Common Bleeding Disorder Research Articles

Activation of the HMGB1-TLR4 pathway impacts the functionality of bone marrow mesenchymal stem cells and disrupts macrophage polarization in immune thrombocytopenia.

Recent evidence suggests that immune thrombocytopenia (ITP), a common bleeding disorder, is linked to an imbalance in macrophage polarization and impaired bone marrow mesenchymal stem cells (BMSCs). However, the relationship between macrophage polarization imbalance and functional defects in BMSCs, as well as the involvement of associated molecules in BMSCs' defects, is not well understood. This study aimed to investigate the regulatory effects of high mobility group protein 1 (HMGB1) on the physiological functions of BMSCs, specifically in relation to macrophage polarization imbalance. Patients with ITP showed dysregulation in monocyte/macrophage polarization and impaired BMSCs function. HMGB1 was found to have a negative impact on the ability of BMSCs to regulate the imbalance in macrophage polarization, especially when inflammatory factors are present. The MyD88-dependent pathway downstream of BMSCs was found to be significantly enhanced with HMGB1 treatment. Furthermore, treatment with toll-like receptor 4 (TLR4) inhibitors successfully restored the regulatory capacity of BMSCs in ameliorating macrophage polarization imbalance and effectively inhibited the activation of the MyD88-dependent pathway. Meanwhile, infusion of si-TLR4-BMSCs reversed HMGB1-induced platelet dysfunction and reduced over-polarization to M1-like macrophages in the ITP mouse model. Consequently, targeting the HMGB1-TLR4 pathway could be a potential approach to restore the immunoregulatory function of BMSCs.

Menorrhagia in inherited bleeding disorders in Iraqi women

Abstract: BACKGROUND: Menorrhagia, or excessive menstrual bleeding, is a common symptom in women with inherited bleeding disorders; they are conditions where the blood ability to clot is impaired. Some of the common bleeding disorders include von Willebrand disease (VWD), clotting factor deficiencies, and platelet function disorders. OBJECTIVE: To assess different types of inherited bleeding disorders in women with menorrhagia referred to the National Center of Hematology/Mustansiriyah University in Baghdad/Iraq. PATIENTS AND METHODS: A prospective study was carried out on 193 women who had experienced menorrhagia for a duration of 3 years, from 2020 to 2023. These women sought consultation at the National Centre of Hematology/Mustansiriyah University. All participants were diagnosed through various laboratory tests, including complete blood count, blood film, blood group and Rh, bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen level, factor assay, von Willebrand factor antigen using ELISA technique, ristocetin cofactor, and platelet function test. RESULTS: Out of the 193 women with menorrhagia who participated in this study, the majority of whom had an unidentified cause (36.3%), followed by VWD (30.1%) and platelet function disorders (21.2%). Other bleeding disorders (thrombocytopenia and factors deficiencies) were 5.7% and 6.7%, respectively. Furthermore, the results showed that there was a significant difference in family history and consanguinity between patients with a hereditary bleeding disorder and nonhereditary bleeding disorder (P < 0.001). CONCLUSIONS: Fifty eight percent of females with Menorrhagia in this study have inherited bleeding disorders(IBDs), VWD, and thrombasthenia account for 51.3% are the most common causes of inherit bleeding disorder (IBD). Consanguineous marriage should be discouraged in Iraqi society to reduce such inherited diseases.

Platelet-Type von Willebrand Disease: Complex Pathophysiology and Insights on Novel Therapeutic and Diagnostic Strategies.

von Willebrand disease (VWD) is the most common well-studied genetic bleeding disorder worldwide. Much less is known about platelet-type VWD (PT-VWD), a rare platelet function defect, and a "nonidentical" twin bleeding phenotype to type 2B VWD (2B-VWD). Rather than a defect in the von Willebrand factor (VWF) gene, PT-VWD is caused by a platelet GP1BA mutation leading to a hyperaffinity of the glycoprotein Ibα (GPIbα) platelet surface receptor for VWF, and thus increased platelet clearing and high-molecular-weight VWF multimer elimination. Nine GP1BA gene mutations are known. It is historically believed that this enhanced binding was enabled by the β-switch region of GPIbα adopting an extended β-hairpin form. Recent evidence suggests the pathological conformation that destabilizes the compact triangular form of the R-loop-the GPIbα protein's region for VWF binding. PT-VWD is often misdiagnosed as 2B-VWD, even the though distinction between the two is crucial for proper treatment, as the former requires platelet transfusions, while the latter requires VWF/FVIII concentrate administration. Nevertheless, these PT-VWD treatments remain unsatisfactory, owing to their high cost, low availability, risk of alloimmunity, and the need to carefully balance platelet administration. Antibodies such as 6B4 remain undependable as an alternative therapy due to their questionable efficacy and high costs for this purpose. On the other hand, synthetic peptide therapeutics developed with In-Silico Protein Synthesizer to disrupt the association between GPIbα and VWF show preliminary promise as a therapy based on in vitro experiments. Such peptides could serve as an effective diagnostic technology for discriminating between 2B-VWD and PT-VWD, or potentially all forms of VWD, based on their high specificity. This field is rapidly growing and the current review sheds light on the complex pathology and some novel potential therapeutic and diagnostic strategies.

