Intravenous Transfusion Research Articles

Impact of a bundle of care (intravenous iron, erythropoietin and transfusion metabolic adjustment) on post-operative transfusion incidence in cardiac surgery: a single-centre, randomised, open-label, parallel-group controlled pilot trial

Red blood cell (RBC) transfusions are frequent in patients after cardiac surgery. This study assessed whether a bundle of care including pre-operative and post-operative administration of erythropoietin (EPO) with intravenous iron supplementation, and restrictive transfusion adjusted for ScvO2 could result in reduced postoperative transfusions. In this single-centre, randomised, open-label, parallel-group controlled pilot study, patients undergoing elective cardiac surgery with high risk of transfusion in a University Hospital were enrolled by the investigator and the randomisation procedure using a central internet-based system was made by the clinical research assistant. Since the trial was open-label, no masking was used. Patients were assigned (1:1) to either the STOP group (40,000 IU subcutaneous EPO combined with 20mg/kg intravenous ferric carboxymaltose if Hb<13g/dL the day before surgery or at ICU admission, and RBC transfusion if Hb≤8g/dL and ScvO2≤65%, or additional EPO dose if 8<Hb<13g/dL) or to the control group (RBC transfusion if Hb≤8g/dL, or, if 8<Hb<13g/dL, intravenous iron sucrose 200mg or 300mg according to weight). Primary outcome was the incidence of postoperative RBC transfusion up to hospital discharge or postoperative day 28. The trial is registered with ClinicalTrials.gov, NCT04141631. Between Jan 20, 2020, and Sept 6, 2022, among 128 patients enrolled, 123 (male, 54.4%, 67/123) were included in the full analysis set: 62 in the STOP group and 61 in the control group. Nine patients (14.5%, 9/62) in the STOP group required RBC transfusion vs 19 (31.2%, 19/61) in the control group (odds ratio 0.37 [95% CI: 0.15-0.91], p=0.03). The median length of follow up to transfusion was 2.6 days (1.5; 4.6) and 3.3 (1.6; 4.2) in control and STOP groups respectively (p=0.61). The bundle of care may reduce postoperative RBC transfusion. The findings should be taken with caution due to the unblinded and exploratory nature of the study. University of Montpellier Hospital and Vifor Pharma.

Phase I trial of hypoxia-responsive CEA CAR-T cell therapy in patients with heavily pretreated solid tumor via intraperitoneal or intravenous transfusion.

3514 Background: Chimeric antigen receptor (CAR) T cell therapy has been successful in hematologic malignancies but not in solid tumors. Homing capacity and tumor microenvironment are key issues to limit CAR-T efficacy to solid tumors. Our previous study has shown that hypoxia-responsive CAR-T cells exhibit reduced exhaustion and enhanced efficacy in solid tumors (Cancer Res 2024). Here, we aimed to optimize the administration route by comparing safety and efficacy of our newly established CEA CAR-T through intraperitoneal (I.P.) and intravenous (I.V.) infusions in solid tumor patients who failed to standard therapy. Methods: In this phase I, open-label, dose-escalation clinical trial, eligible patients were CEA positive and relapsed or refractory to at least second-line treatment. CAR-T cells was administered via I.P. or I.V. with dose escalation including low dose of 1-3 x106 CAR+/kg and high dose of 4-6 x106 CAR+/kg. Adverse events were graded by CTCAE 5.0. Tumor responses were evaluated using RECIST 1.1. Results: Between June 2022 to Jan 2024,40 pts were enrolled and infused CAR-T cells, including 35 CRC pts, 3 GC pts, 1 NSCLC pts and 1 BTC pts. There were 16 pts in the I.P. group and 24 pts in the I.V. group. CRS was observed in 62.5% of the pts at grade 1-2, and no ICANS or treatment related death was reported. Grade 1-2 mucositis was reported in 25% of the patients. Immune-mediated diarrhea and colitis of all grades occurred in 32.5% of the patients, including 17.5% grade 3 events. And 100% of patients experienced grade 3-4 hematologic toxicity. In terms of efficacy, the I.P. group displayed a higher objective response rate (ORR) of 25% (4/16), compared to 8% (2/24) in the I.V. group, alongside a superior disease control rate (DCR) of 88% (14/16) in I.P. compared to 67% (16/24) in I.V. group. Notably, within the high-dose group receiving I.P. infusion, the ORR increased to 28.5%. Moreover, the responded patients in the high-dose group all had sustained tumor remission for more than 5 months, including one patient who had a 76% target lesions regression at six months follow up. CAR-T cells demonstrated robust expansion in both the I.P. and I.V. groups, while no significant difference was found in maximum concentration. Conclusions: The CEA CAR-T cell therapy had acceptable toxicity via I.P. or I.V. infusion. We have observed a promising antitumor potential by I.P. infusion and a prolonged tumor remission in high-dose group. Further investigation is needed to highlight these findings and the corresponding mechanisms. Clinical trial information: NCT05396300 . [Table: see text]

Clinical outcomes, demographics and associative analysis of lung cancer patients with Lambert-Eaton myasthenic syndrome: Insights from the National Inpatient Sample (NIS) database.

