Major Bleeding Events Research Articles

Rectus Sheath Hematoma Following Subcutaneous Enoxaparin Application: A Case Report

BACKGROUND: Thromboprophylaxis for prevention of venous thromboembolism has significantly decreased morbidity and mortality for post-operative patients over the previous decades. However, patients on anticoagulants are at risk for several major bleeding events, such as rectus sheath hematoma. Rectus sheath hematoma is an uncommon, potentially life-threatening complication that can be difficult to diagnose and easily confused with other abdominal pathologies. It most commonly occurs in patients on current prophylactic or therapeutic anticoagulants and can be spontaneous or provoked. Inadvertent damage to the rectus abdominis muscle or epigastric arteries during subcutaneous enoxaparin injection in the abdomen has been identified as a rare cause of this complication. THE CASE: A 68-year-old hospitalized female presented acute abdominal pain in the right lumbar and iliac region accompanied by hypotension and tachycardia eight days after uncomplicated total knee arthroplasty. She was found to have severe anemia on laboratory exam and a right rectus sheath hematoma on abdominal CT scan with a volume of 300cc. After the patient was stabilized via fluid resuscitation and blood transfusion, the hematoma was surgically drained. The surgeons involved noted possible inadvertent puncture of the right inferior epigastric artery during one of the patient’s bi-daily subcutaneous enoxaparin injections. CONCLUSION: This case report emphasizes the importance of recognizing rectus sheath hematoma as a potential complication of subcutaneous enoxaparin injection and the knowledge of its risk-factors and clinical presentation to make an early diagnosis and give adequate treatment.

Efficacy of the bleeding risk scoring system for optimal prophylactic anticoagulation therapy of venous thromboembolism in trauma patients: a single-center, retrospective, observational cohort study

BackgroundWe developed a bleeding risk scoring system (BRSS) using prophylactic anticoagulation therapy to comprehensively assess the risk of venous thromboembolism (VTE) in trauma patients. This study evaluated the usefulness of this system in trauma patients, with a focus on minimizing the rate of bleeding events associated with prophylactic anticoagulation therapy.MethodsWe retrospectively evaluated the efficacy of BRSS in trauma patients who received prophylactic anticoagulation therapy for VTE at the Kitasato University Hospital Emergency and Critical Care Center between April 1, 2015, and August 31, 2020. To compare the incidence of bleeding events, patients were divided into two groups: one group using the BRSS (BRSS group) and another group not using the BRSS (non-BRSS group).ResultsA total of 94 patients were enrolled in this study, with 70 and 24 patients assigned to the non-BRSS and BRSS groups, respectively. The major bleeding event rates were not significantly different between the two groups (BRSS group, 4.2%; non-BRSS group, 5.7%; p = 1.000). However, minor bleeding events were significantly reduced in the BRSS group (4.2% vs.27.1%; p = 0.020). Multivariate logistic regression analysis showed that BRSS was not an independent influencing factor of major bleeding events (odds ratio, 0.660; 95% confidence interval: 0.067-6.47; p = 0.721). Multivariate logistic regression analysis showed that BRSS was an independent influencing factor of minor bleeding events (odds ratio, 0.119; 95% confidence interval: 0.015-0.97; p = 0.047). The incidence of VTE did not differ significantly between groups (BRSS group, 4.2%; non-BRSS group, 8.6%; p = 0.674).ConclusionsBRSS may be a useful tool for reducing the incidence of minor bleeding events during the initial prophylactic anticoagulation therapy in trauma patients. There are several limitations of this study that need to be addressed in future research.

Net clinical benefit of oral anticoagulants in Asian patients with atrial fibrillation based on a CHA2DS2-VASc score

BackgroundThis study was conducted to assess the net clinical benefit (NCB) for oral anticoagulant (OAC) in atrial fibrillation (AF) patients according to the CHA2DS2-VASc score.MethodsPatients with AF were prospectively recruited in the COOL AF Thailand registry from 2014 to 2017. The incidence rate of thromboembolic (TE) events and major bleeding (MB) was calculated. Cox proportional hazards model was used to compare the TE and MB rate in patients with and without OACs in CHA2DS2-VASc score of 0–1 and ≥ 2, respectively. The survival analysis was performed based on CHA2DS2-VASc score. The NCB of OACs was defined as the TE rate prevented minus the MB rate increased multiplied by a weighting factor.ResultsA total of 3,402 AF patients were recruited. An average age of patients was 67.38 ± 11.27 years. Compared to non-anticoagulated patients, the Kaplan Meier curve showed anticoagulated patients with CHA2DS2-VASc score of 2 or more had the lower thromboembolic events with statistical significance (p = 0.043) and the higher MB events with statistical significance (p = 0.018). In overall AF patients, there were positive NCB in warfarin patients with CHA2DS2-VASc score of 3 or more while there were positive NCB in DOACs patients regardless of CHA2DS2-VASc score. Females with CHA2DS2-VASc score of 3 or more had a positive NCB regardless of OACs type. Good anticoagulation control (TTR ≥65%) improved an NCB in males with CHA2DS2-VASc score of 3 or more.ConclusionsAF patients with CHA2DS2-VASc score of 3 or more regardless warfarin or DOACs had a positive NCB. The NCB of OACs was more positive for DOACs compared to warfarin and for females compared to males.

