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A shared decision on the most appropriate agent for the treatment of cancer-associated thrombosis should consider the following factors, which should be reassessed as patients continue along their cancer care pathway: risk of bleeding; tumour site; suitability of oral medications; potential for drug-drug interactions; and patient preference and values regarding choice of drug. Continuing anticoagulation beyond 6 months in patients with cancer-associated venous thromboembolism and active cancer is recommended., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

A double-blind randomized trial was conducted to research a hypercoagulable state rebound after abrupt versus gradual withdrawal of acenocoumarol, 20 patients were included: 10 in the abrupt withdrawal group (AW) and 10 in the gradual withdrawal group (GW). Between days 1 and 15,F1 + 2 was higher in group AW (P < 0.002). A significant increase of D-dimer with time was found (P < 0.001) without difference between the two groups, tPA and PAI-1 levels remained stable throughout without difference between the two groups. No rebound phenomenon was observed. Four thrombotic recurrences were observed: group AW: 1, group GW: 3 (P = 0.29). There is neither clinical nor biological support for a gradual anticoagulation withdrawal.

Cancer-associated venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. Treatment of cancer-associated VTE comes with a heightened risk of anticoagulant-related bleeding that differs by choice of anticoagulant as well as by patient- and disease-specific risk factors. Available data from randomized controlled trials and observational studies in cancer-associated VTE suggest that direct oral anticoagulants are effective, continuing anticoagulation beyond six months is indicated in those with active cancer and that patients who develop 'breakthrough' thrombotic events can be effectively treated. We review the evidence that addresses these key clinical questions and offer pragmatic approaches in individualizing care. While significant investigative efforts over the past decade have made impactful advances, future research is needed to better define the factors that contribute to anticoagulant-related bleeding and VTE recurrence, in order to aid clinical decision-making that improves the care of patients with cancer-associated VTE., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Summary: Data regarding the safety of co‐administration of ibrutinib with anticoagulants in real‐life settings are scarce. Using a nationwide database, we conducted a nested case‐control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow‐up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5‐fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real‐life settings, and similar aOR among oral anticoagulants. [ABSTRACT FROM AUTHOR]

Summary: Selective patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiD) are at high risk for venous thromboembolism (VTE). The SAVED score is a VTE risk prediction model recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines. Using retrospective data from 501 MM patients with new IMiD initiation between 2010 and 2019, we performed the first independent external validation of this model. The cumulative incidence of VTE after IMiD initiation at 6 and 12 months was 32% and 42% in the high‐risk group, versus 6% and 9% in the low‐risk group respectively. The C‐statistic of the SAVED score to predict VTE within 12 months of IMiD‐based treatment start was 0.74 [95% confidence interval (CI): 0.69–0.78], which outperformed several other VTE risk models in MM patients. Our findings suggest that the SAVED score is an accurate risk assessment tool for VTE stratification in patients initiating IMiD‐containing regimens. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post-thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non-blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3 months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D-dimers. Two-hundred and eighty-one patients were recruited, randomised and followed up for 24 months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P < 0·001)] with a non-significant increase in major bleeding [3·54 vs. 1·18 events/100 patient years, aHR 2·99 (95% CI: 0·81-11·05, P = 0·10)]. Outcomes of PTS and QoL were no different between groups. D-dimer results (on anticoagulation) did not predict VTE recurrence. In conclusion, extended anticoagulation reduced VTE recurrence but did not reduce PTS or improve QoL and was associated with a non-significant increase in bleeding. Results also suggest very limited clinical utility of D-dimer testing on anticoagulated patients., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Summary: Vitamin K antagonists (VKAs) are the standard oral anti‐coagulant treatment for patients with cerebral venous thrombosis (CVT). However, the direct oral anti‐coagulants (DOACs) started replacing VKAs also in this setting. We aimed to evaluate safety and efficacy of the DOACs for CVT treatment. We performed a systematic review and meta‐analysis (PROSPERO protocol registration number CRD42020191472). The electronic databases MEDLINE, EMBASE and CENTRAL were searched from inception to January 2022. We included randomised controlled trials (RCTs) and observational studies, enrolling at least 10 adult patients with CVT treated with any DOACs. Twenty‐three studies were included, for a total of 618 CVT patients treated with DOACs (treatment duration range 3–12 months). Mortality rate was 1.76% [95% confidence interval (CI) 0.70%–3.24%; I2 = 0%; 5/428 patients, 18 studies]; major bleeding 2.41% (95% CI 1.26%–3.91%; I2 = 1.5%; 12/534 patients, 21 studies); recurrent thrombosis 2.05% (95% CI 1.04%–3.37%; I2 = 0%; 10/577 patients, 21 studies); excellent neurological outcome 85.9% (95% CI 79.0%–91.7%; I2 = 63.7%; 289/340 patients, 13 studies); vessel recanalisation 89.0% (95% CI 82.9%–93.9%; I2 = 62.7%; 316/359 patients, 16 studies). No significant differences emerged by study design (RCTs vs. observational studies) or by treatment (DOACs vs. VKAs). This systematic review showed that the DOACs might represent a reasonable oral anti‐coagulant treatment option for CVT patients. [ABSTRACT FROM AUTHOR]

