Life-threatening Bleeding Events Research Articles

Dabigatran accumulation in acute kidney injury: is more better than less to prevent bleeding? A case report

Dabigatran is an oral anticoagulant that is mainly renally excreted. Despite its efficacy in preventing thromboembolic events, concerns arise regarding bleeding complications in patients with acute kidney injury. Idarucizumab is its specific antidote and reverses quickly and effectively dabigatran anticoagulation effects in situations of severe bleeding or pending surgical procedures, but its benefit beyond these two indications remains uncertain. We present a case of a woman with atrial fibrillation anticoagulated by dabigatran and admitted with Streptococcus agalactiae meningitis, acute kidney injury and dabigatran accumulation. Idarucizumab was not administered initially as she did not meet its current strict indications. However, subsequently, significant bleeding necessitated its use. A rebound increase in dabigatran concentration was associated with an intracranial hemorrhage, but the combination of additional doses of idarucizumab with hemodialysis lowered the dabigatran concentration and prevented significant rebound increases. Further investigation into the optimal management of dabigatran accumulation and acute kidney injury-associated bleeding is needed to enhance patient outcomes and safety. Early initiation of hemodialysis together with idarucizumab administration may be crucial in preventing life-threatening bleeding events in these patients.

Left atrial appendage clipping during hybrid atrial fibrillation ablation: a very long-term, single-center experience

Abstract Background/introduction Epicardial left atrial appendage (LAA) clipping is an effective strategy for stroke prophylaxis in high thromboembolic (TE) and bleeding risk patients with atrial fibrillation (AF). In addition to LAA exclusion from systemic circulation, clipping promotes concomitant appendage isolation, which might have positive impacts on arrhythmia control. Purpose The aim of this study was to report safety, success rate, and the long-term clinical outcomes of LAA clipping in a large cohort of AF patients undergoing concomitant hybrid ablation. Methods Consecutive patients undergoing hybrid AF ablation between 2013 and 2023 were enrolled. Hybrid ablation was performed in a one-step procedure consisting of thoracoscopic epicardial radiofrequency (RF) ablation followed by endocardial mapping and ablation, if needed. Ablation lesion set included pulmonary vein (PV) and posterior wall (PW) isolation, as well as RF applications to the LAA/posterolateral ridge. LAA clipping was performed via Atriclip exclusion system (Atricure, Inc., The Nederlands) after epicardial ablation. Additional endocardial lesions were performed in case of incomplete epicardial ablation or at physician’s discretion. Results A total of 130 patients were included (mean age: 65±9.4; 72.3% males); among them, 19.2% and 55.4% had persistent or long-standing persistent AF, respectively. Mean CHA2DS2-VASC and HAS-BLED were 3.1±1.1 and 2.3+-0.5. Five patients (3.8 %) had absolute contraindication to long-term oral anticoagulation, 3 (2.3%) had previous life-threatening bleeding events, 17 (13.1%) had a previous TE event. The final clip size was 35mm in 90.7% cases. Acute success was achieved in 97.7%; failure was due to LAA size (n=1), proximity to phrenic nerve (n=1), or bypass graft (n=1). One patient had incomplete occlusion due to a large secondary lobe, which required a second clip. No periprocedural complications related to clipping were documented. At a mean follow-up of 51±35 months, one (0.8%) patient had a stroke and 3 (2.3%) a transient ischemic attack (4 events per 552 patient/years; 0.7%). One patient had a microreentrant tachycardia mapped from the area near the LAA clipping. Conclusion In a large cohort undergoing hybrid AF ablation, epicardial LAA clipping was safe and highly successful. Acute failure was rare and due to LAA morphology or proximity to phrenic nerve and bypass graft. Thromboembolic event rate was very low.

Minimally modified human blood coagulation factor X to bypass direct factor Xa inhibitors

BackgroundDirect oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity. ObjectivesThe ability of FXa variants to bypass the direct oral FXa inhibitors was assessed. MethodsHuman FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography. ResultsF174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients. ConclusionThese human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions.

Expert Opinions on the Management of Hemophilia A in India: The Role of Emicizumab.

Hemophilia A (HA) is a genetic disorder of hemostasis associated with a deficiency or reduced activity of clotting factor VIII (FVIII). This disorder remains unacceptably underdiagnosed in India. Early diagnosis and appropriate management of HA can substantially prevent morbidity and mortality. Currently, HA is managed with regular replacement therapy using standard or extended half-life FVIII concentrates or non-factor drug products. The challenges associated with FVIII concentrates include plateauing of drug effect, issues with its administration and adherence to treatment, breakthrough bleeds, and the development of inhibiting antibodies against administered clotting factors. Emicizumab is a bispecific antibody, launched in India in April 2019, for managing patients with HA. To investigate the role of emicizumab in Indian patients with HA, opinions were sought from 13 eminent hematologists and experts from India on the effectiveness of emicizumab in preventing all bleeds, spontaneous bleeds, perioperative bleeds, and intracranial hemorrhage; resolving target joints; and reducing the rate of hospitalizations and fatality associated with HA in children and adults, with or without inhibitors. The benefits of emicizumab over traditional FVIII concentrates include the subcutaneous route of delivery, less frequent dosing, and a lack of inhibitor development, in addition to providing sustained hemostasis without in-depth monitoring. It is a safe and effective management option for all HA patients, especially for patients with certain archetypes, such as those with inhibitors, those with high annualized bleed rates, those living far away from hemophilia care centers, pediatric patients and infants with intravenous access challenges, and those with a history of life-threatening bleeding events.

