History Of Venous Thromboembolic Events Research Articles

Risk Factors for Thrombosis in Pregnant People with Sickle Cell Disease: A Multinational Study.

Background People with sickle cell disease (SCD) have exceptionally high rates of maternal morbidity, including increased risk for venous thromboembolic events (VTE). Data from the National Inpatient Sample shows that VTE risk in hospitalized Black pregnant people with SCD is 14 times that of unaffected Black and non-Black pregnant people. 1 There is little disease-specific data to inform anticoagulation (AC) use during pregnancy. 2 The purpose of this study is to describe VTE events in a SCD pregnancy cohort and to identify risk factors for VTE during pregnancy and compare maternal-fetal outcomes for subjects with or without VTE in pregnancy. Methods The Mount Sinai Hospital (MSH) Research Ethics Board and The Johns Hopkins Hospital (JHH) Institutional Review Board approved this retrospective study of pregnant people with SCD of ≥ 20 weeks gestation cared for at MSH, Toronto (1990-2017) or JHH (2000-2021). At MSH and JHH, all pregnant people with SCD and VTE history are prescribed antenatal prophylactic LMWH and for 6-weeks postpartum. At MSH, but not JHH, all receive AC prophylaxis for 6-weeks postpartum. At both centers, hospitalized pregnant people receive prophylactic AC. We stratified subjects by VTE occurrence during pregnancy. First, we described the cohort with VTE during pregnancy, including subject characteristics, VTE recurrence and pregnancy outcomes. Second, we compared cases with a first pregnancy with VTE to controls without VTE. We excluded repeat pregnancies in both groups. We compared cases and controls by SCD characteristics, medication use before pregnancy, and pregnancy outcomes. Painful events were defined as pain requiring acute care or hospital admission. Chronic transfusion therapy (CTT) was defined as pregnancies treated with scheduled, prophylactic transfusion; opioid use was defined as receiving an outpatient opioid prescription during pregnancy. We used the Chi-squared test for categorical variables and Wilcoxon signed-rank tests for continuous variables. A p-value of <0.05 was considered significant. Results There were 290 singleton pregnancies in 199 subjects. Half of the pregnancies were first pregnancies (142/290), with fewer second (51/290), third (2/290), fourth (3/290) or fifth (1/290) pregnancies. The cohort comprised of 58% subjects with HbSS/HbSβ 0, while 42% had HbSC/HbSβ+ genotype (Table 1). VTE occurred in 7% of pregnancies (20/290) including deep vein thrombosis (DVT, N=9), pulmonary embolism (PE, N=8), DVT+PE (N=3). Median age was 27 years (IQR 23,30). Before pregnancy, most VTE subjects received hydroxyurea (N=10). During pregnancy, six received CTT. Fourteen subjects had VTE in a single pregnancy; three had VTE recurrence in subsequent pregnancies. All three had HbSS/HbSβ 0. Two subjects had VTE history outside of pregnancy. One had DVT in two consecutive pregnancies and was prescribed AC in both pregnancies due to history of VTE. VTE occurred in first (N=4), second (N=8), third (N=4), fourth (N=1) and fifth (N=4) pregnancies. Most VTE occurred at JHH (11 JHH vs 6 MSH, p=0.008). To investigate SCD-specific risk factors for VTE in pregnancy, we compared characteristics in VTE subjects (N=17) to no-VTE subjects (N=182) by first study pregnancy with an event or first study pregnancy while enrolled in the study. VTE was associated with markers of disease severity including history of VTE before pregnancy (6/17 VTE vs 8/182 no-VTE, p<0.001), ACS during pregnancy (7/17 VTE vs 19/182 no-VTE, p<0.001), painful events requiring acute care during pregnancy (16/17 VTE vs 119/182 no-VTE, p=0.015) and hydroxyurea use before pregnancy (10/17 VTE vs 35/184 no-VTE, p<0.001). There was no difference in age or genotype. VTE was associated with earlier delivery and c-section delivery (Table 1). Conclusion In this study, 7% of cohort pregnancies had VTE. This rate exceeds reports from administrative datasets. 1 This may be due to the acuity of patients cared for at our centers and/or reflect undercounting of VTE in administrative datasets. In pregnant people with SCD, VTE is associated with VTE history, intrapartum painful events and ACS. Interventions to reduce acute events in pregnancy may help reduce VTE risk. While AC can be beneficial in preventing thrombotic events, careful assessment is essential to manage bleeding risks. Prospective data is needed to define the subpopulation of pregnant SCD patients who would benefit from AC prophylaxis antenatally.

675 Chemoprophylactic Anticoagulation Causes a Marked Decrease in Thromboembolic Events Following Lumbar Fusion: Causal Inferences from a Propensity-Matched Analysis of 1302 patients

INTRODUCTION: Chemoprophylactic anticoagulation is commonly used to prevent venous thromboembolic events (VTE) after lumbar fusion. However, the magnitude of the associated risk reduction is not well described, and conventional retrospective statistical methods preclude causal inferences from this association. METHODS: 1302 consecutive lumbar fusions performed at our institution over a six-year period were identified, and relevant clinical and demographic data were collected. VTE events within 30 days postoperatively were identified. Patients who were given chemoprophylaxis and controls were matched according to age, body mass index, sex, Charlson Comorbidity Index, history of VTE, estimated blood loss, length of surgery, transfusion, whether surgery was staged, and whether surgery used an anterior approach. K-nearest neighbor propensity score matching was performed, and covariate adjustments were made to draw causal inferences regarding VTE rate. RESULTS: Unadjusted, there was no difference in the rate of VTE between patients who did (3.8%) and did notreceive chemoprophylaxis (4.4%, OR = 0.86 [0.47, 1.58], p = 0.667). On multivariable regression, and chemoprophylaxis was negatively associated with VTEs (OR = 0.38 [0.15, 0.95], p = 0.039). 589 lumbar fusion patients with and without chemoprophylaxis were successfully matched. After matching, median bias was 1.9%, and overall known bias was reduced by a median of 91.4%. After matching, covariates were well balanced (Rubin's B = 21.8). A covariate adjusted logistic regression model confirmed that chemoprophylaxis was associated with reduced odds of VTE (OR = 0.40 [0.16, 0.98], p = 0.044). The average treatment effect of chemoprophylaxis was a reduction in VTE of 3.7%. The only instance of epidural hematoma occurred in the control group. CONCLUSIONS: Among patients undergoing lumbar fusions, chemoprophylactic anticoagulation causes a marked decrease in VTE.

