Higher Risk Of Venous Thrombosis Research Articles

Incidence and clinical progression of asymptomatic peripherally inserted central catheter–related thrombosis in solid neoplasm patients: ultrasound insights from a prospective cohort study

BackgroundManaging central venous catheters in patients with neoplasms is challenging, and peripherally inserted central catheter PORT (PICC-PORT) has emerged as a promising option for safety and efficacy. However, understanding the clinical progression of catheter-related thrombosis (CRT) in cancer patients with central venous catheters remains limited, especially in certain neoplasm types associated with a higher risk of venous thrombosis. ObjectivesThis study aims to assess the effectiveness of ultrasound-guided management in detecting and treating asymptomatic CRT in cancer patients with PICC. MethodsIn this prospective cohort study of 120 patients with solid neoplasms receiving chemotherapy, we investigated the incidence of isolated upper-extremity superficial vein thrombosis, upper-extremity deep vein thrombosis, and fibrin sheath formation through ultrasound follow-up at 30 and 90 days after catheter insertion. We analyzed risk factors associated with CRT and compared incidence rates between PICC-PORT and traditional PICC. ResultsAmong the cohort, 69 patients (57.5%) had high-risk thromboembolic neoplasm, and 31 cases (25.8%) of CRT were observed, mostly within 30 days, with only 7 cases (22.6%) showing symptoms. Traditional PICC use (odds ratio, 5.86; 95% CI, 1.14-30) and high-risk thromboembolic neoplasm (odds ratio, 4.46; 95% CI, 1.26-15.81) were identified as independent risk factors for CRT. ConclusionThe majority of CRT present asymptomatically within the first 30 days of venous catheter insertion in patients with solid neoplasms. Ultrasound follow-up is valuable for detecting asymptomatic CRT. The risk of CRT was lower with PICC-PORT than with PICC. Additionally, the risk of CRT was found to be higher in patients with high-risk thromboembolic neoplasms. It is crucial for larger studies to confirm the utility of treating asymptomatic thromboses and isolated superficial thrombosis.

Tofacitinib use in ulcerative colitis: An expert consensus for day-to-day clinical practice.

Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advancedtherapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a usefulagent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent andthiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.

Fibrinogen Bonn (p. Arg510Cys) in the Aα-Chain Is Associated with High Risk of Venous Thrombosis.

Inherited dysfibrinogenemia is a qualitative defect of fibrinogen caused by various mutations among three fibrinogen genes. Dysfibrinogenemia can be associated with an increased risk of thrombosis, bleeding, or both. Here, we report a 36-year-old female with dysfibrinogenemia who experienced two successful pregnancies under thromboprophylaxis after cerebral venous sinus thrombosis (CVST). In addition to plasmatic coagulation tests, fibrinogen genes FGA, FGB, and FGG were screened using direct genomic DNA sequencing. The structural-functional implications of the detected mutation were analyzed in silico. Inherited dysfibrinogenemia was diagnosed in an index patient after CVST in a risk situation. Anticoagulation with warfarin was stopped after 12 months when the first pregnancy was planned. Pregnancy and spontaneous delivery (2020) was uncomplicated. A second pregnancy was interrupted because of acute cytomegalovirus infection and the third pregnancy was successful in 2022. Pregnancies were accompanied by thromboprophylaxis with enoxaparin 40 mg once daily until 6 weeks postpartum. Substitution of fibrinogen has not become necessary in the index patient so far. Genetic analysis revealed a novel missense mutation (p. Arg510Cys) in the FGA gene ("fibrinogen Bonn") in the index patient, as well as an asymptomatic sister, and their father who experienced recurrent pulmonary embolism. Surface exposure of wild-type Arg510 suggested the mutated Cys510 to form nonnative disulfide bonds with surface-exposed reactive cysteines from other plasma proteins like albumin leading to formation of aggregates and impaired fibrinolysis. Fibrinogen Bonn might be associated with an increased risk of thrombosis, possibly due to impaired polymerization.

Functions of Heparin Sodium Injection in the Prevention of Peripherally Inserted Central Catheter-Related Venous Thrombosis in NSCLC Patients during Postoperative Chemotherapy.