Summary: Glucocorticoid treatment increases venous thromboembolism (VTE) risk. Whether this is due to the medication or the underlying disease, or affects the risk of VTE recurrence, has been difficult to determine. The aim of our present study was to quantify the risk for first and recurrent VTE associated with oral glucocorticoids use, considering the underlying disease. A total of 2547 patients with VTE from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study were linked to the Dutch Pharmaceutical Statistics register. The risk of first VTE during periods of exposure with oral glucocorticoids was estimated by the self‐controlled case series method and that of recurrent VTE was examined in a cohort design. The incidence rate ratio (IRR) of first VTE in the period of glucocorticoid treatment was 3·51 [95% confidence interval (CI) 2·55–4·80]. This IRR was 2·53 (95% CI 1·10–5·72) in the week before treatment started, 5·28 (95% CI 2·89–9·53) in the first 7 days of treatment, remained elevated afterwards and decreased to 1·55 (95% CI 0·85–3·12) after 6 months, as compared to unexposed periods. The hazard ratio for recurrence was 2·72 (95% CI 1·64–4·78) in treatment periods as compared with no treatment. The increased risk of VTE associated with oral glucocorticoid treatment is due to a combined effect of the treatment and the underlying disease, remaining high during the first months of prescription. [ABSTRACT FROM AUTHOR]

Summary: Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder mediated by a heterogeneous group of autoantibodies collectively known as antiphospholipid antibodies (aPL). They include lupus anticoagulant (LA), IgG and IgM anticardiolipin antibodies (aCL) and anti‐β2‐glycoprotein I (anti‐β2GPI) antibodies. It has been shown that those patients with all three aPL (triple positive) are at highest risk of both a first thrombotic event and of a recurrence, despite anticoagulation. In response to publication of a meta‐analysis and a randomised controlled trial assessing the safety and efficacy of rivaroxaban versus warfarin in triple‐positive APS with venous and/or arterial thrombosis, the Medicines and Healthcare Products Regulatory Agency (MHRA) and European Medicines Agency (EMA) issued recommendations that direct‐acting oral anticoagulant (DOACs) should not be used for secondary prevention of thrombosis in all APS patients (although they did draw specific attention to the high risk of triple‐positive patients). As there is less evidence for patients with single‐ or dual‐positive patients with APS, this may be an over‐interpretation of the data. In this review, we explore the available evidence on safety and efficacy of DOACs in thrombotic APS, the problem of detecting LA while on DOAC, and provide some practical guidance for managing this problem. [ABSTRACT FROM AUTHOR]

Twenty patients were identified, of these the indication for anticoagulation was VTE management in 15, with the remainder requiring anticoagulation for AF. Most patients had well controlled HIV at VTE diagnosis with 77.8% having no detectable plasma HIV RNA (7/9; missing data, I n i = 3). Three patients with acute VTE had been previously anticoagulated for VTE but were not on anticoagulation at the time of recurrence (two with warfarin and one with rivaroxaban). Our experience in 12 patients has been promising and represents the largest published cohort of patients with HIV treated with a DOAC for VTE. [Extracted from the article]

Summary: Understanding of the comparative bleeding risks of oral anticoagulant (OAC) therapies for the primary treatment of venous thromboembolism (VTE) is limited. Therefore, among anticoagulant‐naïve VTE patients, we conducted comparisons of apixaban, rivaroxaban and warfarin on the rate of hospitalised bleeding within 180 days of OAC initation. MarketScan databases for the time‐period from 2011 to 2016 were used and, for each OAC comparison, new users were matched with up to five initiators of a different OAC. The final analysis included 83 985 VTE patients, who experienced 1944 hospitalised bleeding events. In multivariable‐adjusted Cox regression models, rate of hospitalised bleeding was lower among new users of apixaban when compared to new users of rivaroxaban [hazard ratio (95% confidence interval) 0·58 (0·41–0·80)] or warfarin [0·68 (0·50–0·92)]. Overall, the hospitalised bleeding rate was similar when comparing new users of rivaroxaban to new users of warfarin [0·98 (0·68–1·11)], though there was some suggestion that rivaroxaban was associated with lower bleeding risk among younger individuals. Findings from this large real‐world population concur with results from the randomised trial which found lower bleeding risk with apixaban versus warfarin and, for the first time, reveal a lower risk of bleeding in a comparison of apixaban versus rivaroxaban. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: Venous thromboembolism (VTE)‐BLEED, a decision tool for predicting major bleeding during chronic anticoagulation for VTE has not yet been validated in practice‐based conditions. We calculated the prognostic indices of VTE‐BLEED for major bleeding after day 30 and day 90, as well as for recurrent VTE and all‐cause mortality, in 4457 patients enrolled in the international, prospective XALIA study. The median at‐risk time was 190 days (interquartile range 106–360). The crude hazard ratio (HR) for major bleeding after day 30 was 2·6 [95% confidence interval (CI) 1·3–5·2] and the treatment‐adjusted HR was 2·3 (95% CI 1·1–4·5) for VTE‐BLEED high (versus low) risk patients: the corresponding values for major bleeding after day 90 were 3·8 (95% CI 1·6–9·3) and 3·2 (95% CI 1·3–7·7), respectively. The predictive value of VTE‐BLEED was similar in selected patients with unprovoked VTE or those treated with rivaroxaban. High VTE‐BLEED score was associated with higher incidence of all‐cause mortality (treatment‐adjusted HR 11, 95% CI 4·8–23), but not evidently with recurrent VTE (treatment‐adjusted HR 1·5; 95% CI 0·85–2·7). These results confirm the predictive value of VTE‐BLEED in practice‐based data in patients treated with rivaroxaban or conventional anticoagulation, supporting the hypothesis that VTE‐BLEED may be useful for making management decisions on the duration of anticoagulant therapy. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: Increasing use of direct oral anticoagulants (DOACs) has made management of non‐valvular atrial fibrillation and venous thromboembolism easier in most patients. But the presence of co‐existing renal impairment could render the use of DOACs problematic because all of these drugs have varying degrees of renal excretion. In this paper we address misconceptions about the safety and efficacy of DOACs in moderate‐severe renal impairment by presenting a summary of the literature from phase III trials and real‐world studies. It also addresses the important consideration of correct estimate of renal function for DOAC dosing. It is hoped that the review will serve as a valuable resource for clinicians involved in anticoagulation decision‐making in patients with renal impairment to guide the choice of most suitable agent. Accurate dosing is of particular relevance as registry data suggests it is done inconsistently and may be resulting in avoidable thromboembolic and bleeding events. [ABSTRACT FROM AUTHOR]