Cell Product Differences on Incidence of Venous Thromboembolism in Patients Treated with CAR T-Cells for Aggressive B-Cell Lymphomas

Introduction Chimeric antigen receptor T (CAR T)-cell therapy has substantial activity in relapsed lymphoid malignancies. However, it is associated with important complications, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Venous thromboembolic events (VTEs) following CAR T-cells have been reported with variable incidence. Risk factors for the development of VTEs following CAR T-cell therapy are largely unknown, including whether the CAR T-cell construct is associated with increased VTEs. Methods We retrospectively evaluated patients treated at our institution who received CAR T-cell therapy for non-Hodgkin lymphoma between May 2018 and January 2022. Baseline characteristics and outcomes were collected. VTEs included deep venous thrombosis and pulmonary embolism. The cumulative incidence (CI) of VTE was calculated with death as competing risk and comparisons between groups were done with Gray test. Univariate comparisons of baseline parameters were performed with Fisher's exact test evaluating the following covariates: age (older or younger than 70 years), LDH and C-reactive protein levels, ECOG performance status, revised IPI, BMI, personal history of VTE, and stage. Due to the low number of VTEs, we did not attempt multivariate modeling based on baseline characteristics. All analyses were performed using R. This study was approved by our Institutional Review Board. Results We identified 95 patients treated with CAR T-cells between May 2018 and January 2022. The majority had diffuse large B-cell lymphoma (DLBCL) (88, 93%). Baseline characteristics are listed in Table 1. Prior history of VTE occurred in 16 patients and 27 received at least one dose of therapeutic or prophylactic anticoagulation post-CAR T infusion prior to developing VTE. Most patients had central venous access during their hospitalization for CAR T cell therapy (n = 91). A total of 56 patients received axicabtagene ciloleucel (58.9%), 30 patients received tisagenlecleucel (31.6%), 5 patients received brexucabtagene autoleucel (5.3%), and 4 received lisocabtagene maraleucel (4.2%). Post-CAR T VTE occurred in 13 patients (14%); median time to VTE (IQR) was 15 days (7-48), with a 100-day cumulative incidence of 12%. All VTEs were DVTs and the majority were PICC line-associated (10, 77%). The incidence of VTE was higher for patients treated with axicabtagene ciloleucel or brexucabtagene autoleucel in contrast to 41BB-containing constructs (16% vs. 3%, p = 0.03) (Figure 1). Among baseline characteristics, a prior history of VTE was associated with increased risk of subsequent VTE (39% vs. 13% without prior VTE, p = 0.04). The 100-day CI of VTE for patients with and without CRS were 15% and 4% (p = 0.09), while the 100-day CI of patients with and without ICANS were 18% and 7% (p = 0.09). Subgroup analysis of patients treated with CD3ζ/CD28 signaling showed that 100-day VTE CI was higher among patients with a prior history of VTE (33% vs. 12%, p = 0.03) and those with BMI of ≥ 30 (38% vs. 11%, p = 0.03). We did not observe an increased incidence of VTE in patients with baseline ECOG performance status ≥ 2, stage III/IV disease, elevated baseline lactate dehydrogenase or C-reactive protein. After a median follow up of 24 months (IQR 13-36), the median progression free survival (PFS) was 7 months (95% CI = 4-12) while the median overall survival (OS) was 14 months (95% CI = 11-19), there were no statistically significant differences in PFS or OS among patients with and without VTE. Conclusions VTEs are an emerging toxicity associated with CAR T cell therapy. We show that increased VTE incidence at 100 days is associated with the use of CD3ζ/CD28 CAR T-cells. This difference may correlate with differing degrees of systemic inflammatory response, as previous reports have detailed higher incidence of high-grade CRS with axicabtagene ciloleucel vs. tisagenlecleucel, and other construct-specific factors may further increase VTE risk in patients with established VTE risk factors (e.g. history of VTE and obesity). We also observed that a large proportion of post CAR T VTEs corresponded to line-associated DVTs. Taken together, these findings may help identify patients at increased risk of VTE after CAR T-cell therapy and potentially guide decisions on surveillance, choice of central access, or prophylactic anticoagulation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Incidence of Intra-Cardiac Supra-Centimetric Thrombosis and Embolic Complications in Sickle Cell Disease Patients with Dual Lumen Ports

