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Non-severe haemophilia A patients have a life-time risk of developing neutralizing allo-antibodies (inhibitors) against factor VIII (FVIII) with increasing exposure to exogenous FVIII. We summarize the safe and effective individualized management of surgical procedures in three mild haemophilia A patients with a history of inhibitors. His inhibitor kinetically behaved like the inhibitor in acquire haemophilia that did not completely inactivate his mutated FVIII despite a very high titer.10 Ideally the patient should have been under our direct care for the entire 14 days post-operation. His surgery was uneventful covered with DDAVP 30 mcg subcutaneously and tranexamic acid (10 mg/kg, total 1 g) intravenously 30 min before surgery followed by an additional DDAVP dose the next morning. [Extracted from the article]

There is a large population of people with haemophilia in China. However, the development of haemophilia care in China lagged far behind developed countries and was unbalanced across different regions. With the establishment of the Hemophilia Treatment Center Collaborative Network of China (HTCCNC) in 2004 and its collaboration with the Chinese government, the World Federation of Haemophilia (WFH), non‐profit foundations, industries, and experts from other countries, haemophilia care in China have made considerable strides in building capacity. The HTCCNC helped develop clinics throughout the country, promote multidisciplinary care, promote prophylaxis (albeit low‐dose), advance clinical evaluation and treatment, and research. With many collaborative efforts in the past decade, haemophilia care in China has entered a new stage of development. In this review, we summarize these major achievements and efforts within the last decade. [ABSTRACT FROM AUTHOR]

Introduction: During the 1970s and early 1980s, Canada's comprehensive care haemophilic programs were established. Newer therapies led to a rapid increase in quality of life and expected life span for persons with haemophilia (PWH). The outlook was bright. However, beginning in 1982, the appearance of HIV/AIDS transmitted by treatment products led to the 'tainted blood' era with its devastating impact on PWH, recently highlighted in the Canadian Broadcasting Corporation mini‐series 'Unspeakable'. What has received less notice is how the healthcare professionals (HCP) managing these patients then were affected. Aim: To report the emotional effects of that era on HCPs. Methods: In developing an oral history of haemophilic care in Canada we have interviewed 76 HCPs, the majority of whom had worked in haemophilic clinics during that era. During each interview, we asked the interviewee to reflect on what this did to haemophilic care and to him/herself. The interview responses were analysed. Results: HCPs have been markedly affected by the events of the 1980s with feelings that persist more than 30 years later. Most related to the loss of so many of their patients and the inability to alter the rapidly changing course of events at the time. Conclusion: The 'tainted blood' era had persistent strong emotional effects on HCPs. They were helpless to stop or to mitigate the devastating epidemics. Wellness support programs were less well developed then. While the focus is in the Canadian context, we suggest that a parallel can be drawn within haemophilic communities in other countries. [ABSTRACT FROM AUTHOR]

Abstract Platelets are a critical component for effecting hemostasis and wound healing. Disorders affecting any platelet pathway mediating adhesion, activation, aggregation and procoagulant surface exposure can result in a bleeding diathesis. Specific diagnosis even with advanced techniques which are unavailable to most centers is often difficult. Inherited platelet function disorders therefore represent a heterogeneous and complex collection of disorders with a spectrum of bleeding severity, from relatively mild (and easily missed or misdiagnosed) to severe bleeding phenotype with salient diagnostic features. We advocate the use of bleeding assessment tools to help identification of patients and more importantly for assessment of individual patient bleeding phenotype to guide management decisions for treating and preventing bleeding. The complex management of these patients is best coordinated in a multidisciplinary comprehensive care clinic setting expert in managing bleeding disorders and associated complications, with particular attention to the physical and psychosocial health of patients and their families. Depending on the bleeding phenotype, the location and severity of bleeding, and the nature of an invasive procedure, available treatment modalities range from conservative measures using local pressure, topical thrombin, fibrin sealant, antifibrinolytics etc. to the use of systemic haemostatics such as desmopressin (DDAVP), platelets and recombinant human activated factor VII (rFVIIa). This review will provide opinions on the practical aspects and general management of inherited platelet function disorders, with discussion on the mechanism of action, and the pros and cons of various hemostatic agents. Finally, the prospect of curative treatment for patients with severe bleeding phenotype refractory to available treatments and with poor quality of life will be briefly discussed. [ABSTRACT FROM AUTHOR]

Introduction: Peri‐procedural management of von Willebrand disease (VWD) utilizes von Willebrand factor (VWF) concentrates or desmopressin (DDAVP) to increase VWF levels. DDAVP is safe, easily administered, and inexpensive. Currently, a consensus definition for adequate DDAVP response is lacking, and outcomes of peri‐procedural DDAVP use in VWD patients are seldom reported. Aim: This single‐centre retrospective review aims to characterize DDAVP‐responsiveness and assess clinical outcomes of peri‐procedural DDAVP use in VWD. Patients and Methods: We reviewed records for all our adult VWD patients (age ≥18 years) who underwent DDAVP challenge testing between January 2007 and January 2022. DDAVP‐responsiveness was assessed using six definitions. Bleeding outcomes following procedures covered by DDAVP were classified as excessive or expected bleeding. Results: Eighty‐four of 94 (89.4%) patients were DDAVP‐responsive by our definition (1‐h VWF Activity/Factor VIII ≥0.50 IU/mL). However, the proportion of DDAVP‐responders varied from 53.2% to 91.5%, depending on the literature definition used. Ninety‐nine procedures pre‐treated with DDAVP were performed during the study period. Eighty‐six (86.7%) procedures (31 major; 55 minor) were covered with only DDAVP ± tranexamic acid (TXA). Excessive bleeding occurred following 4/31 major procedures and 2/55 minor procedures (both performed in a single patient with a bleeding score of 16). When covered with DDAVP+Factor ± TXA, one each of 10 major and 3 minor procedures (performed in 2 patients with bleeding scores 15–16) resulted in post‐procedural bleeding. Conclusions: Peri‐procedural DDAVP prophylaxis appears to be effective among individuals with VWD. Beyond DDAVP‐responsiveness, patient bleeding history and procedure invasiveness should be considered in determining suitability for DDAVP prophylaxis. [ABSTRACT FROM AUTHOR]

