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Background: Sources of heterogeneity in venous thromboembolism (VTE) risk in COVID-19 are unclear and comparisons to other viruses are lacking., Objectives: To describe VTE risk in patients with COVID-19, explore sources of heterogeneity, and make comparisons with other viral pneumonia., Methods: PubMed and Embase data were searched on March 14, 2021, for studies on VTE in adults hospitalized with viral pneumonia. VTE risk estimates were pooled in a random effects meta-analysis stratified by virus type. Heterogeneity in COVID-19 was explored in multivariable meta-regression., Results: Seventy studies in COVID-19 (intensive care [ICU] [47] vs ward [23]), 4 studies in seasonal influenza (ICU [3] vs ward [1]), 2 ICU studies in H1N1 and 1 ICU study in SARS-CoV-1 were included. For COVID-19 ICU, pooled VTE risk was 19.6% (95% confidence interval [CI], 16.2%-23.5; I 2  = 92.8%) for nonscreening studies and 30.0% (95% CI, 17.9%-45.7%; I 2  = 81.9%) for screening studies. For COVID-19 ward, pooled VTE risk was 3.4% (95% CI, 2.4%-4.7%; I 2  = 91.3%) and 22.5% (95% CI, 10.2%-42.7%; I 2  = 91.6%) for nonscreening and screening studies, respectively. Higher sample size was associated with lower VTE risk. Pooled VTE risk in seasonal influenza and H1N1 at ICU were 9.0% (95% CI, 5.6%-14.2%; I 2  = 39.7%) and 29.2% (95% CI, 8.7%-64.2%; I 2  = 77.9%), respectively. At ward, VTE risk of seasonal influenza was 2.4% (95% CI, 2.1%-2.7%). In SARS-CoV-1, VTE risk was 47.8% (95% CI, 34.0-62.0)., Conclusion: Pooled risk estimates in COVID-19 should be interpreted cautiously as a high degree of heterogeneity is present, which hinders comparison to other viral pneumonia. The association of VTE risk in COVID-19 to sample size suggests publication bias., (© 2023 The Author(s).)

Trends of coagulation parameters during long-term treatment with combination antiretroviral therapy (cART) are unclear. We followed 40 male subjects living with human immunodeficiency virus (HIV). Plasma levels of procoagulant parameters, factor VIII, von Willebrand factor and D-dimer, and anticoagulant parameter Protein S (PS), were measured before start and 3 months, 1 year, and 9 years after. Analyses were adjusted for cardiovascular risk factors (age, smoking, and hypertension) at baseline. At baseline, procoagulant parameters were markedly elevated and PS was in the lower range of normal. CD4/CD8-ratio improved during the complete follow-up period. In the first year, procoagulant parameters were decreasing, but at year 9 an increase was observed. After correction for cardiovascular risk factors, this increase was no longer present. PS remained stable during the first year and slightly increased from one to 9 years. This study indicates that decreasing immune activation by cART reverses the procoagulant state in HIV partially during the first year. These parameters increase in the long term despite an on-going decrease in immune activation. This increase might be related to established cardiovascular risk factors.

Background: Recurrence risk of systemic lupus erythematosus (SLE)-associated venous thromboembolism (VTE) is unclear., Aim: To determine the recurrence risk of SLE-associated VTE overall and by presence of provoking factors and SLE flares., Methods: A multicenter, retrospective cohort study was conducted among patients with first SLE-associated VTE who discontinued anticoagulation. SLE flares were defined as Systemic Lupus Erythematosus Disease Activity Index 2000 greater than 4. The primary outcome was recurrent VTE. Incidence rates and cumulative incidences were calculated by presence of provoking factors and antiphospholipid syndrome (APS) at index VTE. The hazard ratio (HR) for recurrence after SLE flare-associated index VTE was estimated with Cox regression, adjusted for provoking factor presence and APS., Results: Eighty patients were included with 21 recurrent VTEs in median 8 years. For provoked index VTE, the recurrence rate in patients without APS was 1.1 per 100 person-years (PY; 95% confidence interval [CI], 0.1-3.1) and in the presence of APS 3.5 per 100 PY (95% CI, 0.9-8.9), yielding cumulative incidences of 7.5% (95% CI, 1.2%-21.7%) and 31.4% (95% CI, 6.3%-61.6%) respectively. For unprovoked index VTE, these analogous rates were 3.8 per 100 PY (95% CI, 1.2-9.0) and 16.7 per 100 PY (95% CI, 4.5-42.7), with cumulative incidences of 33.7% (95% CI, 10.7%-58.9%) and 54.2% (95% CI, 10.7%-84.5%), respectively. Forty-six index VTEs were flare associated, and the adjusted HR for recurrence was 0.4 (95% CI, 0.1-1.8) compared to those without flares at their index VTE., Conclusion: Antiphospholipid syndrome is the main determinant for recurrence risk of SLE-associated VTE irrespective of presence of a provoking factor. Future research should attempt to confirm that flare-associated VTE has a lower recurrence risk., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background:  Inflammation is present in several conditions associated with risk of venous