Venous Thrombotic Risk Research Articles

Implications of von Willebrand Factor in Inflammatory Bowel Diseases: Beyond Bleeding and Thrombosis.

Inflammatory bowel disease (IBD) displays an increased venous and arterial thrombotic risk despite the common occurrence of intestinal bleeding. While some of the mechanisms leading to these thrombotic complications have been studied, other specific changes in the hemostasis profile of IBD patients have been less explored. One such example relates to von Willebrand factor (VWF) whose plasma levels have been reported to be modulated in IBD. Von Willebrand factor is a plasma glycoprotein crucial for hemostatic functions via roles both in platelet function and coagulation. High plasma VWF is a known risk factor for venous thromboembolism. In addition to its canonical roles in hemostasis, VWF is known to be directly or indirectly involved in other vascular processes such as maintenance of endothelial barrier integrity or proliferation of vascular smooth muscle cells. The purpose of this review is to recapitulate and update the existing data about VWF biology in IBD and to highlight its role both in the existing procoagulant phenotype and in vascular alterations that may occur in IBD.

High-dose oral contraceptives induce hyperinsulinemia without altering immune activation in diet-induced obesity which persists even following a dietary low-fat diet intervention

Combined oral contraceptives (COCs) are known to cause weight gain and alter metabolic and immunological pathways. However, modifications in arterial or venous thrombotic risk profiles of women of reproductive ages on COC remain unclear. The study aimed at assessing the impact of COC on immune activation in diet-induced obesity. We further established whether the dietary intervention of switching from a high-fat diet (HFD) to a low-fat diet (LFD) attenuates immunological responses. Twenty (n=20) five-week-old female Sprague Dawley rats were randomly divided into two diet groups of HFD (n=15) and LFD (n=5) and were monitored for eight weeks. After eight weeks, animals in the HFD group switched diets to LFD and were randomly assigned to receive high-dose COC (HCOC) or low-dose COC (LCOC) for six weeks. Animals on HFD significantly gained weight and had a higher lee index when compared to the LFD group (p < 0.05). Moreover, the triglyceride-glucose index, insulin, and other metabolic parameters also increased in the HFD group compared to the LFD group (p < 0.001). Consistently, the levels of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), were elevated in the HFD group when compared to the LFD group (p < 0.05). Upon switching from a high-fat to a low-fat diet, insulin levels persistently increased in animals receiving HCOC treatment compared to the LFD and HFD/LFD groups (p < 0.05). Thus, in a rat model of HFD-feeding, short-term HCOC treatment induces long-term metabolic dysregulation, which persists despite dietary intervention. However, further studies are recommended to confirm these findings.

Performance of ChatGPT as an AI-assisted decision support tool in medicine: a proof-of-concept study for interpreting symptoms and management of common cardiac conditions (AMSTELHEART-2)

Background It is thought that ChatGPT, an advanced language model developed by OpenAI, may in the future serve as an AI-assisted decision support tool in medicine. Objective To evaluate the accuracy of ChatGPT’s recommendations on medical questions related to common cardiac symptoms or conditions. Methods We tested ChatGPT’s ability to address medical questions in two ways. First, we assessed its accuracy in correctly answering cardiovascular trivia questions (n = 50), based on quizzes for medical professionals. Second, we entered 20 clinical case vignettes on the ChatGPT platform and evaluated its accuracy compared to expert opinion and clinical course. Lastly, we compared the latest research version (v3.5; 27 September 2023) with a prior version (v3.5; 30 January 2023) to evaluate improvement over time. Results We found that ChatGPT latest version correctly answered 92% of the trivia questions, with slight variation in accuracy in the domains coronary artery disease (100%), pulmonary and venous thrombotic embolism (100%), atrial fibrillation (90%), heart failure (90%) and cardiovascular risk management (80%). In the 20 case vignettes, ChatGPT’s response matched in 17 (85%) of the cases with the actual advice given. Straightforward patient-to-physician questions were all answered correctly (10/10). In more complex cases, where physicians (general practitioners) asked other physicians (cardiologists) for assistance or decision support, ChatGPT was correct in 70% of cases, and otherwise provided incomplete, inconclusive, or inappropriate recommendations when compared with expert consultation. ChatGPT showed significant improvement over time; as the January version correctly answered 74% (vs 92%) of trivia questions (p = 0.031), and correctly answered a mere 50% of complex cases. Conclusions Our study suggests that ChatGPT has potential as an AI-assisted decision support tool in medicine, particularly for straightforward, low-complex medical questions, but further research is needed to fully evaluate its potential.

An update on anti-protein Z antibodies

Protein Z (PZ) is a vitamin K-dependent protein that acts as a cofactor for the inhibition of activated factor X by the PZ-dependent protease inhibitor, an anticoagulant protein of the serpin superfamily. The presence of antibodies against PZ (aPZ-Abs) was first described in women with unexplained recurrent embryo loss, pre-eclampsia, or foetal death, independently from habitual antiphospholipid/anti-cofactor antibodies. Other studies suggested that aPZ-Ab could be associated with a small birthweight for the gestational age. The mechanism of action of these antibodies is not yet understood. At this time, even aPZ-Abs are frequently observed in patients with lupus anticoagulant or anticardiolipin antibodies, there is no evidence that aPZ-Abs increase systemic venous or arterial thrombotic risk. The comparison of the various published studies shows that the threshold suggesting an obstetric risk is not clearly defined. At present, it is not known whether one isotype of immunoglobulin (G or M, or both) is particularly involved in certain obstetric manifestations, or these antibodies persist during time, or can be induced by infectious diseases. Consequently, detection of these antibodies is not routinely warranted and should only be performed in randomized clinical trials.