e20134 Background: Lambert-Eaton myasthenic syndrome (LEMS) is a rare neuromuscular junction disorder that may present as a paraneoplastic syndrome or a primary autoimmune disorder. Approximately 60% of LEMS patients have an underlying tumor, with the paraneoplastic form predominantly associated with small cell lung cancer (SCLC). Understanding the clinical outcomes and risks associated in lung cancer patients with LEMS is crucial in effective management of such patients. Methods: This retrospective study utilized inpatient hospitalization data from the National Inpatient Sample (NIS) between January 1, 2016, and December 31, 2019. Data of patients with a primary or secondary discharge diagnosis of lung cancer (ICD10-CM codes C34, C78.0, C46.5, D02.2) were obtained. Then, out of this population, we identified Lambert-Eaton myasthenic syndrome with ICD-10 codes (G70.80, G70.81, G73.1). The objective was to run a descriptive analysis of clinical outcomes, risks, demographics and associations of LEMS in patients with lung cancer. Results: A total of 204 cases of lung cancer hospitalizations with LEMS were analyzed. The mean age was 68.23 years, with a slight female (51.72%) preponderance as compared to male (48.28%). Race distribution revealed increased prevalence in White Caucasians (83%), followed by Black (7%), Hispanic (4.5%), Asian or Pacific Islander (3%), Native American (0.5%), and Other (2%). The majority were covered by Medicare (66.33%), followed by private insurance (26.13%). The mortality rate was 8.9%, with a mean length of stay of 10.35 days and mean hospital charges of $118,676. Clinical outcomes and risks were analyzed, with sepsis occurring in 17.6% of cases, pneumonia in 22.5%, and acute respiratory failure in 26.9%. Intubation/mechanical ventilation was necessary in 18.1% of cases. The incidence of urinary tract infection (UTI) was 16.7%, acute kidney injury (AKI) was 17.2%, and venous thromboembolism (VTE) was 6.4%. Additionally, interventions such as intravenous immunoglobulin (IVIG) therapy and blood transfusions were also noted. Conclusions: This study provides insights into the demographic characteristics and clinical outcomes of lung cancer patients with Lambert-Eaton myasthenic syndrome (LEMS). The findings highlight the need for comprehensive management strategies targeting associated complications like acute respiratory failure, intubation and need for mechanical ventilation, pneumonia, UTI, AKI, and VTE to improve patient outcomes, quality of care and effective patient education with regards to their diagnosis of LEMS in lung cancer.

Fluid balance during acute phase extracorporeal cardiopulmonary resuscitation and outcomes in OHCA patients: a retrospective multicenter cohort study.

The association between fluid balance and outcomes in patients who underwent out-of-hospital cardiac arrest (OHCA) and received extracorporeal cardiopulmonary resuscitation (ECPR) remains unknown. We aimed to examine the above relationship during the first 24 h following intensive care unit (ICU) admission. We performed a secondary analysis of the SAVE-J II study, a retrospective multicenter study involving OHCA patients aged ≥ 18 years treated with ECPR between 2013 and 2018 and who received fluid therapy following ICU admission. Fluid balance was calculated based on intravenous fluid administration, blood transfusion, and urine output. The primary outcome was in-hospital mortality. The secondary outcomes included unfavorable outcome (cerebral performance category scores of 3-5 at discharge), acute kidney injury (AKI), and need for renal replacement therapy (RRT). Overall, 959 patients met our inclusion criteria. In-hospital mortality was 63.6%, and the proportion of unfavorable outcome at discharge was 82.0%. The median fluid balance in the first 24 h following ICU admission was 3673 mL. Multivariable analysis revealed that fluid balance was significantly associated with in-hospital mortality (odds ratio (OR), 1.04; 95% confidence interval (CI), 1.02-1.06; p < 0.001), unfavorable outcome (OR, 1.03; 95% CI, 1.01-1.06; p = 0.005), AKI (OR, 1.04; 95% CI, 1.02-1.05; p < 0.001), and RRT (OR, 1.05; 95% CI, 1.03-1.07; p < 0.001). Excessive positive fluid balance in the first day following ICU admission was associated with in-hospital mortality, unfavorable outcome, AKI, and RRT in ECPR patients. Further investigation is warranted.

Avatrombopag for the salvage treatment of platelet transfusion refractoriness.

Platelet transfusion refractoriness (PTR) is a life-threatening and intractable condition in hematological patients. Thrombopoietin receptor agonists such as avatrombopag promote platelet production and modulate immune intolerance. However, its application in PTR has not been extensively studied. We aimed to compare the platelet response (PR) as well as bleeding events and mortality rate between the best available therapies (BATs) and avatrombopag (Ava) treatments in refractory PTR patients. A total of 71 refractory PTR patients were enrolled at Nanfang Hospital. Intravenous immunoglobulin, steroids, and human leucocyte antigen-matched platelet transfusions were administered to 30 patients in the BATs group. The Ava group included 41 patients. Data of refractory PTR patients were retrospectively collected. The primary endpoint was PR (defined as an increase of platelet count to ⩾50 × 109/L without platelet transfusion support for 7 consecutive days). Secondary endpoints included platelet-transfusion independence rate, cumulative platelet transfusion units, World Health Organization bleeding grades, adverse events, overall survival (OS), and bleeding event-free survival (EFS). There were 75.6% and 13.3% refractory PTR patients who reached PR within 3 months in Ava and BATs groups. The median platelet counts were significantly higher in Ava group from day 7. Platelet-transfusion independence rate in Ava was higher than BATs group. The median cumulative platelet transfusion unit in Ava was lower than that of BATs group. The OS and bleeding events-free EFS rate of Ava group improved within 3 months as compared to BATs group. Cox proportional hazards regression analysis revealed that Ava therapy was a protective factor for the OS and EFS. No primary disease progression or termination of avatrombopag was observed due to intolerability. Our study suggests that avatrombopag is an effective and safe treatment option for refractory PTR patients.