Coagulation Tests and Reversal Agents in Patients Treated with Oral Anticoagulants: The Challenging Scenarios of Life-Threatening Bleeding and Unplanned Invasive Procedures.

In clinical practice, the number of patients treated with direct oral anticoagulants (DOACs) has consistently increased over the years. Since anticoagulant therapy has been associated with an annual incidence of major bleeding (MB) events of approximately 2% to 3.5%, it is of paramount importance to understand how to manage anticoagulated patients with major or life-threatening bleeding. A considerable number of these patients' conditions necessitate hospitalization, and the administration of reversal agents may be imperative to manage and control bleeding episodes effectively. Importantly, effective strategies for reversing the anticoagulant effects of DOACs have been well recognized. Specifically, idarucizumab has obtained regulatory approval for the reversal of dabigatran, and andexanet alfa has recently been approved for reversing the effects of apixaban or rivaroxaban in patients experiencing life-threatening or uncontrolled bleeding events. Moreover, continuous endeavors are being made to develop supplementary reversal agents. In emergency scenarios where specific reversal agents might not be accessible, non-specific hemostatic agents such as prothrombin complex concentrate can be utilized to neutralize the anticoagulant effects of DOACs. However, it is paramount to emphasize that specific reversal agents, characterized by their efficacy and safety, should be the preferred choice when suitable. Moreover, it is worth noting that adherence to the guidelines for the reversal agents is poor, and there is a notable gap between international recommendations and actual clinical practices in this regard. This narrative review aims to provide physicians with a practical approach to managing specific reversal agents.

One-year initial efficacy and safety outcomes of the premounted dry-pericardium Vienna self-expandable transcatheter aortic valve system: A first-in-human VIVA feasibility study.

The dry-pericardium Vienna transcatheter aortic valve system is repositionable and retrievable, already premounted on the delivery system, eliminating the need for assembly and crimping of the device before valve implantation. The VIVA first-in-human feasibility study, a prospective, nonrandomized, single-center trial, evaluated the Vienna aortic valve in 10 patients with severe symptomatic aortic stenosis, who were at intermediate or high surgical risk. This study, registered at ClinicalTrials.gov (NCT04861805), focused on the safety, feasibility, clinical and hemodynamic performance of the Vienna system up to 1-year follow-up. The mean patient age was 79 ± 5 years, 60% male. Valve sizes used: 26 mm (10%), 29 mm (30%), 31 mm (60%). Key hemodynamic improvements were significant: mean aortic valve pressure gradient (mmHg) decreased from 48.7 to 8.1, aortic valve area (cm2) increased from 0.75 to 1.91, and maximum jet velocity through the aortic valve (m/s) decreased from 4.41 to 1.95 (p < 0.0001). No moderate/severe paravalvular leakage was observed, and computed tomography scans revealed no evidence of hypo-attenuated leaflet thickening. The study recorded one life-threatening bleeding event, two cases requiring postprocedural pacemaker implantation, and three ischemic events, with only one causing lasting neurological impairment. Importantly, there were no cases of cardiovascular mortality and only one noncardiovascular death, which was confirmed as unrelated to the device. The study indicates the Vienna valve as a potential option for severe symptomatic aortic stenosis, designed to streamline the procedure and potentially lower healthcare costs by reducing resource and equipment needs, also procedural errors. Further research is essential to thoroughly evaluate its safety and efficacy.

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

The advent of therapeutic recombinant factor VIII (FVIII) and factor IX (FIX) protein infusions revolutionized the care of persons with haemophilia in the 1990s. It kicked off an era with the increasing use of prophylactic factor infusions for patients and transformed conversations around the ideal trough activity levels as well as the ultimate goals in tailored, individualized care. Our knowledge surrounding the immunologic basis of inhibitor development and treatment derives from a time when patients were receiving frequent factor infusions and focused on immune tolerance induction following inhibitor development. More recently, care was revolutionized again in haemophilia A with the approval of emicizumab, a bispecific antibody mimicking activated FVIII function, to prevent bleeding. The use of emicizumab prophylaxis has resulted in a significantly slower accumulation of factor exposure days and continued effective prophylaxis in the case of inhibitor development. While emicizumab is effective at reducing the frequency of bleeding events in patients with haemophilia A, management of breakthrough bleeds, trauma, and surgeries still requires additional treatment. Ensuring that FVIII is a therapeutic option, particularly for life-threatening bleeding events and major surgeries is critical to optimizing the care of persons with haemophilia A. Other novel non-factor concentrate therapies, including rebalancing agents, will dramatically change the landscape for persons with haemophilia B with inhibitors. This review discusses the changing landscape regarding the timing of inhibitor development and management strategies after inhibitor development, stressing the importance of education across the community to continue to vigilantly monitor for inhibitors and be prepared to treat persons with inhibitors.

Increased platelet to red blood cell transfusion ratio associated with acute kidney injury in children with life-threatening bleeding.

