Optimizing resource allocation: Cost-effectiveness of specified D-dimer cut-offs in cancer patients with suspected venous thromboembolism.

An accurate diagnosis of venous thromboembolism (VTE) is crucial, given the potential for high mortality in undetected cases. Strategic D-dimer testing may aid in identifying low-risk patients, preventing overdiagnosis and reducing imaging costs. We conducted a retrospective, comparative analysis to assess the potential cost savings that could be achieved by adopting different approaches to determine the most effective D-dimer cut-off value in cancer patients with suspected VTE, compared to the commonly used rule-out cut-off level of 0.5 mg/L. The study included 526 patients (median age 65, IQR 55-75) with a confirmed cancer diagnosis who underwent D-dimer testing. Among these patients, the VTE prevalence was 29% (n = 152). Each diagnostic strategy's sensitivity, specificity, negative likelihood ratio (NLR), as well as positive likelihood ratio (PLR), and the proportion of patients exhibiting a negative D-dimer test result, were calculated. The diagnostic strategy that demonstrated the best balance between specificity, sensitivity, NLR, and PLR, utilized an inverse age-specific cut-off level for D-dimer [0.5 + (66-age) × 0.01 mg/L]. This method yielded a PLR of 2.9 at a very low NLR for the exclusion of VTE. We observed a significant cost reduction of 4.6% and 1.0% for PE and DVT, respectively. The utilization of an age-adjusted cut-off [patient's age × 0.01 mg/L] resulted in the highest cost savings, reaching 8.1% for PE and 3.4% for DVT. Using specified D-dimer cut-offs in the diagnosis of VTE could improve economics, considering the limited occurrence of confirmed cases among patients with suspected VTE.

Using a Simple Prescription Gap to Determine Warfarin Discontinuation Can Lead to Substantial Misclassification.

BACKGROUND: Warfarin remains widely used and a key comparator in studies of other direct oral anticoagulants. As longer-than-needed warfarin prescriptions are often provided to allow for dosing adjustments according to international normalized ratios (INRs), the common practice of using a short allowable gap between dispensings to define warfarin discontinuation may lead to substantial misclassification of warfarin exposure. We aimed to quantify such misclassification and determine the optimal algorithm to define warfarin discontinuation. METHODS: We linked Medicare claims data from 2007 to 2014 with a multicenter electronic health records system. The study cohort comprised patients ≥65 years with atrial fibrillation and venous thromboembolism initiating warfarin. We compared results when defining warfarin discontinuation by (1) different gaps (3, 7, 14, 30, and 60 days) between dispensings and (2) having a gap ≤60 days or bridging larger gaps if there was INR ordering at least every 42 days (60_INR). Discontinuation was considered misclassified if there was an INR ≥2 within 7 days after the discontinuation date. RESULTS: Among 3,229 patients, a shorter gap resulted in a shorter mean follow-up time (82, 95, 117, 159, 196, and 259 days for gaps of 3, 7, 14, 30, 60, and 60_INR, respectively; p < 0.001). Incorporating INR (60_INR) can reduce misclassification of warfarin discontinuation from 68 to 4% (p < 0.001). The on-treatment risk estimation of clinical endpoints varied significantly by discontinuation definitions. CONCLUSION: Using a short gap between warfarin dispensings to define discontinuation may lead to substantial misclassification, which can be improved by incorporating intervening INR codes.

The Utility of the Markers of Coagulation and Hemostatic Activation Profile in the Management of Embolic Strokes of Undetermined Source.

BACKGROUND: Potential causes of embolic stroke of undetermined source (ESUS) include occult malignancy, venous thrombosis (VTE) with paradoxical embolism, and hypercoagulable disorders. Given the association of markers of coagulation and hemostatic activation (MOCHA) with these causes, the objective of this study was to validate the utility of the MOCHA profile in identifying the underlying cause of stroke. METHODS: We prospectively identified ESUS patients from January 1, 2017 to December 1, 2019 who underwent MOCHA profile (plasma d-dimer, prothrombin fragment 1.2, thrombin-antithrombin complex, fibrin monomer) testing. Abnormal MOCHA profile was defined as ≥ 2 abnormal markers. New diagnoses of malignancy, VTE, hypercoagulable disorders and recurrent stroke were identified during routine clinical follow-up. RESULTS: Of 236 ESUS patients, 104 (44%) patients had an abnormal MOCHA profile. In multivariable analyses the number of MOCHA abnormalities was significantly associated with malignancy, VTE, and hypercoagulable disorders (OR 2.59, CI 95% 1.78-3.76, p<0.001). Sensitivity, specificity, positive predictive value, and negative predictive value of an abnormal MOCHA profile for the combined outcome of malignancy, VTE, and hypercoagulability was 96%, 62%, 23%, and 99% respectively. DISCUSSION: The MOCHA profile was able to identify ESUS patients more likely to have malignancy, VTE, and hypercoagulable disorders during follow-up. Our results show that a normal MOCHA profile in ESUS patients can effectively rule out these potential causes of ESUS.

