Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Duration of anticoagulation after isolated pulmonary embolism.

In the D-dimer and ULtrasonography in Combination Italian Study (DULCIS), serial D-dimer measurement in combination with assessment of residual thrombosis (in patients with deep vein thrombosis (DVT)) identified patients who safely discontinued anticoagulation after an unprovoked venous thromboembolism (VTE).In this subgroup analysis, the value of D-dimer tests was assessed in patients with isolated pulmonary embolism (PE) compared with those with DVT, with or without PE (DVT/PE). The DULCIS database was reanalysed in relation to this target.26.8% of the DULCIS patients had isolated PE as the index event; this was more prevalent in females (34.1%) than in males (21.1%; p<0.0001). The rate of positive D-dimer was similar in isolated PE and DVT/PE. The rate of recurrences was not different in isolated PE or DVT/PE patients (4.8% ppy versus 3.8% ppy; nonsignificant) who stopped anticoagulation for negative D-dimer, but it was markedly high (11.2% ppy; p<0.0001) in those with isolated PE who remained without anticoagulation despite positive D-dimer. Recurrences were more frequently new isolated PE in patients with isolated PE than with DVT/PE (six (46.2%) out of 13 versus two (7.4%) out of 27; p=0.0085).Serial D-dimer assessment can inform on the risk of recurrent VTE and help determine the duration of anticoagulation in patients with isolated PE.

D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study.

The optimal duration of anticoagulation in patients with venous thromboembolism (VTE) is uncertain. We investigated whether persistently negative D-dimers in patients with vein recanalization or stable thrombotic burden can identify subjects at low recurrence risk. Outpatients with a first VTE (unprovoked or associated with weak risk factors) were eligible after at least 3 months (12 in those with residual thrombosis) of anticoagulation. They received serial D-dimer measurements using commercial assays with predefined age/sex-specific cutoffs and were followed for up to 2 years. Of 1010 patients, anticoagulation was stopped in 528 (52.3%) with persistently negative D-dimer who subsequently experienced 25 recurrences (3.0% pt-y; 95% confidence interval [CI], 2.0-4.4%). Of the remaining 482 patients, 373 resumed anticoagulation and 109 refused it. Recurrent VTE developed in 15 patients (8.8% pt-y; 95% CI, 5.0-14.1) of the latter group and in 4 of the former (0.7% pt-y; 95% CI, 0.2-1.7; hazard ratio = 2.92; 95% CI, 1.87-9.72; P = .0006). Major bleeding occurred in 14 patients (2.3% pt-y; 95% CI, 1.3-3.9) who resumed anticoagulation. Serial D-dimer measurement is suitable in clinical practice for the identification of VTE patients in whom anticoagulation can be safely discontinued. This study was registered at clinicaltrials.gov as #NCT00954395.

Measurement of factor XIII (FXIII) activity by an automatic ammonia release assay using iodoacetamide blank-procedure: no more overestimation in the low activity range and better detection of severe FXIII deficiencies.

BACKGROUND: Laboratory investigation with specific factor XIII (FXIII) assays plays a crucial role in diagnosis of FXIII deficiency. According to the International Society on Thrombosis and Hemostasis (ISTH), it is necessary a blank sample with iodoacetamide, provided by the kit or locally prepared, when the ammonia release assays are used, to avoid FXIII activity overestimation. METHODS: In this study we set up a modification of the Berichrom FXIII chromogenic assay, in which iodoacetamide was added by the BCS analyzer in the reaction mixture of the blank sample, without modifications of the original reagents. We analyzed 100 plasma samples of outpatients with clinical symptoms suggestive of a bleeding diathesis (20 samples had FXIII activity <20%). RESULTS: In all samples blank subtraction significantly reduced FXIII activity, mostly in the low activity range group (from 10.1% to 2.4%, p<0.0001). In this group correction with iodoacetamide also increased the agreement with the immunoassay and allowed FXIII activity measure up to 0%. CONCLUSIONS: Despite the low number of samples included in the study, the described automatic procedure seemed to decrease FXIII activity overestimation and, especially for low activity range samples (<20%), to improve the agreement between FXIII activity and concentration. Our data suggested that iodoacetamide correction could allow the detection of severe FXIII deficiencies (activity <5%) otherwise undiagnosed using the original method.

