Lara N. Roberts

Haemostasis and thrombosis in liver disease.

Liver disease impacts on both primary and secondary haemostatic mechanisms and historically these changes were thought to underpin the bleeding diathesis. However, bleeding complications in patients with liver disease are unpredictable, with the majority of haemorrhagic episodes occurring as a result of porto‐systemic varices. Thrombosis is an increasingly recognised complication and systemic hypercoagulability may contribute to the development of parenchymal extinction and accelerated hepatic fibrosis. Routine laboratory tests do not reliably predict the risk of haemorrhage and the optimal management strategy to avert potential bleeding complications is yet to be established. There may be a future role for global coagulation assays, such as thrombelastograpy and thrombin generation, in both stratifying the risk of bleeding and guiding management of these patients.

Anticoagulating obese patients in the modern era.

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.

Venous thromboembolism and ethnicity.

Venous thromboembolism (VTE) has long been considered a disease that affects predominantly white populations, a misconception resulting from a paucity of epidemiological data from non‐Western countries, and the low incidence of hereditary thrombophilia in those of non‐Caucasian background. Over the last decade, interest has grown in this area with the emergence of evidence that VTE is as prevalent, if not more so, in the black population and is also common in Asian groups. Much is still to be learned, as our current knowledge of hereditary thrombophilia and acquired risk factors do not fully explain the risk of VTE in non‐Caucasian groups. This review summarises the current understanding of ethnic variation in VTE and highlights the need for further research in this area.

The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy

Summary.  Background: The metabolism of estrogen contained within hormone replacement therapy (HRT) is influenced by the route of administration, and this may affect the risk of venous thromboembolism. Thrombin generation, a global coagulation assay, is a marker of hypercoagulability and is of potential use in determining the thrombotic risk associated with particular HRT administration routes. Objectives: To determine whether any effect of oral and transdermal HRT on thrombin generation is related to the plasma estrogen profile. Methods: We investigated the effects of oral, transdermal and no HRT (controls) in 52, 39 and 52 postmenopausal women, respectively, on thrombin generation, standard markers of thrombophilia, estradiol level and estrone level. Results: All parameters of thrombin generation were altered in women using oral HRT as compared with controls (P < 0.001 for all comparisons). No such differences were found in women using transdermal HRT. Estrone levels correlated with peak thrombin generation (R = 0.451, P < 0.001) in women using oral HRT, but there was no correlation in women using the transdermal route. Conclusions: Thrombin generation is significantly increased in women who use HRT administered by the oral route. This is probably mediated by the hepatic first‐pass metabolism of estrone, the main metabolite of oral estradiol, which is avoided by the transdermal route. The effect of estrone on thrombin generation may provide the explanation for the higher thrombotic risk seen in women using oral rather than transdermal HRT.

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

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.

Comprehensive VTE Prevention Program Incorporating Mandatory Risk Assessment Reduces the Incidence of Hospital-Associated Thrombosis

BACKGROUND VTE is a common complication of hospitalization and is associated with significant morbidity and mortality. The use of appropriate thromboprophylaxis can significantly reduce the risk of VTE but remains underutilized. In England, a comprehensive approach to VTE prevention was launched in 2010. This study aimed to evaluate the impact of the implementation of the national program in a single center. METHODS A prospective quality improvement program was established at Kings College Hospital NHS Foundation Trust in 2010. The multidisciplinary thrombosis team launched mandatory documented VTE risk assessment and updated thromboprophylaxis guidance. Root cause analysis of hospital-associated thrombosis (HAT) was implemented to identify system failures, enable outcome measurement, and facilitate learning to improve VTE prevention practice. The key outcomes were the incidence of HAT and the proportion of events preventable with appropriate thromboprophylaxis. RESULTS Documented VTE risk assessment improved from <40% to > 90% in the first 9 months. Four hundred twenty-five episodes of HAT were identified over 2 years. A significant reduction in the incidence of HAT was observed following sustained achievement of 90% risk assessment (risk ratio, 0.88; 95% CI, 0.74-0.98; P = .014). The proportion of HAT attributable to inadequate thromboprophylaxis fell significantly from 37.5% to 22.4% (P = .005). CONCLUSIONS Mandatory VTE risk assessment can significantly reduce preventable HAT and thereby improve patient safety.