Objective This study intended to analyze hazardous factors of venous thrombosis by comparing the effect of different doses of heparin sodium injection on the incidence rate of peripherally inserted central catheter (PICC)-related venous thrombosis in non-small cell lung carcinoma (NSCLC) patients during postoperative chemotherapy. Methods 425 NSCLC patients who received PICC catheterization in Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Hospital from July 2019 to July 2021 were collected. Based on their different pathological types, patients were given two different chemotherapy regimens: pemetrexed+cisplatin or paclitaxel+cisplatin. Patients were grouped according to the different doses of heparin sodium injection adopted. Control group (n = 140). Catheters were sealed with 10 mL saline only. Group I (n = 142). In addition to routine maintenance with normal saline, 2 mL of 10 IU/mL heparin sodium injection was sealed in the catheters under positive pressure every time after catheterization. Group II (n = 143). In addition to routine maintenance with normal saline, 5 mL of 10 IU/mL heparin sodium injection was sealed in the same manner as Group I. The baseline characteristics of the three groups of patients were compared by statistical means. Doppler ultrasonography was applied to check the venous thrombosis. The hazardous factors of venous thrombosis were analyzed through correlation analysis and binary logistic regression method. Results The incidence rates of thrombosis in the control group, Group I, and Group II were 20.00%, 7.04%, and 2.09%, respectively, with statistically significant differences (P < 0.01). Additionally, through the collinear correlation analysis of baseline characteristics, a significant correlation between the dosage of heparin sodium injection and the incidence of thrombosis was observed (P < 0.05), but there were no significant differences between other baseline data and the incidence of thrombosis (P > 0.05). Binary logistic regression analysis revealed that postoperative use of heparin sodium injection (Group I: OR = 0.312; P = 0.003; Group II: OR = 0.082, P < 0.001) was a protective factor for preventing thrombosis. In addition, the thromboprophylaxis effect of Group II was better than that of Group I. No serious adverse reactions were found in safety analysis. Conclusion Heparin sodium could significantly lower the incidence rate of PICC-related venous thrombosis in NSCLC patients during postoperative chemotherapy. Heparin sodium injection is safe enough to be promoted among PICC patients with a high risk of venous thrombosis.

Low-risk polycythemia vera treated with phlebotomies: clinical characteristics, hematologic control and complications in 453 patients from the Spanish Registry of Polycythemia Vera

Hematological control, incidence of complications, and need for cytoreduction were studied in 453 patients with low-risk polycythemia vera (PV) treated with phlebotomies alone. Median hematocrit value decreased from 54% at diagnosis to 45% at 12 months, and adequate hematocrit control over time (< 45%) was observed in 36%, 44%, and 32% of the patients at 6, 12, and 24 months, respectively. More than 5 phlebotomies per year in the maintenance phase were required in 19% of patients. Worsening thrombocytosis, age > 60 years, and microvascular symptoms constituted the main indications for starting cytoreduction. Median duration without initiating cytoreduction was significantly longer in patients younger than 50 years (< 0.0001). The incidence rate of thrombosis under phlebotomies alone was 0.8% per year and the estimated probability of thrombosis at 10 years was 8.5%. The probability of arterial thrombosis was significantly higher in patients with arterial hypertension whereas there was a trend to higher risk of venous thrombosis in cases with high JAK2V617F allele burden. Rates of major bleeding and second primary neoplasm were low. With a median follow-up of 9 years, survival probability at 10 years was 97%, whereas the probability of myelofibrosis at 10 and 20 years was 7% and 20%, respectively. Progression to acute myeloid leukemia was documented in 3 cases (1%). Current management of low-risk PV patients is associated with low rate of thrombosis and long survival. New treatment strategies are needed for improving hematological control and, in the long term, reducing progression to myelofibrosis.

Modification of prophylactic anticoagulation regimen reduces the incidence of thrombotic complications after venous reconstruction.