Endogenous fibrinolysis-Relevance to clinical thrombosis risk assessment.

The development of an obstructive luminal thrombus is pathological and considered a failure of endogenous fibrinolysis. The consequences may be fatal, or result in lasting downstream organ damage. Therefore, assessment of endogenous fibrinolytic status in an individual may identify those at risk of occlusive thrombus formation and provide prognostic information. Arterial thrombi are more platelet rich and more resistant to fibrinolysis than venous thrombi. Several recent studies using global tests of fibrinolysis in patients with acute coronary syndromes (ACS) have shown that despite dual antiplatelet therapy, patients with impaired fibrinolytic status have an increased risk of adverse cardiovascular events, compared with those with effective fibrinolytic function. Such data add significantly to the predictive value of established cardiovascular risk factors and conventional biomarkers. Most data reported have been obtained with the Global Thrombosis Test and the turbidimetric plasma clot lysis assay. A few small studies in patients with ischaemic stroke suggest a similar predictive role of fibrinolytic status assessment in these patients. Studies reporting an association between impaired fibrinolysis and future venous thrombotic events are limited, and in the form of case-control studies. Viscoelastic assays may have a role in the prediction of venous thromboembolic risk. Assays of fibrinolytic function should be used to obtain a more accurate risk of future thrombotic events, particularly in the setting of ACS. The availability of point-of-care tests helps facilitate this and should encourage future studies to assess personalised antithrombotic treatment combinations to optimise fibrinolytic status and reduce thrombosis risk.

The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management.

The 2019 coronavirus disease (COVID-19) presents with a large variety of clinical manifestations ranging from asymptomatic carrier state to severe respiratory distress, multiple organ dysfunction and death. While it was initially considered primarily a respiratory illness, rapidly accumulating data suggests that COVID-19 results in a unique, profoundly prothrombotic milieu leading to both arterial and venous thrombosis. Consistently, elevated D-dimer level has emerged as an independent risk factor for poor outcomes, including death. Several other laboratory markers and blood counts have also been associated with poor prognosis, possibly due to their connection to thrombosis. At present, the pathophysiology underlying the hypercoagulable state is poorly understood. However, a growing body of data suggests that the initial events occur in the lung. A severe inflammatory response, originating in the alveoli, triggers a dysfunctional cascade of inflammatory thrombosis in the pulmonary vasculature, leading to a state of local coagulopathy. This is followed, in patients with more severe disease, by a generalized hypercoagulable state that results in macro- and microvascular thrombosis. Of concern, is the observation that anticoagulation may be inadequate in many circumstances, highlighting the need for alternative or additional therapies. Numerous ongoing studies investigating the pathophysiology of the COVID-19 associated coagulopathy may provide mechanistic insights that can direct appropriate interventional strategies.

Does age-adjusted D-Dimer have a role in assessment of VTE recurrence rates?

INTRODUCTION: It is known that D-dimer levels increase with age and several studies have evaluated the use of an age-adjusted (AA) cut-off in the initial assessment of suspected venous thromboembolism (VTE). We performed a retrospective study to assess the effect that using an AA D-dimer in the DASH score would have on the recommended duration of anticoagulant treatment for patients following a first unprovoked episode of VTE and then compared this with the advice that has been given to patients using a fixed cut-off D-dimer in the DASH score. METHODS: Data were collected for the period from April 2014 to October 2017. For each patient, the DASH score by a single cut-off D-dimer value (500 ng/mL) as well as an AA D-dimer cut-off value (D-dimer cut-off value equal to age in years × 10) was calculated for patients over 50 years. The Vienna prediction model was employed alongside this to compare the VTE recurrence risk using a well-established method. RESULTS: A total of 204 patients were eligible for analysis, 145 of whom were over the age of 50 years. In 24 of these patients, the use of the AA D-dimer made a significant impact on the predicted risk of recurrence using the DASH score and would have likely changed the recommendation to offer long-term anticoagulation. CONCLUSION: As an age-adjusted D-dimer cut-off has been assessed in the diagnostic setting, it would be logical and appropriate to also consider this philosophy in the prediction of the risk of recurrence of VTE following a first unprovoked event.

Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors.

Coagulopathy in COVID-19 is a burning issue and strategies to prevent thromboembolic events are debated and highly heterogeneous. The objective was to determine incidence and risk factors of venous thromboembolism (VTE) in COVID-19 inpatients receiving thromboprophylaxis. In this retrospective French cohort study, patients hospitalized in medical wards non-ICU with confirmed COVID-19 and adequate thromboprophylaxis were included. A systematic low limb venous duplex ultrasonography was performed at hospital discharge or earlier if deep venous thrombosis (DVT) was clinically suspected. Chest angio-CT scan was performed when pulmonary embolism (PE) was suspected. Of 71 patients, 16 developed VTE (22.5%) and 7 PE (10%) despite adequate thromboprophylaxis. D-dimers at baseline were significantly higher in patients with DVT (p < 0.001). Demographics, comorbidities, disease manifestations, severity score, and other biological parameters, including inflammatory markers, were similar in patients with and without VTE. The negative predictive value of a baseline D-dimer level < 1.0 µg/ml was 90% for VTE and 98% for PE. The positive predictive value for VTE was 44% and 67% for D-dimer level ≥ 1.0 µg/ml and ≥ 3 µg/ml, respectively. The association between D-dimer level and VTE risk increased by taking into account the latest available D-dimer level prior to venous duplex ultrasonography for the patients with monitoring of D-dimer. Despite thromboprophylaxis, the risk of VTE is high in COVID-19 non-ICU inpatients. Increased D-dimer concentrations of more than 1.0 µg/ml predict the risk of venous thromboembolism. D-dimer level-guided aggressive thromboprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies.

Hypothyroidism and the Risk of Venous Thromboembolism: A Nationwide Cohort Study.

BACKGROUND: Previous studies have shown that hypothyroidism may have an impact on blood coagulation. However, how hypothyroidism and thyroxine replacement therapy (TRT) affect the risk of venous thromboembolism (VTE) remains controversial. This study aimed to examine the associations of hypothyroidism and TRT with VTE risks. MATERIALS AND METHODS: This nationwide population-based cohort study was conducted using Taiwan's National Health Insurance Research Database. We enrolled 10,818 hypothyroid patients (the exposed cohort) and 21,636 non-hypothyroid subjects (the unexposed cohort) between 2001 and 2014 after 1:2 exact matching according to age, sex, and index year. Hypothyroid patients were further divided into two groups depending on whether they received TRT or not. Adjusted hazard ratios (aHRs) for VTE were calculated using Fine and Gray competing risk models. RESULTS: The mean follow-up period was 7.5 years. Hypothyroidism was significantly associated with a higher risk of VTE (aHR = 1.83 [95% confidence interval [CI]: 1.44-2.33, p < 0.001]). Among hypothyroid patients, the TRT subgroup had a non-significant trend of lower VTE risk than the non-TRT subgroup (aHR = 0.73 [95% CI: 0.52-1.01, p = 0.058]). The analysis for individual events revealed a significant association between TRT use and a lower risk of pulmonary embolism among hypothyroid patients (aHR = 0.34 [95% CI: 0.13-0.88, p = 0.026]). CONCLUSION: The data suggest that hypothyroidism was significantly associated with an increased risk of VTE. Among hypothyroid patients, a non-significant trend of lower VTE risk in patients treated with TRT was observed. Further prospective studies or clinical trials are necessary to confirm causality.

Assessment of genetic and non-genetic risk factors for venous thromboembolism in glioblastoma - The predictive significance of B blood group.