Efficacy and Safety of Ticagrelor Monotherapy Versus Dual-Antiplatelet Therapy After Percutaneous Coronary Intervention With Drug-Eluting Stent in Patients With Diabetes Mellitus: A Systematic Review and Meta- analysis

BACKGROUND: Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is the standard for the prevention of thrombotic events in patients undergoing percutaneous coronary intervention (PCI). Type 2 diabetes mellitus (DM) patients are a subgroup with a higher risk of bleeding and thrombotic events after PCI. OBJECTIVES: This meta-analysis aimed to determine whether ticagrelor monotherapy after an initial short-course DAPT is an effective and safe option in preventing thrombotic events among DM patients undergoing PC. METHODS: A systematic review and meta-analysis was done on randomized controlled trials (RCT) comparing ticagrelor monotherapy following short-course DAPT versus conventional DAPT in T2DM patients who underwent PCI. Outcome measures for major bleeding, myocardial infarction, and all-cause mortality were extracted and analyzed using a random-effects model via RevMan version 5.3. RESULTS: A total of three RCTs, with 7482 patients, were analyzed. There were no significant differences in major bleeding (P = 0.26) and myocardial infarction (P = 0.66) events between the ticagrelor and DAPT groups. However, there was a higher rate of all-cause mortality in the DAPT group, which was statistically significant (risk ratio, 0.76; 95% confidence interval, 0.59–0.98; P = 0.03). CONCLUSION: Ticagrelor monotherapy following short-course DAPT and conventional DAPT have similar rates of major bleeding and myocardial infarction among DM patients undergoing PCI with DES. However, conventional DAPT has a higher incidence of all-cause mortality, which suggests that ticagrelor monotherapy after short-course DAPT may be a preferable antiplatelet strategy in DM patients undergoing PCI. KEYWORDS: bleeding, diabetes mellitus, dual-antiplatelet therapy, percutaneous coronary intervention, thrombosis, ticagrelor

Efficacy and Safety of Streptokinase and Tenecteplase in Patients with ST Elevation Myocardial Infarction

Objective: To investigate the efficacy and safety of Streptokinase (STK) and Tenecteplase (TNK) in ST elevation myocardial infarction patients. Study Design: Randomized control trial. Place and duration: Study was conducted at Ch Pervaiz Ellahi institute of cardiology hospital Multan from May 2022 to April 2023. Methodology: Patients of ST elevation myocardial infarction presented within six hours of onset of symptoms were included in the study. Patients were divided into two equal groups (STK and TNK). Patients in STK group were thrombolysed with streptokinase and in TNK group were treated with Tenecteplase. SPSS version 23 was used for data analysis. Results: ST-resolution Pre-PCI at 90 minutes in STK and TNK groups was observed as 68% and 80%, respectively. While post-PCI ST-resolution was found in 80% and 88% patients of STK and TNK groups, respectively. Major bleeding events were found in 8% patients of STK Group and in 4% patients of TNK Group. The differences were statistically insignificant, and no association was found. Conclusion: Both drugs Streptokinase and Tenecteplase are equally effective when given in correct timeline in patients of ST segment myocardial infarction. Efficacy and safety of TNK is also like STK when administered in equal time frame.

Shortened Duration of Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Contemporary Clinical Review

Percutaneous coronary intervention with stent implantation is an integral aspect of minimally interventional cardiac procedures. The technology and techniques behind stent design and implantation have evolved rapidly over several decades. However, continued discourse remains around optimal peri- and post-interventional management with dual antiplatelet therapy to minimise both major cardiovascular or cerebrovascular events and iatrogenic bleeding risk. Standard guidelines around dual antiplatelet therapy historically recommended long-term dual antiplatelet therapy for 12 months (with consideration for >12 months in certain patients); however, emerging data and generational improvements in the safety of drug-eluting stents have ushered in a new era of short-term therapy to reduce the incidence of major bleeding events. This case review will provide an overview of the current state of guidelines around duration of dual antiplatelet therapy and examine recent updates and continued gaps in existing research.

Telemedicine-based medical care compared to in-person medical care for warfarin follow-up: A retrospective propensity score matching cohort study.