Summary: Vitamin K antagonists (VKAs) used for the prevention and treatment of thromboembolic disease, increase the risk of bleeding complications. We developed and validated a model to predict the risk of an international normalised ratio (INR) ≥ 4·5 during a hospital stay. Adult patients admitted to a tertiary hospital and treated with VKAs between 2006 and 2010 were analysed. Bleeding risk was operationalised as an INR value ≥4·5. Multivariable logistic regression analysis was used to assess the association between potential predictors and an INR ≥ 4·5 and validated in an independent cohort of patients from the same hospital between 2011 and 2014. We identified 8996 admissions of patients treated with VKAs, of which 1507 (17%) involved an INR ≥ 4·5. The final model included the following predictors: gender, age, concomitant medication and several biochemical parameters. Temporal validation showed a c statistic of 0·71. We developed and validated a clinical prediction model for an INR ≥ 4·5 in VKA‐treated patients admitted to our hospital. The model includes factors that are collected during routine care and are extractable from electronic patient records, enabling easy use of this model to predict an increased bleeding risk in clinical practice. [ABSTRACT FROM AUTHOR]

Coagulation and innate immunity are linked evolutionary processes that orchestrate the host defence against invading pathogens and injury. The complement system is integral to innate immunity and shares numerous interactions with components of the haemostatic pathway, helping to maintain physiological equilibrium. The term 'immunothrombosis' was introduced in 2013 to embrace this process, and has become an area of much recent interest. What is less apparent in the literature however is an appreciation of the clinical manifestations of the coagulation-complement interaction and the consequences of dysregulation of either system, as seen in many inflammatory and thrombotic disease states, such as sepsis, trauma, atherosclerosis, antiphospholipid syndrome (APS), paroxysmal nocturnal haemoglobinuria (PNH) and some thrombotic microangiopathies to name a few. The growing appreciation of this immunothrombotic phenomenon will foster the drive for novel therapies in these disease states, including anticoagulants as immunomodulators and targeted molecular therapies. [ABSTRACT FROM AUTHOR]

Antiphospholipid antibodies are a heterogeneous group of autoantibodies that have clear associations with thrombosis and pregnancy morbidity, and which together constitute the 'antiphospholipid syndrome' ( APS). However, the pathophysiology of these complications is not well understood and their heterogeneity suggests that more than one pathogenic process may be involved. Diagnosis remains a combination of laboratory analysis and clinical observation but there have been significant advances in identifying specific pathogenic features, such as domain I-specific anti-β2-glycoprotein-I antibodies. This in turn has pointed to endothelial and complement activation as important factors in the pathogenesis of APS. Consequently, although anticoagulation remains the standard treatment for thrombotic APS and during pregnancy, the realisation that these additional pathways are involved in the pathogenesis of APS has significant implications for treatment: agents acting outside the coagulation system, such as hydroxychloroquine for pregnancy complications and sirolimus as an inhibitor of the mammalian target of rapamycin ( mTOR) pathway, are now under evaluation and represent a radical change in thinking for haematologists. Conventional anticoagulation is also under challenge from new, direct acting anticoagulants. This review will provide a comprehensive overview of the evolving understanding of APS pathogenesis and how this and novel therapeutics will alter diagnosis and management. [ABSTRACT FROM AUTHOR]

The article discusses the effect of heparin thromboprophylaxis on thrombin generation in multiple myeloma patients. Topics include how the management of venous thromboembolic (VTE) risk is challenging in patients with multiple myeloma (MM) who are considered to be at high-VTE risk and discusses short in vitro effect of prophylactic doses of LMWH and could explain the observed absence of its clinical effect in VTE prevention.

The article focuses on the DASH score, obesity and hyperpigmentation associated with the anticoagulation in patients with venous thromboembolism (VTE). It talks about the mortality rates in the patients with VTE. It tells about the anticoagulation in patients being influenced by the patient's weight, age and treatment options.