e16250 Background: Surgical treatment for pancreatic cancer (PC) with venous reconstruction is associated with a high risk of venous thrombosis. The purpose of this study was to analyze the dynamics of the blood fibrinolytic system in the postoperative period in PC patients after venous reconstruction. Methods: The study included patients with PC (T3N0-1M0), mean age 63 years. Patients of the main group (n = 11) underwent pancreaticoduodenal or corporocaudal resection with venous reconstruction (portal and superior mesenteric veins), mesenteric cross-clamping time 7-40 minutes (average 23 minutes). Patients of the control group (n = 11) received similar surgical treatment without venous resection. All patients received postoperative prophylactic anticoagulation: standard nadroparin 0.4 ml once a day in the control group and a modified regimen of nadroparin 0.1 ml per 10 kg of body weight per day in a low bleeding risk in the main group. Levels of tPA, uPA, PAI-1 and suPAR, and tPA-act, uPA-act, and PAI-1-act activity were determined in the blood plasma by ELISA (Technoclone, Austria; R&amp;D Systems, USA) on days 1-3, 5-7 and 8-14 after surgery. Results: No thrombotic complications were registered in the main group during the 30-day observation period, while 2 patients (18.2%) in the control group were diagnosed with distal venous thrombosis on days 10-14. The frequency of hemorrhagic complications was similar in both groups (9.1% vs 9.1%). Levels of PAI-1 decreased by 2.4 times in both groups on days 1-3 after surgery, tPA increased by 1.7 times (p &lt; 0.01), and tPA-act increased in the main group by 2.9 times. On days 5-7, no changes were registered in the control group, while patients of the main group showed decreased tPA-act by 3.2 times and elevated suPAR and PAI-1 by 2.2 times (p &lt; 0.01) and PAI-1-act by 3.6 times. However, levels of PAI-1-act decreased by 2.2 times (p &lt; 0.01) in the main group on days 8-14, and in control group PAI-1 increased by 2.4 times (р &lt; 0.05). Thus, patients in the main group had 2.4 times higher levels of tPA on days 1-3, compared to the control group, and higher suPAR on days 5-7 (by 1.8 times, p &lt; 0.01), PAI-1 and PAI-1-act by 2.0 times (p &lt; 0.01), and higher tPA (by 4.4 times) on days 8-14. Conclusions: The proposed scheme of prophylactic anticoagulation showed its efficacy and safety. It activated fibrinolysis 1-3 days after surgery. Further on, we could observe signs of enhanced prothrombotic and pro-inflammatory state despite the ongoing anticoagulant therapy, which, however, was not manifested by thrombotic complications. Levels of tPA increased significantly by days 8-14 after venous reconstruction and intestinal ischemia, while inhibitor levels remained high, which can be considered a change in the balance towards activation of fibrinolysis and enhancement of anti-inflammatory processes.

Increased risk of venous thrombosis in breast cancer patients receiving chemotherapy treatment after COVID-19.

e24106 Background: Immune suppression and coagulopathy development in cancer patients receiving chemotherapy determines a high incidence of complications, including venous thrombosis, and mortality from COVID-19 infection. There are still no explicit data on managing cancer patients when anticancer treatment is resumed after coronavirus disease. According to clinical guidelines for the prevention of venous thromboembolic complications in cancer patients receiving chemotherapy, patients with breast cancer are classified as having a low risk of these complications and do not require prophylactic anticoagulation. The purpose of this study was to assess the parameters of the blood coagulation system and the frequency of venous thrombosis in breast cancer patients with chemotherapy resumption after coronavirus disease. Methods: The study included 30 patients receiving anticancer medical therapy for breast cancer after COVID-19. Anticancer treatment was resumed no earlier than 4 weeks after clinical recovery, absence of SARS-CoV-2 RNAs in nasopharyngeal swabs, infiltrative lung damage according to a chest CT scan, exclusion of venous thrombosis by a lower extremity venous ultrasound. Control group included 20 breast cancer patients without a history of COVID-19. Stage I tumors were registered in 26.6% in the main group vs 15% controls; II - 40% vs 60%; III - 20% vs 15%. Some patients were diagnosed with distant metastases (stage IV- 13.3% vs 10%). Results: Initially, before chemotherapy resumption in the main group, half of the patients had elevated levels of fibrinogen and D-dimer compared with the control group (66.7% vs. 35%, p &gt; 0.05). After a cycle of chemotherapy, a significant difference in the coagulation system parameters was noted (73.3% vs 30%). A lower extremity venous ultrasound after the end of the therapy cycle in the main group showed venous thrombosis in 3 patients (catheter-related n = 2, distal vein thrombosis of the lower extremities n = 1), while no venous thrombotic complications were detected in the control group (10% vs. 0%). Conclusions: Breast cancer patients after coronavirus disease 2019 have hemostasis abnormalities and higher risk of venous thrombosis, and the resumption of anticancer treatment increases the incidence of thrombotic complications. COVID-19 should be considered an additional risk factor of venous thrombosis in cancer patients and requires reconsideration of indications for prophylactic anticoagulation when resuming anticancer treatment for patients with breast cancer.