Telemedicine is underutilized in Saudi Arabia, which is a matter of concern, especially since previous literature has showed its equivalence with office visits in providing access to care and convenience for patients while reducing anticoagulation-related bleeding events when appropriate measures are followed. The purpose of this study is to analyze the efficacy of telehealth-based care compared to in-person visit care for warfarin follow-up. The authors conducted a retrospective chart review comparing the mean percentage of time in the therapeutic range (TTR) of international normalized ratio (INR) values among patients prescribed warfarin from July 2019 to November 2020 at King Faisal Specialist Hospital & Research Center - Jeddah Branch whose anticoagulant therapy was managed via telemedicine or through in-person clinic visits. A subcohort analysis of outcomes in the telemedicine and in-person groups was performed using propensity score matching, and descriptive analysis was done for the entire cohort. A total of 350 patient records were included in this retrospective study. Matched analysis for 148 patients using propensity score matching showed that the mean (SD) percentages of TTR were 62.82% (19.46%) and 70.61% (19.83%) in the telemedicine and in-person groups, respectively (P = 0.017). There was no statistical difference in the incidence of major or minor bleeding events, thromboembolic events, and hospital readmission between the two groups. The study results showed that patients on oral anticoagulation therapy managed through a telemedicine method had a lower overall TTR percentage than a matched group of patients managed through in-person anticoagulant clinic visits, thus demonstrating that using a telemedicine approach alone for warfarin follow-up may not help patients to maintain their INR target level.

Comparing safety and efficacy: MemoLefort versus watchman for left atrial appendage closure

BackgroundThe MemoLefort is a new plug occluder for left atrial appendage closure (LAAC) in patients with atrial fibrillation (AF). This study compares the safety and efficacy of MemoLefort and the well-established Watchman occluder for LAAC. MethodsBetween January 2021 and September 2022, a cohort of 189 consecutive patients who underwent LAAC with MemoLefort or Watchman at The Second Affiliated Hospital of Wenzhou Medical University were included. Patients with MemoLefort or Watchman devices were compared in terms of the primary safety endpoints encompassing major periprocedural complications and major bleeding events at follow-up, the primary efficacy endpoint of all-cause stroke, systemic embolism and cardiovascular/unexplained death, and the combined hazard endpoint, a composite of all the above-mentioned hazards. ResultsOf the MemoLefort group (n = 83) and Watchman group (n = 106), the mean age, CHA2DS2-VASc score, and HAS-BLED score were 67.6 ± 9.2 vs. 69.0 ± 10.6 years, 3.9 ± 1.9 vs. 3.8 ± 1.9, and 1.6 ± 1.0 vs. 1.7 ± 1.2, respectively. After a median follow-up duration of 198 (99–329) vs. 334 (171–497) days, the primary endpoints of efficacy [2/49, 4.1% (MemoLefort) vs. 2/97, 2.1% (Watchman); hazard ratio (HR), 1.50; 95% confidence interval (CI), 0.20–11.08; P = 0.68] and safety (1/49, 2.0% vs. 5/97, 5.2%; HR, 0.26; 95% CI, 0.05–1.31; P = 0.19), as well as the combined hazard endpoint (3/49, 61% vs. 6/97, 6.2%; HR, 0.70; 95% CI, 0.18–2.58; P = 0.59) were similar between groups. ConclusionsIn the short term, LAAC with MemoLefort provided similar efficacy, safety, and net clinical benefit in comparison to Watchman devices.

Management of catheter-related upper extremity deep vein thrombosis in patients with cancer: a systematic review and meta-analysis

BackgroundPatients with cancer commonly require a central venous catheter, which is associated with an increased risk of venous thromboembolism (VTE). Despite the frequent occurrence, the optimal anticoagulation management and outcomes for patients with cancer and catheter-related upper extremity deep vein thrombosis (DVT) are unclear. ObjectiveWe performed a systematic review and meta-analysis to evaluate the rates of recurrent VTE and bleeding in patients with cancer and catheter-related upper extremity DVT. MethodsWe searched MEDLINE, Embase, Scopus, and CENTRAL from inception to June 2, 2023. The primary efficacy outcome was recurrent VTE, and the primary safety outcome was major bleeding. The incidence rates (with 95% CI) of outcomes were pooled using random effects model. ResultsWe included 29 studies (N = 2,836), among which 5 were prospective. The duration of follow-up and anticoagulation varied considerably. The main long-term anticoagulant used was low molecular weight heparin, followed by direct oral anticoagulants. The pooled 3-month recurrent VTE rate from 14 studies (N = 1,128) was 0.56% (95% CI, 0.10%-3.01%; I2 = 0%). The pooled 3-month major bleeding rate from 10 studies (N = 834) was 2.34% (95% CI, 1.14%-4.76%; I2 = 0%). We were unable to pool event rates beyond 3 months, given high heterogeneity. All studies had serious risk of bias. ConclusionsOur study demonstrated a relatively low rate of recurrent VTE and moderate rate of major bleeding events within the first 3 months in patients with cancer and catheter-related upper extremity DVT. However, there was significant heterogeneity in the management and reporting after 3 months.

Intravenous cangrelor use for neuroendovascular procedures: a two-center experience and updated systematic review.