Transfusion may increase the risk of organ failure through immunomodulatory effects. The primary objective of this study was to assess for patient or transfusion-related factors that are independently associated with the risk of acute kidney injury (AKI) and acute respiratory distress syndrome (ARDS) in a cohort of children with life-threatening bleeding from all etiologies. In a secondary analysis of the prospective observational massive transfusion in children (MATIC) study, multivariable logistic regression was performed in an adjusted analysis to determine if blood product ratios or deficits were independently associated with AKI or ARDS in children with life-threatening bleeding. There were 449 children included with a median (interquartile range, IQR) age of 7.3 years (1.7-14.7). Within 5 days of the life-threatening bleeding event, AKI occurred in 18.5% and ARDS occurred in 20.3% of the subjects. Every 10% increase in the platelet to red blood cell transfusion ratio is independently associated with a 12.7% increase in the odds of AKI (adjusted odds ratio 1.127; 95% confidence interval 1.025-1.239; p-value .013). Subjects with operative or medical etiologies were independently associated with an increased risk of AKI compared to those with traumatic injury. No transfusion-related variables were independently associated with the risk of developing ARDS. The use of increased platelet to red blood cell transfusion ratios in children with life-threatening bleeding of any etiology may increase the risk of AKI but not ARDS. Prospective trials are needed to determine if increased platelet use in this cohort increases the risk of AKI to examine possible mechanisms.

Short-Term Efficacy of Combination Therapy with Recombinant Human Thrombopoietin (rh-TPO) and Thrombopoietin Receptor Agonists (TPO-Ra) in Patients with Severe Immune Thrombocytopenia

Introduction: Bleeding manifestations in patients with immune thrombocytopenia (ITP) range from mild skin bruises to lifethreatening intracranial hemorrhage. When the risk of bleeding is becoming high or life-threatening bleeding events occurs, we often use a combination of therapies to rapidly raise platelets to the safe range, including platelet transfusions, high-dose glucocorticoid, and intravenous immunoglobulins. Recombinant human thrombopoietin (rh-TPO) and thrombopoietin receptor agonists (TPO-Ra) are two kinds of thrombopoietic drugs commonly used in China. In patients with severe ITP refractory to glucocorticoids, we lack experience with the use of rh-TPO and TPO-Ra in this emergency situation. Patients and methods： We included ITP patients with platelets &amp;lt;10*10 9/L and bleeding symptoms requiring treatment, who were refractory to glucocorticoids and used thrombopoietic drugs. The bleeding score was calculated with reference to the Chinese guidelines for adult ITP. The patients were divided into three groups according to the medication used: rh-TPO group(rh-TPO 30000IU Qd), TPO-Ra group(Eltrombopag 25mg-75mg/d or Avatrombopag 2.5mg-7.5mg/d or Hetrombopagolamine 20mg-60mg/d), and rh-TPO+TPO-Ra group(combination of two drugs at the same dosage). The platelet count should be rechecked every 1-2 days during the treatment. Platelet transfusion and hemostatic drugs can be used as needed. According to the standardized and international criteria, and taking into account the characteristics of this study, platelet counts were classified as short-term Complete Response(sCR), short-term Response(sR), and short-term No Response (sNR), based on the highest value of platelet counts from the start of treatment to the time of hospital discharge, short-term Overall Response(sOR)=sCR+sR. The three groups were compared the effective time(defined as the time to first sCR/sR after treatment) , peak platelet count after treatment, time to peak platelet count after treatment and other short-term efficacy indicators. Results Nineteen patients were include in this study, with 68.4% (13/19) was female. The median age was 58 years [range 17-79]. 15.8%(3/19) were newly diagnosed with ITP, 10.5%(2/19) had persistent ITP, and 73.7%(14/19) had chronic ITP. All patients were treated with glucocorticoids prior to this treatment, but they had a poor response. The median platelet count was 3*10 9/L [range 1-9] and the median bleeding score was 4 [range 2-9] before treatment. The common bleeding sites were skin ecchymosis and oral mucous membrane hemorrhage in 100%(19/19)and 47.3%(9/19), respectively. Severe bleeding symptoms were the manifestation in 3 cases: including 2 heavy menstrual flow and 1 hemoptysis and gastrointestinal. 100%(19/19) achieved a sOR and 31.6%(6/19) achieved a sCR. The median bleeding score was 0[0-2] after treatment and none had active bleeding symptoms. Platelet transfusion and hemostatic drugs were administered to all patients. Further details are provided in Table 1. Among 19 patients, 7(36.8%) used rh-TPO alone, 6(31.6%) TPO-Ra alone and 6(31.6%) used rh-TPO+TPO-Ra. There was no statistically significant difference in Clinical characteristics, including ages, gender, platelet counts and bleeding score among the three groups of patients before treatment (P=0.727, 0.594, 0.719, 0.299). In terms of treatment efficacy, we were unable to perform a statistical analysis of sOR rates because all three groups reached 100%. The sCR and the peak platelet count after treatment of rhTPO+TPO-Ra group was higher than the other two groups, 28.6%(2/7), 16.7%(1/6) and 50%(3/6) of patients achieved sCR respectively, the peak platelet counts after treatment in the three groups were 62*10 9/L, 72*10 9/L, 79.5*10 9/L respectively in this treatment, but there was no statistically significant difference (P=0.425，0.924). In addition, the effective time and time to peak platelet count after treatment of the three group are also no statistically significant difference(p=0.692,0.505). Further details are provided in Table 2. Conclusion This retrospective study suggests that the patients with severe ITP who were refractory to glucocorticoids, the use of rh-TPO and TPO-Ra may rapidly increase to safe ranges, but the combination is not necessary.

