Recently, we reported an association between asymptomatic carotid atherosclerosis and venous thromboembolism (VTE) of unknown origin. We hypothesized that patients with VTE of unknown origin would be ...at a higher risk of developing symptomatic atherosclerosis than patients with VTE induced by known risk factors.
To examine this hypothesis, we studied 1,919 consecutive patients followed prospectively after their first VTE episode. The primary outcome was non-fatal and fatal symptomatic atherosclerotic disease in patients with VTE of unknown origin as compared to those with secondary VTE. An independent committee assessed all study outcomes, and adjusted hazard ratios (HR) were calculated using the Cox's proportional hazards model.
After a median follow-up of 48 and 51 months, respectively, at least one symptomatic atherosclerotic complication was detected in 160 of the 1,063 patients (15.1%) with VTE of unknown origin, and in 73 of the 856 (8.5%) with secondary VTE. After adjusting for age and other risk factors of atherosclerosis, the HR for symptomatic atherosclerotic complications in patients with VTE of unknown origin compared to those with secondary VTE was 1.6 (95% confidence intervals; CI: 1.2-2.0). When the analysis was restricted to patients without previous symptomatic atherosclerosis, the HR became 1.7 (95% CI: 1.1-2.4).
Patients with VTE of unknown origin have a 60% higher risk of developing symptomatic atherosclerotic disease than do patients with secondary venous thrombosis.
Objective
To evaluate the subsequent rate of thrombosis among women with obstetric antiphospholipid syndrome (Ob‐APS) in a multicentre database of antiphospholipid antibody (aPL)‐positive patients, ...and the clinical utility of the adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients.
Design
Retrospective study.
Setting
The Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking Clinical Database and Repository.
Population
Women with Ob‐APS.
Methods
Comparison of clinical and laboratory characteristics and measurement of aGAPSS in women with Ob‐APS, with or without thrombosis, after initial pregnancy morbidity (PM).
Main outcome measures
Risk factors for thrombosis and aGAPSS.
Results
Of 550 patients, 126 had Ob‐APS; 74/126 (59%) presented with thrombosis, and 47 (63%) of these women developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age at diagnosis of Ob‐APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had a higher aGAPSS compared with women with Ob‐APS alone median 11.5 (4–16) versus 9 (4–13); P = 0.0089.
Conclusion
Based on a retrospective analysis of our multicentre aPL database, 63% of women with Ob‐APS developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high‐risk aPL profile increased the risk. Women with subsequent thrombosis after Ob‐APS had a higher aGAPSS at entry to the registry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL‐positive women.
Tweetable
More than 60% of women with obstetric antiphospholipid syndrome had thrombosis after initial pregnancy morbidity.
Tweetable
More than 60% of women with obstetric antiphospholipid syndrome had thrombosis after initial pregnancy morbidity.
The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose ...individualization. S‐ and R‐warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory EMAX model, with S‐warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S‐warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady‐state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.
Clinical Pharmacology & Therapeutics (2007) 81, 529–538. doi:10.1038/sj.clpt.6100084; published online 14 February 2007
Abstract Diagnosis of antiphospholipid syndrome (APS) is essentially based on the detection of circulating antiphospholipid (aPL) antibodies. Progress have been made on the standardization of tests ...exploring the presence of aPL as guidelines on coagulation and immunological tests were recently published in the literature. Clinical relevance of aPL profile has come from prospective cohort studies in populations with a homogeneous antibody profile supporting the view that triple positivity is a high risk pattern in patients and carriers. In addition to the classic ones, several other tests have been proposed for the diagnosis of APS. The detection of antibodies directed to domain 1 and 4/5 of β2-Glycoprotein I (β2GP1) were found to be particularly sound. Several issues remain to be addressed. We do not yet know what is the physiological function of β2GP1 and the pathophysiology of thrombosis and pregnancy loss in these patients. Moreover, treatment is poorly defined especially in the case of feared catastrophic APS.
