Risk Of Venous Thrombotic Events Research Articles

Immune Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, Therapy and Open Issues.

Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury due to microvascular platelet-rich thrombi. iTTP pathophysiology is based on a severe ADAMTS13 deficiency, the specific von Willebrand factor (vWF)-cleaving protease, due to anti-ADAMTS13 autoantibodies. Early diagnosis and treatment reduce the mortality. Frontline therapy includes daily plasma exchange (PEX) with fresh frozen plasma replacement and immunosuppression with corticosteroids. Caplacizumab has recently been added to frontline therapy. Caplacizumab is a nanobody that binds to the A1 domain of vWF, blocking the interaction of ultra-large vWF multimers with the platelet and thereby preventing the formation of platelet-rich thrombi. Caplacizumab reduces mortality due to ischemic events, refractoriness, and exacerbations after PEX discontinuation. Until now, the criteria for response to treatment mainly took into account the normalization of platelet count and discontinuation of PEX; with the use of caplacizumab leading to rapid normalization of platelet count, it has been necessary to redefine the response criteria, taking into account also the underlying autoimmune disease. Monitoring of ADAMTS13 activity is important to identify cases with a low value of activity (<10IU/L), requiring the optimization of immunosuppressive therapy with the addition of Rituximab. Rituximab is effective in patients with refractory disease or relapsing disease. Currently, the use of Rituximab has expanded, both in frontline treatment and during follow-up, as a pre-emptive approach. Some patients do not achieve ADAMTS13 remission following the acute phase despite steroids and rituximab treatment, requiring an individualized immunosuppressive approach to prevent clinical relapse. In iTTP, there is an increased risk of venous thrombotic events (VTEs) as well as arterial thrombotic events, and most occur after platelet normalization. Until now, there has been no consensus on the use of pharmacological thromboprophylaxis in patients on caplacizumab because the drug is known to increase bleeding risk.

Disease severity drives risk of venous thrombotic events in women with sickle cell disease in a single-center retrospective study

BackgroundEstrogen-containing hormonal contraception (HC) is a well-established risk factor for venous thromboembolism (VTE). Women with sickle cell disease (SCD) also have an increased risk of VTE. However, it is unknown if exposure to HC exacerbates the risk of VTE in women with SCD. ObjectivesAssess the impact of HC on VTE risk in women with SCD and explore additional risk factors contributing to VTE development. MethodsWe analyzed a retrospective cohort of women of reproductive age (15-49 years) with SCD at the University of North Carolina from 2010 to 2022. ResultsWe identified 370 women with SCD, and 93 (25.1%) had a history of VTE. Among 219 women exposed to HC, 38 of 184 (20.6%) had a VTE while actively using HC, whereas 20 of 151 (13.2%) women never exposed to HC had a VTE. Of the patients exposed to HC, 64 of 184 (34.7%) were on estrogen-containing HC, with 120 of 184 (65.3%) using progestin-only formulations. Cox regression analysis found that progestin-only formulations increased VTE risk (hazard ratio: 2.03; 95% CI: 1.107-3.726, P < .05). However, when accounting for disease severity, the association between progestin-only treatment and VTE risk was not significant. Indeed, a nuanced analysis revealed that both severe (odds ratio: 11.79; 95% CI: 5.14-27.06; P < .001) and moderate (odds ratio: 4.37; 95% CI: 1.77-10.76; P = .001) disease increased risk compared with mild disease. Neither genotype nor hydroxyurea use influenced VTE risk. ConclusionOverall, we found that increased thrombotic risk is more likely influenced by disease status than HC exposure and should play a role in shared decision-making with patients.

High Risk of Thrombosis in a Prospective Cohort of Adults with Primary Immune Thrombocytopenia

