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1.  Stent thrombosis caused by metal allergy complicated by protein S deficiency and heparin-induced thrombocytopenia: a case report and review of the literature 
Thrombosis Journal  2015;13:25.
A 43-year-old woman recipient of a bare metal coronary stent during an acute anterior myocardial infarction was repeatedly hospitalized with recurrent stent thrombosis (ST) over the following 3 years. Emergent coronary angiography showed a thrombus in the in-stent segment of the proximal left anterior descending artery. We repeatedly aspirated the thrombus, which immediately reformed multiple times. The discontinuation of heparin and administration of thrombolytics and argatroban, followed by repeated balloon dilatations, ended the formation of new thrombi. The patient was found to be allergic to nickel, protein S deficient and carrier of heparin-induced thrombocytopenia antibody. We discuss this case in the context of a) literature pertaining to acute coronary syndromes in the young, and b) the detailed investigations needed to identify thrombotic risk factors. Steroids may be effective to prevent recurrent ST caused by stent allergy.
PMCID: PMC4512022  PMID: 26207097
Stent thrombosis; Metal allergy; Heparin-induced thrombosis; Protein S deficiency
2.  Inhibition of thrombin generation in human plasma by phospholipid transfer protein 
Thrombosis Journal  2015;13:24.
Plasma phospholipid transfer protein (PLTP) transfers lipids between donors and acceptors (e.g., from HDL to VLDL) and modulates lipoprotein composition, size, and levels. No study has reported an assessment of the effects of PLTP on blood clotting reactions, such as reflected in thrombin generation assays, or on the association of venous thrombosis (VTE) risk with PLTP activity.
The in vitro effects of PLTP on blood coagulation reactions and the correlations between plasma PLTP activity levels and VTE were studied.
Recombinant (r) PLTP concentration-dependently inhibited plasma thrombin generation and factor XII-dependent kallikrein generation when sulfatide was used to stimulate factor XII autoactivation in plasma. However, rPLTP did not inhibit thrombin generation in plasma induced by factor XIa or tissue factor, implicating an effect of PLTP on contact activation reactions. In purified systems, rPLTP inhibited factor XII autoactivation stimulated by sulfatide in the presence of VLDL. In surface plasmon resonance studies, purified factor XII bound to immobilized rPLTP, implying that rPLTP inhibits factor XII-dependent contact activation by binding factor XII in the presence of lipoproteins. Analysis of plasmas from 40 male patients with unprovoked VTE and 40 matched controls indicated that low PLTP lipid transfer activity (≤25th percentile) was associated with an increased risk of VTE after adjustment for body mass index, plasma lipids, and two known thrombophilic genetic risk factors.
These data imply that PLTP may be an antithrombotic plasma protein by inhibiting generation of prothrombotic factor XIIa in the presence of VLDL. This newly discovered anticoagulant activity of PLTP merits further clinical and biochemical studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12959-015-0054-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4504036  PMID: 26185485
Phospholipid transfer protein; Factor XII; Venous thromboembolism; Thrombin generation
3.  The role of soluble fibrin during anticoagulant therapy: a case report 
Thrombosis Journal  2015;13:23.
Warfarin, dabigatran, and apixaban are used for preventing ischemic stroke due to non-valvular atrial fibrillation (NVAF). However, it is often challenging to select the appropriate anticoagulant. We present the case of a 70-year-old male patient with persistent NVAF who developed pulmonary thromboembolism (PTE), deep vein thrombosis (DVT), and left atrial thrombus during anticoagulant therapy with warfarin. Intravenous recombinant tissue plasminogen activator was administered during his acute PTE. Heparin and apixaban were administered over 28 days; heparin was discontinued after the DVT resolved, while apixaban was administered to prevent ischemic stroke. Two days after heparin was discontinued, the patient experienced an ischemic stroke. Dabigatran was administered for secondary ischemic stroke prevention. Soluble fibrin (SF) levels remained elevated during treatment with heparin and apixaban and returned to normal after apixaban was replaced with dabigatran. Monitoring of SF may be useful as an index for selection of anticoagulants.
PMCID: PMC4491884  PMID: 26150759
Soluble fibrin; Pulmonary thromboembolism; Atrial fibrillation; Deep vein thrombosis; Warfarin; Apixaban; Dabigatran
4.  Retrospective cohort analysis comparing the incidence of deep vein thromboses between peripherally-inserted and long-term skin tunneled venous catheters in hemato-oncology patients 
Thrombosis Journal  2015;13:21.
