Incidence Of Thrombotic Events Research Articles

A real-world study of different doses of rivaroxaban in patients with nonvalvular atrial fibrillation.

To explore the anticoagulant effect and safety of utilizing different doses of rivaroxaban for the treatment of patients with atrial fibrillation (AF) in the real world. A retrospective case-control analysis was performed by applying the hospital database, and 3595 patients with non-valvular atrial fibrillation (NVAF) who were hospitalized and taking rivaroxaban at Wuhan Asia Heart Hospital and Wuhan Asia General Hospital from March 2018 to December 2021 were included in the study, and were divided into the rivaroxaban 10 mg and 15 mg groups according to the daily prescribed dose, of which 443 cases were in the 10 mg group and 3152 cases were in the 15 mg group. The patients were followed up regularly, and the incidence of thrombotic events, bleeding events and all-cause deaths were recorded and compared between the 2 groups, and logistic regression was applied to analyze the influencing factors for the occurrence of adverse events. Comparison of the incidence of thrombosis, bleeding and all-cause death between the 2 groups of patients showed that the 10 mg group was higher than the 15 mg group, but the difference was not statistically significant (χ2 = 0.36, 3.26, 1.99, all P > .05); the incidence of total adverse events between the 2 groups of patients was higher in the 10 mg group than in the 15 mg group, with a statistically significant difference (χ2 = 4.53, P = .033); multifactorial logistic regression results showed that age [OR (95% CI) = 1.02 (1.00-1.04)], diabetes mellitus [OR (95% CI) = 1.69 (1.09-2.62)], D-dimer level [OR (95% CI) = 1.06 (1.00-1.11)] and persistent AF [OR (95% CI) = 1.54 (1.03-2.31)] were risk factors for adverse events (P < .05). In the real world, Asian clinicians recommend rivaroxaban 10 mg once daily for NVAF patients for a variety of reasons; however, this dose is not superior or even inferior to the 15 mg group in terms of effectiveness and safety. Advanced age, elevated D-dimer levels, history of diabetes mellitus, and persistent AF are risk factors for adverse events, and the optimal dosage of rivaroxaban or optimal anticoagulation strategy for Asian patients with nonvalvular AF requires further study.

The Incidence of Thrombotic Events After the Concomitant Use of Andexanet alfa and 4-Factor Prothrombin Complex Concentrate

Limited data exists on the safety and efficacy with the concomitant use of 4 factor prothrombic complex concentrate (4F-PCC) and andexanet alfa (AA). This case series describes 7 patients at our institution who received both 4F-PCC and AA for the management of life-threatening bleeding associated with apixaban or rivaroxaban. Four patients received AA due to worsening bleeding after 4F-PCC. Of the 7 patients in this case series, 1 had a documented thrombotic event which was an acute ischemic stroke. The thrombotic event rate in our case series was similar to the incidence of thrombotic events reported with the use of AA alone. In-hospital mortality occurred in 2 of 7 patients with 1 additional patient discharged to hospice care.

Hypoalbuminemia as predictor of thrombotic events in patients with community-acquired pneumonia

BackgroundHypoalbuminemia complicates acute diseases and infections and is associated with a worst prognosis. The aim is to evaluate whether hypoalbuminemia is associated with higher incidence and risk of thrombotic events in community-acquired pneumonia. MethodsWe retrospectively collected data from a prospective study investigating the incidence of thrombotic events in community-acquired pneumonia hospitalized patients from 2011 to 2016 at University-Hospital Policlinico Umberto I. Baseline characteristics and outcomes were collected. Incidence of outcomes were calculated. Kaplan-Meier curves were created, Cox model used to identify predictors for the outcomes, and competing risk analysis performed. ResultsFrom a total of 231 patients, 130 (56.3%) and 101 (43.7%) had or not hypoalbuminemia. Age, proportion of female, BMI, major comorbidities, and severity of pneumonia were similar between two subgroups. A less proportion of patients with hypoalbuminemia received antithrombotic and statin therapy. Median hospital stay was 11 days in both subgroups. Patients with hypoalbuminemia had higher D-dimer and high- sensitivity C-reactive-protein values with an inverse relation between albumin values and these markers. Incidence of thrombotic events was 26 and 11 per 1000 patient-days in patient with and without hypoalbuminemia. At Cox model, hypoalbuminemia was associated with thrombotic events development in univariable (hazard ratio; 2.67, 95% confidence intervals, 1.30–5.40) and multivariable (hazard ratio 3.19; 95% confidence intervals, 1.48–6.89) analysis. ConclusionsMore than a half of patients with community acquired pneumonia had hypoalbuminemia that is associated with a doubled incidence and a three-fold increased risk of thrombotic events. The inverse relation between baseline albumin and D-dimer values confirms this association.

Thrombotic Complications, Disease Progression, and Survivals in BCR::ABL1-Negative Myeloproliferative Neoplasms: A 12-Year Retrospective Study at a Single Center in Thailand

Objective: To assess the incidence of thrombotic events among patients with BCR::ABL1-negative myeloproliferative neoplasm (MPN) within a single center in Thailand. Materials and Methods: Conducted as a retrospective cohort study between 2008 and 2019, the present research focused on patients diagnosed with BCR::ABL1-negative MPN. Diagnoses were reviewed and reclassified based on the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2017). Data collected encompassed demographic details, comorbidities, investigation results, treatments, and outcomes. The primary focus was on thrombosis rates in arterial and venous sites. Secondary outcomes included the incidence of major bleeding, thrombosisfree survival (TFS), and overall survival (OS). Results: One hundred seventy-five patients participated in the present study and comprised of 46 patients (26.3%) with polycythemia vera (PV), 123 (70.3%) patients with essential thrombocythemia (ET), and six patients (3.4%) with primary myelofibrosis (PMF). Most patients were over 60 years old. The rate of overall thrombosis rate was 28.0%, with 43.5% in PV and 23.6% in ET. Common sites of thrombotic events included the cerebral artery at 16.6%, coronary artery at 6.3%, peripheral artery at 4.0% and venous thromboembolism at 3.4%. The overall bleeding event rate was 13.7%, with 70.8% classified as major bleeding. The all-cause mortality rate within the present cohort was 30.9%. TFS and OS stood 72.0% and 69.1%, respectively. Conclusion: Thrombosis emerged as a significant complication in patients with BCR::ABL1-negative MPN, affecting 28.0% of individuals in the present cohort. Arterial thromboses, particularly ischemic stroke and cardiovascular events, were the predominant occurrences. Keywords: Myeloproliferative neoplasm; Polycythemia vera; Essential thrombocythemia; Thrombosis; Bleeding

Thrombopoietin receptor agonists use and risk of thrombotic events in patients with immune thrombocytopenic purpura: A systematic review and meta‑analysis of randomized controlled trials.

