Significance and management of isolated distal deep vein thrombosis.

PURPOSE OF REVIEW: Management of isolated distal deep vein thrombosis (IDDVT) remains controversial. We summarize recent studies regarding the natural history of IDDVT as well as pertinent therapeutic trials. We also provide our management approach. RECENT FINDINGS: IDDVT is more commonly associated with transient risk factors and less often associated with permanent, unmodifiable risk factors than proximal DVT. IDDVT has a significantly lower risk of proximal extension and recurrence than proximal DVT. Cancer-associated IDDVT has a similar natural history to cancer-associated proximal DVT, with substantially less favourable outcomes than noncancer-associated IDDVT. Anticoagulant treatment reduces the risk of proximal extension and recurrence in IDDVT at the cost of increased bleeding risk. Intermediate dosing of anticoagulation may be effective for treating noncancer-associated IDDVT in patients without prior DVT. SUMMARY: IDDVT with a transient risk factor can be treated for 6 weeks in patients without a prior DVT. Unprovoked IDDVT in patients without malignancy can be treated for 3 months. Outpatients without malignancy or a prior DVT can be left untreated and undergo surveillance compression ultrasound in one week to detect proximal extension, but few patients opt for this in practice. Cancer-associated IDDVT should be treated analogously to cancer-associated proximal DVT.

Organized breast screening improves reattendance compared to physician referral: a case control study.

BACKGROUND: The Ontario Breast Screening Program (OBSP) is a population-based breast screening programme, not requiring physician referral. OBSP invites women by mail to book their next screens. However, women who do not participate in the OBSP, may be referred by physicians to non-OBSP mammography facilities, which do not remind women to book their next screen. METHODS: We identified women without breast cancer prior to June 30, 2011, having bilateral mammography (M) during a baseline period at age 50 - 69 at OBSP or non-OBSP facilities, and during a re-exposure period, at the same facility type. We used a case-control design to study the association of facility type and having M during an outcome period. Cases were women failing to receive the outcome M. Controls were matched by age, census tract, and socioeconomic status. Exposure was baseline facility type. Covariates were comorbidity, residential mobility, and primary care physician (PCP) characteristics. Conditional logistic regression analysis was performed. RESULTS: Cases were less likely to have been screened at OBSP facilities. Failure to receive the outcome M was associated with having moved after re-exposure M (OR = 1.61, 95% confidence interval (CI) 1.52, 1.71), having a male PCP (OR = 1.05, 95% CI 1.02, 1.05), or a higher Charlson score (OR = 1.06 per unit increase, 95% CI 1.03, 1.09). Having re-exposure M at an OBSP facility (OR = 0.18, 95% CI 0.18, 0.19)., having a Canadian trained PCP (OR = 0.83, 95% CI 0.8, 0.87), and having a PCP one year after the re-exposure M (OR = 0.81, 95% CI 0.68, 0.97) were protective against failure to receive the outcome M. CONCLUSIONS: The OBSP, not requiring physician referral, and inviting women by mail to book their next screen, is associated with a lower probability of failure to reattend for subsequent screening than screening by PCP referral to non-OBSP facilities.

TILE pilot trial study protocol: Tinzaparin Lead-in to Prevent the Post-Thrombotic syndrome study protocol.

INTRODUCTION: The post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency due to a prior ipsilateral deep venous thrombosis (DVT). This is a frequent complication that develops in 20%-50% of patients after a proximal DVT and is associated with significant healthcare, economic and societal consequences. In the absence of effective and well-tolerated treatment options for established PTS, effective preventative measures are needed. Anticoagulation itself reduces the risk of PTS, and low-molecular-weight heparin may reduce this further through anti-inflammatory properties targeting the initial acute inflammatory phase of DVT. METHODS AND ANALYSIS: The Tinzaparin Lead-In to Prevent the Post-Thrombotic syndrome pilot trial is an investigator-initiated, multicentre, open-label assessor-blinded trial that will randomise patients with first acute symptomatic common femoral or iliac DVT to receive either a 3-week lead-in course of tinzaparin, followed by rivaroxaban (experimental arm) or rivaroxaban alone (control arm). Its primary objectives are to assess: (1) proportion of PTS at 6 months using the Villalta scale and (2) study feasibility, which consists of (a) the proportion of screened patients eligible for the study, (2) the proportion of eligible patients recruited and (c) the proportion of recruited patients adherent to treatment (defined as at least 80% of drug taken). This study will determine the feasibility of a subsequent larger definitive trial. Secondary outcomes include change of quality of life scores, PTS severity, global improvement, patient satisfaction, bleeding, recurrent venous thromboembolism, leg pain, death and lost to follow-up. Target recruitment will be a total of 60 participants, recruited at 5-6 centres. ETHICS AND DISSEMINATION: Primary ethics approval was received from the Sunnybrook Health Sciences Center Research Ethics Board (approval ID 3315). Results of the study will be disseminated via peer-reviewed presentation at scientific conferences and open access publication. TRIAL REGISTRATION NUMBER: NCT04794569.

