Risk and Management of Intracerebral Hemorrhage in Patients with Bleeding Disorders

Intracerebral hemorrhage (ICH) is the most dreaded complication, and the main cause of death, in patients with congenital bleeding disorders. ICH can occur in all congenital bleeding disorders, ranging from mild, like some platelet function disorders, to severe disorders such as hemophilia A, which can cause catastrophic hemorrhage. While extremely rare in mild bleeding disorders, ICH is common in severe coagulation factor (F) XIII deficiency. ICH can be spontaneous or trauma-related. Spontaneous ICH occurs more often in adults, while trauma-related ICH is more prevalent in children. Risk factors that can affect the occurrence of ICH include the type of bleeding disorder and its severity, genotype and genetic polymorphisms, type of delivery, and sports and other activities. Patients with hemophilia A; afibrinogenemia; FXIII, FX, and FVII deficiencies; and type 3 von Willebrand disease are more susceptible than those with mild platelet function disorders, FV, FXI, combined FV–FVIII deficiencies, and type 1 von Willebrand disease. Generally, the more severe the disorder, the more likely the occurrence of ICH. Contact sports and activities can provoke ICH, while safe and noncontact sports present more benefit than danger. An important risk factor is stressful delivery, whether it is prolonged or by vacuum extraction. These should be avoided in patients with congenital bleeding disorders. Familiarity with all risk factors of ICH can help prevent occurrence of this diathesis and reduce related morbidity and mortality.

Cryptogenic oozers and bruisers

Bleeding disorders with normal, borderline, or nondiagnostic coagulation tests represent a diagnostic challenge. Disorders of primary hemostasis can be further evaluated by additional platelet function testing modalities, platelet electron microscopy, repeat von Willebrand disease testing, and specialized von Willebrand factor testing beyond the usual initial panel. Secondary hemostasis is further evaluated by coagulation factor assays, and factor XIII assays are used to diagnose disorders of fibrin clot stabilization. Fibrinolytic disorders are particularly difficult to diagnose with current testing options. A significant number of patients remain unclassified after thorough testing; most unclassified patients have a clinically mild bleeding phenotype, and many may have undiagnosed platelet function disorders. High-throughput genetic testing using large gene panels for bleeding disorders may allow diagnosis of a larger number of these patients in the future, but more study is needed. A logical laboratory workup in the context of the clinical setting and with a high level of expertise regarding test interpretation and limitations facilitates a diagnosis for as many patients as possible.

Comprehensive Multi-Parameter Characterisation of Circulating Extracellular Vesicles from Rivaroxaban-Treated VTE Patients Reveals Reduced Inflammation and Ameliorated Endothelial Dysfunction

