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.

Pharmacotherapy for Venous Thromboprophylaxis following Total Hip or Knee Arthroplasty: A Systematic Review and Network Meta-analysis.

The optimal pharmacological prophylaxis for venous thromboembolism (VTE) after hip or knee arthroplasty is uncertain. We conducted a systematic review and network meta-analysis to compare the efficacy and safety of various medications. We searched multiple databases for randomized clinical trials (RCTs) comparing medications (including factor Xa inhibitors, factor IIa inhibitor, warfarin, unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], aspirin, pentasaccharide) for VTE prophylaxis post-arthroplasty. Outcomes included any postoperative VTE identified with screening, major bleeding, and death. We used LMWH as the main comparator for analysis and performed trial sequential analysis (TSA) for each pairwise comparison. Certainty of evidence was assessed using GRADE (Grading of Recommendations, Assessments, Developments and Evaluations). We analyzed 70 RCTs (55,841 participants). Factor Xa inhibitors decreased postoperative VTE significantly compared with LMWH (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.44-0.68, high certainty). Pentasaccharides probably reduce VTE (OR: 0.61, 95% CI: 0.36-1.02, moderate certainty), while the factor IIa inhibitor dabigatran may reduce VTE (OR: 0.75, 95% CI: 0.40-1.42, low certainty). UFH probably increases VTE compared with LMWH (OR: 1.31, 95% CI: 0.91-1.89, moderate certainty), and other agents like warfarin, aspirin, placebo, and usual care without thromboprophylaxis increase VTE (high certainty). Factor Xa inhibitors may not significantly affect major bleeding compared with LMWH (OR: 1.06, 95% CI: 0.81-1.39, low certainty). No medications had a notable effect on mortality compared with LMWH (very low certainty). TSA suggests sufficient evidence for the benefit of factor Xa inhibitors over LMWH for VTE prevention. Compared with LMWH and aspirin, factor Xa inhibitors are associated with reduced VTE after hip or knee arthroplasty, without an increase in bleeding and likely no impact on mortality.

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.

Hirudin versus citrate as an anticoagulant for ROTEM platelet whole blood impedance aggregometry in thrombocytopenic patients.

Citrate is widely used as an anticoagulant for platelet function tests (PFTs). Due to an intrinsic inhibitory effect of citrate on platelet function, hirudin is used as an alternative. However, studies comparing the effect of these anticoagulants on rotational thromboelastometry (ROTEM) platelet whole blood impedance aggregometry in thrombocytopenic patients are scant. Cross-sectional study was done in 105 patients who entered the critical phase of Dengue hemorrhagic fever with plasma leakage and severe thrombocytopenia (<100 × 109/L). Samples were collected on two consecutive days and considered as a combined data set for analysis, out of which 200 have been included in the data analysis. Platelet count was used from routine full blood count. ROTEM platelet used TRAPTEM assay, which was performed with 3.2% sodium citrate and 525 ATU/ml hirudin anticoagulated blood. Means of all the TRAPTEM parameters were significantly higher in hirudin, compared to citrate samples (p < .05). Significantly higher overall platelet aggregation was observed in hirudinized samples with a significant mean difference (p < .05) compared to citrate in each quartile of platelet count. Higher platelet aggregation was observed with hirudin compared to citrate in ROTEM platelet whole blood impedance aggregometry in thrombocytopenic patients elaborating the importance of using hirudin anticoagulation in PFTs, particularly in patients with severe thrombocytopenia.

Citrate is the most commonly used anticoagulant for coagulation studies including rotational thromboelastometry (ROTEM).Hirudin is an alternative option to be used as an anticoagulant for PFTs because of the inhibitory effect of citrate on platelet function.One study (Nissen et al. (2020)) reported higher precision and platelet aggregation with hirudinized blood of healthy individuals, over citrate using ROTEM platelet.However, none of the studies were performed in patients in actual clinical context.We evaluated the potential benefit of using hirudin anticoagulated blood over citrate in thrombocytopenic patients due to Dengue hemorrhagic fever using ROTEM platelet.We observed higher platelet aggregation with hirudin compared to citrate suggesting the importance of using hirudin anticoagulation in PFTs, particularly in patients with severe thrombocytopenia.