Introduction: Women and girls with haemophilia (WGH) may have spontaneous/traumatic bleeding similar to that in males with haemophilia, and in addition excessive bleeding during menstruation and delivery. Aim: To characterize WGH in China and provide guidance for better management. Methods: We retrospectively analysed the characteristics of WGH registered in the Haemophilia Treatment Center Collaborative Network of China (HTCCNC) Registry, including demographics, diagnosis and treatment, bleeding characteristics, obstetrical and gynaecological experiences, and surgical history. Results: A total of 61 females had confirmed haemophilia. Diagnosis and treatment were typically delayed, longer in mild haemophilia than in severe and moderate. The most frequently reported bleeding manifestations were haemarthrosis in severe and moderate patients, and cutaneous bleeding in mild patients. Among 45 postmenarcheal WGH, 21 (46.7%) had history of heavy menstrual bleeding, but only three received treatments. Prenatal diagnosis and management of perinatal haemorrhage were inadequate. Of 34 deliveries in 30 women, nine deliveries were complicated by postpartum haemorrhage, and 22 offspring carried mutations causing haemophilia. Forty‐four surgical procedures were performed in 29 patients. Those procedures receiving preoperative coagulation factors coverage were significantly less likely to have excessive bleeding than those who did not (P =.003). Conclusion: This is the first and largest study describing WGH in China. There are currently deficiencies in the identification, diagnosis, and management of these patients. Improving health insurance policies, establishing haemophilia centres, and multidisciplinary teams for bleeding and perinatal or perioperative management will help reduce morbidity and mortality. [ABSTRACT FROM AUTHOR]

Introduction: The development of inhibitors against factor FIX (FIX) is the most serious complication of FIX replacement therapy in haemophilia B (HB) patients. Currently, only few cohorts of HB inhibitor patients have been reported worldwide. Aim: This Chinese nationwide study of HB inhibitor patients explored their risk factors for FIX inhibitor development and experience on their management. Methods: We retrospectively analysed patient characteristics, F9 genotypes, treatment strategies and outcomes of HB inhibitor patients registered to the Chinese National Registry and Patient Organization Registry. Results: Forty‐four unique HB inhibitor patients were identified in 4485 unique HB patients registered by year 2021 to the two Registries. Inhibitor diagnosis were usually delayed and the low prevalence (.98%) may suggest some inhibitor patients were not identified. Their median age at inhibitor diagnosis was 7.5 (IQR, 3.0–14.8) years. Most patients (95.5%) had high‐titre inhibitors. Allergic/Anaphylactic reactions occurred in 59.1% patients. Large deletions and nonsense mutations were the most common F9 mutation types in our FIX inhibitor patients. Patients with large F9 gene deletions were more likely to develop inhibitors (p =.0002), while those with missense mutations had a low risk (p <.0001). Thirteen (29.5%) patients received immune tolerance induction (ITI) therapy using low‐dose prothrombin complex concentrate regimens. Twelve completed ITI with three (25.0%) achieving success. Nephrotic syndrome developed in two (16.7%) patients during ITI. Conclusion: This study reports the largest Chinese cohort of HB inhibitor patients. Large deletions were most significantly associated with inhibitor development. Low‐dose ITI might be feasible for FIX inhibitor eradication. [ABSTRACT FROM AUTHOR]

Abstract: Hemophilia is an X-linked bleeding disorder caused by a deficiency of factor VIII or IX activity. We will review the use of blood products, including plasma derived and recombinant coagulation factor concentrates (CFCs), and other hemostatic agents central to the management of bleeding, surgical procedures, prophylaxis and inhibitors. However, management of hemophilia is more than just giving CFCs. Attention to the physical and psychosocial health of persons with hemophilia to improve their quality of life must be the goal. These goals can best be met by comprehensive care hemophilia (bleeding disorders) clinics designed to provide clinical service and education to persons with hemophilia and their families, and to conduct research to improve hemophilia care. [Copyright &y& Elsevier]

