Significant Bleeding History Research Articles

6705 Sheehan syndrome: a case report

Abstract Disclosure: F.S. Rodrigues: None. C.C. Silva: None. W. Da Silva: None. T.M. Caldas: None. L. Rocha: None. Introduction: Sheehan's Syndrome, or postpartum hypopituitarism, is characterized by hyperplasia and an increase in the number of prolactin-secreting cells, secondary to a major hemorrhagic event occurring during or after childbirth. In this situation, the anterior pituitary gland can increase in size and suffer ischemia due to vascular hypoflow. Consequently, there is low production of one or more of the hormones produced by the gland, which can generate heterogeneous clinical presentations. As a preventive treatment, polytransfusion is recommended in cases of large hemorrhage. OBJECTIVE: To present a case of Sheehan’s Syndrome, which developed after a birth complicated by a major hemorrhagic event, even after receiving polytransfusion. CASE REPORT: A woman, 45 years old, being monitored at the endocrinology outpatient clinic for 2 years. As a history, there was a severe hemorrhage during her cesarean section, which occurred 30 years ago, in which she received a blood transfusion of a total of 1.2 liters of packed red blood cells. 7 years ago, she was diagnosed with hypothyroidism and 2 years ago with hyperprolactinemia. In 2022, she was also diagnosed with adrenal insufficiency. At that time, she underwent a magnetic resonance imaging (MRI) scan of the sellaturcica region, which was found to be partially empty. The patient's recent exams showed TSH: 3.15 μUI/mL (0.4-4.0); Free T4: 0.88 ng/dL (0.93-1.7); Cortisol 8h: 8 μg/dL (5-25); LH: 15 mIU/mL (1.1-14.7); FSH: 43 mIU/mL (2.8-9); Estradiol: 8 ng/dL (12.4-398); Prolactin: 28 ng/mL (1.9-25), basal GH 0’ 0.054/30’ 2.51/60’ 2.48/90’ 3.74 ng/mL (up to 10), ACTH 17 pg/mL (up to 46). Since then, she has been undergoing endocrinological monitoring for hormone replacement therapy to treat the hormonal changes caused by late-diagnosed Sheehan Syndrome. DISCUSSION: Sheehan's Syndrome is a rare disease, characterized by low blood flow and necrosis of the pituitary gland due to postpartum hemorrhage. The diagnosis results from obtaining a good clinical history associated with hormonal levels. This patient presented significant bleeding after cesarean section requiring transfusions. However, despite transfusions, the patient developed hypothyroidism, hyperprolactinemia, and adrenal insufficiency. The MRI confirmed the suspected diagnosis, showing the partially empty sellaturcica. Conclusion: The diagnosis of Sheehan Syndrome is based on very broad clinical manifestations, with MRI of the sellaturcica contributing to confirming the diagnosis. Although the preventive treatment is blood transfusion, the patient developed the disease, highlighting the need for continued monitoring of pregnant women with a history of significant bleeding during childbirth. Therefore, outpatient monitoring of the patient is necessary with a focus on hormonal levels so that clinical complications are avoided. Presentation: 6/2/2024

Direct Oral Anticoagulants in Older and Frail Patients with Atrial Fibrillation: A Decade of Experience.

Both the prevalence of atrial fibrillation (AF) and its subsequent use of direct oral anticoagulants (DOACs) are rapidly increasing in patients of older age. In the absence of contra-indications, guidelines advocate anticoagulation based on the CHA2DS2-VASc score for all AF patients aged 75 and above. However, some practitioners are hesitant to prescribe anticoagulants to older and frail patients due to perceived elevated bleeding risks. This review delves into the comparative treatment outcomes of DOACs versus vitamin K antagonists (VKAs) in older patients with AF, particularly focusing on those of advanced age, frailty, increased risk of falling, chronic kidney disease (CKD), or with a history of major bleeding. Additionally, considerations on the use of off-label DOAC doses, the role of left atrial appendage (LAA) closure and future developments in factor XIa-inhibitors will be discussed. While strong evidence supports the use of DOACs in the vital older patients with nonvalvular AF, it remains scant in frail patient groups. There is some evidence from non-randomized studies suggesting that the effect of DOACs compared with VKAs is consistent between frail and nonfrail patients. However, recent findings from a single randomized trial showed increased bleeding risks but comparable thromboembolic outcomes in frail individuals switching from VKAs to DOACs. In patients with an increased risk of falling, data suggest no relevant interaction of increased risk of falling on the effectiveness and safety of DOACs compared with warfarin. Resuming oral anticoagulants in patients with Af after major bleeding seems to be beneficial. Off-label low-dose DOAC is often prescribed to patients who were underrepresented in larger randomized trails because of an elevated risk of bleeding or overexposure to DOACs, but its effect on clinical outcomes remains uncertain. DOACs are the recommended oral anticoagulant for vital older patients with AF. The scarcity of data backing DOAC use in frail individuals, those with renal impairments, or significant bleeding history underscores the necessity for further investigation. However, existing evidence suggests at least similar effectiveness and safety and potential benefits for DOACs in these patient subsets. Therefore, there is no reason to suggest these patients should be treated differently than the established guidelines regarding anticoagulation.