The optimal antiplatelet therapy regimen for certain neuroendovascular procedures remains unclear. This study investigates the safety and feasibility of intravenous dose-adjusted cangrelor in patients undergoing acute neuroendovascular interventions. We conducted a retrospective chart review of all consecutive patients on intravenous cangrelor for neuroendovascular procedures between September 1, 2020, and March 13, 2022. We also conducted an updated systematic review and meta-analysis using PubMed, Scopus, Web of Science, Embase and the Cochrane Library up to February 22, 2023. In our cohort, a total of 76 patients were included [mean age (years): 57.2 ± 18.2, males: 39 (51.3), Black: 49 (64.5)]. Cangrelor was most used for embolization and intracranial stent placement (n = 24, 32%). Approximately 44% of our patients had a favorable outcome with a modified Rankin Scale (mRS) score of 0 to 2 at 90 days (n = 25/57); within 1 year, 8% of patients had recurrent or new strokes (n = 5/59), 6% had symptomatic intracranial hemorrhage [sICH] (4/64), 3% had major extracranial bleeding events (2/64), and 3% had a gastrointestinal bleed (2/64). In our meta-analysis, 11 studies with 298 patients were included. The pooled proportion of sICH and intraprocedural thromboembolic complication events were 0.07 [95% CI 0.04 to 1.13] and 0.08 [95% CI 0.05 to 0.15], respectively. Our study found that intravenous cangrelor appears to be safe and effective in neuroendovascular procedures, with low rates of bleeding and ischemic events. However, further research is needed to compare different dosing and titration protocols of cangrelor and other intravenous agents.

Comparison of the Efficacy and Safety of Left Atrial Appendage Closure and Direct Oral Anticoagulants for Atrial Fibrillation: A Meta-Analysis of Randomized Control Trials and Observational Studies.

The aim of this study was to compare the efficacy and safety of left atrial appendage closure (LAAC) and direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF). This meta-analysis was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. Two investigators performed an online database search on PubMed, Web of Science, and Scopus databases from inception to October 31, 2023, without any language or time restrictions. Outcomes assessed in this meta-analysis included all-cause mortality, cardiovascular mortality, stroke, and major bleeding events. Eight studies were included in this meta-analysis, enrolling 7,629 participants with AF (4,287 in the DOAC group and 3,342 in the LAAC group). The pooled analysis showed that the risk of all-cause mortality was significantly higher in patients in the DOAC group compared to LAAC (relative risk (RR): 1.87, 95% confidence interval (CI): 1.50 to 2.34). The risk of cardiovascular mortality was 1.60 times higher in patients receiving DOACs compared to those receiving LAAC (RR: 1.60, 95% CI: 1.12 to 2.28). The risk of stroke was not significantly different between the two groups (RR: 1.15, 95% CI: 0.95 to 1.41). In conclusion, LAAC for AF patients proves to be safe and effective for stroke prevention, exhibiting a superior profile in terms of all-cause mortality, cardiovascular events, and major bleeding compared to oral anticoagulation (OAC). These findings prompt consideration of LAAC as a preferred treatment for cardiovascular event prevention in high-bleeding-risk patients.

OP176 Integrating Real-world Compliance In The Assessment Of Left Atrial Appendage Closure Versus Anticoagulation Therapy In Non-valvular Atrial Fibrillation

IntroductionIn patients with non-valvular atrial fibrillation (NVAF), left atrial appendage closure (LAAC) has demonstrated non-inferior efficacy and safety relative to life-long oral anticoagulation therapy (OAT) in a four-year randomized controlled trial (RCT) (PRAGUE-17). Sub-optimal compliance to OAT in the real-world setting (Simmons 2016) has been associated with increased risk of stroke (Ozaki 2020) and may alter efficacy estimates derived from RCTs in which compliance is generally higher. The study aims to model disease outcomes in NVAF patients treated with LAAC versus lifelong OAT when applying trial versus real world compliance to OAT.MethodsReal-world compliance to OAT in the Australian setting was investigated in a 10 percent Pharmaceutical Benefits Schedule (PBS) sample scripts analysis which measured treatment adherence and persistence to new oral anticoagulants (NOACs) and warfarin. Design of the 10 percent PBS analysis was informed by the compliance to medicine working group report and included the longest follow-up of any OAT compliance study identified in the literature. A Markov cohort model was developed to estimate the expected numbers of strokes and major bleeding events in NVAF patients.ResultsRates of NOAC discontinuation in PRAGUE-17 was higher at 20 months median follow-up (6.5%) versus compliance in the Australian setting (35.4% and 30.0% according to 3 and 6 month ceasing rules at 20 months follow-up). Applying sub-optimal compliance to lifelong OAT demonstrated in the Australian setting resulted in higher numbers of strokes over a life time modelled time horizon compared with LAAC.ConclusionsReal world compliance to medicines should be a consideration in economic analysis comparing lifelong medications to one-off surgical interventions.

Benefit of Anticoagulation Early After Surgical Aortic Valve Replacement Using Bioprosthetic Valves.

