Raj K. Patel

Long-haul flights and deep vein thrombosis: a significant risk only when additional factors are also present

Summary. To address the association between travel and deep vein thrombosis (DVT) we examined the risk factors for DVT in 568 consecutive patients with suspected DVT attending Kings College Hospital in London. No significant link between DVT and long‐haul travel was demonstrable in this cohort, with an odds ratio of 1·3 (CI 0·6–2·8). Risk of DVT was only increased in long‐haul travellers if one or more additional risk factors were present, with an odds ratio of 3·0 (CI 1·1–8·2). Such individuals may benefit from prophylactic measures to minimize risk.

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.

The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran

Dabigatran is an oral direct thrombin inhibitor (DTI) licensed for stroke prevention in atrial fibrillation and likely to be soon approved in Europe for treatment of venous thrombosis. Predictable pharmacokinetics and a reduced risk of intracranial haemorrhage do not negate the potential risk of haemorrhage. Unlike warfarin, there is no reversal agent and measurement of the anticoagulant effect is not ‘routine’. The prothrombin time/international normalised ratio response to dabigatran is inconsistent and should not be measured when assessing a patient who is bleeding or needs emergency surgery. The activated partial thromboplastin time (APTT) provides a qualitative measurement of the anticoagulant effect of dabigatran. Knowledge of the time of last dose is important for interpretation of the APTT. Commercially available DTI assays provide a quantitative measurement of active dabigatran concentration in the plasma. If a patient receiving dabigatran presents with bleeding: omit/delay next dose of dabigatran; measure APTT and thrombin time (consider DTI assay if available); administer activated charcoal, with sorbitol, if within 2 h of dabigatran ingestion; give tranexamic acid (1 g intravenously if significant bleeding); maintain renal perfusion and urine output to aid dabigatran excretion. Dabigatran exhibits low protein binding and may be removed by dialysis. Supportive care should form the mainstay of treatment. If bleeding is life/limb threatening, consider an additional haemostatic agent. There is currently no evidence to support the choice of one haemostatic agent (FEIBA, recombinant factor VIIa, prothrombin complex concentrates) over another. Choice will depend on access to and experience with available haemostatic agent(s).

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.

Risk factors for venous thrombosis in the black population

Risk factors for venous thrombo-embolism (VTE) in the black population are poorly characterized. Of 142 black cases tested a genetic cause was identified in only 9.1%: 4.2% had protein C deficiency, 2.8% protein S deficiency, 0.7% antithrombin deficiency and 1.4% were heterozygous for FV Leiden. We hypothesised that elevated factor VIII levels constitute a candidate risk factor for venous thrombosis in the black population. Factor VIII (FVIII:C) levels were determined in 100 black patients with VTE and 100 black controls in a case-control study. Of the patients 34% had a FVIII:C above 228 IU/dL (the 90th centile value in normal blacks) compared to 10% controls. Relative to those with FVIII:C below this value, odds ratio (OR) for risk of VTE was 4.64 (95% CI 2.02-10.85). When FVIII:C below 150 IU/dL was used as a comparator, OR was 11.1 (95% CI 4.29-29.43). There was evidence for a dose-response relationship. We propose that raised FVIII:C is a major risk factor for VTE in black subjects with prevalence and odds ratio exceeding those reported for white subjects.

The prevalence of the activating JAK2 tyrosine kinase mutation in chronic porto‐splenomesenteric venous thrombosis

Aliment Pharmacol Ther 31, 1330–1336

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

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Background— The optimal dosing strategy of low-molecular-weight heparins for the treatment of antenatal venous thromboembolism is not known. The physiological changes associated with pregnancy alter the pharmacokinetic profile of low-molecular-weight heparins, which has led to controversy and subsequent variation in practice, when pregnant women with venous thromboembolism are treated with low-molecular-weight heparins. Our objective was to develop a robust pharmacokinetic model of enoxaparin during the antenatal period to address this problem. Method and Results— Women prescribed antenatal enoxaparin were eligible to enroll in the study. Recruited women were reviewed monthly and had up to 3 anti-Xa activities (trough and 1 and 3 hours after dose) drawn at each clinic attendance. Compartmental pharmacokinetic modeling was conducted using nonlinear mixed-effects modeling. One hundred twenty-three patients contributed 795 anti-Xa activities for pharmacokinetic modeling purposes. Both enoxaparin clearance and volume of distribution were increased during pregnancy. Simulations of once- versus twice-daily enoxaparin administration demonstrated that both dosing regimens would reach target 3-hour plasma concentrations throughout the duration of the pregnancy. When trough anti-Xa activity was simulated, both once- and twice-daily regimens exhibited an increase in trough anti-Xa activity with the progression of pregnancy. This is explained by the significant increase in volume of distribution observed during pregnancy. Conclusions— The half-life of enoxaparin is prolonged with the progression of pregnancy, and our work provides compelling evidence for prescribing once-daily enoxaparin for the treatment of antenatal venous thromboembolism. National and international guideline recommendations should be reconsidered.

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.