When Type 1 von Willebrand Disease Lives Together with Hashimoto Thyroiditis, Hypothyroidism, Hypoparathyroidism, Morbid Obesity, and Bariatric Surgery: A Case Report

Von Willebrand disease (vWD) is the most common bleeding disorder with type 1 being the more prevalent, although underdiagnosis is an actual concern. This case is the first clinical report of a type 1 vWD with several comorbidities submitted to bariatric surgery. The authors demonstrate the importance of a diagnosis and the consideration of other diseases or disturbances in vWD patients’ perioperative management. A multidisciplinary approach is crucial for minimizing and preventing bleeding risk.

Abstract We098: Target-Specific Novel Therapeutic Approach for Prevention of Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia

Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic vascular disease with no cure. HHT is characterized by abnormalities in blood vessels that occur in mucocutaneous tissues (telangiectasias) and deep tissues (arteriovenous malformations, AVMs). The tangled, enlarged, fragile, and aberrant vasculature in HHT patients is prone to chronic bleeding or hemorrhage and may cause serious complications, especially in the brain. Problem Statement: While diagnosed AVMs can be surgically treated, there are no FDA-approved drugs to prevent or manage them. Developing targeted therapeutics to manage AVMs has been incredibly challenging as the mechanism of AVM formation is not clearly understood. Rationale: Dysregulation of pro-angiogenic signaling pathways is considered to play a major role in AVM development. For instance, VEGFA-VEGFR2, ANG2–TIE2 and MAP Kinase 1/2 signaling have been implicated individually in HHT pathogenesis. While MAPK 1/2 signaling is difficult to target because of its universal presence, its upstream activators VEGFA and ANG2 are lucrative targets for their relative specificity primarily affecting vasculature (Figure 1). Innovation: We use a novel approach to target VEGFA and ANG2 simultaneously using IgG CrossMab bispecific inhibitor, allowing superior efficacy by inhibiting dual specific targets to prevent genetic vasculature abnormalities. Approach: We use vascular latex casting and molecular quantification techniques to assess the benefits of inhibiting abnormal pro-angiogenic signaling in HHT mice models. Our preliminary data shows improved vasculature development with small doses of MAPK 1/2 inhibitor, but early mortality due to its damaging side effects. Preliminarily, the combined effect of the bispecific inhibitor in smaller doses improves the vasculature defects in the mutant brain more robustly than the individual inhibitors alone, while not negatively affecting the wild-type model (Figure 2). We further expect this dual inhibition to normalize the transcriptomic signature of mutants to mimic the wild-type setting. Societal Impact: The expected beneficial effects of the bispecific inhibitor will provide a pre-clinical assessment of the cerebrovascular AVM management strategies for 1.4 million HHT patients. It will further the mechanistic understanding of AVM development and prevention in HHT, the 2 nd most common bleeding disorder.

Real-world experience of thrombopoietin receptor agonists in pediatric immune thrombocytopenia: a report from a Chinese tertiary children's hospital.

Primary immune thrombocytopenia (ITP) is the most common bleeding disorder in children. There are approximately 20% pediatric ITP patients respond poor to corticosteroids as first-line treatment. Recently thrombopoietin receptor agonists (TPO-RAs) have been used to treat refractory ITP and have achieved certain therapeutic effects. To investigate the efficacy and safety of TPO-RAs in the treatment of pediatric ITP, we conducted this real-world study. Fifty-three pediatric patients with ITP who did not respond well to corticosteroids were treated with TPO-RAs. Clinical data, including therapeutic response rate, changes in platelet (PLT) count, and adverse events (AEs) were collected. Of the 51 evaluable patients, 37 (72.5%) responded to TPO-RAs. Patients aged >4 years had a higher response rate than those aged ≤4 years (81.1% vs. 50.0%, P=0.04). There was no effect of sex, duration of disease, prior therapy, Mycoplasma pneumoniae (MP) immunoglobulin M (IgM) positivity, antinuclear antibody (ANA) positivity, CD4/CD8 ratio or baseline PLT count on the response rate (P>0.05). Other than 10 patients with PLT counts that exceeded the upper limit of normal, AEs were sporadic, including increased aminotransferase levels, cough, headache, and vomiting. TPO-RAs exhibited good clinical efficacy in pediatric ITP patients who failed to respond to first-line treatment, especially patients aged >4 years, and the side effects were minor.

Identification of the Efficient Enhancer Elements in FVIII-Padua for Gene Therapy Study of Hemophilia A.

Hemophilia A (HA) is a common X-linked recessive hereditary bleeding disorder. Coagulation factor VIII (FVIII) is insufficient in patients with HA due to the mutations in the F8 gene. The restoration of plasma levels of FVIII via both recombinant B-domain-deleted FVIII (BDD-FVIII) and B-domain-deleted F8 (BDDF8) transgenes was proven to be helpful. FVIII-Padua is a 23.4 kb tandem repeat mutation in the F8 associated with a high F8 gene expression and thrombogenesis. Here we screened a core enhancer element in FVIII-Padua for improving the F8 expression. In detail, we identified a 400 bp efficient enhancer element, C400, in FVIII-Padua for the first time. The core enhancer C400 extensively improved the transcription of BDDF8 driven by human elongation factor-1 alpha in HepG2, HeLa, HEK-293T and induced pluripotent stem cells (iPSCs) with different genetic backgrounds, as well as iPSCs-derived endothelial progenitor cells (iEPCs) and iPSCs-derived mesenchymal stem cells (iMSCs). The expression of FVIII protein was increased by C400, especially in iEPCs. Our research provides a novel molecular target to enhance expression of FVIII protein, which has scientific value and application prospects in both viral and nonviral HA gene therapy strategies.