Influence of proband's characteristics on the risk for venous thromboembolism in relatives with factor V Leiden or prothrombin G20210A polymorphisms.

In family studies, the risk for venous thromboembolism (VTE) in relatives with factor V Leiden (FVL) or G20210A prothrombin (PT20210A) gene polymorphisms may differ according to genotype and clinical presentation of the proband. To address this hypothesis, a retrospective cohort family study was carried out on 192 kindreds with at least one member with homozygous FVL or PT20210A, for a total of 886 relatives. The proband of the family was heterozygous in 68 and homozygous or with both polymorphisms in 124 kindreds. Twenty-three probands were asymptomatic, 11 had had arterial thrombosis, 7 obstetrical complications, and 151 venous thrombosis (122 VTE and 29 superficial vein thrombosis). The incidence of VTE (per 1000 patient-years) in relatives was higher when the proband had heterozygous rather than homozygous polymorphism (1.25 [95% confidence interval (CI), 0.73-1.91] vs 0.44 [0.19-0.78]) and when the proband had had VTE instead of other or no clinical manifestations (0.95 [0.57-1.42] vs 0.50 [0.19-0.96]). Compared with relatives belonging to kindreds with homozygous probands without VTE, the adjusted hazard ratio of VTE for relatives selected from kindreds with heterozygous probands with VTE was 4.14 (95% CI, 1.17-14.71). The genotype and clinical presentation of the proband influence the risk for VTE in relatives with FVL or PT20210A.

How the direct oral anticoagulant apixaban affects hemostatic parameters. Results of a multicenter multiplatform study.

BACKGROUND: Apixaban is a newly developed direct oral anticoagulant targeting activated factor X (FXa). The degree of interference of apixaban with coagulation parameters has not been thoroughly investigated. METHODS: Increasing amounts of apixaban were added to aliquots of a pooled normal plasma (PNP) to mimic a large range of concentrations (n=8) that are observed in treated patients. Upon preparation, samples were stored frozen and tested for a vast array of coagulation parameters (including procoagulant and anticoagulant factors) in three laboratories, using three widely used coagulation platforms (reagent/coagulometer combinations). RESULTS: Results for each parameter were expressed as ratios of the value corresponding to each apixaban concentration to the value corresponding to the PNP without apixaban. By definition, ratios higher or lower than the unity define overestimation or underestimation, respectively. Prothrombin and activated partial thromboplastin times were barely prolonged by apixaban 200 ng/mL (ratios <1.29 or <1.19, respectively). Conversely, antithrombin was considerably overestimated when the measurement was made with FXa as target enzyme (ratios up to 1.43). Protein C and protein S were overestimated when measured as anticoagulant activities (ratios up to 1.20 or 1.95, respectively), and most measurements for individual coagulation factors (except fibrinogen) were considerably underestimated (ratios from 0.62 to 1.01). CONCLUSIONS: This large multicenter multiplatform study investigating a common set of test plasmas shows that apixaban interferes with the measurement of most coagulation parameters requested for investigation of hemostasis and highlights the need for a careful interpretation of results obtained in patients under treatment.

Rivaroxaban in the Treatment of Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic condition and it is associated with increased in vivo thrombin generation that needs to be treated with non-heparin anticoagulants such as direct thrombin inhibitors (DTIs). DTIs require parenteral administration and are associated with a non negligible risk of major bleeding. We describe a case of HIT treated with rivaroxaban, a direct oral factor Xa inhibitor which could be used to inhibit the generation of thrombin, instead of DTIs. A 68 year-old man with a thrombosis confined to the internal gastrocnemius and soleal veins developed HIT during enoxaparin 80 mg twice a day. Enoxaparin was stopped and rivaroxaban 20 mg once a day was started. Platelet count returned to base line after 6 days from enoxaparin withdrawal. After 3 months rivaroxaban was stopped and the patient had an uneventful course. This case report supports the hypothesis that rivaroxaban may be candidate for treatment of HIT, and larger studies are justified.