Background: Patients with primary Immune thrombocytopenia (ITP) have an increased risk of bleeding but paradoxically also an increased thromboembolic risk. Aim: The aim of this study was to prospectively assess the occurrence and risk factors of symptomatic venous thrombotic events (VTE) and arterial thrombotic events (ATE) in patients with primary immune thrombocytopenia. Methods: This study included 160 adult patients with primary ITP enrolled in the Vienna ITP Biobank, a dual-center cohort study (Medical University of Vienna; Hanusch Hospital) that prospectively collects data of patients diagnosed with primary ITP (EC 1843/2016). Patients with primary ITP and a history of VTE or ATE, as well as those who experienced new or recurrent thrombotic events (TE) during the observation period, were categorized into two groups: with-thrombosis and without-thrombosis. The patient characteristics were compared using a chi-squared or Fisher's exact test for categorical and for numerical data were performed using the Mann-Whitney-U-test. The association between clinical risk factors and thrombosis were performed by univariable analyses using logistic regression model. Results: Of the 160 ITP patients (Table 1), 22 patients (13.8%) had 25 documented ATE or VTE. These events consisted of 11 ATE (44%), including 7 acute myocardial infarctions, 3 cerebral vascular events (stroke or TIA), and 1 peripheral artery thrombosis, and 14 (65%) venous events (1 superficial vein thrombosis, 7 deep vein thromboses, 2 deep vein thromboses with pulmonary embolism and 4 cases of isolated pulmonary embolism). 8 (36.4%) of 22 patients had a history of thrombosis. 17 (77.3%) patients experienced TE during the median observation period of 2.2 (1-3) years. Of them 14 (82.4%) patients had a new TE and 3 (17.6%) recurrent TE. The cumulative 1- and 5-year incidence of TE accounting for competing mortality were 1.9 % and 5.0%. Four (18.2%) patients with thrombosis died during the follow-up period. The cause of death was unclear for three patients, while one patient died from pulmonary embolism. Patients with thrombosis were significantly older (p=0.001) and had more comorbidities than patients without thrombosis (Table 1). There was no difference in the platelet counts between the groups. Antiphospholipid antibodies were present in 14.4% of the patients, and their prevalence was higher in the thrombosis group (p=0.002). In the univariable regression analysis, factors such as older age ≥75 years (OR 1.06; 95%CI 1.03-1.09, p=0.001) diabetes mellitus (OR 4.02; 95%CI 1.20-13.413, p=0.024), presence of antiphospholipid antibodies (OR 6.04; 95%CI 2.01-25.63, p=0.003), particularly lupus anticoagulant positivity (OR 5.39 95%CI 1.8-13.0, p=0.002), and splenectomy (OR 3.07; 95%CI 1.13-12.63, p=0.031) were significantly associated with a higher risk of arterial and venous thrombotic events among ITP patients. Body-Mas-Index, disease duration, tobacco use, hypertension, and use of corticosteroids or thrombopoietin receptor agonist (TPO-RA) were not associated with increased risk of VTE and ATE. Conclusion: We observed a high rate of ATE and VTE in our patients with primary ITP. Additionally, ITP patients commonly present with typical risk factors for thrombotic events, suggesting a strict management of cardiovascular risk factors. Close monitoring and tailored treatment strategies should minimize the risk of bleeding and thrombotic events.

POS0714 POOLED SAFETY ANALYSIS OF BARICITINIB IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS FROM THREE RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, CLINICAL TRIALS

BackgroundBaricitinib (BARI), an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis and atopic dermatitis, has been evaluated in clinical studies in patients with systemic lupus erythematosus (SLE).ObjectivesTo assess the safety profile of BARI in patients with SLE.MethodsPatients with SLE receiving stable background therapy were randomised 1:1:1 to BARI 2-mg, 4-mg, or placebo (PBO) once daily in one 24-week, phase 2 (NCT02708095) and two 52-week, phase 3, PBO controlled studies (NCT03616912 and NCT03616964).ResultsA total of 1,849 patients were included in this pooled analysis, representing 1,463.5 patient years of exposure (PYE). The incidence rates per 100 PYR at risk (IR/100 PYR) for serious adverse events (SAEs) were 9.5, 14.7, and 14.1 respectively for PBO, BARI 2-mg, and BARI 4-mg. There were no clinically meaningful differences between treatment groups for discontinuations due to AEs or death (Table 1).Table 1.Overview of safety measures of baricitinib in patients with SLESafety measurePBOBARI 2-mgBARI 4-mgPooled-BARIN=614N=621N=614N=1235PYE=488.1PYE=494.0PYE=481.4PYE=975.4n(%)n(%)n(%)n(%)PYRPYRPYRPYR[IR; 95%CI][IR; 95%CI][IR; 95%CI][IR; 95%CI]SAEs45 (7.3)70 (11.3)*65 (10.6)*135 (10.9)*473.2476.6461.9938.5[9.5; 6.9, 12.7][14.7; 11.5, 18.6][14.1; 10.9, 17.9][14.4; 12.1, 17.0]Discontinuation of study drug due to AE48 (7.8)58 (9.3)57 (9.3)115 (9.3)485.3492.3480.6973.0[9.9; 7.3, 13.1][11.8; 8.9, 15.2][11.9; 9.0, 15.4][11.8; 9.8, 14.2]Death4 (0.7)1 (0.2)4 (0.7)5 (0.4)488.2494.0481.5975.5[0.8; 0.2, 2.1][0.2; 0.0, 1.1][0.8; 0.2, 2.1][0.5; 0.2, 1.2]Serious infections12 (2.0)22 (3.5)28 (4.6)*50 (4.0)*484.3487.2472.5959.7[2.5; 1.3, 4.3][4.5; 2.8, 6.8][5.9; 3.9, 8.6][5.2; 3.9, 6.9]Herpes Zoster18 (2.9)17 (2.7)29 (4.7)46 (3.7)481.1486.5468.6955.1[3.7; 2.2, 5.9][3.5; 2.0, 5.6][6.2; 4.1, 8.9][4.8; 3.5, 6.4]VTEs#6 (1.2)3 (0.6)1 (0.2)4 (0.4)444.0450.2438.1888.3[1.4; 0.5, 2.9][0.7; 0.1, 1.9][0.2; 0.0, 1.3][0.5; 0.1, 1.2]MACE#01 (0.2)3 (0.6)4 (0.4)443.9450.1438.1888.3[0.0; NA, 0.8][0.2; 0.0, 1.2][0.7; 0.1, 2.0][0.5; 0.1, 1.2]Malignancy excluding NMSC2 (0.3)3 (0.5)2 (0.3)5 (0.4)488.0494.1481.4975.5[0.4; 0.0, 1.5][0.6; 0.1, 1.8][0.4; 0.1, 1.5][0.5; 0.2, 1.2]NMSC2 (0.3)000*486.7494.0481.4975.4[0.4; 0.0, 1.5][0.0; NA, 0.7][0.0; NA, 0.8][0.0; NA, 0.4]Data are n (%) patients PYR [IR; 95% CI]. #Phase 2 study data not included. AE=adverse event; CI=confidence interval; MACE=major adverse cardiac event; NMSC=non-melanoma skin cancers; VTE=venous thrombotic event (includes deep vein thrombosis and pulmonary embolism); IR=incidence rate (100 times the number of patients reporting an adverse event divided by the event-specific exposure to treatment); N=number of patients in the analysis population; n=number of patients in the specified category; PYE=patient-year of exposure; PYR=patient years at risk; SAE=serious adverse event. *p≤0.05 vs placebo.The IR/100 PYR for serious infections were 2.5, 4.5, and 5.9 respectively for PBO, BARI 2-mg, and BARI 4-mg. The risk of Herpes Zoster was higher in BARI 4-mg (4.7%) vs PBO (2.9%) (Table 1).The IR/100 PYR for positively adjudicated venous thrombotic events (VTEs) were 1.4, 0.7, and 0.2 respectively for PBO, BARI 2-mg, and BARI 4-mg. The IR/100 PYR for positively adjudicated major adverse cardiac event (MACE) was numerically higher in BARI 2-mg (0.2) and BARI 4-mg (0.7) vs PBO (0.0), however the pooled-BARI IR/PYR (0.5) was within the range of background disease (1). No increased risk for malignancies was observed.ConclusionThe safety profile of BARI in SLE patients was consistent with the known BARI safety profile. There was no increased risk of VTE in BARI treatment groups.