Outcomes Following Total Hip Arthroplasty in Patients Who Have Von Willebrand Disease Depend on Postoperative Anticoagulation

BackgroundVon Willebrand disease (VWD) is the most common congenital bleeding disorder. This autosomal dominant condition arises from quantitative or qualitative defects of Von Willebrand factor. To our knowledge, this study leveraged a national database to characterize the largest VWD cohort of total hip arthroplasty (THA) patients to date, assessing 90-day postoperative adverse events and 5-year revision-free survival. MethodsAdult patients who underwent primary THA for osteoarthritis were identified from January 2010 to October 2021 in a nationwide database. Patients who had and did not have VWD were matched (4:1) on age, sex, and Elixhauser Comorbidity Index and compared with multivariable logistic regression. Patients were then categorized based upon venous thromboembolism (VTE) chemoprophylaxis prescription patterns to compare bleeding and thrombotic adverse events. ResultsOf 544,851 THA patients, VWD was identified in 309 patients (0.06%). The matched cohorts contained 1,221 patients who did not have VWD and 306 patients who have VWD. On multivariable analysis, VWD patients had increased odds of 90-day VTE (odds ratio [OR] = 1.86) and hematoma (OR = 3.40) (P < .05 for all). No difference in 5-year revision-free survival was found. The VWD patients receiving aspirin or no prescriptions had greater odds of VTE (OR = 2.39, P = .048). Those on other chemoprophylaxis agents had greater odds of hematoma (OR = 4.84, P = .006). ConclusionsPatients with VWD undergoing THA had increased odds of 90-day VTE if using aspirin or no prescriptions, or hematoma if using other chemoprophylaxis. There is a delicate balancing act of clotting versus bleeding that must be considered in managing such patients, but it was reassuring that no difference in overall 5-year revision-free survival was found.

MANAGEMENT OF ASRIGDRA W.S.R. TO DUB- CASE STUDY

In Ayurveda, the most common bleeding disorders in women are referred to as Asrigdara and are characterised by Pradirana (excess excretion) of Raja (menstrual blood). In modern medicine, it is called "Dysfunctional Uter-ine Bleeding." Despite their high costs, hormonal therapy, anti-prostaglandins, and anti-fibrinolytic agents have not proven their definitive efficacy in modern medicine; their side effects have resulted in hormonal imbalances. In Ayurvedic classics, all gynaecological disorders are classified as Yonivyapad. Charaka Acharya Raktapra-dara is described as Pradara Roga by Charaka Aacharya. Excessive vaginal white discharge is referred to as Shweta Pradara and excessive or heavy menstrual bleeding is referred to as Raktapradara. It is known as Pra-dara due to pradirana (excessive excretion) of raja (menstrual blood) and Asrigdara due to dirana (excessive excretion) of Asrk (menstrual blood). Menorrhagia is treated with Haemostatic, analgesic, and hormonal thera-pies in modern medicine, which has limitations. As a result, an integrated and comprehensive therapeutic inter-vention in Ayurveda is required to prevent recurrence. Sodhana and Shamana therapies are recommended, but if Rugnabala is low, only Shamana is recommended. Many herbals and herbo-mineral preparations are mentioned in Ayurveda to treat Asrgdara and related symptoms, and these can be used according to Anubandha Dosha and Lakshana. Because Asrgdara is primarily caused by Vata Pitta Dosha, Kashaya Rasa and Pittashamaka Chikitsa may be used. Ayurvedic formulations aid in the breakdown of Asrgdara pathogeneses and their recur-rence.

Anaesthesiologist’s Role in Patient with Von Willebrand Disease for Elective Adenoidectomy: A Case Report

The most common bleeding disorder is von Willebrand disease (vWD). It is however a complex disease to diagnose. Management of this disease is not well understood by many anaesthesiologists who may experience these patients in elective or even emergency settings. This is a case presentation of a six-year-old patient of Arabic ethnicity who was diagnosed with vWD during preoperative testing and was managed perioperatively with a multidisciplinary team for a good outcome. Keyword: Von Willebrand disease, Von Willebrand factor, Adenoidectomy, Preoperative testing

Trombocitopenia primária imune com púrpura palpável: um relato de caso

Immune thrombocytopenia is a relatively common bleeding disorder characterized by isolated destruction of platelets by autoantibodies, with a typically acute onset, benign course and self-limiting in most cases. The aim of this report is to present a rare case of Primary Immune Thrombocytopenia (ITP) with palpable purpura, an uncommon manifestation in this disease and little described in the literature. This is a 12-year-old female adolescent who presented with palpable purpura, ecchymosis and oral cavity bleeding associated with thrombocytopenia and anemia. Initial investigation excluded autoimmune diseases, vasculitis, lymphoproliferative diseases and coagulation disorders, in addition to the myelogram showing typical findings of ITP: hypercellular bone marrow with megakaryocytic hyperplasia and decreased thrombocytogenesis. Due to the diversity of clinical presentation and the possibility of atypical manifestations, the diagnosis is often challenging, as in the case of this patient in which the main finding on physical examination was the presence of palpable purpura.

Successful treatment with oseltamivir phosphate in children with ITP who failed first-line therapy: a case series report.

Immune thrombocytopenia (ITP) is a common bleeding disorder in children. First-line medicines (glucocorticoids and immunoglobulin) may not be effective for some children, endangering their lives, posing challenges for healthcare facilities, and leading to an unfavorable prognosis. As a sialidase inhibitor, oseltamivir phosphate can reduce the destruction of platelets in liver macrophages by inhibiting the sialylation of platelets, and finally achieve the purpose of increasing platelet count. In this paper, three cases of children with ITP who failed first-line therapy and were cured by oral administration of oseltamivir phosphate granules were reported. The mechanism of action of oseltamivir phosphate granules was clarified.