The introduction of central venous catheters has advanced medical care, particularly in hemato-oncology. However these can be associated with an increased thrombotic risk. Previous studies have compared the rate of thrombotic events between peripherally- inserted (PICCs) and long term skin tunneled catheters (LTSTCs) noting fewer complications associated with the latter, though this has rarely translated into clinical practice. The objectives of our study was to compare the cumulative incidence of thrombotic events between peripherally-inserted and long term skin tunneled venous catheters.
We performed a retrospective, single center cohort analysis of patients with hematological malignancies who had either a PICC or LTSTC line inserted between January 2010 through January 2013. Cumulative incidences of thrombotic events were compared between the two groups, and post-thrombotic complications were also examined.
346 patients had a PICC inserted with cumulative incidence of symptomatic thrombosis of 5.8%, while 237 patients had a LTSTC inserted with a cumulative incidence of 1.7% (p = 0.003). Post-thrombotic complication rates, particularly infection, were higher in the PICC group compared to the LTSTC group (p = 0.597).
Our study showed that the incidence of thrombotic events in hemato-oncology patients was significantly lower in those who had a LTSTC compared to PICC line. As the use of central venous lines increases in hemato-oncology patient care, a randomized trial comparing PICCs and LTSTCs is necessary to address which venous access is most appropriate in this cohort of patients, with minimal risk of morbidity and mortality.
PMCID: PMC4480444  PMID: 26113804
Catheter-related deep vein thrombosis; Cohort study; Doppler ultrasonography; Long term skin tunneled catheterisation; Venous thromboembolism
5.  Cost-effectiveness analysis of treatment of venous thromboembolism with rivaroxaban compared with combined low molecular weight heparin/vitamin K antagonist 
Thrombosis Journal  2015;13:20.
Venous thromboembolism (VTE) is a burden on healthcare systems. Standard treatment involves parenteral anticoagulation overlapping with a vitamin K antagonist, an approach that is effective but associated with limitations including the need for frequent coagulation monitoring. The direct oral anticoagulant rivaroxaban is similarly effective to standard therapy as a single-drug treatment for VTE and does not require routine coagulation monitoring. The objective of this economic evaluation was to estimate the cost-effectiveness of rivaroxaban compared with standard VTE treatment from a UK perspective.
A Markov model was constructed using data and probabilities derived from the EINSTEIN DVT and EINSTEIN PE studies of rivaroxaban and other published sources. Health outcomes included VTE rates, bleeding events avoided, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs).
There was greater discounted quality-adjusted life expectancy with rivaroxaban than with standard therapy, irrespective of indication and treatment duration. Rivaroxaban was associated with per-patient cost savings for each treatment duration modelled (3, 6 and 12 months), and these were greatest with shorter durations. Rivaroxaban was found to be dominant (cheaper and more effective) and, therefore, cost-effective, in both patients with deep vein thrombosis and pulmonary embolism in all three treatment duration groups, and was also cost-effective in patients requiring lifelong anticoagulation (ICERs: £8677 per QALY and £7072 per QALY in patients with index deep vein thrombosis and pulmonary embolism, respectively). The cost-effectiveness of rivaroxaban was largely insensitive to variations in one-way sensitivity analysis. Probabilistic sensitivity analysis demonstrated that at a threshold of £20,000 per QALY, rivaroxaban had a consistent probability of being cost-effective, compared with LMWH/VKA treatment, of around 80% regardless of index VTE or duration of anticoagulation therapy (3, 6, 12 months or lifelong).
This analysis suggests that rivaroxaban represents a cost-effective choice for acute treatment of deep vein thrombosis and pulmonary embolism and secondary prevention of VTE in the UK, compared with LMWH/VKA treatment, regardless of the required treatment duration.
Electronic supplementary material
The online version of this article (doi:10.1186/s12959-015-0051-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4464718  PMID: 26074735
Cost-effectiveness; Rivaroxaban; Venous thromboembolism treatment
6.  Analysis of the accuracy of the Wells scale in assessing the probability of lower limb deep vein thrombosis in primary care patients practice 
Thrombosis Journal  2015;13:18.
The clinical picture of deep vein thrombosis (DVT) is nonspecific. Therefore assessment of the probability of occurrence of DVT plays a very important part in making a correct diagnosis of DVT.
The aim of our prospective study was to assess the accuracy of the Wells scale in primary care setting in diagnostic procedure of suspected deep vein thrombosis.