Inadvertent prolapse of a huge cervical fibroid mimicking acute uterine inversion: A case report

Prolapse of cervical fibroid is a rare but life threatening occurrence. This complication may occur early in some patients while in others it may follow complications like constipation, difficulty in micturition to mention a few. A 47 +o year old Para o lady presented to the Accident and Emergency Unit of our hospital with a two(2) day history of a huge mass protruding per vagina and a history of significant bleeding per vagina. Packed Cell Volume was 19% on admission and she had Four(4) units of blood transfused. She subsequently had examination under general anaesthesia and cervical myomectomy was done. Her Post Operative clinical state was satisfactory.

The Relationship between Low Von Willebrand Factor, Type 1 Von Willebrand Disease and Ageing - Novel Insights from the Lovic and Win Cohort Studies

Introduction For many years, there has been debate about how to optimally diagnose type 1 VWD. Initial guidelines proposed that only individuals with plasma VWF levels < 30 IU/dL should be diagnosed with ‘type 1 VWD’. This was revised in recent ASH/ISTH/WFH/NHF panel which recommended that patients with a significant bleeding history and plasma VWF of 30-50 IU/dL should also be diagnosed with type 1 VWD, as opposed to the discrete ‘Low VWF’ entity proposed in previous guidelines. In this study, we investigated whether Low VWF is a discrete clinical entity, or whether it is instead part of an age-dependent type 1 VWD evolving phenotype. Methods We utilized datasets from two renowned national cohort studies - the Low VWF in Ireland Cohort (LoVIC) and Willebrand in the Netherlands (WiN) studies. In the LoVIC study, patients had a personal bleeding history and historically lowest VWF levels in the 30-50 IU/dL range. In the WiN study, patients had either a personal bleeding history or positive family history, combined with historically lowest VWF levels ≤ 30 IU/dL. Based upon levels at study inclusion versus original diagnosis, WiN patients were categorized into three groups - (i) patients with persistent VWF levels <30 IU/dL; (ii) patients with partial correction in VWF levels into the range of 30-50 IU/dL; and (iii) patients with normalization of VWF levels > 50 IU/dL. The FVIII:C/VWF:Ag ratio was used to assess the synthesis/secretion of VWF and the VWFpp/VWF:Ag ratio was used to assess the clearance of VWF. Results In total, 565 patients were included (403 WiN patients with type 1 VWD and 162 LoVIC patients with Low VWF). Mean age at diagnosis was significantly increased in the LoVIC cohort compared to the three WiN subgroups (32.5 years versus 23.3 years, 26.5 years and 25 years respectively; p<0.001). Conversely, there was no difference in age at time of enrollment into both national studies (p=0.532). To assess the significance of age, we first investigated how plasma VWF:Ag varied over time in WiN type 1 VWD patients compared to the LoVIC cohort. Among the total WiN cohort (with initial VWF levels < 30 IU/dL), 47% of subjects (n=188) had VWF levels that remained < 30 IU/dL despite advancing age. Conversely, 30% of type 1 VWD patients (n=121) increased their plasma VWF levels into the Low VWF range (30-50 IU/dL) over time, whereas 23% (n=94) had age-dependent increments that led to complete normalization in VWF levels > 50 IU/dL. Similarly, 39% (n=63) of patients from the LoVIC study had normalization of VWF levels over time. Crucially, we observed that VWF:Ag in Low VWF patients clearly overlapped with those in normalized (> 50 IU/dL) type 1 VWD subjects, indicating that the LoVIC cohort is a subgroup within the WiN normalized subgroup (Figure 1). To further investigate this concept, we performed multiple regression analysis. Importantly, we observed that plasma VWF:Ag in the LoVIC cohort and the WiN normalized (> 50 IU/dL) subgroup would have not been different had they been diagnosed at the same age (difference of β=0.00 (95% CI -0.03 to 0.04)). Cumulatively, these results indicate that significant heterogeneity exists amongst type 1 VWD patients with respect to the effect of ageing on their plasma VWF levels. In addition, our findings demonstrate that because of age-dependent increases in plasma VWF:Ag, the majority of Low VWF patients would have been diagnosed with type 1 VWD had they undergone assessment earlier in life. Consistently, no difference in prevalence of VWF mutation (36.4% vs 22.6% respectively, p=1.000), FVIII:C/VWF:Ag ratio (1.24 ±0.24 vs 1.46 ±0.27 respectively, p=0.444) or VWFpp/VWF:Ag ratio (1.36 ±0.99 vs 1.75 ±0.38 respectively, p=1.000) was found between LoVIC and normalized WiN patients (Figure 2). Contrarily, WiN patients with persistent VWF levels <30 IU/dL had more often VWF gene variants (93.0%), higher FVIII:C/VWF:Ag ratio (2.65 ±1.62) and higher VWFpp/VWF:Ag ratio (6.14 ±7.05) compared to the other groups (Figure 2, p<0.001). Conclusion Our findings clearly demonstrate that Low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype, as demonstrated by the same VWF levels throughout life, genetic background and pathophysiology. This study has direct consequences for VWD diagnosis, the overall understanding of type 1 VWD as an evolving disease and for patients with low VWF/type 1 VWD.

Evaluation of adolescents with heavy menstrual bleeding using the International Society of Thrombosis Haemostasis- Bleeding Assessment Tool and The Pediatric Bleeding Questionnaire scores.

Heavy menstrual bleeding (HMB) is a common condition in adolescents. However, bleeding disorders are known to be one of the causes of HMB in adolescent girls, so they should be considered. Simple methods that can be used in primary health care are needed to determine whether patients have bleeding disorders. The aim of this study was to evaluate the bleeding score of patients admitted with HMB and to determine the diagnostic value of patients who were symptomatic but whose initial hemostatic tests were normal. A total of 113 adolescents with HMB and 20 healthy adolescent girls were included in the study. The Pediatric Bleeding Questionnaire (PBQ) and the International Society of Thrombosis Haemostasis-Bleeding Assessment Tool (ISTH-BAT) were used for evaluation. Overall, approximately 18% (n= 20) of the adolescents in the study were diagnosed with a bleeding disorder. The cut off value for the `clinically significant bleeding score` was found to be 3.5. The PBQ and ISTH-BAT can help distinguish a significant bleeding history from an otherwise trivial bleeding and can be included in the algorithm for the primary care of adolescents with HMB with suspected bleeding disorders.

Follow-up and Evaluation of the Efficacy of the Hemostatic Treatment in Congenital FVII Deficiency during Development of Inhibitor

Introduction The development of inhibitors is an extremely rare complication in patients with factor (F)VII deficiency treated with replacement therapies such as recombinant activated FVII (rFVIIa), and represents a major therapeutic challenge in the treatment of this disorder. When inhibitors result in loss of response to high doses of rFVIIa, activated prothrombin complex concentrate (aPCC) is often used as an alternative treatment for these patients. The use of high-dose rFVIIa or aPCC might be accompanied by an increased risk of thromboembolic events, so it is important monitoring properly the effect of the hemostatic treatment Here we describe the therapeutic management and follow-up of a patient with elevated inhibitor titres, resistant to rFVIIa treatment who switched to prophylaxis with aPCC, using several global coagulation tests. Methods The coagulation status of the patient and the reponse to in vitro spiking of different doses of rFVIIa or aPCC were assessed with several global tests: Prothrombine time (PT) was tested using HemosIL®RecombiPlasTin 2G. Clot formation was evaluated with Rotational Thromboelastometry (ROTEM®) using blood with CTI (to inhibit contact activation) and activated with a low amount of Tissue Factor (TF) as trigger (dilution 1:50,000 of EXTEM reagent). The thrombin generation (TG) was tested with the Calibrated Automated Thrombogram (CAT) system using plasma collected with CTI and activated with 1 pM TF plus phospholipids (PPP-Low®, Stago). Thrombus formation under flow conditions was assessed with the Total Thrombus-formation Analysis System (T-TAS®) in AR-chips coated with collagen and thromboplastin. The Area under the flow pressure curve (AUC) was calculated over 30 min after starting. Results Three year-old girl affected by severe congenital FVII deficiency (FVII 9.1%) with significant severe bleeding history (spontaneous intracranial hemorrhage at 1st month of life). Since then she is in prophylaxis treatment with rFVIIa. At 6 months of life she developed an inhibitor (9.8 BU). Despite prophylaxis she presents frequent spontaneous mucocutaneous bleedings. When she was 2 years old she needed to be admitted at hospital because of port-A-Cath infection. Due to the administration of intensive treatment with rFVIIa during admission she developed thrombosis of peripheral venous access, so prophylaxis treatment was temporary suspended. After 5 days without prophylaxis treatment, and increasing inhibitor titres, she developed a new intracranial haemorrhage, which needed intensive treatment with continuous rFVIIa infusion (90 µg/Kg/12h), immunoglobulines and rituximab for lowering inhibitor titre. Hemostatic parameters improved during the administration of these treatments and inhibitor level was reduced. After restarting prophylaxis treatment with rFVIIa (50 µg/Kg/48h), inhibitors and a hypocoagulable state were observed with all global coagulation test showing extended PT, clotting time (CT), TG Lag-time (LT) and anomalous thrombus formation (AUC) but presented very good response to low dosis (2.5 IU/Kg) of aPCC in vitro (Table-1). At the age of three years she required admission at hospital because of port-A-Cath infection again, needing its replacement by a new one after administration of high doses of rFVIIa without bleeding complications. After this, inhibitor titre raised again (> 50 BU), presenting frequent bleeding episodes (spontaneous muscle bleedings and tonsillar bleeding), and due to the clinical worsening, treatment was modified to prophylaxis with aPCC (30 UI/Kg/48h). Despite the treatment change she continued presenting bleeding episodes, global tests continued showing an hypocoagulable state, and required 10 times higher doses in vitro of aPCC (25 IU/Kg) to restore all the monitored hemostatic parameters (Table-1), probably related to the important increase in inhibitor titre. This situation led to employing higher doses of aPCC prophylaxis (60 UI/Kg/48 h) to try to avoid bleeding episodes without increasing the risk of suffering thrombotic events. Conclusions Global coagulation tests used in this study were sufficiently sensitive methods to show an abnormal hemostatic profile in FVII-deficient patients with clinical hemorrhagic symptoms with inhibitor development, supporting their use to manage the risk of bleeding or thrombosis in this life-threatening condition. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IX international curse of continuing formation in haemophilia and other congenital coagulopathies. The role of the Laboratory in coagulation disorders. Diagnosis of von Willebrand disease.

Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (VWF). This protein far from simplicity constitutes a very complex molecular model, remaining unravelled yet many aspects of it, even though the VWF gene (VWF) was cloned already in 1985 and the structure of VWF well defined. VWD diagnosis is difficult to achieve in a significant proportion of patients due to both disease heterogeneity and limitations in existing test processes. The cornerstone of diagnosis relies on interpretation of VWF test results, the presence of clinical manifestations of bleeding, especially mucocutaneous, and (in most cases) a positive family history. However, even with a significant bleeding history, a family history may not be positive due to factors of incomplete penetrance and variable expressivity that affect genetic changes. The laboratory diagnosis of VWD can be difficult, as the disease is heterogeneous and an array of assays is required to describe the phenotype. Basic classification of quantitative (type 1 and 3) and qualitative (type 2 variants) VWD requires determination of VWF antigenic (VWF:Ag) levels and assaying of VWF ristocetin cofactor (VWF:RCo) activity. The latter is required for identifying and subtyping VWD, but the assay is poorly standardized. For that reason, novel VWF activity assays have been developed awaiting more extensive comparison data between different methodologies and requiring validation on larger patient series. The qualitative type 2 VWF deficiency can be further divided into four different subtypes (A, B, M and N) using specific assays that measure other activities or the size distribution of VWF multimers. However, frequently, it may be difficult to correctly classify the VWD phenotype, and genetic analysis is through mutation identification may provide a tool to clarify the disorder.

Bleeding Risk in Patients with Multiple Myeloma Treated for Venous Thromboembolism

▪Introduction:Multiple myeloma diagnosis is associated with a 10-15% absolute risk of venous thromboembolism (VTE) due to disease-related (i.e., vascular inflammation, hyperviscosity) and treatment-related risk factors (i.e., immunomodulatory drugs [IMiDs], high-dose dexamethasone). This has led to ongoing clinical trials to determine the best thromboprophylaxis strategy. In contrast, the risk of major bleeding following incident VTE events in patients with MM is not well described. We conducted a real-world analysis of bleeding complications in MM following anticoagulation treatment for VTE.Methods:The IBM MarketScan Commercial Claims Database was used to identify adults with MM diagnosis and an incident VTE event between 2011 and 2019. MM and VTE were defined as 1 inpatient or 2 outpatient claims based on International Classification of Diseases (ICD) 9th and 10 th Revision codes, and at least 1 prescription for anticoagulation within 31 days of first VTE claim. IMiD-related VTE was defined in subjects with an IMiD prescription prior to the VTE event. Major bleeding was defined as bleeding requiring hospitalization using inpatient ICD codes as previously validated (Cunningham algorithm). Patients were followed from index VTE and initiation of anticoagulation to first major bleeding event, disenrollment (due to death or other reasons) or December 31, 2019. Descriptive statistics were used to calculate the rate of major bleeding. Cox regression was used to determine risk factors associated with major bleeding.Results:Our population included 1,605 patients with a diagnosis of multiple myeloma and an incident VTE event requiring treatment. Anticoagulant agent of choice was warfarin in 45.7% (734), low-molecular weight heparin (LMWH) in 29% (466), and direct oral anticoagulants (DOAC) in 25.3% (405). There were no significant differences in age/sex distribution, comorbidity burden, history of significant bleeding, or use of IMiD across the different types of anticoagulation (Table 1). Hospitalized bleeding occurred in 63 (3.9%) patients during an average follow-up of 1.6 years, yielding an overall incidence rate of major bleeding in multiple myeloma patients starting anticoagulation for a new VTE event of 24.1 per 1,000 person-years. Adjusting for age and sex, risk factors significantly associated with risk of major bleeding included Charlson comorbidy index [CCI] (per standard deviation [SD] increment, HR 1.29, 95%CI 1.03 - 1.62), diabetes (HR 1.71, 95%CI 1.06 - 2.92), and liver disease (HR 1.96, 95%CI 1.04 - 3.68). The use of IMiDs was not associated with increased risk of major bleeding (Table 2). The cumulative incidence of major bleeding by VTE anticoagulation strategy in multiple myeloma was 4.8% in warfarin group and 3.2% in the LMWH and DOAC groups, though the difference was not statistically significant after adjusting for age and sex. The estimated incidence rate of bleeding was 25.7, 20.1, and 25.2 per 1,000 person-years for patients treated with warfarin, LMWH, and DOACs, respectively. In an adjusted model for age, sex, CCI, diabetes and liver disease, patients treated with LMWH and DOACs had HR for major bleeding of 0.91 and 0.82, respectively, compared to anticoagulation with warfarin, though this was not statistically significant.Discussion:In a real-world analysis of commercial claims data, the rate of major bleeding in patients with multiple myeloma receiving anticoagulation for VTE appears to be comparable to those reported in other subsets of cancer associated VTE. Surprisingly, almost half of identified patients were treated with warfarin, a non-preferred option in this setting. The point estimate of major bleeding was lower in patients treated with LMWH or DOACs compared to warfarin, though the association was not statistically significant and larger studies are needed. Higher CCI, diabetes and liver disease were clinical factors associated with higher risk of major bleeding and may be included in risk assessment models to help clinicians assess individual bleeding risk in patients with multiple myeloma treated for VTE. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Under the Radar: A Case Report of a Missed Aortoenteric Fistula.