Introduction Aim Methods Results Conclusion Reduced doses of emicizumab improve the affordability among patients in developing countries. However, the relationship between variant dose selection and efficacy in the real world of China is still unclear.This study aimed to investigate the efficacy and safety of emicizumab especially in those on reduced dose regimens in a real‐world setting.We carried out a multicentre study from 28 hospitals between June 2019 and June 2023 in China and retrospectively analysed the characteristics including demographics, diagnosis, treatment, bleeding episodes, and surgical procedures.In total, 127 patients with haemophilia A, including 42 with inhibitors, were followed for a median duration of 16.0 (IQR: 9.0–30.0) months. Median age at emicizumab initiation was 2.0 (IQR: 1.0–4.0) years. Median (IQR) consumption for loading and maintenance was 12.0 (8.0–12.0) and 4.2 (3.0–6.0) mg/kg/4 weeks, respectively. While on emicizumab, 67 (52.8%) patients had no bleeds, whereas 60 (47.2%) patients had any bleeds, including 26 with treated bleeds. Compared to previous treatments, patients on emicizumab had significantly decreased annualized bleeding rate, annualized joint bleeding rate, target joints and intracerebral haemorrhage. Different dosages had similar efficacy except the proportion of patients with treated spontaneous bleeds and target joints. Adverse events were reported in 12 (9.4%) patients. Postoperative excessive bleeding occurred following two of nine procedures.This is the largest study describing patients with HA receiving emicizumab prophylaxis on variant dose regimens in China. We confirmed that nonstandard dose is efficacious and can be considered where full‐dose emicizumab is ill affordable. [ABSTRACT FROM AUTHOR]

Introduction: Recombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) became available in Canada in 2016 and were the only extended half‐life (EHL) factor concentrates available in Canada until 2018. Objectives: We aim to describe the change in product utilization in Canadians who switched to rFVIIIFc/rFIXFc. Methods: This prospective and retrospective cohort study enrolled males aged ≥6 years with moderate or severe haemophilia who switched to rFVIIIFc/rFIXFc and those who remained on standard half‐life (SHL) between 2016 and 2018. Factor utilization and annualized bleeding rates (ABR) were collected at baseline, 1‐year and 2‐years. Due to low prospective enrolment (n = 25 switchers), prospective and retrospective data were pooled. Results: 125 switchers (93 rFVIIIFc, 32 rFIXFc) and 33 non‐switchers were included. The median age was 17 (rFVIIIFc) and 38 years (rFIXFc). Prior to switch, over 80% were on prophylaxis. There was a statistically significant reduction in the prescribed weekly prophylactic dose after the switch to rFVIIIFc/rFIXFc for all age groups, with a corresponding reduction (15‐16%) in actual annualized FIX utilization in switchers (combined adults and children) to rFIXFc, and a smaller non‐significant reduction in actual annualized FVIIII utilization (7%) in children who switched to rFVIIIFc. A significant reduction in the median ABR was only observed in children who switched to rFVIIIFc, but not in adults who switched to rFVIIIFc or rFIXFc. Conclusion: Switching from SHL to EHL products led to a small reduction in factor utilization, while preserving a low ABR in children and adults with haemophilia. Further patient‐reported outcomes data will further elucidate the role of EHL in the haemophilia landscape. [ABSTRACT FROM AUTHOR]

Summary: To investigate the current experience and expertise for haemophilia inhibitor patient management in haemophilia treatment centres (HTCs) in mainland China. Questionnaires were distributed to 'tertiary tier A' hospital HTCs across China to collect information on treatment preferences for bleeding control, prophylaxis and inhibitor eradication, as well as their regimens in real‐world clinical practice. Of 40 questionnaires distributed, 39 were returned. In all, 38 were analysable for treatment preferences and 34 for actual clinical practice. For haemostatic treatment, 76·3% (29/38) HTCs preferred activated recombinant human Factor VII (rFVIIa). In clinical practice, the most widely used by‐pass agent was prothrombin complex concentrate (26 HTCs). Although 65·8% (25/38) of HTCs believed prophylaxis treatment was necessary, it was prescribed in only 12. Similarly, 65·8% (25/38) of HTCs believed immune tolerance induction (ITI) therapy was necessary but only 14·8% (92/622) of patients in 19 HTCs received low‐dose ITI treatment. HTCs in relatively economically developed cities (with higher‐than‐average per‐capita gross domestic product) had better access to haemostatic treatment, coagulation testing and were more likely to provide prophylaxis and ITI in practice. The present survey showed there were gaps in haemophilia inhibitor care between the HTC physicians' preferences and their actual clinical practice. More specific care guidelines, education and clinical decision support tools are needed to guide clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: The majority of clotting factor IX (FIX) resides extravascularly, in the subendothelial basement membrane, where it is important for haemostasis. Aim: We summarize preclinical studies demonstrating extravascular FIX and its role in haemostasis and discuss clinical observations supporting this. We compare the in vivo binding of BeneFIX® and the extended half‐life FIX, Alprolix®, to extravascular type IV collagen (Col4). Methods: Three mouse models of haemophilia were used: the FIX knockout as the CRM− model and two knock‐in mice, representing a CRM+ model of a commonly occurring patient mutation (FIXR333Q) or a mutation that binds poorly to Col4 (FIXK5A). The murine saphenous vein bleeding model was used to assess haemostatic competency. Clinical publications were reviewed for relevance to extravascular FIX. Results: CRM status affects recovery and prophylactic efficacy. Prophylactic protection decreases ~5X faster in CRM+ animals. Extravascular haemostasis can explain unexpected breakthrough bleeding in patients treated with some EHL‐FIX therapeutics. In mice, both Alprolix® and BeneFIX® bind Col4 with similar affinities (Kd~20–40 nM) and show dose‐dependent recoveries. As expected, the concentration of binding sites in the mouse calculated for Alprolix® (574 nM) was greater than for BeneFIX® (405 nM), due to Alprolix® binding to both Col4 and the endothelial cell neonatal Fc receptor. Conclusion: Preclinical and clinical results support the interpretation that FIX plays a role in haemostasis from its extravascular location. We believe that knowing the CRM status of haemophilia B patients is important for optimizing prophylactic dosing with less trial and error, thereby decreasing clinical morbidity. [ABSTRACT FROM AUTHOR]