Risk of venous thromboembolism in children and adolescents with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUNDA two- to three-fold increased risk of venous thrombotic events (VTE) has been demonstrated in patients with inflammatory bowel disease (IBD) compared to the general population, but less is known about the risk of VTE in child- and pediatric-onset IBD. In recent years, several studies have reported the rising incidence rate of VTE in juvenile patients with IBD, and the related risk factors have been explored.AIMTo evaluate the risk of VTE in children and adolescents with IBD.METHODSArticles published up to April 2021 were retrieved from PubMed, Embase, Cochrane Library, Web of Science, SinoMed, CNKI, and WANFANG. Data from observational studies and clinical work were extracted. The outcome was the occurrence of VTE according to the type of IBD. The available odds ratio (OR) and the corresponding 95% confidence interval (CI) were extracted to compare the outcomes. Effect size (P), odds ratio (OR), and 95%CI were used to assess the association between VTE risk and IBD disease. Subgroup analyses stratified by subtypes of VTE and IBD were performed. RESULTSTwelve studies (7450272 IBD patients) were included in the meta-analysis. Child and adolescent IBD patients showed increased VTE risk (P = 0.02, 95%CI: 0.01-0.03). Subgroup analyses stratified by IBD (ulcerative colitis (UC): P = 0.05, 95%CI: 0.03-0.06; Crohn’s disease (CD): P = 0.02, 95%CI: 0.00-0.04) and VTE subtypes (portal vein thrombosis: P = 0.04, 95%CI: 0.02-0.06; deep vein thrombosis: P = 0.03, 95%CI: 0.01-0.05; central venous catheter-related thrombosis: P = 0.23, 95%CI: 0.00-0.46; thromboembolic events: P = 0.02, 95%CI: 0.01-0.03) revealed a significant correlation between VTE risk and IBD. Patients with IBD were more susceptible to VTE risk than those without IBD (OR = 2.99, 95%CI: 1.45-6.18). The funnel plot was asymmetric, suggesting the presence of significant publication bias. Pediatric and adolescent IBD patients have an increased VTE risk. UC and CD patients exhibited a high risk of VTE. The risk of VTE subtypes was increased in IBD patients.CONCLUSIONThe current meta-analysis showed that the incidence and risk of VTE are significantly increased in pediatric and adolescent IBD patients. Thus, IBD might be a risk factor for VTE in children and young adults. High-quality prospective cohort studies are necessary to confirm these findings.

Risk of venous thrombotic events and thrombocytopenia in sequential time periods after ChAdOx1 and BNT162b2 COVID-19 vaccines: A national cohort study in England.

SummaryBackgroundThrombosis with thrombocytopenia, or thrombocytopenia on its own, have been reported after Covid-19 vaccines. We assessed the risk after ChAdOx1 adenovirus-vector and BNT162b2 mRNA vaccines in a national cohort study in England.MethodsHospital admissions for a cerebral venous thrombosis (CVT), other venous thrombosis or thrombocytopenia between 30th November 2020 and 18th April 2021 were linked to the national Covid-19 immunisation register. The incidence of events by dose in pre-defined post-vaccination risk periods relative to the unvaccinated cohort was estimated after adjustment for age, gender, co-morbidities, care home residency and health/social care worker status. Elevated relative incidence (RI) estimates with p<0.001 were considered strong evidence of an association.FindingsThe RI for CVT after a first ChAdOx1 dose in 15-39 and 40-64 year olds was 8.7 (95% confidence interval 5.8-13.0) and 2.2 (1.4-3.2) respectively, p<0.001. The elevated risk period in 15-39 year olds was highest 4-13 days post-vaccination (16.3, 9.9-27.0). The attributable risk (AR) was 16.1 per million doses for 15-39 and 3.2 per million for 40-64 year olds. RIs for other thrombosis admissions were elevated in these age groups with ARs of 36.3 and 16.4 per million respectively as were RIs for thrombocytopenia, with ARs of 11.3 and 10.1 per million respectively. No elevated RIs were found for 65+ year olds or after a second ChAdOx1 dose, nor for BNT162b2 vaccine recipients of any age.InterpretationThis epidemiological study shows an increased risk of thrombotic episodes and thrombocytopenia in adults under 65 years of age within a month of a first dose of ChAdOx1 vaccine but not after the BNT162b2 vaccine.FundingEM receives support from the National Institute for Health Research (NIHR) Health Protection Research Unit in Immunisation at the London School of Hygiene and Tropical Medicine in partnership with Public Health England (Grant Reference NIHR200929).