To compare all-cause mortality and thromboembolic events in patients undergoing surgical aortic valve replacement (sAVR) receiving anticoagulation with warfarin versus patients with no systemic anticoagulation. Using data from the OptumLabs Data Warehouse, we investigated adult patients having bioprosthetic sAVR with or without coronary artery bypass from January 1, 2007, through December 31, 2019. Patients were classified into groups of nonwarfarin or warfarin (≥30 days of continuous prescription coverage after sAVR). One-to-one propensity score (PS) matching was used to adjust for group differences. Of 10,589 patients having sAVR, 7659 (72.3%) were in the nonwarfarin group and 2930 (27.7%) were in the warfarin group. After PS matching, 2930 pairs of patients were analyzed. Median follow-up was 4.1 months (interquartile range [IQR], 2.6-7.4 months) for the warfarin group and 21.3 months (IQR, 7.8-24.0 months) for the nonwarfarin group. Overall mortality was lower for the warfarin group than for the nonwarfarin group (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.47 to 1.00; P=.047), and there was a trend toward decreased cumulative incidence of thromboembolic events (subdistribution HR [SHR], 0.62; 95% CI, 0.35 to 1.07; P=.09). Cumulative incidence of major bleeding events was higher for the warfarin group vs the nonwarfarin group (SHR, 1.94; 95% CI, 1.28 to 2.94; P=.002). Results were similar in a subgroup analysis of patients undergoing isolated sAVR. During the prescription coverage period, warfarin use after bioprosthetic sAVR was associated with lower all-cause mortality and decreased risk of thromboembolism compared with not receiving warfarin. However, warfarin use was associated with an increased risk of major bleeding events.

Combining SSRIs and OACs increases major bleeding events

Evidence-Based Practice ():10.1097/EBP.0000000000001910, May 8, 2023. | DOI: 10.1097/EBP.0000000000001910

Updated Meta-Analysis of Randomized Controlled Trials on Primary Outpatient Thromboprophylaxis (POTP) in Patients with Lung Cancer Receiving Chemotherapy

Introduction Lung cancer (LC) is the leading cause of cancer mortality in the USA. Thrombosis is the second leading cause of death in cancer patients and in recent years, several studies have been conducted to determine beneficial effect of POTP in reduction of VTE (venous thromboembolism) rate in solid cancer patients with the aim to improve the overall survival. We performed an updated meta- analysis of randomized control trials (RCTs) to determine the benefit and risk of POTP with low-molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in patients with LC receiving chemotherapy. Methods We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2023. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results A total of 5,434 patients with LC from five RCTs and subgroups of another five RCTs were included in our meta-analysis. The prophylactic doses of bemiparin, certoparin, dalteparin, nadroparin, semuloparin and tinzaparin, intermediate dose of enoxaparin and prophylactic dose of rivaroxaban and apixaban were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I 2 statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 114 (4.12%) in PATP group and 207 (7.8%) in control group with a RR of 0.53 (95% CI: 0.43 to 0.67, P < 0.00001). The absolute RD in VTE was -0.04 (95% CI: -0.05 to -0.02, P < 0.00001) with an estimate of the number needed to treat (NNT) of 25 to prevent one VTE event. In subgroup analysis of PATP trials treated with LMWHs in study arm, VTE events were reported in 112 (4.2%) in PATP group and 202 (7.9%) in control group with a RR of 0.54 (95% CI: 0.43 to 0.67, P < 0.00001). The absolute RD in VTE was -0.04 (95% CI: -0.05 to -0.02, P < 0.00001). In subgroup analysis of PATP trials treated with DOACs in study arm, VTE events were reported in 2 (2.2%) in PATP group and 5 (5%) in control group with a RR of 0.46 (95% CI: 0.09 to 2.31, P=0.35). The absolute RD in VTE was -0.03 (95% CI: -0.08 to -0.03, P=0.36). Major bleeding (MB) events were reported in 34 (1.6%) patients in POTP group compared to 17 (0.86%) in control group according to an analysis of 7 RCTs. The pooled relative risk for MB was statistically significant at 1.84 (95% CI: 1.06 to 3.22, P = 0.03). Conclusions Our analysis showed that the relative risk reduction is 47% with a NNT of 25 to prevent one VTE with statistically significant increase in MB events in ambulatory patients with LC by providing POTP. In our subgroup meta-analysis of POTP with DOACs, there was no statistically significant difference in reduction of VTE in LC patients with Khorana Score ≥2. Hence, the selection of appropriate patients who are high risk for VTE is crucial and further studies are required to define high risk subsets of LC patients receiving chemotherapy who may benefit from POTP.