Secondary Polycythemia Associated with COVID-19 Is Associated with Higher Mortality but Does Not Seem to Affect Thrombotic Risk

Introduction Reactive polycythemia (without presence of a chronic myeloproliferative neoplasm (MPN)) is commonly observed among patients with chronic pulmonary disease, whereas its significance in the context of COVID-19 is less well known. We aimed to investigate to what extent might polycythemia at the time of hospital admission affect outcomes of acutely ill COVID-19 patients. Methods We retrospectively evaluated a total of 5872 consecutive hospitalized COVID-19 patients treated in a tertiary referral center, UH Dubrava Zagreb, Croatia, in period 3/2020-6/2021. All patients were of white race and adults. All patients were tested positive for SARS-CoV-2 with either PCR or antigen test in the presence of compatible clinical symptoms. Patients with missing laboratory or clinical information or with prior or subsequently proven MPN were excluded from analysis. Hemoglobin threshold levels defined by the World health organization (WHO) criteria for diagnosis of anemia and the 2008 and 2016 WHO criteria for diagnosis of polycythemia vera (PV) were used to stratify patients into four subgroups (anemia, normal hemoglobin values, 2016 but not 2008 WHO polycythemia vera (PV), and 2008 WHO PV hemoglobin criteria fulfilling patients). Patients were evaluated in regard to baseline clinical characteristics, in hospital mortality, venous (VTE), arterial thrombosis and major bleeding. Due to non-normal distribution, numerical variables were presented as median and interquartile range (IQR). The Kruskal Wallis ANOVA, the chi squared test and the logistic regression were used. P values &amp;lt;0.05 were considered statistically significant. All analyses were performed using the MedCalc statistical software version 22.007 (MedCalc Software Ltd, Ostend, Belgium). Results A total of 5872 COVID-19 patients were analyzed. There were 2575 (43.9%) female and 3297 (56.1%) male patients. Median age was 72 years, median Charlson comorbidity index was 4 points. A total of 4166 (70.9%) patients presented with severe and 897 (15.3%) with critical intensity of COVID-19 symptoms. Median hemoglobin level at the time of admission was 128 g/L, IQR (114-141). A total of 3082 (52.5%) patients presented with normal hemoglobin levels, 2607 (44.4%) with anemia, 158 (2.7%) fulfilled 2016 but not 2008 WHO PV hemoglobin criteria and 25 (0.4%) fulfilled 2008 WHO PV hemoglobin criteria. Patients presenting with polycythemia in comparison to those with normal hemoglobin values were significantly older, were more likely to be of male sex, had higher Charlson comorbidity index, higher leukocytes, lower platelets, higher intensity of COVID-19 symptoms, required higher intensity of oxygen supplementation both at the admission and later during hospitalization (P&amp;lt;0.05 for all analyses). Figure 1 depicts the relationship of belonging to different hemoglobin categories with clinical outcomes. Patients presenting with anemia (OR 1.42, P&amp;lt;0.001), WHO 2016 grade (OR 1.63, P=0.003) and WHO 2008 grade polycythemia (OR 4.98, P&amp;lt;0.001) had increased risk of mortality in comparison to patients presenting with normal hemoglobin values. Anemia was associated with higher VTE (OR 1.34, P&amp;lt;0.006) and major bleeding risk (OR 2.27, P&amp;lt;0.001) in comparison to normal hemoglobin values, whereas no significant association of polycythemia with venous or arterial thrombotic or major bleeding risk was observed. Relationship of anemia, WHO 2016 and WHO 2008 grade polycythemia with increased mortality remained significant after adjusting analyses for age, sex, Charlson comorbidity index, COVID-19 severity and need for mechanical ventilation, all independently predicting inferior outcome (P&amp;lt;0.05 for all analyses). Conclusion Secondary polycythemia in non-MPN COVID-19 patients is associated with high mortality, increasing with higher degree of polycythemia, but does not seem to affect thrombotic or major bleeding risk in comparison to normal hemoglobin values. These observations might help in understanding risks associated with polycythemia and increased blood viscosity in the context of other respiratory diseases. These findings might also translate into the context of MPN and COVID-19, suggesting that blood cells other than erythrocytes might play a more important role regarding thrombotic risk. Future studies are warranted.

Venous and arterial thromboembolic risk of Janus kinase inhibitors: a systematic review with meta-analysis.

Preliminary data led licencing authorities to alert clinicians of an increased venous thrombotic risk associated to the use of Janus kinase (JAK) inhibitors (JAKi). We performed a systematic review to estimate the risk of venous and arterial thrombosis associated to JAKi for the treatment of immune-mediated inflammatory diseases (IMIDs). Randomized controlled trials (RCTs) on JAKi in patients with IMIDs were identified by the MEDLINE and EMBASE databases until October 2021. Risk of bias was assessed according to Cochrane criteria. The beta-binomial model was applied to calculate pooled odds ratio (OR) and corresponding 95% CI. The PROSPERO registration number is CRD42022324143. We have included one phase I, 21 phase II, three phase II-III and 36 phase III RCTs for a total of 19 443 patients in the JAKi group and 6354 in the control group. Thirty-one (unweighted rate 0.16%; 95% CI: 0.10, 0.21) events were reported in the JAKi group and 20 (unweighted rate 0.22%; 95% CI: 0.12, 0.32) in the control group in a mean follow-up of 16.8 weeks. IMID patients treated with JAKi did not have an increased thromboembolic risk compared with those treated with placebo (OR 0.82; 95% CI: 0.43, 1.56). No statistically different results were seen in subanalyses for each investigated IMID, drug and dosage. JAKi do not increase thromboembolic risk compared with placebo in IMID patients enrolled in selected RCTs.