Sex Differences in Clinical Presentation of Lower Extremity Deep Vein Thrombosis.

Background: Differences between men and women in the clinical features and extent of lower limb deep vein thrombosis (DVT) may influence DVT diagnostic algorithms involving pretest clinical probability (PTP) assessment, D-dimer, and compression ultrasonography (CUS). Aims: To assess differences in DVT clinical presentation between men and women and their effect on PTP and D-dimer. Methods: We conducted a retrospective study in outpatients referred for suspected DVT of the lower limbs to our vascular emergency department from January 2005 to December 2019. Patients underwent PTP assessment with the Wells score, D-dimer testing, and CUS. Results: More women were referred for suspected DVT than men (M/F: 1,785/2,821; F: 61.4%; p < 0.0001). Women were older than men (median age: 71 vs. 67 years; p = 0.0001), DVT was diagnosed in 436 patients (9.4%) but in more men than women (M: 210 [11.8%] vs. F: 226 [8%]; p = 0.0002), with more proximal DVT in men than women (M: 131 7.3% vs. F: 124 [4.4%]; p = 0.00021). PTP was more likely in men (355 [19.9%]) than women (455 [16.2%]) (p = 0.0011); more men had swelling in the entire limb, increased calf circumference by >3 cm compared with the contralateral limb, and pitting edema, than women. D-dimer levels (available in 65% of patients) were more frequently positive in women with DVT than in men (94.6% vs. 85.7%; p = 0.016). However, a positive D-dimer and/or likely PTP was similarly frequent in men (92%) and women (96%) with DVT. Conclusions: More women than men are referred for suspected DVT, and men have a higher prevalence of proximal DVT. However, current algorithms for DVT diagnosis perform similarly in men and in women.

D-dimer and risk of venous thromboembolism recurrence: Comparison of two studies with similar designs but different laboratory and clinical results.

BACKGROUND: D-dimer testing may help deciding the duration of anticoagulation in subjects at high risk of venous thromboembolism (VTE) recurrence. Two management studies on this issue have been published (DULCIS in 2014 and APIDULCIS in 2022). They had similar designs but had important different results. Aim of this article is to compare their results. METHODS: Both studies were finalized to extend anticoagulation [with vitamin K anticoagulants (VKAs) in DULCIS or apixaban 2.5 mg BID (kindly provided by BMS-Pfizer Collaboration) in APIDULCIS] only in patients with positive D-dimer results. RESULTS: More D-dimer assays resulted positive in APIDULCIS than in DULCIS (61.1 % vs 47.7 %, respectively; p < 0.0001). While only 4 (0.5 %) refused low dose apixaban in APIDULCIS, the 22.6 % of patients with positive D-dimer refused to resume VKAs in DULCIS; their rates of recurrence were 187 and 8.8 per 100 person-years, respectively (incidence rate ratio [IRR]: 21.2). The incidence of bleeding was low in those receiving apixaban vs those who resumed VKAs (0.4 vs 2.3 per 100 person-years, respectively; IRR 0.17;). While the recurrence rate was low and similar in the studies in subjects who resumed anticoagulation, it was significantly higher in APIDULCIS than in DULCIS in those who stopped anticoagulation for negative D-dimer (5.6 vs 3.0 per 100 person-years, respectively; IRR 1.9). CONCLUSION: The low dose Apixaban for extended VTE treatment is effective and safe, and well accepted by patients. Why subjects who stopped anticoagulation for negative D-dimer had a higher recurrence rate in APIDULCIS than in DULCIS remains to be explained.

MORE EARLY BLEEDS ASSOCIATED WITH HIGH BASELINE DIRECT ORAL ANTICOAGULANT LEVELS IN ATRIAL FIBRILLATION: THE MAS STUDY.

Treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) patients is effective and safe. However, bleeding complications still occur. Whether the measurement of DOAC levels may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" (MAS) