Prior History Of Venous Thromboembolism Research Articles

Pharmacologic Anticoagulation Is Associated With a Lower Risk of Recurrent Venous Thromboembolic Events During Janus Kinase Inhibitor Use for Patients With a Prior Thrombosis.

Janus kinase (JAK) inhibitors tofacitinib and upadacitinib are effective therapies for inflammatory bowel disease and rheumatologic disorders but currently possess a warning for increased venous thromboembolism (VTE) risk. Some patients with a history of VTE may benefit from a JAK inhibitor, but the risk of recurrent VTE with JAK inhibitor use is unclear. Our goal was to observe rates of new VTE events after starting JAK inhibitor therapy in patients with a prior VTE, and observe whether concurrent anticoagulation (AC) reduces this risk. We conducted a review of adults prescribed tofacitinib or upadacitinib between January 1, 2000, and June 30, 2023, with a prior history of VTE. Patient charts were reviewed for demographic data, disease type, and VTE date(s), and to verify duration of JAK inhibitor use along with any concurrent AC. VTEs following JAK inhibitor initiation were identified by International Classification of Diseases-Tenth Revision code and verified by physician documentation and imaging. We identified 79 patients with a documented VTE history before initiating JAK inhibitors, 47 of whom began a JAK inhibitor with concurrent AC. Of these, 15 patients discontinued AC while receiving JAK inhibitors. In total, 5 new VTE events were observed during 55.42 patient-years of JAK inhibitor treatment without concurrent AC (9.0 events per 100 patient-years), while no new VTE events occurred during 65.2 patient-years of JAK inhibitor treatment with concurrent AC, demonstrating a lower risk of recurrent VTE (P = .020). These results suggest that for patients with a prior VTE history there is a high risk for recurrent VTE while receiving JAK inhibitors. Concurrent use of AC with JAK inhibitors appears to be protective against recurrent VTEs in this population.

Venous Thromboembolism in Total Hip and Total Knee Arthroplasty

The optimal pharmacologic thromboprophylaxis agent after total hip and total knee arthroplasty is uncertain and consensus is lacking. Quantifying the risk of postoperative venous thromboembolism (VTE) and bleeding and evaluating comparative effectiveness and safety of the thromboprophylaxis strategies can inform care. To quantify risk factors for postoperative VTE and bleeding and compare patient outcomes among pharmacological thromboprophylaxis agents used after total hip and knee arthroplasty. This retrospective cohort study used data from a large health care claims database. Participants included patients in the United States with hip or knee arthroplasty and continuous insurance enrollment 3 months prior to and following their surgical procedure. Patients were excluded if they received anticoagulation before surgery, received no postsurgical pharmacological thromboprophylaxis, or had multiple postsurgery thromboprophylactic agents. In a propensity-matched analysis, patients receiving a direct oral anticoagulant (DOAC) were matched with those receiving aspirin. Aspirin, apixaban, rivaroxaban, enoxaparin, or warfarin. The primary outcome was 30-day cumulative incidence of postdischarge VTE. Other outcomes included postdischarge bleeding. Among 29 264 patients included in the final cohort, 17 040 (58.2%) were female, 27 897 (95.2%) had inpatient admissions with median (IQR) length of stay of 2 (1-2) days, 10 948 (37.4%) underwent total hip arthroplasty, 18 316 (62.6%) underwent total knee arthroplasty; and median (IQR) age was 59 (55-63) years. At 30 days, cumulative incidence of VTE was 1.19% (95% CI, 1.06%-1.32%) and cumulative incidence of bleeding was 3.43% (95% CI, 3.22%-3.64%). In the multivariate analysis, leading risk factors associated with increased VTE risk included prior VTE history (odds ratio [OR], 5.94 [95% CI, 4.29-8.24]), a hereditary hypercoagulable state (OR, 2.64 [95% CI, 1.32-5.28]), knee arthroplasty (OR, 1.65 [95% CI, 1.29-2.10]), and male sex (OR, 1.34 [95% CI, 1.08-1.67]). In a propensity-matched cohort of 7844 DOAC-aspirin pairs, there was no significant difference in the risk of VTE in the first 30 days after the surgical procedure (OR, 1.14 [95% CI, 0.82-1.59]), but postoperative bleeding was more frequent in patients receiving DOACs (OR, 1.36 [95% CI, 1.13-1.62]). In this cohort study of patients who underwent total hip or total knee arthroplasty, underlying patient risk factors, but not choice of aspirin or DOAC, were associated with postsurgical VTE. Postoperative bleeding rates were lower in patients prescribed aspirin. These results suggest that thromboprophylaxis strategies should be patient-centric and tailored to individual risk of thrombosis and bleeding.

Investigating Thrombosis Risk Factors in Sickle Cell Disease Utilizing Archetypal Analysis

Background: Thrombosis in sickle cell disease (SCD) affects both the arterial and venous vasculature with devastating consequences. Individuals with SCD have an increased risk of venous thromboembolism (VTE). The risks are multifactorial with prior studies identifying both VTE-specific and SCD-specific risk factors. Machine learning (ML) offers the potential to detect non-linear relationships in complex multifactorial diseases and has successfully predicted outcomes in deeply phenotyped patients. We investigated whether archetypal analysis (AA), a method of ML would identify clinical and laboratory factors associated with arteriovenous thrombosis in patients with SCD. Methods: We retrospectively analyzed a prospective longitudinal cohort of patients with SCD (NCT00011648) studied between 2000-2017. A prior history of VTE and/or stroke at the time of study entry as captured by the electronic medical record was used to define index “cases”. SCD patients without a history of thrombosis were “controls”. The demographic and clinical characteristics of cases and controls were compared using Wilcoxon rank-sum test for continuous and Fisher's exact test for categorical variables. Unsupervised AA was used to identify patterns of clinical and laboratory test characteristics within the entire cohort of patients including cases and controls. AA identifies patterns are on the convex hull that encloses all patients in the cohort in the high-dimensional feature space. Once specific archetypes were identified, the frequency of each archetype was determined within cases and controls. In addition, we describe the age and laboratory characteristics of the archetypes that were significantly more prevalent in cases as compared to controls. Results: The cohort consisted of 633 out of 862 patients that had their whole exome sequenced. A combined total of 160 arterial and venous thrombosis events was detected in 148/633 patients (24%) with half (n=79) attributable to arterial stroke and half (n=81) attributable to VTE [Table 1]. A small proportion of patients had both arterial and venous thrombosis (n=12). The median age (31 years, p=0.94) and sex were similar between the cases (n=148) and controls (n=485). The distribution of genotypes was similar between the two groups (p=0.09). A significantly higher proportion of patient with thrombosis had a prior history of blood transfusion (p<0.0001) and history of insertion of a central venous access device (p=<0.0001) [Table 1]. History of medical management with hydroxyurea was similar among the cases and controls (p=0.70). Compared to controls, the cases had elevated laboratory parameters including AST levels (p=0.02), and serum ferritin (p<0.0001), while HbS percentages were significantly lower (p<0.0001). Based on the minimum error in matrix factorization, a total of 15 archetypes were identified in the cohort [Figure 1]. Each patient was decomposed as a weighted combination of the 15 archetypes. The contributing archetypes for each patient were those archetypes that have non-zero weights. Among those 15 archetypes, archetypes 9, 14 and 15 were significantly more enriched among the cases compared to controls (p<0.02) [Figure 1]. We observed elevated serum ferritin levels and low levels of HbS across the three archetypes, which are consistent with the previously identified risk factors [Figure 1]. Conclusions: Machine-identified archetypes are objective and reproducible feature representations. Archetype analysis-based machine learning appears to hold promise to identify both traditional VTE and SCD-specific risks for clinical thrombosis. Future studies will utilize archetypal analysis to investigate associations between clinical, laboratory and genetic markers for thrombosis and assess their reproducibility using validation cohorts.