Abstract Background A relationship between antibody profile and pregnancy outcome in patients with a previous diagnosis of primary antiphospholipid syndrome (APS) has not been clearly documented. ...Methods Women attending our Center with primary APS characterized by the presence in the blood of one or more of the following: Lupus Anticoagulant (LA), IgG/IgM anticardiolipin (aCL), IgG/IgM anti-human β2-Glycoprotein I (aβ2GPI) antibodies (confirmed after a minimum of 3 months) were considered eligible for this study. Women who became pregnant during the study period with the exception of those with congenital thrombophilia or other congenital abnormalities were included in our analysis. Primary outcome events, defined as early abortion or fetal death, were evaluated in relation to the laboratory classification category assigned to each patient at the time they were diagnosed with APS. Results A total of 97 pregnancies occurring in 79 primary APS patients during the study period were analyzed. Twelve out of 97 pregnancies were unsuccessful, 11 out of 65 (16.9%) in category I patients (more than one positive laboratory test) and 1 out of 32 (3.1%) in category II patients (single positive test; adjusted hazard ratio 1.9; 95% CI, 0.2 to 18.9, p = 0.6). Pregnancy loss took place in 10 out of 19 pregnancies (52.6%) in women belonging to category I with triple positivity and in 1 out of 46 pregnancies (2.2%) in patients with double positivity. The rate of pregnancy loss was more frequent in the 19 pregnancies of patients with triple positivity than in the 46 pregnancies of double positive patients (adjusted hazard ratio 23, 95% CI, 1.3 to 408, p = 0.03). Conclusion Poor pregnancy outcomes occur more frequently in category I than in category II primary APS patients. However, it has been seen that a greater predictability is achieved when category I patients are grouped into triple and double positivity states.
Non–vitamin K antagonist oral anticoagulants (NOACs) do not need routine laboratory monitoring but measurement of drug concentration is important in emergency conditions. Specific laboratory tests ...are not readily available or not implemented in every hospital. Point-of-Care Tests (POCT) may bridge this gap and be used as a bedside solution.
Feasibility of POCT to assess plasma levels of dabigatran, rivaroxaban and apixaban.
Activated Coagulation Time-Low Range (ACT - LR) using a portable Hemochron Signature Elite for dabigatran and prothrombin time (expressed as INR) by Coaguchek XS Pro for rivaroxaban and apixaban were obtained at trough and peak in 136 consecutive patients taking NOACs (70 on dabigatran, 45 on rivaroxaban and 20 on apixaban). Using a paired study design, drug concentrations were concurrently determined by functional specific tests.
The correlation between NOACs concentration and the values obtained using the POCTs was high for dabigatran and rivaroxaban (r = 0.80 and r = 0.82, respectively) and low for apixaban (r = 0.21). ACT-LR ≤ 188 s better detected dabigatran levels ≤ 50 ng/ml, with a sensitivity of 87.5% and a specificity of 84.1%. ACT-LR values > 217 s better discriminated value of dabigatran > 200 ng/ml, with a sensitivity of 86.7% and a specificity of 81.4%. INR Coaguchek values ≤ 1.2 better identified patients with rivaroxaban values < 100 ng/ml, with sensitivity of 90%, specificity of 88.5%. This analysis was not possible for apixaban.
In emergency situations POCT use may provide useful immediate information on dabigatran and rivaroxaban concentration.
•In certain clinical situations NOACs monitoring may be of value.•Peak and trough POCT and plasma concentration levels of NOACs were assessed.•There was a good correlation between POCT and plasma levels of dabigatran and rivaroxaban.•POCT might be a feasible tool to guide decisions certain situations in NOACs receiving patients.
Antiphospholipid Syndrome (APS) is characterized by the presence of circulating antiphospholipid antibodies in patients with thrombosis or pregnancy morbidity. Antibodies involved in these disorders ...are mainly those directed against β(2)-Glycoprotein I (β(2)GPI) with the major epitope apparently located on discontinuous antigen with several parts of Domain I (DmI) involved. The relation between anti-DmI antibodies and patients' risk categories is unknown.
The synthetic full-length and correctly-folded DmI (1-64) to set up a competitive inhibition enzyme-linked immunoadsorbent assays (ELISA) was used. Plasma of 22 patients with APS and triple positivity Lupus Anticoagulant positive (LAC+), IgG anti-cardiolipin positive (aCL+), IgG anti-β(2)GPI positive (a β(2)GPI +), 15 with double positivity (IgG aCL+, IgG aβ(2)GPI+), 9 with single positivity (IgG aβ(2)GPI+) and 20 controls were evaluated.