To Determine the Incidence of Various Subtypes of VWD with Specified VWF:RCof/ VWF:Ag Ratio’s In Pediatric Patients

Background: VWD is the most common inherited bleeding disorder characterized by defects in the concentration, structure, or function VWF. There are three main types of VWD that differ according to the degree of disease severity and inheritance pattern (Type 1, Type 2A, 2B, 2M, 2N and Type 3). Methodology: This is 05 years study (Feb 2016–Jan 2021) conducted in hematology section. In present study, amongst total inherited bleeding disorders, Incidence of VWD is 27%, Hemophilia (50%), inherited platelet disorders (14%) and remainder are undiagnosed. Amongst VWD, Type 1 VWD is the most common subtype studied, comprising 66% of total cases. Type 2 &amp; 3 VWD comprised 23% and 10% of total cases showing good correlation with the literature and other studies. Discussion: The European cross-sectional study yielded a population-based estimate of 0.05 per 100,000 for type 3 VWD. Estimates by VWD type from Europe and Western Pacific reported higher prevalence estimates for type 1 disease than type 2 or type 3: 2.7–7.2 per 100,000 for type 1 VWD, 0.8–2.5 per 100,000 for type 2, and 0.1–0.3 per 100,000 for type 3. Conclusion: VWD usually presents with mild bleeding symptoms (except in type 3 VWD) the diagnosis is often delayed. Prompt diagnosis and management can help to avoid potentially life-threatening bleeding events and unnecessary exposure to blood products.

One-year clinical outcomes and the impact of procedural configurations in patients with left atrial appendage occlusion

Abstract Background To evaluate the long-term clinical performance, the impact of procedural configurations and post-procedure medications in atrial fibrillation patients with percutaneous left atrial appendage occlusion (LAAO). Methods The RECORD study was a prospective, all-comers registry conducted in 39 Chinese centers that consecutively enrolling patients who received LAAO between 1st April 2019 and 31st October 2020 with minimum inclusion and exclusion criteria. Events including any death, any stroke, systemic embolism and bleeding event were collected at 1 year and adjudicated by an independent clinical event committee. Cox proportional hazard models with multivariable adjustments were applied to estimate hazard ratios (HRs) for each outcome. Results Of the 3,096 participants, 3,082 successfully received an LAAO implant and 3,013 (97.8%) completed the 1-year follow-up. Participants had a high risk of stroke (mean CHA2DS2-VASc score of 4.0) and a moderate-to-high risk of bleeding (mean HAS-BLED score of 2.4). Local anesthetic was performed in 1,287 (41.6%) patients and fluoroscopy guidance in 492 (16.0%) patients. In 1295 (42.0%) cases, one-stage combination procedures of LAAO and radiofrequency ablation or cryoablation (CA) were performed. At 1 year, the composite ischemic endpoint of death, stroke, and systemic embolism occurred in 133 (4.51%) patients. Any life-threatening, disabling or major bleeding events occurred in 71 (2.36%) patients. There was no significant association between the type of anesthesia (general versus local), modality of image guidance (TEE, ICE, or fluoroscopy) with the ischemic or bleeding events. Combination procedures of LAAO plus CA was associated with a significantly lower rate of death, stroke, or systemic embolism than performing LAAO only (3.5% versus 5.2%, HRadjusted:0.69, 95%CI:0.48-0.98, P=0.041). The commonest antithrombotic strategy was OAC | APT | APT (38.1%; corresponded to medication prescribed at discharge | 45 days | 6 months), followed by OAC | OAC | APT (27.0%). Compared with OAC | APT | APT, the OAC | OAC | APT group was associated with a higher risk of life-threatening, disabling or major bleeding (1.2% versus 2.5%, HRadjusted:0.50, 95%CI: 0.25-0.99, P=0.47); whereas the risk of death, stroke and SE was numerically similar (2.9% versus 3.0%, HRadjusted:1.05, 95%CI: 0.61-1.78, P=0.867). There was no significant difference between OAC | APT | APT and OAC+APT | APT | APT groups regarding ischemic events; however, in patients with HAS-BLED ≥ 3, OAC | APT | APT was associated with lower rates of life-threatening, disabling or major bleeding events (1.1% versus 4.8%, HRadjusted:4.55, 95%CI: 1.31-15.81, P=0.017). Conclusion In Chinese centers, patients with a WATCHMAN LAAO device had low rates of ischemic and bleeding events at 1 year. One-stage combination procedures of LAAO and catheter ablation was associated with a significantly lower rate of ischemic events than performing LAAO only.Procedural configurations to outcomesPost-LAAO antithrombotic medications

The efficacy and safety of novel oral anticoagulants versus vitamin k antagonist in transcatheter aortic valve replacement patients with indications for anticoagulation