In Sickle Cell Disease (SCD) patients with cerebral vasculopathy and/or other severe complications, a transfusion program is indicated. A sustainable venous access is vital for patients engaged in these programs (5-10% of patients with SCD). Dual lumen ports (Vortextechnology) have emerged has a way to bypass the frequent local complications associated with arteriovenous fistulae. Between July 2015 and December 2020, a dual lumen port was implanted in 27 SCD patients in transfusion program at Necker Hospital. Over a 30 months period, we observed 20 venous thromboembolic events (VTE) in 12 patients (44%): 18 were voluminous intracardiac thrombosis (Fig 1), asymptomatic (n=15) or complicated of pulmonary embolism (n=3), one jugular thrombosis and one superior cellar syndrome, leading to long-term curative anticoagulation, except in cases of contraindication such as Moya-Moya. VTE were diagnosed on average 18 months after implantation (range 1 to 29 months). This observation has considerably limited the use of the device, even though no complications were observed in 56% of patients, suggesting that a subgroup of patients may be at lower risk of thrombosis and could still benefit from a Vortex. We conducted a clinical study aiming to identify potential biological markers related to Vortex thrombosis in SCD patients. Among the biological markers, alterations of thrombin generation and fibrino-formation, as well as potentially procoagulants items altered in SCD, such as microvesicules (MV), red blood cell (RBC) deformability and the intensity of splenic dysfunction were explored. Between January and June 2021, 11 healthy donors and 58 patients with SCD treated by erythrapheresis in the biotherapy department of Necker Hospital were included, 23 patients with a Vortex with (n=12) or without (n=11) intra-cardiac and/or other VTE and 36 patients without a Vortex (including 8 with a history of VTE). Thrombin generation Assay (TGA) in plasma and standard coagulation assays were performed on pre-transfusion sample, including Prothrombin Time (PT), activated partial thromboplastin time (APTT) and fibrinogen, dosage of FII, FV, FVII, FX and FXII, Protein C (PC), Protein C (PS), Antithrombin (AT) dosage. All samples were pretreated by activated carbon for removal of Direct Oral Anticoagulants from plasma. Quantification and characterization of plasma MV, determination of erythrocyte deformability and point of sickling (ektacytometry with oxygenscan) and assessment of splenic function (quantification of pocked RBC and Howell Jolly bodies) were also performed. We found a significant decrease in the mean levels of PC (69.7 vs 109.1%, p=0.0002) and PS (58.4 vs 99.4, p<0.0001) in SCD patients when compared to healthy donors while AT levels were only slightly decreased (91 vs 98,6%, p=0,04). We also observed a significant decrease in vitamin-K dependent coagulation factors: FII (77.5 vs 100.6%, p<0,0001), FVII (61.9 vs 84.5% p=0.005) and FX (71.8 vs 96.8%, p=0.0001) while FV (80.1 vs 93.8% p=0.02) was only slightly decreased and fibrinogen levels were comparable (2.62 vs 2.57g/L p=0.86). No significant differences were noted between SCD patient groups (with or without thrombosis). Thrombin generation Assay (TGA) in plasma showed an increase in endogenous thrombin potential (ETP; 714 vs 451nM.min, p=0.04) and Peak (161 vs 95 nM.min, p=0.03) in SCD patients compared to healthy donors but no differences were found between patient groups. Assessment of splenic function, point of sickling in oxygenscan and deformability of RBC measured by ektacytometry showed no differences between patient groups. Patients with SCD had a significant increase of circulating CD235+ MV (93268 vs 15 207/µL, p<0.0001), Annexin 5 MV (473553 vs 248404 /µL) and CD235+ erythrocyte ghosts (1757 vs 61/µL) compared to healthy donors. Again, no differences were seen between patient study groups. In conclusion, no biological predictive factors for intra cardiac Vortex thrombosis could be demonstrated by our study despite an extensive study of biological factors known to date to favor thrombosis. Given the high incidence of intracardiac thrombosis and the impossibility to date of predicting the risk of occurrence, we recommend that Vortex technology be reserved for patients who are already receiving effective anticoagulant therapy or for whom no other solution can be found, while maintaining a close surveillance of echocardiography.

Anterior approach lumbar fusions cause a marked increase in thromboembolic events: Causal inferences from a propensity-matched analysis of 1147 patients

ObjectiveAnterior lumbar fusions are thought to be associated with elevated venous thromboembolic event (VTE) rates, but the magnitude of this increase in VTE is not well described. The objective of this study was to quantify any increase in VTE caused by anterior approach lumbar fusion. Methods1147 consecutive lumbar fusions performed at our institution over a six-year period were identified, and clinical and demographic data were collected. K-nearest neighbor propensity score matching and propensity score adjusted regression were performed. Patients undergoing anterior versus posterior approach lumbar fusions were matched according to age, body mass index, sex, VTE history, estimated blood loss, length of surgery, transfusion, selection for postoperative intensive care unit (ICU) admission, comorbid disease burden, and use of chemoprophylactic anticoagulation. ResultsAnterior approach surgery (OR=4.29, p < 0.001), a history of VTE (OR=8.67, p < 0.001), age (OR=1.53, p = 0.014), length of surgery (OR=1.16, p = 0.044), and selection for postoperative ICU admission (OR=4.60, p = 0.005) were independently associated with VTE on multivariable regression. 1058 anterior or posterior approach fusion patients were matched. After matching, overall bias was reduced by 71.0 %, no covariates remained significantly different between groups, and propensity scores were well balanced between populations (Rubin’s B≤0.25, 0.5 ≤Rubin’s R≤2.0). Significantly more patients in the anterior group underwent lower extremity duplex ultrasonography (LED) (36.9 % vs. 14.8 %, OR=3.36 [2.38, 4.76], p < 0.0001), and a statistically insignificantly higher proportion of LEDs were positive among patients in the anterior group (23.2 % vs. 13.2 %, OR=1.99 [0.92, 4.25], p = 0.108). After matching, the rate of VTE was 8.6 % for the anterior group and 1.3 % for the posterior group, with anterior approach surgery causing an increase in VTE by 7.2 % (95 % CI [2.28 %, 12.16 %], p = 0.004). ConclusionAmong patients undergoing lumbar fusions, anterior approach surgery causes an increase in VTE by 7.2%, which is a multifold increase in the proportion of patients with thromboembolic complications.

DOES TYPE OF TRIGGER INFLUENCE OOCYTE MATURITY IN PATIENTS UNDERGOING OOCYTE CRYOPRESERVATION, EMBRYO BANKING AND IN VITRO FERTILIZATION CYCLES USING LETROZOLE?

Letrozole is an aromatase inhibitor that is used during oocyte cryopreservation cycles to lower estradiol levels in patients with conditions such as breast cancer, lymphoma, seizures, BRCA mutation carriers and history of venous thromboembolic events (VTE). Many studies have determined that using letrozole has no effect on the number of oocytes retrieved or maturity. The purpose of this study is to determine if the type of trigger affected the percent of mature oocytes retrieved in patients undergoing controlled ovarian stimulation with letrozole.