Thrombopoietin receptor agonists (TPO-RAs) have a role in second-line immune thrombocytopenic purpura (ITP) treatment, binding to and activating thrombopoietin receptors on megakaryocyte membranes in the bone marrow. This promotes megakaryocyte maturation and increases platelet production. Despite a 2-6% incidence of thrombotic events during TPO-RA treatment, it remains uncertain whether TPO-RAs elevate thrombosis rates. A comprehensive search of electronic databases was conducted using the relevant search criteria. To assess the risk of bias, the included studies were assessed using the revised Cochrane Risk of Bias Assessment Tool 2.0, and a meta-analysis was performed using RevMan 5.4.1. A total of 1,698 patients with ITP were included from randomized controlled trials (RCTs). There were 26 thromboembolic events in the TPO-RAs group and 4 in the control group. However, there was no significant difference in the incidence of thrombotic events between the two groups [odds ratio (OR)=1.76, 95% confidence interval (CI): 0.78-4.00, P=0.18], even if the duration of treatment was >12 weeks (OR=2.46, 95% CI: 0.81-7.43, P=0.11). Subgroup analysis showed that none of the four drugs significantly increased the incidence of thrombotic events (romiplostim: OR=0.92, 95% CI: 0.14-6.13, P=0.93; eltrombopag: OR=2.32, 95% CI: 0.64-8.47, P=0.20; avatrombopag: OR=4.15, 95% CI: 0.20-85.23, P=0.36; and hetrombopag: OR=0.76, 95% CI: 0.03-18.76, P=0.87). There was also no significant difference in the results of the double-blinded placebo-controlled RCTs (OR=1.21, 95% CI: 0.41-3.58, P=0.73). Compared to patients with ITP who did not receive TPO-RA treatment, those receiving TPO-RA treatment did not exhibit a significantly increased risk of thrombotic events.

Macular perfusion changes in people administered two types of COVID-19 vaccines: optical coherence tomography angiography study.

To evaluate macular chorioretinal flow changes on optical coherence tomography angiography, in participants who received inactivated and messenger RNA (mRNA) vaccines to prevent Coronavirus disease 2019 (COVID-19). In this prospective cohort study, healthy participants who received two doses of an inactivated COVID-19 vaccine (CoronaVac) and then one dose of an mRNA vaccine (BNT162b2) were examined before and after each vaccination. Ophthalmologic examination and imaging with optical coherence tomography angiography were performed during each visit. We evaluated vascular densities in the superficial and deep capillary plexuses in foveal, parafoveal, and perifoveal areas; the foveal avascular zone; and choriocapillaris flows (in 1- and 6-mm-diameter areas). One eye in each of the 24 participants was assessed. Superficial capillary plexus vascular densities in the parafoveal area were significantly lower after the second dose of the CoronaVac vaccine than after the first dose. In the deep capillary plexus, vascular attenuation was observed only in the parafoveal region after the first CoronaVac dose. However, in all regions, the deep capillary plexus vascular densities and subfoveal choriocapillaris flow were significantly decreased after the second CoronaVac dose. After the BNT162b2 dose, the superficial capillary plexus vascular densities, the deep capillary plexus vascular densities, and subfoveal choriocapillaris flow of most regions were significantly lower than those before vaccinations. Vascular attenuation, observed particularly after the second dose of the CoronaVac vaccine, may explain the pathogenesis of postvaccine ocular ischemic disorders reported in the literature. However, these disorders are extremely rare, and the incidence of thrombotic events caused by COVID-19 itself is higher.

Expression level of Wilms' tumor 1 gene and its correlation with clinical features in patients with myeloproliferative neoplasms

Objective: To investigate the expression level of WT1 gene in patients with classical Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPN) and its correlation with clinical features. Methods: A retrospective study included 252 patients with newly diagnosed MPN in Zhongnan Hospital of Wuhan University from January 2015 to March 2023, including 128 males and 124 females, aged［M（Q1，Q3）］62 (53, 69) years. The WT1-positive group (n=93) and the WT1-negative group (n=159) were split based on the level of WT1 gene expression, and the variations in clinical indicators between the two groups were compared. Its levels of expression in each subtype and its relationships to thrombotic events and clinically significant variables were analyzed. As of March 31, 2023, the follow-up period [M (Q1, Q3)] was 12.0(6.5,21.0)months. The risk factors of thrombosis in MPN patients were analyzed by using the logistic regression analysis. Results: The WT1 gene expression level in the overall bone marrow samples of 252 patients with newly diagnosed MPN was 0.30% (0.10%, 1.10%). The expression level in primary myelofibrosis (PMF) patients was 1.45% (0.41%, 3.24%), which was higher than 0.15% (0.02%, 0.32%), 0.37% (0.16%, 1.09%) in essential thrombocythemia (ET) and polycythemia vera (PV) patients (both P<0.05). Positive correlations were found between WT1 gene expression levels and JAK2V617F gene mutation load, RDW, MPV (r=0.478, 0.346, 0.236, all P<0.01). While negative correlations between WT1 gene expression levels and PLT, LYM, PTTA, LDH were found (r=-0.339, -0.170, -0.206, -0.388, all P<0.01). Patients in the WT1-positive group exhibited a higher percentage of somatic symptoms, splenomegaly, positive JAK2V617F gene mutation, and higher levels of RDW, LDH, NEUT, and MPV compared to the WT1-negative group. In contrast, the proportion of triple-negative (negative for all three hot mutations of JAK2V617F, CALR and MPL) was lower, and the levels of PLT, LYM and PTTA were lower (all P<0.05). The thrombotic event rates of WT1-positive group and WT1-negative group were 32.3% (30/93) and 32.1% (51/159), respectively, and the difference was not statistically significant (P=0.883). Logistic regression analysis showed that male (OR=2.41,95%CI:1.02-5.71,P=0.046) and positive JAK2V617F gene mutation (OR=3.96,95%CI:1.50-10.42,P=0.005) were risk factors for thrombotic events in ET patients. Conclusions: WT1 gene expression is elevated in PMF patients and correlated with indicators of disease progression and transformation in MPN patients. It can be utilized as an auxiliary diagnostic indicator for classical MPN staging but is not correlated with the incidence of thrombotic events. Male and positive JAK2V617F gene mutation are risk factors for thrombotic events in ET patients.