Abstract Introduction Thrombotic events from atrial fibrillation, clinical and subclinical leaflet thromboses continue to be a major concern in Transcatheter Aortic Valve Replacement (TAVR) patients despite technological advancement and operator expertise. The proportion of TAVR patients who have or eventually develop indications for anticoagulation is not negligible and thus may warrant oral anticoagulants. However, the choice of anticoagulation is this select patients remained debatable. Thus, this study was conducted to determine whether current collective data support the efficacy and safety of novel oral anticoagulants (NOACS) versus vitamin K antagonists (VKAs). Purpose Oral anticoagulation (OAC) is necessary but the patients who needed it the most have baseline high bleeding risks. Anticoagulation carries a high bleeding risk especially among majority of a typical post TAVR patients with indications for anticoagulation. The paucity of data among asian TAVR patients were propensity to bleed are prevailing issues with anticoagulation owing perhaps to genetic or race predisposition and lower body weights or BMI compared to non-Asian counterparts. Currently the high court is still out to settle the optimum choice of anti-thrombotic therapy after TAVR. With TAVR now being performed in our local setting, we find this a relevant issue, hence we conducted a meta-analysis. Methods A literature search from Pubmed, Embase, and Cochrane databases for relevant RCTs and observational studies published until February 2022 were conducted. The pooled estimates of all-cause mortality, stroke and major bleeding events were measured using RevMan version 5.4.1 software. Results Eleven eligible studies (9 observational studies and 2 RCTs) allocated 29,156 TAVR patients with indications for anticoagulation either to receive NOACS (n = 11,718) or VKAs (n = 17,468). The effect estimate using random effects model showed no significant differences in all-cause mortality (RR 0.79, 95% CI 0.42–2.25, p = 0.07), stroke (RR 0.96, 95% CI 0.54–2.79, p = 0.70), and major bleeding events (RR 0.82, 95% CI 0.48–1.44, p = 0.08) between the NOACs and VKAs treatment arms. Conclusion NOACs demonstrated non-inferiority over VKA in reducing all-cause mortality, stroke and major or life-threatening bleeding events in TAVR patients with indications for anticoagulation.

Abstract 14742: Clinical Predictors of Bleeding Complications Following Percutaneous Ventricular Assist Device Insertion: Insights From the J-PVAD (Japanese Registry for Percutaneous Ventricular Assist Device) Registry

Introduction: Bleeding complications are significant concerns in clinical use of percutaneous ventricular assist devices (PVAD). This study aimed to identify predictors of bleedings in PVAD use. Methods: We analyzed 3059 cases from the J-PVAD registry, a comprehensive national registry of PVAD use in Japan, excluding 53 cases without follow-up data. Patients were stratified based on whether they had acute coronary syndrome (ACS) on the onset or not, and incidence of bleeding was evaluated within each stratum, considering the clinically selected variables, including other mechanical circulatory support (MCS) use. Risk factors were explored through multivariate analyses. The primary outcome measure was any bleeding, while major bleeding was defined as a composite of cerebral bleeding, severe bleeding (defined as life-threatening, hospitalization-requiring, disability-causing, or congenital anomaly-inducing bleeding events), and blood transfusions. Results: The median follow-up period was 32 days. The cohort included 1459 patients with ACS and 1575 without ACS. The incidence of any bleeding did not differ significantly between the ACS and Non-ACS stratum (30-day incidence: 25.4% and 27.6%, P = 0.57, respectively). We observed the same trends for major bleeding. Most any bleeding or major bleeding occurred on the day of insertion of PVAD or within a few days. The groups with MCS had significantly more bleeding complications than those without MCS in each stratum (Figure). In a multivariate analysis using the Cox proportional hazards model, adding MCS on PVAD was the most potent predictor of any bleeding in both strata, with the effects of other variables being modest by comparison. Conclusions: Bleeding complications post-PVAD insertion are often severe and occur shortly after the procedure. Although the incidence of bleeding complications did not differ significantly according to the onset type, the MCS use strongly predicted bleeding complications.

Efficacy and Safety of Hetrombopag in Promoting Platelet Engraftment after Allogeneic Hematopoietic Stem Cell Transplantation: A Prospective, Multicenter, Randomized Controlled Clinical Trial