Venous Thromboembolism (VTE) remains a significant cause of morbidity and mortality worldwide. Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties, however, these remain poorly characterized. Extracellular vesicles (EVs) are important circulating messengers regulating a myriad of biological and pathological processes and may be highly relevant to the pathophysiology of VTE as they reflect alterations in platelet and endothelial biology. However, the effects of Rivaroxaban on circulating pro-inflammatory EVs in VTE patients remain unknown. We hypothesized that rivaroxaban's anti-inflammatory properties are reflected upon differential molecular profiles of circulating EVs. Single-episode VTE patients anticoagulated with 20 mg Rivaroxaban or warfarin at a target INR of 2.0-3.0, respectively, who had commenced therapy no sooner than 3 months previously were recruited following informed written consent at the Mater Misericordiae University Hospital, Dublin, Ireland. Patient data including age, sex, BMI, prevalent risk factors and comorbidities were collected. Patients on warfarin therapy had a time in therapeutic range of at least 55% and an INR in target range at time of blood sampling. Exclusion criteria included known pro-inflammatory conditions, active malignancy, recurrent VTE, antiphospholipid syndrome, bleeding or platelet function disorders, use of anti-platelet drugs, and thrombocytopenia. To address the hypothesis, we firstly used a combination of Nanoparticle Tracking Analysis (NTA) and flow cytometry to comprehensively characterise differences in the concentration and size of small (0-200 nm) and large (200-1000 nm) circulating EVs, respectively. Statistical analysis revealed a trend towards reduced levels of circulating small and large EVs in Rivaroxaban-treated VTE patients compared with matched warfarin controls. Moreover, small and large EVs measured in the patients plasma correlated strongly and highly significantly (r=0.804, p<0.0001), indicating a concomitant decrease in both populations. As circulating EVs are considered pro-coagulant and pro-inflammatory, these results may point towards an ameliorated baseline pro-inflammatory state of VTE patients anticoagulated with Rivaroxaban. To further uncover Rivaroxaban-mediated alterations, we next compared proteomic profiles of circulating EVs. We robustly quantified over 300 vesicular proteins. Statistical analysis of the protein expression level using a student's t-test with a false discovery rate of 5% and a minimal fold change of 0.1 identified differential protein expression of a tightly regulated cluster of proteins involved in negative feedback regulation of inflammatory and coagulation pathways in Rivaroxaban-treated patients, which may in part contribute to the superior outcomes of Rivaroxaban-treated patients seen in recent clinical trials. Furthermore, we recently established that Rivaroxaban potentially ameliorates endothelial dysfunction in a cohort of non-valvular atrial fibrillation patients. Therefore, we aimed to also assess circulating markers of endothelial activation (Intercellular Adhesion Molecule 1 [ICAM-1] and Tissue Factor Pathway Inhibitor [TFPI]). Intriguingly, Rivaroxaban-treated patients exhibited an increase in plasma TFPI levels with a simultaneous decrease in soluble ICAM-1, potentially pointing towards ameliorated endothelial dysfunction in Rivaroxaban-treated VTE patients relative to warfarin. Collectively, we established that EV proteomic signatures are powerful biological sensors of Rivaroxaban's anti-inflammatory potential. Moreover, Rivaroxaban therapy may ameliorate endothelial dysfunction relative to warfarin. These findings are of translational relevance towards characterizing the anti-inflammatory and cardiovascular-protective mechanisms associated with Rivaroxaban therapy. Disclosures Kevane: Leo Pharma: Research Funding. Murphy: Bayer Pharma: Research Funding. Ni Ainle: Daiichi-Sankyo: Research Funding; Actelion: Research Funding; Leo Pharma: Research Funding; Bayer Pharma: Research Funding. Maguire: Bayer Pharma: Research Funding; Actelion: Research Funding.

Surgery-Associated Bleeding Risk in Patients with Platelet Function Disorders - a Cross Sectional Study with the American Thrombosis and Hemostasis Network Dataset (ATHNdataset)