Assessing the Feasibility of Thromboprophylaxis with Apixaban in JAK2-Positive Myeloproliferative Neoplasm Patients: The Airport-MPN Trial

Introduction: Thrombosis is a major cause of mortality and morbidity in myeloproliferative neoplasms (MPN). In patients classified as high-risk for thrombosis, current guidelines recommend the use of cytoreduction therapy and low-dose aspirin (e.g., ASA 81 mg daily) to decrease the risk of thrombotic events. However, use of low-dose aspirin is based on limited evidence and is associated with a significant failure rate. Thromboprophylaxis with low-dose direct oral anticoagulants (e.g., apixaban 2.5 mg BID) is an appealing option in MPN, specifically when patients carry the JAK2 mutation, based on the pathophysiology of thrombus formation associated with this driver mutation. In other populations, thromboprophylaxis with a low-dose direct oral anticoagulant has been associated with a reduced risk of arterial and venous thrombotic complications, when compared to low-dose aspirin. Hence, we conducted a pilot trial to assess the feasibility of conducting a randomized controlled trial evaluating the efficacy and safety of apixaban (2.5 mg BID) compared to aspirin (81 mg daily) to prevent thrombotic complications in patients with JAK2-positive MPN (JAK2MPN). Methods: This was a multi-centre, prospective, open-label, blinded endpoint pilot trial (NCT04243122), conducted in three Canadian centers (Ottawa, Calgary, Sherbrooke). Adult patients with a confirmed diagnosis of polycythemia vera, JAK2-positive essential thrombocythemia or JAK2-positive pre-fibrotic myelofibrosis (per local clinical definitions) requiring low-dose aspirin for thromboprophylaxis were eligible. Both patients with an incident diagnosis of JAK2MPN (defined as diagnosed within 1 year) and patients with prevalent disease were targeted for recruitment. Exclusion criteria included a contraindication to thromboprophylaxis or the need for a specific anticoagulant or non-aspirin anti-platelet agent. Patients with a prior history of venous thromboembolism were eligible if they had completed a minimum of 6 months of anticoagulation therapy. Participants were randomized 1:1 to receive apixaban 2.5mg BID or aspirin 81mg daily, along with cytoreductive therapy (per guidelines). The study treatment duration was 6 months. Follow-up occurred at 3, 6 and 7 months after allocation of the study medication. The primary study outcome for feasibility was the monthly recruitment rate per study site over a 6-month follow-up period. Secondary outcomes included rates of thrombotic and bleeding complications. The total estimated sample size was 44 participants (22 per arm). Due to the COVID-19 pandemic, not all sites were able to start recruitment at the same time and the total recruitment period spanned over 24 months. Results: During this 24-month recruitment period, 93 JAK2MPN patients were screened for eligibility. Of these, 69 were eligible and 64% of eligible patients consented to participate. We therefore recruited 44 participants, for a recruitment rate of 0.8 patient per centre per month. Baseline characteristics of participants are presented in Table 1. A total of 29 prevalent cases and 15 incident cases were included. Secondary efficacy, safety, and feasibility outcomes (relating to thrombotic events, bleeding complications, and study compliance) will be available at the ASH Meeting, since all participants will have completed the 6-month treatment duration by October 2023. Discussion: Despite the challenges of the COVID-19 pandemic, we have recruited 100% of our target population. Given the chronicity of MPN, most outpatient clinics functioned remotely during the pandemic, precluding recruitment. Nevertheless, by adapting to the realities of the pandemic, we achieved our recruitment target demonstrating feasibility of a larger trial. The strategies adopted during this pilot trial to recruit participants, such as active screening of clinic lists for potential participants and direct communication with MPN specialists, will be applied to our larger scale trial. Conclusion: This pilot trial demonstrated the feasibility of conducting a large-scale trial evaluating the superiority of apixaban over aspirin for the thromboprophylaxis of JAK2MPN patients. As JAK2MPN are rare diseases, we have partnered with counterparts in France to conduct an international study on the efficacy and safety of direct oral anticoagulant thromboprophylaxis in JAK2MPN patients.

External validation of venous thromboembolism risk prediction models in patients with multiple myeloma in a community setting: A retrospective cohort study.

e20027 Background: Newly diagnosed Multiple Myeloma (MM) patients have a 10 to 20 times higher risk of developing venous thromboembolism (VTE) than the general population. Three risk prediction models have been recently established to ascertain the degree of VTE risk: SAVED (Surgery, Asian race, VTE history, Elderly and Dexamethasone), IMPEDE VTE (Immunomodulatory drugs (IMiD), BMI, Pelvic fracture, Erythropoietin stimulating agent, Dexamethasone/Doxorubicin, Asian Ethnicity, VTE history, Tunneled line, Existing thromboprophylaxis) and PRISM scores (Prior VTE, Race, IMiD, Surgery, Metaphase Cytogenetics). Our primary objective was to assess the external validity of three VTE risk prediction models in a community hospital setting. Methods: All consecutive newly diagnosed MM treated at Saint Vincent Hospital from 1/1/2012 to 12/22/2022 were included in our analysis. Patients receiving therapeutic anticoagulation for other indications or a diagnosis of VTE within 6 months prior to MM diagnosis were excluded. Variables were collected by retrospective chart review at the time of MM treatment initiation. Model discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUROC). Logistic regression was used to calculate the odds ratio (OR) of VTE occurrence with candidate variables in the risk prediction model. Results: The 160 patients with newly diagnosed MM and available data on VTE occurrence were included. The median age of our cohort at treatment initiation was 74 years (range 31-96); 55% were male, and 75% were Caucasians. IMiD-based induction regimen was used in 68.1 % of patients. The median SAVED score was 1 (IQR:0-2), IMPEDE VTE was 4 (IQR: 2-6), and PRISM score was 2 (IQR: 0-2). The most common thromboprophylactic agent used was aspirin (53.8%). The median time to VTE from induction was 4.8 months. The cumulative incidence of VTE at 12 months was 13.1%. Each 1-point increase in the score was associated with a significantly higher chance of VTE occurrence across all three models (Table). Factors significantly associated with the development of VTE were prior VTE history (OR:2.28, 95% CI:1.31-3.97,p = 0.003) and age greater than 80 years (OR:4.03, 95% CI:1.47-11.02,p = 0.006). Conclusions: Our findings suggest that all three PRISM (AUROC = 0.70), SAVED (AUROC = 0.72), and IMPEDE VTE (AUROC = 0.73) scores could statistically predict VTE outcomes in our patient population. The inclusion of more parameters in the IMPEDE VTE score may have led to its outperformance in risk stratification. [Table: see text]

Risk of thromboembolism in patients with COVID-19 who are using hormonal contraception.