High Prevalence of a Rare Bleeding Disorder: A Report from Glanzmann Thrombasthenia Registry of Al-Madinah, Saudi Arabia

Introduction Glanzmann thrombasthenia (GT) is a hereditary bleeding disorder caused by a defect or deficiency of platelet glycoprotein IIbIIIa. Though GT is considered a rare bleeding disorder, some countries in the Middle East report a high prevalence of GT. Aim Description of GT patients' prevalence, demographic, clinical, and genetic features in AlMadinah, Saudi Arabia. Methods This is a 20-year report from the AlMadinah GT registry in the Madinah Hemophilia Comprehensive Care Center. The registry has included all patients with a confirmed diagnosis of GT. To label a patient as GT, He must have absence or abnormal response in all agonists except ristocetin plus absence or reduced expression of platelet glycoprotein IIbIIIa on Flowcytometry. Next-generation sequencing is used to target sequencing for Molecular testing. The extracted data underwent an analysis process, where 136 GT patients were identified. Only 125 cases have complete data in records. Statistical analysis made via a statistical package of social sciences (SPSS) version 23. The research and ethical committee approved the study. Results The prevalence of GT among Saudis in AlMadinah, Saudi Arabia, based on the Saudi population in 2022, is 1:10,000. One hundred twenty-five GT patients were studied: 67 (54%) females and 58 (46%) males. The median age at the time of the report was 16.5 (10 days to 56 years). Ninety-nine (79%) patients have type 1 GT. Out of 108 (86%) whose Consanguinity status was recorded, 106 (98%) GT patients are products of consanguineous marriage. Seventy (65%) patients were products of first-degree cousin parents. Family history of GT was reported in 107 (86%) cases. Twenty-five families have more than one sibling (2-5) with GT. A single tripe has 50 members with GT. The median age at presentation is 2 years (7 days to 11 years). The most common symptoms are gum bleeds, Epistaxis, and Bruises. Eighteen (16%) patients suffered from a severe bleeding course (defined as bleeding continued for more than 3 days, drop in hemoglobin for more than 2 g / L from the baseline, or needed admission to the intensive care unit). Forty (35%) patients had a moderate course (bleeding requiring hospital admission and not filling the criteria for severe one). Fifty-seven (50%) patients had a mild clinical course (bleeding can be stopped at home). Eighteen (17%) patients had bleeding episodes more than once a month, 34 (32%) had six or fewer bleeds per year, and 57 (52%) patients had one bleeding episode per year. Menorrhagia affected 35 (86%) ladies and girls. Hormonal therapy has been used at least once in their lives to interfere with the menstrual cycle in 39 (95 %) patients. Twenty-eight pregnancies were reported, producing 24 babies (13 girls and 11 boys). A postpartum hemorrhage took place after 18 deliveries (75%). Mild to moderate pregnancy-related bleeding occurred in 7 pregnancies. Iron deficiency anemia was found in 66 (66%) patients out of 100 whose iron status was reported. Eighteen mutations have been identified: 15 mutations in the ITGA2B gene and 3 mutations in the ITGB3 gene (table 1). The mutation ITGA2B:exon13:c.1210+5G&amp;gt;A is a novel mutation found only in one tripe, where all 12 GT patients in this tripe carry this mutation. The mutation ITGA2B: exon20:c.1879-2A&amp;gt;G is the most frequent mutation affecting one tribe only, and all 42 GT patients who descend from this tribe carry this mutation. The second frequent mutation is ITGB3:exon13:c.2112delC, involving 28 GT patients. Though we could not find a correlation between genotype and phenotype, we noticed GT patients carrying mutations exon13:c.2112delC and exon13:c.1210+5G&amp;gt;A running a more severe clinical course compared to patients affected by the mutation ITGA2B: exon20:c.1879-2A&amp;gt;G. Anti-platelet antibodies have been detected in 11 (9%) patients, 2 of them during pregnancy. Apart from Menorrhagia, 10 out of 15 GT patients running severe clinical courses improved when they reached puberty. Conclusions GT is the commonest bleeding disorder in AlMadinah, Saudi Arabia, with a prevalence of 1:10,000. With a high rate of menorrhagia and IDA. The high rate of consanguineous marriage could be a reason for the high prevalence of GT.

Understanding the Disease Burden of Severe Von Willebrand Disease in a Resource Poor Country: An Indian Cohort Study