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. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants ( DOACs), including the direct thrombin inhibitor, dabigatran, and the direct factor Xa ( FXa) inhibitors, rivaroxaban, apixaban and edoxaban, are approved for thromboembolism prevention and treatment. These drugs do not require routine coagulation monitoring but, in some circumstances, measurement of drug level or anticoagulant effect may be necessary. Although traditional coagulation tests lack analytical sensitivity and specificity, they are widely available and inexpensive, and can provide useful information regarding the residual anticoagulant effect of DOACs. Hemoclot® and ecarin-based assays can be used to quantify dabigatran level and calibrated chromogenic anti- FXa assays are suitable for measuring rivaroxaban, apixaban and edoxaban levels, but these tests are not yet widely available. [ABSTRACT FROM AUTHOR]

Four-factor prothrombin complex concentrate ( PCC) 50 iu/kg is able to swiftly restore haemostatic parameters in healthy subjects on rivaroxaban. We hypothesized that lower dosages of PCC may be sufficient to restore normal haemostasis. In this double-blind, crossover, placebo-controlled study, we compared the effects of PCC 37·5 iu/kg, PCC 25 iu/kg, and placebo on thrombin generation (endogenous thrombin potential, ETP) and prothrombin time in six healthy subjects receiving twice-daily rivaroxaban 15 mg for 2·5 days. Fifteen min after infusion of PCC 37·5 iu/kg, ETP increased from 47 ± 16% to 64 ± 22% ( P = 0·03; pre-rivaroxaban ETP: 92 ± 14%) and remained higher than after placebo over 24 h ( P = 0·001). PCC 25 iu/kg did not modify ETP within 15 min (53 ± 11% to 59 ± 12%; P = 0·14) and was not different from placebo over 24 h ( P = 0·31). ETP reached pre-rivaroxaban levels within 6 h after PCC 37·5 iu/kg infusion and within 12-24 h after PCC 25 iu/kg infusion. Both dosages restored rivaroxaban-induced prothrombin time prolongation after 15 min ( P < 0·001). Placebo did not have an effect on coagulation parameters. 37·5 iu/kg of PCC leads to partial restoration of thrombin generation, whereas 25 iu/kg does not. PCC 37·5 iu/kg may be insufficient for immediate full reversal of peak therapeutic rivaroxaban levels. [ABSTRACT FROM AUTHOR]

The article discusses research on the treatment of superficial vein thrombosis (SVT) involving the long saphenous vein with prophylactic low-molecular-weight heparin (LMWH). Outpatient management of SVT at King's College Hospital NHS Foundation Trust was restrospectively reviewed from January 2013 to June 2016 wherein 106 patients were diagnosed with isolated SVT. Patients were treated with enoxaparin, but research findings support LMWH or fondaparinux treatment for SVT.

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. [ABSTRACT FROM AUTHOR]

Superficial vein thrombosis ( SVT) was considered to be a benign and self-limiting condition. However, it is now appreciated that a significant proportion of those presenting with SVT will have concomitant deep vein thrombosis or pulmonary embolism, or are at significant risk of developing deep venous thromboembolism. Potential therapeutic options include topical preparations, compression therapy (stockings, bandages), medication such as non-steroidal anti-inflammatory drugs ( NSAIDs) or anticoagulants (therapeutic or prophylactic doses) and surgery, ligation or stripping, of superficial veins. The treatment of choice is therapeutic/intermediate dose low molecular weight heparin or prophylactic dose fondaparinux administered for 4-6 weeks. The cost-effectiveness of treatment is a concern and more targeted therapy is required. [ABSTRACT FROM AUTHOR]

The article focuses on guidelines of the British Committee for Standards in Haematology related to self-testing and self-management of oral anticoagulation with vitamin K antagonists by patients as of December 2014. Topics discussed include guidelines for point-of-care (POCT) devices, quality assurance in the POCT setting and cost-effectiveness of self-testing and self management.

The article discusses a guideline from the British Committee for Standards in Haematology, focusing on the non-coumarin anticoagulants and its effect on haemostasis. It states that the guideline was designed to provide a clear guidance for healthcare professionals on issues relative to laboratory assessment of non-coumarin anticoagulants. Other topics include effect of dabigatran on haemostasis tests, monitoring of unfractionated heparin, and the use of bivalirudin as an alternative heparin.

Major obstetric haemorrhage ( MOH) remains an important medical challenge worldwide, contributing to significant maternal morbidity and mortality. Prompt and appropriate management is essential if we are to improve outcomes and reduce substandard care that may result in adverse consequences. This review describes the current understanding of the pathophysiological aspects of MOH together with the principles of transfusion and haemostatic therapy, with emphasis on a coordinated multidisciplinary approach. We also highlight the current lack of evidence available from randomized controlled trials to inform best practice and the need to prioritize research in this key clinical area. [ABSTRACT FROM AUTHOR]

Orally active small molecules that selectively and specifically inhibit coagulation serine proteases have been developed for clinical use. For some patients these oral direct inhibitors ( ODIs) offer substantial benefits over oral vitamin K antagonists ( VKA). However, for the majority of patients with good anticoagulant control with VKAs the advantages of the ODIs are primarily convenience and few drug interactions. The drugs are prescribed at fixed dose without the need for monitoring or dose adjustment in the majority of patients and the rapid onset of anticoagulation and short half-life make initiation and interruption of anticoagulation considerably easier than with VKAs. As yet, specific antidotes to ODIs are not available for clinical use but these are in development as rapid reversal agents. As with all anticoagulants produced so far, there is a correlation between intensity of anticoagulation and bleeding. Consequently, the need to consider the balance of benefit and risk in each individual patient is no less important than with VKA therapy. Dabigatran and rivaroxaban have been chosen for this review as examples of a thrombin inhibitor and an inhibitor of factor Xa respectively. The clinical application of these drugs is the focus of the review. [ABSTRACT FROM AUTHOR]

Central venous catheters are commonly used in haematology departments for the administration of chemotherapy, blood products and parenteral nutrition in patients with haematological malignancy. Thrombosis is a recognized complication of such devices especially in oncology patients. Catheter-related thrombi ( CRT) may lead to pulmonary embolism and infection, as well as catheter failure and potential delays in treatment. The vast majority of CRT are asymptomatic, thus a high index of suspicion is required in making the diagnosis. Doppler ultrasound or venography may be employed to identify CRT. Once confirmed, the initiation of treatment is a balance between the risks of anticoagulation against potential complications of CRT. A number of risk factors for CRT are discussed along with an overview of catheter types, their appropriate choice and intravascular positioning. [ABSTRACT FROM AUTHOR]

The close relationship between malignancy and venous thromboembolism ( VTE) is well established, with malignancy increasing VTE risk and accounting for a substantial proportion of presentations with VTE. Moreover, VTE impacts significantly on morbidity and mortality in cancer patients. Anticoagulation for prevention and treatment of VTE requires a patient-centred approach due to the heterogeneous patient population and inherent increased thrombotic and bleeding risks. In recent years, low molecular weight heparin ( LMWH) injections have come to be the mainstay for treatment and prevention of cancer-related VTE. For treatment, this is usually administered for at least 6 months and continued in patients with active cancer or those receiving treatment for cancer. The use of LMWH for thromboprophylaxis in hospitalised cancer patients is also well accepted, but out-of-hospital prophylaxis remains contentious. The development of risk assessment models may help identify the patients at highest risk. The role of the new oral factor Xa and thrombin inhibitors in this setting remains to be determined. [ABSTRACT FROM AUTHOR]

Despite the availability of comprehensive evidence-based guidelines there are difficult and controversial areas in the management of venous thromboembolism. Institutions and even countries disagree on the importance of calf vein thrombosis, with some rigorously detecting and treating it and others deliberately not looking for it. The need to treat proximal deep vein thrombosis and pulmonary embolism is accepted but which patients with an unprovoked first event should have long-term anticoagulation has become a difficult clinical decision. We are uncertain how to reduce the incidence of post-thrombotic syndrome seen in a substantial number of patients. How hard to look for an undiagnosed underlying cancer has become a contentious issue particularly in the United Kingdom following the recent publication of a guideline from the National Institute for Health and Clinical Excellence. Whilst we are wrestling with these dilemmas we are entering an era of new anticoagulants and have to solve the logistical problems of introducing them into clinical practice despite cost pressures. These issues will be explored in this review. [ABSTRACT FROM AUTHOR]

Elevated levels of circulating tissue factor-bearing microparticles ( TFMP) have been associated with an increased risk of developing venous thromboembolism ( VTE) in cancer patients. We performed a randomized phase II study to evaluate the cumulative incidence of VTE in advanced cancer patients with lower levels of TFMP not receiving thromboprophylaxis and those with higher levels of circulating TFMP randomized to enoxaparin or observation. The cumulative incidence of VTE at 2 months in the higher TFMP group randomized to enoxaparin ( N = 23) was 5·6% while the higher TFMP group observation arm ( N = 11) was 27·3% (Gray test P = 0·06). The cumulative incidence of VTE in the low TFMP was 7·2% ( N = 32). No major haemorrhages were observed in the enoxaparin arm. The median survival for patients with higher levels of TFMP followed by observation was 11·8 months compared with 17·8 months on enoxaparin ( P = 0·58). In a prospective randomized trial, increased numbers of circulating TFMP detected by impedance flow cytometry identified cancer patients with a high incidence of VTE. Enoxaparin demonstrated a clear trend towards reducing the rate of VTE in patients with elevated levels of TFMP, with an overall rate of VTE similar in magnitude to the lower TFMP group. [ABSTRACT FROM AUTHOR]

Large population-based studies are needed to establish the magnitude and duration of the recently suggested association between arterial and venous thromboembolism. In 1997-98, all inhabitants of Groningen, the Netherlands, aged 28-75 years ( n = 85 421), were invited to participate in a study that followed and monitored responding subjects ( n = 40 856) for venous and arterial thromboembolism until 2009. Thromboembolism was verified with national registries of hospital discharge diagnoses and death certificates, anticoagulation clinic and medical records. During a median follow-up of 10·7 years, 549 participants developed venous thromboembolism and 3283 developed arterial thromboembolism. Annual incidence of arterial thromboembolism after venous thromboembolism was 2·03% [95% confidence interval ( CI), 1·48-2·71], compared to 0·87% (95% CI, 0·84-0·90) in subjects without venous thromboembolism. The hazard ratio ( HR) of arterial thromboembolism after venous thromboembolism was 1·40 (95% CI, 1·04-1·88) after adjustment for age, sex and cardiovascular risk factors. This risk was highest during the first year after venous thromboembolism [annual incidence, 3·00% (95% CI, 1·64-5·04); adjusted HR, 2·01 (95% CI, 1·19-3·40)] and after an unprovoked event [annual incidence, 2·53% (95% CI, 1·68-3·66); adjusted HR, 1·62 (95% CI, 1·11-2·34)]. This study showed that subjects with venous thromboembolism are at increased risk for arterial thromboembolism, particularly in the first year after venous thromboembolism and after an unprovoked event. [ABSTRACT FROM AUTHOR]

