Advances and current research in primary thromboprophylaxis to prevent hospital-associated venous thromboembolism.

Hospital-associated venous thromboembolism (VTE) is defined as any case of VTE occurring during hospital admission and for up to 90 days post discharge. It accounts for over 50% of all cases of VTE internationally; indeed, there are an estimated 10 million cases of hospital-associated VTE annually. Over the last decade, there has been increasing interest in improving VTE risk assessment and thromboprophylaxis. This review summarises all the recent and ongoing major research studies and future challenges in the different areas, including medical, surgical and obstetric patients, as well as special areas such as lower limb immobilisation. We include sections on both pharmacological and mechanical thromboprophylaxis.

Prevention of hospital-associated venous thromboembolism - Insight from the Getting It Right First Time thrombosis survey in England.

A national Venous Thromboembolism (VTE) Prevention Programme was introduced in England in 2010, with limited subsequent study of its impact. Whilst the National Outcomes Framework reports VTE deaths related to hospitalisation annually, there are little data regarding VTE prevention practice or non-fatal VTE associated with hospitalisation. We report the first national thrombosis survey undertaken in collaboration with Getting It Right First Time. 98 Trusts (103 sites, 67% of 144 invited) participated in at least one survey, contributing data regarding VTE prevention in 9553 patients. Anti-coagulant thromboprophylaxis was prescribed to 88% (when indicated), with 8.1% of patients missing doses. Written patient information was provided to 31%. Of 4595 episodes of hospital-associated VTE, 13% were considered potentially preventable. The survey highlights the success of the national programme and areas for improvement in delivery of thromboprophylaxis and patient information.

Clinical outcomes and the impact of prior oral anticoagulant use in patients with coronavirus disease 2019 admitted to hospitals in the UK - a multicentre observational study.

Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease 2019 (COVID-19). Patients on oral anticoagulants (OAC) prior to diagnosis of COVID-19 may therefore have better outcomes. In this multicentre observational study of 5 883 patients (≥18 years) admitted to 26 UK hospitals between 1 April 2020 and 31 July 2020, overall mortality was 29·2%. Incidences of thrombosis, major bleeding (MB) and multiorgan failure (MOF) were 5·4%, 1·7% and 3·3% respectively. The presence of thrombosis, MB, or MOF was associated with a 1·8, 4·5 or 5·9-fold increased risk of dying, respectively. Of the 5 883 patients studied, 83·6% (n = 4 920) were not on OAC and 16·4% (n = 963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis [hazard ratio (HR) 1·05, 95% confidence interval (CI) 0·93-1·19; P = 0·15] or in an adjusted propensity score analysis (HR 0·92 95% CI 0·58-1·450; P = 0·18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulation prior to diagnosis of COVID-19 was admission to the Intensive-Care Unit (ICU) (HR 1·98, 95% CI 1·37-2·85). Thrombosis, MB, and MOF were associated with higher mortality. Our results indicate that patients may have benefit from prior OAC use, especially reduced admission to ICU, without any increase in bleeding.

Postdischarge venous thromboembolism following hospital admission with COVID-19.

The association of severe coronavirus disease 2019 (COVID-19) with an increased risk of venous thromboembolism (VTE) has resulted in specific guidelines for its prevention and management. The VTE risk appears highest in those with critical care admission. The need for postdischarge thromboprophylaxis remains controversial, which is reflected in conflicting expert guideline recommendations. Our local protocol provides thromboprophylaxis to COVID-19 patients during admission only. We report postdischarge VTE data from an ongoing quality improvement program incorporating root-cause analysis of hospital-associated VTE (HA-VTE). Following 1877 hospital discharges associated with COVID-19, 9 episodes of HA-VTE were diagnosed within 42 days, giving a postdischarge rate of 4.8 per 1000 discharges. Over 2019, following 18 159 discharges associated with a medical admission; there were 56 episodes of HA-VTE within 42 days (3.1 per 1000 discharges). The odds ratio for postdischarge HA-VTE associated with COVID-19 compared with 2019 was 1.6 (95% confidence interval, 0.77-3.1). COVID-19 hospitalization does not appear to increase the risk of postdischarge HA-VTE compared with hospitalization with other acute medical illness. Given that the risk-benefit ratio of postdischarge thromboprophylaxis remains uncertain, randomized controlled trials to evaluate the role of continuing thromboprophylaxis in COVID-19 patients following hospital discharge are required.

Effect of type 1 diabetes and type 2 diabetes on the risk of venous thromboembolism.