ARL67156, a small-molecule CD39 inhibitor, enhances natural killer cell cytotoxicity against gastric cancer cells in vitro and in nude mice

To investigate the effect of ARL67156, a small-molecule inhibitor of CD39, on cytotoxicity of natural killer (NK) cells against gastric cancer cells. Human peripheral blood-derived primary NK cells isolated and purified using a magnetic bead antibody method were treated with 100 μmol/L ARL67156 for 24 h, and the signaling pathway of NK cell activation was detected by Western blotting. The level of interferon-γ (IFN-γ) in the supernatant of NK cells co-cultured with gastric cancer cells was detected using ELISA, and NK cell CD107a degranulation was measured with flow cytometry. The cytotoxicity of NK cells against co-cultured gastric cancer cells was evaluated using flow cytometry. In a nude mouse model bearing subcutaneous gastric cancer xenografts, the therapeutic effect of intravenous transfusion of NK cells and intraperitoneal injection of ARL67156 was assessed by measuring the changes in tumor volume. (25.97 ± 5.69) % of peripheral blood NK cells from healthy individuals positive for CD39 expression. Treatment with ARL67156 significantly upregulated the activation molecules including NKG2D, DAP10, CD57, and CD16 and reduced the expressions of the inhibitory receptors TIGIT and KIR, thereby promoting the secretion of IFN-γ and CD107a degranulation in NK cells (P < 0.05). In both the in vitro and in vivo experiments, ARL67156 significantly enhanced the cytotoxicity of NK cells against gastric cancer cells (P < 0.05). ARL67156 activates NK cells through the vav1-Syk signaling pathway to enhance their cytotoxicity against gastric cancer cells, which may serve as a new strategy for NK cell immunotherapy for gastric cancer.

Fahr's syndrome with hypoparathyroidism, thrombocytopenia, and seizure: a rare case report.

A 32-year-old male was brought with a repeated history of twitching of hands, tingling sensation, and uncontrolled seizure despite medications. Computed tomography findings showed bilateral basal ganglia, cerebellar dentate nuclei, and subcortical cerebral white matter calcifications. Laboratory studies revealed reduced levels of calcium, parathyroid hormone, and thrombocyte count. Based on these investigations Fahr's syndrome probably due to hypoparathyroidism with thrombocytopenia was diagnosed. The patient was initially treated with intravenous calcium gluconate and platelet transfusion followed by oral calcium supplementation. Fahr's syndrome due to hypoparathyroidism should be suspected in any patient with neurological symptoms and hypocalcemia. Seizures in the patient of Fahr's syndrome with thrombocytopenia could be very detrimental due to the risk of intracranial hemorrhage. Hence, treatment should be started as early as possible.

Sjúkratilfelli Skyndileg aftanskinublæðing

A 50-year old male presented to our emergency department with sudden abdominal pain. Upon arrival he was diaphoretic, pale and tachycardic. A CT showed retroperitoneal hemorrhage with suspected tumor at the left adrenal gland. He was quickly stabilized with intravenous fluids and blood transfusion. Rebleed occurs roughly a week after discharge and a new CT showed a visceral pseudoaneurysm from the left middle adrenal artery. The pseudoaneurysm was embolized and the patient discharged in good condition. Follow-up MRI depicted reabsorption of the hematoma and no adrenal tumor. Thus, the etiology of the previous retroperitonal hemorrhage is considered spontaneous.

Hemorrhagic Shock After Endoscopic Biopsy of Sigmoid Cancer: Pseudoaneurysm of the Rectal Superior Artery.

CASE REPORT An 86-year-old man without significant comorbidity presented with weight loss, diarrhea, and iron deficiency anemia. No signs of gastrointestinal bleeding were noticed. Colonoscopy was performed, and sigmoid cancer was suspected (a). Biopsies were obtained, which confirmed colonic adenocarcinoma. Eight hours after the endoscopy, the patient developed massive hematochezia, followed by hemodynamic instability (blood pressure 60/30 mm Hg; heart rate 120 bpm; and hemoglobin drop from 9.8 g/dL to 6.1 g/dL within 2 hours). After stabilization with intravenous fluids, norepinephrine, and transfusion of 1 unit of red blood cells, endoscopy was repeated and ruled out ongoing bleeding. A computed tomography scan confirmed a mass of the sigmoid colon, which extended along the inferior mesenteric artery and to the os sacrum. Within the sigmoid wall, extravasation of the contrast medium was seen into a structure of 2.3 × 1.7 cm. Computed tomography reconstructions suspected pseudoaneurysm of the inferior mesenteric artery (Figures B, C). In the absence of distant metastases, surgical resection was attempted urgently. However, owing to infiltration of the aortic wall, curative resection was impossible and colostomy was performed. Angiography confirmed a large pseudoaneurysm of the rectal superior artery, and embolization was performed successfully. The further course was unremarkable. Pseudoaneurysm of the inferior mesenteric artery is rare. To our knowledge, a case with hemorrhagic shock after endoscopic biopsy caused by cancer-associated pseudoaneurysm has not been reported so far. DISCLOSURES Author contributions: A. Probst: conception and design, analysis and interpretation of the data, drafting of the article. M. Ayoub, F. Sommer, and F. Schwarz: analysis and interpretation of the data. H. Messmann: critical revision of the article, final approval of the article. Financial disclosure: None to report. Informed consent was obtained for this case report.

Chronic Radiation cystitis: a review of medical and surgical management

Radiation cystitis is a complication of radiation treatment given for pelvic malignancies. Radiation cystitis can present as mild symptoms of dysuria, frequency, and hematuria to severe life-threatening complications like intractable hematuria, bladder perforation and contracted non-functional urinary bladder, fistula etc. Treatment is tailored according to the severity of symptoms and available treatment modalities sequentially. Initial treatment of hematuria is intravenous fluids, blood transfusions, cystoscopy and fulguration, irrigation with intravesical agents like alum, hyperbaric oxygen therapy, angioembolisation, urinary diversion and surgery (cystectomy). Radiation cystitis is associated with short- and long-term complications in pelvic malignancies patients. Early diagnosis, follow up, treatment is crucial for decreasing morbidity and mortality in these patients. In this review article we describe the current protocol in diagnosing and managing radiation cystitis.&#x0D; Keywords Pelvis, Radiation, Hematuria, intravesical treatments, Alum, formalin

Coagulation dysfunction of severe burn patients: A potential cause of death.