INTRODUCTION: Venous thromboembolism (VTE) is a common problem among patients with glioblastoma multiforme (GBM) and with some other cancers. Here, we evaluated genetic and non-genetic potential risk factors for VTE among GBM patients. MATERIALS AND METHODS: A cohort of 139 patients treated with concomitant radiotherapy and temozolomide were included in the study. Next generation sequencing and genotyping approaches were applied to assess genetic risk factors in the haemostatic system. Clinical data including surgery, reoperation as well as blood group and patient information such as age and gender were available from patient records. Logistic regression analysis was performed to asses VTE risk. RESULTS: In the study 47 patients (34%) were diagnosed for VTE during the course of their disease. When genetic and non-genetic potential risk factors were evaluated, only B blood group was found to be significantly associated with VTE incidence (odds ratio [OR] = 6.91; confidence interval [CI] = 2.19-24.14; P = 0.001). In contrast, A and O blood groups did not correlate with VTE risk. Frontal lobe tumor location also seemed to slightly increase VTE risk compared to other brain sites (OR = 3.14; CI = 1.1-10.7) although the significance level was at borderline (P = 0.05). Current study identified B blood group as the component in non-O blood groups that is responsible for increased VTE risk. CONCLUSION: In conclusion, these results suggest for the first time that B blood group is predictive for VTE incidence among patients with glioblastoma, information that may be potentially valuable when selecting GBM patients who are at risk for VTE for anticoagulant prophylaxis.

Assessment of Anti-Factor Xa Levels of Patients Undergoing Colorectal Surgery Given Once-Daily Enoxaparin Prophylaxis: A Clinical Study Examining Enoxaparin Pharmacokinetics.

Importance: Between 4% and 12% of patients undergoing colorectal surgery and receiving enoxaparin, 40 mg per day, have a postoperative venous thromboembolism (VTE) event. An improved understanding of why "breakthrough" VTE events occur despite guideline-compliant prophylaxis is an important patient safety question. Objective: To determine the proportion of patients undergoing colorectal surgery who received adequate anticoagulation based on peak anti-factor Xa (aFXa) levels while receiving enoxaparin at 40 mg per day. Design, Setting, and Participants: This prospective, nonrandomized clinical trial was conducted between February 2017 and July 2018 with 90-day follow-up at a quaternary academic medical center in the Intermountain West and included patients undergoing colorectal surgery who had surgery after receiving general anesthesia, were admitted for at least 3 days, and received enoxaparin, 40 mg once daily. Interventions: All patients had aFXa levels measured after receiving enoxaparin 40 mg per day. Patients whose aFXa level was out of range entered the trial's interventional arm where real-time enoxaparin dose adjustment and repeated aFXa measurement were performed. Main Outcomes and Measures: Primary outcome: in-range peak aFXa levels (goal range, 0.3-0.5 IU/mL) with enoxaparin, 40 mg per day. Secondary outcomes: (1) in-range trough aFXa levels (goal range, 0.1-0.2 IU/mL) and (2) the proportion of patients with in-range peak aFXa levels from enoxaparin, 40 mg once daily, vs the real-time enoxaparin dose adjustment protocol. Results: Over 16 months, 116 patients undergoing colorectal surgery (65 women [56.0%]; 99 white individuals [85.3%], 13 Hispanic or Latino individuals [11.2%], and 4 Pacific Islander individuals [3.5%]; mean [range] age, 52.1 [18-85] years) were enrolled. Among 106 patients (91.4%) whose peak aFXa level was appropriately drawn, 72 (67.9%) received inadequate anticoagulation (aFXa < 0.3 IU/mL) with enoxaparin, 40 mg per day. Weight and peak aFXa levels were inversely correlated (r2 = 0.38). Forty-seven patients (77%) had a trough aFXa level that was not detectable (ie, most patients had no detectable level of anticoagulation for at least 12 hours per day). Real-time enoxaparin dose adjustment was effective. Patients were significantly more likely to achieve an in-range peak aFXa with real-time dose adjustment as opposed to fixed dosing alone (85.4% vs 29.2%, P < .001). Conclusions and Relevance: This study supports the finding that most patients undergoing colorectal surgery receive inadequate prophylaxis from enoxaparin, 40 mg once daily. These findings may explain the high rate of "breakthrough" VTE observed in many clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT02704052.

Anticoagulation risk assessment for patients with non-valvular atrial fibrillation and venous thromboembolism: A clinical review.