The novel coronavirus disease (COVID-19) has led to significant mortality and morbidity, including a high incidence of related thrombotic events. There has been concern regarding hormonal contraception use during the COVID-19 pandemic, as this is an independent risk factor for thrombosis, particularly with estrogen-containing formulations. However, higher estrogen levels may be protective against severe COVID-19 disease. Evidence for risks of hormonal contraception use during the COVID-19 pandemic is sparse. We conducted a living systematic review that will be updated as new data emerge on the risk of thromboembolism with hormonal contraception use in patients with COVID-19. To determine if use of hormonal contraception increases risk of venous and arterial thromboembolism in women with COVID-19. To determine if use of hormonal contraception increases other markers of COVID-19 severity including hospitalization in the intensive care unit, acute respiratory distress syndrome, intubation, and mortality. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach. ⁠⁠⁠⁠⁠⁠We searched CENTRAL, MEDLINE, Embase, CINAHL, Global Index Medicus, Global Health, and Scopus from inception on March 2023, and monitored the literature monthly. We updated the search strategies with new terms and added the database Global Index Medicus in lieu of LILACS. We included all published and ongoing studies of patients with COVID-19 comparing outcomes of those on hormonal contraception versus those not on hormonal contraception. This included case series and non-randomized studies of interventions (NRSI). One review author extracted study data and this was checked by a second author. Two authors individually assessed risk of bias for the comparative studies using the ROBINS-I tool and a third helped reconcile differences. For the living systematic review, we will publish updates to our synthesis every six months. In the event that we identify a study with a more rigorous study design than the current included evidence prior to the planned six-month update, we will expedite the synthesis publication. We included three comparative NRSIs with 314,704 participants total and two case series describing 13 patients. The three NRSIs had serious to critical risk of bias in several domains and low study quality. Only one NRSI ascertained current use of contraceptives based on patient report; the other two used diagnostic codes within medical records to assess hormonal contraception use, but did not confirm current use nor indication for use. None of the NRSIs included thromboembolism as an outcome. Studies were not similar enough in terms of their outcomes, interventions, and study populations to combine with meta-analyses. We therefore narratively synthesized all included studies. Based on results from one NRSI, there may be little to no effect of combined hormonal contraception use on odds of mortality for COVID-19 positive patients (OR 1.00, 95% CI 0.41 to 2.40; 1 study, 18,892 participants; very low-certainty evidence). Two NRSIs examined hospitalization rates for hormonal contraception users versus non-users. Based on results from one NRSI, the odds of hospitalization for COVID-19 positive combined hormonal contraception users may be slightly decreased compared with non-users for patients with BMI under 35 kg/m2 (OR 0.79, 95% CI 0.64 to 0.97; 1 study, 295,689 participants; very low-certainty evidence). According to results of the other NRSI assessing use of any type of hormonal contraception, there may be little to no effect on hospitalization rates for COVID-19 positive individuals (OR 0.99, 95% CI 0.68 to 1.44; 1 study, 123 participants; very low-certainty evidence). We included two case series because no comparative studies directly assessed thromboembolism as an outcome. In a case series of six pediatric COVID-19 positive patients with pulmonary embolism, one (older than 15 years of age) was using combined hormonal contraception. In a second case series of seven COVID-19 positive patients with cerebral venous thrombosis, one was using oral contraceptives. One comparative study and one case series reported on intubation rates, but the evidence for both is very uncertain. In the comparative study of 123 COVID-19 positive patients (N = 44 using hormonal contraception and N = 79 not using hormonal contraception), no patients in either group required intubation. In the case series of seven individuals with cerebral venous thromboembolism, one oral contraceptive user and one non-user required intubation. There are no comparative studies assessing risk of thromboembolism in COVID-19 patients who use hormonal contraception, which was the primary objective of this review. Very little evidence exists examining the risk of increased COVID-19 disease severity for combined hormonal contraception users compared to non-users of hormonal contraception, and the evidence that does exist is of very low certainty. The odds of hospitalization for COVID-19 positive users of combined hormonal contraceptives may be slightly decreased compared with those of hormonal contraceptive non-users, but the evidence is very uncertain as this is based on one study restricted to patients with BMI under 35 kg/m2. There may be little to no effect of combined hormonal contraception use on odds of intubation or mortality among COVID-19 positive patients, and little to no effect of using any type of hormonal contraception on odds of hospitalization and intubation for COVID-19 patients. We noted no large effect for risk of increased COVID-19 disease severity among hormonal contraception users. We specifically noted gaps in pertinent data collection regarding hormonal contraception use such as formulation, hormone doses, and duration or timing of contraceptive use. Differing estrogens may have different thrombogenic potential given differing potency, so it would be important to know if a formulation contained, for example, ethinyl estradiol versus estradiol valerate. Additionally, we downgraded several studies for risk of bias because information on the timing of contraceptive use relative to COVID-19 infection and method adherence were not ascertained. No studies reported indication for hormonal contraceptive use, which is important as individuals who use hormonal management for medical conditions like heavy menstrual bleeding might have different risk profiles compared to individuals using hormones for contraception. Future studies should focus on including pertinent confounders like age, obesity, history of prior venous thromboembolism, risk factors for venous thromboembolism, and recent pregnancy.

MP46-06 DOES PERIOPERATIVE BLOOD TRANSFUSION INCREASE THE RISK OF VENOUS THROMBOEMBOLISM AFTER RADICAL CYSTECTOMY?

You have accessJournal of UrologyCME1 Apr 2023MP46-06 DOES PERIOPERATIVE BLOOD TRANSFUSION INCREASE THE RISK OF VENOUS THROMBOEMBOLISM AFTER RADICAL CYSTECTOMY? Kays Chaker, Yassine Ouanes, Anouar Madani, Nizar Cherni, Boutheina Mosabhi, Rania Cherif, Mokhtar Bibi, Nouha Harouni, Moez Rahoui, Kheireddine Mrad Dali, Karem Abid, Ahmed Sellami, Adel Ammous, and Yassine Nouira Kays ChakerKays Chaker More articles by this author , Yassine OuanesYassine Ouanes More articles by this author , Anouar MadaniAnouar Madani More articles by this author , Nizar CherniNizar Cherni More articles by this author , Boutheina MosabhiBoutheina Mosabhi More articles by this author , Rania CherifRania Cherif More articles by this author , Mokhtar BibiMokhtar Bibi More articles by this author , Nouha HarouniNouha Harouni More articles by this author , Moez RahouiMoez Rahoui More articles by this author , Kheireddine Mrad DaliKheireddine Mrad Dali More articles by this author , Karem AbidKarem Abid More articles by this author , Ahmed SellamiAhmed Sellami More articles by this author , Adel AmmousAdel Ammous More articles by this author , and Yassine NouiraYassine Nouira More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003292.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radical cystectomy (RC) is associated with significant morbidity including perioperative blood transfusion. The aim of this study was to develop a model that would provide information on the relationship between perioperative blood transfusion and the development of venous thromboembolism (VTE) after RC. METHODS: All patients who underwent open RC between between january 2006 and december 2021 at our institution were reviewed retrospectively. Patient with a history of prior VTE, those taking anticoagulation prior to surgery, patients with metastatic bladder cancer or with missing data were excluded. A venous thromboembolism was defined as either a deep venous thrombosis or pulmonary embolism. Patients who developed a VTE within 90 days after surgery were compared to those who did not. Logistic regression was performed to assess the association between covariates and the probability of VTE within 90 days after surgery. RESULTS: A total of 372 cases were enrolled in this study. Almost 224 patients (60.21%) received a perioperative blood transfusion, with a median of 1 (IQR: 0-4) unit transfused. Forty-two patients (11.29%) of whom developed a VTE within 90 days after surgery. There was no significant difference in age, sex, race, Charlson score, clinical stay, BMI. Patient who developed a VTE experienced a longer mean operative time (367.84 vs 311.5 minutes, p=0.01), had adverse pathology (≥pT3 or node positive) (p=0.005) and received a greater mean number of transfused units of blood during their stay (2.42 vs 1.26, p=0.02). The variables included in the model were selected based on the univariate analysis and on an a priori basis and included blood transfusion, age, BMI, Charlson score, smoking status, pathologic tumor stage, pathologic nodal stage and operative time. On multivariable logistic regression, each unit of transfused blood given during a patient's hospital stay was significantly associated with development of VTE (OR 1.22, 95% CI 1.12-1.44), as was operative time (OR 1.47, 95% CI 1.16-1.88). CONCLUSIONS: The incidence of perioperative blood transfusion is significant at the time of radical cystectomy. This study demonstrates that blood transfusion was associated with an increased risk for developing the VTE. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e632 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kays Chaker More articles by this author Yassine Ouanes More articles by this author Anouar Madani More articles by this author Nizar Cherni More articles by this author Boutheina Mosabhi More articles by this author Rania Cherif More articles by this author Mokhtar Bibi More articles by this author Nouha Harouni More articles by this author Moez Rahoui More articles by this author Kheireddine Mrad Dali More articles by this author Karem Abid More articles by this author Ahmed Sellami More articles by this author Adel Ammous More articles by this author Yassine Nouira More articles by this author Expand All Advertisement PDF downloadLoading ...

Risk of thromboembolism in patients with COVID-19 who are using hormonal contraception.