Background : The national economic status impacts identification of rare diseases which also reflects access to standard healthcare infrastructure.Though VWD is the commonest bleeding disorder, the disease remains under-recognized and underdiagnosed in India due to its phenotypic and clinical heterogeneity and the need for multiple and complex diagnostic tests. The hospital based data shows a contrasting prevalence to that of the west, in that type 3 is the commonest subtype followed by type 1 and type 2 subtype. The treatment patterns of VWD too differs between countries and geographical regions. Unlike hemophilia, the bleed patterns and treatment details are not very well defined. There is a need to identify the unmet needs in the area of diagnosis and management. Aim : The study is aimed to increase understanding of clinical manifestations, treatment practices along with Quality of life (qoL) in severe VWD patients from India Methods : This is a cross-sectional, patient reported retrospective analysis of severe VWD patients from India. The eligibility criteria is confirmed diagnosis of VWD with documented laboratory reports. An informed consent was taken from each patient before participation in the study and the study was initiated after obtaining approval from Institute Ethics Committee. The EQ-5D instrumentswere used to measure patient reported health related QoL. Results : A total of sixty two severe VWD patients were included in the present study. Mean age of the patients was 23.8 years (SD + 13.2 years); median 22 years (range 5-56 years) and the mean age of diagnosis was 4.9 years (SD + 6.9 years). The mean ABR was 12.6 (SD + 8.9). Twenty five patients (40%) had a positive family history and 37 (60%) of the patients reported parental consanguinity. Common bleeding symptoms were of mucocutaneous nature like epistaxis, ecchymoses and gingival bleed .Prolonged bleed from cuts was reported by 46 (74%) of patients and 14 out of 27 women (52%) in the reproductive age group complained of severe menorrhagia ( Table 1). In approximately 76% of the patients, the major treatment product was intermediate purity FVIII whereas 3 patients were still being treated with either cryprecipitate or fresh frozen plasma. The EQ-5D data reported a worse health state in the EQ-5D-5L dimensions of pain/discomfort (34% moderate and 8% moderate to severe problems),usual activities (21% moderate problems and 3% moderate to severe problems), self-care (21% moderate problems) and anxiety (moderate 21% and 2% moderate to severe).There were two deaths due to bleeding in the previous 10 years . Conclusion : In a resource limited country like India, type 3 is the predominant subtype presenting in the treatment centers. All patients had mucocutaneous bleeding with epistaxis being the predominant manifestation, but joint bleeding is also not uncommon. The study also reveals much lower than optimal QoL in all patients, mobility being the least affected parameter. Despite India being the pharmacy of the world, these conditions are neglected by stakeholders.

Bleeding Disorders in Women- a Unique Challenge Requiring a Unique Approach

Introduction: Bleeding disorders in women, particularly in developing countries, have been largely neglected due to various factors such as social stigma, limited access to comprehensive laboratory facilities, and the misconception of physiological bleeding during menstruation. Heavy menstrual bleeding (HMB) is a common symptom in women, and a significant percentage of cases may be associated with inherited bleeding disorders. However, the underreporting and underdiagnosis of these conditions remain prevalent, partly due to the stigma surrounding menorrhagia, leading to delayed medical care seeking. This study aims to explore the clinical and laboratory profiles of females with bleeding disorders who presented to our institute. Methods: A consecutive series of female patients referred to our advanced coagulation laboratory for complete workup with bleeding manifestations or abnormal screening coagulogram over a 59-month period (September 2018 to July 2023) were assessed. Patients with liver disease, chronic inflammation, or on anticoagulation therapy were excluded. Data on age at presentation and diagnosis, ISTH BAT score, annual bleeding rate, family history, hospitalizations, surgical interventions, and follow-up were retrospectively retrieved from our database. Heavy menstrual bleeding was subjectively defined based on specific criteria. Various laboratory parameters were analyzed for all patients. Data were presented using median/range and percentage. Missing data were not imputed, and MS Excel 2016 was used for analysis. Results: Over the study duration, 1019 patients were evaluated at our institute, with 488 females (47.9%) and 531 males (52.1%). Among the 235 patients (23%) diagnosed with bleeding disorders, 87 (37%) were women. The median age at diagnosis was 29 years (range: 9 months-84 years), while the median age of first symptom was 15 years (range: 7 days-81 years). The median time interval between presentation and diagnosis was 8 years (range: 6 months-30 years). The most common presenting symptom was HMB (34.4%), followed by ecchymotic patches (17.2%) and epistaxis (16%). Significant ISTH BAT scores (&amp;gt;6) were found in 17 patients (19.5%). A family history of bleeding was observed in 4.5% of patients, with 3 of them born to consanguineous parents. Incidentally detected abnormal screening coagulogram was present in 12.6% of patients. The most common bleeding disorder diagnosed was VWD (35.6%), followed by Factor VII deficiency (13.8%), Vitamin K dependent coagulation factor deficiency (9.2%), and Acquired Haemophilia A (9.2%). Intracranial bleeding (4.5%) was primarily associated with specific deficiencies. No carriers were detected in the study. Conclusion: Addressing bleeding disorders in women requires specific attention. The ISTH BAT score proved to be a user-friendly yet powerful tool, with 19.5% of patients showing significant scores that prompted comprehensive diagnostic workup. This study highlights the long latent period between the age of first symptom and the age of diagnosis, emphasizing the need to raise awareness among patients and primary physicians, especially gynaecologists. Menorrhagia starting from menarche was the most common bleeding symptom, emphasizing the importance of prompt and accurate diagnosis to prevent life-threatening bleeds. The consideration of acquired hemophilia A is crucial in cases of unexplained postpartum hemorrhage. Developing countries face additional challenges due to limited specialized laboratories, leading to outsourcing and increased testing costs. To improve diagnosis and care, early identification of female bleeders is essential, facilitated by outreach programs and advanced coagulation testing centers.