Thrombosis in patients with post-polycythemia vera myelofibrosis: incidence and risk factors

IntroductionPost-polycythemia vera (PV) myelofibrosis (Post-PV MF) is an advanced phase of natural progression of PV. Thrombosis is a major cause of morbidity and mortality in PV; however, the characteristics of thrombosis in post-PV MF have not been characterised. MethodsThe clinical and laboratory characteristics of 163 patients with post-PV MF were analysed. Kaplan–Meier and multivariate Cox analyses were used to estimate risk factors for thrombosis. ResultsDuring follow-up, 84 (51.5%) patients developed thrombosis, 11 (6.7%) progressed to acute leukemia, 35 (21.5%) died (20% due to thrombosis). Thrombosis-free survival (TFS) in post-PV MF was lower than that of sex- and age-matched patients with PV (P < 0.0001). The incidence of venous thrombosis was significantly higher after diagnosis of post-PV MF than before or at diagnosis; Those with V617F% ≥ 75% or absolute monocyte count (AMC) ≥1.5 × 109/L demonstrated a higher risk for venous thrombosis (P < 0.05). According to multivariate Cox regression, palpable splenomegaly (hazard ratio [HR] 3.284 [95% confidence interval (CI) 1.373–7.855]; P = 0.008), age ≥ 60 years (HR 1.604 [95%CI 1.004–2.56]; P = 0.048), history of thrombosis (HR 2.767 [95%CI 1.735–4.412]; P < 0.001) were risk factors for thrombosis. In multivariable models, median TFS in post-PV MF in extremely high -, high -, intermediate -, low-risk groups were 2, 4, 9 and 13 years, respectively. ConclusionPatients with post-PV MF demonstrated a higher incidence of thrombosis. Palpable splenomegaly, age ≥ 60 years, history of thrombosis were independent risk factors for thrombosis.

Predicting Venous Thrombosis in Osteoarthritis Using a Machine Learning Algorithm: A Population-Based Cohort Study.

Osteoarthritis (OA) is the most common joint disease associated with pain and disability. OA patients are at a high risk for venous thrombosis (VTE). Here, we developed an interpretable machine learning (ML)-based model to predict VTE risk in patients with OA. To establish a prediction model, we used six ML algorithms, of which 35 variables were employed. Recursive feature elimination (RFE) was used to screen the most related clinical variables associated with VTE. SHapley additive exPlanations (SHAP) were applied to interpret the ML mode and determine the importance of the selected features. Overall, 3169 patients with OA (average age: 66.52 ± 7.28 years) were recruited from Xi’an Honghui Hospital. Of these, 352 and 2817 patients were diagnosed with and without VTE, respectively. The XGBoost algorithm showed the best performance. According to the RFE algorithms, 15 variables were retained for further modeling with the XGBoost algorithm. The top three predictors were Kellgren–Lawrence grade, age, and hypertension. Our study showed that the XGBoost model with 15 variables has a high potential to predict VTE risk in patients with OA.

COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort.

IntroductionInfection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort.MethodsWe used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression.ResultsThere were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38–1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95–1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98–1.25) and MI (HR 0.93, 95% CI 0.85–1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19–1.56) and PE (HR 1.82, 95% CI 1.57–2.10) in patients with COVID-19.ConclusionIn a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.

JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis

Arterial (AT) and venous (VT) thrombotic events are the most common complications in patients with polycythemia vera (PV) and are the leading causes of morbidity and mortality. In this regard, the impact of JAK2V617F variant allele frequency (VAF) is still debated. The purpose of the current study was to analyze the impact of JAK2V617F VAF in the context of other established risk factors for thrombosis in a total of 865 2016 WHO-defined PV patients utilizing two independent cohorts: University of Florence (n = 576) as a training cohort and Policlinico Gemelli, Catholic University, Rome (n = 289) as a validation cohort. In the training cohort VT free-survival was significantly shorter in the presence of a JAK2V617F VAF > 50% (HR 4; p < 0.0001), whereas no difference was found for AT (HR 0.9; p = 0.8). Multivariable analysis identified JAK2V617F VAF > 50% (HR 3.8, p = 0.001) and previous VT (HR 2.2; p = 0.04) as independent risk factors for future VT whereas diabetes (HR 2.4; p = 0.02), hyperlipidemia (HR 2.3; p = 0.01) and previous AT (HR 2; p = 0.04) were independent risk factors for future AT. Similarly, JAK2V617F VAF > 50% (HR 2.4; p = 0.01) and previous VT (HR 2.8; p = 0.005) were confirmed as independent predictors of future VT in the validation cohort. Impact of JAK2V617F VAF > 50% on VT was particularly significant in conventional low-risk patients, both in Florence (HR 10.6, p = 0.005) and Rome cohort (HR 4; p = 0.02). In conclusion, we identified JAK2V617F VAF > 50% as an independent strong predictor of VT, supporting that AT and VT are different entities which might require distinct management.

