximately 80% of patients experience significant bleeding, and mortality has been quoted in the range of 8-22%. Thus, treatment usually includes an attempt to eradicate the inhibitor with immune suppression. In our series, 60% of the patients experienced recurrent and refractory bleeding, and mortality was also 20%, suggesting that a similar approach should be considered in those with acquired von Willebrand disease. Disclosures: No relevant conflicts of interest to declare.

Mild haemophilia B from a novel missense mutation Ser350Ala of the F9 gene

Haemophilia B is an X-linked recessive bleeding disorder caused by mutations in the F9 gene on Xq27.1, which lead to deficient coagulation factor IX (FIX). The mild form of haemophilia B has been known to be underdiagnosed due to mild clinical symptoms and minimally prolonged activated partial thromboplastin time. We herein describe a sporadic case of mild haemophilia B from a novel missense mutation of F9. The proband was a 4-year-old boy with a mild bleeding history. He had no family history of bleeding tendency. Coagulation screening tests revealed prolonged aPTT at 42.6s (STA-PTT Automate, reference range, 29.1-41.9s) and a decreased FIX activity at 13% in factor assays. Molecular genetic analysis of F9 revealed that he was hemizygous for a missense mutation, c.1048T>G (p.Ser350Ala), which has not been reported previously. His mother was a carrier of the mutation. This case represents a novel missense mutation from non-CpG transversion of F9.

Early Diagnosis and Successful Treatment of Idiopathic Autoimmune Factor XIII Deficiency Complicated by Intracerebral Hemorrhage

Abstract 4634 Summary:Autoimmune factor XIII (FXIII) deficiency is an extremely rare bleeding disorder that can be life-threatening without prompt diagnosis and treatment. Many clinicians, even experienced hematologists, are unaware of this critical disorder. The causes and mechanisms of autoimmune FXIII deficiency remain unclear, but patients should be given top priority in receiving FXIII concentrate and immunosuppressive drugs when this is suspected to avoid fatal hemorrhage. We report the first Japanese case of autoimmune FXIII deficiency presenting as acute intracerebral hemorrhage. The clinical manifestations allowed prompt diagnosis and effective treatment in the form of emergency open drainage and infusion of FXIII concentrates combined with prednisolone therapy, leading to success in saving the life of this patient. Case:A 68-year-old man was hospitalized in another department of our hospital with abdominal pain and diffuse purpura of the abdominal skin in the absence of any history of trauma. He did not have a family history of bleeding tendency. Since he had been receiving low-dose aspirin because of a previous stroke, he received a transfusion of red cell concentrate and was discharged after cessation of aspirin. Two weeks later, he was taken to an emergency room with left hemiplegia. Computed tomography (CT) revealed an intracerebral hemorrhage measuring 4 cm in diameter. Sixteen hours after hospitalization, emergency open drainage was performed because of decreased levels of consciousness due to an expanding intracerebral hemorrhage measuring 7 cm with midline shift. Bleeding was controlled during the operation and CT showed no evidence of further bleeding after surgery. However, on postoperative day 2, subcutaneous bleeding spontaneously developed on the patient's head. Platelet counts and coagulation tests were normal, and other tests showed no evidence of factor VIII, factor IX or von Willebrand factor deficiencies. Given the lack of evidence of other autoimmune disorders or family history of bleeding tendency, we suspected idiopathic autoimmune FXIII deficiency and immediately initiated administration of FXIII concentrate. After treatment with FXIII concentrate, subcutaneous bleeding on the head was arrested and level of consciousness had recovered at all. 3 days after it was confirmed that FXIII activity was as low as 11%, and was not corrected by normal plasma at 1:1 in the cross-mixing test, suggesting the presence of anti-FXIII inhibitor and corroborating our clinical diagnosis. Based on the detection of anti-FXIII A autoantibodies in dot blot assay, we immediately started immunosuppressive therapy using prednisolone at 1 mg/kg combined with FXIII concentrate. Three weeks later, inhibition of FXIII activity was partly improved. FXIII activity was 36%, and 1:1 cross-mixing test was corrected, indicating that immunosuppressive therapy with prednisolone was proving successful. Four weeks later, his surgical wound had healed and FXIII concentration injection was discontinued. Prednisolone tapering was started, and after 8 weeks, with prednisolone tapered to 35 mg, FXIII activity was elevated to 53%. This was not yet sufficient, but anti-FXIII A subunit autoantibodies had disappeared completely, first as free-form antibody and then as bound/complexed antibody. Successful results were achieved in response to short-term treatment. In fact, in some of the 28 cases reported from Japan, anti-FXIII inhibitors were continued despite immunosuppressive therapy for a few years. The next target was to stop prednisolone therapy, because the major causes of death in patients with autoimmune FXIII deficiency is bleeding or infection. Why and when the patient developed autoantibodies remains unclear, as he had no evidence of other autoimmune disorders. This report describes a remarkably successful case in which early diagnosis and treatment of autoimmune FXIII deficiency achieved good outcomes for a case complicated by intracerebral hemorrhage. All clinicians should consider the possibility of this rare disease when they encounter patients who present with life-threatening bleeding and normal coagulation tests are inconclusive. Prompt diagnosis and treatment are crucial in saving the life of the patient. Disclosures:No relevant conflicts of interest to declare.

Research for bleeding tendency in patients presenting with significant epistaxis

To evaluate the association of inherited coagulopathies and acquired conditions (e.g. hypertension, aspirin use) with emergency department admission due to epistaxis. Patients admitted to the emergency department with epistaxis were included. A questionnaire for personal and family history of any bleeding disorder was used. Physical examination including ear, nose and throat examination was performed. Platelet counts, International Normalized Ratio, activated partial thromboplastin time, factors VIII, IX and XI, von Willebrand factor and ristocetin cofactor activity levels were determined. Nineteen patients were included in the study. Personal history of mucocutaneous bleeding was present in four cases and family history in two cases. Only one case (5%) had a decreased von Willebrand factor level (45%), and also had a personal and family history of bleeding tendency. Ten patients (53%) had a history of aspirin use. Thirteen (68%) patients had hypertensive values on admission. Aspirin use and hypertension were the leading causes of emergency service admission in adults due to epistaxis in this study, although the number of the patients was relatively low. Regarding the low prevalence of inherited coagulopathies, detailed coagulation tests should be reserved for adult patients with positive personal and/or family history of bleeding.