Chemoprophylactic Anticoagulation Following Lumbar Surgery Significantly Reduces Thromboembolic Events After Instrumented Fusions, Not Decompressions.

Retrospective cohort. To quantify any reduction in venous thromboembolic events (VTEs) caused by chemoprophylaxis among lumbar surgery patients. Chemoprophylactic anticoagulation (chemoprophylaxis) is used to prevent VTE after lumbar surgery. However, the treatment effect of chemoprophylaxis has not been reported among spine surgery patients, as conventional statistical methods preclude such inferences. A total of 1243 consecutive lumbar fusions and 1433 noninstrumented lumbar decompressions performed at our institution over a six-year period were identified, and clinical and demographic data were collected, including on VTE events within 30 days postoperatively. Instrumented lumbar fusions and noninstrumented lumbar surgeries were analyzed separately. Patients who were given chemoprophylaxis (treatment) and controls were matched according to known VTE risk factors, including age, body mass index, sex, diabetes, chronic kidney disease, history of VTE, estimated blood loss, length of surgery, transfusion, whether surgery was staged, and whether surgery used an anterior approach. K-nearest neighbor propensity score matching was performed, and the treatment effect of chemoprophylaxis was calculated. Unadjusted, there was no difference in the rate of VTE between treatment and controls in either population. Baseline clinical and demographic characteristics differed significantly between treatment and control groups. In all, 575 lumbar fusion patients and 435 noninstrumented lumbar decompression patients were successfully propensity score matched, yielding balanced models (Rubin B <25, 0.5<Rubin R <2.0) and >60% reduction in known bias for both populations. The treatment effect of chemoprophylaxis after lumbar fusion in our patient population was a reduction in VTE incidence from 9.4% to 4.2% ( P <0.05), and propensity score adjusted regression confirmed a reduced odds of VTE with chemoprophylaxis (odds ratio=0.37, P =0.035). The treatment effect was not significant for noninstrumented lumbar decompression patients. Among patients undergoing instrumented lumbar fusions, chemoprophylactic anticoagulation causes a significant reduction in VTE, but causes no significant reduction among patients undergoing noninstrumented lumbar decompression.

Venous thromboembolic events in glioblastoma patients: An epidemiological study.

Background and purposeVenous thromboembolic events (VTEs) are a major complication in cancer patients, and therefore, also in brain cancer patients, anticoagulants are considered appropriate in the treatment of VTEs.MethodsFrequency, risk factors, and treatment of VTEs, as well as associated complications, were assessed in a population‐based cohort of glioblastoma patients in the Canton of Zurich, Switzerland. Correlations between clinical data and survival were retrospectively analyzed using the log‐rank test and Cox regression models.ResultsFour hundred fourteen glioblastoma patients with isocitrate dehydrogenase wild‐type status were identified. VTEs were documented in 65 patients (15.7%). Median time from tumor diagnosis to the occurrence of a VTE was 1.8 months, and 27 patients were diagnosed with VTEs postoperatively (within 35 days; 42.2%). History of a prior VTE was more common in patients who developed VTEs than in those who did not (p = 0.004). Bevacizumab treatment at any time during the disease course was not associated with occurrence of VTEs (p = 0.593). Most patients with VTEs (n = 61, 93.8%) were treated with therapeutic anticoagulation. Complications occurred in 14 patients (23.0%), mainly intracranial hemorrhages (n = 7, 11.5%). Overall survival did not differ between patients diagnosed with VTEs and those who had no VTE (p = 0.139). Tumor progression was the major cause of death (n = 283, 90.7%), and only three patients (1.0%) died in association with acute VTEs.ConclusionsVenous thromboembolic events occurred early in the disease course, suggesting that the implementation of primary venous thromboembolism prophylaxis during first‐line chemoradiotherapy could be explored in a randomized setting.

Menopause-associated risk of cardiovascular disease.

Cardiovascular disease (CVD) is of major concern in women entering menopause. The changing hormonal milieu predisposes them to increased CVD risk, due to a constellation of risk factors, such as visceral obesity, atherogenic dyslipidemia, dysregulation in glucose homeostasis, non-alcoholic fatty liver disease and arterial hypertension. However, an independent association of menopause per se with increased risk of CVD events has only been proven for early menopause (<45 years). Menopausal hormone therapy (MHT) ameliorates most of the CVD risk factors mentioned above. Transdermal estrogens are the preferable regimen, since they do not increase triglyceride concentrations and they are not associated with increased risk of venous thromboembolic events (VTE). Although administration of MHT should be considered on an individual basis, MHT may reduce CVD morbidity and mortality, if commenced during the early postmenopausal period (<60 years or within ten years since the last menstrual period). In women with premature ovarian insufficiency (POI), MHT should be administered at least until the average age of menopause (50–52 years). MHT is contraindicated in women with a history of VTE and is not currently recommended for the sole purpose of CVD prevention. The risk of breast cancer associated with MHT is generally low and is mainly conferred by the progestogen. Micronized progesterone and dydrogesterone are associated with lower risk compared to other progestogens.

Venous Thromboembolic Events in African American Lupus Patients in Association With Antiphospholipid Antibodies Compared to White Patients.