Introduction: Platelet function disorders (PFDs) are a group of heterogenous bleeding disorders with varying bleeding phenotype. Intraoperative and post-operative bleeding are serious complications among patients with PFDs undergoing surgery. There are very few studies in literature that have specifically investigated surgery associated bleeding complications in PFDs. The aim of this study was to utilize a large national dataset to describe surgeries performed in patients with PFD, characterize the bleeding associated with these surgical procedures and outline the therapeutic approaches adopted. Methods: In this retrospective study, the ATHNdataset was queried for demographic data, PFD diagnosis, surgeries among patients with PFD, intraoperative and post-operative bleeding episodes and treatment. Descriptive statistics were used. The ATHNdataset captures information from patients with bleeding and clotting disorders from over 140 federally funded hemophilia and thrombosis treatment centers (HTCs) in the US. Patients authorize inclusion of their demographic and clinical information in this de-identified Health Insurance Portability and Accountability Act (HIPAA)-compliant data set. Results: From January 2010 to March 2020, the ATHNdataset captured 2767 patients with PFDs, of which 1769 (63.93%) were female and 998 (36.1%) were male, with 1393 patients between 0-18 years (50%) and 1374 (50%) adults >18 years. PFDs identified include 32 patients with Bernard Soulier syndrome (1.16%), 131 patients with Glanzmann thrombasthenia (4.7%), 4 patients with Gray platelet syndrome (0.14%), 29 patients with Hermansky Pudlak syndrome (1%), 1548 patients with storage pool deficiency (55.9%), and 1023 patients diagnosed as PFD (36.9%). A total of 3252 procedures were reported between 2010 and 2020; 1271 patients (46%) patients with at least one documented procedure. Figure 1 shows common procedures among patients with PFDs. Surgery-associated bleeding episodes (includes intraoperative and post-operative bleeds) were reported with 69 procedures (2.1%), which included intraoperative bleeds reported for 18 procedures (0.5%) and post-operative bleeds reported for 51 procedures (1.6%). Of the 60 procedures in patients with Glanzmann thrombasthenia, surgery-associated bleeding episodes were reported after 9 dental procedures (41%), 1 circumcision (25%) and 11 other surgeries/procedures (18.3%). Of the 6 procedures in patients with Bernard Soulier syndrome, no intraoperative or post-operative bleeding episodes were reported. Of 1688 procedures in patients with storage pool deficiency, surgery-associated bleeding episodes were reported after 26 dental procedures (1.5%) and 62 other surgeries/procedures (3.67%). No intraoperative or post-operative mortality was reported among these patients. Of 1272 patients who underwent at least 1 procedure, 646 patients (50.7%) received some form of treatment before/during/after a procedure. Among these 646 patients, 2794 exposure days of hemostasis medications were used before/during/after procedures. Among these, 49% were prior to the procedure, 0.7 % during the procedure and 49.5% after the procedure. Treatments used are shown in figure 2. Conclusion: Our study shows that patients with PFDs have a substantial risk of bleeding associated with surgery. Identifying the risk of bleeding by type and providing appropriate pre-surgical prophylaxis can decrease rates of surgery-associated bleeding in PFDs. Figure 1 Figure 1. Disclosures Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. Ahuja: Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: DSMB member ; XaTek, Inc: Patents & Royalties; Sanofi: Membership on an entity's Board of Directors or advisory committees.

A Multi-Institution Retrospective Study to Assess Bleeding Phenotype Among Patients with Platelet Function Disorders

Introduction: Platelet function disorders (PFD) clinically manifest with wide variability in mucocutaneous bleeding and significant hemorrhage post-surgery or trauma. The overall prevalence of PFD is not known, as there have not been large population-based studies. Treatment of these patients vary based on their bleeding phenotype. Additionally, the exact bleeding phenotype of many qualitative platelet defects are not well described in literature. This study aims to describe the bleeding phenotype among patients with different (PFD). Methods: This is a retrospective study among patients with PFD conducted at 3 Hemophilia Treatment centers - HOG Center for Bleeding and Clotting Disorders of CHOA, Children's Mercy hospital HTC and Rainbow babies & Children's hospital HTC. Institutional IRB approval was obtained at all 3 institutions. We collected data on demographics, bleeding symptoms at presentation, bleeding episodes, management of these bleeds over a 6-year time period (2015-2020). Results: We identified 131 patients with PFDs at 3 institutions. This included 67 males (51.2%) and 64 females (48.8%). Among 131 patients, 72 patients (55%) had a defect in platelet agonist interaction/receptor defect (ADP/Epinephrine/Collagen/TXA2/Arachidonic acid), 37 patients (28.2%) had delta storage pool defect, 8 patients (6.1%) had Glanzmann thrombasthenia, 7 patients (5.3%) had a platelet release defect, 3 patients (2.3%) with an alpha granule defect, 2 patients (1.5%) with Bernard Soulier syndrome and 1 patient (0.76%) with Wiskott Aldrich syndrome. The most common bleeding symptoms at presentation were epistaxis (40.4%), followed by easy bruising (31.3%), heavy menstrual bleeding (15.2%), gum bleeding (6.87%) and gastrointestinal bleeding (4.58%). From 2015-2020, a total of 162 bleeds were documented, and 68 patients (51.9%) with at least 1 documented episode of bleeding. 67.2% of these bleeds were spontaneous, 12.3% were secondary to trauma, 4.9% after a dental procedure, 2.5% after surgery and 0.6% after child birth. The most common type of bleeding episode in diagnosed patients included epistaxis (50%), heavy menstrual bleeding (17.9%), skin/soft tissue bleed (5.5%), gastrointestinal (5.5%) and dental/tooth related (4.9%). 93 bleeding episodes (57.4%) required some form of treatment in various settings - home (73%), clinic (15%), emergency room (7.5%), hospitalization (14%) and ICU stay (2%). Treatments included antifibrinolytics (68.8%), recombinant factor VIIa (11.8%), desmopressin (9.6%), hormonal therapy (9.6%) and platelet transfusions (5.3%). Conclusions: Our study helps characterize the bleeding phenotype and management in patients with various PFD. This data is crucial in understanding the burden of illness among different types of PFD, and to understand health care utilization to better serve the needs of these poorly characterized patients. Disclosures Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. Silvey: Genentech: Speakers Bureau; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees. Ahuja: XaTek, Inc: Patents & Royalties; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: DSMB member ; Genentech: Membership on an entity's Board of Directors or advisory committees.