Inflammatory Markers and Thromboembolic Risk in Patients with Non-Muscle-Invasive Bladder Cancer

Introduction: Patients with bladder cancer have a high risk of venous thrombosis that represents a key challenge for physicians in the decision-making for initiating anticoagulation therapy. Non-muscle-invasive bladder cancer (NMIBC) represents more than 70% of all diagnosed bladder malignancies; therefore, we aimed to evaluate the relationship of the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and risk of thrombosis by using the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score as well as the risk of bleeding by using the IMPROVE Bleeding Risk Assessment Score in a study cohort. Material and Methods: This was a retrospective observational study involving 130 patients who met the inclusion criteria: age > 18 years, stage pTa-pT1 NMIBC. The exclusion criteria were age < 18 years; stage pT2 or higher; or a presentation of metastasis, inflammatory, liver or autoimmune diseases, or other systemic neoplasms. In order to evaluate the risk of thromboembolic events as well as those of bleeding, the IMPROVE scores were calculated for each patient. Subjects were categorized in a Low IMPROVE group (< 4 points) or a High IMPROVE group. By using uni- and multivariate regression models, we analyzed CBC-derived parameters which could be associated with a higher risk of venous thrombosis in subjects with low or high IMPROVE scores. Results: Patients with IMPROVE score greater than 4 were associated with higher NLR, LMR and lymphocyte values (p < 0.05). In a multivariate regression model, the IMPROVE score was significantly influenced by lymphocyte count (p = 0.007) as well as the NLR value (p < 0.0001). Conclusions: In our study population, subjects with NMIBC with low lymphocytes and NLR > 3 were at a higher risk of developing venous thromboembolic events, reflected by an IMPROVE score of greater than 4. The IMPROVE and IMPROVE Bleeding Risk Assessment Scores are easy to use, and, complemented with the CBC-derived lymphocyte to monocyte ratio as a prothrombotic marker, could aid in the decision of prophylactic anticoagulation therapy during admission.

A JAK2V617F Variant Allele Frequency Greater Than 50% Identifies Patients with Polycythemia Vera at High Risk for Venous Thrombosis

▪Background: Thrombosis is the main cause of morbidity and mortality in pts with Polycythemia Vera (PV). Current risk stratification is based on 2 variables: age >60y and history of thrombosis. Additional thrombotic risk factors in PV are generic cardiovascular risk factors and leukocytosis. JAK2V617F (JAK2VF) variant allele frequency (VAF) at diagnosis is highly heterogeneous. A VAF>75% was associated with higher rate of all thrombosis after diagnosis (Vannucchi AM et al, Leukemia 2007), and a VAF ≥ 60% correlated with increased rate of venous thrombosis (VT) in high-risk pts (Guglielmelli P et al, ASH 2018); however, predictive role of JAK2VF VAF is still debated.Aim: To evaluate the impact of JAK2VF VAF on rate of arterial and venous thrombosis in PV pts.Patients and methods: A cohort of 576 strictly 2016 WHO-defined PV pts followed at Univ. of Florence (1981-2020) were included. All pts were annotated for JAK2VF VAF, determined <3 years from diagnosis, and thrombosis at diagnosis and follow-up (FU). Arterial thromboses (AT) included stroke, transient ischemic attacks, retinal artery occlusion, coronary artery disease, and peripheral arterial disease; VT included cerebral venous thrombosis, deep vein thrombosis, pulmonary embolism. Splanchnic vein thromboses (SVT) were excluded. Only first occurring event was considered. Cox proportional hazard regression model was used for univariate and multivariable analysis. Kaplan-Meier (KM) analysis was used for time-to-event assessment, compared by log-rank test.Results: Median age was 61.4 y (range, 16.2-91.8), 58.2% were male; 62% were high-risk based on current classification. Median JAK2VF VAF was 41.5% (range, 0.3-100). A total of 76 (13.2%) pts had an AT event before/at PV diagnosis and 49 (8.5%) pts had an AT during FU. As regards VT, 64 (11.1%) and 39 (6.8%) pts had a VT before/at or after PV diagnosis, respectively. We found that JAK2 VAF as a continue variable was correlated with the risk of VT in FU (p=0.003) but not with AT (p=0.8). ROC analysis to determine the best cut-off level for JAK2 VAF predicting VT had an AUC of 0.72 and a best cut-off value of VAF=50%. VT at FU were significantly enriched in pts with VAF >50%: 14.5% versus 2.4%, p=<0.0001. VT -free survival (VT-FS) by KM was significantly shorter in the presence of a JAK2 VAF >50% (HR 4, CI 1.9-8.6, p<0.0001) (Figure 1A), whereas no difference was found for AT (HR 0.9). In addition to JAK2VF VAF>50%, univariate analysis for VT-FS identified history of VT (HR 2.9; CI 1.4-6.1, p=0.006), leukocytosis ≥11x10 9/L (HR 1.9; CI 1.1-3.4, p=0.02) and palpable splenomegaly (HR 1.9, CI 1-3.6; p=0.04) as risk factors. Multivariable analysis confirmed VAF>50% (HR 3.8, CI 1.8-8.1, p=0.0006) and previous VT (HR 2.4, CI 1.1-5.1; p=0.02) as independent risk factors for future VT. In contrast, univariate analysis for AT-free survival (AT-FS) identified history of AT (HR 2.5; CI 1.3-4.9, p=0.007), diabetes (HR 3.3; CI 1.6-6.5, p=0.0007), hyperlipidemia (HR 3.1; CI 1.7-5.6, p=0.0003) and hypertension (HR 2, CI 1.1-3.8; p=0.03) as predictors of future AT; age >60y showed only a trend (p=0.08). Multivariable analysis for AT-FS identified diabetes (HR 2.4, CI 1.2-5; p=0.02), hyperlipidemia (HR 2.3; CI 1.2-4.3, p=0.01) and previous AT (HR 2.1, CI 1-4.2; p=0.04) as independent predictors of future AT.Validation: Our findings were validated in an independent cohort of 315 2016-WHO defined PV pts from Policlinico Gemelli, Catholic Univ., Rome. After exclusion of 26 pts with SVT, analysis was conducted on 289 pts, 38 of them with thrombosis as heralding event (21 AT and 17 VT). Multivariable analysis confirmed JAK2VF VAF >50% (HR 2.3, CI 1.03-5.0, p=0.04) and previous VT (HR 4.5, CI 2.0-10.1; p=0.0003) as independent risk factors for future VT. In pts with VAF >50%, the rate of VT at FU was 19.9% vs 7.7%, P=0.005. KM curve showed that VT-FS was significantly shorter in pts with a JAK2VF VAF >50% (HR 2.2, CI 1.2-4.2; p=0.01) (Figure 1B). Of note, impact of JAK2 VAF>50% on VT at FU was statistically significant particularly in conventionally low-risk pts, accounting for an HR of 9.4 (CI 1.2-72) and HR 3.6 (CI 1.3-10) in Florence and Rome cohorts, respectively.Conclusions: These data support JAK2VF VAF as a strong independent predictor for future venous thrombosis in PV, in association with history of prior venous events, reinforcing that AT and VT are associated with unique risk factors in pts with PV.Supported by AIRC, Project Mynerva n.21267 [Display omitted] DisclosuresVannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