Renal Function and Risk of Arterial Thrombotic Events in Patients Positive for Lupus Anticoagulant

Background: Patients with lupus anticoagulant (LA) are at risk for arterial and venous thromboembolic events. Recent work suggests that LA positive patients who experience thrombotic events in different vascular beds constitute distinct subgroups. To risk stratify patients, further work is needed to better characterize predictors for thromboembolic events in these subgroups.Aims: The aim of this study was to identify baseline characteristics and laboratory parameters associated with the development of arterial or venous thrombotic events.Methods: Patients with at least 2 previous positive LA tests were serially monitored for thrombotic events within the prospective Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Patients without clinical follow-up were excluded from this analysis. Statistical analysis was performed with RStudio (Version 1.1.442).Results: One-hundred-eighty-seven patients were followed (Table 1) for a median of 11.4 years and 1865 follow-up visits (median visit/patient=9). Fifty-seven prospective thrombotic events (TE), including 27 arterial thrombotic events (ATE) and 30 venous thrombotic events (VTE), were observed. This corresponded to 10-year prospective ATE, VTE and overall thrombosis incidences of 13.9% [95%CI: 8.3, 19.6], 18.8% [12.2, 25.4], and 32.0% [24.1, 39.8], respectively. (Figure 1). Thirty-seven of the 57 events occurred in patients with a prior history of thrombosis (“recurrent thrombosis”).In univariable competing risk analysis, age (subdistribution hazard ratio (SHR) = 1.02, 95% CI: 1.00-1.05, p=0.019), body mass index (BMI, 1.05, 1.00-1.11, p=0.042), history of ATE (3.14, 1.45-6.81, p=0.0038), active smoking (2.16, 1.00-4.62, p=0.049), diabetes (4.16, 1.47-11.8, p=0.0073), VKA use at baseline (0.42, 0.18-0.97, p=0.042), aCL IgM positivity (2.48, 1.05-5.83, p=0.038), aβ 2GPI IgM positivity (2.86, 1.18-6.93, p=0.020), mean platelet volume (1.17, 1.06- 1.30, p=0.0024), creatinine (3.76, 1.32- 10.7, p=0.013), and estimate glomerular filtration rate (eGFR, 0.98, 0.96-0.99, p=0.0011) were associated with prospective risk of ATE (Table 2). Conversely, the prospective risk of VTE was univariably associated only with prior history of VTE (3.26, 1.40-7.68, p=0.0061).After adjusting for traditional arterial thrombotic risk factors (age, sex, BMI, active smoking, diabetes,), history of ATE (SHR = 3.97, 95% CI: 1.71-9.025, p=0.0014), prior history of both ATE and VTE (3.87, 1.06-14.16, p=0.041), creatinine (3.93, 1.22-12.66, p=0.022), and eGFR (CKD-EPI, 0.96, 0.96-0.99, p=0.0037) remained independently associated with prospective risk of ATE (Table 2).In detail, the 10-year cumulative risk of ATE was 24.9% [95%CI: 8.8, 41.0], 15.0% [5.8, 24.2], and 6.7% [2.2, 13.8] in patients with a baseline eGFR less than 60 mL/min/1.73m 2, between 60 and 89 mL/min/1.73m 2, and greater than or equal to 90 mL/min/1.73m 2, respectively (Gray's test, p=0.019, Figure 2).Conclusion: Approximately 14% of patients persistently positive for LA experienced an ATE over 10 years. After adjusting for traditional arterial risk factors, decreased renal function was associated with an increased prospective risk of ATE. Notably, decreased renal function was not associated with development of VTE and the association with ATE was also independent of underlying SLE, LLD, or rheumatic disease (data not shown). Clinically, LA positive patients with decreased renal function may represent a subgroup that might benefit from more aggressive anti-thrombotic therapy or anti-thrombotic prophylaxis. [Display omitted] DisclosuresPabinger: Bayer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Daiichi Sanchyo: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NovoNordisk: Consultancy, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding.

