Retrospective chart review of GI bleeding in people with von Willebrand disease.

INTRODUCTION: Gastrointestinal (GI) bleeding events (BEs) in von Willebrand disease (VWD) are difficult to diagnose and often recurrent. Limited data from clinical trials has led to lack of consensus on treatment options. AIM: Describe current treatments and outcomes for GI BEs in people with VWD. METHODS: This retrospective, observational, multicentre chart review study was conducted from January 2018 through December 2019 and included patients with inherited VWD with ≥1 GI BE in the preceding 5 years. Baseline characteristics, number and aetiology of BEs, associated GI-specific morbidities/lesions, treatment and outcomes were analysed descriptively. RESULTS: Sixty bleeds were reported in 20 patients with type 1 (20%), type 2 (50%) and type 3 (30%) VWD. During the 5-year study period, 31 (52%) BEs had one identified or suspected cause; multiple causes were reported in 11 (18%). Most GI BEs (72%) were treated with a combination of von Willebrand factor (VWF), antifibrinolytics and/or other haemostatic or non-haemostatic treatments. Time to resolution did not differ by VWF treatment use; however, BEs treated with non-VWF treatments tended to resolve later. In patients with GI-specific morbidities/lesions, 84% resolved with first-line treatment; time to resolution tended to be longer than in patients without such morbidities/lesions. Thirteen BEs occurred in patients receiving prophylaxis and 47 in patients receiving on-demand treatment; 18 BEs resulted in a switch to prophylaxis after bleed resolution. CONCLUSIONS: This study confirms the unmet need for the management of recurrent GI BEs in people with VWD and the need for prospective data, especially on prophylaxis.

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

INTRODUCTION: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). AIM: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. METHODS: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

The B-Natural study-The outcome of immune tolerance induction therapy in patients with severe haemophilia B.

INTRODUCTION: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher. AIM: To evaluate the use and outcome of ITI in patients with HB and inhibitors. METHODS: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural-an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded. RESULTS: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment. CONCLUSION: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted.

Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural).

INTRODUCTION: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research. AIM: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations. METHODS: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing. RESULTS: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis. CONCLUSION: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

Primary thromboprophylaxis to prevent thrombotic events in pediatric oncology patients with a malignant mediastinal mass.

Children with malignant mediastinal masses have increased thrombotic events (TE). Eligible subjects with malignant mediastinal masses between January 2000 and December 2017 were evaluated for TE, with 19 among 76 subjects receiving enoxaparin thromboprophylaxis. There were 13 TEs among 76 subjects for an incidence of 17.1%. Mediastinal compression directly led to TE in 9.2% of subjects who also had statistically significant superior vena cava compression at diagnosis. Primary thromboprophylaxis did not significantly affect TE occurrence; however, larger studies are warranted to consider strategic thromboprophylaxis guided by radiological monitoring of dynamic vascular compression to improve TE outcomes.

Assessment of provider practices regarding venous thromboembolism management and prevention in pediatric acute leukemia patients.

Despite the known occurrence of venous thromboembolism (VTE) in the pediatric oncology population, there are no leukemia-specific VTE treatment guidelines. The primary objective of this study was to assess current practices regarding the management and prevention of VTE in the pediatric acute lymphoblastic leukemia (ALL) population. We performed a cross sectional, anonymous, electronic survey of members of the American Society of Hematology and the pediatric subcommittee of VENUS (VTE Network US of the Hemostasis and Thrombosis Research Society). Survey items included questions on demographics and clinical practice. Of 870 surveys distributed, 154 were submitted, giving a 17.7% response rate. Treatment duration, re-imaging timeline, and class of anticoagulants used were reported for catheter-associated deep vein thrombus, pulmonary embolism, and cerebral venous sinus thrombosis. While there are some common themes regarding VTE management, there is notable variation in the overall practice as well as with the decision to continue anticoagulation in the presence of thrombocytopenia. Given the variation seen, a multi-center, prospective clinical trial is urgently needed for developing consensus guidelines for the management of VTE in children with ALL.

Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway.

Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder hemophilia A. HA typically begins with hemophilic synovitis that resembles inflammatory arthritides, such as rheumatoid arthritis, and frequently results in bone loss in patients. A major cause of rheumatoid arthritis is inappropriate release of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by the TNF-α convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-α also has a pivotal role in mediating HA. Here, we show that addition of blood or its components to macrophages activates iRhom2/ADAM17-dependent TNF-α shedding, providing the premise to study the activation of this pathway by blood in the joint in vivo. For this, we turned to hemophilic FVIII-deficient mice (F8-/- mice), which develop a hemarthrosis following needle puncture injury with synovial inflammation and significant osteopenia adjacent to the affected joint. We found that needle puncture-induced bleeding leads to increased TNF-α levels in the affected joint of F8-/- mice. Moreover, inactivation of TNF-α or iRhom2 in F8-/- mice reduced the osteopenia and synovial inflammation that develops in this mouse model for HA. Taken together, our results suggest that blood entering the joint activates the iRhom2/ADAM17/TNF-α pathway, thereby contributing to osteopenia and synovitis in mice. Therefore, this proinflammatory signaling pathway could emerge as an attractive new target to prevent osteoporosis and joint damage in HA patients.

Are children with SARS-CoV-2 infection at high risk for thrombosis? Viscoelastic testing and coagulation profiles in a case series of pediatric patients.

The coagulopathy of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented in adults, with increases in D-dimer and prothrombin time found to be strong predictors of mortality, and anticoagulation shown to decrease this mortality. Viscoelastic parameters such as elevations in maximum clot firmness (MCF) on rotational thromboelastometry (ROTEM) have correlated with a hypercoagulable state in adults with SARS-CoV-2. We report our experience in children infected with SARS-CoV-2, with noted elevations in D-dimer and MCF on ROTEM (indicating hypercoagulability). Exploration of viscoelastic testing to provide additional laboratory-based evidence for pediatric-specific risk assessment for thromboprophylaxis in SARS-CoV-2 is warranted.

Potential of the Community Counts registry to characterize rare bleeding disorders.

INTRODUCTION: Rare bleeding disorders (RBDs) comprise of heterogeneous coagulation factor deficiencies and platelet disorders that are underreported worldwide. AIM: First report on RBD data from United States haemophilia treatment center network (USHTCN). METHODS: A national surveillance system for the federally recognized USHTCN developed in collaboration with the Centers for Disease Control and Prevention (CDC) and American Thrombosis and Haemostasis Network (ATHN) was queried for patients with RBDs. Patient counts were extracted from the HTC Population Profile (HTC PP) component including limited data on patients followed through the USHTCN, and from the Registry component, including patient authorized, detailed clinical data. The prevalence of RBDs in the United States was estimated based on the HTC PP data and compared to the expected national prevalence based on data extrapolated from Orphanet, an international registry. RESULTS: Based on the estimated prevalence of RBD in the overall 2017 US population, the cases in the HTC network were lower than expected for FI, FII, FX, and FV + FVIII deficiencies by 36%, 61%, 75% and 94%, respectively, and higher than expected for FXIII, FV, FVII, and FXI deficiencies by 7%, 14%, 33% and 185%, respectively. The proportion of RBD patients reported in the HTC PP, enrolled in the Registry, was 10.8%. CONCLUSIONS: There is a clear need to identify individuals with RBDs who could benefit from the comprehensive care provided in the USHTCN. In addition, increased enrolment of people with all RBDs in the Registry is needed to improve knowledge of treatment outcomes of patients with RBDs in the United States.

Inherited disorders of the fibrinolytic pathway.

Deficiencies or excessive activation of the fibrinolytic system can result in severe, lifelong bleeding disorders. The most severe clinical phenotype is caused by α2-Antiplasmin (α2-AP) deficiency which results in excess fibrinolysis due to the inability to inhibit plasmin. Another bleeding disorder due to a defect in the fibrinolytic pathway results from Plasminogen activator inhibitor-1 (PAI-1) deficiency causing enhanced fibrinolysis due to the decreased inhibition of plasminogen activators resulting in increased conversion of plasminogen to plasmin. Both these disorders are rare and have an autosomal recessive pattern of inheritance. They can remain undetected as routine coagulation and platelet function tests are normal. A unique gain-of-function defect in fibrinolysis causes the Quebec platelet disorder (QPD) which is characterized by profibrinolytic platelets containing increased urokinase-type plasminogen activator (uPA) in the α-granules. A high index of suspicion based on clinical phenotype along with the availability of specialized hemostasis testing is required for timely and accurate diagnosis. Antifibrinolytic agents, such as tranexamic acid or ε-aminocaproic acid, are the mainstays of treatment which inhibit fibrinolysis by preventing the binding of plasminogen to fibrin and thereby stabilizing the fibrin clot. The purpose of this review is to summarize the pathogenesis, clinical phenotype, approaches to diagnosis and treatment for these three major disorders of fibrinolysis.