Anticoagulation for Splanchnic Vein Thrombosis in Patients with Myeloproliferative Neoplasms: A Systematic Review and Meta-Analysis

Introduction: Splanchnic vein thrombosis (SVT) is a common manifestation of myeloproliferative neoplasms (MPN). The optimal anticoagulation strategies in MPN-SVT remain unclear due to the challenge of balancing the concurrent prothrombotic state of MPN with the risk for SVT complications, such as gastrointestinal bleeding. Methods: We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of anticoagulation in patients with MPN following SVT incidence. This study protocol was registered on PROSPERO (#CRD42023414120). On April 07, 2023, we comprehensively searched multiple databases from Cochrane Library, EMBASE, and PubMed/MEDLINE. Retrospective or prospective studies in English with at least ten adult patients with MPN-SVT were included. Study screening by title/abstract, full text, and data extraction were performed in duplicate. Primary outcomes included recurrence of venous thrombosis (SVT and non-SVT), arterial thrombosis, and major bleeding. The risk of bias was assessed with MINORS scale. Pooled risk ratio (RR) of recurrent thrombosis and major bleeding events with respective 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method with random-effects model. Pooled rates of recurrent thrombosis and major bleeding events with respective 95% CI were calculated by DerSimonian and Laird method using random-effects model. Inter study heterogeneity was evaluated using the Cochran Q test and I 2 statistic. Results: Of a total of 4624 studies that were identified on the initial abstract screen, full texts were obtained and reviewed for 192 records. We included five retrospective and one prospective study that provided outcome rates for 387 patients with MPN treated with anticoagulation following SVT. All patients receiving anticoagulation in the six studies included in this analysis were treated with vitamin K antagonists (VKA). Of note, one additional study evaluating MPN-SVT with rivaroxaban was not included in the analysis because of short follow-up compared to the other six studies. Most studies were conducted in Europe (n=4), one was international, and one was done in the United Kingdom. The median follow-up was 3.2 years (follow-up was not reported in one study) and median age of patients at SVT diagnosis was 47.5 years old. JAK2V617F positivity was reported in 311/387 (80.3%). Regarding quality assessment and bias risk, four of the studies had moderate and two high risk of bias by the MINORS scale. Pooled incidence rates showed that subsequent venous thrombosis was the most common complication while on anticoagulation (Pooled rate 9.6%; 95% CI 5.6 - 15.8; I 2=27%), followed by major bleeding (Pooled rate, 9%; 95% CI, 3.7 - 20.3; I 2=72%). Four of the six studies provided data comparing management with anticoagulation vs. no anticoagulation in 288 patients. The rates of venous (SVT and non-SVT) and arterial thrombosis following SVT were similar between the anticoagulation vs. no anticoagulation group (venous: RR 0.90; 95% CI, 0.412 - 1.966; I 2 = 0%, Figure 1 and arterial: RR, 1.01; 95% CI, 0.36 - 2.80; I 2=0%). Similarly, there was no significant difference in the risk of major bleeding between the two groups (RR, 0.52; 95% CI, 0.23- 1.14; I 2=0%). (Figure 2) Conclusion: Risk of recurrent thrombosis and bleeding in patients with MPN-SVT are considerable. Anticoagulation with VKA in MPN patients following SVT was not associated with a reduction in the risk of subsequent venous or arterial thrombosis or increased risk of major bleeding. Further studies with larger populations are warranted to elucidate the optimal medical management for MPN-SVT.

Prevalence of Rare Bleeding Disorders in the Central California Cohort: A Retrospective Single Institution Analysis

Abstract Rare bleeding disorders (RBD) constitute 3- 5% of all inherited clotting factor deficiencies and include inherited deficiencies of fibrinogen (FI), factors II, V, VII, X, XI and XIII, and combined factor V and VIII, and affect both sexes in an autosomal recessive manner. Rare platelet disorders can also present with bleeding diathesis which are recessively inherited. Significant clinical heterogeneity is present in these disorders with varying bleeding symptomatology causing diagnostic and therapeutic challenges. The objective of this study was to analyze the prevalence, characteristics, and treatment of rare bleeding disorders at the Valley Children's Hemophilia Treatment Center(HTC) in Central California.We conducted a retrospective analysis of all individuals who were referred for abnormal bleeding to our institution from 2018- 2023. We analyzed the clinical features, laboratory variables, and treatment of patients identified with RBD. Rare platelet disorders were included in this study. We excluded factor VIII, IX deficiencies and Von Willebrand disease (VWD) from this analysis. Results We identified a total of 157 patients (age range 18 months-46 years old) with RBD, 46% were of female gender (Table 1). Majority of the patients (n=92, 58%) were of Hispanic ethnicity. Major RBD in the cohort was Factor 7 (F7) deficiency (n= 96, 60.4%). F11 deficiency constituted 10.1%, followed by fibrinogen deficiency (6.3%), and F13 deficiency (5.7%). F2 and Plasminogen activator inhibitor-1 (PAI-1) deficiency was identified in one individual each. Glanzmann thrombasthenia was the most common platelet disorder noted in our population (n=7, 4.4%), followed by giant platelet disorder (n=6, 3.8%). MYH9- related disorder was identified in 5 (3.1%) individuals with macrothrombocytopenia and bleeding. Wiskott-Aldrich Syndrome was detected in 3 (1.9%) cases of RBD. Combined bleeding disorders (CBDs) were observed in 15 individuals (9.5%) (Table 2). These disorders were distinguished by genotyping, factor activity, and chromogenic activity assays. F7 and Type 1 VWD combined disorder was observed in 46.7% (n=7) of these individuals. Genetic testing was done in 38% (n=60) of the affected individuals. Genetic analysis was done through American Thrombosis & Hemostasis Network (ATHN 10) in 19% (n=30). F7 gene mutation was the most commonly identified mutation and variants c.1238G>A (p.Arg413Gln), c.1172G>A (p.Arg353Gln), and c.1091G>A (p.Arg364Gln) were observed in those with F7 deficiency. All individuals with F7 deficiency with variants of uncertain significance were presumed to be positive. Treatment was specific to the factor deficiency. Most individuals received additional anti-fibrinolytic therapy during acute bleeding episodes. Recombinant F7 was used in platelet disorders for bleeding. Major bleeding events and death in the cohort was 1.2% (n= 2), and 2 individuals with F13 deficiency developed inhibitors to F13 concentrate. These individuals have been managed with recombinant F7 and anti-fibrinolytic therapy. Conclusion Ethnically diverse distribution of rare bleeding disorders was evident in our Central California cohort. Similar to previous reports, F7 deficiency was of the highest prevalence. A high prevalence of CBDs was also observed in this cohort. Genetic testing enabled diagnosis in some complex cases and needs to be used more widely to facilitate timely and accurate identification, and treatment of CBDs, and RBD in general. Further, these results help to identify novel mutations in different ethnicities, and provide additional information in understanding the clinical impact of new mutations.