PATH-HHT, a Double-Blind, Randomized, Placebo-Controlled Trial in Hereditary Hemorrhagic Telangiectasia Demonstrates That Pomalidomide Reduces Epistaxis and Improves Quality of Life

Introduction Hereditary hemorrhagic telangiectasia (HHT), the second most common bleeding disorder worldwide, affects 1 in 5000 people and is characterized by extensive formation of telangiectasia and arteriovenous malformations (AVM) in mucosa, lung, brain, and liver. The primary clinical manifestation is recurrent, often severe epistaxis which commonly results in iron deficiency anemia, emergency room visits, hospitalizations, and reduced quality of life (QOL). Though non-randomized and/or underpowered studies have suggested that systemic bevacizumab or thalidomide may be effective in treating HHT, there have been no pivotal studies and therefore no FDA or EMA approved therapies. Methods PATH-HHT was an NHLBI-funded, randomized, placebo-controlled clinical trial conducted at 13 centers in the US to determine the safety and efficacy of pomalidomide for bleeding in HHT. Pomalidomide was supplied by Celgene and Bristol Myers Squibb. Patients were randomized in a 2:1 ratio to receive pomalidomide 4 mg daily or matching placebo for 6 months. Dose reductions were allowed for toxicity. The primary endpoint was the change in the Epistaxis Severity Score (ESS), a well-validated bleeding score in HHT, from baseline (randomization) to the end of the six-month treatment period, analyzed using a mixed model for repeated measures with adjustment for baseline value, center, treatment, visit, and treatment by visit interaction. Key secondary endpoints included 1) change in the average daily self-reported epistaxis duration from the four weeks preceding the baseline visit to weeks 20-24 of treatment, 2) amount of parenteral iron infused or blood transfused, and 3) change in QOL measurements, including an HHT-specific QOL score. Results PATH-HHT opened in November 2019 and was closed to enrollment by the NHLBI in June 2023 after a planned 75% interim analysis met a prespecified threshold for efficacy. A total of 144 patients were randomized and treated (95 pomalidomide, 49 placebo). Early study discontinuation was 25% in pomalidomide: 14% AE, 11% withdrawn, 1 unrelated death, compared with placebo (4% withdrawn). Across groups, 8% were terminated after 12 weeks for early study closure. Participants included 48% females, 11% non-white race; mean (± SD) age was 58.8±12.2 years. The mean ESS at baseline was 5.0±1.5 (4.9 pomalidomide, 5.2 placebo), consistent with moderate to severe epistaxis. At 24 weeks, the ESS in patients treated with pomalidomide decreased by a mean [95% CI] of -1.84 [-2.24, -1.44] and in the placebo group decreased by -0.89 [-1.39, -0.39] (mean difference -0.95 [-1.58, -0.32], p = 0.003) (Figure, Panel A). Difference between groups was apparent by 12 weeks (mean difference -0.52, 95% CI [-1.04, -0.01], p = 0.045). The HHT-specific QOL score, which ranges from 0 to 16 with higher scores indicating more limitations, also decreased more in the pomalidomide (mean -2.6, 95% CI [-3.3, -1.9]) vs the placebo group at 24 weeks (mean -1.2, 95% CI [-2.1, -0.3], p = 0.015) (Figure, Panel B). Adverse events that occurred more in the pomalidomide group included mild to moderate neutropenia (45% vs. 10%), constipation/diarrhea (60% vs. 37%), and rash (36% vs. 10%). Venous thrombosis occurred in 2% of patients in each group. Conclusion PATH-HHT is the largest and the first adequately powered, randomized trial of systemic therapy in HHT. The study demonstrated a significant and highly clinically relevant reduction in epistaxis in pomalidomide-treated patients as well as an improvement in the HHT-specific QOL score. Pomalidomide may offer a novel approach to management of HHT. Since plasma was collected from patients in this study before and at the end of treatment, additional studies may identify biomarkers predicting pomalidomide responses.

Biomarker MSC-C5b-9-Guided Master Therapies for Resistant/Recurrent ITP: A Prospective, Randomized, Open-Label, Multicenter Trial

Introduction: Immune thrombocytopenia (ITP) is an acquired organ-specific autoimmune disorder and a common bleeding disorder that poses a considerable risk to human health. Steroids, as the first-line treatment, do not provide long-term relief. Our previous clinical trials have confirmed the efficacy and safety of all-trans retinoic acid (ATRA) in the treatment of ITP and identified that the biomarker MSC-C5b-9 may be a stratification marker for evaluating the efficacy of ATRA (Haematologica, 2019; Lancet Haematol. 2017; 2021). This research aims to develop a new treatment approach for steroid-resistant/recurrent ITP based on the marker MSC-C5b-9. Method: We conducted a prospective, randomized, open-label, multicenter trial to evaluate the efficacy and safety of ATRA combined with eltrombopag based on MSC-C5b-9 as a novel treatment for steroid-resistant/recurrent ITP. Following enrollment, all patients underwent bone marrow aspiration to assess MSC-C5b-9 levels. Subsequently, patients were randomly assigned in a 1:1 ratio to either the eltrombopag group or the eltrombopag + ATRA group. In both treatment groups, the initial dose of eltrombopag was 50 mg daily, with dose adjustments based on platelet levels. For patients assigned to the ATRA group, ATRA was given at a dose of 10 mg twice daily. Peripheral blood cell counts and adverse drug reactions were regularly monitored. The primary endpoint was the sustained response rate at 18 months after randomization, and secondary endpoints include Complete Remission, Partial Remission, Relapse rate, Early Response, Initial Response, Adverse Events, and Adverse Events graded using the National Cancer Institute Common Terminology Criteria (NCI CTCAE) v5.0 criteria. The study has been registered at clinicaltrials.gov. NCT05438875. Result: From March 2023 to July 2023, a total of 30 patients with steroid-resistant/recurrent ITP were enrolled in the study and randomized 1:1 to receive eltrombopag combined with ATRA (ATRA group, n=15, MSC-C5b-9 +6, -9) or eltrombopag alone (control group, n=15, MSC-C5b-9 +6, -9) in 5 centers, and all enrolled patients were included in the intention-to-treat (ITT) analysis. In the ATRA group, the median age was 38 years (range, 29-64), consisting of 8 male patients. In the control group, the median age was 44 years (range, 23-75), consisting of 9 male patients. There were no statistically significant differences observed in the baseline clinical characteristics between the two groups. There was no difference in the bleeding score and ECOG score between the two groups (P=0.717; P=1.000). The median platelet count was comparable between the ATRA group and the control group (17 (1-28) vs. 16 (2-26), P=0.850). Comorbidities at random, such as hypertension, were comparable between the two groups (26.7% (4/15) vs. 33.3% (5/15), P=1.000). Combined autoantibody abnormalities were compared between the two groups (6.7% (1/15) vs. 6.7% (1/15), P=1.000). The rate of Early Response in the ATRA group was higher than that in the control group, but the difference was not significant (73.3% (11/15) vs. 53.5% (8/15), P=0.256). As of July 29, 2023, a total of 24 patients had been enrolled for a duration exceeding 4 weeks. Similarly, the Initial Response rate was higher in the ATRA group, but no significant difference was observed between the two groups (84.6% (11/13) vs. 63.6% (7/11), P=0.357). Nevertheless, it is noteworthy that the 4-week CR rate in the ATRA group was higher than that in the control group (76.9% (10/13) vs. 36.4% (4/11), P=0.045). What's more, the overall efficacy of the ATRA group was better than that of the control group. The mean platelet count at weeks 1, 2, 3, and 4 posttreatment, along with the mean maximum platelet count posttreatment, exhibited higher values in the ATRA group than in the control group; however, these disparities did not reach statistical significance (P=0.310; P=0.568; P=0.779; P=0.618; P=0.355). ATRA was well tolerated, and only one patient developed grade I dry mouth and headache, which improved after dose reduction. There was no difference between the ATRA and control groups in terms of medication adverse effects (13.3% (2/15) vs. 13.3% (2/15), P=1.000). Conclusions: Eltrombopag plus ATRA is an effective and well-tolerated approach for treating steroid-resistant/recurrent ITP. Eltrombopag plus ATRA can enhance patients' complete remission and is well tolerated.