Non-valvular atrial fibrillation and venous thromboembolism anticoagulation risk assessment tools have been increasingly utilized to guide implementation and duration of anticoagulant therapy. Anticoagulation significantly reduces stroke and recurrent venous thromboembolism risk, but comes at the cost of increased risk of major and clinically relevant non-major bleeding. The decision for anticoagulation in high-risk patients is complicated by the fact that many risk factors associated with increased thromboembolic risk are simultaneously associated with increased bleeding risk. Traditional risk assessment tools rely heavily on age, sex, and presence of cardiovascular comorbidities, with newer tools additionally taking into account changes in risk factors over time and novel biomarkers to facilitate more personalized risk assessment. These tools may help counsel and inform patients about the risks and benefits of starting or continuing anticoagulant therapy and can identify patients who may benefit from more careful management. Although the ability to predict anticoagulant-associated hemorrhagic risk is modest, ischemic and bleeding risk scores have been shown to add significant value to therapeutic management decisions. Ultimately, further work is needed to optimally implement accurate and actionable risk stratification into clinical practice.

Application value of Caprini risk assessment model and elevated tumor-specific D-dimer level in predicting postoperative venous thromboembolism for patients undergoing surgery of gynecologic malignancies.

AIM: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in gynecologic malignant patients after surgery. We aimed to validate the Caprini risk assessment model (RAM) and elevated tumor-specific D-dimer as predictive marker of postoperative VTE for patients undergoing surgery of gynecologic malignancies. METHODS: Inpatients were divided into five groups (low: score = 0-1; moderate: score = 2; high: score = 3-4; higher: score = 5-7; sup-high: score > 7) and treated according to their risk level after the surgery during the hospitalization according to the Caprini RAM. D-dimer level was detected during the perioperative period. If D-dimer did not fall to normal reference range on the seventh day after operation, the use of low-molecular-weight heparin was prolonged to 28 days after surgery. RESULTS: The majority (853/974, 87.6%) of the patients was in the Caprini score ≥5, with an overall VTE incidence of 1.75%. The VTE group had significantly higher Caprini score, CA125, vascular invasion rate and lymph node metastasis rate. If 1.5 µg/mL was used as the D-dimer cut-off value to predicting VTE, the sensitivity was 87.5%, the specificity was 93.8% and the negative predictive value was 99.2%. The D-dimer level was a marker for prolonging the anticoagulants use during the perioperative period, especially for the sup-high group. CONCLUSION: The Caprini RAM is an effective and reliable VTE risk prediction tool for patients undergoing gynecological malignant tumor surgery. The group (score ≥ 5) can be divided into two subgroups (higher: score = 5-7 and sup-high: score > 7), which may better predict the occurrence of VTE for malignant tumor patients. Great than 1.5 µg/mL D-dimer before operation should be given more attention for the presence of VTE.

Risk assessment and management of preoperative venous thromboembolism following femoral neck fracture.

BACKGROUND: Limited studies are available to investigate the prevalence of preoperative venous thromboembolism (VTE) in elderly patients with femoral neck fractures. Our primary aim was to determine the incidences of VTE and its risk or protective factors in such patient population. The secondary objective was to evaluate the need of therapeutic anticoagulation for isolated calf muscular venous thrombosis (ICMVT) prior to femoral neck fracture surgery. METHODS: This is a retrospective case-control study, including 301 femoral neck fracture patients who were admitted to our institution between January 2014 and March 2017. Bilateral Doppler ultrasonography was performed in each of the patients as a preoperative VTE screening. The event rate of VTE was calculated, and significant risk or protective factors were determined by using a multivariate logistic regression model. Patients with ICMVT were divided into anticoagulation and no anticoagulation groups to assess the efficacy and safety of preoperative therapeutic anticoagulation. Intraoperative blood loss, drainage volume, blood transfusion, perioperative hemoglobin change, and rate of thrombosis extension were compared between the two groups. RESULTS: The overall preoperative incidence of VTE in patients with femoral neck fracture was 18.9% (57/301), in which deep vein thrombosis (DVT) was 18.9% and pulmonary embolism (PE) was 1%. Among the DVT cases, 77.2% (44/57) were ICMVTs. Multiple fractures (odds ratio [OR] = 9.418; 95% confidence interval [CI] = 2.537 to 34.96), coexisting movement disorder (OR = 3.862; 95% CI = 1.658 to 8.993), bed rest for more than 7 days (OR = 2.082; 95% CI = 1.011 to 4.284) as well as elevated levels of D-dimer (OR = 1.019; 95% CI = 1.002 to 1.037) and fibrinogen (OR = 1.345; 95% CI = 1.008 to 1.796) led to an increase in the risk of VTE, while the recent use of antiplatelet drug (OR = 0.424; 95% CI = 0.181 to 0.995) and prophylactic anticoagulation (OR = 0.503; 95% CI = 0.263 to 0.959) decreased the risk of VTE. For the 39 patients with ICMVT undergoing femoral neck fracture surgery, there were no significant differences in the rate of thrombosis extension between anticoagulation and no anticoagulation groups, but significantly decreased postoperative hemoglobin was observed in the anticoagulation group. CONCLUSION: Our findings showed a high prevalence of preoperative VTE in elderly patients with femoral neck fracture, with risk factors identified. We found that the most detected VTE were ICMVTs. Our study suggested that a direct surgery without preoperative use of therapeutic anticoagulation for ICMVT would not reduce the risk of thrombus extension, and the therapeutic use of anticoagulation may worsen postoperative anemia.