Thromboprophylaxis with Intermediate Dose Low Molecular Weight Heparin in Adults Undergoing Induction with L-Asparaginase for Acute Lymphoblastic Leukemia

Introduction Adolescents and young adults (AYA, defined as age 15-39 years) with acute lymphoblastic leukemia (ALL) have a poorer prognosis than their pediatric counterparts. To replicate the success of ALL treatment in children, pediatric-inspired regimens have been incorporated into the treatment of AYA and often include the use of L-asparaginase. Rates of thrombosis in adults receiving L-asparaginase for treatment of ALL have been reported to be as high as 34%, compared to only about 5% in pediatric patients. The risk of thrombosis is elevated primarily during the induction phase of treatment. Several strategies have been studied in adults, including antithrombin III replacement, fresh frozen plasma replacement, and prophylactic dosing of anticoagulation, however no clear guidelines exist on how to prevent thrombosis in these high-risk patients. To prevent L-asparaginase-induced thrombotic events, our institution implemented a standard practice of 1mg/kg/day of low molecular weight heparin (LMWH), a dose in-between prophylactic and therapeutic dosing, administered to all adults with ALL who were treated with L-asparaginase during induction chemotherapy. In this current study, we report data from patients who have been treated with this strategy from 2012 to present, focusing on the antithrombotic efficacy and safety of 1mg/kg/day LMWH in this population. Methods This retrospective chart review included 62 patients who received prophylactic anticoagulation with the LMWH enoxaparin (1mg/kg/day) while undergoing induction chemotherapy with L-asparaginase for ALL at the Oregon Health & Science University from 2012 to present. Anticoagulation with enoxaparin was initiated with the first dose of L-asparaginase and continued until the day of discharge or day 30 of induction. The primary outcome was the incidence of thrombosis within the first 30 days of L-asparaginase administration. Minor and major bleeding events, as defined by the International Society of Thrombosis and Haemostasis (ISTH), were recorded. Statistical analysis with univariate regression models was performed to evaluate the association of thrombotic events with demographic, disease and treatment variables. Results Sixty-two patients received 1mg/kg/day LMWH prophylaxis during ALL induction between January 2012 and June 2023 (43 with B-ALL and 19 with T-ALL). Median age at induction was 25.7 years (range 18-39 years). A majority of patients (83.9%) received the maximum dose of 2500mg/m 2 of L-asparaginase. Four patients (6.5%; 95% CI 1.8%-15.7%) experienced a thrombotic event within the first 30 days of induction with L-asparaginase; 3 of the events were catheter-associated and were treated supportively or with catheter removal, and 1 patient developed a distal lower extremity deep vein thrombosis related to myositis. Median time to thrombosis was 13.5 days (range 11-22 days). There were no significant associations between development of thrombotic events with age, gender, B- or T-cell precursor, or dose of L-asparaginase. No thrombosis-related deaths or major bleeding events occurred. Conclusions Prophylactic anticoagulation with intermediate dose 1mg/kg/day LMWH in adults with ALL undergoing induction chemotherapy with L-asparaginase is a safe and an effective strategy to prevent serious thrombotic events. Our institutional rate of 6.5% of patients experiencing thrombotic events during induction with L-asparaginase, with all of the events being clinically low risk, compares favorably to historically reported rates in adults and approaches the low rates reported in children. Further prospective research is warranted.