Involvement of Inflammation in Venous Thromboembolic Disease

Recent evidence has been established that the inflammatory process is involved in the pathophysiology of Venous Thrombotic Events (VTE) and may have a significant role in prediction of the disease. It is likely that classical and non-classical risk factors modulate thrombosis through inflammatory mediators. Inflammation of the venous wall promotes the release of tissue factor inhibit the release of anticoagulant factors and hamper endogenous fibrinolysis. Recent studies also indicated that increased inflammatory response (interleukin storm) is related to prothrombotic state and thromboembolic events in patients with COVID-19. Inflammatory markers are also negatively related to thrombolysis and restoration of blood flow in the acute phase of Venous Thrombosis (VT). Despite the growing evidence of the involvement of inflammation in pathogenesis of VTE, the importance of anti-inflammatory treatment of this disease was overlooked. Aspirin was shown to be effective in the prevention of recurrent venous thrombosis after treatment with anticoagulant drugs. Some anti-inflammatory drugs like nonsteroidal anti-inflammatory agents may have prothrombotic effect and increase risk of VTE. Therefore, the recent research was dedicated to searching new specific anti-inflammatory drug inhibitors of inflammatory markers, which were shown to be involved in the pathogenesis of VTE. As thrombus formation is based on the activation of coagulation system, provoked by inflammation, prevention and treatment of VTE, should include both anticoagulant and anti-inflammatory agents. To reduce bleeding complications of combined treatment, sub-therapeutic doses of both drugs should be used to improve the efficacy of management of VTE without increasing risk of bleeding.

Use of Glucocorticoids and Risk of Venous Thromboembolism: A Narrative Review.

Glucocorticoids are potent anti-inflammatory agents that are widely used for the treatment of many inflammatory, autoimmune, and neoplastic disorders. However, their beneficial effect is associated with several side effects, including an increased risk of cardiovascular complications, such as myocardial infarction and stroke. Whether their use also contributes to a procoagulant state, and therefore increases the risk of venous thromboembolism (VTE), is still a matter of debate. As an increased risk of venous thrombotic events is described in patients with Cushing's syndrome, which is characterized by endogenous hypercortisolism, it is reasonable to speculate that the chronic administration of glucocorticoids may induce a hypercoagulable state. However, it seems virtually impossible to separate the role of the drug from the underlying condition, which itself predisposes to the development of VTE. Actually, some evidence suggests that the use of exogenous glucocorticoids for the treatment of underlying disease and its exacerbations may further amplify the risk of VTE. Moreover, a procoagulant state has also been reported in healthy participants receiving oral glucocorticoids versus placebo. We have performed a concise narrative review on available data on the influence of exogenous glucocorticoids on hemostasis and their clinical impact on the risk of VTE.

Impact of inflammatory bowel disease on hospital outcomes in acute ischemic stroke: a nationwide cohort study.

Patients with inflammatory bowel disease (IBD) have an increased risk of venous thrombotic events. The impact IBD has on arterial thrombosis is not well characterized. We aimed to identify the impact of IBD on hospital outcomes in patients admitted for acute ischemic stroke (AIS). This is a retrospective cohort study utilizing the 2017 National Inpatient Sample. We identified all adult patients with a principal diagnosis of AIS and compared those with a concurrent diagnosis of IBD to those without-subgrouped by ulcerative colitis (UC) and Crohn's disease (CD). Outcomes were mortality and healthcare usage among IBD patients with AIS. Multivariate analysis was used to control for confounders. Analyses were performed using STATA. Five hundred twenty-four thousand and forty-five patients were admitted for AIS in 2017; of them 2200 (0.41%) had a concurrent diagnosis of IBD. The presence of IBD did not significantly affect in-hospital mortality (4.09% vs. 4.01%) among patients admitted for AIS [OR 1.07 95% CI: 0.65-1.76], with similar findings upon subgroup analysis of UC [OR 0.91, 95% CI: 0.39-2.09] and CD [OR 1.17, 95% CI: 0.62-2.19]. Mean hospital length of stay and charges/costs in AIS were similar irrespective of IBD. UC and CD do not appear to be associated with a higher risk of mortality or increased healthcare usage in AIS. AIS risk assessment in patients with IBD is important but should be done in a similar fashion to the general population.

In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID‐19 patients on anticoagulation

BackgroundCOVID‐19 is associated with a substantial risk of venous thrombotic events, even in the presence of adequate thromboprophylactic therapy. ObjectivesWe aimed to better characterize the hypercoagulable state of COVID‐19 patients in patients receiving anticoagulant therapy. MethodsWe took plasma samples of 23 patients with COVID‐19 who were on prophylactic or intensified anticoagulant therapy. Twenty healthy volunteers were included to establish reference ranges. ResultsCOVID‐19 patients had a mildly prolonged prothrombin time, high von Willebrand factor levels and low ADAMTS13 activity. Most rotational thromboelastometry parameters were normal, with a hypercoagulable maximum clot firmness in part of the patients. Despite detectable anti‐activated factor X activity in the majority of patients, ex vivo thrombin generation was normal, and in vivo thrombin generation elevated as evidenced by elevated levels of thrombin‐antithrombin complexes and D‐dimers. Plasma levels of activated factor VII were lower in patients, and levels of the platelet activation marker soluble CD40 ligand were similar in patients and controls. Plasmin‐antiplasmin complex levels were also increased in patients despite an in vitro hypofibrinolytic profile. ConclusionsCOVID‐19 patients are characterized by normal in vitro thrombin generation and enhanced clot formation and decreased fibrinolytic potential despite the presence of heparin in the sample. Anticoagulated COVID‐19 patients have persistent in vivo activation of coagulation and fibrinolysis, but no evidence of excessive platelet activation. Ongoing activation of coagulation despite normal to intensified anticoagulant therapy indicates studies on alternative antithrombotic strategies are urgently required.