IntroductionAn aortoenteric fistula (AEF) is an abnormal connection between the aorta and the gastrointestinal tract that develops due to a pathologic cause. It is a rare, but life-threatening, cause of gastrointestinal (GI) bleeding. Although no single imaging modality exists that definitively diagnoses AEF, computed tomography angiography (CTA) of the abdomen and pelvis is the preferred initial test due to widespread availability and efficiency.Case ReportMany deaths occur before the diagnosis is made or prior to surgical intervention. We describe a case of a patient with a history of aortic graft repair who presented with active GI bleeding.ConclusionAlthough CTA can make the diagnosis of AEF, it cannot adequately rule it out. In patients with significant GI bleeding and prior history of aortic surgery, vascular surgery should be consulted early on, even if CTA is equivocal.

Management of elective procedures in low von Willebrand factor patients in the LoVIC study

BackgroundMost individuals with mild to moderate reductions in plasma von Willebrand factor (VWF) levels do not demonstrate increased bleeding. However, some patients with plasma VWF levels of 30–50 IU/dl do have a significant bleeding phenotype. Management of these “low VWF” patients, who may have significant bleeding scores >10, around times of elective procedures continues to pose a common clinical challenge because of a lack of evidence. ObjectiveTo investigate the safety and efficacy of different periprocedural management options for adult patients with low VWF. MethodsTreatment and outcomes were retrospectively reviewed for 160 invasive procedures performed in 60 patients with well characterized low VWF enrolled in the previously described Low Von Willebrand factor Ireland Cohort study. ResultsWe demonstrate that 1‐desamino‐8‐D‐arginine vasopressin is efficacious in preventing bleeding for both minor or major elective procedures in adult low VWF patients, even in those with significant bleeding histories. In addition, tranexamic acid alone is effective for low VWF patients undergoing nondental minor procedures. Importantly, age‐related increases in plasma VWF:antigen levels above 50 IU/dl were not necessarily associated with complete correction of bleeding phenotype. Procedure‐related bleeding complications were increased in low VWF patients who did not receive any hemostatic cover before their procedure. ConclusionElective procedures in adult patients with low VWF should be managed in liaison with a comprehensive care tertiary referral center so that personalized treatment plans may be implemented before all minor or major elective procedures.

Carvenous hemangioma of the uterine cervix: A case report

Carvenous hemangioma of the uterine cervix is a rare clinical condition which has the potential of being life threatening. This rare clinical condition can manifest with patients presenting with abnormal uterine bleeding, menorrhagia with eventual anaemia. The case report here is that of a 27 year old Para o+o lady who was admitted to the Accident and Emergency Unit of our hospital with a day history of a huge mass protruding per vagina and a history of significant bleeding per vagina. Packed cell volume was 16% on admission and she had 4 units of blood transfused. She subsequently had examination under anaesthesia and excision of the prolapsed mass done via the vaginal route. Histology of the excised mass was in keeping with cavernous hemangioma of the uterus. Her Postoperative clinical state was satisfactory.

Utility of repeat testing in the evaluation for von Willebrand disease in pediatric patients

BackgroundVon Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by quantitative and qualitative defects in von Willebrand factor (VWF). The laboratory diagnosis of VWD in pediatric patients is complicated by VWF interassay and intra‐assay variability, stress‐induced elevations in VWF levels, and a lack of significant bleeding history with which to correlate test results. ObjectiveGuidelines recommend repeat testing in patients with a high suspicion of VWD and unclear laboratory assay results; however, no studies have evaluated the utility of repeat VWF testing in pediatric patients. MethodsThis retrospective single‐center cohort study aimed to determine clinical variables associated with requiring more than one test to diagnose VWD and to establish a cutoff VWF value above which further testing is not informative. ResultsOf 811 patients evaluated for a suspected bleeding disorder, 22.2% were diagnosed with VWD, with ~70% diagnosed on the first test. Patients with VWD were younger (5.8 vs. 8.5 years, P = .002) and more likely to have a family history of VWD (38% vs. 22%, P < .001) than those without VWD. Univariate analysis failed to identify any clinical variables that correlated with needing multiple tests for a VWD diagnosis. A cutoff of 100 IU/dL for VWF antigen or activity on the first test yielded negative predictive values >95%. ConclusionsWe demonstrate that the majority of pediatric patients had diagnostic VWF values on the first set of testing. Pediatric patients without a family history of VWD and VWF levels >100 IU/dL may not need further testing to rule out the diagnosis of VWD.