Summary: The development of alloantibodies (inhibitors) against coagulation factor VIII (FVIII) is the most serious complication of FVIII replacement therapy in patients with haemophilia A (HA). We carried out a nationwide study focussing on patients with HA with inhibitors in China to evaluate the condition and management of this population. The study retrospectively analysed patient characteristics, clinical history, manifestation, treatment strategy as well as individual haemophilia care of 493 patients with inhibitors (466 with severe HA and 27 with non‐severe HA) registered all over China. The median (interquartile range) age at diagnosis of FVIII inhibitors was 13 (5–28) years in patients with severe HA and 24 (10·5–39·5) years in patients with non‐severe HA. Most patients (85%) had high‐titre inhibitors. Prothrombin complex concentrate and recombinant activated coagulation factor VII were used respectively in 76·2% and 29·2% of patients for acute bleeding. Only 22·3% of patients underwent immune tolerance induction (ITI) treatment, of whom 64·9% achieved negative inhibitor titre. In patients who did not undergo ITI, the inhibitors turned negative in 17·7%, and patients with low peak inhibitor titre were more likely to acquire negative titre spontaneously (odds ratio 11·524, 95% confidence interval 5·222–25·432; P = 0·000). We recorded that 3·2% of the patients died from haemophilia‐related life‐threatening bleeding. [ABSTRACT FROM AUTHOR]

Objective: To identify lessons learned from haemophilia care experience in Wuhan (COVID‐19 outbreak epicenter in China) and Tianjin (with relatively low COVID‐19 incidence) in the pandemic. Methods: We compared the challenges in haemophilia management attributed to local COVID‐19 containment policies, healthcare resource availability, clotting factors supply, daily living restrictions and coping strategies employed. Results: Wuhan was in lockdown with strict traffic controls, enforced quarantine and overwhelmed resources. Tianjin was in relatively relaxed countermeasures to COVID‐19. In Wuhan, haemophilia treatment (for bleeding, prophylaxis, multidisciplinary team care, immune tolerance induction) and patient education were severely affected, while the challenges in Tianjin were less. In both cities, patients' fear for COVID‐19 infection also affected their management. Coping strategy in Wuhan included channelling of clotting factors supply from hospitals to nine pharmacies; timely transfers of in‐need patients to healthcare facilities by a volunteer service network jointly coordinated by the government, hospitals and the community. Although factor concentrate supply in each city was adequate, patients still worried whether there would be enough supply to last through the pandemics. Consequently, many downgraded their treatment regimens resulting in increased bleeding episodes. In both cities, telemedicine was promoted for patient care and education. Conclusions: The COVID‐19 pandemic had varying adverse impacts on haemophilia care depending on the local infection incidence. Our experience suggests that haemophilia management strategies in the pandemic need to be established according to the local virus containment/mitigation policies, daily living restrictions and resource availability. [ABSTRACT FROM AUTHOR]

Shorter interval-time from inhibitor detection to starting immune tolerance induction (ITI) might predict better ITI outcomes for severe Hemophilia A (SHA) patients with high-risk-inhibitors. However, the prediction-impact of interval-time for these patients on low-dose ITI strategy remained unclear. To explore the relationship between interval-time and low-dose ITI outcomes in Chinese SHA children with high-risk-inhibitors. This was a single-center, retrospective study on SHA children with high-risk-inhibitors (each with immediate pre-ITI inhibitor titer>10 Bethesda Units/mL) undergoing low-dose ITI strategy for ≥24 months. ITI outcomes and their predictive factors were evaluated at the 24th month treatment for each patient. The predictive ability of interval-time on ITI success was determined using receiver operating characteristic (ROC) curve. Among 47 patients investigated, 34 (72.3 %) achieved success. Independent predictor for ITI-outcome on multivariate analysis included the interval-time (p = 0.007) and peak inhibitor-titer (p = 0.011). Shorter interval-time predicted ITI success [cut-off value = 22.3 months, area under ROC-curve (AUC) = 0.701] and early-ITI success within 12 month (cut-off value = 9.4 months AUC = 0.704). Linear regression analysis suggested each month interval-time delay delayed success by 0.1552 month. Unlike the interval-time, peak inhibitor-titer had no success-predictive value in high-peak inhibitor-titer patients on ITI with immunosuppressants. Interval-time represented a strong predictive value for outcomes in our low-dose ITI strategy for SHA patients with high-risk-inhibitors. Shorter interval-time was associated with higher success rate and earlier success achievement. The respective interval-time cut-off values were 22.3 months for ITI success and 9.4 months for early-success. • The interval-time is the time from inhibitor detection to starting ITI. • Interval-time for predicting low-dose ITI outcomes remained unclear, for high-risk-inhibitors patients. • Interval-time had a strong predictive value for outcomes in our low-dose ITI strategy. • Interval-time cut-off values were 22.3 for success and 9.4 months for early-success. [ABSTRACT FROM AUTHOR]

• Refractoriness was inability to achieve negative inhibitor titer over at least 12 months period taking LD-ITI+Rituximab-IS. • There is therefore a need to explore rescue-regimen(s) for refractory patients. • MMF might exert T-cell immunosuppression not covered by Rituximab which focuses on B-cell suppression. • The sequential MMF-rescue-regimen had efficacy in the patients refractory to our initial LD-ITI+Rituximab-IS regimen. [ABSTRACT FROM AUTHOR]