Median of percentage inhibition was 25.5% interquartile range (IQR)17.2-33.0 in triple positive patients. Significantly lower inhibition was observed in patients with double positivity, median inhibition 5.0% (IQR 0.0-27.0) and in patients with single positivity median inhibition was 2.0% (IQR 0.5-8.0) (p<0.0001). No inhibition was detected in control subjects or using β(2)GPI peptides (40-52 and 57-70), or when antithrombin, an insignificant control protein was used.
High risk patients with APS and triple laboratory positivity as compared with double and single positivity patients have significantly higher titre of anti-DmI antibodies as evaluated by an inhibition test.
Abstract Background Determination of the three recommended tests for the diagnosis of antiphospholipid syndrome Lupus Anticoagulant (LA), anticardiolipin (aCL) and anti β2-Glycoprotein 1 (aβ2GP1) ...antibodies allow physicians to allocate patients into classification (risk) categories. Objectives To measure antibodies of IgG isotype directed towards Domain 4/5 (Dm4/5) of β2GP1. Patients/Methods. In this cross-sectional study we measured IgG aβ2GP1-Dm4/5 in a group of individuals positive for IgG aβ2GP1 and classified as triple (LAC +, IgG aCL +, IgG aβ2GP1 +, n = 32), double (LAC-, IgG aCL +, IgG aβ2GP1 +, n = 23) or single positive (LA-, IgG aCL-, IgG aβ2GP1 +, n = 10). Results Geometric mean and standard deviation of IgG aβ2GP1 values expressed as Chemiluminescent Units (CU) in triple, double, single positive groups and in 40 healthy individuals were 1795 ± 783, 321 ± 181, 29 ± 8 and 5.0 ± 1.0, respectively (ANOVA p < 0.0001). Geometric mean and standard deviation of IgG aβ2GP1-Dm4/5 expressed as Optical Density (OD) in triple, double and single positive groups and in 40 healthy individuals were 0.16 ± 0.13, 0.16 ± 0.15 and 0.26 ± 0.15, 0.13 ± 0,11, respectively (ANOVA p < 0.002). Individuals in the single positive group, expressed significantly higher values with respect to triple (p = 0.04) and double (p = 0.03) positive groups. Approximate OD cut-off value (99° percentile) calculated in 40 normal control subjects is 0.404. Positivity to IgG aβ2GP1-Dm4/5 according to this cutoff was found in only 5 individuals, 3 in triple positive and 2 in single positive groups and was not associated with thromboembolism. Conclusion Mean level of IgG aβ2GP1-Dm4/5 is higher in single positive group. There is no association between positivity to IgG aβ2GP1-Dm4/5 and thromboembolic events.
To determine whether the diagnosis of lupus anticoagulant (LAC) in a large cohort of positive patients was confirmed at a reference laboratory.
Over a 1-year period, each participating center ...collected samples from LAC-positive patients. Plasma was filtered and kept deep-frozen until it was sent on dry ice to the reference laboratory by express courier. Centers returned detailed laboratory information and clinical data from each patient. The reference laboratory screened plasma samples by diluted Russell viper venom time (dRVVT) and kaolin clotting time (KCT). When these were prolonged, 1:1 mixing studies were carried out, and confirmatory tests were performed as appropriate. Positive samples were further tested by thrombin time (TT). The presence of heparin was checked by measuring antifactor Xa activity when TT was prolonged. Negative samples were tested by activated partial thromboplastin time using hexagonal phospholipids.
Plasma samples from 302 patients from 29 anticoagulation clinics were analyzed. LAC was excluded in 71 samples (24%), because dRVVT and KCT screening test results were normal (34) or reversed to normal by mixing studies (35). The remaining two samples were considered negative because they contained heparin. LAC-negative patients showed different characteristics from those in whom diagnosis was confirmed. They were significantly older (49.7 vs. 45.0 years, P < 0.03), were more often first diagnosed (66% vs. 41%, P < 0.001), and were more frequently judged as mild in LAC potency (60% vs. 25%, P < 0.0001). Moreover, anticardiolipin and anti-beta(2)-glycoprotein I antibody values were more often normal in LAC-negative (82%) than in LAC-positive (42%) samples (P < 0.0001). LAC-positive samples identified by both dRVVT and KCT (146/231, 63%) showed a LAC potency that was significantly stronger than that in samples in which LAC diagnosis was made by a single test.
A false-positive LAC diagnosis is not uncommon across specialized centers. Patients' characteristics and a complete antiphospholipid antibody profile may help to identify these individuals.
PDF