Neutrophil to Lymphocyte Ratio (NLR) at Diagnosis Is a Predictor of Venous Thrombosis and Poor Outcome in Patients with Prefibrotic Primary Myelofibrosis

Background Thrombosis is a common complication in patients (pts) with myeloproliferative disease: it represents the product of a dysfunctional interaction between erythrocytes, platelets, leukocytes and endothelium. A pro-inflammatory microenvironment appears to be associated with an increased thrombotic risk. Neutrophil-to-lymphocyte ratio (NLR) reflects the balance between systemic inflammation and immunity and is emerging as a prognostic biomarker in several diseases, including hematological ones. Recently Carobbio et al. [BCJ, 2022] described NLR as a predictor of venous thrombosis in Polycythemia Vera. No score was specifically developed to assess thrombotic risk in myelofibrosis (MF), and even less is known in the setting of prefibrotic primary myelofibrosis (pre-MF). Aims In a multicenter cohort of pre-MF pts, we retrospectively investigated the relationship between NLR values at diagnosis and the risk of: 1) thrombosis 2) disease progression into overt-MF, accelerated (AP) or blast phase (BP); 3) overall survival (OS). Methods We collected clinical, histopathological and hematological data of 176 pts with a diagnosis of pre-MF, revised according to 2016 World Health Organization criteria, followed at 4 Hematological Centers between 2002 and 2022. NLR values were calculated using data obtained from the complete blood count at diagnosis, as the ratio between absolute neutrophilic count (ANC) and absolute lymphocyte (ALP) count. Pts were dichotomized using the best threshold identified by ROC analysis. Thrombotic complications included arterial (ischemic stroke, myocardial infarction, peripheral arterial disease) and venous (deep vein thrombosis, pulmonary embolism, cerebral and splanchnic vein thrombosis) events. Thrombosis-free survival (TFS) and OS were determined from pre-PMF diagnosis to the first thrombotic event and to death or last contact, respectively. TFS/OS were estimated by Kaplan-Meier analysis; the log-rank test was used to compare TFS/OS differences between risk stratified groups. Results Overall, 176 pts were included in this study. Median age was 63.6 (range 25-80) years; 88 (50%) were male. Majority of pts were JAK2V617F mutated (76,1%). Median NLR value at diagnosis was 3 (range 0,64-41,5). By ROC analysis, 6 was identified as the best cut-off value to dichotomize pts based on NLR; 23 pts (13%) presented NLR >6 at diagnosis. A major thrombotic event occurred before or at diagnosis in 53 pts (30,1%): 29 arterial and 25 venous (one patient had both a venous and arterial event). During the follow-up (FU), 30 pts (17%) developed a thrombosis, for a total of 38 thrombotic events (20 venous and 18 arterial events, accounting for an incidence rate of 1,67 and 1,50 per 100 pts-year, respectively). In statistical analysis, factors significantly associated to thrombosis during the FU were previous thrombosis (p=0.05) and JAK2 V617F mutation (p=0.03). Total leucocyte and platelets count, as well as age, sex and IPSET thrombosis score did not correlate with thrombotic events. Pts with ANC > 9 x10^9/L or ALP count < 1,5x10^9/L at diagnosis showed a trend towards a greater incidence of thrombosis in FU (p=0.06 and p=0.07, respectively). Pts with NLR value > 6 at diagnosis had a significantly higher incidence of venous thrombotic events (p=0.03) and a shorter venous TFS (p=0.004, Figure 1) compared to patients with NLR <6. The NLR value was not predictive of arterial thrombotic risk. After a median FU of 6.14 years (range 0,5-27,96) years, 32 pts (18,2%) died; 22 pts (12,5%) had disease progression: of them, 13 (7,4%) experienced overt MF and 9 (5,1%) evolved into an AP or BP. Pts with NLR value > 6 at diagnosis had a significant shorter OS compared to the group with NLR <6 (median OS 4,93 vs 6,22 months respectively, p=0.02). Conclusions This multicenter study investigated for the first time whether the NLR value at diagnosis could be a predictive marker of thrombotic risk and poor outcome in pre-PMF setting. Previous thrombosis and JAK2V617F mutation are confirmed to be risk factors for thrombotic events also in pre-MF setting. Notably, NLR > 6 at diagnosis emerged as a simple marker to identify pts at higher risk of thrombosis and poor outcome in the pre-PMF setting: pts with a NLR value > 6 have a significantly higher venous thrombotic risk and a shorter venous TFS. Furthermore, NLR group > 6 appears to have a shorter OS. These data are promising but require to be confirmed on a larger scale. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venous and Arterial Thrombosis Following Abemaciclib Therapy for Metastatic Breast Cancer