The risk of thrombotic events is elevated in patients with systemic lupus erythematosus (SLE) compared to the general population and has been attributed to both systemic inflammation and to the presence of antiphospholipid antibodies (aPLs). Our objective was to examine differences in aPL prevalence in White and African American patients with SLE and venous thromboembolic (VTE) events, and to compare inflammatory markers at the time of a VTE event. Records of White and African American patients with SLE and VTE events were retrieved from a rheumatology practice based at an academic hospital. A clinically significant aPL profile was defined as anti-cardiolipin IgG/IgM and/or anti-β2 -glycoprotein I IgG/IgM ≥40 units, and/or positive lupus anticoagulant ≥1.3. Logistic regression was used to determine predictors of a clinically significant aPL profile. Ninety-seven patients fulfilled American College of Rheumatology and/or 2012 Systemic Lupus Erythematosus International Collaborating Clinics classification criteria for SLE, had a history of VTE events, and had available aPL tests (59 White and 38 African American patients). African American patients were 66% less likely (95% confidence interval 0.12-0.96; P = 0.04) to have a clinically significant aPL profile compared to White patients in multivariable regression. Triple positivity was most frequent among White patients, while 7 of 8 African American patients had a positive lupus anticoagulant test. At the time of a VTE event, African American patients had significantly higher levels of anti-double-stranded DNA (P = 0.02), lower hemoglobin (P = 0.01), and higher erythrocyte sedimentation rate (P = 0.008). Among patients with SLE and VTE events, African American patients were less likely to have a clinically significant aPL profile compared to White patients, indicating that a negative aPL profile in African American patients does not decrease VTE risk.

Waiting for JAK inhibitor safety data

The US Food and Drug Administration (FDA) has recently added a new ‘black box warning’ on all currently approved Janus kinase (JAK) inhibitors indicated for the treatment of arthritis and...

Management of Recurrent Deep Vein Thrombosis in a Transgender Woman

Background: Transgender people using hormone treatment require lifelong medical care. Although cross-sex hormone treatment (CSHT) is usually considered safe, serious adverse events may occur. Here we report a case of deep vein thrombosis associated with estradiol treatment in an otherwise healthy young transgender woman. Case Presentation: A 21-year-old transgender woman using CSHT applied to our outpatient clinic with the complaint of painful swelling in her left leg. She was diagnosed with deep vein thrombosis (DVT) in the same leg one year earlier when she was admitted to the emergency room of another hospital with similar symptoms, and was given warfarin treatment for 3 months which has improved the symptoms. Three months after cessation of warfarin, symptoms re-occurred, but she was only able to apply to our clinic after another 3 months due to COVID-19 pandemic. Physical examination was unremarkable except asymmetrical swelling in the left leg. She has been receiving oral estradiol 6 mg/day and spironolactone 200 mg/day for 2 years. She denied taking estradiol in higher doses than recommended. She did not have any predisposing factors for DVT including obesity, immobilization and smoking. She had no prior history of venous thromboembolic events (VTE). Family history was also negative for thrombophilia except her uncle was diagnosed with ischemic cerebrovascular event at the age of 60. Lower extremity venous doppler ultrasonography revealed a thrombus in the left popliteal vein that caused total obstruction of blood flow to the distal. Plasma levels of d-dimer and fibrinogen were 0.35 mg/L and 262 mg/dL, respectively. Serum levels of sex hormones were estradiol: 204 pg/mL, total testosterone: 22.4 ng/dL, FSH: 0.22 mIU/mL, LH: 1.5 mIU/mL. Thrombophilia panel revealed a homozygous mutation in MTHFR (1296), and heterozygous mutations in both Factor V Leiden and plasma activator inhibitor (4G/5G). She was given enoxaparin in addition to warfarin until INR was elevated up to desired levels. Oral estradiol treatment was switched to transdermal route. Life-long anticoagulant treatment was suggested since the thrombotic event was triggered by estradiol treatment which will be continued. Conclusions: Limited data are available on incidence and management of VTE associated with estradiol treatment in male-to-female individuals. As in general population, routine screening for thrombophilia is not recommended in transgender women prior to the initiation of CSHT if no personal or family history of VTE is present. Even in the absence of predisposing factors, life-long anticoagulant therapy may be considered since the VTE-provoking estradiol treatment will be continued. Switching the route of estradiol treatment from oral to transdermal may be beneficial.

A Retrospective Review of Outcomes in Intensive Care Unit Patients Infected With SARS-Cov2 in Correlation to Admission Acute Physiologic Assessment and Chronic Health Evaluation II Scores.

IntroductionCoronavirus disease 2019 (COVID-19) has emerged as a global pandemic that has placed an unprecedented burden on intensive care services worldwide. Identification of a reliable risk-stratification tool for COVID-19 patients is necessary for appropriate resource allocation, selection of clinical management pathways, and guidance of goals of care conversations with families and caregivers in the critical care setting. The Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scoring system is one of several predictive models used to classify illness severity and estimate mortality risk on admission to the intensive care unit (ICU). Our retrospective study sought to evaluate the prognostic ability of the APACHE II score in COVID-19 patients according to endpoints of mortality and length of stay (LOS) as well as unfavorable clinical outcomes, including development of acute renal failure (ARF) requiring renal replacement therapy (RRT) and acute venous thromboembolic events (VTE).MethodsThis multicenter retrospective cohort study evaluated a randomized sample of 3,102 patients with confirmed COVID-19 disease admitted to the ICU from January 2020 to May 2020. A total of 395 patients with complete data points for appropriate APACHE II score calculation, absence of the preexisting comorbidities end-stage renal disease, and history of VTE were included. Linear and logistic regression models were employed to evaluate primary outcomes of mortality and LOS as well as secondary outcomes of VTE and ARF requiring continuous renal replacement therapy (CRRT) or hemodialysis (HD).Key resultsAmong the 395 patients enrolled, total percent mortality and mean LOS were 37.0% and 12.92 days, respectively. Primary outcome analysis revealed a statistically significant increase in odds of mortality as well as in mean LOS with every additional point increase in APACHE II score from a baseline of zero. Specifically, for every point increase in the APACHE II score, odds of mortality increased by 12% (p value < 0.001), and average LOS increased by 0.2 days (p value < 0.001). In our secondary outcome analysis, 14.43% and 62.2% of the total sample population developed ARF requiring RRT and VTE, respectively. For every additional point increase in APACHE II score from a baseline of zero, odds of requiring CRRT or HD increased by 10% on average (95% CI (1.06, 1.15); p value < 0.001). Similarly, for every additional point increase in the APACHE II score from a baseline of zero, there was a corresponding increase in odds of VTE by 19% (95% CI (1.14, 1.24); p value < 0.001).ConclusionsThe APACHE II score is an effective predictive model of in-hospital mortality and unfavorable clinical outcomes, including prolonged LOS, ARF requiring CRRT or HD, and development of VTE. As therapeutic interventions for COVID-19 evolve, application of this risk-stratification tool may guide clinical management decisions in the critical care setting.