Management of rare coagulation disorders in 2018.

Rare bleeding disorders (RBDs) comprise inherited deficiencies of factors I (fibrinogen), II (prothrombin), V, VII, X, XI, and XIII as well as combined factor V + VIII and vitamin K-dependent factors. They represent 3-5% of all congenital bleeding disorders and are usually transmitted as autosomal recessive traits. These disorders often manifest during childhood and have varied clinical presentations from mucocutaneous bleeding to life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Bleeding manifestations generally vary within the same RBD and may also vary from 1 RBD to the other. Laboratory diagnosis is based on coagulation screening tests and specific factor assays, with molecular techniques providing diagnostic accuracy and enabling prenatal counseling. The approach to treatment of bleeding episodes and invasive procedures needs to be individualized and depends on the severity, frequency and procedure-related risk of bleeding. The first line of treatment of RBDs is replacement of the deficient factor, using specific plasma-derived or recombinant products and using fresh frozen plasma or cryoprecipitate when specific products are not available or in resource-limited countries. Prophylaxis may be considered in individuals with recurrent serious bleeding and especially after life-threatening bleeding episodes. Novel no-replacement strategies promoting hemostasis by through different mechanisms need to be studied in RBDs as alternative therapeutic options.

PT-VWD posing diagnostic and therapeutic challenges - small case series.

Despite the increased worldwide awareness, over the last decade, of the platelet-type von Willebrand Disease (PT-VWD), many uncertainties remain around this rare platelet bleeding disorder. This report aims to correctly identify and study the phenotype of new patients and highlights the diagnostic and therapeutic challenges this disease remains to pose. We describe four PT-VWD cases confirmed by genetic analysis in which either the diagnosis and/or the treatment posed challenge. We provide the details of the clinical presentation, laboratory analysis, and the treatment and the responses in each case. We show that in addition to type 2B VWD, PT-VWD can be misdiagnosed as idiopathic thrombocytopenic purpura, neonatal alloimmune thrombocytopenia, and unexplained gestational thrombocytopenia. The disease can be diagnosed as early as 1 year of age and with phenotypically normal parents. Bleeding in some patients can be managed successfully using Humate P and DDAVP combined with tranexamic acid with no significant thrombocytopenia. We provide for the first time an evidence of an efficient response to rFVIIa in PT-VWD. Anaphylactic reaction to VWF preparations may be related to PT-VWD and the development of HLA antibodies is not uncommon. Progressive thrombocytopenia with normal VWF levels can be seen with PT-VWD and the platelet count was normalized at 2.5 weeks postpartum in one case. We conclude that these studies represent a record of clinical observations/interventions that help improve diagnoses/management of PT-VWD, highlight the variations in age and clinical presentations, laboratory diagnostic approaches, the importance of genetic testing for accurate diagnosis and consideration of therapeutic alternatives.

The homozygous VHL(D126N) missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension.

von Hippel-Lindau (VHL) protein is the principal negative regulator of hypoxia sensing mediated by transcription factors. Mutations in exon 3 of the VHL gene lead to Chuvash (VHL(R200W)) and Croatian (VHL(H191D)) polycythemias. Here, we describe an infant of Bangladesh ethnicity with a novel homozygous VHL(D126N) mutation with congenital polycythemia and dramatically elevated erythropoietin (EPO) levels, who developed severe fatal pulmonary hypertension. In contrast to Chuvash polycythemia, erythroid progenitors (BFU-Es) did not reveal a marked EPO hypersensitivity. Further, NF-E2 and RUNX1 transcripts that correlate with BFU-Es EPO hypersensitivity in polycythemic mutations were not elevated.