Venous thromboembolism ( VTE) is effectively treated with anticoagulant therapy. After an initial treatment phase, extended treatment is effective to prevent recurrence after a first event but this is at the expense of a continued risk of bleeding. Ideally, patients at a high risk of recurrence and low risk of bleeding continue anticoagulant therapy, and for those at low risk of recurrence the duration of treatment can be limited. Identifying these patients, however, is difficult. Duration of treatment after a first VTE provoked by a transient risk factor should be limited to 3 months. Although guidelines suggest extended treatment for all patients after unprovoked VTE unless bleeding risk is high, we emphasize that the long-term risks of recurrent VTE off anticoagulation are uncertain whereas the risk of bleeding associated with anticoagulant therapy increases with age. In the absence of evidence of replaced mortality or improved quality of life with extended anticoagulant treatment, we suggest a limited duration for most patients after a first VTE. Extended treatment can be considered, based mainly on patient preference. [ABSTRACT FROM AUTHOR]

Summary Bleeding risk is not predictable in patients with factor XI (FXI; F11) deficiency. In this prospective study, our objectives were to determine the biological determinants for bleeding risk in patients with heterozygous FXI deficiency. Patients were classified as either bleeding patients or non-bleeding patients by calculating the bleeding score (BS) described for von Willebrand disease. Primary haemostasis, thrombin generation, thromboelastometry, procoagulant proteins, inhibitors, fibrinolysis, and F11 gene mutations were compared between bleeding and non-bleeding patients. Thirty-nine patients were included. BS significantly correlated with clinical assessment ( P = 0·001), and a score over 3 discriminated between bleeding ( n = 15) and non-bleeding ( n = 24) patients ( P = 0·034). Despite normal values, von Willebrand factor (VWF) and thrombomodulin (TM) plasma levels were significantly lower in bleeding patients than non-bleeding patients [ristocetin cofactor activity (VWF:RCo) = 80·6 ± 29·7 iu/dl and 101·8 ± 29·5 iu/dl respectively, P = 0·043; and VWF antigen (VWF:Ag) = 84·0 ± 28·0 iu/dl and 106·3 ± 36·1 iu/dl respectively, P = 0·035; and TM = 17·7 ± 11·7 ng/ml and 23·6 ± 9·7 ng/ml respectively, P = 0·043]. When considering BS as a continuous variable, only VWF:RCo remained significant ( P = 0·042), which accounted for 11% of the variability in BS. [ABSTRACT FROM AUTHOR]

Summary The prevalence of obesity has increased substantially over recent years. Clinicians are increasingly being challenged with making uncertain anticoagulant dosing decisions, as the optimal dosing strategy for most anticoagulants in the obese patient population remains unknown. Research published to date suggests that the clearance of anticoagulants increases with weight. As obesity is associated with an increased risk of venous thromboembolism and arterial disease, there is an urgent need to establish appropriate anticoagulation regimens for this patient group. Research studies applying the method of pharmacokinetic-pharmacodynamic modelling and simulation could establish an appropriate evidence base and provide direction and reassurance to prescribing clinicians. [ABSTRACT FROM AUTHOR]

Pulmonary embolism (PE) is a major cause of community and in-hospital mortality. This study aimed to compare the performance of the British Thoracic Society (BTS) score to the Wells' score in diagnosing PE. Data from two separate prospective diagnostic PE studies were analysed. All patients underwent gold standard investigation to determine the presence or absence of PE, together with a 3-month follow-up. The posttest prevalence of PE was compared using both scores and the receiver operating characteristic (ROC) curves. Seven hundred and seventy-nine patients were consented and investigated for PE. In patients with pleuritic chest pain, respiratory rate <20 breaths/min and absence of dyspnoea, 4·0% [95% confidence interval (CI) 1·9-7·9%] had PE. The BTS score allocated 463/779 patients as low probability, compared to 565/779 according to the Wells' score. Both scores identified a low risk group in the Manchester Investigation of Pulmonary Embolism Diagnosis cohort, however the BTS low probability group in the Thromboembolism Assessment and Diagnosis study had a prevalence of 9·7% (95% CI 5·8-15·9%). For the BTS score, the areas under the ROC curves were 0·67 (95% CI 0·61-0·72) and 0·71 (95% CI 0·61-0·75). For the Wells' score these were 0·76 (95%CI 0·71-0·81) and 0·68 (95%CI 0·64-0·73). Given the lack of BTS validation studies to date, the Wells' score appears to be the safer assessment option. [ABSTRACT FROM AUTHOR]

Treatment guidelines recommend strong consideration of thrombolysis in patients with acute symptomatic pulmonary embolism (PE) that present with arterial hypotension or shock because of the high risk of death in this setting. For haemodynamically stable patients with PE, the categorization of risk for subgroups may assist with decision-making regarding PE therapy. Clinical models [e.g. Pulmonary Embolism Severity Index (PESI)] may accurately identify those at low risk of overall death in the first 3 months after the diagnosis of PE, and such patients might benefit from an abbreviated hospital stay or outpatient therapy. Though some evidence suggests that a subset of high-risk normotensive patients with PE may have a reasonable risk to benefit ratio for thrombolytic therapy, single markers of right ventricular dysfunction (e.g. echocardiography, spiral computed tomography, or brain natriuretic peptide testing) and myocardial injury (e.g. cardiac troponin T or I testing) have an insufficient positive predictive value for PE-specific mortality to drive decision-making toward such therapy. Recommendations for outpatient treatment or thrombolytic therapy for patients with PE necessitate further development of prognostic models and conduct of clinical trials that assess various treatment strategies. [ABSTRACT FROM AUTHOR]