Hemoglobin F and Incidence of Thrombotic Event in Sickle Cell Disease

Introduction Characterized by abnormally sickle-shaped erythrocytes disrupting blood flow in small vessels, Sickle Cell Disease (SCD) continues to be the most common hemoglobinopathy in the United States, affecting approximately 100,000 people (Onimoe &amp; Rotz, 2020). A 2017 cohort study of SCD patients found that there is an increased risk and earlier incidence of venous thromboembolisms compared to their matched controls (Brunson et al., 2017). Fetal hemoglobin (HbF) is the best characterized modifier of disease severity in SCD, and historically, patients with low HbF percentages are at a higher risk of developing vaso-occlusive complications, organ damage, and early death (Agrawal et al., 2014). We hypothesize that having a higher hemoglobin F (unaffected by sickle cell mutation), would confer some protection from hemolysis and would be inversely related to the incidence of thrombosis in sickle cell disease patients. Methods This study uses a descriptive and cross-sectional design to analyze existing, secondary medical record data of 496 SCD patients that received care from the Center for Blood Disorders in Augusta, Georgia. Data abstraction included history of thrombotic event (TE) and HbF values closest to the TE, along with, presence of SCD clinical complications, use of blood thinning medications, specific lab values, hemoglobin electrophoresis, and history of COVID-19. For those without a history of TE, the most recent data in these categories was collected. To test the association of HbF with a categorical variable such as medical history of thrombosis, we used a two-sample t-test. To test the association of HbF with a continuous variable such as D-dimer, we computed Pearson's correlation coefficient and used Fisher's z-test. Patients with SCD who developed thrombosis were further divided into quantiles based on HbF levels [Table 1]. We collected mean age at thrombosis and mean D-dimer for these quantiles and ANOVA was used for statistical analysis. All analyses were performed using R version 4.2.3. Results Of the 496 charts reviewed, 131 patients had a history of TE and 27 of those patients have more than one recorded TE (total=189). Twenty patients did not have HbF data close to TE and were not included in this analysis. The mean HbF for patients without history of TE was 8.89 (SD 10.0), whereas the mean HbF for patients with history of TE was 10.1 (SD 10.3). A two-sample t-test comparing these two groups produced a p-value of 0.2126. Mean age of thrombosis in each quantile were 31.6 (SD 14.6), 28.7 (SD 10.5), 34.8 (SD 11.7), and 37.1 (SD 11.9), respectively, with ANOVA producing a p-value of 0.008059. Mean D-dimer in each quantile were 1017 (SD 1408), 1417 (SD 1415), 1404 (SD 1493), and 2921 (SD 8898), respectively, with ANOVA producing a p-value of .6645. Conclusions While there is no significant relationship between mean HbF levels and development of thrombosis in this cohort of 496 SCD patients, the mean age of development of thrombosis was significantly higher in higher quantiles of HbF, compared to lower quantiles, suggesting that patients with higher HbF are protected longer from thrombosis. There was no relationship between mean D-dimer level and development of thrombosis in the patients we analyzed. In SCD patients with thrombosis, D-dimer was not significantly associated with thrombosis even between different quantiles of HbF. To our knowledge, this is the first study evaluating association between HbF level, D-dimer, and development of thrombosis in SCD patients. Current therapies for SCD focus on symptom management and disease modification. While the mechanism is still not completely understood, Hydroxyurea increases the number of red blood cells (RBCs) with detectable HbF, protecting RBCs from sickle hemoglobin polymerization, thus interrupting the natural disease pathophysiology (Steinberg, 2020). Some gene therapy for sickle cell disease aims at increasing HbF in SCD patients (Abraham &amp; Tisdale, 2021). Would such therapy be protective against increased risk of thrombosis associated with SCD, remains to be determined. One limitation of this project is the restricted sample size of SCD patients with thromboembolism, and larger data size of sickle cell patients may better elucidate a relationship between Hemoglobin F and thrombosis in SCD patients.

Oral Anticoagulant Therapy in Patients with Philadelphia-Negative Myeloproliferative Neoplasms: A Real-Life Comparison between Vitamin K Antagonists and Direct Oral Anticoagulants

BACKGROUND Chronic myeloproliferative neoplasms (MPN) are characterized by an high risk of thrombosis and bleeding. Historically, vitamin K inhibitors (VKAs) have been the preferred oral anticoagulant therapy (OAT) for these patients (pts). However, nowadays, VKAs are being used less frequently, and direct oral anticoagulants (DOACs) are becoming more popular. Despite this trend, there is still limited evidence in the literature regarding the efficacy and safety of these drugs in the context of MPN. Specifically, there is a lack of data directly comparing VKAs and DOACs in a real-world clinical setting. AIMS The study aimed to conduct a real-world analysis comparing the efficacy and safety of DOACs and VKAs in patients with MPN. Both medications were prescribed for the treatment and secondary prevention of venous thromboembolism (VTE) or for the prevention of thrombosis in pts with atrial fibrillation (AF). The secondary endpoints were to assess the influence of common demographic, clinical, and hematological variables on the incidence of thrombotic events (TE) and bleeding events (BE) METHODS We conducted an observational retrospective monocentric study that enrolled all consecutive pts with MPN, followed at the MPN Clinic of the IRCCS Foundation S. Gerardo dei Tintori - Monza between 1993 and 2022, who received OAT with VKAs or DOACs for VTE or AF. For each pts, we collected demographic, clinical, biological, therapeutic, and hematological data. TE were categorized based on their type (arterial or venous) and location. BE were classified as minor, major, or clinically relevant non-major bleeding, according to the ISTH classification. Thrombosis-free survival (TFS) and bleeding-free survival (BFS) were assessed from the initiation of OAT until the occurrence of the first TE or BE, respectively, and estimated using Kaplan-Meier analysis. The other analyses were conducted using common statistical methods. Multivariable analyses included previously established risk factors for BE and TE. RESULTS A total of 156 pts were enrolled: 89 were women (57%). The median age was 69 years (range 25-92); 61 were affected by myelofibrosis, 35 by polycythemia vera, and 48 by essential thrombocythemia. 64 pts received OAT with VKAs (41%), and 92 with DOACs (59%). For 82 pts OAT was prescribed for AF (52.6%), and for 74 for VTE (47.4%). 17 pts treated with DOACs for VTE received a reduced-dose extended treatment (45.9%). The median exposure time to OAT was 5.8 years in the VKAs group (range 0.2-20 years) and 1.77 years in the DOACs group (range 0.2-10 years). After a median follow-up of 3,2 years, 14 TE were reported: 5 (35.7%) in the DOAC-treated group, of which 4 were arterial (80%), and 9 (64.3%) in the VKA-treated group (7 arterial - 77.8%). The incidence rate of TE was 2.11 thrombosis/pts/year in the VKAs group and 2.14 thrombosis/pts/year in the DOACs group. There were no significant differences in terms of TFS between the two groups, whether considering the entire population or analyzing the therapeutic indications separately (respectively p=0.72, p=0.53, p=0.55). Overall, there were 27 BE: 13 in the DOACs group (51.9%), 14 in the VKAs group (48.1%). Among these, we report 8 major BE, 4 in both groups. The incidence rate of BE was 5.6/pts/year in the DOACs group and 3.3/pts/year in the VKAs group. We did not observe significant differences in terms of BFS analyzing the whole population and the VTE group (respectively p=0.13 and p=0.75), while we found a trend for lower BFS in pts treated with DOACs for AF (p=0.08, Fig. 1). In a multivariate model, adjusted for time of exposition to OAT, age, gender and antiplatelet treatment, the risk of BE was associated solely with DOACs administration (hazard ratio 3.7, p=0.01) We found no significant differences in the risk of TE and BE when considering the various types of DOACs used. Moreover, 45 (28.8%) patients received concomitant antiplatelet therapy, and we found no significant differences in the risk of BE or TE compared to the other group (p=0.39 and p=0.41, respectively). CONCLUSIONS To our knowledge, this is the largest study investigating the safety and efficacy of DOACs compared to VKAs for the treatment and prevention of TE in pts with MPN and VTE or AF. Our findings suggest that DOACs are as effective as VKAs, but they appear to exhibit a trend towards a higher overall risk of BE, especially in the AF group. More data from prospective multicentric studies are necessary to validate our results.

A Real-World Evidence Review of Post-Marketing Safety and Compliance with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) in the US

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic condition characterized by complement-mediated, life-threatening hemolysis and thrombosis which are associated with significant impacts on health-related quality of life (HRQoL). Pegcetacoplan is the first targeted complement component 3 (C3) therapy approved for adults with PNH (US) and adults with PNH plus anemia despite receiving a complement component 5 inhibitor (C5i) for ≥3 months (EU). In clinical trials including patients with PNH who were C5i-experienced or -naive, pegcetacoplan significantly improved levels of hemoglobin (Hb) and lactate dehydrogenase (LDH) and reduced transfusion burden. Pegcetacoplan had a favorable safety profile in parent studies and an ongoing long-term, rollover, open-label extension study (NCT03531255). Compliance with pegcetacoplan treatment was high across all clinical studies. In the US real-world OPERA and Adelphi PNH Disease Specific Programme™ (DSP) patient-reported outcomes (PRO) studies, improvements in levels of Hb and LDH, along with self-reported fatigue and cognitive outcomes, were observed. Pegcetacoplan treatment also led to reductions in the frequency and severity of PNH symptoms (including shortness of breath and fatigue) and improvements in social, physical, and emotional HRQoL domains in the US real-world Voice of the Patient PRO study. Further, both patient and physician satisfaction with pegcetacoplan treatment was high in the Adelphi PNH DSP study. However, to date, compliance and safety with pegcetacoplan treatment in the real-world setting have not been described. The objective of this real-world evidence review study was to evaluate compliance and safety with pegcetacoplan treatment in patients with PNH in the US post-marketing setting. Methods: Post-marketing data from the US, including the number of patients who received pegcetacoplan and reported safety events, were collected and analyzed from the pegcetacoplan Risk Evaluation and Mitigation Strategies (REMS) program which controls the distribution of pegcetacoplan and the pharmacovigilance safety database through May 13, 2023. Treatment compliance was calculated as the proportion of days a patient had the drug in possession, divided by the total number of days of follow-up, using central pharmacy prescription refill data. Thrombosis (a leading cause of death in patients with PNH prior to the availability of complement inhibitors) and meningococcal infections (a potential risk with complement inhibitors) were safety events of interest. To reduce the risk of serious meningococcal infections, clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae; N meningitidis types A, C, W, Y, and B; and Haemophilus influenzae type B before starting treatment with pegcetacoplan. If pegcetacoplan treatment must be initiated before vaccination, the US label mandates prophylactic antibiotic use. In this study, the rates of thrombosis and meningococcal infection per 100 patient-years were estimated based on the total number of thrombosis and meningococcal infection events reported in the REMS program. Results: As of May 13, 2023, the cumulative pegcetacoplan exposure was 273.10 patient-years in the US post-marketing setting. Based on prescription refill data, compliance with pegcetacoplan treatment was ~98%. There were 2 confirmed thrombotic events reported and the incidence of thrombotic events was 0.73 events/100 patient-years in 273.10 patient-years. Similar to clinical trials, no meningococcal infections were reported in the US post-marketing setting. Conclusions: The high compliance rate and favorable safety profile of pegcetacoplan in the US post-marketing setting were consistent with clinical trial observations. These data, coupled with the effectiveness on hematologic parameters and improvements in symptoms and HRQoL reported in pegcetacoplan real-world PRO studies, support a positive benefit:risk profile for pegcetacoplan in the real-world setting.

Effect of Hetrombopag Combined with Rhtpo in Patients with Severe Immune Thrombocytopenia

Background: Severe Immune Thrombocytopenia (ITP) is a life-threatening acquired hemorrhagic disease with dramatically decreased platelet number and clinical bleeding symptoms. Some patients with severe ITP did not respond to first-line treatment including steroids and Intravenous Immunoglobulin (IVIG). It was critical for them to use effective treatments to promote platelet and reduce the risk of fatal bleeding. Clinical practice guidelines have recommended the use of thrombopoietin receptor agonist (TPO-RA) as a second-line treatment for ITP. Recombinant human thrombopoietin (rhTPO) and hetrombopag are two distinct TPO-RAs with different mechanisms. As reported, there remains no study assessing the efficacy and safety of hetrombopag combined with rhTPO in the treatment of ITP. Therefore, the present study aimed to investigate the efficacy of hetrombopag plus rhTPO in Chinese patients with severe ITP, focusing on the short rather than the long-term efficacy, such as quickly increasing platelet count and significantly reducing bleeding, which would be more meaningful for severe patients whose platelet count &amp;lt;10 × 10 9/L. Methods: This was a prospective, open-label, single-center study with a planned enrollment of 30 patients. The inclusion criteria were patients ≥ 18 years, diagnosed with primary immune thrombocytopenia, platelet count &amp;lt;10 × 10 9/L, or bleeding score ≥ 5. Patients receiving other ITP drugs as maintenance therapy were eligible if previous glucocorticoid therapy doses were stable, and rituximab was used for at least 2 months and other immunosuppressants were stable for at least 4 weeks. Patients who had received IVIG, avatrombopag, eltrombopag, or romiplostim within 2 weeks prior to enrollment were excluded. Histories of platelet transfusion one week before treatment were excluded. Hetrombopag was given at 5 mg/day for 28 days, while rhTPO was administered at 300 U/kg subcutaneously daily for 14 days. When PLT &amp;gt; 100 × 10 9/L, rhTPO should be discontinued. When PLT &amp;gt; 150 × 10 9/L, the dosage of hetrombopag was reduced to 2.5mg/day, and it would be discontinued if PLT &amp;gt; 250 × 10 9/L. The primary endpoints were proportion of subjects with platelet count ≥30×10 9/L and at least doubled the baseline platelet count within 28 days. Secondary endpoints included bleeding score, incidence of thrombotic events, and adverse events (AEs). Results: As to July 27, 2023, a total of 20 patients were included in this study, with a median age of 36 years and a male proportion of 50%. Among them, 70% (14 cases) were newly diagnosed ITP patients. 50% of patients have received ≥ 1 line of previous treatment, of which 2 patients have received IVIG treatment and both have achieved CR (PLT ≥ 100 × 10 9/L). The baseline median platelet count was 5 × 10 9/L, and 95% (19 cases) of patients had active bleeding with a bleeding score of ≥ 1 point. The median duration for hetrombopag at dose of 5mg is 8.0 days, and rhTPO is 6.5 days. After combined treatment, the median time for platelet counts reached 30, 50, and 100 × 10 9/L was 4.5 days, 6 days, and 7 days, respectively. Among them, the median platelet count reached 103 × 10 9/L after 7 days treatment and 214.5 × 10 9/L after 15 days. Within 15 days of combined treatment, 15% (3 cases) of patients achieved partial platelet reaction (PLT &amp;gt; 50 × 10 9/L, without bleeding), and 85% (17 cases) achieved complete platelet reaction (PLT &amp;gt; 100 × 10 9/L, without bleeding). In terms of safety, two patients experienced liver function abnormalities, both of which were grade 1-2. One was related to treatment drugs, and the other was associated with underlying autoimmune liver disease. No thrombotic events occurred in all patients. Conclusion: This study innovatively explores the efficacy and safety of combination therapy with hetrombopag and rhTPO in the treatment of severe ITP. It is preliminarily confirmed that this combination therapy can effectively and quickly improve the early platelet response of ITP patients, avoid bleeding damage, and is expected to become a new treatment choice for severe ITP patients. We also look forward to the overall efficacy evaluation results of all patients after completing treatment in the future.