The risk factors for a family with VWD presenting with an ischemic stroke (IS) were explored. FVIII activity (FVIII:C), VWF antigen (VWF:Ag), and protein S activity were measured. Next generation sequencing (NGS) was performed targeting F8, F9, VWF, PROC, and PROS1. Sanger sequencing validation was performed on family members. The proband and his sister both had low FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) levels, confirming the diagnosis of type 3 VWD. His father had nearly normal levels of FVIII:C (58 IU/dL) and VWF:Ag (57 IU/dL). His daughter had type 1 VWD with decreased FVIII:C (46 IU/dL) and VWF:Ag (19 IU/dL). NGS identified a heterozygous VWF c.2328delT (p.A778Lfs*23) frame shift mutation only in the proband and his sister. Another VWF missense mutation, c.6521G > T (p.C2174F), was found heterozygous in all members studied. A PROS1 mutation, c.946C > T (p.R316C), previously reported to relate to ischemic stroke, was found heterozygous in the patient, his father, and his daughter. Only the proband and daughter have a slightly decreased plasma protein S level. This may be the first case with type 3 VWD with severe VWF/FVIII deficiency presented with ischemic stroke contributed to by a protein S defect. [ABSTRACT FROM AUTHOR]

Introduction: Development of haemophilia B inhibitors (HBI) results in the ineffectiveness of FIX replacement therapy. Inhibitor eradication by immune tolerance induction (ITI) is therefore necessary. In HBI, ITI even at high FIX dose is less effective and has a higher risk of severe complications. Aim: To characterize clinical features and outcome of ITI on HBI. Methods: This retrospective study was conducted in Haemophilia Paediatric Comprehensive Care Centre of China. We used low‐dose ITI (25–50 FIX IU/kg/three‐times‐weekly to every‐other‐day) with domestic prothrombin complex concentrate (PCC), combined with two successive immunosuppressive (IS) regimens. Results: Sixteen HBI children, representing 5.7% of all and 14.4% of our severe registered HB patients, were enroled. Seven cases reported allergic reactions (ARs) proximal to inhibitor development. The historic peak inhibitor titre was median 54.2 (range 4.7–512) BU, and 15 (93.8%) had high‐titre inhibitors. Twelve patients adherent to ITI were analysable. Of the nine ITI patients who received rituximab/prednisone (IS Regimen‐1), four achieved tolerization in 1.4–43.3 months. Two subsequently relapsed but re‐tolerized after a second course of IS Regimen‐1. During ITI, the median treated bleed was.39/month (82.7% reduction from before ITI), and the incidence of AR and nephrotic syndrome (NS) complications was each at 22% (2/9). Three ITI patients received modified 'Beutel' protocol (IS Regimen‐2) using multiple‐IS‐drugs, and two had rapid tolerization (.8 and 1.8 months). Conclusions: Inhibitor eradication could be achieved by low‐dose ITI protocol using PCC combined with IS. Larger studies are needed to confirm if ITI with IS Regimen‐2 is more effective with less complications. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the characteristics of the sickle cell disease population in a city of low prevalence and compare them to those reported in the literature. We performed a retrospective cross-sectional study of all sickle cell disease patients seen in the Calgary Health Region, Calgary, Alberta, Canada from 2006 to 2010. Data on clinical endpoints including emergency department (ED) visits, hospital admissions, transfusions, as well as laboratory parameters were collected. A total of 37 adult sickle cell disease patients were identified. Over 5 years, they were represented by a total of 49.2 ED presentations/year, 29.2 (59.0%) of these requiring admission. Eighty-three percent of these presentations were for acute pain episodes. We concluded that the number of ED visits, hospital admissions and several other parameters in our cohort were similar to those in other centers of higher prevalence. This suggests that guidelines representing regions of high prevalence may be applicable to smaller centers, where patients experience similar clinical outcomes. [ABSTRACT FROM AUTHOR]

Platelets may be pivotal mediators of the thrombotic and coagulopathic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. Both PE and gestational hypertension (GH) fall within the spectrum of hypertensive complications of pregnancy, with GH being a risk factor for preeclampsia. However, it is unclear what biomarkers distinguish PE from GH. Using a discovery size cohort, we aimed to characterize specific plasma and platelet thrombo-inflammatory drivers indicative of PE and differentiate PE from GH. We performed multiplex immunoassays, platelet and plasma quantitative proteomics and metabolomics of PE patients, comparing with non-pregnant (NP), healthy pregnant controls (PC) and GH participants. The expression pattern of plasma proteins and metabolites in PE/GH platelets was distinct from that of NP and PC. Whilst procoagulation in PC may be fibrinogen driven, inter-alpha-trypsin inhibitors ITIH2 and ITIH3 are likely mediators of thrombo-inflammation in GH and PE, and fibronectin and S100A8/9 may be major procoagulant agonists in PE only. Also enriched in PE were CCL1 and CCL27 plasma cytokines, and the platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42), whose effects on platelets were explored using STRING analysis. Through protein-protein interactions analysis, we generated a new hypothesis for platelets' contribution to the thrombo-inflammatory states of preeclampsia. [ABSTRACT FROM AUTHOR]