Extended-Duration Thromboprophylaxis Among Acute Medically Ill Patients: An Unmet Need.

Acute medical illnesses are associated with a prolonged elevation in inflammatory markers that predisposes patients to thrombosis beyond the duration of their hospital stay. In parallel, both observational and randomized data have demonstrated a rate of postdischarge venous thromboembolic events that often exceeds that observed in the hospital setting. Despite this significant residual risk of venous thromboembolic events following discharge among acute medically ill patients, no therapeutic strategies have been recommended to address this unmet need. Available randomized trials have demonstrated the efficacy of extending the duration of thromboprophylaxis with available anticoagulants; however, the efficacy is offset, at least in part, by an increase in bleeding events. Identification of the optimal therapeutic strategies, treatment duration, and risk assessment tools that reconcile both efficacy and safety of extended-duration thromboprophylaxis among acute medically ill patients is an area of ongoing investigation.

Comprehensive Assessment of the Hemostatic System in Polycystic Ovarian Syndrome.

Polycystic ovarian syndrome (PCOS) affects 12 to 19% of women and has reproductive and metabolic features (endothelial dysfunction, increased diabetes, and cardiovascular risk factors). It also appears to have altered coagulation and fibrinolysis with a prothrombotic state with epidemiological evidence of increased venous thromboembolism. We aimed to comprehensively assess hemostasis in women with PCOS versus control women. In an established case-control cohort of lean, overweight, and obese women with (n = 107) and without PCOS (n = 67), with existing measures of plasminogen activator inhibitor 1 (PAI-1), asymmetric dimethylarginine (ADMA), hormonal, and metabolic markers, we also assessed prothrombin fragments 1 and 2 (PF1 & 2), plasminogen, tissue plasminogen activator (tPA), and thrombin generation (TG). Higher levels of ADMA (0.70 vs. 0.39 µmol/L, p < 0.01), PAI-1 (4.80 vs. 3.66 U/mL, p < 0.01), and plasminogen (118.39 vs. 108.46%, p < 0.01) were seen in PCOS versus controls, and persisted after adjustment for age and body mass index (BMI). PF1 & 2 was marginally lower (180.0 vs. 236.0 pmol/L, p = 0.05), whereas tPA and TG were not different between groups, after adjustment for age and BMI. Significant relationships were observed between hormonal and metabolic factors with ADMA and PAI-1. We demonstrate impaired fibrinolysis in PCOS. In the context of abnormal endothelial function and known hormonal and metabolic abnormalities, this finding may underpin an increased risk of cardiovascular disease and venous thrombosis in PCOS.

Thrombin generation and factor X assays for the assessment of warfarin anticoagulation in thrombotic antiphospholipid syndrome.