thromboembolism. The gut microbiome might be a source of systemic inflammation and activation of coagulation, by translocation of lipopolysaccharides from gram-negative bacteria to the systemic circulation., Objective:  To investigate whether a vancomycin-induced shift of the gut microbiome in a gram-negative direction influences systemic inflammation and plasma factor (F) VIII procoagulant activity (FVIII:C)., Methods and Results:  We performed a randomized controlled trial including 43 healthy volunteers aged 19 to 37 years. Twenty-one were randomized to 7 days of oral vancomycin intake and 22 served as controls. Feces and blood were sampled at baseline, the day after the end of intervention, and 3 weeks after intervention. Gut microbiome composition was assessed by amplicon sequencing., Fviii: C was measured using an activated partial thromboplastin time-based assay, cytokines were measured using multiplex technology, complement activation was measured using the enzyme-linked immunosorbent assay, and high-sensitivity C-reactive protein (CRP) was measured by an immunoturbidimetric assay. Vancomycin intake reduced gut microbiome diversity and increased the abundance of gram-negative bacteria. Change in FVIII:C in the intervention group was +4 IU/dL versus -6 IU/dL ( p  = 0.01) in the control group. A similar change was observed for log-transformed CRP (+0.21 mg/dL vs. -0.25 mg/dL, p  = 0.04). The cytokines and complement activation markers remained similar in the two groups., Conclusion:  The found slight increases in FVIII:C and CRP levels might support the hypothesis that a vancomycin-induced gram-negative shift in the gut microbiome could induce increased systemic inflammation and thereby a procoagulant state., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the risk of recurrent VTE in PWH compared to controls and to identify risk factors for recurrence within this population., Methods and Findings: PWH with a first VTE were derived from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort (2003-2015), a nationwide ongoing cohort following up PWH in care in the Netherlands. Uninfected controls were derived from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) follow-up study (1999-2003), a cohort of patients with a first VTE who initially participated in a case-control study in the Netherlands who were followed up for recurrent VTE. Selection was limited to persons with an index VTE suffering from deep vein thrombosis in the lower limbs and/or pulmonary embolism (PE). Participants were followed from withdrawal of anticoagulation to VTE recurrence, loss to follow-up, death, or end of study. We estimated incidence rates, cumulative incidence (accounting for competing risk of death) and hazard ratios (HRs) using Cox proportional hazards regression, adjusting for age, sex, and whether the index event was provoked or unprovoked. When analyzing risk factors among PWH, the main focus of analysis was the role of immune markers (cluster of differentiation 4 [CD4]+ T-cell count). There were 153 PWH (82% men, median 48 years) and 4,005 uninfected controls (45% men, median 49 years) with a first VTE (71% unprovoked in PWH, 34% unprovoked in controls) available for analysis. With 40 VTE recurrences during 774 person-years of follow-up (PYFU) in PWH and 635 VTE recurrences during 20,215 PYFU in controls, the incidence rates were 5.2 and 3.1 per 100 PYFU (HR: 1.70, 95% CI 1.23-2.36, p = 0.003). VTE consistently recurred more frequently per 100 PYFU in PWH in all predefined subgroups of men (5.6 versus 4.8), women (3.6 versus 1.9), and unprovoked (6.0 versus 5.2) or provoked (3.1 versus 2.1) first VTE. After adjustment, the VTE recurrence risk was higher in PWH compared to controls in the first year after anticoagulant discontinuation (HR: 1.67, 95% CI 1.04-2.70, p = 0.03) with higher cumulative incidences in PWH at 1 year (12.5% versus 5.6%) and 5 years (23.4% versus 15.3%) of follow-up. VTE recurred less frequently in PWH who were more immunodeficient at the first VTE, marked by a better CD4+ T-cell recovery on antiretroviral therapy and during anticoagulant therapy for the first VTE (adjusted HR: 0.81 per 100 cells/mm3 increase, 95% CI 0.67-0.97, p = 0.02). Sensitivity analyses addressing potential sources of bias confirmed our principal analyses. The main study limitations are that VTEs were adjudicated differently in the cohorts and that diagnostic practices changed during the 20-year study period., Conclusions: Overall, the risk of recurrent VTE was elevated in PWH compared to controls. Among PWH, recurrence risk appeared to decrease with greater CD4+ T-cell recovery after a first VTE. This is relevant when deciding to (dis)continue anticoagulant therapy in PWH with otherwise unprovoked first VTE., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: CR reports grants from Gilead, Merck, and personal fees from Gilead, ViiV, Janssen-Cilag. JFBH and EDP report no conflicts of interest. YIGVT was employed by the Dutch National Health Institute during analysis and