Heavy menstrual bleeding on rivaroxaban

Direct oral anticoagulants (DOACs) offer many advantages over vitamin K antagonists (VKA) whilst maintaining an equivalent efficacy and safety profile. Major bleeding events with DOACs are reported as equivalent or reduced compared to VKA (Ruff et al, 2014). While the female gender has been associated with a higher risk of major and clinically relevant non-major bleeding when prescribed anticoagulant therapy, including with DOACs (Alotaibi et al, 2013), the clinical implications of gender-specific bleeding with DOACs are unknown. Further, real-world experience might reveal different patterns of bleeding that require specific management in clinical practice. One such manifestation is heavy menstrual bleeding (HMB), affecting 10–30% women during some point of their child bearing years in the absence of anticoagulation (Lethaby & Farquhar, 2003; Liu et al, 2007), which is a well-recognized adverse event with VKA treatment though not frequently reported (Sjalander et al, 2007; Huq et al, 2011). HMB is often overlooked as an adverse effect of anticoagulation. Indeed, a recent meta-analysis of published clinical trials evaluating bleeding observed with rivaroxaban therapy has no specific mention of HMB (Wasserlauf et al, 2013). Perhaps this should come as no surprise, as the International Society on Thrombosis and Haemostasis (ISTH) definition of clinically relevant non-major bleeding (Schulman & Kearon, 2005) does not specify HMB as a sub-category of bleeding to report. This lack of formal recognition perpetuates the absence of specific information in the literature on this important area and, although rarely associated with serious events, HMB has an overall negative impact on women0s quality of life, incurring significant direct and indirect costs (Liu et al, 2007). Patients anticoagulated with DOACs for venous thromboembolism (VTE) include a younger demographic compared with those receiving anticoagulation for stroke prevention. These patients have much to gain from the advantages that DOACs have to offer on one hand, and much to lose with reduced quality of life associated with HMB, on the other. It is therefore important to explore any potential associations between increased bleeding and specific patient characteristics, in order to better counsel and manage potential complications during anticoagulation with DOACs in order to optimise adherence and patient satisfaction. Early experience from our clinic suggests an increase in HMB in females taking rivaroxaban, currently the main DOAC used for VTE treatment in the UK. The clinical course of women aged between 16 and 55 years, treated with rivaroxaban between September 2012 and September 2014 was reviewed. From a total of 128 women, HMB was reported in 26 (20%) with a mean age of 38 7 years. Fifteen were of African-Caribbean origin, 9 Caucasian and 2 of unspecified ethnicity ((Table I). The predominant indication for anticoagulation in the whole cohort was deep vein thrombosis in 67% (n = 89) followed by pulmonary embolism in 15% (n = 19), as compared to 84% (n = 22) and 12% (n = 3) respectively in the group of women with documented HMB (Table I). Long-term anticoagulation was intended for 50% of the whole cohort (n = 64) and 62% (n = 16) of those with HMB. (Table I). Forty-seven women (37%) were anticoagulated with an alternative agent prior to rivaroxaban, of whom 5 (11%) had previous reports of HMB. When prescribed rivaroxaban, 10 of

Presenting D-dimer and early symptom severity are independent predictors for post-thrombotic syndrome following a first deep vein thrombosis.

Post‐thrombotic syndrome (PTS) is the most common complication of deep vein thrombosis (DVT). Current preventative strategies are limited to the daily wear of graduated compression stockings (GCS). The aim of this study was to evaluate early predictors of PTS. One hundred and twenty‐two consecutive patients with a first DVT were prospectively recruited from diagnosis and followed for up to 6 months post‐end of anticoagulation. D‐dimer was measured in 107 participants at presentation and Villalta scale was evaluated in 70 participants at a median of 2 weeks following diagnosis. PTS developed in 51·6% of participants. GCS were obtained by 78·1% of participants, with 33·7% reporting daily wear at the end of follow‐up. Mean early Villalta scale was significantly higher in those with PTS (8·1 ± 3·7) compared to those without (2·6 ± 2·7, P < 0·001). Median D‐dimer was significantly higher in those with PTS [3260 ng/ml, interquartile range (IQR) 820–8000 ng/ml] compared to those without (1540 ng/ml, IQR 810–2520 ng/ml, P < 0·001). The adjusted odds ratio for every one point increase in early Villalta scale was 1·78 [95% confidence interval (CI), 1·19–2·64; P = 0·005] and for D‐dimer >1910 ng/ml it was 2·71 (95% CI, 1·05–7·03; P = 0·04). These markers could enable targeted counselling regarding GCS for those at high risk of PTS.

Post-thrombotic syndrome is an independent determinant of health-related quality of life following both first proximal and distal deep vein thrombosis

Post-thrombotic syndrome (PTS) is a common complication of deep vein thrombosis (DVT), affecting between 20 and 50%.[1][1] DVT and PTS have been demonstrated to adversely impact on disease-specific and generic measures of health-related quality of life (QOL).[2][2],[3][3] We sought to establish

Prevalence and clinical outcomes of the 46/1 haplotype, Janus kinase 2 mutations, and ten‐eleven translocation 2 mutations in budd‐chiari syndrome and their impact on thrombotic complications post Liver Transplantation

Latent myeloproliferative disorders (MPDs) can be identified by Janus kinase 2 (JAK2) mutations in patients with idiopathic Budd‐Chiari syndrome (BCS). The incidence and clinical outcomes of JAK2 mutations, novel ten‐eleven translocation 2 (TET2) mutations, and the 46/1 haplotype in BCS are unknown for liver transplantation (LT). We undertook molecular studies of 66 patients presenting with BCS and correlated the results with the clinical outcomes. An overt MPD was present in 20% of the cases, and a latent MPD confirmed by the presence of a JAK2 mutation was detected in 45%. Testing for a TET2 mutation identified MPDs at the molecular level in another 7% of the subset of patients with BCS who were evaluated. The 46/1 haplotype frequency was significantly greater in BCS patients versus the general population (P < 0.001). The presence of JAK2 and TET2 mutations had no impact on 1‐year survival. Thirty‐six patients underwent LT, and 12 developed liver‐related thrombotic complications (33%). Ten of these 12 patients required retransplantation. Retransplantation was more likely in those patients who developed liver‐related thrombotic complications (P < 0.001). A JAK2 mutation was highly associated with the development of thrombotic complications after LT (P = 0.005). In conclusion, the presence of JAK2V617F predicts hepatic and extrahepatic thrombotic complications after LT. Testing for TET2 mutations can identify another 7% of idiopathic BCS patients with molecular MPDs. Liver Transpl, 2012.