Evaluation of the Safety and Efficacy of Enoxaparin Once-Daily Versus Twice-Daily Dosing for Prophylaxis in Pediatric Patients.

OBJECTIVES: Enoxaparin for the prevention of venous thromboembolism (VTE) in pediatric patients is -typically dosed twice a day. The use of once-daily dosing like that used in adult patients is limited because of a lack of safety and efficacy data. The aim of this study was to evaluate the safety and efficacy of -once-daily versus twice-daily dosing of enoxaparin for pediatric VTE prophylaxis based on incidence of thrombotic and bleeding events. METHODS: This was a 3-year retrospective chart review of enoxaparin received for VTE prophylaxis at -Cohen Children's Medical Center, New Hyde Park, NY. Exclusion criteria were age 18 years or older, and renal dysfunction. RESULTS: A total of 177 enoxaparin courses (81 in the once-daily and 96 in the twice-daily group) were included. The median dose in the once-daily group was 0.68 mg/kg/dose with dose capping at 40 mg/dose in 70% of patients. One patient in the once-daily group had a VTE, whereas no patients in the twice-daily group experienced a VTE. One major bleeding event occurred in the once-daily group (p = 0.46); however, minor bleeding events were comparable between the 2 groups (p = 0.69). CONCLUSIONS: Once-daily enoxaparin prophylaxis appears to be safe and effective based on minimal -differences in incidence of thrombotic and bleeding events when compared to twice-daily dosing. Based on this study, it may be reasonable to consider once-daily enoxaparin dosing for prophylaxis, especially in older children. A larger multicenter cohort study evaluating once-daily dosing for prophylaxis is warranted to validate the safety and efficacy specifically for risk-based dosing strategies.

Exploration of rotational thromboelastometry (ROTEM) to characterize the coagulation profiles of newly diagnosed pediatric leukemia patients.

BACKGROUND: Viscoelastic testing has been used in adult hematologic malignancies in conjunction with conventional coagulation tests (CCTs) to predict coagulopathies and tailor blood product replacement. However, there is a paucity of similar pediatric studies. OBJECTIVES: Analyze and correlate leukemia-associated coagulopathy in newly diagnosed pediatric leukemia patients using CCT's and Rotational Thromboelastometry (ROTEM). METHODS: Pediatric patients with newly diagnosed acute leukemia underwent testing with ROTEM and CCTs on days 0, 15 and 29 of induction chemotherapy. RESULTS: Sixty-two patients were enrolled. At presentation, 54.8 % of patients had platelets <50 K/µL, 73 % had prolonged PT, 1.6 % had fibrinogen <150 mg/dL. Fifteen patients (24.2 %) had WHO grade 1 bleeding and two patients (3 %) had WHO grade 4 bleeding. EXTEM/INTEM values at presentation (day 0) reflected hypocoagulability, however FIBTEM revealed hypercoagulability. Patients showed a progressive hypocoagulability in all ROTEM assays by day 15 (day 0 vs day 15, p < 0.001), with improvement by day 29 (day 15 vs day 29, p < 0.001). Day 0 ROTEM parameters were comparable to day 29. Fibrinogen strongly correlated with ROTEM at all three time points (p < 0.0001), along with platelet count with moderate correlations (p < 0.001). CONCLUSION: Fibrinogen and platelets appear to be the drivers of leukemia associated coagulopathy in the pediatric population, suggesting the utility of using CCTs and ROTEM in this population to better evaluate hemostatic function and guide blood product replacement.

Management of pregnancy and delivery in congenital fibrinogen disorders: communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen.

Congenital fibrinogen disorders (CFDs) are a heterogeneous group of rare congenital quantitative and/or qualitative fibrinogen deficiencies. The spectrum of molecular anomalies is broad, leading to several subtypes of fibrinogen disorders (ie, afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia). Pregnancy in women with CFDs is a high-risk clinical situation, with an increased tendency for miscarriages, bleeding, and thrombosis. Even though it is well established that management of such pregnancies requires a multidisciplinary approach involving specialists (hematologists and maternal/fetal medicine experts with expertise in the management of inherited bleeding disorders), specific guidelines are lacking. In this International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee communication, we aim to propose an expert consensus opinion with literature evidence where available on the strategy for management of pregnancy, delivery, and puerperium in CFDs.