SOFA Score as a Reliable Tool to Detect High Risk for Venous Thrombosis in Patients With Critical Stage SARS-CoV-2.

Background: Severe acute respiratory syndrome from coronavirus-2 (SARS-CoV-2) has been associated with an increased risk of venous thromboembolism (VTE). Different anticoagulation protocols have been applied in several studies in the absence of clear evidence. A reliable deep venous thrombosis (DVT) indicator in critical patients with SARS-CoV-2 could guide the anticoagulation treatment; however, it has not yet been identified, and clinical applicability of the most common markers is debatable. The aim of our study was to determine the actual incidence of DVT in critically ill SARS-CoV-2 patients and to find a reliable tool to identify patients who might benefit from therapeutic-intensity anticoagulation.Methods: From March 1, 2020 to May 31, 2020, all patients admitted to the intensive care unit (ICU) for SARS-CoV-2 at Ospedale Regionale di Locarno, Locarno, Switzerland, were prospectively enrolled and screened daily with ultrasound for DVT. Following international consensus, a higher-intensity thromboprophylaxis was administered to all patients who were not at increased risk for bleeding. Sepsis-induced coagulopathy (SIC) and sequential organ failure assessment (SOFA) scores were calculated and time-to-DVT event in a COX proportional-hazard regression model was performed. A receiver operating characteristic (ROC) curve was used to determine sensitivity and specificity and the Youden's Index to establish the best threshold.Results: A total of 96 patients were enrolled. Deep venous thrombosis was detected in 37% of patients. Sepsis-induced coagulopathy and SOFA scores were both correlated to DVT. A SIC score of 1 vs. ≥2 showed a close association with DVT, with sensitivity, specificity, and positive and negative predictive values of 90.0, 48.1, and 49.1, and 89.7%, respectively. Most significantly though, a SOFA score of 1 or 2 points was shown to be the most accurate value in predicting the absence of DVT, indicating no need for therapeutic-intensity anticoagulation. Its sensitivity, specificity, and positive and negative predictive values were 87.9, 100, and 100, and 93.7%, respectively. The D-dimer test showed lower sensitivity and specificity whereas platelet count and aPTT were not found to be correlated to DVT.Conclusions: Patients with SOFA scores of 1 or 2 are at low risk of developing DVT and do not require therapeutic-intensity anticoagulation. Conversely, patients with scores ≥3 are at high risk of developing DVT.