The novel coronavirus disease (COVID-19) has led to significant mortality and morbidity, including a high incidence of related thrombotic events. There has been concern regarding hormonal contraception use during the COVID-19 pandemic, as this is an independent risk factor for thrombosis, particularly with estrogen-containing formulations. However, higher estrogen levels may be protective against severe COVID-19 disease. Evidence for risks of hormonal contraception use during the COVID-19 pandemic is sparse. We therefore conducted a living systematic review that will be updated as new data emerge on the risk of thromboembolism with hormonal contraception use in patients with COVID-19. To determine if use of hormonal contraception increases risk of venous and arterial thromboembolism in women with COVID-19. To determine if use of hormonal contraception increases other markers of COVID-19 severity including hospitalization in the intensive care unit, acute respiratory distress syndrome, intubation, and mortality. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach. ⁠⁠⁠⁠⁠⁠We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Global Health, and Scopus from inception to search update in March 2022. For the living systematic review, we monitored the literature monthly. We included all published and ongoing studies of patients with COVID-19 comparing outcomes of those on hormonal contraception versus those not on hormonal contraception. This included case series and non-randomized studies of interventions (NRSI). One review author extracted study data and this was checked by a second author. Two authors individually assessed risk of bias for the comparative studies using the ROBINS-I tool and a third author helped reconcile differences. For the living systematic review, we will publish updates to our synthesis every six months. In the event that we identify a study with a more rigorous study design than the current included evidence prior to the planned six-month update, we will expedite the synthesis publication. We included three comparative NRSIs with 314,704 participants total and two case series describing 13 patients. The three NRSIs had serious to critical risk of bias in several domains and low study quality. Only one NRSI ascertained current use of contraceptives based on patient report; the other two used diagnostic codes within medical records to assess hormonal contraception use, but did not confirm current use nor indication for use. None of the NRSIs included thromboembolism as an outcome. Studies were not similar enough in terms of their outcomes, interventions, and study populations to combine with meta-analyses. We therefore narratively synthesized all included studies. Based on results from one NRSI, there may be little to no effect of combined hormonal contraception use on odds of mortality for COVID-19 positive patients (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.41 to 2.40; 1 study, 18,892 participants; very low-certainty evidence). Two NRSIs examined hospitalization rates for hormonal contraception users versus non-users. Based on results from one NRSI, the odds of hospitalization for COVID-19 positive combined hormonal contraception users may be slightly decreased compared with non-users for patients with body mass index (BMI) under 35 kg/m2 (OR 0.79, 95% CI 0.64 to 0.97; 1 study, 295,689 participants; very low-certainty evidence). According to results of the other NRSI assessing use of any type of hormonal contraception, there may be little to no effect on hospitalization rates for COVID-19 positive individuals (OR 0.99, 95% CI 0.68 to 1.44; 1 study, 123 participants; very low-certainty evidence). We included two case series because no comparative studies directly assessed thromboembolism as an outcome. In a case series of six pediatric COVID-19 positive patients with pulmonary embolism, one (older than 15 years of age) was using combined hormonal contraception. In a second case series of seven COVID-19 positive patients with cerebral venous thrombosis, one was using oral contraceptives. One comparative study and one case series reported on intubation rates, but the evidence for both is very uncertain. In the comparative study of 123 COVID-19 positive patients (N = 44 using hormonal contraception and N = 79 not using hormonal contraception), no patients in either group required intubation. In the case series of seven individuals with cerebral venous thromboembolism, one oral contraceptive user and one non-user required intubation. There are no comparative studies assessing risk of thromboembolism in COVID-19 patients who use hormonal contraception, which was the primary objective of this review. Very little evidence exists examining the risk of increased COVID-19 disease severity for combined hormonal contraception users compared to non-users of hormonal contraception, and the evidence that does exist is of very low certainty. The odds of hospitalization for COVID-19 positive users of combined hormonal contraceptives may be slightly decreased compared with those of hormonal contraceptive non-users, but the evidence is very uncertain as this is based on one study restricted to patients with BMI under 35 kg/m2. There may be little to no effect of combined hormonal contraception use on odds of intubation or mortality among COVID-19 positive patients, and little to no effect of using any type of hormonal contraception on odds of hospitalization and intubation for COVID-19 patients. At a minimum, we noted no large effect for risk of increased COVID-19 disease severity among hormonal contraception users. We specifically noted gaps in pertinent data collection regarding hormonal contraception use such as formulation, hormone doses, and duration or timing of contraceptive use. Differing estrogens may have different thrombogenic potential given differing potency, so it would be important to know if a formulation contained, for example, ethinyl estradiol versus estradiol valerate. Additionally, we downgraded several studies for risk of bias because information on the timing of contraceptive use relative to COVID-19 infection and method adherence were not ascertained. No studies reported indication for hormonal contraceptive use, which is important as individuals who use hormonal management for medical conditions like heavy menstrual bleeding might have different risk profiles compared to individuals using hormones for contraception. Future studies should focus on including pertinent confounders like age, obesity, history of prior venous thromboembolism, risk factors for venous thromboembolism, and recent pregnancy.

Incidence, Risk Factors, Risk Assessment Model and Compliance of Patients on Anticoagulants for Asymptomatic Venous Thromboembolism in Nononcological Urological Inpatients.

To study the incidence, risk factors for developing asymptomatic venous thromboembolism and the compliance of patients on anticoagulants for asymptomatic venous thromboembolism (VTE) in nononcological urological medium-high risk inpatients, and build a risk assessment model (RAM) for early screening for asymptomatic VTE. We conducted a retrospective analysis of 573 inpatients admitted to a nononcological urological ward of a tertiary hospital in China from January 1, 2017, to June 30, 2019. Data were collected using the electronic medical record system, and patients underwent a follow-up by phone 6 months after discharge. Among the 573 medium-high risk inpatients, 73 (15.4%) were diagnosed with VTE, including 20 (4.2%) symptomatic and 53 (11.2%) asymptomatic. Prior history of VTE, a history of anticoagulants or antiplatelet agents before admission, and D-dimer ≥ 1 were the potential risk factors identified for asymptomatic VTE. Patients with poor awareness of VTE and its dangers, and patients who lived more than 1 hour away from the hospital had a high probability of poor compliance with anticoagulation therapy after discharge. Using D-dimer (1.785 μg/ml), we built a RAM for the early diagnosis of asymptomatic VTE. We found that patients with urinary nontumor VTE had low compliance with anticoagulation therapy after discharge. The key factors for determining asymptomatic VTE in nononcological urological inpatients included prior history of VTE, a history of taking anticoagulants or anti-platelet agents before admission, and D-dimer ≥ 1. Furthermore, we found that the threshold of D-dimer should be elevated to 1.785 μg/ml to predict asymptomatic VTE.

Independent predictors and timing of portomesenteric vein thrombosis after bariatric surgery.

Portomesenteric vein thrombosis (PVT) is a rare complication following bariatric surgery but can result in severe morbidity as well as death. Identification of risk factors for PVT to facilitate targeted management strategies to reduce incidence. Prospective, statewide bariatric-specific clinical registry. We identified all patients who underwent primary bariatric surgery between June 2006 and November 2021 (n = 102,869). Patient characteristics, procedure type, operative details, and 30-day postoperative complications were analyzed with multivariable logistic regression to evaluate for independent predictors of PVT. A total of 117 patients (.11%) developed a postoperative PVT, with 6 (5.1%) associated deaths. The majority of PVTs occurred in patients who underwent sleeve gastrectomy (109 patients; 93.2%), and the PVT occurred most commonly during the second (37%), third (31%), and fourth weeks (23%) after surgery. Independent risk factors for PVT included a prior history of venous thromboembolism (odds ratio [OR] = 3.1; 95% confidence interval [CI]: 1.64-5.98; P = .0005), liver disorder (OR = 2.3; 95% CI: 1.36-4.00; P = .0021), undergoing sleeve gastrectomy (OR = 12.4; 95% CI: 4.98-30.69; P < .0001), and postoperative complications including obstruction (OR = 12.5; 95% CI: 4.65-33.77; P < .0001), leak (OR = 7.9; 95% CI: 2.76-22.64; P = .0001), and hemorrhage (OR = 7.6; 95% CI: 3.57-16.06; P < .0001). Independent predictors of PVT include a prior history of venous thromboembolism, liver disease, undergoing sleeve gastrectomy, and experiencing a serious postoperative complication. Given that the incidence of PVT is most common within the first month after surgery, extending postdischarge chemoprophylaxis during this time frame is advised for patients with increased risk.

