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Aim: To compare health-related quality of life (HRQoL) descriptions and utility scores in newly diagnosed peripheral arterial disease (PAD) patients, using two most widely used instruments, EuroQol 5D (EQ-5D) and Medical Outcome Study 36-item Short-Form Health Status Survey (SF-36)., Methods: Patients' self-assessment of HRQoL was measured by the Dutch versions of the EQ-5D and SF-36 in the 204 patients., Results: Mean utility scores ranged from 0.675 for Short-Form Six-Dimension, 0.648 for the EQ-5D UK tariff and 0.715 for the Dutch EQ-5D tariff. A moderate correlation between the utility scores was found due to different valuation techniques of these instruments., Conclusion: Both instruments have clinical validity for use in the PAD and can be used alongside each other to provide a holistic assessment of the HRQoL. Before using these two instruments interchangeably for utility score calculations and healthcare resource allocation, a thorough sensitivity analysis is necessary to explore the robustness of the value argument based on these utility scores.

Impaired coagulation factor synthesis in cirrhosis causes a reduction of most pro- and anticoagulant factors. Cirrhosis patients show no clear bleeding or thrombotic phenotype, although they are at risk for both types of hemostatic event. Thrombin generation (TG) is a global coagulation test and its outcome depends on underlying pro- and anticoagulant processes (prothrombin conversion and thrombin inactivation). We quantified the prothrombin conversion and thrombin inactivation during TG in 30 healthy subjects and 52 Child-Pugh (CP-) A, 15 CP-B and 6 CP-C cirrhosis patients to test the hypothesis that coagulation is rebalanced in liver cirrhosis patients. Both prothrombin conversion and thrombin inactivation are reduced in cirrhosis patients. The effect on pro- and anticoagulant processes partially cancel each other out and as a result TG is comparable at 5 pM tissue factor between healthy subjects and patients. This supports the hypothesis of rebalanced hemostasis, as TG in cirrhosis patients remains within the normal range, despite large changes in prothrombin conversion and thrombin inactivation. Nevertheless, in silico analysis shows that normalization of either prothrombin conversion or thrombin inactivation to physiological levels, by for example the administration of prothrombin complex concentrates would cause an elevation of TG, whereas the normalization of both simultaneously maintains a balanced TG. Therefore, cirrhosis patients might require adapted hemostatic treatment.

Physical exercise is recommended for a healthy lifestyle. Strenuous exercise, however, may trigger the haemostatic system, increasing the risk of vascular thrombotic events and the incidence of primary cardiac arrest. Our goal was to study the effects of strenuous exercise on risk factors of cardiovascular disease. Blood was collected from 92 healthy volunteers who participated in the amateur version of the pro-tour Amstel Gold cycling race, before and directly after the race. Thrombin generation showed a shortening of the lag time and time to peak and an increase of the velocity index. Interestingly, the endogenous thrombin potential measured in plasma decreased due to reduced prothrombin conversion. Platelet reactivity increased and this effect was stronger in men than in women. Lower fibrinogen and higher D-dimer levels after exercise indicated higher fibrin formation. On the other hand, fibrinolysis was also elevated as indicated by a shortening of the clot lysis time. Exercise activated the endothelium (von Willebrand factor (VWF) and active VWF levels were elevated) and the immune system (concentrations IL-6, IL-8, MCP-1, RANTES and PDGF increased). Additionally, an increased cardiac troponin T level was measured post-exercise. Strenuous exercise induces a temporary hyperreactive state in the body with enhanced pro- and anticoagulant responses. As strenuous exercise has a more pronounced effect on platelet function in male subjects, this gives a possible explanation for the higher incidence of sudden cardiac death during exercise compared to women. This trial is registered at www.clinicaltrials.gov as NCT02048462.