Serum amyloid A4 is a procoagulant apolipoprotein that it is elevated in venous thrombosis patients

BackgroundSerum amyloid A4 (SAA4) is an apolipoprotein that is in the SAA family and it is constitutively translated. Previously, acute‐phase SAA1 and SAA2 levels were associated with venous thromboembolism (VTE). ObjectiveWe investigated the association of plasma SAA4 with VTE and the role of SAA4 in coagulation. Patients and MethodsThe association of SAA4 with VTE in a case‐control study of adult VTE subjects (N = 113 each group) and the effects of recombinant SAA4 on plasma blood coagulation assays and prothrombin activation initiated by factor Xa were evaluated. ResultsPlasma SAA4 levels in VTE subjects were higher vs. controls (48.1 vs. 38.4 µg/mL; P < .001). Elevated plasma SAA4 level (above the 90th percentile of controls) was associated with increased VTE occurrence (odds ratio, 3.8; 95% confidence interval, 1.8‐8.0). This association remained significant after the adjustment for acute‐phase SAA level, suggesting that SAA4 associated with VTE is independent of acute‐phase SAA. Two isoforms of SAA4, that is, glycosylated and nonglycosylated SAA4 isoforms, were each higher in VTE patients. When recombinant SAA4 was added to plasma, it shortened factor Xa‐1‐stage clotting times, showing that it enhances clotting in plasma. In reaction mixtures containing purified factors Xa and Va and prothrombin, recombinant SAA4 increased prothrombin activation, showing that it enhances prothrombinase activity. ConclusionElevated plasma constitutive SAA4 levels were linked to VTE in adults, and SAA4 can enhance thrombin generation in plasma. Our data highlight a previously unknown procoagulant activity of SAA4 that appears to be related to risk of venous thrombotic events.

Safety and Efficacy of Dabigatran Etexilate vs Dose-Adjusted Warfarin in Patients With Cerebral Venous Thrombosis

Patients with cerebral venous thrombosis (CVT) are at risk of recurrent venous thrombotic events (VTEs). Non-vitamin K oral anticoagulants have not been evaluated in randomized controlled trials in CVT. To compare the efficacy and safety of dabigatran etexilate with those of dose-adjusted warfarin in preventing recurrent VTEs in patients who have experienced a CVT. RE-SPECT CVT is an exploratory, prospective, randomized (1:1), parallel-group, open-label, multicenter clinical trial with blinded end-point adjudication (PROBE design). It was performed from December 21, 2016, to June 22, 2018, with a follow-up of 25 weeks, at 51 tertiary sites in 9 countries (France, Germany, India, Italy, the Netherlands, Poland, Portugal, Russia, and Spain). Adult consecutive patients with acute CVT, who were stable after 5 to 15 days of treatment with parenteral heparin, were screened for eligibility. Patients with CVT associated with central nervous system infection or major trauma were excluded, but those with intracranial hemorrhage from index CVT were allowed to participate. After exclusions, 120 patients were randomized. Data were analyzed following the intention-to-treat approach. Dabigatran, 150 mg twice daily, or dose-adjusted warfarin for a treatment period of 24 weeks. Primary outcome was a composite of patients with a new VTE (recurrent CVT, deep vein thrombosis of any limb, pulmonary embolism, and splanchnic vein thrombosis) or major bleeding during the study period. Secondary outcomes were cerebral venous recanalization and clinically relevant non-major bleeding events. In total, 120 patients with CVT were randomized to the 2 treatment groups (60 to dabigatran and 60 to dose-adjusted warfarin). Of the randomized patients, the mean (SD) age was 45.2 (13.8) years, and 66 (55.0%) were women. The mean (SD) duration of exposure was 22.3 (6.16) weeks for the dabigatran group and 23.0 (5.20) weeks for the warfarin group. No recurrent VTEs were observed. One (1.7%; 95% CI, 0.0-8.9) major bleeding event (intestinal) was recorded in the dabigatran group, and 2 (3.3%; 95% CI, 0.4-11.5) (intracranial) in the warfarin group. One additional patient (1.7; 95% CI, 0.0-8.9) in the warfarin group experienced a clinically relevant non-major bleeding event. Recanalization occurred in 33 patients in the dabigatran group (60.0%; 95% CI, 45.9-73.0) and in 35 patients in the warfarin group (67.3%; 95% CI, 52.9-79.7). This trial found that patients who had CVT anticoagulated with either dabigatran or warfarin had low risk of recurrent VTEs, and the risk of bleeding was similar with both medications, suggesting that both dabigatran and warfarin may be safe and effective for preventing recurrent VTEs in patients with CVT. ClinicalTrials.gov identifier: NCT02913326.

Thrombosis as a treatment complication in Hodgkin lymphoma patients: a comprehensive analysis of three prospective randomized German Hodgkin Study Group (GHSG) trials.