Longitudinal Patient Analysis Suggests a Positive Correlation of IL-10/IL-6 and FVIII Inhibitor Amount

Hemophilia A (HA) is the most common X-linked bleeding disorder caused by a deficiency in coagulation factor VIII (FVIII). Inhibitor development in up to 30% of HA patients is the most challenging complication in HA treatment and has been associated with several patient-related risk factors such as gene mutation and residual plasma factor VIII concentrations. Treatment related risk factors are under debate. However, HCV infections were recently shown to correlate with low level inhibitor abundance, potentially as a result of chemokine and cytokine regulation. Therefore, the aim of this study was to evaluate a potential connection between proinflammatory cytokine levels and FVIII-specific B cell responses in HA patients without infections, but with other comorbidities that might modulate cytokine levels. Thus, several clinical parameters and concentrations of plasmatic proinflammatory cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12p70, TNF, IFNa, IFNg, TNFa, MCP-,1 IL-17A, IL-18, IL-23 and IL-33) were quantified from different patient samples. At first, the influence of proinflammatory cytokines on inhibitor development was assessed in a HA patient, who had an intron 22 inversion and was also diagnosed with type 1 diabetes. Prophylactic treatment began at the age of 9 months with 30IU/kg Octanate, and after four days of exposure, the formation of inhibitors was initially detected. Longitudinal cytokine analysis in plasma samples of that patient revealed differential regulation patterns of cytokines. IL-1b, IFNg, TNFa, IL-6, IL-10 and IL-12p70 tended to increase upon inhibitor occurrence, whereas other cytokines remained unchanged (MCP-1, IL-8, IL-17A, IL-18 and IL-23) or decreased (IFNa2 and IL-33). Next, a correlation analysis was performed, assuming that proinflammatory cytokines might stimulate B cells to produce antibodies. This analysis involved all cytokines that were found to be elevated upon inhibitor formation. The comparison of clinical and laboratory data from that patient revealed a strong association of inhibitor levels and IL-10 expression (Pearson r = 0,9391; R squared = 0,8818) as well as with IL-6 (Pearson r = 0,9290; R squared = 0,8630). Furthermore, a modest correlation was observed for IL-1b (Pearson r = 0,5277; R squared = 0,2785), IFNg (Pearson r = 0,3413; R squared = 0,1165), IL-12p70 (Pearson r = 0,3547; R squared = 0,1258), and TNFa (Pearson r = 0,3070; R squared = 0,09422). Other proinflammatory cytokines with a rather stable profile upon inhibitor initiation like MCP-1 (Pearson r = -0,06810; R squared = 0,004638) and IL-18 (Pearson r = 0,2245; R squared = 0,05042) seemed not to be directly correlated with inhibitor occurrence. Finally, we aim to investigate the potential impact of IL-10 and IL-6 on inhibitor production and/or FVIII immune tolerization across various patient groups and conditions. Therefore, we will compare patients with detectable inhibitor titers, those who have successfully eradicated inhibitors, and individuals without inhibitor titers (with normal recovery). Preliminary data suggest a positive correlation between both cytokines and active inhibitor presence. However, to reach a definitive conclusion, the sample size will be/should be increased.