AIMS: Whether diabetes increases venous thromboembolism (VTE) is unclear. Any greater risk may relate to insulin resistance, but many studies did not differentiate between type 1 diabetes and type 2 diabetes for VTE risk. METHODS: Retrospective cohort study of the Royal College of General Practitioners Research and Surveillance Centre, comprising over 530 primary care practices. We determined whether type 1 diabetes and/or type 2 diabetes are independent risk factors for VTE. The index date was 1 January 2009, individuals were followed to 31 December 2018, or censoring. Cox proportional hazard regression analysis was used to investigate the risk of VTE in people with type 1 diabetes and type 2 diabetes relative to no diabetes. The primary outcome was occurrence of VTE. The model was adjusted for potential confounders for VTE. RESULTS: There were 7086 people with type 1 diabetes and 95,566 with type 2 diabetes, diagnosed before 1 January 2009. The non-diabetes group consisted of 1,407,699 people. In the unadjusted analysis, there was no increased risk of VTE with type 1 diabetes (HR 1.00, 95% CI 0.76-1.33) but there was for type 2 diabetes (HR 2.70, 95% CI 2.57-2.84). In the fully adjusted model, VTE risk was increased in type 1 diabetes (HR 1.46, 95% CI 1.11-1.92), but not with type 2 diabetes (HR 1.06, 95% CI 0.98-1.14). CONCLUSIONS: Type 1 diabetes was associated with a greater risk for VTE while type 2 diabetes was not. Further work is needed to determine the reason(s) for this.

The effect of microgravity on the human venous system and blood coagulation: a systematic review.

NEW FINDINGS: What is the central question of this study? Recently, an internal jugular venous thrombus was identified during spaceflight: does microgravity induce venous and/or coagulation pathophysiology, and thus an increased risk of venous thromboembolism (VTE)? What is the main finding and its importance? Whilst data are limited, this systematic review suggests that microgravity and its analogues may induce an enhanced coagulation state due to venous changes most prominent in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability in microgravity and its analogues. However, whether such changes precipitate an increased VTE risk in spaceflight remains to be determined. ABSTRACT: Recently, an internal jugular venous thrombus was identified during spaceflight, but whether microgravity induces venous and/or coagulation pathophysiology, and thus, an increased risk of venous thromboembolism (VTE) is unclear. Therefore, a systematic (Cochrane compliant) review was performed of venous system or coagulation parameters in actual spaceflight (microgravity) or ground-based analogues in PubMed, MEDLINE, Ovid EMBASE, Cochrane Library, European Space Agency, National Aeronautics and Space Administration, and Deutsches Zentrum für Luft-und Raumfahrt databases. Seven-hundred and eight articles were retrieved, of which 26 were included for evaluation with 21 evaluating venous, and five coagulation parameters. Nine articles contained spaceflight data, whereas the rest reported ground-based analogue data. There is substantial variability in study design, objectives and outcomes. Yet, data suggested cephalad venous system dilatation, increased venous pressures and decreased/reversed flow in microgravity. Increased fibrinogen levels, presence of thrombin generation markers and endothelial damage were also reported. Limited human venous and coagulation system data exist in spaceflight, or its analogues. Nevertheless, data suggest spaceflight may induce an enhanced coagulation state in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability. Whether such changes precipitate an increased VTE risk in spaceflight remains to be determined.

Incidence of Bleeding and Thrombosis in Patients with Liver Disease.

Historically, liver disease has been associated with a bleeding tendency. Global hemostatic assays have demonstrated that hemostasis is overall rebalanced, in both acute liver failure and chronic liver disease. It is now recognized that many bleeding events in chronic liver disease are mediated by portal hypertension rather than an underlying hemostatic defect. This is acknowledged in recent guidelines, which recommend against coagulation testing prior to low risk procedures in this patient group, with avoidance also of attempts at correction of prolonged coagulation times. Over time, the incidence of bleeding events has decreased in both chronic liver disease and acute liver failure, with improved supportive care, targeted treatments for underlying cause of liver disease, and the advent of liver transplantation. Concurrently, there has been increased recognition of the risk of thrombosis in chronic liver disease, with a predilection for the splanchnic vasculature. This review describes the incidence of bleeding and thrombosis in chronic liver disease and acute liver failure, including the periprocedural and liver transplantation setting.

What are the difficulties in conducting randomised controlled trials of thromboprophylaxis in myeloma patients and how can we address these? Lessons from apixaban versus LMWH or aspirin as thromboprophylaxis in newly diagnosed multiple myeloma (TiMM) feasibility clinical trial.