Prognostic Characteristics of Hospitalized Patients Without Overt GI Bleeding With Subacute Drop in Hemoglobin

Introduction: Patients admitted to the hospital with a principal diagnosis that does not include GI bleeding who subsequently develop overt GI bleeding with corresponding drop in Hb are known to have higher morbidity and mortality. Little is known about these patients who have a subacute drop in Hb without evidence of GI bleeding. Although the causes of a subacute drop in Hb is likely multifactorial, GI consultation and subsequent endoscopy is often requested and performed. Our aim is to identify prognostic factors that affect the likelihood of finding a GI source in hospitalized patients with a principal diagnosis that does not include GI bleeding who subsequently develop a subacute drop in Hb. Methods: The electronic health records from our community hospital were used to identify all patients admitted from October 2016 to May 2018 who underwent any of the CPT codes associated with endoscopy. From these patients, we excluded those with an admitting diagnosis for GI bleed, GI hemorrhage, melena, hematochezia, and hematemesis using their ICD-10 Codes. This left a group of patients who had undergone an endoscopy during a hospitalization for a non GI bleed admitting diagnosis. Data mining was undertaken to include patients who had a subacute drop in their Hb defined as drop in Hb ≥ 3 over their hospitalization. Patients with history of significant GI bleeding defined as hospitalization and blood transfusion were also excluded. From this study group, characteristics were obtained and compared to endoscopic findings. The intent is to perform a multivariate analysis on those characteristics that are statically significant or presented most frequently. Results: Characteristics will include age, admitting diagnosis, use of anticoagulation, surgeries, number of phlebotomies, +FOBT, history of chronic anemia, liver disease and kidney disease. Using the endoscopy report, we will determine if a GI etiology was discovered. Each of the above characteristics will be compared to the outcomes in a univariate manner. Characteristics that are statistically significant or occur with most frequency will be evaluated in a multivariate analysis to identify characteristics that may be prognostic. Conclusion: The focus of this investigation is to identify characteristics that can be used to determine the likelihood of endoscopy revealing the cause of subacute drop in Hb in patients hospitalized with a principal diagnosis other than GI bleeding. These characteristics can be used in future prospective studies.

Patients with bleeding of unknown cause and joint hypermobility: Clinical assessment and genetic screening

Symptomatic joint hypermobiliy has been associated with bleeding tendency, suggesting that collagen disorders could be the cause in some cases of bleeding. The aim of this study was to examine the clinical characteristics of patients with bleeding tendency of unknown cause and joint hypermobility and to perform a genetic study based on Next-Generation Sequencing (NGS). This was a single-centre, prospective, observational study. Patients included were a Haemophilia Centre (HC) for bleeding symptoms of unknown cause (normal or abnormal haemostatic tests not explaining the bleeding phenotype) and having joint laxity and Musculoskeletical Rehabilitation Unit (RHB) for joint laxity and reporting bleeding symptoms. Bleeding severity was assessed by the haematologist using the ISTH Bleeding assessment tool (ISTHBAT) and joint hyperlaxity by the physiatrist by the Beighton score. Molecular analysis was performed using TruSight One Sequencing Panel Kit (Illumina). Quality and population frequency filters were applied and the search was limited to 78 genes related with Heritable Disorders of Connective Tissue (HDCT). Forty-three patients were included between June 2016 and January 207. All were females; median age was 38.6 years (range 17–62 years). Median ISTH-BAT score was 8 (range 3–17) and Beighton score 7 to 9 (range 3–9). ISTH-BAT score was abnormal in 77% and Beighton score in 80%. In 25 patients, both scores were abnormal. A total of 175 potential mutations were identified in HDCT related genes for all except one patient. In 46.5% a direct correlation between the identified mutation and the clinical phenotype could be established. In 10 patients, mutations in COL5A1 , COL5A2 , COL1A1 and COL1A2 genes were identified and validated by Sanger sequencing. Clinical assessment for symptomatic joint hypermobility should be considered in patients with significant bleeding history of unknown cause. NGS could be a useful tool for the study of the responsible genes and the classification of patients.

Deletion of RUNX1 exons 1 and 2 associated with familial platelet disorder with propensity to acute myeloid leukemia

Familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML) associated with RUNX1 mutations is an autosomal dominant disorder included in the group of the myeloid neoplasms with germ line predisposition. We describe two brothers who were diagnosed with hematological malignancies (one with AML and the other with T-cell lymphoblastic lymphoma). There was a history of leukemia in the paternal family and two of their siblings presented with low platelet counts and no history of significant bleeding. A microdeletion encompassing exons 1-2 of RUNX1 (outside the cluster region of the Runt Homology domain and the transactivation domain) was detected in six family members using array-CGH and MLPA validation. A low platelet count was not present in all deletion carriers and, therefore, it should not be used as an indication for screening in suspected families and family members.