▪Introduction:Over the past several years, inhibitors of cyclin-dependent kinases 4 and 6 (CDK 4/6) have revolutionized the treatment of hormone receptor (HR)-positive breast cancer. However, evidence suggests an increased risk of venous thromboembolism (VTE) with use of these agents. Recent studies additionally suggest higher VTE rates in real-world populations receiving palbociclib as compared with the highly selected population of published clinical trials. Such study in real-world patients has not been performed for abemaciclib, a newer CDK 4/6 inhibitor with unique pharmacokinetic and pharmacodynamic properties. This study evaluated rates and predictors of thrombosis in patients receiving abemaciclib for metastatic breast cancer.Methods:We conducted a multicenter observational cohort study of patients with metastatic breast cancer receiving abemaciclib at 5 affiliated hospitals. A research patient data repository was queried to identify all patients receiving abemaciclib and manual chart review was used to extract all data. Patient demographics, concurrent medications, labs, Khorana risk score, tumor characteristics, and relevant venous and arterial thrombotic risk factors (including age, BMI, prior thrombosis, recent surgery, hereditary thrombophilia, systemic inflammatory diseases, presence of brain metastases, hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation, heart failure, and atherosclerosis) were collected for all patients. The primary endpoint was thrombosis during abemaciclib treatment or within 30 days of discontinuation. Multivariable logistic models assessed predictors of VTE and a multivariable Cox proportional hazards model was used to compare mortality in patients developing VTE with those who did not. Data are presented as median (IQR) or number (%).Results:Patient Cohort and Thrombosis Risk Factors. 364 patients were included in the analysis. 360 (98.9%) patients were female, with median (interquartile range) age of 61 (53-71) years. 320 (88.7%) were post-menopausal and 291 (79.9%) were concurrently on endocrine therapy (of which 19 (5.2%) were on tamoxifen). At the time of abemaciclib initiation, 51 (14.0%) were receiving long-term anticoagulation and 47 (12.9%) were receiving aspirin. Khorana scores were between 0-3 with 339 (93.1%) patients having a score of 0 or 1. 267 (73.4%) and 46 (12.6%) were diagnosed with invasive ductal and lobular carcinoma, respectfully. Brain metastases were present in 71 (19.5%) patients. Venous and arterial thrombosis risk factors for this cohort are highlighted in TABLE 1. The median duration of abemaciclib therapy was 5.5 (2.8-13.0) months and median duration of follow-up was 12.7 (6.2-22.1) months.Thrombotic Events. 27 patients (7.4%) developed one or more thrombotic event (17 VTE, 9 arterial thrombosis, 1 both). Events are described in TABLE 2.Risk Factors for VTE. In a multivariable logistic model including age, race, BMI, receipt of long-term anticoagulation, receipt of aspirin, brain metastases, Khorana risk score, receipt of tamoxifen, prior VTE, systemic autoimmune disease, and known thrombophilia, HER2 positivity was predictive of VTE during or after abemaciclib treatment (odds ratio 5.20, 95% CI 1.29-20.93, P=0.020).Association of VTE with Mortality. In a multivariable Cox model controlling for age, race, HER2 status, receipt of long-term anticoagulation, receipt of aspirin, brain metastases, Khorana risk score, receipt of tamoxifen, prior VTE, systemic autoimmune disease, and known thrombophilia, patients developing VTE during abemaciclib therapy had a significantly higher risk of death (hazard ratio, 2.04, 95% CI, 1.03-4.01, P=0.040), FIGURE 1. Median survival in patients developing a VTE vs. those who did not was 9.6 months vs. 25.8 months, respectively.Conclusions:In this study, we provide the first real-world data describing risk of venous and arterial thrombosis in a large cohort of patients with metastatic breast cancer treated with the CDK 4/6 inhibitor abemaciclib. As the role of abemaciclib continues to expand both within and beyond the metastatic disease setting, understanding the VTE risk of this agent has become critical. Thrombosis occurred in 7.4%, and in multivariable models controlling for relevant covariates, HER2 positivity predicted for development of VTE, and patients developing VTE had an approximate 2-fold risk of mortality. [Display omitted] DisclosuresAl-Samkari: Moderna: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Rigel: Consultancy; Argenx: Consultancy; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

Venous Thromboembolism Prophylaxis and Thrombotic Risk Stratification in the Varicose Veins Surgery-Prospective Observational Study.

Background: An invasive phlebological treatment is still not free from complications such as thrombosis. As in other surgical populations, not only the treatment modality, but also patient condition-related venous thromboembolism (VTE) risk factors matter. The current protocols used in varicose vein surgery centers are based mostly on individual risk assessment as well as on an implementation and extrapolation of general surgery VTE prophylaxis guidelines. In the presented study, the efficacy of routine VTE pharmacological thromboprophylaxis in patients undergoing saphenous varicose vein surgery was prospectively evaluated. In the result assessment, VTE risk factor evaluation and Caprini score results were included; however, due to the limited size of the projected study group, as well as expected limited deep vein thrombosis (DVT) prevalence in this clinical scenario, it was not possible to perform the validation of the Caprini model efficacy in the projected study model. Methods: In the study, 141 patients undergoing saphenous vein stripping and miniphlebectomy in spinal anesthesia were included. In all of the patients, VTE risk factors (including Caprini score evaluation) were assessed, and the routine thromboprophylaxis with enoxaparin 40 mg for 10 days was used. The venous ultrasounds were undertaken before the surgery and on the 10th and 30th day after surgery. The study endpoint was the presence of symptomatic or asymptomatic DVT confirmed in the imaging study. The study safety endpoint was major bleeding occurrence intraoperatively or within 30 days after surgery. Results: The presence of a postoperative DVT was diagnosed in five cases (3.5%) In all of these cases, only distal DVT was confirmed. Despite extensive saphenous varicose vein surgery with stripping and miniphlebectomy performed in nontumescent but spinal anesthesia, no proximal lower leg episode was diagnosed. Three out of five DVT cases were diagnosed on day 10 postoperative control, while a further two were confirmed in the ultrasound examination performed 30 days after procedure. No clinically documented pulmonaly embolism (PE) as well as no bleeding episodes were noticed. Among the factors related to the statistically significant higher DVT occurrence, the results of the Caprini score were identified with odds ratio (OR) = 2.04 (95% CI = (0.998; 4.18)). Another factor that became statistically significant in terms of the higher postoperative DVT prevalence was the reported Venous Clinical Severity Score (VCSS) results (OR = 1.98; 95% CI (1.19; 3.26)). In the multiple logistic regression analysis, the patient age (OR = 0.86; 95% CI (0.75–0.99)), Caprini score evaluation results (OR = 4.04; 95% CI (1.26–12.9)) and VCSS results (OR = 2.4; 95% CI (1.23–4.7)) were of statistical significance as predictors for postoperative DVT occurrence, with a p value of 0.029 for age, and p = 0.017 and p = 0.009 for Caprini score results and VCSS results, respectively. Due to the confirmed limited number of the DVT events in our study cohort, as well as the descriptive and explorative nature of the achieved results, the final clinical potential and significance of the identified parameters, including Caprini score rate and VCSS rate, should be interpreted with caution and studied in the further trials in these clinical settings. Conclusion: All the patients undergoing varicose vein surgery should undergo VTE risk evaluation based on the individual assessment. In VTE risk evaluation, patient and surgical procedure characteristics based on the factors included into the Caprini score but also on specific chronic venous disease-related factors should be taken into consideration. Further studies are needed to propose an objective and validated VTE risk assessment model, as well as a validated antithrombotic prophylaxis protocol in this particular patient group.