In the period of 20 - months (from 2007 to 2009) a group of residents from one of the urban districts of Warsaw, who reported to family doctors (22 primary care physicians were involved in the study) with symptoms of DVT were assessed on the probability of occurrence of deep vein thrombosis using the Wells scale. Family doctors were aware of symptoms of DVT and inclusion patients to this study was based on clinical suspicion of DVT.
Patients were divided into three groups, reflecting probability of DVT of the lower limbs.
To confirm DVT a compression ultrasound (CUS) test was established.
We analyzed the relationship between a qualitative variable and a variable defined on an original scale (incidence of DVT versus Wells scale count) using the Mann–Whitney test. Chi-square test compared rates of DVT events in all clinical probability groups.
Patient were follow up during 3 months in primary care setting.
In the period of 20 months (from 2007 to 2009) a total number of 1048 patients (male: 250 , female: 798 mean age: 61.4) with symptoms suggestive of DVT of the lower extremities entered the study. Among the 100 patients classified in the group with a high probability of DVT of the lower extremities, 40 (40%) patients (proximal DVT - 13; distal DVT - 27) were diagnosed with it (95% CI [30.94% -49.80%]). In the group with a moderate probability consisting of 302 patients, DVT of the lower extremities was diagnosed in 19 (6.29%) patients (95% CI [4.06% -9.62%]), (proximal DVT – 1; distal DVT - 18). Of the 646 patients with a low probability of DVT of the lower extremities distal DVT was diagnosed in 1 (0.15%) patient (95% CI [0.03% -0.87%]).
The Wells scale used in primary care setting demonstrated a high degree of accuracy.
PMCID: PMC4455328  PMID: 26045696
Wells scale; Deep vein thrombosis; Primary care
7.  Implementation of non-vitamin K antagonist oral anticoagulants in daily practice: the need for comprehensive education for professionals and patients 
Thrombosis Journal  2015;13:22.
Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used for the prevention and treatment of venous thromboembolism and for stroke prevention in patients with atrial fibrillation. NOACs do not require routine coagulation monitoring, creating a challenge to established systems for patient follow-up based on regular blood tests. Healthcare professionals (HCPs) are required to cope with a mixture of patients receiving either a vitamin K antagonist or a NOAC for the same indications, and both professionals and patients require education about the newer drugs. A European working group convened to consider the challenges facing HCPs and healthcare systems in different countries and the educational gaps that hinder optimal patient management. Group members emphasised the need for regular follow-up and noted national, regional and local variations in set-up and resources for follow-up. Practical incorporation of NOACs into healthcare systems must adapt to these differences, and practical follow-up that works in some systems may not be able to be implemented in others. The initial prescriber of a NOAC should preferably be a true anticoagulation specialist, who can provide initial patient education and coordinate the follow-up. The long-term follow-up care of patients can be managed through specialist coagulation nurses, in a dedicated anticoagulation clinic or by general practitioners trained in NOAC use. The initial prescriber should be involved in educating those who perform the follow-up. Specialist nurses require access to tools, potentially including specific software, to guide systematic patient assessment and workflow. Problem cases should be referred for specialist advice, whereas in cases for which minimal specialist attention is required, the general practitioner could take responsibility for patient follow-up. Hospital departments and anticoagulation clinics should proactively engage with all downstream HCPs (including pharmacists) to ensure their participation in patient management and reinforcement of patient education at every opportunity. Ideally, (transmural) protocols for emergency situations should be developed. Last but not least, patients should be well-informed about their condition, the treatment, possible risk scenarios, including the consequences of non-adherence to prescribed therapy, and the organisation of follow-up care.
PMCID: PMC4484703  PMID: 26124699
Anticoagulation clinic; Educational pathways; Non-vitamin K antagonist oral anticoagulant; Patient education
8.  Autoinflammatory diseases: a possible cause of thrombosis? 
Thrombosis Journal  2015;13:19.
Autoinflammatory diseases are a group of disorders due to acquired or hereditary disfunction of innate immune system and characterized by systemic or localized manifestations. The prototype is Familial Mediterranean Fever, a monogenic hereditary disorder, whose causing gene (MeFV gene) was identified in 1997 and opened the way to a new fascinanting chapter of rheumatology. A growing body of monogenic and poligenic autoinflammatory disorders has been described since then.
Arterial and venous thrombosis is a common medical problem, with significant morbidity and mortality. Strong evidences from basic research and clinical epidemiological studies support the theory that inflammation and thrombosis can be associated.