Performance of D-Dimers in Patients with Prior History of Venous Thromboembolism Based on Anticoagulation Status

Background: D-dimers frequently stay elevated in patients with prior history of venous thromboembolism (VTE). Moreover, D-dimers seem to have lower diagnostic yield in patients presenting with a suspicion of recurrent VTE and it is not clear how D-dimers perform in patients on anticoagulation. Aim: To evaluate the performance of D-dimers in patients with a history of VTE based on anticoagulation status. Methods: The PREDICTORS study is an international prospective multicenter observational cohort study of outpatients with suspected VTE recurrence. The aim is to improve the performance of diagnostic strategies in patients with a suspicion of recurrent VTE. Pre-test clinical probability was assessed, and D-dimers were performed based on local clinical practices. Negative D-dimers were determined based on the manufacturer's threshold for every commercial assay used in each center. Recurrent VTE events (defined as proximal deep venous thrombosis or segmental or more proximal pulmonary embolism) at enrollment and during the 3-month follow-up were assessed and all suspected recurrent events were independently adjudicated. Results: D-dimer measurements were used in the diagnostic management of 482 patients, of which, 168 patients were on anticoagulation and 314 were not on anticoagulation. At enrollment, the prevalence of recurrent VTE was 29.9% (144/482). Moreover, at the index suspicion, 35.1% (169/482) had negative D-dimers. Amongst patients on anticoagulation, 4/90 (4.4%; 95%CI 1.2%-11.0%) and 21/78 (26.9%) had recurrent VTE at enrollment in patients with negative and positive D-dimers, respectively. During follow-up, no recurrent VTE occurred in patients with negative D-dimers. Amongst patients without anticoagulation, 2/79 (2.5%; 95%CI 0.3%-8.9%) and 117/235 (49.8%) had recurrent VTE at enrollment in patients with negative and positive D-dimers, respectively. One recurrent VTE occurred during follow-up amongst patients with initial negative D-dimers (1.3%; 95%CI 0.0-7.0%). Conclusion: In patients presenting with a suspected recurrent VTE, the prevalence of VTE was high, including in patients receiving anticoagulant therapy. Prevalence of VTE based on D-dimers positivity was comparable between patients on anticoagulation and patients without anticoagulation. False negative rate of D-dimers appears to be higher in patients with a suspicion of recurrent VTE than in patients with a suspected first thromboembolic event. Further studies are needed to assess if a change in the D-dimers cut-off could improve diagnostic yield.

Monogenic and Polygenic Contributions to Venous Thromboembolism (VTE) and Splanchnic Thrombosis in Patients (pts) with Pancreatic Cancer (PC)

BACKGROUND Cancer-associated VTE is a significant cause of morbidity and mortality. The Khorana score (KS), which includes cancer type, body mass index, and prechemotherapy laboratory studies, is commonly used to stratify the risk of cancer-associated VTE (1). KS has low discriminative ability in some clinical situations (2) and does not include genomic information. We investigated a cohort of 753 pts with PC for germline and somatic predictors of VTE and splanchnic thrombosis and developed a PC-specific polygenic risk score (PC-PRS) to predict VTE. METHODS We manually abstracted clinical risk factors for VTE in pts of European ancestry with PC, sequenced at Dana-Farber Cancer Institute (DFCI). VTE was defined as 1) thrombosis in deep veins of the lower extremities/upper extremities or 2) pulmonary embolism. Splanchnic thrombosis was separately analyzed and defined as thrombosis of the portal, hepatic, splenic, or superior/inferior mesenteric veins. Incident VTE/splanchnic thrombosis was defined as the first occurrence of thrombosis or thrombosis-related death. KS was calculated using pretreatment laboratory values obtained prior to cancer treatment. A genome-wide association study (GWAS) was conducted for time to VTE across 5.35 million common imputed germline variants. A germline PRS was computed by cross-validation: 1) the cohort was split into 5 subsets; 2) GWAS was conducted within 4/5 subsets and PRS weights calculated using pruning and thresholding; 3) each score was predicted into the held out 1/5 subset; 4) this was repeated five times; 5) significance of the association between held-out PRS and VTE was evaluated by permutation. Associations between both PC-PRS and KS and time to VTE were determined. To assess PRS and GWAS specificity, we conducted an association analysis of 5760 solid tumors sequenced at DFCI and treated with anti-neoplastic therapy for which VTE information was available. Pathogenic somatic variants in tumor suppressor genes included truncating variants, splice-site variants affecting consensus nucleotides, or homozygous deletions. For proto-oncogenes, pathogenic calls included gene amplifications and missense variants with functional impact determined using SIFT(3) and Polyphen-2(4). False discovery rate was applied using Benjamini Hochberg (FDR<10%) RESULTS Of 753 pts with PC, 305 (40.5%) underwent PC surgery and 661 (87.8%) received chemotherapy within 6 months (mo) of diagnosis. During a median follow-up of 4.4 years, 223 (29.6%) incident VTEs and 94 (12.5%) splanchnic thromboses were identified. For 529 pts with available KS, 131 (24.8%) were intermediate-risk while the remaining were high-risk. GWAS across 753 samples identified 1 locus that was genome-wide significant for VTE (p<5x10-8). The lead SNP was rs13327332, with the minor allele associated with a significantly lower risk of VTE (HR=0.13, p=2.8x10-8, fig 1) in the PC cohort. The variant was not associated with VTE in other solid tumors. To investigate genome-wide polygenic effects, a risk score was estimated using all GWAS SNPs and evaluated by cross-validation (PC-PRS). Individuals in the top 20% of PC-PRS were at 5-fold higher risk for developing a VTE in the first 6 mo relative to the lowest 20% of PC-PRS, after accounting for the competing risk of death. Cumulative incidence of VTE in the first 6 mo was similar between pts with intermediate and high KS (fold-change=1). After adjusting for sex, age, chemotherapy within 6 months, history of prior VTE, surgery for pancreatic cancer, metastatic disease at time of VTE, and tumor purity, PC-PRS was significantly associated with time to incident VTE (HR=1.9, p=0.02) while KS was not (HR=1, p=0.96, fig 2). The PC-PRS was specific to PC and was not associated with other solid tumors. Analyzing 445 genes for associations between pathogenic somatic alterations and time-to-VTE, CNV amplifications in CIC were associated with significantly higher risk of VTE (HR=2.5, p=0.0001, FDR<10%). MAP3K1 gene alterations (n=12) were associated with 9.3x higher risk of splanchnic thrombosis (p=0.0001, FDR<10%). CONCLUSION We suggest a role for PC-PRS in VTE risk stratification and identify multiple somatic alterations with high effects on VTE incidence. Implementation of PC-PRS and integration with somatic data may provide a more refined risk estimation of VTE risk in PC than current clinical tools permit. Further validation in independent cohorts is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anticoagulation Use for Secondary Prophylaxis Against Recurrent Venous Thromboembolism in Hospitalized Children: A Report from the Children's Hospital-Acquired Thrombosis (CHAT) Consortium