JAK2 V617F Prevalence Study: Associations in the General Population and Vascular Disease Populations

Introduction Clonal hematopoiesis (CH) is defined as an expansion of blood stem cell clones that bear advantageous somatic mutations. JAK2V617F is not only the most common mutation association with MPN, it is the fifth most common lesion implicated in CH. While the JAK2V617F positive MPN are rare diseases, CH occurs at relatively common rates in the aging population. CH carriers, and in particular JAK2V617F CH carriers, similar to MPN patients, are at increased risk of developing blood cancers, and arterial and venous thromboses. While many large-scale general population studies have examined prevalence of JAK2V617F CH, a comprehensive assessment of associations to disease has not been performed. Methods We identified all published studies that evaluated the prevalence of the JAK2V617F and CALR exon 9 mutations in the general population and in vascular disease risk populations. We used PUBMED, EMBASE, and SCOPUS databases. Two reviewers independently performed study selection and extracted study characteristics. Studies were included if they met the following criteria : analysis of JAK2/CALR mutations was performed according commonly accepted criteria and study inclusion of at least 40 patients. Results We identified 5793 abstracts/manuscripts that met our search criteria. After title/abstract review, 104 manuscripts were included in the meta-analysis (Figure 1). Thirteen of these studies examined the prevalence of JAK2V617F and CALR exon 9 mutations in a general, unselected population. Among 546,504 participants included in these studies, 1,850 (0.34%) were positive for the JAK2V617F mutation. In contrast, 32 out of 19,958 (0.16%) were positive for CALR exon 9 mutations. In the general population, the JAK2V617F mutation was most commonly associated with male sex, increased age, and smoking. Three studies reported increased blood counts, predominantly platelets and white blood cells. Four studies noted an increased risk of MPN or hematologic cancer in those with the JAK2V617F mutation. The JAK2V617F mutation was associated with an increased risk of venous thrombosis in 3 studies and ischemic heart disease/MI in 2 studies. JAK2V617F variant allele fraction (VAF) when reported ranged 0.004% to 86%. The prevalence of the JAK2V617F in patients with venous or arterial vasculopathy was examined in 91 studies with a total of 35,982 participants. Of these, 26,279 individuals had a history of thrombotic disease and 8,944 were controls. Of the participants with a history of any type of vascular disease, 1,279 (4.9%) were noted to have the JAK2V617F mutation with VAF, when reported, ranging from 0.2-96.2%. On subgroup analysis, patients with splanchnic vein thrombosis had the highest prevalence of the JAK2V617F mutation (18.7%) followed by patients with ischemic stroke (8.5%) and cerebral vein thrombosis (6.0%) (Table 1). The prevalence of the JAK2V617F mutation in patients with DVT/PE and peripheral arterial disease (PAD) was 1.6% and 3.1% respectively. The prevalence of JAK2V617F among all of the vascular disease subsets was substantially higher than the control populations. Similarly, the prevalence of CALR was noted to be high in studies of splanchnic vein thrombosis and cerebral vein thrombosis. (Table 2). Conclusions JAK2V617F and CALR mutations are associated with alterations of blood counts and thrombosis. Even at very low VAF, JAK2V617F is a thrombosis risk factor in the general population and is over-represented in populations with thrombosis. In every thrombosis group, the prevalence in JAK2V617F in thrombosis patients was higher than that in the control population, suggesting the JAK2V617F mutation may contribute to both arterial and venous thrombotic risk, whether in the MPN or CH population context. Disclosures Naik: Elsevier: Consultancy; Rigel: Research Funding. Moliterno:Pharmessentia: Consultancy; MPNRF: Research Funding.

Serum Metabolome Changes in Relation to Prothrombotic State Induced by Combined Oral Contraceptives with Drospirenone and Ethinylestradiol

The association between hypercoagulability and use of drospirenone (DRSP) and ethinylestradiol (EE) containing combined oral contraceptives (COCs) is an important clinical concern. We have previously reported that the two formulations of DRSP combined with EE (namely, DRSP/20EE and DRSP/30EE) bring about a prothrombotic state in hemostatic traits of female users. We report here the serum metabolomic changes in the same study cohort in relation to the attendant prothrombotic state induced by COC use, thus offering new insights on the underlying biochemical mechanisms contributing to the altered coagulatory profile with COC use. A total of 78 healthy women participated in this study and were grouped as follows: control group not using oral contraceptives (n = 25), DRSP/20EE group (n = 27), and DRSP/30EE group (n = 26). Untargeted metabolomics revealed changes in amino acid concentrations, particularly a decrease in glycine and an increase in both cysteine and lanthionine in the serum, accompanied by variations in oxidative stress markers in the COC users compared with the controls. Of importance, this study is the first to link specific amino acid variations, serum metabolites, and the oxidative metabolic profile with DRSP/EE use. These molecular changes could be linked to specific biophysical coagulatory alterations observed in the same individuals. These new findings lend evidence on the metabolomic substrates of the prothrombotic state associated with COC use in women and informs future personalized/precision medicine research. Moreover, we underscore the importance of an interdisciplinary approach to evaluate venous thrombotic risk associated with COC use.

Impact of ALK Rearrangement on Venous and Arterial Thrombotic Risk in NSCLC.