Because of their recurrent/chronic inflammatory nature, autoinflammatory diseases are a putative cause of thrombotic manifestations. In the present work, we reviewed the available evidences about monogenic autoinflammatory disorders, complicated by thrombotic manifestations.
PMCID: PMC4428094  PMID: 25969671
Autoinflammatory diseases; Familial mediterranean fever; Criopyrinopathies; Pyrinopathies; Periodic fevers; Venous thrombosis; Venous thromboembolism; Arterial thrombosis; Stroke; Myocardial infarction
9.  Contact pathway of coagulation and inflammation 
Thrombosis Journal  2015;13:17.
The contact system, also named as plasma kallikrein-kinin system, consists of three serine proteinases: coagulation factors XII (FXII) and XI (FXI), and plasma prekallikrein (PK), and the nonenzymatic cofactor high molecular weight kininogen (HK). This system has been investigated actively for more than 50 years. The components of this system and their interactions have been elucidated from in vitro experiments, which indicates that this system is prothrombotic by activating intrinsic pathway, and proinflammatory by producing bioactive peptide bradykinin. Although the activation of the contact system have been implicated in various types of human disease, in only a few instances is its role clearly defined. In the last 10 years, our understanding of the contact system, particularly its biology and (patho)physiology has greatly increased through investigations using gene-modified animal models. In this review we will describe a revitalized view of the contact system as a critical (patho)physiologic mediator of coagulation and inflammation.
PMCID: PMC4421925  PMID: 25949215
Contact system; Coagulation; Inflammation; Platelet; Infection; Autoimmune disease; Vascular biology
10.  Systemic lupus erythematosus and thrombosis 
Thrombosis Journal  2015;13:16.
Systemic Lupus Erythematosus (SLE) is an acquired, multiorgan, autoimmune disease. Clinical presentation is extremely variable and heterogeneous. It has been shown that SLE itself is an independent risk factor for developing both arterial and venous thrombotic events since SLE patients have an Odds Ratio (OR) for thrombosis that varies depending on the clinical and laboratory characteristics of each study cohort. The risk of developing a thrombotic event is higher in this setting than in the general population and may further increase when associated with other risk factors, or in the presence of inherited or acquired pro-thrombotic abnormalities, or trigger events. In particular, a striking increase in the number of thrombotic events was observed when SLE was associated with antiphospholipid antibodies (aPL). The presence of aPLs has been described in about 50% of SLE patients, while about 20% of antiphospholipid syndrome (APS) patients have SLE. While APS patients (with or without an autoimmune disease) have been widely studied in the last years, fewer studies are available for SLE patients and thrombosis in the absence of APS. Although the available literature undoubtedly shows that SLE patients have a greater prevalence of thrombotic events as compared to healthy subjects, it is difficult to obtain a definite result from these studies because in some cases the study cohort was too small, in others it is due to the varied characteristics of the study population, or because of the different (and very copious) laboratory assays and methods that were used. When an SLE patient develops a thrombotic event, it is of great clinical relevance since it is potentially life-threatening. Moreover, it worsens the quality of life and is a clinical challenge for the clinician.
PMCID: PMC4407320  PMID: 25908929
Systemic lupus erythematosus; Thrombosis; Risk factors
11.  Thrombosis in vasculitis: from pathogenesis to treatment 
Thrombosis Journal  2015;13:15.
In recent years, the relationship between inflammation and thrombosis has been deeply investigated and it is now clear that immune and coagulation systems are functionally interconnected.
Inflammation-induced thrombosis is by now considered a feature not only of autoimmune rheumatic diseases, but also of systemic vasculitides such as Behçet’s syndrome, ANCA-associated vasculitis or giant cells arteritis, especially during active disease.
These findings have important consequences in terms of management and treatment. Indeed, Behçet’syndrome requires immunosuppressive agents for vascular involvement rather than anticoagulation or antiplatelet therapy, and it is conceivable that also in ANCA-associated vasculitis or large vessel-vasculitis an aggressive anti-inflammatory treatment during active disease could reduce the risk of thrombotic events in early stages.
In this review we discuss thrombosis in vasculitides, especially in Behçet’s syndrome, ANCA-associated vasculitis and large-vessel vasculitis, and provide pathogenetic and clinical clues for the different specialists involved in the care of these patients.
PMCID: PMC4399148  PMID: 25883536
Inflammation-induced thrombosis; Thrombo-embolic disease; Deep vein thrombosis; ANCA associated vasculitis; Large vessel vasculitis; Behçet syndrome
12.  Thrombosis in inflammatory bowel diseases: what’s the link? 
Thrombosis Journal  2015;13:14.