Outcomes and Incidence of Thrombotic Events in Patients with Pancreatic Cancer: Insights from the National Inpatient Database from 2016 to 2020

Introduction: Pancreatic cancer represents the seventh cause of mortality in cancer-related deaths, and despite efforts to improve this, survival rates have not decreased. Additionally, in the last decade, there has been an increase in its incidence, and there is a rising concern regarding earlier age of onset. Its clinical presentation at earlier stages varies from asymptomatic to vague abdominal pain, jaundice, and thrombotic events. Regarding thromboembolic events, pancreatic cancer is one of the most common malignancies associated with a hypercoagulable state, reported in around 12-36% of the cases. One of the hypotheses proposed is based on the elevated expression of tissue factor and activation of extracellular tramps. We aimed to study the prevalence, trends, and outcomes of thrombotic events in patients admitted with pancreatic cancer over six years. Methods: We quired the National Inpatient Sample Database from 2016-2020 by identifying hospitalization with corresponding international disease classification ICD-10 for pancreatic cancer and further stratifying the cohort into those with pulmonary embolism (PE), deep venous thrombosis (DVT), portal vein thrombosis (PVT), and mesenteric ischemia. We also analyzed the hospital resource utilization by examining the length of stay (LOS), and total hospital Charge (TOTCHG) Results: Univariate analysis revealed a significant correlation between acute pancreatic cancer and the incidence of all thromboembolic events with an odds ratio (OR) of 7.13 (95% CI: 6.99-7.27, P &amp;lt; 0.01). For specific events, the OR was 6.11 (95% CI: 5.93-6.30, P &amp;lt; 0.01) for PE, 5.97 (95% CI: 5.82-6.12, P &amp;lt; 0.01) for DVT, and a notably high 28.53 (95% CI: 27.44-29.67, P &amp;lt; 0.01) for PVT. After adjusting for potential confounding factors in the multivariate analysis, the odds ratios reduced but remained significant: 4.15 (95% CI: 1.53-1.98, P &amp;lt; 0.01) for all thromboembolic events, 4.19 (95% CI: 1.21-1.45, P &amp;lt; 0.01) for PE, 3.40 (95% CI: 1.12-1.48, P &amp;lt; 0.01) for DVT, and 12.40 (95% CI: 2.16-3.49, P &amp;lt; 0.01) for PVT. Regarding clinical outcomes such as mortality and acute kidney injury (AKI), thromboembolic events like PE, DVT, PVT, and mesenteric ischemia are significantly associated with increased mortality and AKI. For example, PE had an OR of 1.75 (95% CI: 1.54-1.99, P &amp;lt; 0.01) for mortality and 0.82 (95% CI: 0.74-0.91, P &amp;lt; 0.01) for AKI. The study also evaluated the impact of these thromboembolic events on hospital resource utilization. PE, for instance, was associated with an increase in the length of stay (LOS) by 0.55 days (95% CI: 0.28-0.82, P &amp;lt; 0.01) and additional costs of $6272.16 (95% CI: $2985.40-$9558.93, P &amp;lt; 0.01) Conclusion: Thromboembolic events in patients with pancreatic cancer have increased mortality rates and hospital costs. It is essential to quantify and better understand this association to formulate adequate strategies to improve early diagnosis and survival. Further studies are needed to better characterize ways to prevent thromboembolic events cost-effectively in an attempt to improve mortality rates in this patient population.

Transferrin and Erythropoietin Increased Levels Correlate with Thrombosis at High Altitude