Impact of Anticoagulant Function By the Addition of Heparinoid in Vitro in the Plasmas from Patients with Hemophilia and Von Willebrand Disease

Background: Heparinoid (Hirudoid ®) is a local anticoagulant preparation as skin application that relieves pain and inflammation with addition to promoting healing in superficial thrombophlebitis and bruising. Heparinoid is mainly composed of chondroitin sulfate and has high moisturizing ability due to the large number of hydrophilic group. Thus, it is used as topical treatments for sebum deficiency in Japan. Since heparinoid has a structure similar to heparin, the package insert states the contraindication for hemorrhagic diseases such as hemophilia and von Willebrand disease (VWD) in Japan. Hemophilia A and B (HA/HB) are inherited bleeding disorders caused by a defect in factor (F) VIII and FIX coagulant protein, respectively. Based on its activity levels, the clinical severity is classified as severe (&amp;lt;1 IU/dL), moderate (1-5 IU/dL), and mild (&amp;gt;5-40 IU/dL). VWD is the common congenital bleeding disorders and is caused by a deficiency of von Willebrand factor (VWF). VWD is classified into partial deficiency (type 1), qualitative deficiency (type 2), and complete quantitative deficiency (type 3) of VWF, based on the VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) level. In the clinical practice, there are cases of hemorrhagic patients using heparinoid at the discretion of their families. However, the influence of heparinoid on coagulant function in human subjects remains to be investigated, and it is unclear if the patients with hemophilia and VWD can use heparinoid safely. Aim: To examine the impact of anticoagulant function of heparinoid in vitro in the plasmas from patients with hemophilia and VWD. Methods: The maximum blood concentration from absorbed heparinoid was estimated to be 2.5 µg/mL, based on the previous report, when heparinoid was applied to the skin as stated in package insert. Heparinoid (0-6.5 µg/mL) or unfractionated heparin (0-0.6 IU/mL) were added to normal plasma (NP), followed by measuring activated partial thromboplastin time (aPTT) by one-stage clotting assay. A modified clot waveform analysis (CWA) using an aPTT reagent were performed on the CS-2400™ (Sysmex), followed by measuring clotting time (CT) and adjusted maximum coagulation velocity (Ad|min1|). Heparinoid was also added to the patients' plasmas with HA, HB, or VWD, followed by CWA assessment. The CT and Ad|min1| of 20 healthy individuals were 31.1±0.1 sec and 6.90±0.05 (median±SEM). Results: aPTT and CT values in NP by the spike of heparinoid were prolonged and Ad|min1| was decreased dose-dependently. The addition of 2.5 µg/mL heparinoid showed that aPTT (34.3 sec; 1.2-fold of control (no heparinoid)), CT (36.3 sec; 1.2-fold of control), and Ad|min1| (9.5; 0.96-fold of control) were comparable to the effect of ~0.2 IU/mL heparin, suggesting that heparinoid exhibited slight anticoagulant effect for NP. To examine the effect of heparinoid on HA/HB plasmas, recombinant (r) FVIII or rFIX (0-50 IU/dL) were added to FVIII- or FIX-deficient plasmas (3 lots each) together with heparinoid (0-6.3 µg/mL), respectively. The addition of heparinoid had prolonged the CT and decreased the Ad|min1| at each concentration of FVIII and FIX dose-dependently. The addition of 2.5 µg/mL heparinoid showed modest anticoagulant effect for HA and HB at each concentration of FVIII and FIX (CT; 1.3- and 1.5-fold of control, Ad|min1|; 0.82- and 0.87-fold of control). Next, the effect of heparinoid on the plasma from one VWD patient each with type 1 (VWF:Ag/VWF:RCo 28 IU/dL/26 IU/dL), type 2 (20 IU/dL/9 IU/dL), and type 3 (&amp;lt;2 IU/dL/&amp;lt;3 IU/dL) was assessed. The addition of 2.5 µg/mL heparinoid showed slight anticoagulant effect for each type of VWD (CT; ~1.3-fold of control, Ad|min1|; ~0.91-fold of control). Conclusion: The presence of heparinoid demonstrated mild anticoagulant effect in vitro in the plasmas of patients with hemophilia and VWD. It might be possible to apply the heparinoid-contained product as skin treatment for these patients.

Neurological Complications Associated with Hereditary Bleeding Disorders.

Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS) bleeding, of which intracranial hemorrhage (ICH) is the most dreaded complication. In this review, we will discuss the pathophysiology of specific hereditary bleeding disorders, namely, hemophilia A, hemophilia B, and von Willebrand disease (vWD); their clinical manifestations with a particular emphasis on neurological complications; a brief overview of management strategies pertaining to neurological complications; and a review of literature guiding treatment strategies. ICH is the most significant cause of morbidity and mortality in patients with hemophilia. Adequate control of bleeding with the administration of specific factors or blood products, identification of risk factors for bleeding, and maintaining optimal coagulant activity are essential for appropriately managing CNS bleeding complications in these patients. The administration of specific recombinant factors is tailored to a patient's pharmacokinetics and steady-state levels. During acute bleeding episodes, initial factor activity should be maintained between 80 and 100%. Availability of monoclonal antibody Emicizumab has revolutionized prophylactic therapies in patients with hemophilia. Management of ICH in patients with vWD involves using plasma-derived factor concentrates, recombinant von Willebrand factor, and supportive antifibrinolytic agents individualized to the type and severity of vWD. Hemophilia and vWD are the most common hereditary bleeding disorders that can predispose patients to life-threatening CNS complications-intracranial bleeds, intraspinal bleeding, and peripheral nerve syndromes. Early care coordination with a hematologist can help develop an effective prophylactic regimen to avoid life-threatening bleeding complications in these patients. Further research is needed to evaluate using emicizumab as an on-demand treatment option for acute bleeding episodes in patients with hemophilia.