Allergic reactions to FIX have been associated with nephrotic syndrome and poor ITI outcome.3 Both our cases did, with case 2 having allergic reactions simultaneously with inhibitor development. This is consistent with previous observations that NS development was closely related to a significant decline in inhibitor titre.2 Interestingly, the NS in case 2 was preceded by a second allergic reactions to the ITI regimen and in case 1 by a fluctuation of inhibitor titres during ITI-rituximab. Patients with haemophilia B (HB) may develop factor IX (FIX) inhibitors with a cumulative incidence of 10.2% following FIX replacement therapy by 500 exposure days.1 In 50-60% cases, occurrence of severe allergic reactions may precede or occur simultaneously with the inhibitor development.2 The propensity for FIX to induce allergic reactions (compared to FVIII) may be related to the extravascular distribution of the smaller FIX molecules.3 Immune tolerance induction (ITI) therapy to eradicate FIX inhibitors has a poor success rate of only 13-31%.2,4 There is also a risk of developing nephrotic syndrome (NS) in 17-33% cases. Nephrotic syndrome in two haemophilia B children with inhibitor under low-dose immune tolerance induction combined with rituximab-based immunosuppressant protocol. [Extracted from the article]

The mean (±SD) annual joint bleeding frequency for all 214 patients with information was 16.53 (±22.03), being 19.72 (±23.50) for adult patients, and 10.75 (±17.81) for paediatric patients. It is notable that the number of patients with moderate haemophilia in this study was more than twice that of severe haemophilia, and that the bleeding phenotype of both groups were similar suggesting some of the moderate patients actually had severe haemophilia. Among 823 patients with treatment information, most ( I n i = 702 patients, 85.3%) received on-demand therapy, of whom 17% ( I n i = 121) patients received treatment only for severe bleeding and 10.4% ( I n i = 73) patients received on-demand with periodic prophylaxis. In addition, 526 (42.9%) patients had deformed joints, mean (±SD) number being 2.44 (±1.87) for all HB patients, 2.63 (±1.88) for the severe, 2.38 (±1.95) for the moderate, 2.22 (±1.60) for the mild patients. [Extracted from the article]

A low-dose immune tolerance induction (ITI) protocol incorporating immunosuppressive agents in haemophilia A children with high-titre factor VIII inhibitor and poor-ITI prognostic risk These were all on good-ITI risk patients with inhibitor titre <10 BU at the initiation of ITI and historical peak inhibitor titre <200 BU. Nineteen haemophilia A inhibitor children with poor-ITI risk (historical peak inhibitor titre >=100 BU and/or inhibitor titre >=40 BU at ITI initiation) (Table 1) were enrolled from September 2016 through April 2019. Various ITI regimens achieved an overall success rates of 60%-80%.2,3 According to the UK guideline,4 low-dose ITI (50 IU/kg, every-other-day) was only suggested for using in patient with low-titre inhibitors (historical peak inhibitors <5 BU). [Extracted from the article]

Objectives: To explore the long‐term joint outcomes of low‐dose prophylaxis in Chinese children with severe haemophilia A and to analyse their related factors. Methods: We retrospectively analysed follow‐up data from 21 severe haemophilia A children on regular low‐dose prophylaxis for 6–10 years. We used International Prophylaxis Study Group magnetic resonance imaging score (IPSG MRI score), Hemophilia Joint Health Score (HJHS), number of target joints, and Hemophilia‐Specific Quality of Life Index (Haemo‐QoL) to evaluate joint outcomes. Factors associated with these outcomes were evaluated by statistical analysis. Results: (1) The children were 1.75 to 17 years age at prophylaxis initiation. Median prophylactic factor VIII dose was 22.9 IU/kg per week. (2) At the end of follow‐up: (a) The total IPSG MRI scores were 2–24 with 90.5% children exhibiting moderate to severe joint involvement (score 7–24); (b) The HJHS ranged 2–27, with 0–10 for 46.7% children and >10 for 53.3% children. There was a positive correlation between the MRI score and HJHS (p <.05); (c) Compared to their on‐demand treatment period before prophylaxis, target joints numbers decreased, and no child needed auxiliary devices to walk; (d) Joint outcomes were positively correlated with the age at initiation of low‐dose prophylaxis (p <.05) and negatively correlated with the treatment dose. Conclusion: Long‐term low‐dose prophylaxis had positive effect on joint outcomes compared with on‐demand treatment. However, a certain degree of joint damage remained in all children indicating the need for improving the current strategy of low‐dose prophylaxis. [ABSTRACT FROM AUTHOR]

Background: In countries with limited resource, haemophilia patients have to choose low‐dose prophylaxis or on‐demand treatment (ODT) because of economic constraints. Whether low‐dose prophylaxis can achieve better joint function outcome than ODT over long‐term remains unclear. Aim: To investigate the long‐term effect of low‐dose tertiary prophylaxis versus ODT on joint health in severe haemophilia A children. Methods: This was a retrospective study. We enrolled and followed 34 severe haemophilia boys in China receiving on‐demand treatment (n = 18) or low‐dose prophylaxis (10‐15 IU/kg, 2‐3 times per week) for a medium‐term (6‐18 months, n = 9) or longer‐term (19‐30 months, n = 7). We evaluated their haemophilia joint health score (HJHS) 2.1 and functional independence score in haemophilia (FISH) at baseline and at their 6‐year follow‐up visits. Their annual bleeding rate (ABR) and annual joint bleeding rate (AJBR) were also recorded. Results: During the 6‐year follow‐up period, ABR and AJBR were similar between the 2 prophylaxis groups, with each of the 2 prophylaxis group rates being significantly better (lower) than the ODT group (P <.05). Compared to baseline values, evaluation at 6‐year follow‐up showed HJHS improvement in both prophylaxis groups, although significantly (P <.05) only in the longer‐term prophylaxis group. The FISH score showed insignificant change in patients in each prophylaxis cohort, compared to significant worsening (P <.05) in the ODT group. Conclusion: Low‐dose tertiary prophylaxis reduced ABR and AJBR of children with severe haemophilia and better maintained their functional independence by the FISH over the long term. Longer‐term prophylaxis also improved their joint health status by the HJHS. [ABSTRACT FROM AUTHOR]