Monitoring warfarin anticoagulation in patients with thrombotic antiphospholipid syndrome (APS) may be complicated by the sensitivity of different thromboplastins to lupus anticoagulant. The aim of this study was to compare the degree of anticoagulation intensity in thrombotic APS and non-APS patients (50 in each group) on long-term warfarin, by measurement of the INR with two widely available thromboplastins with instrument-specific ISI values, and to investigate the potential role of amidolytic FX levels and thrombin generation (TG) testing in the assessment of anticoagulant intensity in thrombotic APS patients. There were no overall differences in INR between reagents or patient groups, but 20% (10/50) of APS patients showed ≥0.5 INR unit difference between reagents, which would have resulted in altered clinical management in some patients. FX levels were useful in assessing anticoagulation intensity for INR 2.0-3.0, but showed poor utility at INR ≥3.5 where the lowest measured FX level was 12IU/dL. In contrast, ETP and peak thrombin showed significant inverse correlations with the INR, suggesting that TG testing may be helpful in the determination of true anticoagulant intensity in APS patients, including those with ≥3.5 INR. TG testing also highlighted a subgroup of APS patients with increased peak thrombin relative to the intensity of anticoagulation as assessed by INR and FX, suggesting that TG testing may be useful in identifying an ongoing prothrombotic state in patients with apparently adequate anticoagulation intensity as assessed by INR.

Negative health implications of sickle cell trait in high income countries: from the football field to the laboratory.

Worldwide, sickle cell trait is a highly prevalent gene carrier state. While generally a benign condition with a normal life expectancy, it is becoming increasingly clear that the sickle trait is associated with certain adverse outcomes. This article will focus on three of these outcomes, namely exertional rhabdomyolysis and sudden death, chronic renal dysfunction, and venous thromboembolism. In each case, the epidemiological evidence for the association is reviewed, together with the existing data on potential underlying mechanisms. Because newborn screening programmes for sickle cell anaemia also identify those with sickle cell trait, it is imperative that further studies determine what, if any, preventive measures can be taken to reduce the burden of these uncommon but potentially morbid complications in affected individuals.

A clinical and pharmacologic assessment of once-daily versus twice-daily dosing for rivaroxaban.

Altering doses and regimens of a drug has consequences for the drug's pharmacokinetic and pharmacodynamic profile. Based on a half-life of 5-13 h, it is expected that the Factor Xa inhibitor rivaroxaban would be best suited to a twice-daily rather than a once-daily dose regimen. However, although rivaroxaban is used as a twice-daily regimen for the initial treatment of venous thromboembolism (VTE) and secondary prevention after acute coronary syndromes, the approved dosing is once-daily for prevention of VTE after orthopaedic surgery, long-term secondary prevention of VTE and stroke prevention in patients with non-valvular atrial fibrillation. Rivaroxaban dosing was based on the evaluation of the efficacy and safety of several rivaroxaban doses and regimens in phase II trials. A clear overall advantage of twice-daily dosing compared with once-daily dosing was not documented for indications for which once-daily dosing was subsequently selected. Once-daily dosing was therefore selected for these indications because it is expected to be associated with better compliance than twice-daily dosing, and potentially, with improved outcomes. These studies and data obtained with another Factor Xa inhibitor, edoxaban, in addition to previous experience with low molecular weight heparins, indicate that the clinical impact of once-daily versus twice-daily doses on outcome in terms of efficacy and safety cannot be reliably predicted from pharmacology data, e.g. elimination half-life, obtained during pre-clinical and early phase I clinical studies but rather should be ascertained empirically in phase II and III clinical trials.

Clinical and health costs impact of progress in diagnosis and treatment in venous thromboembolic disease: evolution in 15 years.

BACKGROUND: The therapeutic and diagnostic approach in deep vein thrombosis (DVT) has changed enormously in the last two decades with the introduction of ultrasound, low-molecular-weight heparin (LMWH), and premature motion. The aim of this study is to evaluate these changes and analyze their clinical and economic aspects. METHODS: We registered all inpatients with a diagnosis of DVT during 1994 (n=110) and 2009 (n=75) and their sociodemographic and clinical features in a descriptive observational design. We performed a comparison of diagnostic techniques, length of stay, inpatient complications, and costs thus derived for both series, based on 2009 prices, so that we could get comparable results. RESULTS: Ninety-one percent of inpatients in 1994 were diagnosed by venography, whereas, in 2009, the diagnosis was based on clinical features, D-dimer, and ultrasound in 100% of patients. Inpatient treatment went from 7% LMWH in 1994 to 96% in 2009, and as outpatient from 82% acenocumarol to 90.6% LMWH. Complications decreased by 13.3%. Length of stay was 2.7 higher in 1994. Globally, the cost per patient decreased by 63.39%, based primarily on reduced length of stay. CONCLUSIONS: The current diagnostic and therapeutic approach in DVT allows for effective treatment, fewer complications, and a drastic reduction in inpatient costs.