Emergency Autotransfusion for Managing Iatrogenic Hemorrhagic Pericardial Effusion

Iatrogenic hemorrhagic pericardial effusion (IHPE) is one of the major complications encountered in daily percutaneous intracardiac interventions. A 79-year-old man was scheduled for percutaneous left atrial appendage closure (PLAAC) at our department. He had non-valvular atrial fibrillation, with a contraindication to oral anticoagulants because of a history of recurrent significant intestinal bleeding with angiodysplasia. During the deployment of the PLAAC device (Watchman device), patient became hemodynamically unstable with a typical decrease in the systolic arterial pressure of more than 10 mm Hg during inspiration (pulsus paradoxus) because pericardial tamponade occurred due to perforation of the left atrial appendage. We report our successful experience with management of IHPE by immediate pericardiocentesis, insertion of percutaneous catheter drainage (PCD), and retransfusing drained pericardial blood through a central venous line. IHPE is not uncommon complication in daily percutaneous intracardiac interventions. Pulsus paradoxus is the most important clinical sign of cardiac tamponade. Our approach by immediately retransfusing drained pericardial blood through a central venous line allowed rapid physiologically appropriate recovery. Future consensus of opinion of experts focusing on autotransfusion in such cases is needed. J Med Cases. 2017;8(4):114-116 doi: https://doi.org/10.14740/jmc2789w

Novel Insights into the Clinical Phenotype and Pathophysiology Underlying Low VWF Levels: The Low Von Willebrand Factor in Ireland Cohort (LoVIC) Study

▪Cohort studies have identified VWF gene mutations in ~65% of patients with type 1 Von Willebrand Disease (VWD). However, in patients with mild reductions in Von Willebrand Factor (VWF) levels, VWF mutations are less common and linkage studies suggest that the reduced plasma VWF levels are often independent of the VWFgene. Important clinical questions therefore remain unanswered regarding diagnosis and management of patients with Low VWF (levels 30-50 IU/dL). Evidence-based diagnostic criteria are needed for establishing the diagnosis of Low VWF, and the relationship between Low VWF levels and bleeding phenotype needs to be defined. Furthermore, the molecular mechanisms responsible for the reduced plasma VWF levels remain unclear. To address these questions, we established the Low VWF Ireland Cohort (LoVIC) study. In contrast to previous Type 1 VWD studies, this prospective longitudinal cohort study recruited only patients with Low VWF levels, (defined by bleeding history and lowest VWF levels 30-50 IU/dL on two occasions, three months apart) and recruited 140 adult Irish patients.Although Bleeding Assessment Tools (BATs) have been used in type 1 VWD, their utility has not been studied in patients with Low VWF. As determined using either the ISTH BAT or the Condensed MCMDM-1 VWD score, we observed significant bleeding histories in the majority of LoVIC patients. For example, among female patients (n=112), 77% had positive ISTH BAT scores (≥6) and 72% had positive MCMDM-1 scores (≥4). Importantly, bleeding tendency did not correlate with plasma VWF levels within the 30-50 IU/dL range. To further investigate this bleeding phenotype, hemostatic studies (including platelet aggregation and coagulation factor assays) were performed. Additional mild coagulation defects were identified in only 10 subjects. Furthermore, abnormal multimer patterns were identified in only 3 patients. To investigate the pathophysiology underlying Low VWF levels, plasma FVIII:C and VWF propeptide (VWF:pp) levels were defined. Interestingly, plasma FVIII:C/VWF:Ag ratios were significantly increased in LoVIC patients compared to normal controls (mean 1.3 versus 1.07; p<0.001). In contrast, increased plasma VWF:pp/VWF:Ag ratios > 3 were observed in only 6% of the total cohort. Taken together, these data demonstrate that the reduced plasma VWF levels in patients with Low VWF are predominantly attributable to decreased VWF synthesis and/or secretion rather than enhanced VWF clearance. To determine whether quantitative and/or qualitative abnormalities in platelet (plt)-VWF may influence bleeding phenotype in patients with Low VWF, we studied plt-VWF:Ag and VWF:CB in 50 consecutive LoVIC patients. In keeping with the hypothesis that reduced VWF synthesis plays a key role in the pathogenesis underlying Low VWF levels, plt-VWF:Ag and plt-VWF:CB levels were both significantly reduced in LoVIC patients compared to controls (mean plt-VWF:Ag 0.16 versus 0.21 IU/109/L, p<0.05; mean plt-VWF:CB 0.18 versus 0.34 IU/109/L, p<0.001).To further study the molecular mechanisms underlying Low VWF levels, plasma VWF:Ag and VWF:RCo responses following desmopressin (DDAVP) administration were examined. In 88% of patients, the post-DDAVP peak levels exceeded 100 IU/dL. Importantly, the response to DDAVP was also sustained with both VWF:Ag and VWF:RCo above 100 IU/dL after 4 hours in 72% subjects. These DDAVP responses demonstrate that Weibel Palade body stores of VWF are maintained in patients with Low VWF, and that the regulated pathway of VWF secretion is intact. Furthermore, the sustained plasma VWF response observed following DDAVP supports the hypothesis that enhanced VWF clearance does not play a major role in the pathogenesis of Low VWF levels.In conclusion, we demonstrate that Low VWF levels are associated with a significant bleeding phenotype. In addition, we further show that in the majority of patients with Low VWF levels, the bleeding phenotype cannot be explained by the presence of concomitant bleeding disorders. Finally, our novel data demonstrate that Low VWF levels are due in large part to reductions in VWF synthesis and/or constitutive secretion. Although enhanced VWF clearance may contribute to the pathophysiology in a minority of individuals with Low VWF, the absolute reduction in VWF plasma half-life is usually mild and not sufficient to significantly impact upon the duration of DDAVP-induced VWF response. DisclosuresLavin:Baxalta: Consultancy, Research Funding. O'Sullivan:Pzifer: Research Funding. O'Connell:Baxalta: Consultancy, Research Funding. James:Octapharma: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Biogen: Consultancy; Basalt: Consultancy. Di Paola:CSL BEhring: Consultancy; Biogen: Consultancy. O'Donnell:Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees.

Interventional left atrial appendage closure vs novel anticoagulation agents in patients with atrial fibrillation indicated for long-term anticoagulation (PRAGUE-17 study)

To determine whether percutaneous LAA occlusion is noninferior to treatment with NOAC in AF patients indicated for long-term systemic anticoagulation. The trial will be a prospective, multicenter, randomized noninferiority trial comparing 2 treatment strategies in moderate to high-risk AF patients (ie, patients with history of significant bleeding, or history of cardiovascular event(s), or a with CHA2DS2VASc ≥3 and HAS-BLED score ≥2). Patients will be randomized into a percutaneous LAA occlusion (group A) or a NOAC treatment (group B) in a 1:1 ratio; the randomization was done using Web-based randomization software. A total of 396 study participants (198 patients in each group) will be enrolled in the study. The primary end point will be the occurrence of any of the following events within 24months after randomization: stroke or transient ischemic attack (any type), systemic cardioembolic event, clinically significant bleeding, cardiovascular death, or a significant periprocedural or device-related complications. The PRAGUE-17 trial will determine if LAA occlusion is noninferior to treatment with NOAC in moderate- to high-risk AF patients.

Unclassified bleeding disorders: outcome of haemostatic challenges following tranexamic acid and/or desmopressin.

In a minority of patients with a significant bleeding history no cause is found despite extensive testing and we diagnose such cases as unclassified bleeding disorders (UBD). UBDs may have diverse underlying causes and currently no standard management strategy exists in the event of a haemorrhage or to cover surgery. To document the clinical characteristics and response to treatment of UBDs. We performed a retrospective chart review of all patients with UBDs who had an invasive procedure at our centre between 1998 and 2014. The commonest symptoms were menorrhagia (89%) and bleeding at the time of surgery (88%) or dental extraction (85%). A total of 33 patients underwent 78 minor and major haemostatic challenges. Haemostatic cover was provided in 28 procedures with tranexamic acid alone, two with desmopressin and 45 with both agents in combination. A successful haemostatic outcome was observed in 70/78 (90%) cases. No patient required additional surgical intervention to achieve haemostasis, but one patient required a platelet transfusion to control postoperative bleeding. This is the first study to report on the investigation and treatment of UBD. Future studies are needed to further our understanding of the bleeding phenotype and identify any underlying causes.

Utility of a Paediatric Bleeding Questionnaire as a screening tool for von Willebrand disease in apparently healthy children.

von Willebrand disease (VWD), an inherited bleeding disorder caused by deficiency or dysfunction of von Willebrand factor (VWF) is diagnosed when a personal and often a family history of excessive mucocutaneous bleeding is present along with abnormal laboratory studies. An accurate assessment of haemorrhagic symptoms is key in suspecting VWD but presents a challenge especially in children due to overlap between normal and abnormal bleeding. Bleeding questionnaire (BQ) scores have been validated in adults and have recently been validated in children with VWD for assessing bleeding severity. However, there are limited data supporting their use prospectively in healthy children with bleeding complaints. The objectives of this study were to obtain normative data from children and validate a paediatric BQ (PBQ) to determine the discriminative ability of its total score and its individual components for identifying children likely to have VWD. The PBQ was administered to 1281 multiethnic, healthy children between 30days and 18years of age presenting to a general paediatric office and to 35 children with VWD based on VWF antigen, activity and multimer pattern. When children with total BQ scores of 3 or more were predicted to have VWD, the sensitivity was 97.2%, the specificity was 97.1%, the positive predictive value was 48.6% and the negative predictive value was 99.9%. The PBQ may help discriminate a significant bleeding history from trivial bleeding, may be integrated into the primary care algorithm for evaluating children suspected with VWD.