Research on coagulation dysfunction following burns is controversial. This study aimed to describe the coagulation changes in severe burn patients by examining coagulation parameters. Patients with third-degree total body surface area (TBSA) burns of ≥30% were enrolled between 2017 and 2020. Platelet (PLT) count and coagulation indexes (including APTT, INR, FIB, DD, and AT Ⅲ) were measured at admission and once weekly for 8 weeks, and statistical analysis was performed. The patient medical profiles were reviewed to extract demographic and clinical data, including TBSA, third-degree TBSA, and inhalation injury. The total intravenous fluids and transfusions of crystalloids, fresh frozen plasma (FFP), and red blood cells (RBC) were calculated during the forty-eight-hour period. The number of sepsis cases was recorded. We enrolled 104 patients , and while the overall coagulation trend fluctuated, inflection points appeared around one week and demonstrated hypercoagulability. INR was significantly higher in the non-survival group than in the survivors' group from admission to three weeks after burn (all p<0.01). From post-injury week 1 to post-injury week 3, the APTT in the non-survival group was greater than in the survival group, but the non-survival group's PLT count was lower than that in the survival group (all p<0.05). At two and three weeks after burns, the FIB levels in the non-survival group were significantly lower than those of the survival group (both p<0.01). The prevalence of inhalation injury and the proportion of sepsis cases were significantly higher in the non-survival group than in the survival group ( p ＜ 0.05, p ＜ 0.001, respectively). At the time of death, APTT, INR, and FDP levels were significantly higher in the non-survival group in the survivor group, and FIB, ATIII, and PLT were significantly lower than in the survivor group (all p<0.01). On the day of death, nine of the 12 dead patients had disseminated intravascular coagulation (DIC). Coagulation dysfunction was most prominent in severe burn patients 1 week after injury and presented as hypercoagulability. Large-area burn injury, large amounts of fluid resuscitation, inhalation injury, and sepsis may all contribute to coagulation dysfunction, which can further develop into DIC and even death in severe burns patients.

A CASE OF POSTPARTUM HEMORRHAGE DUE TO PLACENTA ACCRETA DIAGNOSED BY ANATOMOPATHOLOGY EXAM

Placenta accreta is a rare but potentially life-threatening condition in which the placenta invades the myometrium of the uterus. It is more common in women with a history of previous cesarean delivery, placenta previa, or uterine surgery. The diagnosis of placenta accreta can be challenging and is often madeintraoperatively or postoperatively. A 36-year-old gravida 4 para 3 woman presented with postpartum hemorrhage due to placenta accreta that was diagnosed by an anatomopathology exam. The management of postpartum hemorrhage typically involves several steps to stabilize the patient and control bleeding. In this case, the patient was resuscitated with intravenous fluids and blood transfusions, given uterotonic medications, and underwent emergency laparotomy to remove her uterus. An anatomopathology exam confirmed the diagnosis of placenta accreta, which had not been suspected during the initial assessment. The patients postoperative course was uneventful, and she was discharged on the seventh postoperative day. The management of PPH due to placenta accreta requires a multidisciplinary approach involving obstetricians, anesthesiologists, hematologists, and interventional radiologists. The initial management of PPH involves resuscitation and stabilization of the patient. The next step is to control bleeding by uterine massage and administration of uterotonic agents. If bleeding persists despite uterine massage and administration of uterotonic agents, surgical intervention should be considered, which includes uterine artery embolization, hysterectomy, and conservative management. The choice of surgical management depends on the severity of bleeding, hemodynamic stability, and the extent of placental invasion. Early diagnosis and management of placenta accreta are essential for the prevention of adverse outcomes, and a multidisciplinary approach is crucial for the successful management of this condition.

Efficacy and association of hyperbaric oxygen therapy combined with butylphthalide and oxiracetam with serum levels of inflammatory markers in vascular cognitive impairment after acute ischemic stroke.

This study evaluated the efficacy of hyperbaric oxygen therapy (HBOT) combined with butylphthalide (NBP) and oxiracetam (OXR) for vascular cognitive impairment after acute ischemic stroke and investigated the association between such combination therapy and the serum levels of inflammatory markers. This was a prospective study which included eighty patients with post-AIS cognitive impairment (PAISCI) treated in Dongguan City People's Hospital from January 2020 to January 2022. They were randomized into study group and control group. The control group was provided with conventional therapy consisting of NBP for intravenous transfusion and oral OXR, while the study group received combination therapy of HBOT, NBP, and OXR. A comparison was drawn between the two groups regarding clinical outcomes, levels of recovery of cognitive and neurological function and intelligence, changes in inflammatory markers, and incidence of adverse drug reactions (ADRs). The response rate of the study group was significantly higher than that of the control group (p=0.04). The cognitive function scores of the study group were significantly better than those of the control group at the end of treatment (p<0.05). The post-treatment levels of inflammatory markers were significantly reduced in the study group when compared with the control group (p<0.05). At two weeks after treatment, the ADR rate of study group was significantly lower than the control group (p=0.03). The combination therapy of HBOT, NBP, and OXR demonstrates robust efficacy in patients with PAISCI. It is deemed to be a safe and effective treatment regimen.