Higher prevalence of pulmonary macrothrombi in SARS-CoV-2 than in influenza A: autopsy results from 'Spanish flu' 1918/1919 in Switzerland to Coronavirus disease 2019.

Similar to the influenza A pandemic in 1918/1919, the new Coronavirus disease 2019 (COVID‐19) has spread globally. The causes of death in COVID‐19 are frequently compared to a seasonal influenza outbreak. Complete COVID‐19 autopsy studies were almost non‐existent in the first months of the outbreak and are still rare with respect to the number of deaths. It has been recently reported that capillary microthrombi are significantly more prevalent in patients with COVID‐19 than in patients with influenza A. To date, the contribution of macrothrombi, i.e. visible thrombi in pulmonary arteries, to the death of patients with influenza A in comparison to COVID‐19 remains unaddressed. Here, we report autopsy findings in 411 patients who died from the ‘Spanish’ influenza A pandemic between May 1918 and April 1919 at the University Hospital Zurich, Switzerland. We compare these results with influenza A autopsies from 2009 to 2020, other influenza A autopsy series and all COVID‐19 autopsies published to date. No descriptions of any macroscopic thromboembolic events were mentioned in influenza A autopsy reports. In 75 published COVID‐19 autopsies, pulmonary artery thrombosis/embolism was reported in 36%. The direct comparison of macroscopic autopsy findings suggests a significantly greater degree of grossly visible pulmonary macrothrombi in patients with COVID‐19 in comparison to influenza A autopsies even though most patients received empiric thromboprophylaxis. This is consistent with the concept of a SARS‐related de novo coagulopathy with generalised in situ clot formation, which could explain the high incidence of pulmonary thrombosis/embolism with or without underlying deep vein thrombosis and in the absence of a history of venous thromboembolic events.

Venous thromboembolic events in glioblastoma patients: Common complication but not a major reason for death.

e14530 Background: Venous thromboembolic events (VTE) are a major complication in cancer patients. Anticoagulant use is the appropriate treatment for acute VTE in cancer patients, although associated with increased risk for bleeding, especially in brain tumor patients. In glioblastoma patients it remains unclear whether occurrence of VTE is associated with survival and to what extent thromboprophylaxis is necessary and efficient. Methods: Frequency, risk factors, and treatment of VTE as well as its complications were assessed in an epidemiological glioblastoma cohort in the Canton of Zurich, Switzerland, in the years 2005 to 2014. Association of clinical data with survival were retrospectively analyzed using the log rank test. Results: Four-hundred-nineteen patients diagnosed with isocitrate dehydrogenase wildtype glioblastoma were identified in the 10-year time-frame. Median overall survival (OS) was 12.4 months (95% CI 11.4-13.4) with a median follow up of 64.5 months (95% CI 46.6-82.4).VTE were seen in 65 patients (15.7%; 5 patients with missing information on VTE).Median time from diagnosis of glioblastoma to occurrence of VTE was 2.0 months (95% CI 0.8-3.1). A history of VTE was found in 6 patients (9.2%). Thirty-nine patients were on steroids (62.5%; 1 patient with missing data) at time of diagnosis of VTE, and 35 patients (56%; 3 patients with missing data) had a Karnofsky Performance Score of less than 70%. At the time patients were diagnosed with VTE the majority of patients (93.8%) were treated with therapeutic anticoagulation. Complications resulting in stop of anticoagulation occurred in 11 patients (18.0%; 4 patients had no anticoagulation) mainly because of intracranial bleedings (9 patients). OS was not different (p = 0.355) between patients who were diagnosed with VTE and those who were not. Tumor progression (283 patients, 77.3%) was the major reason for death (366 patients with confirmed death) in this patient cohort, only 3 patients (0.8%) died because of confirmed VTE and another 5 patients (1.4%) had an unexpected sudden death. Conclusions: Although VTE was identified in 65 patients (16%) diagnosed with glioblastoma, VTE was no major reason for death. On a population-based level these data do not support the implementation of primary thromboprophylaxis in this cohort of patients.

Benefit of prophylactic anticoagulation before and during first-line chemotherapy on patients with metastatic germ cell tumors.

402 Background: Recent trials randomising patients (pts) receiving systemic cancer therapy showed that prophylactic anticoagulation (PAK) halves the risk of venous thromboembolic events (VTE) and doubles the risk of bleeding (Khorana et al. &amp; Carrier et al., both NEJM 2019). In pts with metastatic germ cell tumors (mGCT) VTE is a frequent complication but it remains unclear whether PAK should be recommended because the number of mGCT pts in those trials was small. We aimed to determine the risk of VTE before, during and after chemotherapy and in mGCT pts without and with risk factors for VTE (retroperitoneal lymph nodes, Khorana score, venous access device) and to calculate the number needed to treat (NNT) and number needed to harm (NNH) of PAK. Methods: This retrospective analysis included mGCT pts treated with first-line platinum-based chemotherapy. We excluded patients who received PAK, with a known history of coagulopathy or VTE and extracted data about VTE and bleeding events. Cumulative VTE incidence was calculate for patients without and with increasing number of known risk factors for VTEs. NNT and NNH were calculated by assuming similar hazard ratios (HR) to reduce VTEs and increase bleeding as previously published (HR 0.66 and 1.96, Khorana et al., NEJM 2019). Results: Out of 1039 pts, 132 (13%) presented with VTE, 6 (1%) with bleeding. One patients died of VTE and 1 because of bleeding. Patients without any VTE risk factors experience VTE in 20/347 (5%) which translated into a NNT of 55 compared to the NNH of 84 respectively. Before start of chemotherapy 52 (5%) pts (NNT=60) presented with VTE of which 22 were reported symptomatic 21 asymptomatic/incidentally detected VTE on staging scans (9 unknowns). During chemotherapy 79 (8%) pts (NNT=40) were diagnosed with VTE whereas 19 (2%) pts (NNT=162) were diagnosed with VTE after chemotherapy. Conclusions: Our analysis revealed that even mGCT patients without risk factors for VTE show a relevant cumulative VTE incidence of 7%. Especially before and during but not after chemotherapy the benefits of PAK to prevent VTE outweighs the small increased risk of bleeding.