Introduction: An increased bleeding tendency has been shown in female haemophilia carriers compared to healthy females. Bleeding assessment tools (BATs) have mainly been performed in western cultures. It is unclear how they perform in populations with different healthcare, health/wellness concepts and awareness, as well as family planning practices. Aim: To (a) describe and compare the bleeding symptoms in carriers with healthy females, particularly for bleeding after surgical abortion and intrauterine device (IUD) placement which are performed frequently for family planning in China; (b) quantify scores of International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH‐BAT) and Chinese‐BAT (C‐BAT) developed to include surgical abortion and IUD placement as separate categories in Chinese haemophilia carriers; (c) correlate bleeding scores (BS) with factor levels. Methods: We conducted a multicentre, cross‐sectional study on obligate haemophilia carriers and healthy controls using ISTH‐BAT and C‐BAT. Results: We enrolled 125 haemophilia carriers and 106 controls. Carriers, compared to controls, had significantly higher median BS (3 vs 1 by both ISTH‐BAT and C‐BAT) and lower factor level (63.5 vs 101.8 IU/dL). Bleeding after surgical abortion and IUD placement was significantly associated with carrier status. Bleeding scores from neither ISTH‐BAT nor C‐BAT showed significant correlation with factor levels. Conclusion: Haemophilia carriers in China experienced abnormal bleeding. Unique to the Chinese carriers is significant bleeding after surgical abortion (3rd highest incidence of bleeding symptom) and IUD placement (4th highest). However, both ISTH‐BAT and C‐BAT exhibited no correlation between BS and factor levels in this population and neither could identify carriers with low factor level (of <50 IU/dL). [ABSTRACT FROM AUTHOR]

Introduction: Desmopressin is an effective haemostatic agent for patients with non‐severe haemophilia A; however, response may differ between patients of similar severity. Responsiveness is classified based on various cut‐off values for plasma levels of FVIII post‐desmopressin administration. Patients may be classified differently depending on the values chosen. Aim: To classify desmopressin response in non‐severe haemophilia A patients with respect to current test‐response definitions. Also, to characterize relationships between test response and clinical outcome of desmopressin use. Methods: Current desmopressin test‐response definitions were obtained from the literature. We adopted peak FVIII level (at 1 hour post‐administration) ≥50 IU/dL and <20 IU/dL as complete and no response, respectively, thereby satisfying most reported definitions. Test‐responses and clinical outcomes of use between 2007 and 2017 for adult mild/moderate haemophilia A patients were reviewed and correlated. Results: All patients classified as complete responders (n = 31; peak FVIII ≥50 IU/dL) and the majority of partial responders (n = 11; peak FVIII ≥20 to <50 IU/dL) had good clinical outcomes after desmopressin use for a variety of bleeding episodes and procedures. Two non‐responders (peak FVIII <20 IU/dL) given desmopressin for minor bleeding/procedures also had good clinical outcomes. One patient with a partial test‐response (peak FVIII 23 IU/dL) required additional factor concentrate to achieve haemostasis. Conclusions: Based on our review, we suggest that the determination of desmopressin responsiveness should consider both the change in plasma FVIII levels as well as clinical outcomes associated with prior therapeutic use. [ABSTRACT FROM AUTHOR]