The article presents clinical testing guidelines and treatment recommendations from the British Committee for Standards in Hematology for testing for heritable thrombophilia. It says that these guidelines relate specifically to laboratory tests, hence reference is made to grading quality of evidence and strength of recommendations for diagnostic tests and strategies. Apart from the guidelines, the article also presents recommendations for treatment of thrombosis related medical complications.

Hospital-acquired venous thromboembolism (VTE) remains the number one safety issue in hospitals and is estimated to cause more preventable deaths than the more publicized hospital-acquired infection. There has been a failure of implementation of thromboprophylaxis (TP), mainly because of lack of awareness among health professionals, despite the large number of evidence-based studies available. The situation in the UK is gradually changing because of tireless campaigning by politicians, a charity and key opinion leaders. In response, the Department of Health has issued a national risk assessment tool, and National Institute of Clinical Excellence (NICE) guidelines for the prevention of VTE in all hospitalised patients, which will be available in August 2009. Although NICE guidelines are only applicable in England, it is to be hoped Northern Ireland, Wales and Scotland will also follow. Despite this, the consensus of expert opinion is that TP needs mandating to prevent pockets of non-adherence. Low molecular weight heparins are currently the gold standard pharmacological agent for TP; but are likely to be superseded within the next 5 years by new classes of oral anticoagulants, such as dabigatran and rivaroxiban, which are already licensed for TP after orthopaedic surgery. [ABSTRACT FROM AUTHOR]

Thrombophilia can be identified in about half of all patients presenting with venous thrombosis. Testing has increased tremendously for various indications, but whether the results of such tests help in the clinical management of patients has not been settled. Here, we review the most commonly tested thrombophilic abnormalities, i.e. protein C, protein S, and antithrombin deficiencies, the F5 R506Q (factor V Leiden) and F2 G20210A (prothrombin G20210A) mutations, and elevated levels of coagulation factor VIII, and their association with venous and arterial thrombosis as well as pregnancy complications. We conclude that testing for hereditary thrombophilia generally does not alter the clinical management of patients with venous or arterial thrombosis or pregnancy complications. Because testing for thrombophilia only serves limited purpose this should not be performed on a routine basis. [ABSTRACT FROM AUTHOR]

The majority of hospitalised patients are at risk of venous thrombosis and one in ten hospital deaths are due to pulmonary embolism. A report from the House of Commons Health Committee published in 2005 stated that each year over 25 000 people in England die from venous thromboembolism developing during hospitalisation. The report also stated that, whilst many of these deaths are preventable by thromboprophylaxis, this is not as widely used as it should be. This article reflects on the background prompting the report of the Health Committee and the subsequent response to this, including the publication of a National Institute for Health and Clinical Excellence guideline on reducing the risk of venous thromboembolism in patients undergoing surgery and the strategy for venous thrombosis prevention outlined by the Chief Medical Officer for England. It is anticipated that, by 2009, risk assessment will be mandatory for all hospitalised patients in England; the same strategy is likely for the whole UK. [ABSTRACT FROM AUTHOR]

Acute venous thromboembolism (VTE) is a serious and potentially fatal disorder, which often complicates the course of hospitalized medical patients. This is particularly true for carriers of malignant diseases. While the introduction of thromboprophylactic measures has probably affected the occurrence of postoperative VTE, there is an increasing awareness of the importance of medical conditions in determining thromboembolic events. Simple and clinically relevant risk assessment models are available to facilitate VTE risk assessment in hospitalized medical patients. Their validation in prospective studies is in progress. Randomized controlled clinical trials have consistently documented the efficacy of heparins and fondaparinux for prevention of VTE in hospitalized medical patients with a minimal haemorrhagic risk. Recognition of the incidence and clinical importance of thrombosis will probably encourage more widespread use of antithrombotic prophylaxis in medical patients and especially in some particular types of malignancies. [ABSTRACT FROM AUTHOR]

Venous thrombosis is more frequent in patients treated for acute lymphoblastic leukaemia (ALL) than other malignancies and has distinctive causes, clinical features and remedies. The reported incidence varies from 1% to 36%, depending on the chemotherapy protocol and whether the reported cases are symptomatic or detected on screening radiography. The risk is thought to arise from increased thrombin generation at diagnosis combined with reduced thrombin inhibitory capacity due to depletion of circulating anti-thrombin (AT) by asparaginase. A number of patient and treatment variables have been reported to influence the risk of thrombosis including hereditary thrombophilia, early insertion of central venous catheters and exposure to a combination of steroids and asparaginase during induction. Erwinia asparaginase is associated with a lower risk of thrombosis compared with Escherichia coli asparaginase. The majority of symptomatic thromboses are related to central venous catheters and involve the upper venous system. Central nervous system thrombosis involving the cerebral venous sinuses is a unique feature of asparaginase-related thrombosis and is reported to occur in 1–3% of patients. Conclusive evidence to support the use of anti-coagulant treatment or AT concentrates for primary prevention is lacking, as is evidence for the efficacy of AT concentrates in the management of established thrombosis. Preventative strategies are hampered by conflicting data on factors that would enable identification of those at highest risk of thrombosis. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about venous thromboembolism during coumarin therapy.

The Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology has produced a concise practical guideline to highlight the key issues in the management of heparin-induced thrombocytopenia (HIT) for the practicing physician in the UK. The guideline is evidence-based and levels of evidence are included in the body of the article. All patients who are to receive heparin of any sort should have a platelet count on the day of starting treatment. For patients who have been exposed to heparin in the last 100 d, a baseline platelet count and a platelet count 24 h after starting heparin should be obtained. For all patients receiving unfractionated heparin (UFH), alternate day platelet counts should be performed from days 4 to 14. For surgical and medical patients receiving low-molecular-weight heparin (LMWH) platelet counts should be performed every 2–4 d from days 4 to 14. Obstetric patients receiving treatment doses of LMWH should have platelet counts performed every 2–4 d from days 4 to 14. Obstetric patients receiving prophylactic LMWH are at low risk and do not need routine platelet monitoring. If the platelet count falls by 50% or more, or falls below the laboratory normal range and/or the patient develops new thrombosis or skin allergy between days 4 and 14 of heparin administration HIT should be considered and a clinical assessment made. If the pretest probability of HIT is high, heparin should be stopped and an alternative anticoagulant started at full dosage unless there are significant contraindications while laboratory tests are performed. Platelet activation assays using washed platelets have a higher sensitivity than platelet aggregation assays but are technically demanding and their use should be restricted to laboratories experienced in the technique. Non-expert laboratories should use an antigen-based assay of high sensitivity. Only IgG class antibodies need to be measured. Useful information is gained by reporting the actual optical density, inhibition by high concentrations of heparin, and the cut-off value for a positive test rather than simply reporting the test as positive or negative. In making a diagnosis of HIT the clinician's estimate of the pretest probability of HIT together with the type of assay used and its quantitative result (enzyme-linked immunosorbent assay, ELISA, only) should be used to determine the overall probability of HIT. Clinical decisions should be made following consideration of the risks and benefits of treatment with an alternative anticoagulant. For patients with strongly suspected or confirmed HIT, heparin should be stopped and full-dose anticoagulation with an alternative, such as lepirudin or danaparoid, commenced (in the absence of a significant contraindication). Warfarin should not be used until the platelet count has recovered. When introduced in combination with warfarin, an alternative anticoagulant must be continued until the International Normalised Ratio (INR) is therapeutic for two consecutive days. Platelets should not be given for prophylaxis. Lepirudin, at doses adjusted to achieve an activated partial thromboplastin time (APTT) ratio of 1·5–2·5, reduces the risk of reaching the composite endpoint of limb amputation, death or new thrombosis in patients with HIT and HIT with thrombosis (HITT). The risk of major haemorrhage is directly related to the APTT ratio, lepirudin levels and serum creatinine levels. The patient's renal function needs to be taken into careful consideration before treatment with lepirudin is commenced. Severe anaphylaxis occurs rarely in recipients of lepirudin and is more common in previously exposed patients. Danaparoid in a high-dose regimen is equivalent to lepirudin in the treatment of HIT and HITT. Danaparoid at prophylactic doses is not recommended for the treatment of HIT or HITT. Patients with previous HIT who are antibody negative (usually so after >100 d) who require cardiac surgery should receive intraoperative UFH in preference to other anticoagulants that are less validated for this purpose. Pre- and postoperative anticoagulation should be with an anticoagulant other than UFH or LMWH. Patients with recent or active HIT should have the need for surgery reviewed and delayed until the patient is antibody negative if possible. They should then proceed as above. If deemed appropriate early surgery should be carried out with an alternative anticoagulant. We recommend discussion of these complex cases requiring surgery with an experienced centre. The diagnosis must be clearly recorded in the patient's medical record. [ABSTRACT FROM AUTHOR]

The article presents several guidelines and recommendations on the use and monitoring of heparin. Consensus revised the draft guidelines. The guideline was reexamined by a multidisciplinary sounding board, the British Committee for Standards in Haematology and the British Society for Haematology and comments incorporated were appropriate. Healthcare professionals involved in the management of patients receiving heparin are the target audience of the guidelines.

Laboratory testing for the identification of heritable thrombophilia in high-risk patient groups have become common practice; however, indiscriminate testing of all patients is unjustified. The objective of this study was to evaluate the cost-effectiveness of universal and selective history-based thrombophilia screening relative to no screening, from the perspective of the UK National Health Service, in women prior to prescribing combined oral contraceptives and hormone replacement therapy, women during pregnancy and patients prior to major orthopaedic surgery. A decision analysis model was developed, and data from meta-analysis, the literature and two Delphi studies were incorporated in the model. Incremental cost-effectiveness ratios (ICERs) for screening compared with no screening was calculated for each patient group. Of all the patient groups evaluated, universal screening of women prior to prescribing hormone replacement therapy was the most cost-effective (ICER £6824). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER £202 402). Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism was more cost-effective than universal screening in all the patient groups evaluated. [ABSTRACT FROM AUTHOR]