Routine thromboprophylaxis (TP) in newly-diagnosed multiple myeloma (NDMM) patients comprises either aspirin for standard risk patients or low molecular weight heparin for high risk patients. Studies using DOACs in cancer patients include few with myeloma. The aim of this feasibility clinical trial was to establish the foundations for creating a multicentre trial and identify any safety concerns with apixaban. Patient perspectives were sought. NDMM patients were stratified according to VTE risk and randomised to either standard TP or apixaban 2.5 mg BD and reviewed every 3 weeks throughout their chemotherapy. Two focus groups were carried out on 2 occasions at King's College Hospital and Guy's Hospital, London. Each lasted an hour, were recorded, transcribed and themes explored using NVivo 11. Ten patients were recruited, 2 considered high risk and received apixaban and 8 standard risk; 4 randomised to aspirin and 4 to apixaban. Five patients and 2 carers participated in the focus groups. There were no major bleeding or VTE events. Patients were not aware of the thrombotic risk associated with cancer. There is a lack of both written and verbal information on this topic. Myeloma patients were happy to be included in more than one trial simultaneously. Our study provides information on the difficulties facing physicians and patients on obtaining evidence of the safety of DOACs in the context of myeloma. Despite patients being happy to co-recruit into thromboprophylaxis trials along with chemotherapy trials this is not current practice.EudraCT Number: 2015-002668-18.

Venous thromboembolism and women's health.

The prevention and treatment of venous thromboembolism (VTE) poses distinct gender-specific challenges. Women of childbearing age are at an increased risk of VTE secondary to the transient risk factors of combined hormonal contraception (CHC) and pregnancy. Cancers specific to women are associated with a significant burden of VTE; whilst the incidence of VTE in localised breast cancer is 5 per 1000 person-years, more cases are seen due to the prevalence of breast cancer. Treatment of VTE in women can be complicated by abnormal uterine bleeding, now increasingly reported with direct oral anticoagulants (DOACs) as well as vitamin K antagonists. Divergence between international guidelines regarding the use of CHC following an oestrogen-associated VTE and appropriate withdrawal of such contraception requires clarification for clinicians. Additionally, there is uncertainty as to whether to consider such events provoked or unprovoked and, consequently, the optimal duration of treatment in these women remains unclear. During pregnancy and the puerperium, the traditional anticoagulants remain the agents of choice with no further advances in DOAC safety data, and similarly in lactation. Further studies evaluating the safety and optimal treatment strategies in these women are awaited.

Annotation: Developing a national programme for VTE prevention.

The National Venous Thromboembolism Prevention Programme was launched in England, in 2010. Its central objective was to reduce morbidity and mortality from preventable deep vein thrombosis and pulmonary embolism through introduction of a comprehensive systematic approach. The cornerstone of the programme was the introduction of mandatory documented risk assessment for venous thromboembolism, supported by national thromboprophylaxis guidance. Despite widespread uptake of risk assessment, measuring the impact of the national programme on outcomes has proved challenging. The aim of this paper is to review the implementation and outcomes of the national programme.

Changing paradigms in the management of deep vein thrombosis.

In adults diagnosed with deep vein thrombosis (DVT), challenges remain in the management of the acute event whilst remaining alert to long-term morbidity. The addition of non-vitamin K antagonist oral anticoagulants (NOACs) to the pharmacopoeia represents the first of a number of recent advancements in the management of DVT. Worldwide, uptake of these agents has been avid, although drug selection, reversal and chronic treatment effects continue to be controversial areas. Multi-centre studies to evaluate the impact of NOACs on long-term outcomes, including thrombosis recurrence and post-thrombotic syndrome (PTS), are ongoing. Validation of tools capable of predicting PTS would enable patient selection for early aggressive intervention, such as local thrombolysis. Such interventional strategies are gaining momentum as initial approaches and would benefit from large randomized controlled trials.

Management of Bleeding and Thrombosis in Critically Ill Patients with Liver Disease.

Bleeding frequently complicates end-stage chronic liver disease, and may follow procedures which are required for effective care of patients with liver failure. Thrombosis is increasingly recognized as common, important, and potentially preventable. Standard laboratory tests may not be useful in predicting bleeding or thrombotic risk or guiding therapy, and functional testing serves a more useful role. A state of rebalanced hemostasis exists in many patients, with hypocoagulability present only in a minority. Approaches to management are poorly supported by high-quality evidence; in this review, a practical pragmatic approach to care and minimization of procedure-related risk is discussed. General measures include the correction of systemic factors that may affect coagulation status, prevention and treatment of infection, and individualized coagulation support therapies for specific clinical situations and procedures.

Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation.