A Multicenter Study of Safety, Tolerability, and Effectiveness of Antithrombotic Therapy in Hereditary Hemorrhagic Telangiectasia

Introduction: With a prevalence of 1 in 5000 persons, hereditary hemorrhagic telangiectasia (HHT) is the second-most common hereditary bleeding disorder in the world. As HHT is a bleeding disorder with a concomitant elevated thrombotic risk, antithrombotic therapy (anticoagulation and antiplatelet therapy) is frequently needed, but data describing its use is extremely limited. Antithrombotic therapy recommendations in the recently published Second International HHT Guidelines are based on this very limited data (largest prior cohort study including 28 patients) or expert opinion alone. Methods: We evaluated outcomes in a 5-hospital observational cohort study of adults with HHT receiving antithrombotic therapy over a 26-year period. Patients were identified via electronic database query, and eligibility was confirmed and data collection performed via manual chart review. Multivariable logistic modeling was used to assess for predictors of premature antithrombotic therapy discontinuation and hematologic characteristics and healthcare utilization before and after initiation of antithrombotic therapy were evaluated using paired t-tests (continuous data) and chi-square tests (categorical data). Results:Patients and Episodes: 119 HHT patients with 187 discrete antithrombotic therapy episodes were included. Median (range) age was 70 (27-92) years and 69 patients (58%) were female. Most common antithrombotic indications were venous thromboembolism (61 episodes), coronary artery disease (29 episodes), and atrial fibrillation (29 episodes). Most common antithrombotic agents used (by number of episodes) were aspirin (57), warfarin (35), low molecular weight heparin (26), apixaban (15), rivaroxaban (8), and multiple simultaneous medications (41). Tolerability and Effectiveness Overall and by Antithrombotic Therapy Class: 59 patients (50%) prematurely discontinued and/or dose-reduced therapy (including 52 patients [44%] who discontinued) due to worsening bleeding. Initiation at reduced dose-intensity had a similar premature discontinuation rate (49%) as initiation at standard dose-intensity (43%). Difficulty receiving indicated therapy may have resulted in increased thromboembolic recurrence (20 patients, 17%). Rates of dose-reduction and/or premature discontinuation were similar regardless of anticoagulant class (warfarin, 46%; heparin-based, 48%; direct oral anticoagulant [DOAC], 44%) or with multiple simultaneous agents (44%) but slightly lower with single-agent antiplatelet therapy (37%). Predictors of Therapy Discontinuation: In a multivariable logistic model, a history of GI bleeding was associated with 3.25-fold odds of discontinuation (P=0.001, Figure). Adverse Events Associated with Antithrombotic Therapy: Hemoglobin was significantly lower (10.8 g/dL vs 12.2 g/dL, P<0.001), and need for intravenous iron and RBC transfusion significantly higher (29 patients vs 12 patients, P=0.004), in the 3 months after antithrombotic therapy initiation versus the 3 months before (Table); number of patients requiring ED visits and/or hospital admissions due to bleeding also increased. 75 patients (63%) developed worsened epistaxis (of whom 33% dose-reduced or discontinued antithrombotic therapy due to epistaxis) and 44 patients (37%) developed newly-diagnosed or worsened gastrointestinal bleeding (of whom 59%, dose-reduced or discontinued antithrombotic therapy due to GI bleeding). Conclusions: Successful administration of antithrombotic therapy is challenging in HHT, resulting in objectively higher morbidity and healthcare utilization from worsened bleeding. Discontinuation rates approached 50% regardless of dose-intensity at initiation or type of antithrombotic agent used and were higher in patients with a history of gastrointestinal bleeding. These findings, from the largest and most comprehensive evaluation of antithrombotic therapy in HHT to date, challenge at least two recommendations made based on limited prior data or expert opinion alone in the Second International HHT Guidelines: the recommendation for use of warfarin or heparin-based therapy over DOACs and the avoidance of multiple simultaneous agents even when otherwise indicated due to concern for higher bleeding risk. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thalidomide and Sucralfate Reduce Gastrointestinal Bleeding in Adults with Hereditary Hemorrhagic Telangiectasia: The Mexican Experience