Lymphoma-Specific Venous Thromboembolism Score (LyV-Score): Use of Lymphoma Subtype to Refine Risk Prediction

Background: Patients (pts) diagnosed with non-Hodgkin lymphoma (NHL) have increased risk of venous thromboembolic event (VTE). Retrospective studies have observed the risk of VTE is not the same across lymphoma subtypes, with aggressive subtypes having higher risk than indolent lymphomas. Current VTE prediction models such as the Khorana score (K-Score) consider all lymphomas as having equal risk of VTE. We conducted retrospective time - based analyses to develop a VTE prediction model that includes lymphoma subtype as a risk factor. Methods: We accessed the Hematologic Malignancies Database at University Hospitals Seidman Cancer Center and collected records of pts diagnosed with diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) between 2000 and 2016. Pts with CNS involvement or active anticoagulation were excluded. FL grade 3B pts were included in the DLBCL cohort. Information retrieved included demographic characteristics, baseline disease and laboratory parameters, as well as comorbidities and diagnosis of VTE, including radiographic confirmation. Time to VTE was measured from the date of NHL diagnosis to the date of VTE incidence or censored at the date of last follow-up for those without VTE. Cumulative incidence of VTE was estimated using Kaplan-Meier method and its difference among groups was examined by log-rank test. Cumulative incidence of VTE was also calculated considering death as competing risk and comparisons done using the Gray test. Cox proportional hazards model was used to evaluate the effect of continuous and categorical covariates on cumulative incidence of VTE and to identify prognostic factors of VTE. Fifty percent of the study participants were randomly assigned to training cohort or reserved as an independent validation cohort. Performance of multivariate models was evaluated using the Akaike Information Criterion (AIC) and Concordance Index (C-Index). The final models built using the training dataset were further validated using the validation cohort. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Results: We identified 627 pts with DLBCL (n=421) or FL (n=206) with available baseline characteristics, (Table 1). After a median follow up of 48 months (range 1-191), 77 pts experienced a VTE after NHL diagnosis. The cumulative incidence of VTE at 4 years for the whole cohort was 10.5% (95% CI 8.3-13.2). DLBCL pts had a significantly higher 4 - year cumulative incidence of VTE: 13.7% (95% CI 10.8-17.5) vs. 4.0% (95% CI 2.0 - 7.9) in FL pts (p &lt;0.0001)(Figure 1). Univariate analysis on the training cohort showed that lymphoma subtype (DLBCL vs. FL) was associated with incidence of VTE (p = 0.02); other baseline variables associated with VTE include ECOG performance status, bulky disease, history of VTE, and serum albumin, calcium, WBC count and WBC subtypes (Table 2). Analysis of overall performance of multivariate models, including the K-Score as well as the variables identified in univariate analysis, demonstrated that the addition of lymphoma subtype and albumin to the K-Score improved the C-Index and the AIC (Table 3). The Lymphoma-specific VTE Score (LyV-Score) including lymphoma subtype, presence of bulky disease, baseline WBC and serum albumin resulted in improved performance, with C-Index of 0.775 and AIC of 234.913. To further evaluate the performance of the LyV-Score model, we performed time - dependent ROC and calibration analyses. When applied to the training cohort, 2 and 4-year AUC for the LyV-Score were 0.7767 and 0.7463, respectively, whereas for the K-Score 2 and 4-year AUC were 0.6215 and 0.6032 (Figure 2). Time - based ROC analyses in the validation cohort confirmed the higher AUC achieved by the LyV-Score. Cumulative incidence analyses show the LyV-Score and the K-Score identified groups with statistically significant differences in VTE risk (Figure 3), these differences were more marked between groups identified by the LyV-Score. Conclusions: VTE risk models have considered all lymphoma subtypes as risk factor for VTE. We show this risk is not equivalent for all lymphoma subjects, with aggressive lymphoma patients presenting higher VTE risk. We have developed the LyV-Score as a VTE prediction model that incorporates NHL histologic subtype. This model shows improved performance over historic VTE risk models and can help identify lymphoma patients that may benefit from interventions to prevent VTE. Disclosures Malek: Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy. Metheny:Takeda: Speakers Bureau; Incyte: Speakers Bureau. Caimi:Genentech: Research Funding; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau.

The Pro-Adhesive and Reduced Angiogenic Properties of Endothelial Colony Forming Cells (ECFC) from JAK2V617F MPN Patients Are Not Related to the Expression of the JAK2 mutation in These Cells: A Potential Role of ADAM17