Inflammatory bowel disease affects more than 2 million people in Europe, with almost 20% of patients being diagnosed in pediatric age. Patients with inflammatory bowel disease are at increased risk of thromboembolic complications which may affect patients’ morbidity and mortality. The risk of the most common thromboembolic events, such as deep venous thrombosis and pulmonary embolism, are estimated to be three-fold increased compared to controls, but many other districts can be affected. Moreover, patients with ulcerative colitis and Crohn’s disease experience thromboembolic events at a younger age compared to general population. Many factors have been investigated as determinants of the pro-thrombotic tendency such as acquired risk factors or genetic and immune abnormalities, but a unique cause has not been found. Many efforts have been focused on the study of abnormalities in the coagulation cascade, its natural inhibitors and the fibrinolytic system components and both quantitative and qualitative alterations have been demonstrated. Recently the role of platelets and microvascular endothelium has been reviewed, as the possible link between the inflammatory and hemostatic process.
PMCID: PMC4393581  PMID: 25866483
Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Thrombosis
13.  Remarkable regression of massive deep vein thrombosis in response to intensive oral rivaroxaban treatment 
Thrombosis Journal  2015;13:13.
Deep vein thrombosis (DVT) is a common disease and is associated with pulmonary embolism (PE). Proximal iliofemoral DVT may lead to severe PE and chronic venous insufficiency. The standard therapy for DVT is anticoagulant therapy using heparin and a vitamin K antagonist, but a recent clinical study showed that rivaroxaban, an oral Xa inhibitor, was comparable to standard therapy and had less bleeding complications. Intensive high-dose anticoagulation is recommended during the initial 3 weeks of DVT treatment. The present report describes a case of a 77-year-old male showing a remarkable regression of DVT in response to rivaroxaban treatment within the initial 3 weeks of therapy and who did not experience any adverse events. His DVT was massive and was accompanied by proximal iliofemoral vein thrombus and iliac vein compression syndrome. Rivaroxaban, especially in intensive high-dose treatment, might be a safe and effective therapeutic choice for massive DVT.
PMCID: PMC4364575  PMID: 25788868
Rivaroxaban; Deep vein thrombosis; Anticoagulation; Iliac vein compression; Thrombus regression
14.  “Role of the adipocyte hormone leptin in cardiovascular diseases – a study from Chennai based Population” 
Thrombosis Journal  2015;13:12.
Obesity is currently regarded as a pro-inflammatory condition during which leptin (Ob gene product) might act as a risk factor for Cardiovascular Diseases (CVD) including Acute Myocardial Infarction (AMI). There is a marked increase in circulating leptin concentrations and inflammatory markers such as Tumor Necrosis Factor-α (TNF-α) in AMI patients but still the association of leptin with inflammation during AMI is not known. The present study suggest that elevated levels of leptin might elicit the risk for CVD by signaling for the secretion of inflammatory cytokines especially, TNF-α.
Blood samples were collected from 100 CVD subjects diagnosed for AMI immediately after their admission to the hospital and serum leptin, insulin, glucose, lipids and inflammatory marker such as TNF-α were measured. 5 ml random (non-fasting) blood was collected from 100 non-CVD (control) subjects and the results obtained in case of AMI subjects were compared with that of the control subjects. The subjects under study included both men and women belonging to the age group of 35 – 75 and they were classified based on their BMI as normal weight, overweight and obese.
Circulating levels of leptin are found to be elevated in obese control subjects and in patients with AMI irrespective of their Body Mass Index (BMI). In addition, leptin is also found to be positively correlated to serum triglycerides, insulin and TNF-α in AMI subjects. MANOVA analysis suggests that leptin might influence the synthesis of insulin and TNF-α. This is the first report relating leptin to TNF-α in Chennai based population, India.
Hyperleptinemia might act as a risk marker for AMI. The present study suggests that at elevated levels, leptin may favor atherosclerosis by promoting the synthesis of TNF-α and insulin. However, our report warrants further investigation both in vitro and in vivo to determine the exact mechanism behind the pro-atherogenic role of leptin. The observed positive correlation between leptin and BMI in both AMI and control subjects suggests that obese subjects manifest leptin resistance and hence, they possess a greater risk for the incidence of CVD.
PMCID: PMC4355465  PMID: 25762868
Leptin; Insulin; Tumor necrosis factor-α; Obesity; Acute Myocardial Infarction; Cardiovascular Diseases
15.  Reviewer acknowledgement 2014 
Thrombosis Journal  2015;13:11.