Introduction Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder, occurring in 1/5,000 to 1/10,000 persons. Has an autosomal dominant transmission and can occur de novo. Telangiectases occurs at characteristics sites: lips, oral cavity, fingers and nose; but visceral lesions are common, affecting gastrointestinal tract (GIT), liver, lung, brain and spinal arteriovenous formations. Nosebleed and GIT can lead to iron deficiency anemia. HHT is an underrecognized disease and delay in diagnose can increase morbidity and mortality as more telangiectases develop with aging. Thalidomide treatment for moderate and severe bleedings, that are defined by requirements of intravenous iron replacement and/or transfusions, has been used since more than a decade with good results (Blood 2021;137:888-895 and Hematology Am Soc Educ Program 2021;1:469-477). Material and methods Anemic adults with HHT based in Curaçao clinical diagnosis criteria, three to four from: a) telangiectases, b) epistaxis, c) visceral involvement and d) direct family history (Am J Med Genet 2009;91:66-67); and positive endoscopic study with moderate to severe GIT bleeding; some patients had a full body CT Scan and showed telangiectasi in al GIT as in Figure 1, the bone window reveal fill blooded telangiectasia. Thalidomide was initiated at 100 mg daily for a month and increased to 200 mg daily if tolerated for 12 months; aspirin 100 mg daily for thrombosis prevention; and omeprazole 20 mg with sucralfate 1 gr twice a day for GIT mucosal protection; transfusion to maintain hemoglobin level at 7-8 g/L and iron carboxymaltose to increase Hb levels and maintain ferritin above 50 ng/mL End points before and after treatment: a) number of episodes of GIT bleeding, b) number of red blood cells transfusions, and c) hemoglobin levels. Results Fifteen patients were included, 9 men and 6 females. Age from 28 to 74 years, median 56. All patients tolerated thalidomide 200 mg daily with minimum side effects and no hematologic toxicity, and completed 12 months period. The number episodes per month of GIT bleeding for all the group before treatment were 28, all patients have at least one monthly episode and two patients more than three; after three months and until end of treatment the number of episodes per month reduced to 5 for all the group. The number of red blood cells transfusion for all the group before treatment were 65 units per month, after three months of treatment reduced to 9 units and at end of treatment to 4 units. The mean of Hb level before treatment were 5.86 g/L, after three months of treatment were 9.2 g/L, and at end of treatment were 11.7 g/L. As a secondary observation the nosebleed episodes were reduced to zero after three months of treatment, from 9 episodes before treatment. No thrombotic complications were observed. Median time to increase the GIT bleeding was 9 months after end of treatment. Discussion In HHT, GIT bleeding is a common symptom in older adults over than 50 years due many factors: nosebleed had received various lines of treatment, ageing of the GIT mucosa that leads to the development of more telangiectases and use of medications for chronic diseases, among others. In this case thalidomide with sucralfate are tolerated and have very good results diminishing the GIT bleeding and the red blood cells transfusions, allowing to increase the Hb levels using IV iron. The response is observed in the three first months of treatment and is maintained until nine months after the end of it. Thalidomide as antiangiogenic and Sucralfate as a local healing substance are useful as an option in this kind of patients in low income countries because Bevacizumab, Pomalidomide and other antiangiogenics are more expensive. More trials using thalidome alone or in combination would help to have strong data in results and improve the quality of life of these patients. Finally, after ellectronic search this is the only Mexican experience in the treatment of HHT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Machine-Learning Derived Red Blood Cell Morphology Tool Enables Differential Diagnosis and Novel Single-Cell Analyses

Microscopic examination of red blood cell (RBC) morphology in a peripheral blood smear is a standard clinical test with broad utility even in resource-limited settings. Yet this analysis remains subjective, semi-quantitative, and low throughput, limiting its potential in clinical practice and translational research. Prior attempts to develop quantitative RBC morphology tools have been hampered by limited scope, reproducibility challenges, and sparse clinical validation. Here, we present a novel, open-source machine-learning approach leveraging durable geometric features to quantify clinically relevant RBC morphologies-elliptocytes, microcytes, macrocytes, schistocytes, sickle cells, spiculated cells, and teardrop cells-and generate an RBC differential ('RBC-diff'), analogous to the widely used white cell differential. Analysis of >300 thousand smear images across two medical centers shows algorithm concordance with expert human morphology estimates at both the individual cell and full-field smear level, and when compared to standard clinical grading of smears. This algorithm illustrates high intra-sample reproducibility while providing greatly improved speed and resolution comparative to current standards. To test the utility of this new tool we examined: (i) diagnostic signatures in the RBC differential, (ii) large-scale cohort prognostics, (iii) single-cell mechanistic studies, and (iv) an animal model of hematologic disease. Diagnostic RBC differential signatures were discovered by applying the RBC-diff to a cohort of patients with thrombotic microangiopathy (TMA). In particular, the RBC-diff facilitated rapid identification and differential diagnosis of patients with thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), providing greater specificity than manual review (72% vs. 41%, p < 0.001), while maintaining high sensitivity (94-100%). Because TTP is a life-threatening disorder requiring immediate therapy, this new rapid diagnostic tool may provide significant benefit, as existing gold-standard diagnostic tests for TTP are slow (hours to days). Large-scale cohort prognostic value was uncovered through an analysis of smears from a general cohort of 58,950 inpatients that found that elevated schistocyte counts are associated with increased all-cause mortality (9.5% six-month mortality for >1% schistocytes vs. 4.7% for schistocytes < 0.5%, p < 0.001), after adjusting for patient demographics, comorbidities, and manual smear review flags. This tool also allowed for analysis of morphologically annotated single-cell volume distributions, providing insights into how dysmorphology can affect mean corpuscular volume (MCV) and the red cell distribution width (RDW); note that current technology provides only whole-population measures for these variables. For example, in iron-deficient patients who underwent intravenous iron transfusions, this technique highlighted that successful hematologic resolution involved volume increases for all cell types, rather than an isolated reduction in microcyte levels. Finally, without any retraining the model was successfully applied to animal-derived blood smears, highlighting expected differences between a wild-type (WT) and sickle cell disease mouse model (SCD) (0% sickle cells for WT, 1.2% for SCD), demonstrating potential value for basic research investigations. Usage of the red cell differential has the potential to greatly benefit hematologic research and clinical practice. Here we present the RBC-diff, an extensively validated method for efficient calculation of this differential from commonly collected blood smear images. As a resource to the community, we provide open-source code for calculating the RBC-diff. We also provide a repository of 5000 individual RBC images, and 50 full-field smears, each manually labelled by a team of expert pathologists, to facilitate further developments of improved computational methods of RBC classification. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Autoimmune Hemolytic Anemia during Pregnancy or Post-Partum: An International Multi-Center Experience

Autoimmune hemolytic anemia (AIHA) developing or relapsing during pregnancy or postpartum is a rare finding, and few is known about maternal and fetal outcomes. Furthermore, AIHA management during pregnancy and lactation is not standardized and drug use is often limited by safety concerns. Here, we report the results of a multi-center retrospective cohort study evaluating AIHA impact on pregnancy focusing on disease severity, treatment need and maternal and fetal outcome. Forty-one pregnancies occurring in 31 women were registered from 1997 to 2022 at 11 European centers in Italy, Denmark, France, the Netherlands, USA, and Spain. AIHA was classified according to the direct antiglobulin test as warm, cold, mixed or atypical. Outcomes were compared with a control group of 56 healthy women matched for age at pregnancy and decade of pregnancy. Overall, we observed 21 warm AIHA (13 IgG; 8 IgG+C3d), 2 cold agglutinin diseases, 3 mixed and 5 atypical forms (Table 1). Evans syndrome (i.e., association of AIHA and immune thrombocytopenia or neutropenia) was present in 5 women. Mean age at AIHA diagnosis was 27 (3-39) years and at pregnancy 32 (21-41) years. AIHA diagnosis predated pregnancy in 16 women and had required at least 1 therapy line in all of them, and ≥2 lines in 13 (rituximab, N=8; cytotoxic immunosuppressants, N=6; splenectomy, N=5). Among these 16 patients, 7 had a relapse during pregnancy, 3 during postpartum and 9 were on active treatment at the time of pregnancy (steroids, N=7; cyclosporine, N=1; steroids plus azathioprine, N=1; the latter stopped after positive pregnancy test). A patient with a previous AIHA, relapsed as immune thrombocytopenia during pregnancy. Further 9 patients developed AIHA during gestation and 2 in the postpartum. A patient had AIHA onset during the postpartum of the 1st pregnancy and relapsed during the 2nd one. In total, we observed 22 hemolytic events in 21 women during pregnancy/postpartum. Median Hb and LDH levels were 6.4 g/dL (3.1 - 8.7) and 599 IU/L (269-1631), respectively. Management consisted in blood transfusions (N=11, 50%) and prompt establishment of steroid therapy +/- intravenous immunoglobulins (N=22, 100%), all with response (complete N=15, partial N=7). After delivery, rituximab was necessary in 4 patients and cyclosporine was added in one. Anti-thrombotic prophylaxis was given in 7 patients. Overall, we registered 10 maternal complications (10/41, 24%), including 4 early miscarriages, a premature rupture of membranes, a placental detachment, 2 preeclampsia, a postpartum infection and a biliary colic. Notably, 8/10 complications occurred during active hemolysis and treatment for AIHA. Ten fetal adverse events (10/41, 24%) were reported: a transitory respiratory distress of the newborn in a mother with active AIHA; 4 cases of fetal growth restriction; a preterm birth; an infant reporting neurologic sequelae; a case of AIHA of the new-born requiring intravenous immunoglobulins, blood transfusions and plasma exchange; and 2 perinatal deaths. The latter two occurred in women on active AIHA therapy and were secondary to a massive placental detachment and a symptomatic SARS-CoV-2 infection. Finally, the comparison between AIHA women and the control group showed a similar prevalence of maternal complications (24% in AIHA versus 18% in controls). At variance, AIHA was marked by a significant increase of fetal adverse events versus control group (24% versus 5%, p=0.008), with more severe complications in the former. In conclusion, AIHA developing/reactivating during pregnancy or postpartum is rare but mainly severe, requiring red cell transfusions in half of cases and steroid therapy in all patients. Notably, severe maternal and fetal complications may occur in up to a quarter of cases mostly associated with active hemolysis. Finally, AIHA was significantly associated with severe fetal complications compared with healthy population, further pinpointing the importance of maintaining a high level of awareness. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ALK2 Inhibition and a Modified Activin Receptor Type Iia Ligand Trap Cotherapy Maximized Hematologic Improvements in a Mouse Model of Anemia of Inflammation

Introduction: Anemia of inflammation (AI) is commonly seen in patients with chronic diseases, including chronic kidney disease (CKD). Current therapeutic options to mitigate anemia in AI include treating the underlying inflammatory disease, oral or intravenous iron supplementation, erythropoietin, and blood transfusions. The persistent release of inflammatory cytokines in AI not only induces the iron regulator hepcidin to inhibit iron absorption and recycling, but also directly impacts the marrow to suppress erythropoiesis, further worsening the ineffective, iron-restricted erythropoiesis. Therefore, targeting both iron and erythropoiesis could comprehensively address anemia in AI. We previously showed that ALK2 inhibition was sufficient to reduce serum hepcidin and improve hemoglobin in a CKD mouse model. We also demonstrated that a modified activin receptor IIA ligand trap RKER-050 increased hemoglobin and red blood cell production by promoting erythroid differentiation in mice. Here, we explored the potential of additive improvements in hematologic parameters that could be achieved with a combination of hepcidin suppression by ALK2 inhibition and increased hematopoiesis with RKER-050 in a mouse model of AI. Methods: C57BL/6 mice were fed a control or 0.2% adenine with 40 ppm iron diet (Ade 40) for 5 weeks to induce CKD. After confirming anemia, CKD mice were subcutaneously treated with 3 mg/kg isotype control or KTI-m216, a neutralizing antibody against ALK2, twice a week for 4 weeks while continuing the Ade 40 diet or switching to a 0.2% adenine with 3 ppm low iron diet (Ade 3). Combination therapy was evaluated in CKD mice on Ade 40 diet receiving biweekly isotype or KTI-m216 and also received either weekly PBS or 7.5 mg/kg RKER-050 intraperitoneally for 4 weeks. Results: CKD mice developed impaired kidney function and characteristics of AI, including increased serum IL-6 and hepcidin, hypoferremia, tissue iron retention, and anemia compared to control mice. Serum hepcidin was reduced >95% in KTI-m216 treated mice on both Ade diets compared to mice receiving isotype control (CKD control). Transferrin saturation (TSAT) increased 65% in KTI-m216 treated mice on Ade 40 diet, with a similar trend in mice on Ade 3 diet. When compared to CKD control of the same diet, KTI-m216 treated mice had similar hematologic improvements: hemoglobin (+2.2 g/dL), hematocrit (+5.4%), red blood cells (+1.1 M/μl), and reticulocyte hemoglobin (CHr, +1.8 pg). These data support that increased circulating iron by KTI-m216 mediated hepcidin suppression can increase erythropoiesis in CKD mice. Data also suggest that dietary iron contribution is negligible in supporting erythropoiesis in this context. With combination therapy, mice receiving KTI-m216 alone (KTI-m216 and PBS) and a combined KTI-m216 and RKER-050 therapy had a similar reduction in serum hepcidin (>91%) and a similar increase in TSAT (>1.7-fold), compared to mice receiving vehicle (isotype and PBS) controls. Mice treated with KTI-m216 alone increased hemoglobin to 11.4 g/dL compared to vehicle treated mice with hemoglobin of 8.0 g/dL. Treatment with a combined KTI-m216 and RKER-050 therapy showed a further increase in hemoglobin to 13.5 g/dL. Additionally, red blood cell production was 6.4 M/μl in mice given vehicle controls and increased to 8.3 M/μl in KTI-m216 alone and 9.8 M/μl in combined KTI-m216 and RKER-050; hematocrit was 23.4% in vehicle control, 32.5% in KTI-m216 alone and 38.7% in combined KTI-m216 and RKER-050. Although hematocrit was not fully rescued, hemoglobin and red blood cells in mice receiving a combined KTI-m216 and RKER-050 therapy were not different from the non-CKD controls. Conclusion: These data illustrate that inhibition of ALK2 with KTI-m216 could potentially release sufficient iron from the recycling pathway to ameliorate anemia, but not restore RBC parameters to normal levels. Combined treatment with activin receptor ligand trap, RKER-050 and KTI-m216 normalized the RBC production in this preclinical model. These data support that increasing erythropoiesis with RKER-050 combined with iron mobilization with KTI-m216 has the potential to achieve the maximal amelioration of anemia in AI.