INTRODUCTION: JAK2V617F mutation is independently associated with a higher risk of venous thromboembolic events (VTE) in myeloproliferative neoplasms (MPN). We have previously shown that endothelial colony-forming cells (ECFCs) from JAK2V617F MPN patients do not express this mutation but exhibit a pro-adhesive phenotype with a lower in vitro angiogenic potential. Here, we explore the mechanisms through which ECFCs from JAK2V617F MPN patients behave differently from ECFCs from healthy individuals. METHODS: We selected 38 patients with newly or previously diagnosed MPN, regardless of current or prior hydroxyurea therapy, with or without a history of VTE. Plasma levels of ADAMTS13, P-selectin, soluble VCAM, soluble ICAM, PDGF-AA, PDGF-AB/BB, IL-8, IL-1β, and soluble CD40 ligand were measured through the use of a multiplex assay. We then tried to isolate ECFCs from 20 of the JAK2V617F patients as well as 14 healthy individuals. Successfully isolated ECFCs were then submitted to co-culture with red blood cells (RBC), after which RNA was extracted from ECFCs. ADAMTS13, P-selectin, sVCAM, and sICAM were measured in the supernatant from ECFCs and RBC co-culture with multiplex assay. ECFCs' surface expression of P-selectin, VCAM, ICAM, and E-selectin was measured with the use of flow cytometry. Gene expression in RNA from co-cultured ECFCs was assessed with two 84-gene RT-PCR arrays for endothelial cell biology and signal transduction pathways (RT2 Profiler PCR array, Qiagen®). RESULTS: Recruited patients had polycythemia vera (PV) (n=17), primary myelofibrosis (PMF) (n=7) and essential thrombocythemia (ET) (n=14); 34% of them had had a previous VTE (6/17 PV; 3/14 ET and 4/7 PMF). Median age was 59 years (26-88), 23% were male. Compared with JAK2wt, JAK2V617F MPN patients (n=29) showed higher median concentrations of sVCAM (1063 vs. 786.5 ng/ml, p=0.0315), sCD40L (339 vs. 166.4 ng/ml, p=0.0065), PDGF-AA (430.6 vs. 136.5 ng/ml, p=0.03) and PDGF-AB/BB (1068 vs. 365.8 ng/ml, p=0.004). Success in ECFC isolation was 9/20 (45%) in JAK2V617F MPN patients and 8/14 (57%) in healthy individuals. None of the ECFCs from JAK2V617F MPN patients expressed this mutation. In comparison with ECFCs from healthy individuals, ECFCs from JAK2V617F MPN patients did not show a higher expression of either VCAM1, ICAM, P-selectin, and E-selectin, as measured by flow cytometry after co-culture with RBCs. Multiplex assay on the supernatant of this co-culture did not show any difference in the levels of ADAMTS13, sVCAM, sICAM, and sP-selectin. RNA PCR array from the ECFCs after co-culture with RBCs showed no difference in the expression of adhesion molecules when compared with ECFCs from healthy individuals, except for the increased expression of ADAM17 (fold regulation: 5.46, p=0.006), a metalloprotease involved in the shedding of adhesion molecules, among them VCAM1. ECFCs from MPN patients did not show higher activation of the JAK-STAT pathway but had a lower expression of WNT5 (fold regulation: -2.22, p=0.03), indicating a reduced activation of the Hedgehog pathway, suitable with the reduced in vitro angiogenesis capacity of these cells. CONCLUSIONS: JAK2V617F MPNs are associated with an increase in circulating adhesion molecules, such as sVCAM, and platelet activation markers. The pro-adhesive phenotype and lower angiogenic potential of ECFCs JAK2V617F MPN patients are not related to this mutation, which is not expressed in these cells and might be related to an increased expression of ADAM17 and reduced activation of the Hedgehog pathway. Disclosures Ozelo: BioMarin: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding.

Characteristics, risk factors and management of venous thromboembolism in immune thrombocytopenia: a retrospective multicentre study.

An increased risk of thrombosis has been reported in immune thrombocytopenic purpura (ITP), but the characteristics, risk factors of occurrence, recurrence and management of venous thromboembolic events (VTE) have been poorly investigated. To describe VTE and ITP characteristics, distribution of VTE risk factors and their impact on VTE features and recurrence. A retrospective study of patients with ITP and VTE registered in databases of three reference French centres of ITP. Among 49 patients, 66 VTE were recorded. The platelet count at the time of the first VTE was <100 × 109 /L for 28/43 (65%) patients. In total, 19/48 (40%) patients had at least one positive antiphospholipid test result. For the 10 VTE occurring in eight patients with platelet count <50 × 109 /L, ITP treatment was efficient in 7. One haemorrhagic complication associated with anticoagulant (AC) therapy was recorded. For 31/49 (63%) patients, long-term AC therapy could have been discussed after the first VTE, but only 13 received it. A second VTE occurred in 13 (27%) patients. The risk of recurrence was increased in patients with unprovoked VTE before ITP diagnosis or active cancer. VTE in ITP mainly occurred in the presence of multiple risk factors of TE. A low platelet count does not protect against VTE. Management with AC therapy despite persistently low platelet count seems possible. Risk of VTE recurrence is high, particularly with a history of unprovoked VTE or active cancer. In this setting, indefinite AC therapy could be discussed.

Venous thromboembolism prophylaxis in inflammatory bowel disease flare-ups.

Background:Inflammatory bowel disease (IBD) is a set of chronic inflammatory diseases associated with significant morbidity. Generally, IBD patients have twice the risk of venous thromboembolism (VTE) compared to healthy controls. VTE in IBD is associated with greater morbidity and mortality. This is compounded by the underutilization of pharmacological anticoagulation in hospitalized patients with IBD. One study showed that half the IBD patients who developed VTE were not receiving any thrombotic prophylaxis.Method:We carried out a retrospective chart review of VTE prophylaxis use and safety in patients admitted with IBD flare-up between 2014 and 2017.Results:We evaluated 233 patients (mean age 36.7 years; 53.6% male). Of these patients, 55.2% were Caucasian and 40.5% were African American; 72.5% had Crohn’s disease and 21% ulcerative colitis. About one-third of our patients were on chronic steroids. Pharmacological prophylaxis was used in 39.7% of the patients. This significantly correlated with male sex, recent surgery, history of VTE, smoking, and chronic steroid use. Meanwhile, hematochezia, aspirin use, and a history of gastrointestinal bleeding were correlated with less use of pharmacological prophylaxis. Patients receiving pharmacological prophylaxis showed no difference in the incidence of bleeding events.Conclusions:Multiple factors were associated with the use of pharmacological prophylaxis in hospitalized patients, including sex, steroid use, history of VTE events or gastrointestinal bleeding, and hematochezia. The incidence of major bleeding was not significantly greater in IBD patients receiving pharmacological prophylaxis.