Background: Warfarin-associated intracerebral hemorrhage (WAICH) is a devastating disease with increasing incidence. In this setting, treatment with prothrombin complex concentrates (PCC) is essential to correct coagulopathy. Yet despite the availability of coagulopathy correction strategies, significant treatment delays can occur in emergency departments (EDs), which may be overcome using stroke prenotification strategies. To explore this, we compared arrival-to-treatment times with PCC for WAICH between two different stroke response systems that used the same international normalized ratio (INR) correction protocol. Methods: We established a registry of consecutive patients presenting with WAICH and treated with PCC presenting to two Canadian tertiary-care academic stroke centers: one with a stroke prenotification system, and one with a traditional ED assessment, treatment and referral system. In this comparative cohort design, we defined the WAICH diagnosis time as the earliest time point where both INR and CT were available. We compared median times from arrival to treatment, as well as arrival to diagnosis, and diagnosis to treatment. Results: Between 2008 and 2010, we collected data from 123 consecutive patients with intracranial hemorrhage who received PCC for INR correction (79 from ED referral, and 44 prenotification). Onset-to-arrival times, demographics, Glasgow Coma Scale scores, and baseline INR were similar between the two systems. Arrival-to-treatment times were significantly shorter in the prenotification system as compared to the traditional ED referral system (135 vs. 267 min; p = 0.001), which was driven by both decreased arrival-to-diagnosis time (49 vs. 117 min; p = 0.006), as well as decreased diagnosis-to-treatment time (56 vs. 112 min; p < 0.001). Arrival-to-scan times and arrival-to-INR times were similarly shorter in the prenotification system (68 vs. 118 min and 20.5 vs. 47 min, respectively). Conclusion: Stroke prenotification was associated with shorter arrival-to-treatment times for emergent INR correction in patients with WAICH, which was driven by both faster diagnosis and treatment. Our results are consistent with those seen in ischemic stroke, suggesting that prenotification systems present an opportunity to optimize acute intracerebral hemorrhage therapy. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: A substantial clinical need exists for an alternate to vitamin K antagonists for treating deep vein thrombosis in many patients. Long-term low-molecular-weight heparin (LMWH), body-weight adjusted, avoids anticoagulant monitoring and may be associated with less bleeding. We evaluated the effectiveness and safety of long-term LMWH compared with vitamin K antagonist therapy in a broad spectrum of patients with proximal vein thrombosis.Methods: We performed a multicenter, randomized, open-label clinical trial using objective outcome measures comparing therapy for 3 months. Outcomes were assessed at 3 and 12 months.Results: Of 737 patients, 18 of 369 receiving tinzaparin (4.9%) had recurrent venous thromboembolism at 3 months compared with 21 of 368 (5.7%) receiving usual care (absolute difference, -0.8%, 95% confidence interval -4.1-2.4). Hemorrhagic complications occurred less frequently in the LMWH group largely because of less minor bleeding: 48 of 369 patients (13.0%) versus 73 of 368 patients (19.8%) receiving usual-care anticoagulation (absolute difference -6.8%; P = .011; risk ratio = 0.66). New major bleeding events ceased early (by day 23, P = .034) for patients receiving LMWH but persisted throughout the study treatment interval for patients receiving vitamin K antagonist therapy. No mortality advantage was shown for LMWH.Conclusion: Our study shows that LMWH is similar in effectiveness to the usual-care vitamin K antagonist treatment for preventing recurrent venous thromboembolism in a broad spectrum of patients. It causes less harm and enhances the clinicians' therapeutic options for patients with proximal deep vein thrombosis. Our findings reported here suggest the possibility of a broader role for long-term LMWH in selected patients. [ABSTRACT FROM AUTHOR]

Purpose: A substantial clinical need exists for an alternative to vitamin K antagonists for treating deep-vein thrombosis in cancer patients who are at high risk of both recurrent venous thromboembolism and bleeding. Low-molecular-weight heparin, body-weight adjusted, avoids anticoagulant monitoring and has been shown to be more effective than vitamin-K-antagonist therapy.Subjects and Methods: Subjects were patients with cancer and acute symptomatic proximal-vein thrombosis. We performed a multi-centre randomized, open-label clinical trial using objective outcome measures comparing long-term therapeutic tinzaparin subcutaneously once daily with usual-care long-term vitamin-K-antagonist therapy for 3 months. Outcomes were assessed at 3 and 12 months.Results: Of 200 patients, 100 received tinzaparin and 100 received usual care. At 12 months, the usual-care group had an excess of recurrent venous thromboembolism; 16 of 100 (16%) versus 7 of 100 (7%) receiving low-molecular-weight heparin (P=.044; risk ratio=.44; absolute difference -9.0; 95% confidence interval [CI], -21.7 to -0.7). Bleeding, largely minor, occurred in 27 patients (27%) receiving tinzaparin and 24 patients (24%) receiving usual care (absolute difference -3.0; 95% CI, -9.1 to 15.1). In patients without additional risk factors for bleeding at the time of randomization, major bleeding occurred in 0 of 51 patients (0%) receiving tinzaparin and 1 of 48 patients (2.1%) receiving usual care. Mortality at 1 year was high, reflecting the severity of the cancers; 47% in each group died.Conclusion: Our findings confirm the limited but benchmark data in the literature that long-term low-molecular-weight heparin is more effective than vitamin-K-antagonist therapy for preventing recurrent venous thromboembolism in patients with cancer and proximal venous thrombosis. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Home-LITE compared long-term treatment at home with tinzaparin or usual care in terms of efficacy, safety, patients'' treatment satisfaction, incidence of post-thrombotic syndrome, and associated venous leg ulcers. Methods: This multicenter, randomized, controlled trial enrolled 480 patients with documented, acute, proximal deep vein thrombosis. Patients received tinzaparin 175 IU/kg subcutaneously once daily for 12 weeks, or tinzaparin for ≥5 days plus oral warfarin, commenced on day 1, international normalized ratio-adjusted, and continued for ≥12 weeks (“usual care”). Patients received 1 in-clinic injection, then home treatment. Results: The rate of recurrent venous thromboembolism at 12 weeks was 3.3% in both groups (absolute difference 0%; 95% confidence interval −3.2-3.2), and at 1 year was 10.4%/8.3% in the tinzaparin/usual-care groups, respectively (difference 2.1%; 95% confidence interval −3.1-7.3). There were no between-group differences in deaths at 12 weeks or 1 year, or bleeding at 12 weeks. Patients in the tinzaparin group expressed significantly greater treatment satisfaction (P = .0024), particularly regarding freedom from the inconvenience of blood monitoring; were less likely to report signs/symptoms of post-thrombotic syndrome (individual odds ratios 0.66 to 0.91, overall odds ratio 0.77, P = .001); and reported fewer leg ulcers at 12 weeks: 1 (0.5%) versus 8 (4.1%) (P = .02) with usual care. Conclusions: Long-term home treatment with tinzaparin or usual care resulted in similar rates of recurrent venous thromboembolism, death, and bleeding. The significantly lower incidence of post-thrombotic syndrome and leg ulcers observed in the tinzaparin group is a potentially important benefit and deserves further study. [Copyright &y& Elsevier]