High penetrance of inferior vena cava system atresia in severe thrombophilia caused by homozygous antithrombin Budapest 3 variant: Description of a new syndrome

Atresia of inferior vena cava (IVC) is a rare congenital malformation associated with high risk of venous thrombosis that still has unknown etiology, although intrauterine IVC thrombosis has been suggested to be involved. The identification of IVC atresia in a case with early idiopathic venous thrombosis and antithrombin deficiency caused by the homozygous SERPINC1 c.391C > T variant (p.Leu131Phe; antithrombin Budapest 3) encouraged us to evaluate the role of this severe thrombophilia in this vascular abnormality. We have done a cross-sectional study in previously identified cohorts of patients homozygous for the Budapest 3 variant (N=61) selected from 1118 patients with congenital antithrombin deficiency identified in two different populations: Spain (N=692) and Hungary (N=426). Image analysis included computed tomography and phlebography. Atresia of the IVC system was observed in 17/24 cases (70.8%, 95% confidence interval [CI]: 48.9%-87.3%) homozygous for antithrombin Budapest 3 with available computed tomography (5/8 and 12/16 in the Spanish and Hungarian cohorts, respectively), 16 had an absence of infrarenal IVC and one had atresia of the left common iliac vein. All cases with vascular defects had compensatory mechanisms, azygos-hemiazygos continuation or double IVC, and seven also had other congenital anomalies. Short tandem repeat analysis supported the specific association of the IVC system atresia with SERPINC1. We show the first evidence of the association of a severe thrombophilia with IVC system atresia, supporting the possibility that a thrombosis in the developing fetal vessels is the reason for this anomaly. Our hypothesis-generating results encourage further studies to investigate severe thrombophilic states in patients with atresia of IVC.

Correlation of Hemostatic Parameters with Poly (ADP-ribose) Polymerase-1 (PARP-1) Polymorphisms, Mutations, Laboratory, and Clinical Characteristics in 114 Patients with Philadelphia-Negative Myeloproliferative Neoplasms

Patients with Philadelphia-negative myeloproliferative neoplasms (PN-MPN) are at a higher risk for venous thrombosis. Thromboelastometry may prove efficient to evaluate the patient’s thrombotic risk. In this study, based on data from 114 patients with PN-MPN from a single center in Greece, hemostatic profile was assessed with routine coagulation tests, Rotational Thromboelastometry (ROTEM®), and Platelet Function Analyzer (PFA)-100 and correlated with clinical, laboratory, treatment characteristics, gene mutations and polymorphisms of poly (ADP-ribose) polymerase-1 (PARP-1).

Predictors of venous thromboembolic complications in patients with pancreatic cancer.

e16220 Background: Patients with pancreatic cancer are at high risk for venous thrombosis. Thrombotic episodes are most often recorded at the tumor diagnosis, surgical treatment and chemotherapy courses, or the disease recurrence. This complication postpones the beginning of treatment of the underlying disease and increases the mortality rate of cancer patients. The purpose of the study was to reveal the relationship between clinical characteristics and disorders of hemostasis indicators in patients with pancreatic cancer, and to identify predictors of venous thrombosis. Methods: 246 patients diagnosed with pancreatic cancer were recruited in 2019. The most common histological tumor type was pancreatic ductal adenocarcinoma (91.9%). The most common tumor site was the head of the pancreas (68.3%). Almost half of the patients were initially diagnosed with stage IV cancer (TanyNanyM1). Surgery was performed in 28% of patients. VTEC incidence during the 12-month follow-up period was 15.4%. Results: Analysis of the clinical characteristics and initial hemostasis parameters in patients with and without venous thrombosis revealed that the risk of thrombosis was higher in patients with larger tumors and the presence of distant metastases. High levels of D-dimers at diagnosis doubled the risk of venous thrombosis during antitumor treatment. Conclusions: The most significant predictors of venous thrombosis in patients with pancreatic cancer are tumor size, stage IV, and initially high levels of D-dimer. The study of hemostasis indicators at the stage of diagnosis of pancreatic cancer (D-dimer) can help to identify patients with a high risk of VTEC, for whom anticoagulant prophylaxis with a low hemorrhagic risk is advisable.