Unique case of 19p13 syndrome with storage pool disease

Introduction/Objective Microdeletion of a region of the short arm of chromosome 19 results in a very rare syndrome called 19p13.3 deletion syndrome, which manifest itself in developmental delay as well as structural abnormalities such as facial dysmorphism and macrocephaly. Methods/Case Report We present a case of 14-month-old patient, born at term and was large for her gestational age. She had dysmorphic facial features including posterior cleft palate for which, she required placement of G-tube. Post-delivery, she experienced respiratory distress as well as hypoglycemic episodes. Over the period of time, her mother also noticed occasional bleeding through her gums with teething. Genetic workup was performed, which revealed 2.4 Mb of microdeletion at chromosome 19 region p13.3, including deletion of PIAS4, MAP2K2, GNA11, TBXA2R, RAX2 genes. TBXA2R mutation is associated with bleeding disorder due to a defect in platelet aggregation. The mutation in TBXA2R can lead to platelet type 13 bleeding disorder. For this purpose, a platelet aggregation study was performed to evaluate platelet function disorders. However, the result of the platelet aggregation study was inconclusive as it showed decrease responses to all agonists including arachidonic acid, epinephrine, ADP, collagen and ristocetin. Further work-up by electron microscopy (EM) of platelets (PL) revealed a significant decrease of delta granules (DG) (0.89 DG/PL, normal 4-6 DG/PL), consistent with delta granule storage pool deficiency (δ-SPD). Other abnormalities observed by EM included occasional gray platelets, platelets with immature and/or decreased numbers of α-granules, and rare giant α-granules. Results (if a Case Study enter NA) NA Conclusion To the best of our knowledge, no other case of 19p13.3 microdeletion syndrome with δ-SPD and associated abnormalities in α-granules has previously been described in the literature. Although it is unclear if there is any relationship between δ-SPD and 19p13.3 deletion syndrome, further investigation is warranted.

Platelet storage pool disorder in pregnancy: Utilising thromboelastography to guide a risk-based delivery plan

We present a case of a 33-year-old woman in her third pregnancy diagnosed with platelet storage pool disorder who had previously suffered two postpartum major obstetric haemorrhages. Platelet storage pool disorder is a rare bleeding disorder where the platelet count is normal but platelet function is impaired due to deficiency of dense granules. A peripartum plan devised by an extensive multi-disciplinary team using principles for managing other bleeding and platelet function disorders helped minimise her risk of major haemorrhage. We also describe how point-of-care thromboelastography can help guide management and enable an individualised risk-benefit discussion with the woman about her anaesthetic choices.

Women and bleeding disorders: diagnostic challenges

Women with bleeding disorders suffer from multiple bleeding symptoms, including easy bruising, epistaxis, bleeding from minor wounds and the oral cavity, and bleeding after dental work or surgery. However, women with bleeding disorders especially suffer from gynecologic and obstetrical bleeding. These symptoms often are not recognized as abnormal, and many women are left undiagnosed and without access to appropriate medical care. Additional challenges to diagnosing women with bleeding disorders include lack of access to appropriate laboratory testing and issues around disease classification and nomenclature. Efforts have been undertaken to address these challenges, including the development and validation of bleeding assessment tools and strategies to clarify diagnostic thresholds and algorithms for von Willebrand disease (VWD) and platelet function disorders. Efforts to improve communication with the nomenclature used for hemophilia carriers are also underway.