Introduction: Most venous thromboembolism (VTE) in children are provoked and have an overall low risk for recurrence, especially if the original provoking factor is mitigated. Nonetheless, certain factors heighten VTE recurrence risk, including hospitalization. In fact, the rate of VTE in hospitalized children has increased more than 200% since 20011. This staggering discovery emphasizes the dire need for more effective tactics aimed at VTE prevention. Historically, pediatric providers have been hesitant to initiate pharmacologic (i.e. anticoagulant) measures in children for a number of reasons. In our recent survey of practice patterns of secondary prevention against recurrent VTE in pediatrics, we found low use (<25%) of pharmacologic prophylaxis in high-risk children2. Additionally, most respondents did not feel comfortable initiating secondary pharmacologic prophylaxis in younger children2. In the wake of the COVID-19 pandemic, numerous trials have been conducted to evaluate anticoagulation for VTE prevention in affected individuals. The recently published COVID-19 Anticoagulation in Children- Thromboprophylaxis trial showed safety of low-dose enoxaparin in children hospitalized with COVID-19 or multisystem inflammatory syndrome in children (MIS-C)3. Furthermore, trials of direct oral anticoagulants have also shown safety and efficacy in secondary VTE prevention in children4. Importantly, these studies have consistently demonstrated low rates of bleeding. Methods: The CHAT Registry is an IRB-approved registry that captures clinical data on hospital-acquired VTE in children <21 years of age and non-VTE controls. Subjects were enrolled from 2012-2021 across 8 participating pediatric hospitals. Using this REDCap database, we performed a retrospective study of enrolled subjects to explore trends for secondary anticoagulation prophylaxis use in hospitalized children. Subjects (cases and controls) were included if they had a history of VTE. Descriptive statistics were used to analyze demographics/characteristics and VTE prophylaxis measures. Results: Fifty-two subjects (%) out of 2219 total CHAT subjects (1273 cases, 946 controls) reviewed had a prior history of VTE. Characteristics of these subjects are presented in Table 1. The mean age was 9.6 years with a slight male predominance (54%). Regarding VTE prophylaxis (Figure 1), 18 (35%) received VTE prophylaxis (mechanical and/or pharmacologic) during hospitalization. Of these, 11 subjects (61%) were prescribed pharmacologic prophylaxis either alone (8) or in combination with mechanical prophylaxis (3). The remaining seven (39%) received only mechanical prophylaxis. Four subjects were already on anticoagulation at the time of admission. Forty-four (85%) subjects experienced a hospital-acquired VTE recurrence. Only 16 (36%) of these had received some method of VTE prophylaxis. Of those who did not receive pharmacologic prophylaxis, only 3 had a documented contraindication. The most commonly documented contraindications to pharmacologic prophylaxis pertained to risk of bleeding, and included uncorrected coagulopathy, ongoing/uncontrolled hemorrhage and thrombocytopenia. The median time between admission and VTE event was 9 days. Conclusion: There is a high rate of recurrent VTE in hospitalized children with a history of prior VTE. These results underscore the significance of implementing consistent pharmacologic prophylaxis in high-risk children where appropriate. As the landscape is actively changing in terms of available anticoagulant formulations available for children, providers may feel more confident in initiating secondary pharmacologic prophylaxis particularly as new data confirm the safety. Nevertheless, ongoing definitive studies are required to better understand which particular factors yield the highest rates of VTE and hence warrant pharmacologic prophylaxis above standard mechanical measures. We want to acknowledge the CHAT Consortium sites who contributed to the CHAT Registry. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Accuracy and Prediction of D-Dimers for Pulmonary Embolism in Patients with COVID-19 Infection

Background: D-dimer values in patients with SARS-2 COVID-19 infection are known to be elevated and have been shown to be a predictor for disease severity, mortality, and venous thromboembolism (VTE). Patients presenting with COVID-19 infection may endorse many of the same symptoms as patients with pulmonary emboli (PE) and the associated elevation of the d-dimer as a component of the inflammatory state has led to unanswered questions regarding the diagnostic utility of d-dimer testing. Methods: Computed tomography (CT) scans of the chest with intravenous contrast were searched from a unified data platform between 1/1/2020 and 5/31/2022 across the Mayo Clinic enterprise. Imaging was matched to patients with COVID-19 if it occurred between 10 days before and 30 days after the laboratory confirmed COVID-19 infection. Next, patients were matched to laboratory records of d-dimer testing within 1 day of the imaging. D-dimer testing was performed using the HemosIL D-dimer HS 500 kit on the Instrumentation Laboratory ACL TOP instrument. A negative result is ≤500ng/ml fibrinogen equivalent units (FEU) with a lower limit of detection of 220ng/ml. The primary outcome was acute PE on the imaging study as determined by a validated natural language processing algorithm. Results: A total of 6,747 d-dimer/CT pairs were examined in 5,971 unique patients with COVID-19. Pulmonary emboli were identified on 7.7% of CTA of the pulmonary arteries (n=6,222), 6.6% of CTA-other (n=241), and 3.9% of CTs with IV contrast (n=284). Patients diagnosed with PE were older (median age 67 vs 61, p<0.001), more likely to be male (60.0% vs 53.8%, p=0.03), white (91.3% vs 87.3%, p=0.02), and have dementia, cancer, hyperlipidemia, or ischemic stroke (Table 1). Median d-dimer values in patients found to have PE was 5432ng/ml compared 941ng/ml in those without PE. A prior history of VTE (by ICD-10 codes) was seen more frequently in the group diagnosed with PE (41.4% vs 6.8%, p =0.03). In the overall group of patients with CT imaging of the chest with some form of intravenous contrast, the sensitivity at the standard d-dimer threshold was 99.2% [negative predictive value (NPV) 99.3%], decreased to 98.0% with the age-adjusted cutoff (NPV 99.0%), and decreased further with an increased d-dimer threshold of 1000ng/ml (NPV 98.5%) (Table 2). Due to the strong association seen between patients with a history of VTE and positive findings of PE with COVID-19 infection, we performed additional sensitivity and specificity testing after excluding patients with prior VTE. Within this group and among CTA of the pulmonary arteries only, the sensitivity of the d-dimer was 99.0% using the standard threshold of 500ng/ml, was 98.4% using the age-adjusted d-dimer cutoff, and was 92.1% at an elevated threshold of 1000ng/ml. The NPV of d-dimer was high irrespective of the threshold used: 1000ng/ml (99.2%), age-adjusted cutoff (99.4%) and standard cutoff (99.3%). Conclusion: This study of COVID-19 positive patients more than doubles the number of patients examining the diagnostic utility of d-dimer in PE diagnosis compared to recent meta-analyses and with a consistent d-dimer methodology performed in close proximity to diagnostic imaging. D-dimer was highly predictive of PE with strong and expected NPVs at standard thresholds and using age-adjusted thresholds. We demonstrate that a higher d-dimer threshold of 1000ng/ml would maintain a very high NPV and overall AUC. A fixed and higher d-dimer threshold in patients with COVID-19 infection with possible PE would significantly reduce the need for CT angiography (by 42%). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Characteristics of Cohort of 113 Patients with Cancer-Associated Non Bacterial Thrombotic Endocarditis

Background: Clinical presentation of cancer-associated non-bacterial thrombotic endocarditis (Ca-NBTE) patients including type of malignancy, cardiac valves involved, type of thrombotic complications and hematological indices is limited to cases reports and one small clinical series. Patients and Methods: An electronic search of Mayo Clinic clinical and laboratory records (03/31/2002-06/30/2022) with subsequent manual review was performed to identify adult patients with echocardiographically detected NBTE, diagnosis of active cancer, no infectious endocarditis or lupus anticoagulant/antiphospholipid antibodies. Results: Ca-NBTE was diagnosed in 113 patients (mean age 63.3±9.7 years, 67.0% female). Majority of our patients had advanced cancer with 94 out of 107 (87.8%) with either stage IV (n=80) or stage III (n=14). Only 3 patients had stage I cancer. The most common origin of malignancy was lung cancer representing 42 cases (37.2%) and pancreatic cancer (n=19, 16.8%) followed by 15 cases (14.1%) of gynecological malignancies (including 9 ovarian, 4 endometrial, and 2 cervical cancers). Eight Ca-NBTE patients (7.1%) had gastrointestinal cancer equally distributed into upper and lower tract. Hematologic malignancy was diagnosed in 7 patients (6.2%) with 3 patients having myeloid malignancy and 4 lymphoid. Five patients in our cohort had two active cancers at the time of Ca-NBTE diagnosis. The predominant histological type of cancer was adenocarcinoma (n=80, 70.8 %). All pancreatic, over 90% of lung, near 90% of gastrointestinal, and almost half of genitourinary cancers were adenocarcinomas. Vast majority of patients had thrombotic complications at the time of diagnosis with 92 (81.4%) patients with embolic complications to the brain, 10 (8.9%) to the spleen, 9 (8.0%) kidney, 6 (5.3) coronary and 3 (2.7%) to the extremities. The platelet count ranged from 10 to 459 x 109/L with almost 50% of patients having thrombocytopenia (<150,000) at the time of Ca-NBTE diagnosis. There were no patients with creatinine clearance less than 30. Prior history of venous thromboembolism was noted in 61 (54.0%) patients of our cohort. Most often affected valve was mitral (n=68) followed by aortic (n=61). Only one heart valve was affected by Ca-NBTE in 93 patients (48 mitral, 42 aortic, and 3 tricuspid). Eighteen patients had Ca-NBTE affecting 2 valves (16 mitral and aortic, 1 mitral and tricuspid) with one patient having all 4 valves involved. Of 104 anticoagulated patients, 76 received low molecular weight heparin, 16 apixaban, 22 unfractionated heparin, 16 warfarin, and 6 rivaroxaban. Conclusion: Ca-NBTE is more common in female patients with underlying pulmonary and pancreatic cancers and will usually present with acute stroke. Mitral valve is the most common involved, but nearly 20% of patients had multiple valves involved. In our cohort most patients were treated with low molecular weight heparin.