Living at high altitude involves great interest because of the challenging multiple adaptive responses to a hypoxic environment. Native Bolivian Andeans have lived at an altitude of 4000 m in The Andes mountains for about 14,000 years exposed to a low atmospheric pressure (453 mmHg) and low oxygen concentration (12,7%). It was described Andeans adaptation to high altitude is mainly related to cardiovascular issues (PMID: 29100088), with a low significantly genetic selection in HIF pathway components responsible of erythropoiesis regulation (PMID: 36980912), so that they have adapted to exist with increased hemoglobin concentrations. Thus, Andeans can be prevalent to undergone hematological and thromboembolic disorders. Thrombotic events have been reported to be increased at high altitude, and this recently associated to increased transferrin (Tf) (PMID: 36040436), likewise to increased erythropoietin (Epo) (Amaru, RevMed 2022). Increased Tf were described to be induced by both iron deficiency and hypoxia via HIF (PMID: 9242677). In addition, iron deficiency was postulated to inhibit the function of prolyl hydroxylase 2 (PHD2) in the hydroxylation of HIF-2, necessary for recognition and degradation by VHL (PMID:22304911). Under normal conditions, Tf is bound to fibrinogen at a molar ratio of 4:1, leading to plasma Tf sequestration by fibrinogen and leaving little Tf free in the circulation. While at hypoxia conditions, abnormally upregulated Tf potentiates thrombin, factor XIIa and inhibits antithrombin, inducing hypercoagulability (PMID:36040436). Similarly, increased HIF1a at high altitude increases Tf promoting the transferrin gene expression, which contains HIF-1α binding sites in its enhancer region (PMID:36844187). HIF is a DNA-binding transcription factor for activating expression of Epo gene (PMID:32561149). Epo, in turn, is increased due to the hyperegulation of HIF as expected at low atmospheric pressure environments. Epo activates the hypoxia-inducible factor that leads to Epo synthesis to stimulate red blood cell production, which also increases the demand for iron to synthesize hemoglobin (PMID:21078592). This, added to a decreased iron and increased HIF 1a, gives rise to a hyperregulation of Tf. Epo has been described to have prothrombotic properties and be related to thrombotic events (PMID:10779449; Amaru, RevMed 2022). In this sense, to further observe a correlation of transferrin and erythropoietin increased levels with the risk of thrombotic events at high altitude, we studied patients with erythrocytosis, anemia and polycythemia vera. We analyzed clinical, lab tests and epidemiological data of 920 patients with Chronic Mountain Sickness erythrocytosis (CMS-e) (n=560), anemia (n=372), and Polycythemia Vera (PV) (n=20), all Bolivian Andeans born and residing at 4000 m. Considering at this altitude normal hemoglobin concentrations vary from 14-17 g/dl in women and 15-18 g/dl in men, erythrocytosis condition comprises Hb levels &amp;gt;18 g/dl in women and &amp;gt;19 g/dl in men (Amaru et al, Rev Hematol Mex, 2016); similarly, it embraces Hb &amp;lt;12 g/dl for women and &amp;lt;13 g/dl for men in anemias (PMID: 23317073). Positive JAK F617V tests were corroborated in PV patients. Iron deficiency correlation considered serum ferritin &amp;lt;30 ug/L and MCV &amp;lt;80 fL (Clark et al, Nutrition, 2008). Eco-doppler study records confirmed the occurrence of thrombotic events. Data analysis was performed through Excel 16.29.1 and SPSS program, Chi-squared, Fishers and Pearson tests were done. We observed significative increased Tf levels in erythrocytosis, anemia, and PV patients mainly on those presenting iron levels deficiency. Epo was highly increased in erythrocytosis patients with iron deficiency. These results correlated with the incidence of thrombotic events in erythrocytosis (CMS-e) and anemia patients with iron deficiency. Age was also relevant in both groups. (Table 1). The increase of Epo levels correlated with thrombosis in erythrocytosis and PV patients with iron deficiency (Table 1). Transferrin and Erythropoietin increased levels at high altitude correlated with thrombosis in Chronic Mountain Sickness erythrocytosis and iron deficiency anemia patients. However, Increased Tf did not correlate with thrombosis in PV patients at high altitude. Our data confirm that increased Tf and Epo have prothrombogenic properties in CMS-e, iron deficiency anemia patients at high altitude.

Patient Outcomes after Initial High Dose Versus Low Dose Romiplostim for Inpatient Management of Immune Thrombocytopenia

Introduction: Romiplostim is a thrombopoietin receptor agonist approved by the US FDA for chronic immune thrombocytopenia (ITP) in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The recommended dose is 1 mcg/kg/week subcutaneously, escalated weekly by increments of 1 mcg/kg to achieve and maintain a platelet count of 50 x 10 9 /L g ( Kuter et al 2021). It has been postulated that starting at the maximum recommended dose of 10 mcg/kg/week in patients with severe bleeding may swiftly increase platelets and minimize bleeding ( Roumier et al 2021). However, this approach may also increase the risk of major thrombotic events (TE). It is unclear if the more aggressive dosing strategy results in more rapid, robust responses and a tolerable safety profile compared to the FDA approved approach. Methods: This retrospective chart review included adult patients who initiated romiplostim while admitted for ITP at a Mayo Clinic Enterprise site from May 2018 to May 2022. Outcomes included rate of TE at 30 days and 90 days and time to first TE in patients receiving initial romiplostim doses of &amp;lt; 5 mcg/kg (low dose, LD) and &amp;gt; 5 mcg/kg (high dose, HD), median time to platelet response (defined as platelets &amp;gt; 30 x10 9/L and &amp;gt; 50 x10 9/L on 2 separate checks) in LD vs HD, and cost to the institution comparing LD to HD. Outcomes were summarized using descriptive statistics. Statistical analysis was done using BlueSky. Fischer's exact test and chi-squared were performed for categorical data, and Wilcoxon rank sum test were done for continuous variables. Results: Forty-five patients met eligibility criteria: 33 (73%) received initial romiplostim doses &amp;lt; 5 mcg/kg and 12 (27%) received doses &amp;gt; 5 mcg/kg. The majority of patients (43/45 (96%)) presented with platelets &amp;lt; 50 x 10 9/L. The median age was 65 years (68 in LD vs 57 HD). There were 24 (73%) males in the LD group vs five (42%) in the HD group. At baseline, 64% (n = 21) of LD patients and 75% (n = 9) of HD patients presented with bleeding. Major bleeding (defined by 2019 ASH ITP guidelines) was present in 21% (n= 7) vs 17% (n = 2) of patients, LD versus HD, respectively ( Neunert et al 2019). The overall incidence of TE in this study was 24% (n = 11): LD 5 (15%) and HD 6 (50%) (p = 0.044) at 90 days. Median days to TE was 21 days, 12 days in LD group (range 5-21) vs 24.5 days (range 14-58) in HD group (p = 0.067). TE included deep vein thrombosis (DVT, n = 6), DVT with pulmonary embolism (n = 1), portal vein thrombus (n = 1), multiple brain infarcts (n = 1), splenic vein thrombus (n = 1), and left atrial appendage thrombus (n = 1). The median platelet count at the time of TE was 304 x 10 9/L, 415 x 10 9/L (range 58-900) in the LD group vs 323 x 10 8/L (range 33-1427) in the HD group (p = 0.79). Thirty-two (71%) out of 45 patients had a response to romiplostim: 22 in the LD group (71%) vs 10 (83.3%) in the HD group (p = 0.698). Of the patients that responded, the median time to response was 6 days in the LD group vs 11.5 days in the HD group (p = 0.09) The median dose at time of initial response was 2 mcg/kg in the LD group and 6 mcg/kg in the HD group. Wholesale Acquisition Cost (WAC) was used to determine the cost per dose, rounded to the nearest vial size. The average WAC for the initial dose in LD patients was $1806.80 compared to $6061.79 in HD patients. Conclusion:There was a significantly increased incidence of thrombosis in patients admitted with ITP that received initial romiplostim doses &amp;gt; 5 mcg/kg, with no differences in the time to platelet response. Careful consideration of risks versus benefits should be given prior to initiating romiplostim at doses higher than recommended doses.