Sex, age and venous thrombosis—Are men and women indeed from different planets?

“Mars or Venus” titled Elliot and Rubin their editorial that accompanied the landmark study which described for the first time the strikingly higher risk of recurrent venous thromboembolism (VTE) in men compared with women [1,2]. This finding was unexpected, as - if at all - many people regarded women and not men at a higher risk of venous thrombosis. Indeed, large epidemiologic studies indicate slightly higher incidence rates of a first VTE in women, particularly in those at a younger age [3]. Using the data set of the MEGA study, Roach et al.

Direct oral anticoagulants in antiphospholipid syndrome: Meta-analysis of randomized controlled trials.

The gold standard for secondary thromboprophylaxis in APS is long term anticoagulation with vitamin K antagonists (VKAs). Because of their widespread use and potential advantages of directs oral anticoagulants (DOACs) over VKAs, they have been prescribed in APS without definitive evidence of their safety and efficacy in this context. Recent specific randomized controlled trials (RCT) in APS and results from pivotal RCTs comparing DOACs vs VKAs are now available. Their results are conflicting but these studies have been conducted in different APS populations. To summarize available data from RCT and determine risks of recurrent thrombosis and bleeding. Four studies were included and 23 and 10 thrombotic events were recorded among 282 and 294 APS patients treated with DOACs and warfarin respectively. Overall recurrent thrombotic events were not significantly increased during DOACs treatment (OR=2.22 [95% CI, 0.58-8.43]) compared to VKAs. However, when different types of thrombosis were analyzed separately, there was an increased risk of recurrent arterial thrombosis (5.17 [95% CI, 1.57-17.04]) with DOACs compared to warfarin but no significant higher risk of venous thrombosis (OR 0.69 [95% CI, 0.23-2.06). No increased risk of bleeding was found. In APS patients treated with DOACs compared to those treated with warfarin, no evidence of a higher risk of recurrent venous thromboembolism was found however there was a significantly increased risk of recurrent arterial thrombosis. Moreover risk of recurrent arterial thrombosis tended to be more frequent in patients with a history of arterial thrombosis. These results are in line with international guidelines which recommend not to use DOACs in APS patients with a history of arterial thrombosis but raise the question of the efficacy of DOACs to prevent venous thrombosis in a subset of APS patients without a history of arterial thrombosis.

Progestin type affects the increase of heparanase level and procoagulant activity mediated by the estrogen receptor.

Does progestin have an effect on heparanase level and procoagulant activity? Progestin increases the heparanase level and procoagulant activity via the estrogen receptor and the magnitude of the effect depends on the progestin type. Users of combined oral contraceptives (COCs) containing third- and fourth-generation progestins have a higher risk of venous thrombosis compared to those employing second-generation progestins. Heparanase protein is capable of degrading heparan sulfate (HS) chains and enhancing activation of the coagulation system. We have previously demonstrated that estrogen enhances the expression and procoagulant activity of heparanase. Estrogen and progestin receptor positive breast carcinoma cell lines: EMT6, T47D and MCF-7 were compared to the MDA-231 breast carcinoma cell line devoid of these receptors. This observational study incorporated 45 users of third-generation COCs progestins, 21 users of fourth-generation COCs progestins and 28 individuals not using hormonal therapy and not pregnant per history. Second-generation progestin-levonorgestrel, third-generation progestin-desogastrel (DSG), an estrogen receptor antagonist-ICI 182.780 and a progestin receptor antagonist-mifepristone, were added to cell lines. Heparanase level and procoagulant activity, HS levels, tissue factor (TF) activity and factor Xa levels were evaluated in the plasma of the study group. Levonorgestrel and DSG increased heparanase levels in the cells and medium. The effect of DSG was more prominent and additive to that of estrogen. The effect was inhibited by ICI 182.780. In the plasma of COC users, heparanase procoagulant activity, HS levels, TF activity and factor Xa levels were significantly higher compared to controls. In COC pills containing the same dose of estrogen, the procoagulant effect of drospirenone was significantly stronger than that of DSG and gestodene. The limitations of the study include a small number of participants in each study group, although the results are statistically significant and evaluated by several different coagulation parameters. The study demonstrates a new mechanism through which progestin affects coagulation system activation and shows that this effect is progestin type-dependent. Development of a progestin derivative with an attenuated effect on heparanase procoagulant activity may reduce thrombotic risk. No external funding was sought for this study. Y.N. is named in a European patent application No. IL201200027 filed on 18 January 2012. Other authors have no conflict of interest to declare. N/A.