Background: Thus far, validated whole blood assays used in in vitro fibrinolysis experiments using thromboelastometry (ROTEM) are lacking or have yet to be tested in humans. The objective was first, to establish a standardized modified ROTEM approach to detect both hypo- and hyperfibrinolysis. And second, to perform a technical and clinical validation of the assay., Methods: Blood was used of healthy volunteers, patients with sepsis, patients after cardiothoracic surgery, pregnant women, and cirrhotic liver disease patients. A whole blood tissue factor (TF) activated ROTEM assay with and without the addition of recombinant tissue plasminogen activator (rTPA) was developed. Plasma fibrinolysis determinants were measured in all volunteers and patients., Results: Thirty five pM TF and additions of 125 and 175 ng/ml rTPA resulted in full lysis within 60 min in healthy volunteers. Coefficients of variation were below 10 % without and below 20 % with rTPA addition. In sepsis the hypofibrinolytic ROTEM profiles with 175 ng/ml rTPA were in line with the plasma determinants (high PAI-1, high fibrinogen, low tPA activity, and high d-dimers). After cardiothoracic surgery, reduced fibrinogen and platelet levels accounted for the reduced maximum clot firmness. The hypofibrinolytic profile is attributed to tranexamic acid use and elevated PAI-1 levels. The lowest rTPA concentration in cirrhosis resulted in hyperfibrinolysis in only few of the patients. In pregnancy normal profiles were found., Discussion: Our high rTPA concentration demonstrates hypofibrinolytic profiles adequately in sepsis and after cardiothoracic surgery. Our low rTPA concentration of 125 ng/ml seems too high for demonstrating hyperfibrinolysis in cirrhotic liver disease., Conclusions: We were able to present a validated whole blood ROTEM approach to fibrinolysis testing using added rTPA, which can be of added value next to classical plasma based fibrinolysis assays.

Background: Peripheral arterial disease (PAD) is a progressive vascular disease associated with a high risk of cardiovascular morbidity and death. Antithrombotic prevention is usually applied by prescribing the antiplatelet agent aspirin. However, in patients with PAD aspirin fails to provide protection against myocardial infarction and death, only reducing the risk of ischemic stroke. Platelets may play a role in disease development, but this has not been tested by proper mechanistic studies. In the present study, we performed a systematic evaluation of platelet reactivity in whole blood from patients with PAD using two high-throughput assays, i.e. multi-agonist testing of platelet activation by flow cytometry and multi-parameter testing of thrombus formation on spotted microarrays., Methods: Blood was obtained from 40 patients (38 on aspirin) with PAD in majority class IIa/IIb and from 40 age-matched control subjects. Whole-blood flow cytometry and multiparameter thrombus formation under high-shear flow conditions were determined using recently developed and validated assays., Results: Flow cytometry of whole blood samples from aspirin-treated patients demonstrated unchanged high platelet responsiveness towards ADP, slightly elevated responsiveness after glycoprotein VI stimulation, and decreased responsiveness after PAR1 thrombin receptor stimulation, compared to the control subjects. Most parameters of thrombus formation under flow were similarly high for the patient and control groups. However, in vitro aspirin treatment caused a marked reduction in thrombus formation, especially on collagen surfaces. When compared per subject, markers of ADP- and collagen-induced integrin activation (flow cytometry) strongly correlated with parameters of collagen-dependent thrombus formation under flow, indicative of a common, subject-dependent regulation of both processes., Conclusion: Despite of the use of aspirin, most platelet activation properties were in the normal range in whole-blood from class II PAD patients. These data underline the need for more effective antithrombotic pharmacoprotection in PAD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The coagulopathy in cirrhosis is associated with thrombosis and bleeding., Objectives: To gain better insights into the coagulopathy in patients with cirrhosis, we evaluated plasma thrombin generation and whole blood clot formation in a cross-sectional study., Methods: Blood was collected from 73 patients with all-cause cirrhosis (Child-Pugh-A n = 52, B n = 15, C n = 6) and 20 healthy controls. Activity of the coagulation pathways was measured with assays for factor (F) VIIa and FIXa-antithrombin and FXa-antithrombin complexes, respectively. Thrombin generation by calibrated automated thrombography was determined in platelet-poor plasma using a 1 or 5 pm tissue factor trigger with/without thrombomodulin. ROTEM measurements were performed in whole blood triggered with 35 pm tissue factor without/with 175 ng mL(-1) tissue plasminogen activator (the latter refered to as 'tPA-ROTEM')., Results: We observed an increased generation of FVIIa and a moderately elevated amount of FIXa (in complex with antithrombin) without apparent increase in FX activation in patients with cirrhosis. In accordance with this prothrombotic state, markers of thrombin generation potential were also increased upon increasing severity of cirrhosis. In the whole blood clotting assay we observed delayed clot formation and decreased clot strength associated with increased severity of cirrhosis. No significant differences were found for tPA-ROTEM parameters of clot degradation., Conclusion: These results indicate that cirrhosis patients have an overall procoagulant plasma milieu but a decreased whole blood clot formation capacity with an apparently unaltered resistance to clot lysis., (© 2014 International Society on Thrombosis and Haemostasis.)