External Validation of the Saved Score for Venous Thromboembolism Risk Stratification in Patients with Multiple Myeloma Receiving Immunomodulatory Drugs

Background: High thrombogenicity is a well-established phenomenon in multiple myeloma (MM) and can lead to high morbidity and mortality. The risk of venous thromboembolism (VTE) is particularly elevated in the subset of MM patients treated with immunomodulatory drug (IMiD) containing regimens. The National Comprehensive Cancer Network (NCCN) and International Myeloma Working Group (IMWG) have implemented VTE risk assessment models, and recommend prophylactic anticoagulation based on individual patient, disease, or treatment-related factors specifically for MM patients receiving IMiD. With the recent incorporation of the SAVED (PMID 31319391) scoring system in the NCCN guidelines for VTE risk stratification, we sought to externally validate this risk assessment model and evaluate its predictive ability in our MM patient cohort. Methods: We retrospectively evaluated 501 adult patients with either newly diagnosed or relapsed/refractory MM who were newly initiated on an IMiD-based regimen between 2010 and 2019. Patients already on therapeutic or prophylactic anticoagulation were excluded from the study (aspirin was allowed). The SAVED score was calculated at IMiD initiation according to the following five parameters: surgery within last 90 days (+2), Asian race (-3), prior VTE history (+3), age ≥80 years (+1), dexamethasone use (+2 for high dose [>160 mg/30-day], or +1 for standard dose [120-160 mg/30-day]). Patients with SAVED scores of <2 and ≥2 were considered of low and high risk, respectively, for developing VTE after IMiD initiation. Time to VTE was estimated by Kaplan-Meier failure method. Logistic regression model was used to test components of the SAVED score with 1-year VTE status. Model discrimination was assessed via c statistic by calculating the area under the receiver operating characteristic curve (AUC) with bootstrapped 95% confidence interval (CI). Results: The median age of our cohort at the IMiD initiation was 64 years (range 34-89); 264 (53%) patients were male and 378 (75%) were white. IgG and IgA heavy chain subtypes were present in 280 (56%), and 105 (21%) patients respectively, whereas 110 (22%) patients had light chain disease only. The International Staging System (ISS) was I, II, III, and unknown for 161 (32%), 149 (30%), 136 (27%), and 55 (11%) of patients, respectively. Most patients (94%) received lenalidomide, whereas 14 (3%) and 15 (3%) patients were treated with thalidomide and pomalidomide, respectively. The distribution of SAVED covariates is shown in Table 1. The cumulative incidence of VTE at 12-month after IMiD initiation for the entire cohort was 16% (95% CI: 13-20%). Among the 84 patients who developed new VTE after IMiD initiation, 60 (71%) had lower extremity deep venous thrombosis (DVT), 10 (12%) had pulmonary embolism, 9 (11%) had both DVT and PE, and 5 (6%) had upper extremity DVT. The SAVED score stratified 112 patients (22%) as high-risk and 389 patients (78%) as low-risk (similar proportion as the original derivation study). Cumulative incidence of VTE at 6 and 12 months was 31% and 41% in the high-risk group, versus 6% and 9% in the low-risk group, respectively (Figure 1). Each point of SAVED score increase was associated with significantly higher chance of VTE within 1-year post IMiD initiation with excellent discrimination (odds ratio = 2.10 [95% CI 1.71-2.56], c statistic (AUC) = 0.76 [95% CI 0.70-0.81]). Conclusion: Our results successfully externally validated the SAVED model to predict IMiD-associated VTE in a real-life cohort of patients with MM. Patients with SAVED score of ≥2 had significantly higher incidence for VTE. This indicates that more aggressive pharmacologic thromboprophylaxis is needed in this specific patient population. The SAVED score outperformed several other similar VTE prediction models that were also validated in the current cohort (c statistic=0.68 for IMPEDE [PMID: 33997961] and 0.62 for PRISM [PMID: 35772005]). In contrast to other risk models that focused on all patients with MM, the SAVED score was derived and now validated specifically for patients starting IMiD as this it is the only cancer population with a strong guideline recommendation for ambulatory thromboprophylaxis. Future prospective validation would be useful to determine the predictive nature of SAVED while evaluating safety and efficacy of thromboprophylaxis with direct oral anticoagulant in high-risk patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Venous Thromboembolism in Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplant

Introduction: Venous thromboembolism (VTE) is a common complication that could affect multiple myeloma (MM) patients. Previous studies suggested the incidence of VTE in MM patients not on VTE prophylaxis to be as high as 10.7% in the peri-transplant period. Usage of antiplatelet or anticoagulant VTE prophylaxis is often a challenging clinical decision especially in patients with profound thrombocytopenia. Here, we aimed to explore the incidence and risk factors for VTE in MM patients undergoing AHCT. Methods: The electronic medical records of all MM patients who underwent AHCT at Cleveland Clinic between January 1st, 2011 and January 15th, 2021 were reviewed. We evaluated the incidence and type of venous thrombosis occurring in the immediate peri-transplant period, defined as extending from the start of stem cell apheresis up to 30 days post-AHCT. Baseline patient, demographic, disease, and transplant factors were evaluated to analyze risk factors for VTE occurrence within the studied period. Statistical Package for Social Sciences (SPSS) was used for statistical analysis. Results: A total of 493 patients with available records were included in our study. The median age was 61.4 years (range 33.1-77.7 years) at the time of AHCT with a male preponderance of 59%. Symptomatic VTE was recorded in 23 events involving 17 patients (3.5%) within the defined peri-transplant period, of which 34.8% of the events occurred between the start of stem cell apheresis and the date of transplant (i.e. day 0). Around 34.8% of VTE events, involving 6 (35.3%), patients occurred during hospitalization for the transplant procedure. All VTEs were non-catheter related, and most were lower extremity deep venous thromboses (DVT) (52.2%), followed by pulmonary emboli (17.4%), DVT of upper extremities (13%), internal jugular thromboses (13%) and superficial vein thrombosis (4.4%). Of the 17 VTE patients, 41% had history of previous VTE prior to the defined peri-transplant period, 88.2% were recently on immunomodulatory drugs (IMiD), 76.5% were on either antiplatelet (41.2%) or anticoagulant (53%) therapy or both (17.7%), while 23.5% were on none. Most of the VTE patients were never smokers (70.6%), while the rest (29.4%) were ex-smokers. Of note, 35.3% of VTE patients had thrombocytopenia (Platelets <150 x109/L) but median platelet count of 184 x109/L. Patients who developed VTE were of similar age (median 62.1 vs 61.4 years, P=0.9) but had a higher female preponderance (64.7 vs 40.1%, P=0.04) compared to those who did not. In addition, they had similar albumin levels at diagnosis (75 vs 71.7% ≥ 3.5 g/dL, P=0.8), similar cytogenetic risk categorization (high risk in 35.3 vs 25.8%, P=0.4), ISS stages (P=0.5), disease remission status prior to AHCT (P=0.3), mobilization regimens (G-CSF + Plerixafor in 88.2 vs 88.2%, P=0.1), and recent IMiD use (88.2 vs76.7, P=0.26) (Table 1). However, VTE patients were more likely to have IgG MM (70.6 vs 62%, P=0.06), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) ≥1 (100 vs 81.1%, P=0.05), infection at AHCT (12.5 vs 3.2%, P=0.05), longer length of AHCT hospital stay (median 17 vs 14.9 days, P<0.0001), and had higher prevalence of prior history of VTE (41.2 vs 11.6%, P<0.0001) (Table 1). With regards to prophylaxis therapy, VTE patients were less likely to be on antiplatelets (41.2 vs 65.6%, P=0.039), were on similar prophylactic anticoagulation (11.8 vs 19.5%, P=0.42), but were more likely to be on therapeutic anticoagulation (41 vs 14%, P=0.002) compared to non-VTE pts, suggesting a higher impact of a history of prior VTE than therapeutic anticoagulation on recurrence of VTE during the studied time period. Among patients with no history of previous VTE, non-VTE patients were more likely to be on either antiplatelet or prophylactic anticoagulation (82.6 vs 50%, P=0.02). Interestingly, no difference was seen in the incidence of VTE with antiplatelet vs prophylactic anticoagulation in patients without history of previous VTE (1.86 vs 0%, P=0.9). Moreover, among those with a history of previous VTE, the addition of antiplatelets to therapeutic anticoagulation did not significantly lower the risk of VTE recurrence in the studied time period (9 vs 16%, P=0.9). Conclusion: The use of VTE prophylaxis among MM patients undergoing AHCT may lower its incidence. The main risk factors for VTE are female sex, history of previous VTE, infections at AHCT, HCT-CI ≥1, and longer hospital stay. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Management of Antithrombin Deficiency in Pregnancy.

Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. The risk of venous thromboembolism (VTE) is increased in AT-deficient women during pregnancy and the postpartum period and is especially high in women with a prior history of VTE. A thorough assessment of VTE risk is recommended in pregnant AT-deficient women, comprising the degree and type of AT deficiency, genetic mutations, personal and family history, and additional preexisting or pregnancy-specific risk factors. Due to a lack of adequate study data, there is limited guidance on the management of AT deficiency in pregnancy, including the need for prophylactic anticoagulation, the appropriate dose of low-molecular-weight heparin (LMWH), and the role of AT substitution. LMWH is the medication of choice for the pharmacological prophylaxis and treatment of VTE in pregnancy. Patients with a history of VTE should receive full-dose LMWH during pregnancy and the postpartum period. AT concentrates are a treatment option when anticoagulation is withheld in potentially high-risk events such as childbirth, bleeding, or surgery and in cases of acute VTE despite the use of therapeutic dose anticoagulation. Women with AT deficiency should be counseled at specialized centers for coagulation disorders or vascular medicine, and close cooperation between obstetricians and anesthesiologists is warranted before delivery and during the peripartum period.

Acute pulmonary embolism: in hospital outcome from a prospective observational registry (M-PER) from a low-and middle-income country

Abstract Background Acute Pulmonary embolism the third most common cause of cardiovascular death in the world. Despite the large burden of acute pulmonary embolism, there is a paucity of prospective data from low-and middle-income countries. Purpose To study the clinical characteristics, treatment strategies employed, in-hospital outcome, one-year follow up results, and the prognostic factors in patients with acute pulmonary embolism from a low-and middle-income country. Methods All consecutive patients diagnosed with and treated for acute pulmonary embolism at our institution from November 2016 to November 2021 were included in the registry. Pulmonary embolism was diagnosed using clinical features (Wells' criteria of ≥3) supported by either CT angiogram or echocardiogram. Detailed history, clinical examination, preliminary basic blood investigations, cardiac troponins along with coagulation workup, ECG and ECHO were done for all patients. Patients were classified as having massive or high risk, submassive or intermediate risk and low risk pulmonary embolism based hemodynamic status, sPESI score, echocardiogram and cardiac troponins. Treatment was at the discretion of treating physician. In general, all patients with massive pulmonary embolism were considered for thrombolysis. All patients received anticoagulation with unfractionated heparin. Outcomes included hospital lengths of stay, all-cause in-hospital mortality and one year mortality Results 186 patients with acute pulmonary embolism were prospectively enrolled during period. 62% were male. Mean age was 42.38±13.4 years. The risk factors noticed include prior history of venous thromboembolism, active malignancy, recent surgery, trauma, immobilisation, diabetes, hypertension, and chronic obstructive pulmonary disease in 18%, 5%, 10%, 8%, 14%, 17%, 10% and 3% of our patients respectively. Shortness of breath (98%), chest pain (37%), leg swelling (37%), cough (33%), shock (27%), syncope (15%) and haemoptysis (12%) were the reasons for presentation. Sinus tachycardia was the commonest finding (80%). Right ventricular (RV) strain pattern was present in 68%, S1Q3T3 pattern in 56% and RBBB in 32%. RV dilatation was present in 93% and RV dysfunction in 75%. Thrombus was visualised in the pulmonary artery in 37% and right heart chambers in 12% (714). 26% were classified as high risk, 60% as intermediate risk and 13.4% as low risk acute pulmonary embolism. Overall 50% (92% of high-risk and 41% of intermediate risk) patients received fibrinolytic therapy. In hospital mortality was 16% (29 patients) of which 72% were from high-risk group. In the high-risk group those who were fibrinolysed had a lower mortality compared to those not lysed. (75% vs 40%). This difference was not observed in the intermediate risk group. Conclusion Acute pulmonary embolism is a disease with high in-hospital mortality. Fibrinolytic therapy with streptokinase has a lifesaving potential in high risk patients. Funding Acknowledgement Type of funding sources: None.

Routine Postoperative Aspirin for VTE Chemoprophylaxis in Primary Total Ankle Arthroplasty

Category: Ankle Arthritis; Ankle; Other Introduction/Purpose: The use of low-dose aspirin for postoperative venous thromboembolism (VTE) chemoprophylaxis has been widely studied and validated in adult reconstruction surgery with little to no reported adverse reactions. In total ankle arthroplasty (TAA) literature, low-molecular-weight heparin (LMWH) has been the predominant chemoprophylactic agent used, despite little evidence supporting it. To date, no studies have assessed the role of aspirin for VTE chemoprophylaxis after total ankle arthroplasty and no formalized clinical practice guideline exists. The purpose of this study was to evaluate outcomes of a large consecutive series of patients undergoing primary TAA at a single institution, in relation to routine postoperative aspirin administration. Methods: A prospective telephone survey and retrospective chart review was performed of patients undergoing primary TAA at a single institution by two fellowship trained foot and ankle surgeons. All patients were prescribed oral aspirin 81 mg BID for at least 2 weeks postoperatively, (or while weight-bearing was restricted). The primary outcome variable was postoperative development of deep vein thrombosis (DVT), pulmonary embolism (PE), or VTE related mortality within 3 months postoperatively. Venous ultrasounds were also queried. The secondary outcome variable was assessment of aspirin related adverse reaction including delayed wound healing and gastrointestinal (GI) bleeding. Patients with a history of bleeding disorder or history of prior VTE requiring non-Aspirin VTE chemoprophylaxis were excluded. Results: There were 217 patients included for retrospective review, and 81 patients completed the telephone survey (34% response rate). Concomitant procedures included gastrocnemius recession (104), teno-Achilles lengthening (20), ligament repair (17), tendon repair (3), tendon transfer (12), and plantar fasciectomy (1). The cohort included 119 males (54.8%), with a mean age 62.6 +/- 10.3 years (range 24 to 88), and mean BMI 30.6 +/- 5.6 (range 21.3 to 52.6). There were no GI bleeding or VTE events, yet 46/217 (21.2%) cases of delayed wound healing. Eleven patients underwent venous ultrasounds that all were negative. Sex (p=0.458), age (p=0.443), and BMI (p=0.335) were not associated with delayed wound healing, but current/former smoking status trended toward significant association (p=0.077). Time to weight-bearing was mostly bi-modal, between 1.5-3.5 weeks (37.8%) or 5.5-7.5 weeks (45.1%). Time to weight-bearing approached significance with delayed wound healing (p=0.05), which may represent surgeon intervention to promote healing. Conclusion: This study demonstrates effective use of aspirin in preventing VTE events after primary TAA in patients without risk factors for VTE and PE, which is cheaper and more widely available all around the world. Further randomized controlled studies may better elucidate any role of aspirin with regards to delayed wound healing, which had an an approximate incidence of 20% in our cohort. Limitations of the study include those inherent to a retrospective review, such as lack of a control group.