Clinical venous thromboembolism (VTE) risk prediction scores, such as the Khorana Risk Score, perform poorly in NSCLC, possibly because the tumor molecular subtype is omitted. Previous studies suggest a possible increased VTE risk in ALK-rearranged NSCLC, but data are conflicting. We performed a retrospective cohort study of patientswith advanced-stage NSCLC diagnosed between 2009 and 2019. Multivariable, time-to-event analyses modeling the risk of first venous or arterial thrombosis in ALK and non-ALK NSCLC groups, controlling for covariates known to impact thrombosis risk (15 in VTE model and 17 in arterial thrombosis model), were performed using Cox proportional hazards regression and competing-risks regression. Multivariable negative binomial regression modeled the total VTE rate. A total of 422 patients with ALK-rearranged and 385 patients with non-ALK-rearranged NSCLC were included. Patientswith an ALK rearrangement were younger, had better performance status, and had lower rates of most thrombotic risk factors but had significantly higher rates of initial VTE (42.7% versus 28.6%, p < 0.0001), recurrent VTE (13.5% versus 3.1%, p < 0.0001), and similar rates of arterial thrombosis (5.0% versus 4.4%, p = 0.71) compared with non-ALK NSCLC. VTE risk attributable to ALK was significant (Coxmodel: hazard ratio 3.70, [95% confidence interval [CI]: 2.51-5.44, p < 0.001], competing risks: subhazard ratio 3.91 [95% CI: 2.55-5.99, p < 0.001]). Negative binomial modeling revealed higher VTE rates in patients with an ALK rearrangement (incidence rate ratio 2.47 [95% CI: 1.72-3.55, p < 0.001]). The OR for recurrent VTE was 4.85 (95% CI: 2.60-9.52, p < 0.001). Arterial thrombosis risk attributable to ALK was significant (Cox model: hazard ratio 3.15 [95%CI: 1.18-8.37, p= 0.021], competing risks: subhazard ratio 2.80 [95% CI: 1.06-7.43, p= 0.038]). In time-to-event analyses controlling for thrombosis risk factors, the ALK rearrangement conferred a fourfold increase in VTE risk and a threefold increase in arterial thrombosis risk in NSCLC. These patients may benefit from pharmacologic thromboprophylaxis.

The Peri-Operative Management of Anticoagulants: Systemic Review of Guidelines

Introduction Venous thromboembolism (VTE) and atrial fibrillation are thrombotic disorders resulting in significant morbidity and mortality, if left untreated. In Canada, 45,000 people, or 1-2 cases per 1000 people, per year will experience an acute VTE, and it is estimated that 200,000 Canadians have atrial fibrillation. The treatment of VTE and atrial fibrillation often includes the use of anticoagulants. Patients on anticoagulation may need interruption of treatment for surgeries and procedures. To evaluate differences in perioperative anticoagulation management strategies we conducted a systematic review of the peri-operative clinical practice guidelines for anticoagulants. Methods A protocol using the Preferred Reporting Items for Systematic review and Meta-analysis Protocols (PRISMA-P) was developed. Relevant primary clinical practice guidelines were identified using MEDLINE, EMBASE, and guideline-specific databases. All guidelines from the preceding 20 years up to January 11, 2019 were screened. Eligible manuscripts were reviewed by two independent reviewers. Data abstraction was independently completed in duplicate for included guidances and categorized according to thrombotic risks and bleeding risks. Guidances on emergency surgeries were not included for the purposes of this review. Information on anticoagulation interruption, bridging regimens, laboratory testing, and reversal strategies were collected. Results Eight guidelines met inclusion criteria and 6 contained sufficient information for peri-operative management of anticoagulants. One guideline focused on patients presenting with bleeding events and restated the same peri-operative guidelines as had been published a year prior by the same group, and was excluded. Another guideline only addressed emergency surgeries and was also excluded from this review. The majority of the guidelines had similar definitions of risk factors for venous and arterial thrombotic events (see table 1). There were no conflicting guidance recommendations identified, but there were differences in the component of peri-operative management addressed by each guideline, ie bridging, reversal agents, laboratory tests. The levels of evidence used to develop recommendations varied between guidelines. All guidelines provided recommendations on warfarin and low molecular weight heparins (LMWH) management and only one guideline provided suggestions for direct oral anticoagulants (DOACs). The findings for perioperative anticoagulation management for patients with atrial fibrillation and VTE are presented in Tables 2 and 3, respectively. For high bleeding risk surgeries, most guidelines cited similar studies resulting in similar recommendations for interruption of warfarin and bridging in high venous and arterial thrombotic risk patients. In high bleeding risk procedures and low thrombotic risk patients, no bridging is recommended. For low bleed risk procedures, regardless of thrombotic risk, guidelines recommended for continuation of anticoagulant therapy. Discussion This systematic review identified 6 guidelines of non-urgent peri-operative management recommendations of primarily warfarin and LMWH in patients with VTE and atrial fibrillation. While no major discrepancies in the guideline suggestions were noted, the scope of data examined (medication management, bridging, blood tests, reversal of agents) differed amongst the various agencies. The guidelines that were most consistent for recommendations of anticoagulant management and bridging tended to be from hematologic societies. The only guideline that addressed perioperative management of DOACs was the 2018 ASH guideline on management of VTE which was against measurement of DOAC levels prior to procedures. The lack of thorough guidance for DOACs is likely due to the year of publication of the guidelines examined and paucity of contributing studies. In terms of reversal agents, all clinical practice guidelines except for the ASH guidelines were prior to specific DOAC reversal agents such as idaracizumab. Future Directions We anticipate that there will be other guidelines developed that address specifically the use of DOACs in the perioperative setting, as well as their reversal agents. Disclosures Shivji: BMS-Pfizer Thrombosis Canada: Other: Fellowship award. Castellucci:BMS: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Sanofi: Honoraria; Aspen: Honoraria; Servier: Honoraria.

VAMP8 and serotonin transporter levels are associated with venous thrombosis risk in a Spanish female population. Results from the RETROVE Project

IntroductionPlatelet hyper-reactivity has been associated with thrombosis and high levels of human vesicle-associated membrane protein 8 (VAMP8) and serotonin transporter (SERT). Two polymorphisms (rs1010 of VAMP8 gene and in SERT gene (SLC6A4)) are associated with arterial thrombosis. AimTo determine if levels of serotonin, SERT and/or VAMP8 and these polymorphisms are associated with the risk of venous thrombosis. Material and methodsA total of 324 individuals were included in the RETROVE Study (Riesgo de Enfermedad TROmboembólica VEnosa).VAMP8, SERT and serotonin were determined by ELISA; polymorphisms of SLC6A4 and VAMP8 by polymerase chain reaction (PCR) and real time PCR. The venous thrombotic risk was calculated by a logistic regression method to estimate the crude and adjusted OR (adjusted for sex, age, body mass index and venous thrombosis risk co-factors). ResultsStatistically significant high levels of VAMP8 and SERT were found in patients, but not in controls. In contrast, serotonin showed lower levels in patients than in controls. When individuals were studied by gender, only women exhibited a statistically significant difference: the OR for VAMP8 was 3.25 (1.61–6.56 95% CI). The adjusted OR did not change. The OR for SERT was 2.76 (1.36–5.60 95% CI), the adjusted OR was maintained also. For serotonin with OR of 2.62 (1.40–4.92 95% CI), the adjusted OR was not significant. In contrast males did not show significant differences.No statistically differences between patients and controls were found for both polymorphisms. ConclusionsVAMP8 and SERT levels are associated with venous thrombosis in a female Spanish population.