Background and Objective: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used to treat hematological malignancies and non-malignant hematological diseases. However, the incidence of thrombocytopenia after transplantation is common, and within 60 days after HSCT, around 5-38% of patients experienced delayed platelet engraftment or persistent isolated thrombocytopenia. Thrombocytopenia after transplantation was significantly associated with life-threatening bleeding events and reduced overall survival rate. Previous studies have found that the biphenyl structure may have hepatotoxicity, Hetrombopag (TPORA) replaces it with a heterocyclic carboxyl group to reduce hepatotoxicity, which can also enhance the lipophilicity and improve the efficacy by report. Hetrombopag was proved safe and effective in treating ITP and aplastic anemia. The aim of this study is to evaluate efficacy and safety of Hetrombopag in promoting platelet engraftment after allo-HSCT. Methods: Patients undergoing allo-HSCT were randomly grouped on day 3 after stem cell infusion. The experimental group treated with Hetrombopag 2.5mg/d or 5mg/d orally till platelet reconstitution, instead the control group was given thrombopoietin (TPO) 300U/kg/d. Platelet engraftment was defined as platelet count ≥20×10 9/L for consecutive 7 days without platelet transfusion. The primary endpoint is the time for platelet engraftment. The secondary endpoints include the time to granulocyte engraftment, platelet transfusion units, medical costs during hematopoietic reconstitution, and side effects. Results: Currently, 26 patients were enrolled in the Hetrombopag experimental group and 26 in the TPO control group. The median age of experimental group was 35 years (14-62 years), with 9 AML patients, 9 ALL, 5 MDS/MPN, 2 AA, and 1 MPAL. Among them, 12 received haplo-transplantation, and 14 underwent HLA-identical transplantation. The average number of transfused mononuclear cells (MNCs) was 8.6 (5.28-12.79) ×10 8/kg, and the average number of CD34 + cells was 5.93 (2.39-9.37) ×10 6/kg. The mean time for granulocyte and platelet engraftment was 15.26±3.37 and 15.20±4.06 days respectively. Primary graft failure of platelet occurred in 1 patient (3.8%). The median age of the control group was 36 years (19-63 years), with 12 patients diagnosed AML, 9 ALL, 2 MDS/MPN, 2 AA, 1 plasma cell leukemia, and 1 NKTCL. 19 of them received haplo-transplantation, while 7 receivedHLA-identical transplantation. The average numbers of transfused MNCs and CD34 + cells were 9.05 (5.39-16.22) ×10 8/kg and 6.4 (1.96-10.45) ×10 6/kg respectively. The mean days of granulocyte and platelet reconstitution were 17.38±5.82 and 18.18±4.62 days, respectively. PGF occurred in 4 patients (15.4%). Compared with the control group, the experimental group had a significantly earlier engraftment of granulocytes ( P=0.03) and platelets ( P=0.01). During platelet reconstitution, the control group was transfused 6.87±3.93U of platelets and the experimental group was transfused less (3.92±3.45U, P = 0.0009). The medical cost of using TPO and Hetrombopag was 12555.39±5222.33 yuan in the control group and 2783.90±1020.04 yuan in the experimental group ( P &amp;lt; 0.0001). The above data are the interim analysis results of this study. Liver transaminases were elevated in 4/26 cases in the experimental group and 2 cases in the TPO group, after one week of drug administration; Different degrees of organ bleeding (digestive tract, urinary tract, etc.) occurred in 6 cases in the experimental group and in 9 cases in the control group. Notably, the above data are only interim analyses and the side effects may not only be due to the study medication, as allo-HSCT itself includes very complex factors. Conclusion: Hetrombopag can safely promote rapid platelet engraftment, shorten the time difference between granulocyte and megakaryocyte reconstitution, reduce platelet transfusion, and decrease the economic burden of patients after allo-HSCT. Keywords: Hetrombopag, Allo-HSCT, TPORA, Platelet engraftment.

Successful Use of Haploid Hematopoietic Stem Cell Transplantation for Severe Glanzmann's Thrombasthenia

Objective: Glanzmann's thrombasthenia (GT) is a rare autosomal recessive disorder, which characterized by the clinical manifestations from purpura to severe bleeding. It was caused by mutations of the ITGA2B or ITGB3 gene on chromosome 17, which lead to deficits or reduced expression of the platelet membrane glycoprotein GPIIb/IIIa. We report 5 pediatric patients with severe Glanzmann's thrombasthenia who underwent allogeneic hematopoietic stem cell transplant, to observe the outcomes of allo-HSCT in children with severe Glanzmann's thrombasthenia. Methods: We retrospectively summarized the clinical and genetic profiles of five patients with Glanzmann's thrombasthenia who underwent allo-HSCT from June 2021 to July 2023. All patients were reduced intensity conditioning (Bufulsan 3.2-6.4mg/kg, CTX 120mg/kg, FLU 180mg/m 2, ATG 10mg/kg). After conditioning chemotherapy, all the patients received stem cells collected via bone marrow harvest and/or peripheral blood apheresis (PBSC) with CD34 dose of 2.89-7.2×10 6/kg and received graft vs. host disease (GvHD) prophylaxis with cyclosporine (CSA) and methotrexate (MTX). Results: There were five children were involved in this observation, one patient suffered from recurrent epistaxis bleeding which was life-threatening; the second suffered from gastrointestinal bleeding and could only accept liquid diet to 10-years-old; other patients also suffered from epistaxis bleeding, gum bleeding or gastrointestinal bleeding. For all the patients, regular red cell transfusions were required, platelet transfusions and recombinant factor VIIa were also used in severe and life-threatening bleeding events. Two of the five developed antiplatelet antibodies before HSCT. All the patients were successfully treated with allo-HSCT. One case received non-relative matched donor of 10/10 HLA, one case with sibling matched donor, and 3 cases with haploid transplantation of HLA 5-6/10 matched. The mean time to neutrophil engraftment was 11 days (11-12 days), and the mean time to platelet engraftment was 16 days (15-18 days). One case had CMV reactivation, one case had HHV-6b infection, one case had grade II acute GVHD of the skin which was controlled rapidly. There was no evidence of chronic GVHD for all the patients. The platelet disorder was corrected to a normal level after allo-HSCT, with no significant complication related to the transplantation. Comparing with HLA matched donor, either from sibling or non-related, the patients receiving haploid transplantation with 5-6/10 HLA matched got similar outcome. Conclusions: We proposed haploid transplantation treated with the reduced intensity conditioning regimens produced similar outcomes as HLA matched did which could be recommended as an alternative donor for severe Glanzmann's thrombasthenia.