Contributing reviewers
The Editors of Thrombosis Journal would like to thank all of our reviewers who have contributed to the journal in Volume 12 (2014) and whose valuable support is fundamental to its success.
PMCID: PMC4339003  PMID: 25713502
16.  A survey of thrombosis experts evaluating practices and opinions regarding venous thromboprophylaxis in patients with active cancer hospitalized with an acute medical illness 
Thrombosis Journal  2015;13:10.
Current clinical practice guidelines recommend the use of prophylactic doses of low molecular weight heparins for cancer patients requiring hospitalization for acute medical illness. However, a recently published meta-analysis suggested that the risk-benefit ratio of current thromboprophylaxis regimens administered to all cancer patients admitted for medical illness is unclear. We sought to assess the clinical equipoise in using thromboprophylaxis for hospitalized medically ill cancer patients.
An electronic survey was conducted. The target sample included Thrombosis experts and members of Thrombosis Canada or the VECTOR research group.
The survey was distributed 54 participants. The final response rate was 67% (36/54). The majority (75%; 95% CI: 60.3 to 85%) of responders indicated that the benefits of pharmacological parenteral thromboprophylaxis outweigh the risks. However, 63.9% (95% CI: 50.6 to 77.3%) believe that there is still clinical equipoise around the use of thromboprophylaxis in this patient population, and 88.9% (95% CI: 77.3 to 95.8%) would consider participating in a randomized trial—30.6% and 58.3% in a placebo-controlled or comparison of different agents/dosing-controlled randomized trial, respectively. For participants who would consider a randomized-controlled trial comparing different doses of thromboprophylaxis agents, the MCID was 2% between the two arms. The most common drug to be compared was enoxaparin (26%), and the two suggested doses were 30 mg and 40 mg SC twice daily.
Our clinical survey of thrombosis experts confirms that there is equipoise regarding the use of current regimens of parenteral pharmacological thromboprophylaxis in medically ill cancer patients. A majority of physicians would participate in a randomized-controlled trial comparing different dose of LMWH. The MCID in the risk of VTE identified was 2%.
PMCID: PMC4338621  PMID: 25713501
17.  Global assays and the management of oral anticoagulation 
Thrombosis Journal  2015;13:9.
Coagulation tests range from global or overall tests to assays specific to individual clotting factors and their inhibitors. Whether a particular test is influenced by an oral anticoagulant depends on the principle of the test and the type of oral anticoagulant. Knowledge on coagulation tests applicable in monitoring status and reversal of oral anticoagulation is a prerequisite when studying potential reversal agents or when managing anticoagulation in a clinical setting. Specialty tests based on the measurement of residual activated factor X (Xa) or thrombin activity, e.g., are highly effective for determining the concentration of the new generation direct factor Xa- and thrombin inhibitors, but these tests are unsuitable for the assessment of anticoagulation reversal by non-specific prohemostatic agents like prothrombin complex concentrate (PCC) and recombinant factor VIIa (FVIIa). Global coagulation assays, in this respect, seem more appropriate. This review evaluates the current status on the applicability of the global coagulation assays PT, APTT, thrombin generation and thromboelastography in the management of oral anticoagulation by vitamin K antagonists and the direct factor Xa and thrombin inhibitors. Although all global tests are influenced by both types of anticoagulants, not all tests are useful for monitoring anticoagulation and reversal thereof. Many (pre)analytical conditions are of influence on the assay readout, including the oral anticoagulant itself, the concentration of assay reagents and the presence of other elements like platelets and blood cells. Assay standardization, therefore, remains an issue of importance.
PMCID: PMC4355453  PMID: 25762867
PT; APTT; Thrombin generation; Thromboelastography; Apixaban; Rivaroxaban; Dabigatran; Vitamin K antagonists; Prothrombin complex concentrate; Anticoagulation reversal
18.  Assays of different aspects of haemostasis – what do they measure? 
Thrombosis Journal  2015;13:8.
Haemostasis is a complex process affected by many factors including both cellular and plasma components. It is a multistep process starting with platelet adhesion to damaged endothelium and ending in clot fibrinolysis. There are several methods available to study different aspects of haemostasis including adhesion, aggregation, coagulation and fibrinolysis. This review describes the different methods, what aspects of haemostasis they measure and their limitations. Methods discussed include methods to study adhesion (e.g. PFA-100, cone and platelet(let) analyzer and perfusion chambers) and aggregation (e.g. Multiplate, VerifyNow and Plateletworks). Furthermore the principles behind viscoelastic haemostatic assays are presented as well as methods that can analyse aspects of haemostasis in plasma or platelet-rich-plasma samples (thrombin generation, overall haemostasis potential and Thrombodynamics Analyzer).