Thrombotic Risk from Chemotherapy and Other Cancer Therapies.

Cancer patients have an increased risk of thrombosis. The development of cancer thrombosis is dependent on a number of factors including cancer type, stage, various biologic markers, and the use of central venous catheters. In addition, cancer treatment itself may increase thrombotic risk. Tamoxifen increases the risk of venous thromboembolism (VTE) by two- to sevenfold, while an impact on risk of arterial thrombosis is uncertain. Immunomodulatory imide drugs (IMiDs) such as thalidomide and lenalidomide increase the risk of VTE in patients with multiple myeloma (MM) by about 10-40% when given in combination with glucocorticoids or other chemotherapy agents; the risk of VTE in MM patients treated with IMiD-containing regimens necessitates that such patients receive thromboprophylaxis with aspirin, low-molecular-weight heparin, or warfarin. Among cytotoxic chemotherapy agents, cisplatin, and to a lesser extent fluorouracil, has been described in association with thrombosis. L-asparaginase in treatment of acute lymphoblastic leukemia is significantly associated with increased thrombosis particularly affecting the CNS, which may be due to acquired antithrombin deficiency; at some centers, plasma infusions or antithrombin replacement is used to mitigate this. Bevacizumab, an inhibitor of vascular endothelial growth factor, increases arterial and possibly venous thrombotic risk, although the literature is conflicting about the latter. Supportive care agents in cancer care, such as erythropoiesis-stimulating agents, granulocyte colony stimulating factor, and steroids, also have some impact on thrombosis. This review summarizes the mechanisms by which these and other therapies modulate thrombotic risks and how such risks may be managed.

Single-Center Retrospective Review of Radiofrequency Wire Recanalization of Refractory Central Venous Occlusions

PurposeTo retrospectively review the effectiveness and safety of radiofrequency (RF) wire recanalization of refractory central venous occlusions (CVOs) and compare recurrent and nonrecurrent CVOs in terms of patient and occlusion characteristics. Materials and MethodsTwenty CVOs were treated in 18 patients (age 40 y ± 13; 9 women) with 11 superior vena cava (SVC) or brachiocephalic vein occlusions (ie, supradiaphragmatic) and 9 inferior vena cava or iliac vein occlusions (ie, infradiaphragmatic). Indications included pain, edema, ulceration, and/or dialysis arteriovenous fistula dysfunction peripheral to the CVO(s). All patients had multiple venous thrombotic risk factors, including mechanical venous compression, endothelial injury, and/or coagulopathies. CVO traversal was first attempted with standard and advanced techniques before RF wire recanalization and followed up with computed tomographic venography and clinic visits approximately 1, 3, 6, and 12 months after treatment. ResultsSixteen CVOs (80%) were successfully transversed and associated with symptom relief. One major complication occurred involving SVC perforation into the pericardial space. Primary CVO patency rate was 56% at a median follow-up of 14.1 months (interquartile range [IQR], 9.2–20.0 mo). Recurrent CVOs tended to be infradiaphragmatic (71% vs 12% for supradiaphragmatic; P = .02), longer (12.9 cm ± 10.0 vs 2.3 cm ± 1.3; P < .01), and associated with implanted venous stents, filters, or cardiac pacer/defibrillator leads (86% vs 22%; P = .01). Median time to restenosis/occlusion was 1.5 months (IQR, 1.1–6.1 mo). ConclusionsRF wire recanalization is a relatively effective and safe option for refractory CVOs. Patients with longer, infradiaphragmatic CVOs associated with indwelling devices may require closer follow-up for CVO recurrence.

ACUTE PULMONARY EMBOLISM FOLLOWING TWO DOSES OF INTRAVENOUS CONJUGATED ESTROGEN

SESSION TITLE: Medical Student/Resident Pharmacotherapeutics SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Estrogens can increase the synthesis of several clotting factors and increase platelet aggregation.Intravenous estrogen therapy is used to manage uterine bleeding in hospitalized patients.The intravenous route is preferred for a more rapid response.Venous thromboembolism (VTE) is a potentially life-threatening consequence of estrogen therapy.This report describes a case of acute pulmonary embolism following two doses of intravenous conjugated estrogen in a female with no identifiable risk factors for VTE CASE PRESENTATION: 41 year old G3 P3 003 female presented with recurrent heavy vaginal bleed associated with clots and fatigue.Three weeks prior to this, she was admitted with weakness, fatigue, vaginal bleed was found to have a hemoglobin of 3.5g/dl, received 4 units of packed red blood cells.Transvaginal ultrasound at the time revealed a fibroid in the lower uterine segment and she was discharged with oral iron supplementation with her hemoglobin at discharge being 8.7g/dl. She was then referred for surgical management of the bleed. During the current admission for recurrent vaginal bleeding, hemoglobin was 9.8/dl. Physical examination revealed a prolapsed fibroid encompassing the cervical os. She received a one dose of 25mg of intravenous Premarin (conjugated estradiol).The same afternoon while receiving the second dose, she experienced severe chest pain and shortness of breath with desaturation, with an oxygen saturation of 79%. A Computed tomography angiography showed filling defects in the right lateral and posterior lower lobe segmental pulmonary artery embolus. She was started on a heparin drip and eventually underwent uterine artery embolization, which helped control her presenting symptoms. The intravenous Premarin was discontinued and she was transferred to the Intensive care unit.She was discharged on Rivaroxaban for 6 months. Given the fact that she was ambulatory and had no other risk factors for thromboembolic disease, Premarin was the presumed cause of her pulmonary embolus. DISCUSSION: Given that our patient is a young female with no comorbidities who was ambulatory, non-obese and a non-smoker with no family history of thrombophilia developed a pulmonary embolus during her inpatient stay, we would attribute the most likely cause of the event to be the dose of premarin that she received. Use of the Naranjo probability scale indicated a possible relationship between IV estrogen and development of pulmonary embolism in this patient.(1) CONCLUSIONS: The causal effect of dose of estrogen and the risk of thromboembolism has been previously established in those using oral contraceptives.(2) It has been determined that there is a direct correlation with dose and incidence of VTE and has been found to be the highest within the first three months of use. It would be of interest to analyze the risk of thromboembolic events with minimal estrogen exposure such as in our patient. Reference #1: Naranjo CA et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239245. Reference #2: van Hylckama Vlieg A et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type. BMJ 2009 Aug 13 DISCLOSURES: No relevant relationships by Nikhil Jagan, source=Web Response No relevant relationships by Mridula Krishnan, source=Web Response No relevant relationships by Mark Malesker, source=Web Response No relevant relationships by Michael Sanley, source=Web Response