A Single-Center Study of Patients with Isolated Acquired Clotting Factor Deficiency: Clinical Features, Treatments, and Prognosis

Introduction and aim: As a group of rare hemorrhagic disorders, isolatedacquired clotting factor deficiency (ACFD) is mainly caused by the existence of anti-factor antibodies or substances with absorbability of clotting factors. The most widely spread isolated ACFD is the acquired FVIII deficiency known as acquired hemophilia (AHA), and the remaining factors of deficiency are much less prevalent. Isolated ACFD is characterized by bleeding diathesis ranging from mild to life-threatening bleeding events. Their rarity and heterogeneity may lead to difficulty in diagnosis and management. We performed a retrospective study to analyze the characteristics of isolated ACFDs other than AHA, including acquired factor (F) II, FV, FIX, FX, FXI, FXII, FXIII, and VWF deficiencies, to enhance our understanding of these diseases. Methods: All patients with isolated ACFD other than AHA admitted to the Blood Disease Hospital, Chinese Academy of Medical Sciences, from July 1997 to December 2021, were retrospectively enrolled in the present study. The follow-up time started from when the patient was admitted to our center till March 2022. Clinical information, such as demographics, associated diseases, manifestations, laboratory tests, treatments, and prognosis, was collected. Results: A total of 54 patients with isolated ACFD admitted to our center were enrolled in our final analysis, including 28 males and 26 females. Acquired factor V deficiency (AFVD) was the most frequently diagnosed (20/54, 37.0%) isolated ACFD, followed by acquired factor X deficiency (AFXD) (n=16, 29.6%). The median age at diagnosis of all isolated ACFD patients was 55 (4-78) years. However, all four patients with acquired FII deficiency (AFIID) were young women (&amp;lt; 20 years). The median time from presenting bleeding diathesis or being found with an abnormal laboratory test to be diagnosed as isolated ACFD for all patients was 60 (2-2555) days. Underlying conditions were found in 35 (64.8%) patients with isolated ACFD, including malignancies (n=19, 35.2%), autoimmune diseases (n=12, 22.2%), and infections (n=4, 7.4%). Of the 19 patients associated with malignancies, 18 patients were secondary to hematologic malignancies. Plasma cell dyscrasias were the primary etiologies for patients with AFXD, with a proportion of 75.0% (12/16). A total of 44 (81.5%) patients with isolated ACFD experienced at least one bleeding episode. Subcutaneous hemorrhage was the most common bleeding phenotype affecting 61.4% (27/44) of patients. One acquired factor IX deficiency (AFIXD) patient and one AFXIID patient showed venous thromboembolism (VTE). Anti-factor neutralizing antibodies were detected in about half of the patients with isolated ACFD (24/54, 44.4%). Inhibitors were not found in two (10.0%) AFVD patients, one (6.3%) AFXD patient, two (50.0%) acquired factor XI deficiency (AFXID) patients, and five (100.0%) acquired factor XII deficiency (AFXIID) patients (Figure 1). Prothrombin complex concentrate (PCC) was administered to 20 (37.0%) isolated ACFD patients and fresh frozen plasma (FFP) was administered to 33 (61.1%) isolated ACFD patients. Thirty-seven (37/54, 68.5%) isolated ACFD patients underwent immunosuppressive therapy (IST). In addition, chemotherapy was administered to six (6/16, 37.5%) AFXD patients with light chain (AL) amyloidosis and four (4/5, 80%) AFXIID patients with hematologic malignancies to treat primary diseases. Overall, a majority of isolated ACFD patients achieved a high CR rate (≥ 50.0%) other than patients with AFXD, who achieved an extremely low CR rate of 18.2%. The efficiency of IST varied among different types of isolated ACFDs, ranging from 20.0% to 100.0%. The factor levels normalized in one (1/6, 16.7%) AFXD patient and all (4/4, 100.0%) AFXIID patients after receiving chemotherapy. The median time to achieve CR was shorter for AFVD patients compared with the AFXD patients (p &amp;lt; 0.05). Four (4/17, 23.5%) AFVD patients, four (4/11, 36.4%) AFXD patients, and one (1/2, 50.0%) acquired FXIII deficiency (AFXIIID) patient died. Four bleed-related deaths occurred in two AFVD patients, one AFXD patient, and one AFXIIID patient. Conclusions: Isolated ACFD is underestimated, delayed diagnosed, and lacks effective therapy. Therefore, clinicians should raise awareness for recognizing and managing isolated ACFD patients to avoid morbidity and mortality.

Woman With Hematochezia.