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.

Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination - A report of two UK cases.

Recent reports have highlighted rare, and sometimes fatal, cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia following the Vaxzevria vaccine. An underlying immunological mechanism similar to that of spontaneous heparin-induced thrombocytopenia (HIT) is suspected, with the identification of antibodies to platelet factor-4 (PF4), but without previous heparin exposure. This unusual mechanism has significant implications for the management approach used, which differs from usual treatment of CVST. We describe the cases of two young males, who developed severe thrombocytopenia and fatal CVST following the first dose of Vaxzevria. Both presented with a headache, with subsequent rapid neurological deterioration. One patient underwent PF4 antibody testing, which was positive. A rapid vaccination programme is essential in helping to control the COVID-19 pandemic. Hence, it is vital that such COVID-19 vaccine-associated events, which at this stage appear to be very rare, are viewed through this lens. However, some cases have proved fatal. It is critical that clinicians are alerted to the emergence of such events to facilitate appropriate management. Patients presenting with CVST features and thrombocytopenia post-vaccination should undergo PF4 antibody testing and be managed in a similar fashion to HIT, in particular avoiding heparin and platelet transfusions.

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.

Annotation: travel and thrombosis.

Travel appears to be a weak risk factor for venous thromboembolism (VTE) and is more relevant for passengers with additional VTE risk factors. The association is not limited to air travel and is related to duration of travel. Life-threatening pulmonary embolism (PE) is rare. There is limited evidence to support interventions, including 'sensible measures', graduated compression stockings (GCS) and low-molecular-weight heparin (LMWH). It is difficult to confidently define a population who would benefit from thromboprophylaxis and no validated risk assessment exists for this purpose. LMWH has traditionally been used for flight thromboprophylaxis but a direct oral anticoagulant (DOAC) would be a more appealing oral option.

Progress in the monitoring of direct oral anticoagulant therapy.

The availability of direct oral anticoagulants (DOACs) has led to a paradigm shift in the field of anticoagulation, with DOACs increasingly being prescribed for patients in preference to vitamin K antagonists and low molecular weight heparin. Despite good experience with the use of these agents at fixed doses, there are clinical scenarios where monitoring is recommended. Data from phase III studies of the DOACs and small real-world studies suggest a relationship between DOAC concentration and clinical events. The DOACs have differing impacts on the common tests of haemostasis and it is important that clinicians are familiar with the sensitivity of the reagents used in their laboratory to individual DOACs. The specific DOAC drug concentrations can be assayed in the laboratory, when required, to guide appropriate clinical decision-making. Studies from the real world with sufficient numbers evaluating the association of DOAC concentrations with outcomes should be a research priority in order to understand if we could do better through dose individualisation.

Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in at-risk patient groups: pregnancy, elderly and obese patients.