Evaluation of the Efficacy and Safety during Treatment with TPO-Ras in 40 SLE-ITP and APS-ITP Patients

Objectives: Thrombopoietin receptor agonists (TPO-RAs) have emerged over the last decade as a therapeutic option in primary immune thrombocytopenia (ITP). TPO-RAs have demonstrated their efficacy in more than 70% of cases and are taking an increasingly important place in second line therapy. However, to date, no prospective cohort has been able to question the efficacy and safety of TPO-RAs in systemic lupus erythematosus (SLE-ITP) and antiphospholipid syndrome (APS-ITP) patients, particularly regarding venous and arterial thrombosis risks in this population. Methods: This multicenter retrospective cohort study was conducted from 2012 to 2023 in seven hospitals belonging to the French national network for adult ITP. We assessed the efficacy and the tolerance of TPO-RAs on a large retrospective cohort with a long follow-up of patients with ITP associated with 1) SLE or 2) primary or secondary APS or 3) with antinuclear antibodies (ANA) and anti-dsDNA or anti-Sm antibodies or 4) with ANA and at least one antiphospholipid antibody (APA) without thrombotic events (TEs). We studied the efficacy according the international criteria of response (Rodeghiero et al, Blood 2009) and the incidence of TEs, the risk factors for the occurrence of thrombosis, the management of TPO-RAs and their combination with antiplatelet agents or anticoagulants. Results: We included 40 ITP patients treated with TPO-RAs; 28 SLE-ITP, four APS-ITP, four with both SLE and APS, and four with significant ANA and APA positivity without definite SLE or APS. Five patients were triple positive for APA. The median duration of follow up was 46 months (1-132). The overall response rate was 84.2% for patients treated with romiplostim and 71% for those treated with eltrombopag after failure of standard treatments such as corticosteroids, intravenous immunoglobulins, rituximab and immunosuppressive agents. Eight TEs occurred in seven (17.5%) patients at a median of 119 days (IQR=171.5) after eltrombopag (n=4) or romiplostim (n=4) initiation with a median exposure duration of 37 days (13-119) for romiplostim and 255 days (30-807) for eltrombopag. Two venous TEs were observed including one cerebral vein thrombosis and one pulmonary embolism. We observed six arterial thrombotic events, such as myocardial infarctions and ischemic strokes including one fatal catastrophic APS. Four of these patients had a history of APS, and most had thrombotic risk factors and positive APA. TPO-RAs were continued after TEs in two patients for a total duration of 20 and 53 months in association with an antiplatelet agent for one patient and a combination of an antiplatelet agent and an anticoagulant for the second one without a new TE thereafter. TPO-RAs were transiently stopped and then reintroduced due to ITP flare in two patients. A new episode of myocardial infarction occurred in one of them despite association with antiplatelet agents requiring TPO-RAs definitive arrest. Conclusion: We confirmed the effectiveness of TPO-RAs in over 70% of SLE-ITP and APS-ITP patients who failed to respond to corticosteroids, intravenous immunoglobulins, rituximab and/or standard immunosuppressive agents. Nevertheless, these findings highlight the need to carefully consider the potential benefits and thrombotic risks before initiating TPO-RAs, especially in elderly patients with thrombotic risk factors and positive APA or a confirmed APS. Further studies are needed to evaluate more precisely the TEs risk factors of these agents in this specific population, in order to better select SLE and APS-ITP patients who could benefit from them.

Antiphospholipid antibodies are enriched post-acute COVID-19 but do not modulate the thrombotic risk

Background and objectivesCOVID-19-associated coagulopathy, shown to increase the risk for the occurrence of thromboses and microthromboses, displays phenotypic features of the antiphospholipid syndrome (APS), a prototype antibody-mediated autoimmune disease. Several groups have reported elevated levels of criteria and non-criteria antiphospholipid antibodies (aPL), assumed to cause APS, during acute or post-acute COVID-19. However, disease heterogeneity of COVID-19 is accompanied by heterogeneity in molecular signatures, including aberrant cytokine profiles and an increased occurrence of autoantibodies. Moreover, little is known about the association between autoantibodies and the clinical events. Here, we first aim to characterise the antiphospholipid antibody, anti-SARS-CoV-2 antibody, and the cytokine profiles in a diverse collective of COVID-19 patients (disease severity: asymptomatic to intensive care), using vaccinated individuals and influenza patients as comparisons. We then aim to assess whether the presence of aPL in COVID-19 is associated with an increased incidence of thrombotic events in COVID-19. Methods and resultsWe conducted anti-SARS-CoV-2 IgG and IgA microELISA and IgG, IgA, and IgM antiphospholipid line immunoassay (LIA) against 10 criteria and non-criteria antigens in 155 plasma samples of 124 individuals, and we measured 16 cytokines and chemokines in 112 plasma samples. We additionally employed clinical and demographic parameters to conduct multivariable regression analyses within multiple paradigms. In line with recent results, we find that IgM autoantibodies against annexin V (AnV), β2-glycoprotein I (β2GPI), and prothrombin (PT) are enriched upon infection with SARS-CoV-2. There was no evidence for seroconversion from IgM to IgG or IgA. PT, β2GPI, and AnV IgM as well as cardiolipin (CL) IgG antiphospholipid levels were significantly elevated in the COVID-19 but not in the influenza or control groups. They were associated predominantly with the strength of the anti-SARS-CoV-2 antibody titres and the major correlate for thromboses was SARS-CoV-2 disease severity. ConclusionWhile we have recapitulated previous findings, we conclude that the presence of the aPL, most notably PT, β2GPI, AnV IgM, and CL IgG in COVID-19 are not associated with a higher incidence of thrombotic events.

Four-factor prothrombin complex concentrate versus andexanet alfa for direct oral anticoagulant reversal

BackgroundOptimal reversal agent for direct oral anticoagulant (DOAC)–associated major bleeding has not been described. Before the approval of andexanet alfa (AA) in 2018, 4-factor prothrombin complex concentrate (4F-PCC) was recommended by major guidelines. Currently, AA is recommended as the first-line agent by most guidelines. With a paucity of literature comparing the 2 agents, there is clinical value in assessing hemostatic efficacy and safety of the 2 agents. ObjectiveThis study aimed to evaluate hemostatic efficacy and safety of AA and 4F-PCC in all DOAC-associated major bleedings. MethodsA multicenter, retrospective chart review was performed of adult subjects who were admitted for a DOAC-associated major bleeding and received 4F-PCC from February 2018 to May 2019 or AA from May 2019 to September 2021. Some of the exclusion criteria included not receiving a DOAC, receiving multiple reversal agents during the same hospitalization, receiving reversal for any nonmajor bleeding indication, and not receiving the full dose of a reversal agent. The primary outcome was hemostatic efficacy 24 hours after the end of the reversal agent administration. Secondary outcomes included time to administration, hospital mortality, length of stay, need for surgery, and need for additional blood product. Safety outcome was incidence of thrombotic events. ResultsThere were 99 subjects included in the 4F-PCC group and 84 subjects in the AA group. Hemostatic efficacy was achieved in 69 subjects (69.7%) in the 4F-PCC group and 63 subjects (75%) in the AA group (P = 0.927). In-hospital mortality was seen in 20 subjects (20.2%) in the 4F-PCC group and 10 subjects (11.9%) in the AA group. Thrombotic events were seen in 7 subjects (7.1%) in the 4F-PCC group and 6 subjects (7.1%) in the AA group. ConclusionsThere were no significant differences in hemostatic efficacy, in-hospital mortality, and number of thrombotic events between 4F-PCC and AA.