The prognosis of Hodgkin lymphoma (HL) is excellent rendering research into treatment complications highly important. An important complication of cancer and its treatment is thrombosis. Thrombotic events are regularly observed in HL patients but precise information on incidence and risk factors is lacking and the value of prophylactic anticoagulation unclear. Thus, we comprehensively studied thrombotic events in 5773 patients from the German Hodgkin Study Group (GHSG) HD13-15 trials in early-favorable, intermediate and advanced HL. We estimated the incidence of and identified risk factors for thrombotic events. Additionally, we provide detailed data on the time course and characteristics of thrombotic events. A total of 193 thrombotic events occurred for an incidence of 3.3%. Out of these, 175 (90.7%) were venous thromboses, 3 (1.5%) newly emerging post-thrombotic syndromes and 15 (7.8%) arterial thromboses. There were 11 (0.7%) events in early-favorable, 27 (1.3%) in early-unfavorable and 155 (7.3%) in advanced patients, the latter incidence being significantly higher (P < 0.001). The most common locations were deep vein thrombosis of the arm (46.3%) and leg (24.6%). Most venous thrombotic events occurred during chemotherapy (78.9%). We observed 59 (30.6%) catheter-associated events and a descriptively increased risk of venous thrombotic events in patients with oral contraception use during treatment (6.8% versus 3.9%). In advanced HL, the incidence of venous thrombotic events was increased upon treatment with BEACOPP-14 (9.4%, P = 0.0079) compared with 5.1% with 6×BEACOPPesc and 5.7% with 8×BEACOPPesc. Among commonly applied risk factors, including the Khorana score, only age and smoking were prognostic. The incidence of thrombotic events in advanced stage HL is comparable to other high-risk cancer patients, especially if treated with dose-dense regimens. Additional risk factors are higher age and smoking. Selected HL patients could benefit from prophylactic anticoagulation, however, further interventional studies are needed before general recommendations can be made.

Incidence of a first venous thrombotic event in people with HIV in the Netherlands: a retrospective cohort study

The risk of venous thrombotic events is elevated in people with HIV, but overall risk estimates and estimates specific to immune status and antiretroviral medication remain i mprecise. In this study, we aimed to estimate these parameters in a large cohort of people with HIV in the Netherlands. In this retrospective cohort study, we used the Dutch ATHENA cohort to estimate crude, age and sex standardised, and risk period-specific incidences of a first venous thrombotic event in people with HIV aged 18 years or older attending 12 HIV treatment centres in the Netherlands. Crude and standardised incidences were compared with European population-level studies of venous thrombotic events. We used time-updated Cox regression to estimate the risk of a first venous thrombotic event in association with HIV-specific factors (CD4 cell count, viral load, recent opportunistic infections, antiretroviral medication use) adjusted for traditional risk factors for venous thrombotic events. With data collected from Jan 1, 2003, to April 1, 2015, our study cohort included 14 389 people with HIV and 99 762 person-years of follow-up, with a median follow-up of 7·2 years (IQR 3·3-11·1). During this period, 232 first venous thrombotic events occurred, yielding a crude incidence of 2·33 events per 1000 person-years (95% CI 2·04-2·64) and an incidence standardised for age and sex of 2·50 events per 1000 (2·18-2·82). CD4 counts less than 200 cells per μL were independently associated with higher risk of a venous thrombotic event: adjusted hazard ratio (aHR) 3·40 (95% CI 2·28-5·08) relative to counts of 500 cells per μL. A high viral load (aHR 3·15, 95% CI 2·00-5·02; >100 000 copies per mL vs <50 copies per mL) and current or recent opportunistic adverse events (2·80, 1·77-4·44) were also independently associated with higher risk of a venous thrombotic event. There were no associations between any specific antiretroviral drugs and risk of a venous thrombotic event. Rates associated with pregnancy (9·4, 95% CI 4·6-17·3), malignancy (16·7, 10·6-25·1), and hospitalisation (24·4, 19·1-30·6) were lower than primary thromboprophylaxis thresholds suggested by the respective guidelines. Our findings support neither prescribing primary outpatient thromboprophylaxis nor avoiding any type of antiretroviral medication in people with HIV at high risk of a venous thrombotic event. Dutch Ministry of Health, Welfare and Sport.

Incidence and Risk Factors of Symptomatic Venous Thromboembolism Following Foot and Ankle Surgery.

The incidence rate of venous thrombotic events (VTEs) following foot and ankle surgery is low. Currently, there is no consensus regarding postoperative prophylaxis or evidence to support risk stratification. A 2-part study assessing the incidence and factors for the development of VTE was conducted: (1) a retrospective observational cohort study of 22 486 adults to calculate the overall incidence following foot and/or ankle surgery from January 2008 to May 2011 and (2) a retrospective matched case-control study to identify risk factors for development of VTE postsurgery. One control per VTE case matched on age and sex was randomly selected from the remaining patients. The overall incidence of VTE was 0.9%. Predictive risk factors in bivariate analyses included obesity, history of VTE, history of trauma, use of hormonal replacement or oral contraception therapy, anatomic location of surgery, procedure duration 60 minutes or more, general anesthesia, postoperative nonweightbearing immobilization greater than 2 weeks, and use of anticoagulation. When significant variables from bivariate analyses were placed into the multivariable regression model, 4 remained statistically significant: adjusted odds ratio (aOR) for obesity, 6.1; history of VTE, 15.7; use of hormone replacement therapy, 8.9; and postoperative nonweightbearing immobilization greater than 2 weeks, 9.0. The risk of VTE increased significantly with 3 or more risk factors ( P = .001). The overall low incidence of VTE following foot and ankle surgery does not support routine prophylaxis for all patients. Among patients with 3 or more risk factors, the use of chemoprophylaxis may be warranted. Level III, retrospective case series.