BACKGROUND: Venous thromboembolism (VTE) accounts for an estimated 900,000 cases per year in the US alone and constitutes a considerable burden on healthcare systems across the globe. OBJECTIVE: To understand why the burden is so high, qualitative and quantitative research was carried out to gain insights from experts, guidelines and published studies on the unmet clinical needs and therapeutic strategies in VTE prevention and treatment in three populations identified as being at increased risk of VTE and in whom VTE prevention and treatment were regarded as suboptimal: pregnant women, the elderly and obese patients. METHODOLOGY: A gap analysis methodology was created to highlight unmet needs in VTE management and to discover the patient populations considered most at risk. A questionnaire was devised to guide qualitative interviews with 44 thrombosis and haemostasis experts, and a review of the literature on VTE in the specific patient groups from 2015 to 2017 was completed. This was followed by a Think Tank meeting where the results from the research were discussed. RESULTS: This review highlights the insights gained and examines in detail the unmet needs with regard to VTE risk-assessment tools, biomarkers, patient stratification methods, and anticoagulant and dosing regimens in pregnant women, the elderly and obese patients. CONCLUSIONS: Specifically, in pregnant women at high risk of VTE, low-molecular-weight heparin (LMWH) is the therapy of choice, but it remains unclear how to use anticoagulants when VTE risk is intermediate. In elderly patients, evaluation of the benefit of VTE prophylaxis against the bleeding risk is particularly important, and a head-to-head comparison of efficacy and safety of LMWH versus direct oral anticoagulants is needed. Finally, in obese patients, lack of guidance on anticoagulant dose adjustment to body weight has emerged as a major obstacle in effective prophylaxis and treatment of VTE.

Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in high-risk patient groups: cancer and critically ill.

BACKGROUND: Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups. OBJECTIVE: To present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill. METHODOLOGY: To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts. RESULTS: The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment. CONCLUSIONS: Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug-drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins.

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.

Current challenges and future prospects in oral anticoagulant therapy.

The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed-dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex 'real-world' patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting.

Adherence to long-term anticoagulation treatment, what is known and what the future might hold.

Adherence to medication, commonly reported as being 50% in chronic diseases, is of great concern in healthcare. Medication non-adherence is particularly apparent in chronic diseases, where treatment is often preventative and may provide little or no symptomatic relief or feedback for the patient. A lot of research has been undertaken to describe the extent of non-adherence to long-term anticoagulation therapy, particularly with vitamin K antagonists and more recently with direct oral anticoagulants. However, the literature is scarce with respect to describing adherence to anticoagulation in terms of the behavioural aspects that influence medicine use. Utilizing the COM-B (capability, opportunity, motivation and behaviour) psychological model of non-adherence, we present the available evidence, not only in terms of describing the extent of the non-adherence problem, but also describing why patients do not adhere, offering theory-driven and evidence-based solutions to improve long-term adherence to chronic anticoagulation therapy. Lessons learned are not only applicable within the field of anticoagulation but throughout haematology.

Maternal and pregnancy characteristics affect plasma fibrin monomer complexes and D-dimer reference ranges for venous thromboembolism in pregnancy.

BACKGROUND: D-dimers have a high negative predictive value for excluding venous thromboembolism outside of pregnancy but the use in pregnancy remains controversial. A higher cut-off value has been proposed in pregnancy due to a continuous increase across gestation. Fibrin monomer complexes have been considered as an alternative diagnostic tool for exclusion of venous thromboembolism in pregnancy due to their different behavior. OBJECTIVE: We sought to establish normal values of fibrin monomer complexes and D-dimer as a diagnostic tool for the exclusion of venous thromboembolism in pregnancy and examine the effect of maternal and obstetric factors on these markers. STUDY DESIGN: Plasma D-dimer and fibrin monomer complexes were measured by quantitative immunoturbidimetry in 2870 women with singleton pregnancies attending their routine first-trimester hospital visit in a prospective screening study for adverse obstetric outcome. Multiple regression analysis was used to determine maternal characteristics and obstetric factors affecting the plasma concentrations and converting these into multiple of the median values after adjusting for significant maternal and obstetric characteristics. RESULTS: Plasma fibrin monomer complexes increased with maternal weight and were lower in women with a history of cocaine abuse and chronic hypertension. D-dimers increased with gestational age and maternal weight and were higher in sickle cell carriers and in women of African and South Asian racial origin compared to Caucasians. CONCLUSION: Fibrin monomer complexes and D-dimers are affected by maternal and obstetric characteristics rather than only gestational age. The utility of these fibrin-linked markers as a tool for exclusion of venous thromboembolism in pregnancy might be improved by adjusting for patient-specific characteristics.