Effectiveness of high- versus low-dose four-factor prothrombin complex concentrate on hemostasis and thromboembolism in patients with oral factor Xa inhibitor-associated intracranial hemorrhage

Abstract Background Four-factor prothrombin complex concentrate (4F-PCC) is frequently used off-label for the reversal of oral factor Xa inhibitor-associated bleeding. Dosing of 4F-PCC in routine practice remains inconsistent as published observational studies and clinical guidelines have provided conflicting results. Purpose We evaluated the incidence of hemostatic effectiveness and thromboembolism with high- versus low-dose 4F-PCC in a cohort of patients with oral factor Xa inhibitor-associated intracranial hemorrhage (ICH). Methods We identified patients treated with 4F-PCC during a hospitalization for apixaban- or rivaroxaban-associated ICH between December 2016 and August 2020. Patients were included if they were ≥18 years old, had a radiographically confirmed ICH, and received their last dose of apixaban or rivaroxaban &amp;lt;24 hours prior. Patients with a hematoma volume &amp;gt;60 mL, a Glasgow Coma Scale score &amp;lt;7, or planned surgery within 12 hours were excluded. Patients were divided into cohorts based on 4F-PCC dose administered: high- (≥35 IU/kg) or low-dose (&amp;lt;35 IU/kg). Our primary outcome was hemostatic effectiveness, defined as ≤35% increase in hematoma size from index to repeat scan at 12±5 hours after administration of 4F-PCC. If no repeat scan was available within that timeframe, the worst scan within 24 hours was used. If no repeat scan was available within 24 hours, hemostatic effectiveness was adjudicated based upon clinical findings by two trained investigators. Our secondary outcome was development of thromboembolism within 5 days of receiving 4F-PCC. To adjust for potential differences in baseline characteristics between 4F-PCC dosing groups, propensity score-overlap weighted logistic regression was used. Results are reported as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Results Ninety-five patients, 24 in the high- and 71 in the low-dose group, were included. Mean ± standard deviation (SD) age of the total study cohort was 80.3 ± 9.1 years, time from initial imaging to start of reversal was 2.4 ± 2.1 hours, and time from end of reversal to repeat scan was 6.8 ± 4.6 hours. Intracerebral ± intraventricular bleeds were most common (46.6%), with 7.4% of patients having infratentorial involvement, and 13.5% having bleeds ≥10 mL/≥10 mm in size. Most ICHs were single compartment (91.8%) and were of traumatic origin (68.7%). Following propensity score-overlap weighted logistic regression, no difference in hemostatic effectiveness was observed between patients receiving high- (80.3%) or low-dose (77.2%) 4F-PCC (OR 1.20; 95%CI 0.28 to 5.15). No cases of thromboembolism were observed in either 4F-PCC dosing arm. Conclusion High-dose (≥35 IU/kg) 4F-PCC was not associated with increased odds of achieving hemostatic effectiveness compared to the low-dose (&amp;lt;35 IU/kg) in patients experiencing apixaban- or rivaroxaban-associated ICH, with no incidence of thrombotic events.

Adverse events that occurred in patients with rheumatoid arthritis during long-term follow-up

Comorbid diseases and adverse events that occur in patients with rheumatoid arthritis (RA) negatively affect the outcomes of RA (radiological progression, joint function, the occurrence of low-energy fractures, thrombotic events, etc.). Objective: to study the structure of comorbid diseases and adverse events that occurred in patients with RA over the period of long-term prospective follow-up, to study the impact of these events on the dynamics of the functional status and working capacity of patients. Materials and methods. Аn open, cohort, prospective, long-term non-interventional study included 103 women with a definite diagnosis of RA (mean age 63.5 ± 8.3 years, follow-up period 8,5 ± 1,3 years). At baseline and in dynamics, standard laboratory and X-ray examinations were carried out. Results and discussion. There was a decrease in the DAS28 index and the number of patients with high or moderate activity [from 82 (85 %) to 67 (69 %), p = 0.02] against the background of an increase in the number of patients with remission or low activity [from 15 (15 %) to 30 (31 %), p = 0.012], at the same time there was an increase in the number of patients with ankylosis of joints [from 25 (24 %) to 41 (40 %), p = 0.017], functional class III [from 3 (3 %) to 15 (15 %), p=0.004], concomitant diseases [from 81 (79 %) to 94 (91 %), p = 0.015], thrombotic events [from 7 (7 %) to 18 (17 %), p = 0.027]. In 43 (42 %) patients 55 low-energy fractures were registered, in 24 (56 %) of them fractures occurred for the first time and in 19 (44 %) – repeatedly. Conclusion. As the prospective long-term follow-up shows, despite the decrease in RA activity, the number of patients with ankylosis, joint dysfunction and concomitant diseases increased. In the structure of concomitant diseases coronary heart disease and arterial hypertension dominated. A high incidence of thrombotic events, repeated and first-time low-energy fractures was noted. The number of disabled patients increased fivefold.

Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury

Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute fibrinogen deficiency. Management is fibrinogen replacement with cryoprecipitate transfusions or fibrinogen concentrate, usually administered relatively late during hemorrhage. To assess whether survival could be improved by administering an early and empirical high dose of cryoprecipitate to all patients with trauma and bleeding that required activation of a major hemorrhage protocol. CRYOSTAT-2 was an interventional, randomized, open-label, parallel-group controlled, international, multicenter study. Patients were enrolled at 26 UK and US major trauma centers from August 2017 to November 2021. Eligible patients were injured adults requiring activation of the hospital's major hemorrhage protocol with evidence of active hemorrhage, systolic blood pressure less than 90 mm Hg at any time, and receiving at least 1 U of a blood component transfusion. Patients were randomly assigned (in a 1:1 ratio) to receive standard care, which was the local major hemorrhage protocol (reviewed for guideline adherence), or cryoprecipitate, in which 3 pools of cryoprecipitate (6-g fibrinogen equivalent) were to be administered in addition to standard care within 90 minutes of randomization and 3 hours of injury. The primary outcome was all-cause mortality at 28 days in the intention-to-treat population. Among 1604 eligible patients, 799 were randomized to the cryoprecipitate group and 805 to the standard care group. Missing primary outcome data occurred in 73 patients (principally due to withdrawal of consent) and 1531 (95%) were included in the primary analysis population. The median (IQR) age of participants was 39 (26-55) years, 1251 (79%) were men, median (IQR) Injury Severity Score was 29 (18-43), 36% had penetrating injury, and 33% had systolic blood pressure less than 90 mm Hg at hospital arrival. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs 25.3% in the cryoprecipitate group (odds ratio, 0.96 [95% CI, 0.75-1.23]; P = .74). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs cryoprecipitate group (12.9% vs 12.7%). Among patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empirical high-dose cryoprecipitate to standard care did not improve all cause 28-day mortality. ClinicalTrials.gov Identifier: NCT04704869; ISRCTN Identifier: ISRCTN14998314.