reporting on this study. CS reports grants from Netherlands Ministry of Health, Welfare and Sport, National Institute for Public Health and the Environment, Centre for Infectious Disease Control, during the conduct of the study. FW reports personal fees from Gilead Sciences, personal fees from ViiV Healthcare, outside the submitted work. PR reports independent scientific grant support to his institution from Gilead Sciences, Janssen Pharmaceuticals Inc., Merck & Co., Bristol-Myers Squibb, and ViiV Healthcare; fees to his institution for his participation on scientific advisory boards for Gilead Sciences ViiV Healthcare, Merck & Co., Teva pharmaceutical industries, and on a data safety monitoring committee for Janssen Pharmaceuticals Inc. BR reports grants from Gilead, grants from MSD, nonfinancial support from MSD, nonfinancial support from Gilead, nonfinancial support from BMS, nonfinancial support from Janssen-Cilag, nonfinancial support from ViiV, nonfinancial support from Abbvie, personal fees from Gilead, personal fees from ViiV, personal fees from Great-Lakes pharmaceuticals, outside the submitted work; and financial compensation payed to institution for advisory board participation organized by Gilead, ViiV, BMS, Janssen-Cilag, and MSD. KM received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; consulting fees from Uniqure (outside the submitted work, all fees go to the institution). WBW reports reimbursement payed to institution for investigator-initiated study from Janssen-Cilag, financial compensation payed to institution for multicenter study by GSK and catering of a symposium by Janssen-Cilag, all outside the submitted work. SCC is a member of the Editorial Board of PLOS Medicine. WML reports no conflicts of interest.

A role for transient infections in the aetiology of venous thrombosis (VT) has been suggested. This study aimed to determine whether individuals who receive antibiotic treatment (as a proxy for infections) have an increased risk of first and recurrent VT and whether infections should be seen as a provoking risk factor for VT. We used the self-controlled case series method to study the risk of first VT during antibiotic prescriptions. The risk of recurrent VT during antibiotic use was estimated by of time-dependent Cox-regression. A total of 2547 patients with a first VT were included and followed for a median of 5·9 years for recurrence (1999-2010), in whom 114 first events occurred during antibiotic use. We found a five-fold increased risk of first VT during antibiotic treatment: [incidence-rate-ratio 5·0; 95% confidence interval (CI), 4·0-6·1]. Antibiotic use was associated with a 2·0-fold (95% CI, 1·1-4·0) increased risk of recurrent VT. Patients with an unprovoked first VT who used antibiotics shortly before this event, had a similar risk of recurrence as patients with a provoked first VT (adjusted hazard ratio 1·1; 95% CI, 0·7-1·7). Individuals who receive antibiotics have an increased risk of first and recurrent VT and infections should be considered a provoking risk factor for VT., (© 2017 John Wiley & Sons Ltd.)

We determined in a prospective cohort of patients treated with vitamin K antagonists for venous thrombosis, the course of factor VIII (FVIII:C), C-reactive protein (CRP) and fibrinogen levels, to assess the influence of the acute phase reaction on FVIII:C levels. Second, we hypothesized that patients with preceding infectious symptoms might have higher levels of FVIII:C at baseline than patients without those. We included 75 patients. Blood was sampled at baseline, once during treatment (t=1) and at the end of treatment (t=2). Mean levels of FVIII:C were 207, 186 and 175IU/dL (p for trend 0.003) at baseline, t=1 and t=2 respectively. Eight-eight percent of patients had an elevated FVIII:C at baseline, 75% at t=1 and 72% at t=2 (p for trend 0.045). Mean levels of FVIII:C were not different in patients with or without preceding infectious symptoms (206 versus 205IU/dL respectively). A baseline CRP level below 62mg/L could best distinguish between patients who will keep an elevated FVIII:C and those who will drop below 150IU/dL. We conclude that FVIII:C levels are partially influenced by the acute phase reaction, especially in patients who keep a persistent elevated FVIII:C during treatment. Preceding infectious symptoms did not influence baseline FVIII:C levels., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A 46-year-old woman who was treated in the past for locally advanced breast cancer, presented with signs of acute liver failure. FDG PET revealed a massive hot liver with increased activity without any pathologic FDG uptake elsewhere in the body. Therefore, the term hepatic superscan was chosen because intense diffuse hepatic FDG uptake was seen in combination with a surprisingly low cardiac and in minor degree of low brain uptake, similar to the superscan pattern encountered in conventional skeletal scintigraphy. This very unusual finding was the indicator of extensive hepatic involvement caused by breast cancer.