Randomized, double-blind, placebo-controlled, crossover trial of oral doxycycline for epistaxis in hereditary hemorrhagic telangiectasia

BackgroundVascular malformations in hereditary hemorrhagic telangiectasia (HHT) lead to chronic recurrent bleeding, hemorrhage, stroke, heart failure, and liver disease. There is great interest in identifying novel therapies for epistaxis in HHT given its associated morbidity and impact on quality of life. We aimed to measure the effectiveness of oral doxycycline for the treatment of epistaxis and explore mechanisms of action on angiogenic, inflammatory and pathway markers in HHT using a randomized controlled trial.Methods13 HHT patients with epistaxis were recruited from the Toronto HHT Center at St. Michael’s Hospital. Recruitment was stopped early due to COVID-19-related limitations. The study duration was 24 months. Patients were randomly assigned to the treatment-first or placebo-first study arm. We compared the change in weekly epistaxis duration and frequency, biomarkers, blood measurements, and intravenous iron infusion and blood transfusion requirements between treatment and placebo.ResultsThere was no significant difference in the change in weekly epistaxis duration (p = 0.136) or frequency (p = 0.261) between treatment and placebo. There was no significant difference in the levels of MMP-9, VEGF, ANG-2, IL-6 or ENG with treatment. Hemoglobin levels were significantly higher (p = 0.0499) during treatment. Ferritin levels were not significantly different between treatment and placebo. There was no significant difference in RBC transfusions between treatment periods (p = 0.299).ConclusionOverall, our study did not demonstrate effectiveness of doxycycline as a treatment for epistaxis in patients with HHT, though the study was underpowered. Secondary analyses provided new observations which may help guide future trials in HHT.Trial Registration ClinicalTrials.gov, NCT03397004. Registered 11 January 2018 – Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT03397004

The effectiveness of noradrenaline for preventing hypotension during spinal anesthesia for cesarean delivery

Background: Spinal anesthesia-induced hypotension is a common complication which can cause many severe maternal and fetal consequences. Therefore, the prevention and treatment of this complication play an important role. The vasopressor recently suggested to prevent hypotension during spinal anesthesia has been noradrenaline. The aim of this study is to evaluate the efficacy and side effects of noradrenaline intravenous transfusion and bolus for prevention of spinal anesthesia-induced hypotension during cesarean delivery. Methods: In the randomized controlled study, 110 pregnants undergoing cesarean delivery with spinal anesthesia were randomly divided into two groups: Group T: noradrenaline transfusion at a dose of 0.05 μg/kg/min (n = 55), and group B: noradrenaline intravenous injection 6 μg (n = 55). Both groups were recorded the incidence of hypotension, levels of hypotension, maternal side effects and neonatal APGAR scores at 1 and 5 minutes. Results: Four parturients in group B were excluded from the study due to the failure of spinal anesthesia. Maternal hypotension and level of hypotension of 20 - 30% of baseline systolic blood tension were less frequent in group T than in group B. The level of hypotension above 30% of baseline systolic blood tension and maternal side effects in both groups were low and comparable. The neonatal APGAR scores at 1 minute and 5 minutes in both groups were ≥ 8 and ≥ 9 respectively… Conclusion: Noradrenaline prophylactic infusion at dose of 0.05 μg/kg/min was more effective than noradrenaline intravenous bolus of 6 μg for maintaining blood pressure and decreasing the incidence of hypotension, level of hypotension. In addition, both groups of prophylactic noradrenaline didn’t cause detrimental adverses for parturients and their babies. Key words: hypotensive prophylaxis, cesarean delivery, noradrenaline.