PMCID: PMC4329663  PMID: 25688179
Coagulation; Haemostasis; Platelets; Coagulation assays; Platelet function testing
19.  Superior vena cava syndrome revealing a Behçet’s disease 
Thrombosis Journal  2015;13:7.
Behçet’s disease (BD) is a rare vasculitis in sub-Saharan Africa. Vascular thrombosis, especially venous, is common in this condition and also constitutes a basic diagnostic criterion. Its affection of the superior vena cava is rather rare with only a few cases described in the literature.
Case report
A 42-year-old male patient was seen at consultation presenting with a pulsatile, warm and slightly painful right latero-cervical swelling extending to the supraclavicular fossa with the presence of collateral venous circulation for three weeks prior to presentation associated with a mild headache. There were oral and genital ulcerations and erythematous skin lesions associated with a history of inflammatory recurrent arthralgia. Chest computed tomo-angiography showed cruoric internal jugular vein thrombosis extending to the superior vena cava with significant venous collateral circulation. The patient was treated with prednisolone (1 mg/kg/day) and colchicine (2 mg/day), as well as anticoagulation with heparin and vitamin K antagonist (Acenocoumarol) with regular INR monitoring. Clinical evolution was favorable during hospitalization, with residual discrete right supraclavicular swelling. There was no bleeding associated with anticoagulants use.
The case stresses the importance of maintaining a high degree of suspicion for Behçet’s disease in all cases of venous thrombosis.
PMCID: PMC4321387  PMID: 25667567
Superior vena cava syndrome; Thrombosis; Behçet; Dakar
20.  A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery 
Thrombosis Journal  2015;13:6.
Edoxaban is an oral, direct, factor Xa inhibitor approved in Japan for thromboembolic prophylaxis after lower-limb orthopedic surgery (LLOS), but contraindicated in patients with severe renal impairment (SRI; creatinine clearance [CLCR] ≥15 to <30 mL/min).
This open-label study compared the safety of edoxaban 15 mg once daily in Japanese patients with SRI to that of edoxaban 30 mg in patients with mild renal impairment (MiRI; CLCR ≥50 to ≤80 mL/min; N = 30) undergoing LLOS. Patients with CLCR ≥20 to <30 mL/min were randomized to receive edoxaban 15 mg (N = 22) or subcutaneous fondaparinux 1.5 mg once daily (N = 21). All patients with CLCR ≥15 to <20 mL/min received edoxaban 15 mg (N = 7). Treatment was administered for 11 to 14 days.
Major or clinically relevant non-major bleeding occurred in 6.7%, 3.4%, and 5.0% of patients in the MiRI edoxaban 30-mg, SRI edoxaban 15-mg, and SRI fondaparinux groups, respectively; there were no major bleeding events. No thromboembolic events occurred. At all time points assessed, edoxaban plasma concentrations and changes in coagulation biomarkers were similar between the SRI and MiRI groups.
These results suggest edoxaban 15 mg once daily is well tolerated in Japanese patients with SRI undergoing LLOS.
Trial registration Identifier: NCT01857583.
Electronic supplementary material
The online version of this article (doi:10.1186/s12959-014-0034-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4316611  PMID: 25653574
Edoxaban; Renal impairment; Thromboprophylaxis; Orthopedic surgery
22.  Global assays of hemostasis in the diagnostics of hypercoagulation and evaluation of thrombosis risk 
Thrombosis Journal  2015;13:4.
Thrombosis is a deadly malfunctioning of the hemostatic system occurring in numerous conditions and states, from surgery and pregnancy to cancer, sepsis and infarction. Despite availability of antithrombotic agents and vast clinical experience justifying their use, thrombosis is still responsible for a lion’s share of mortality and morbidity in the modern world. One of the key reasons behind this is notorious insensitivity of traditional coagulation assays to hypercoagulation and their inability to evaluate thrombotic risks; specific molecular markers are more successful but suffer from numerous disadvantages. A possible solution is proposed by use of global, or integral, assays that aim to mimic and reflect the major physiological aspects of hemostasis process in vitro. Here we review the existing evidence regarding the ability of both established and novel global assays (thrombin generation, thrombelastography, thrombodynamics, flow perfusion chambers) to evaluate thrombotic risk in specific disorders. The biochemical nature of this risk and its detectability by analysis of blood state in principle are also discussed. We conclude that existing global assays have a potential to be an important tool of hypercoagulation diagnostics. However, their lack of standardization currently impedes their application: different assays and different modifications of each assay vary in their sensitivity and specificity for each specific pathology. In addition, it remains to be seen how their sensitivity to hypercoagulation (even when they can reliably detect groups with different risk of thrombosis) can be used for clinical decisions: the risk difference between such groups is statistically significant, but not large.