Short closure time values in PFA–100® are related to venous thrombotic risk. Results from the RETROVE Study

IntroductionPlatelets play a role in the pathophysiology of venous thromboembolism (VTE). Some studies have not found an association between VTE and platelet aggregation. The PFA–100® analyser is an in vitro assay for assessing primary haemostasis. But, there are no studies to evaluate its association with VTE. We investigated the contribution of the global platelet function and aggregation in the development of VTE. Material and methodsWe analysed 800 individuals who were included in the RETROVE Study (Riesgo de Enfermedad TROmboembólica VEnosa). Global platelet function was evaluated as closure times (CT) with the agonists ADP and epinephrine using a PFA–100® analyser. Platelet aggregation was evaluated by Multiplate™ analyser. The VTE risk for all the parameters was calculated by unconditional logistic regression analyses considering the potential confounders: age, gender, body mass index (BMI), factor VIII (FVIII), the von Willebrand factor (vWF) and the ABO blood group system. ResultsThe unadjusted odds ratio (OR) values ≤10th percentile for the PFAadp and PFAepi were 4.02 (95% CI, 2.76–5.95) and 3.33 (2.27–4.97). Also, after adjusting for vWF, we obtained lower OR for the PFAadp and for PFAepi: 2.24 (1.44–3.49) and 1.63 (1.04–2.59). But, the whole blood aggregation parameters did not shown an association with VTE risk. ConclusionWe demonstrated an association between short CT and VTE risk. Although, the whole blood aggregation parameters did not show an association with the VTE risk. This striking contrast suggests that there are other platelet function mechanisms (e.g. adhesion) that are responsible of VTE risk.

Influence of decreased fibrinolytic activity and plasminogen activator inhibitor-1 4G/5G polymorphism on the risk of venous thrombosis.

: Objective of our study is to determine whether decreased fibrinolytic activity or plasminogen activator inhibitor (PAI)-1 4G/5G polymorphism influence the risk of venous thrombosis.Our case-control study included 100 patients with venous thrombosis, and 100 random controls. When patients were compared with random controls, unconditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs).Decreased fibrinolytic activity yielded a 2.7-fold increase in risk for venous thrombosis than physiological fibrinolytic activity (OR 2.70; 95% CI 1.22-5.98), when comparing patients with random controls. Adjustment for several putative confounders did not change the estimate (OR 3.02; 95% CI 1.26-7.22). Analysis of venous thrombotic risk influenced by PAI-1 genotype, showed no influence of PAI-1 4G/5G gene variant in comparison with 5G/5G genotype (OR 0.57 95% CI; 0.27-1.20).Decreased fibrinolytic activity increased, whereas PAI-1 4G/5G polymorphism did not influence venous thrombosis risk in this study.

Cardiovascular risk factors are major determinants of thrombotic risk in patients with the lupus anticoagulant

BackgroundPatients with the lupus anticoagulant (LA) are at an increased risk of thrombotic events, which in turn increase the risk of death. Understanding the determinants of thrombotic risk in patients with LA may pave the way towards targeted thromboprophylaxis. In the Vienna Lupus Anticoagulant and Thrombosis Study (LATS), we systematically evaluate risk factors for thrombotic events in patients with LA.MethodsWe followed 150 patients (mean age: 41.3 years, female gender: n = 122 (81.3%), history of thrombosis or pregnancy complications: n = 111 (74.0%)), who tested repeatedly positive for LA until development of thrombosis, death, or censoring. The primary endpoint was a composite of arterial or venous thrombotic events (TEs).ResultsDuring a median follow-up of 9.5 years (range: 12 days–13.6 years) and 1076 person-years, 32 TEs occurred (arterial: n = 16, venous: n = 16; cumulative 10-year TE incidence: 24.3%). A prolonged lupus-sensitive activated partial thromboplastin time (aPTT-LA) (adjusted subdistribution hazard ratio (SHR) = 2.31, 95% CI: 1.07–-5.02), diabetes (adjusted SHR = 4.39, 95% CI: 1.42–13.57), and active smoking (adjusted SHR = 2.31, 95% CI: 1.14–5.02) emerged as independent risk factors of both arterial and venous thrombotic risk. A risk model that includes a prolonged lupus-sensitive aPTT, smoking, and diabetes enabled stratification of LA patients into subgroups with a low, intermediate, and high risk of thrombosis (5-year TE risk of 9.7% (n = 77), 30.9% (n = 51), and 56.8% (n = 22).ConclusionsLong-term thrombotic risk in patients with LA is clustered within subjects harboring typical cardiovascular risk factors in addition to a prolonged lupus-sensitive aPTT, whereas patients with none of these risk factors represent a large subgroup with a low risk of thrombosis.