Lower extremity artery disease (LEAD) is a sign of wide spread atherosclerosis also affecting coronary, cerebral and renal arteries and is associated with increased risk of cardiovascular events. Many economic evaluations have been published for LEAD due to its clinical, social and economic importance. The aim of this systematic review was to assess modelling methods used in published economic evaluations in the field of LEAD. Our review appraised and compared the general characteristics, model structure and methodological quality of published models. Electronic databases MEDLINE and EMBASE were searched until February 2013 via OVID interface. Cochrane database of systematic reviews, Health Technology Assessment database hosted by National Institute for Health research and National Health Services Economic Evaluation Database (NHSEED) were also searched. The methodological quality of the included studies was assessed by using the Philips' checklist. Sixteen model-based economic evaluations were identified and included. Eleven models compared therapeutic health technologies; three models compared diagnostic tests and two models compared a combination of diagnostic and therapeutic options for LEAD. Results of this systematic review revealed an acceptable to low methodological quality of the included studies. Methodological diversity and insufficient information posed a challenge for valid comparison of the included studies. In conclusion, there is a need for transparent, methodologically comparable and scientifically credible model-based economic evaluations in the field of LEAD. Future modelling studies should include clinically and economically important cardiovascular outcomes to reflect the wider impact of LEAD on individual patients and on the society.

Peripheral artery disease (PAD) is associated with an increased risk for cardiovascular events. D-dimers are a marker for hypercoagulability and are linked with thrombotic events in patients with venous as well as arterial thrombosis. The predictive value of plasma D-dimer levels in relation to cardiovascular events in patients with PAD is not unambiguously established. It was our objective to gather evidence evaluating the value of D-dimer as a predictor of arterial thrombotic events patients with PAD. The Pubmed, Embase, and Cochrane databases were searched (January 1980-November 2012), and 65 abstracts were found. The strategy was supplemented with manual review of reference lists. Case-control, cohort or prospective cohort studies that measured fibrin D-dimer in patients with PAD, were included. Studies were excluded if there was no follow-up for arterial thrombotic events or when no specific information on D-dimer was available. The search yielded 10 studies for our analysis, comprising 2,420 patients with PAD, with a total of 1,036 cardiovascular events in 10,599 patient-years. Two studies with a follow-up of one year showed that fibrin D-dimer predicts both deterioration of PAD and subsequent thrombotic events. Five out of six studies with a median follow-up of 2-4 years revealed that an increased D-dimer is predictive of various arterial thrombotic events including mortality. Two studies with a longer follow-up (over 6 years) did not show an independent association between increased D-dimer levels, arterial thrombotic events and CVD mortality. In conclusion, an increased D-dimer appeared to be independently associated with a two times increased risk of near-term cardiovascular events (relative risk 2.30, 95% confidence interval 1.43-3.68). However formal meta-analysis was only feasible for four out of 10 included studies. Due to the extended heterogeneity of the included studies cautious interpretation of these data is warranted.