Prevention of the Postthrombotic Syndrome with Anticoagulation: A Narrative Review.

The postthrombotic syndrome (PTS) is chronic venous insufficiency secondary to a prior deep vein thrombosis (DVT). It is the most common complication of venous thromboembolism (VTE) and, while not fatal, it can lead to chronic, unremitting symptoms as well as societal and economic consequences. The cornerstone of PTS treatment lies in its prevention after DVT. Specific PTS preventative measures include the use of elastic compression stockings and pharmacomechanical catheter-directed thrombolysis. However, the efficacy of these treatments has been questioned by large randomized controlled trials (RCTs). So far, anticoagulation, primarily prescribed to prevent DVT extension and recurrence, appears to be the only unquestionably effective treatment for the prevention of PTS. In this literature review we present pathophysiological, biological, radiological, and clinical data supporting the efficacy of anticoagulants to prevent PTS and the possible differential efficacy among available classes of anticoagulants (vitamin K antagonists [VKAs], low molecular weight heparins [LMWHs] and direct oral anticoagulants [DOACs]). Data suggest that LMWHs and DOACs are superior to VKAs, but no head-to-head comparison is available between DOACs and LMWHs. Owing to their potentially greater anti-inflammatory properties, LMWHs could be superior to DOACs. This finding may be of interest particularly in patients with extensive DVT at high risk of moderate to severe PTS, but needs to be confirmed by a dedicated RCT.

Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis, the Ottawa Protocol.

Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat patients with highly active multiple sclerosis (MS) refractory to disease-modifying therapy. Briefly, cyclophosphamide and filgrastim are used to mobilize autologous hematopoietic stem cells (HSC) into the circulation. HSC are harvested by leukapheresis, purified using a CD34 immunomagnetic selection process, and cryopreserved. Busulphan, cyclophosphamide, and rabbit anti-thymocyte globulin are used to destroy the patient's autoreactive immune system, followed by infusion of the previously collected HSC, which reconstitute a naïve and self-tolerant immune system. Many MS patients experience durable remissions with no evidence of new disease activity following aHSCT. Treatment-related toxicity is rare, but potentially life-threatening complications necessitate appropriate patient selection by MS neurologists and HSCT physicians. AHSCT must be performed with a highly trained multidisciplinary team expert to minimize morbidity and mortality. We present the current aHSCT procedure for an MS indication at The Ottawa Hospital, developed from our program's 20-year experience. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Candidate selection Basic Protocol 2: Autologous hematopoietic stem cell mobilization, collection, purification, and cryopreservation Basic Protocol 3: Autologous hematopoietic stem cell transplantation Basic Protocol 4: Supportive care following recovery from aHSCT (Beyond 100 days) Basic Protocol 5: Ongoing evaluation of multiple sclerosis.

Prevention and Management of the Post-Thrombotic Syndrome.