Management of Catheter-Related Upper Extremity Deep Vein Thrombosis in Patients with Cancer: A Systematic Review and Meta-Analysis

Background: Patients with cancer commonly require a central venous catheter (CVC) for delivery of cancer therapies and/or supportive care. The presence of a CVC is associated with an increased risk of venous thromboembolism (VTE). Despite the frequent occurrence, the optimal anticoagulation management and outcomes for patients with cancer and catheter-related upper extremity deep vein thrombosis (DVT) are unclear. Objective: We performed a systematic review and meta-analysis to evaluate the rates of recurrent VTE and bleeding complications in patients with cancer and catheter-related upper extremity DVT. Methods: We searched MEDLINE, Embase, Scopus, and CENTRAL (Cochrane) from inception to June 2, 2023. We aimed to include randomized controlled trials (RCTs) (if any), prospective and retrospective cohort studies, and case-control studies (including ≥ 10 patients) evaluating adult patients with cancer and catheter-related upper extremity DVT. The primary efficacy outcome was recurrent VTE, and the primary safety outcome was major bleeding as defined by individual studies. Secondary outcomes included clinically relevant non-major bleeding, total bleeding events, and all-cause mortality. By using R software (version 4.0.3), the incidence rates (with 95% confidence interval [CI]) of recurrent VTE and bleeding outcomes at different time points were pooled using random effects model. Results: After screening 4,264 records, we included 29 studies (N=2,848 patients) in the systematic review. There were no RCTs, 5 prospective cohort studies (including 260 patients), and 24 retrospective cohort studies. Most studies had modest sample size (N<100). Overall from 24 studies with reported tumor types, the most common malignancy was hematological malignancy (50.4%), followed by gastrointestinal (13.6%), breast (10.2%), and lung (5.5%) cancers. The median or mean follow-up duration varied widely from 1 to 20 months. Duration of anticoagulation also varied considerably with median or mean duration of 20 days to 6 months. The main long-term anticoagulant used was low-molecular-weight heparin (58.1%), followed by direct oral anticoagulants (24.3%). Only two studies (N=87 patients) specifically reported the management and associated outcomes after catheter removal. Thirteen studies (N=1105 patients) reported a 3-month recurrent VTE rate, with the pooled rate of 1% (95% CI 0-3%, I 2 = 0%) (Figure 1). Nine studies (N=811 patients) reported a 3-month major bleeding rate, with the pooled rate of 2% (95% CI 1-5%, I 2 = 0%) (Figure 2). We were unable to pool event rates beyond 3 months given high degree of heterogeneity in the follow-up duration, bleeding definition, and duration of anticoagulation. Conclusions: Our systematic review and meta-analysis demonstrated relatively low rates of recurrent VTE and major bleeding events within the first 3 months in patients with cancer and catheter-related upper extremity DVT. However, there was significant heterogeneity in the management and reporting after 3 months, and available data are poor to guide treatment strategies and duration of anticoagulation. The optimal management after catheter removal was also unclear. Future large prospective studies are needed.

Risk and Outcomes of Hospitalizations in Patients with Anti-Phospholipid Syndrome Admitted with Autoimmune Hemolytic Anemia: A Nation-Wide Analysis

Introduction: Autoimmune hemolytic anemia (AIHA) can occur as a primary disorder or as a secondary manifestation of an underlying autoimmune condition. The coexistence of anti-phospholipid syndrome (APS) and AIHA can be very complex and challenging to manage given the intertwining of the prothrombotic and hemolytic states. In this study, we explored the outcomes of underlying antiphospholipid syndrome in autoimmune hemolytic anemia hospitalizations. Method: The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases (ICD) codes to identify hospitalizations for AIHA and then the data was subclassified into hospitalizations with and without APS. Demographics, comorbidities, and outcomes were identified using appropriate ICD 9/10 codes. Propensity score matched cohorts were generated for APS status and adjusted for age, race, sex, smoking, obesity, DM, CHF, CKD/ESRD, and liver disease. Results: A total of 7,609 AIHA hospitalizations were included, with 76 patients having underlying APS and 7,533 did not have APS. Mean age was younger in the APS cohort and there were also more females, blacks and Hispanics compared to the non-APS cohort. Propensity score matching was used to generate two cohorts, adjusting for age, race, sex, and for co-morbidities including obesity, smoking, DM, CHF, CKD/ESRD and liver disease. The adjusted analysis showed an 8.59 times higher risk of developing venous thromboembolic events (VTE) in AIHA with APS as compared to those hospitalizations without APS (Odds ratio (OR): 8.59, CI: 1.05-70.5; p=0.03). There was also a statistically significant increase in mean hospitalization cost in the APS group (p=0.001). A trend towards more arterial athero-embolic events (AAE), major bleeding events, and AKI as well as longer length of stay was seen in hospitalizations with APS, but it did not reach statistical significance. No significant difference in in-hospital mortality was seen between the two groups. The results are summarized in the Figure 1. Conclusion: APS confers additional risk to AIHA hospitalizations with significantly higher VTE events and added costs. Further studies should address the complex management of anticoagulation and prothrombotic risk in APS in the setting of active hemolytic anemia.