Roopen Arya

Virchow and his triad: a question of attribution.

Virchow’s triad describes three factors that contribute to the development of venous thrombosis: hypercoagulability, stasis and endothelial injury. Yet, extensive review of the historical literature casts doubt on the existence of a triad described by Virchow in the form it is currently quoted throughout contemporary medical literature. Certainly his work involved extensive study of venous thrombosis and pulmonary embolism, with these two terms being coined by Virchow, but a triad of factors relating to the development of venous thrombosis is elusive. Interestingly, Virchow only began to be routinely credited with this triad one hundred years after publication of his work on venous thrombosis. This acknowledgement coincided with the accumulation of experimental evidence for the role these factors play in thrombogenesis. Controversial as the origins of Virchow’s triad might be, it is apt given his substantial contribution to our knowledge of venous thromboembolism, and the fact that the triad continues to be clinically relevant today that a triad pertaining to Virchow should remain.

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.

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.

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.

Frequency, demographics and risk (according to tumour type or site) of cancer-associated thrombosis among patients seen at outpatient DVT clinics

Venous thromboembolism (VTE) is a clinically important complication for both hospitalised and ambulatory cancer patients. In the current study, the frequency, demographics and risk (according to tumour site) of VTE were examined among patients seen at outpatient DVT (deep-vein thrombosis) clinics. Of 10,015 VTE cases, 1,361 were diagnosed with cancer, for an overall rate of cancer-associated VTE of 13.6% in this outpatient population. Patients with cancer-associated VTE were significantly older than cancer-free VTE cases (66.4 +/- 12.7 vs. 58.8 +/- 18.5 years; p<0.0001). The frequency of cancer-associated VTE peaked earlier among females than males, occurring in the sixth (137/639, 21.4% vs. 98/851, 11.3%; p<0.001) and seventh decades (213/980, 21.7% vs. 197/1096, 18%; p=0.036). VTE was described most frequently in common cancers - breast, prostate, colorectal and lung (56.1% of cases). The risk of VTE varied widely across 17 cancer types. Calculating odds ratios (OR) to assess the effect size of cancer type on VTE risk, the highest odds were observed for patients with pancreatic cancer (OR 9.65, 95% confidence interval [CI] (5.51-16.91). Tumours of the head and neck had higher odds than previously reported (OR 8.24, 95% CI 5.06-13.42). Reduced risk estimates were observed for skin cancers (melanoma and non-melanoma: OR 0.89, 95% CI 0.42-1.87; OR 0.74, 95% CI, 0.32-1.69, respectively). We conclude that outpatients have a similar rate of cancer-associated VTE as VTE patient populations previously reported, that cancer-associated VTE occurs in an older age group and earlier in females and that outpatients exhibit distinct tumour site-specific risk from that described among hospitalised cancer patients.

Measurement of the Direct Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in Human Plasma Using Turbulent Flow Liquid Chromatography With High-Resolution Mass Spectrometry

Background: Direct oral anticoagulants (DOACs) are prescribed for systemic anticoagulation. Fixed doses are recommended, but dose individualization may be warranted. Functional coagulation assays may be available, but their use requires knowledge of the drug taken. To provide alternative methodology for guiding dosage, we have developed and validated a liquid chromatography–mass spectrometric assay for apixaban, dabigatran, edoxaban, and rivaroxaban at the concentrations attained during therapy. Methods: Samples, calibrators, and internal quality controls (100 &mgr;L) were mixed with internal standard solution (50 &mgr;g/L both dabigatran-13C6 and rivaroxaban-13C6 in acetonitrile) and, after centrifugation (16,400g, 4 minutes), supernatant (100 &mgr;L) was injected onto a Cyclone-C18-P-XL TurboFlow column. Analytes were focused onto an Accucore PhenylHexyl (2.1 × 100 mm, 2.6 &mgr;m) analytical column and eluted using a methanol + acetonitrile (1 + 1):aqueous ammonium acetate (10 mmol/L) gradient. Data were acquired using high-resolution mass spectrometry in full-scan mode (100–2000 m/z) with data-dependent fragmentation to confirm peak identity. Calibration was linear (1–500 &mgr;g/L all analytes). Results: Total analysis time was 6 minutes. Intra-assay imprecision (% RSD) at 1 &mgr;g/L was 2.6%, 4.2%, 17.3%, and 9.5% for apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. Mean recovery was 96%–101%. No signal suppression or enhancement was observed. Apixaban, dabigatran, and rivaroxaban were stable over 3 freeze–thaw cycles, after storage at room temperature, and at 2–8°C for up to 2 weeks. Edoxaban was stable over 3 freeze–thaw cycles but showed a mean deterioration of 16% if stored at 2–8°C (2 weeks) and of 18% and 70% (1 day and 2 weeks, respectively) at room temperature. Conclusions: The method is suitable for high-throughput therapeutic drug monitoring of DOACs. The acquisition of full scan data allows for the retrospective identification of metabolites. The method can be used to identify a particular DOAC if information on the drug taken is lacking.

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.

Pregnancy loss and thrombophilia: the elusive link

Recurrent pregnancy loss (RPL) affects 1% pregnancies and is multi‐factorial in origin. The role of the acquired thrombophilia antiphospholipid syndrome (APS) as a common and potentially treatable cause of RPL is well established but this is less so for inherited thrombophilia. In obstetric APS the combination of aspirin and heparin has improved outcomes. By analogy, the use of low molecular weight heparin (LMWH) has become commonplace in women with inherited thrombophilia and also those with unexplained miscarriage to help safeguard the pregnancy. This review will examine the pathophysiological role of thrombophilia in pregnancy loss, and the evidence for anticoagulant‐based intervention. The limited data supporting the use of heparin for women with RPL and inherited thrombophilia suggests adoption of a more cautious and judicious approach in this setting.