Drospirenone-containing oral contraceptives and venous thromboembolism: an analysis of the FAERS database.

IntroductionSubstantial evidence suggests that drospirenone-containing oral contraceptives may cause a higher risk of venous thrombotic events than earlier-generation oral contraceptives.MethodsTo gain insight into recent real-world implications, we conducted an analysis using the US Food and Drug Administration’s Adverse Event Reporting System.ResultsVenous thrombotic events continue to be reported at a much higher rate with drospirenone-containing oral contraceptives than the general background. The disproportionality has been rising since 2010. The same behavior is not seen with levonorgestrel-containing oral contraceptives.ConclusionOur results are consistent with decreased physician and patient awareness of risks associated with drospirenone-containing oral contraceptives.

Need for tissue plasminogen activator for central venous catheter dysfunction is significantly associated with thrombosis in pediatric cancer patients.

Central venous catheter (CVC) dysfunction is a common complication among pediatric cancer patients. Tissue plasminogen activator (tPA) is administered to resolve CVC dysfunction. The present study was designed to determine risk factors associated with requirement of tPA for CVC dysfunction and to assess the clinical impact of CVC dysfunction in terms of CVC loss and venous thrombotic events (VTE). Case records of all pediatric patients with cancer from the Maritimes, Canada were reviewed following ethics approval. Data regarding demographics, clinical diagnosis, CVC dysfunction, characteristics of CVCs, and VTE were pooled from multiple data sources. Seven hundred and forty-one patients required ≥1 CVC. 26.3% of patients required tPA for ≥1 episodes of CVC dysfunction. Requirement of one or more doses of tPA for episodes of CVC dysfunction increased the odds of VTE by two times (95% confidence interval, 1.1-3.6). Patients that required ≥1 doses of tPA required significantly more CVCs (2.05±1.29 per individual patient, 55% of the patients needed >1 CVCs) as compared to the remainder (1.52±0.95 per individual patient, 32% needed >1 CVCs) (P=0.0001). Multivariate analysis revealed age>10 years, diagnosis of sarcoma, and tunneled line were independently associated with tPA requirement. We determined independent risk factors associated with requirement of tPA for CVC dysfunction. Requirement of tPA for CVC dysfunction was associated with significantly increased risk of VTE and requirement of more CVCs. These observations can assist in identification of patients at increased risk of CVC dysfunction and inform approaches to reduce CVC loss and VTE.

Safety of Retrievable Inferior Vena Cava Filter Placements in High-Risk Bariatric Surgery Patients

Background: Bariatric surgery patients are at a higher risk for venous thrombotic events. Inferior vena cava filter (IVCf) placement to prevent thrombotic complications is still considered controve...

Risk of Venous Thrombotic Events (VTE) in Patients with Myelodysplastic Syndromes with 5q Deletion during Lenalidomide Therapy: Single Institution Experience

Abstract Introduction: Lenalidomide (LEN) has been known to increase the risk of venous thromboembolism (VTE) in patients treated for multiple myeloma, non-Hodgkin lymphomas and myelodysplastic syndrome (MDS) with and without 5q deletion. The current recommendations are to place patients on anticoagulation. We hereby describe the frequency of VTE in patients with MDS with 5q Syndrome treated with single agent LEN off protocol in a single institution. Methods: We performed data extraction from Mayo clinic records (October 1993 to March 2016) for patients with confirmed 5q Syndrome (5q + one abnormality except -7/7qdel and bone marrow blast Results: Out of 1222 patients with MDS, 39 patients (3%) were identified with confirmed diagnosis of 5q Syndrome; 19 (2%) of which were treated with LEN. Median age was 69 years (56-87), with 58% being males. Median hemoglobin was 10.4 gm/dL (7.7-11.7), white blood cell count (WBC) 4.7 x109/L (1.1-8.7), platelets of 153 x109/L (63-805), and median bone marrow blasts 1%(0-7). Risk stratification per IPSS-R was either very low or low risk in 38% and 62%, respectively. Median erythropoietin level prior to LEN start was 90 (21-1937). Transformation into acute myeloid leukemia was found in 16% of the cases, with a median overall survival of 52 months. Hematological improvement (HI) was achieved in 58% of the patients. In 11 cases repeat bone marrow biopsies and cytogenetic reassessment was done, 4 (40%) patients achieved complete cytogenetic remission. Median response duration was 25.9 months. Thirteen (68%) of the 19 patients were taking anticoagulation (3 warfarin, 1 rivaroxaban) or antiplatelet therapy (9 aspirin) while 6 patients did not take any anticoagulation during LEN therapy. VTE was found in 2 (11%) patients both of which were on anticoagulation (1 on aspirin, and one on warfarin). None of the 6 patients who were not taking anticoagulation therapy developed VTE. Conclusion: MDS 5q Syndrome subgroup is a small cohort of patients representing 3% of all MDS patients. Anticoagulation was done in majority of patients with 5q Syndrome when treated with LEN. VTE was found to be an infrequent complication (11%) in patients treated with LEN and happened despite being on prophylactic anticoagulation. Larger size cohorts are needed to study this correlation further. Disclosures No relevant conflicts of interest to declare.