Background: Thrombin generation assays are sensitive methods for assessment of the overall clotting potential of plasma, but, despite their common use in thrombosis research, standardization of preanalytic conditions is lacking. In order to set up a standardized protocol, we analyzed different preanalytic variables and validated the calibrated automated thrombogram method., Methods and Results: Thrombin generation was assessed with 0, 1 and 5 pm tissue factor (TF). Variations in thrombin generation were mostly attributable to the type of collection tube, mainly because of variations in contact activation. The collection tube also determined the influence of other preanalytic variables on thrombin generation, e.g. the need for a discard tube, the storage of whole blood, and the centrifugation method. Regarding the collection system, blood drawn through intravenous catheters or butterfly needles showed significantly more hemolysis than blood obtained with venipuncture using conventional needles. The results showed that a discard tube is still needed for thrombin generation measurements. After blood collection, whole blood is best centrifuged immediately, to prevent activation or degradation of coagulation proteins, and a second centrifugation step at 10,000 × g is recommended. After thawing, plasma is best analyzed immediately, as storage resulted in thrombin generation results outside the 10% range of the reference sample. On the basis of these results, we set up an in-house standardized protocol, which was used for validation, resulting in coefficients of variations of < 15% for all derived parameters with both the 1 and 5 pm TF triggers., Conclusion: Thrombin generation was greatly influenced by preanalytic conditions, demonstrating the need for an international standardized protocol., (© 2012 International Society on Thrombosis and Haemostasis.)

Ribavirin in combination with interferon-α is the standard treatment for chronic hepatitis C, but often induces severe anemia forcing discontinuation of the therapy. Whereas suppression of bone marrow by interferon may impact on the production of erythrocytes, it has been suggested that accumulation of ribavirin in erythrocytes induces alterations causing an early removal of these cells by the mononuclear phagocytic system. Externalization of phosphatidylserine, which is exclusively present in the cytoplasmic leaflet of the plasma membrane, is a recognition signal for phagocytosis in particular of apoptotic cells. Here, we demonstrate that surface exposure of phosphatidylserine upon prolonged treatment of erythrocytes with ribavirin results mainly from inactivation of the aminophospholipid translocase, an ATP-dependent lipid pump, which specifically transports phosphatidylserine from the outer to the inner leaflet of the plasma membrane. Inactivation is due to severe ATP depletion, although competitive inhibition by ribavirin or its phosphorylated derivatives cannot be excluded. Phospholipid scramblase, responsible for collapse of lipid asymmetry, appears to be of minor importance as erythrocytes of patients with the Scott syndrome, lacking Ca(2+)-induced lipid scrambling, are equally sensitive to ribavirin treatment. Neither the antioxidant N-acetylcysteine nor the pan-caspase inhibitor Q-VD-OPH did affect ribavirin-induced phosphatidylserine exposure, suggesting that oxidative stress or apoptotic-related mechanisms are not involved in this process. In conclusion, we propose that spontaneous loss of lipid asymmetry, not corrected by aminophospholipid translocase activity, is the mechanism for ribavirin-induced phosphatidylserine exposure that may contribute to ribavirin-induced anemia., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The blood coagulation system is a key survival mechanism that has developed to protect man against lethal bleeding. A second function of blood coagulation is its close interaction with immunity. The immune-mediated coagulation responses may broadly be regarded as an element of response to injury. Pathological coagulation responses, including thromboembolism and disseminated intravascular coagulation (DIC), could therefore be regarded as excessive immune responses to a vessel wall injury. Virchow's triad, which comprises changes in the components of the blood, the state of the vessel wall, and the blood flow, was originally proposed for venous thrombosis. However, lately it appears that the same principles can be applied to arterial thrombosis and even DIC. It has even been postulated that all forms of thrombosis may be part of a continuous spectrum of the same disease. Over the past few years, an accumulation of evidence has shown that the etiopathogenetic mechanisms behind venous and arterial thrombosis are quite similar. The traditional elements of Virchow's triad are found to apply to both arterial and venous thrombosis. Yet, nowadays more emphasis is placed on the vessel wall and vascular bed specificity and the interaction with inflammation and hypercoagulability. This narrative review will discuss recent advances in research on the possible interactions between coagulation, the vascular endothelium, and atherosclerosis as well as the consequences of such interactions for venous and arterial thrombosis.