As a consequence of cirrhosis, portal hypertension causes resistance to blood flow and leads to the formation of varices. However, colonic variceal hemorrhages are rarely reported but could be a lethal cause of lower gastrointestinal hemorrhage. Currently, there is no consensus on the management of colonic variceal hemorrhage. Variceal ligation, injection sclerotherapy, transjugular intrahepatic portosystemic shunt placement, and balloon-occluded retrograde transvenous obliteration or a combination of the above therapies have been reported with inconsistent success rates. We advocate considering colonic variceal bleeding as a crucial differential diagnosis of lower gastrointestinal bleeding in cirrhotic patients and initiating time-sensitive, definite operative treatment or combination therapy as soon as possible in colonic variceal patients with life-threatening bleeding events, which are often refractory to conservative treatment.

MAGT1 deficiency in XMEN disease is associated with severe platelet dysfunction and impaired platelet glycoprotein N-glycosylation

BackgroundX-linked immunodeficiency with magnesium defect, Epstein–Barr virus infection, and neoplasia (XMEN) disease is a primary immunodeficiency due to loss-of-function mutations in the gene encoding for magnesium transporter 1 (MAGT1). Furthermore, as MAGT1 is involved in the N-glycosylation process, XMEN disease is classified as a congenital disorder of glycosylation. Although XMEN-associated immunodeficiency is well described, the mechanisms underlying platelet dysfunction and those responsible for life-threatening bleeding events have never been investigated. ObjectivesTo assess platelet functions in patients with XMEN disease. MethodsTwo unrelated young boys, including one before and after hematopoietic stem cell transplantation, were investigated for their platelet functions, glycoprotein expression, and serum and platelet-derived N-glycans. ResultsPlatelet analysis highlighted abnormal elongated cells and unusual barbell-shaped proplatelets. Platelet aggregation, integrin αIIbβ3 activation, calcium mobilization, and protein kinase C activity were impaired between both patients. Strikingly, platelet responses to protease-activated receptor 1 activating peptide were absent at both low and high concentrations. These defects were also associated with decreased molecular weights of glycoprotein Ibα, glycoprotein VI, and integrin αIIb due to partial impairment of N-glycosylation. All these defects were corrected after hematopoietic stem cell transplantation. ConclusionOur results highlight prominent platelet dysfunction related to MAGT1 deficiency and defective N-glycosylation in several platelet proteins that could explain the hemorrhages reported in patients with XMEN disease.

Tranexamic acid for the prevention of postpartum bleeding: Protocol for a systematic review and individual patient data meta-analysis.

Tranexamic acid (TXA) reduces the risk of death and is recommended as a treatment for women with severe postpartum bleeding. There is hope that giving TXA shortly before or immediately after birth could prevent postpartum bleeding. Extending the use of TXA to prevent harmful postpartum bleeding could improve outcomes for millions of women; however we must carefully consider the balance of benefits and potential harms. This article describes the protocol for a systematic review and individual patient data (IPD) meta-analysis to assess the effectiveness and safety of TXA for preventing postpartum bleeding in all women giving birth, and to explore how the effects vary by underlying risk and other patient characteristics. Methods: We will search for prospectively registered, randomised controlled trials involving 500 patients or more assessing the effects of TXA in women giving birth. Two authors will extract data and assess risk of bias. IPD data will be sought from eligible trials. Primary outcomes will be life-threatening bleeding and thromboembolic events. We will use a one-stage model to analyse the data. Subgroup analyses will be conducted to explore whether the effectiveness and safety of TXA varies by underlying risk, type birth, maternal haemoglobin (Hb), and timing of TXA. This protocol is registered on PROSPERO (CRD42022345775). Conclusions: This systematic review and IPD meta-analysis will address important clinical questions about the effectiveness and safety of the use of TXA for the prevention of postpartum bleeding that cannot be answered reliably using aggregate data and will inform the decision of who to treat. PROSPERO registration: CRD42022345775 Keywords Anti-fibrinolytics; Tranexamic acid; childbirth; postpartum haemorrhage; meta-analysis.

Tranexamic acid for the prevention of postpartum bleeding: Protocol for a systematic review and individual patient data meta-analysis

Background: Tranexamic acid (TXA) reduces the risk of death and is recommended as a treatment for women with severe postpartum bleeding. There is hope that giving TXA shortly before or immediately after birth could prevent postpartum bleeding. Extending the use of TXA to prevent harmful postpartum bleeding could improve outcomes for millions of women; however, we must carefully consider the balance of benefits and potential harms. This article describes the protocol for a systematic review and individual patient data (IPD) meta-analysis to assess the effectiveness and safety of TXA for preventing postpartum bleeding, and to explore how the effects vary by underlying risk and other patient characteristics. Methods: We will search for prospectively registered, randomised controlled trials involving 500 patients or more assessing the effects of TXA in women giving birth. Two authors will extract data and assess risk of bias. IPD data will be sought from eligible trials. Primary outcomes will be life-threatening bleeding and thromboembolic events. We will use a one-stage model to analyse the data. Subgroup analyses will be conducted to explore whether the effectiveness and safety of TXA varies by underlying risk, type birth, maternal haemoglobin (Hb), and timing of TXA. Conclusions: This systematic review and IPD meta-analysis will address important clinical questions about the effectiveness and safety of the use of TXA for the prevention of postpartum bleeding that cannot be answered reliably using aggregate data and will inform the decision of who to treat. PROSPERO registration: CRD42022345775