BACKGROUND & AIMS: Patients with liver disease often show profound abnormalities in their haemostatic system. Studies using thrombin generation demonstrate rebalanced coagulation in patients with chronic liver disease. Our aim was to evaluate the haemostatic profile in patients with acute liver injury/failure (ALI/ALF) compared with healthy controls. METHODS: Thrombin generation was measured in the presence and absence of thrombomodulin (TM) to activate protein C (PC) with endogenous thrombin potential (ETP; the area under the thrombin generation curve) a key parameter. Routine coagulation assays were also performed. RESULTS: Thirty two patients with ALI/ALF and 40 controls were recruited. Patients had grossly abnormal coagulation profiles with decreased pro- and anticoagulant factors compared with controls (P < 0.001 for all comparisons), except for median Factor VIII which was increased 247 U/dl [interquartile range: 214-347] in patients compared with 120 U/dl [97-139; P < 0.001] in controls. Mean ETP was significantly lower in patients 886 nM.min (± 436) compared with controls 1596 nM.min (± 259; P < 0.001). However, when the assay was repeated with TM to activate PC, there was no significant difference in mean ETP + TM between patients and controls (632 ± 418 vs 709 ± 301 nM.min respectively; P = 0.666). Furthermore, the ETP ratio (ETP + TM/ETP) was significantly higher in patients 0.89 (0.60-0.97) compared with controls 0.48 (0.3-0.6; P = 0.002) and negatively correlated with PC (R = -0.487, P = 0.003) and Factor V (R = -0.431, P = 0.01). CONCLUSION: ALI/ALF patients have normal ETP in the presence of TM. This supports rebalanced coagulation mediated by acquired PC resistance because of the reduction in PC, Factor V and concomitant increase in Factor VIII.

Changes in thrombin generation and D-dimer concentrations in women injecting enoxaparin during pregnancy and the puerperium.

BACKGROUND: It is well accepted that the gravid state is hypercoagulable and a significant cause of both maternal morbidity and mortality in the Western world. Although thrombin generation is reported to be increased in pregnant women, uncertainty exists on the pattern of thrombin generation change during this time. The aim of this study is to describe thrombin generation changes and D-dimer concentrations in women injecting enoxaparin during pregnancy the postnatal period. METHODS: One hundred and twenty-three women injecting enoxaparin had their thrombin generation, as measured by Calibrated Automated Thombinography (CAT), repeatedly assayed during pregnancy, once in each trimester, at delivery and 8 weeks post-partum. Furthermore, to understand the impact enoxaparin has on D-dimer concentrations during pregnancy, D-dimer concentrations were measured monthly in the recruited women. RESULTS: Thrombin generation was found to increase in the first trimester (mean endogenous thrombin potential (ETP): 1391 nmol/L.min), further increasing during the second trimester (mean ETP: 1757 nmol/L.min), after which it plateaued through to delivery, where it peaked (mean ETP: 1857 nmol/L.min) and then fell back at 8 weeks post-partum (ETP: 1293 nmol/L.min). In contrast D-dimer concentrations increased exponentially during the antenatal period, despite the enoxaparin prescription. CONCLUSION: Our results provide further evidence on alterations of thrombin generation during pregnancy and the postnatal period.

Anticoagulation for stroke prevention in atrial fibrillation and treatment of venous thromboembolism and portal vein thrombosis in cirrhosis: guidance from the SSC of the ISTH.

While advanced liver disease was previously considered to be an acquired bleeding disorder, there is increasing recognition of an associated prothrombotic state with patients being at higher risk of atrial fibrillation (AF) and stroke and venous thromboembolism (VTE) including portal vein thrombosis (PVT). We review the available literature on epidemiology, pathophysiology, and risk factors and provide guidance on anticoagulant management of these conditions in adults with cirrhosis. In patients with Child-Pugh A or B cirrhosis and AF, we recommend anticoagulation with standard-dose direct oral anticoagulants (DOACs) in accordance with cardiology guideline recommendations for patients without liver disease. In those with Child-Pugh C cirrhosis, there is inadequate evidence with respect to the benefit and risk of anticoagulation for stroke prevention in AF. In patients with cirrhosis and acute deep vein thrombosis or pulmonary embolism, we recommend anticoagulation and suggest use of either a DOAC or low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) in Child-Pugh A or B cirrhosis and LMWH alone (or as a bridge to VKA in patients with a normal baseline international normalized ratio) in Child-Pugh C cirrhosis. We recommend anticoagulation for patients with cirrhosis and symptomatic PVT. We suggest anticoagulation for those with asymptomatic, progressing PVT and recommend continuing extended anticoagulation for liver transplant candidates with PVT.