PMCID: PMC4310199  PMID: 25635172
Global assays of hemostasis; Hypercoagulation; Thrombosis
23.  Impact of a high-fat meal on assessment of clopidogrel-induced platelet inhibition in healthy subjects 
Thrombosis Journal  2015;13:3.
Ideal conditions for platelet reactivity testing are critical for optimal selection of a P2Y12 inhibitor. Data are inconsistent regarding the impact of high-fat meals on test assessment.
Participants included 12 healthy subjects not taking antiplatelet drugs after a 12-hour fast. After baseline assessment, subjects were given a 600 mg dose of clopidogrel. Four hours later, maximum platelet inhibition was tested in the fasting state by light transmission aggregometry (LTA), VerifyNow P2Y12, vasodilator-stimulated phosphoprotein (VASP), and whole blood aggregometry (WBA). Subjects were then provided a high-fat meal, and platelet function was evaluated two hours later. Change in measured platelet aggregation by LTA was the primary endpoint of the study. The Wilcoxon Rank Sum test was used to compare the change in platelet reactivity between fasting and non-fasting conditions. The Spearman rho (ρ) correlation coefficient was used to evaluate the association between fasting platelet reactivity and the change following a high-fat meal.
No significant change occurred in maximal light transmission, as assessed by LTA with 5 μM ADP (p = 0.15) and with 20 μM ADP (p = 0.07). There was a significant change in the area under the curve with 5 μM ADP (p = 0.03) but not with 20 μM ADP (p = 0.18). Although there was no significant change with the VerifyNow P2Y12 assay (p = 0.16), the change was correlated with the initial fasting value (Spearman’s rho p = 0.008). The VASP assay and WBA varied minimally.
The high-fat meal did not significantly alter platelet function assessment of commonly used platelet function tests. Greater intra-subject variability existed for the optically-dependent compared with non-optically dependent tests.
Trial registration
PMCID: PMC4312467  PMID: 25642145
Clopidogrel; Blood platelets; Platelet function tests; P2Y12 purinoceptor antagonist; Diet; High-fat
24.  Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism – the J-EINSTEIN DVT and PE program 
Thrombosis Journal  2015;13:2.
The global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban.
We conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5–2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding.
Eighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, -3.4–23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group.
The findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program.
Trial registration NCT01516840 and NCT01516814.
Electronic supplementary material
The online version of this article (doi:10.1186/s12959-015-0035-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4339301  PMID: 25717286
Deep vein thrombosis; Japan; Pulmonary embolism; Randomized trial; Rivaroxaban; Unfractionated heparin; Venous thromboembolism; Warfarin
25.  Severe hyperhomocysteinemia due to cystathionine β-synthase deficiency, and Factor V Leiden mutation in a patient with recurrent venous thrombosis 
Thrombosis Journal  2014;12:30.
Homocysteine is an amino acid that is toxic to vascular endothelial cells, and plasma elevations have been associated with venous thromboembolism. Severe hyperhomocysteinemia (>100 μmol/L) may result from mutations in the genes coding for enzymes in the trans-sulfuration or the folate/vitamin B12-dependent re-methylation pathways. Here, we report the case of a young woman with severe, recurrent thrombo-embolic events associated with severe hyperhomocysteinemia (111 μmol/L). We identified a homozygous mutation in the cystathionine β -synthase gene (p.I278T) and the presence of the Factor V Leiden mutation. Family study shows segregation of elevated homocysteine in heterozygous relatives for the mutation in the cystathionine β -synthase gene. Management consisted of anticoagulation with warfarin and supplementation with folate, vitamin B6 (pyridoxine) and vitamin B12. After twelve years of follow-up, plasma homocysteine levels remain in the moderate range (~20 μmol/L, reference range 8-12 μmol/L) and no further thromboembolic events were identified.
PMCID: PMC4266910  PMID: 25516723

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