The post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency secondary to prior deep vein thrombosis (DVT). It affects up to 50% of patients after proximal DVT. There is no effective treatment of established PTS and its management lies in its prevention after DVT. Optimal anticoagulation is key for PTS prevention. Among anticoagulants, low-molecular-weight heparins have anti-inflammatory properties, and have a particularly attractive profile. Elastic compression stockings (ECS) may be helpful for treating acute DVT symptoms but their benefits for PTS prevention are debated. Catheter-directed techniques reduce acute DVT symptoms and might reduce the risk of moderate-severe PTS in the long term in patients with ilio-femoral DVT at low risk of bleeding. Statins may decrease the risk of PTS, but current evidence is lacking. Treatment of PTS is based on the use of ECS and lifestyle measures such as leg elevation, weight loss and exercise. Venoactive medications may be helpful and research is ongoing. Interventional techniques to treat PTS should be reserved for highly selected patients with chronic iliac obstruction or greater saphenous vein reflux, but have not yet been assessed by robust clinical trials.

Physiological fluctuations in white matter are increased in Alzheimer's disease and correlate with neuroimaging and cognitive biomarkers.

The objective of this study was to determine whether physiological fluctuations in white matter (PFWM) on resting-state functional magnetic resonance images could be used as an index of neurodegeneration and Alzheimer's disease (AD). Using resting-state functional magnetic resonance image data from participants in the Alzheimer's Disease Neuroimaging Initiative, PFWM was compared across cohorts: cognitively healthy, mild cognitive impairment, or probable AD. Secondary regression analyses were conducted between PFWM and neuroimaging, cognitive, and cerebrospinal fluid biomarkers. There was an effect of cohort on PFWM (t = 5.08, degree of freedom [df] = 424, p < 5.7 × 10(-7)), after accounting for nuisance effects from head displacement and global signal (t > 6.16). From the neuroimaging data, PFWM was associated with glucose metabolism (t = -2.93, df = 96, p = 0.004) but not ventricular volume (p < 0.49) or hippocampal volume (p > 0.44). From the cognitive data, PFWM was associated with composite memory (t = -3.24, df = 149, p = 0.0015) but not executive function (p > 0.21). PFWM was not associated with cerebrospinal fluid biomarkers. In one final omnibus model to explain PFWM (n = 124), glucose metabolism (p = 0.04) and cohort (p = 0.008) remained significant, as were global and head motion root-mean-square terms, whereas memory was not (p = 0.64). PFWM likely reflects end-arteriole intracranial pulsatility effects that may provide additional diagnostic potential in the context of AD neurodegeneration.

BOLD fMRI in the white matter as a marker of aging and small vessel disease.

PURPOSE: Determine whether white matter signal fluctuation on T2* weighted BOLD contrast images are associated with aging and cerebral small vessel disease (SVD). METHODOLOGY: Resting state BOLD data were collected with a 250 ms repetition time (TR) to achieve unaliased, ungated cardiac sampled BOLD (cs-BOLD) images on 11 young adult controls, 10 healthy older adult controls and 7 adults with extensive white matter hyperintensities (WMH) from SVD. Tissue classes (WM and GM) were segmented on T1 images. WMH were identified on FLAIR images in the SVD group. Raw physiological noise (σphysio) and cardiac pulsatility (i.e. fluctuations at the cardiac frequency) were calculated voxel wise and group differences were tested by ANOVA. It was also possible to calculate σphysio in 2s TR cardiac aliased whole-brain BOLD (wb-BOLD) data (N = 84) obtained from the International Consortium for Brain Mapping. RESULTS: CS-BOLD metrics showed an aging and SVD effects (p<0.0005). Covariates such as thermal noise, WM volume and partial volume did not influence the significant aging effect seen on the cardiac pulsatility metric (p<0.017) but did influence the σphysio (p = 0.184). As a verification of the cs-BOLD findings, the wb-BOLD also showed a linear aging effect of σphysio in WM. In the SVD adults, cardiac pulsatility and σphysio were lower in WMH regions compared to normal appearing white matter (NAWM) regions (p<0.0013 and p<0.002, respectively). Cardiac pulsatility was better able to distinguish WMH regions from NAWM than σphysio as measured by effect size (Cohen's d 2.2 and 0.88, respectively). CONCLUSION: NAWM was found to have graded increases in cardiac pulsations due to age and SVD, independently. Within SVD participants, WMH lesions had reduced physiological noise compared to NAWM. Cardiac pulsatility in resting BOLD data may provide a complementary dynamic measure of WM integrity to add to static FLAIR anatomical images.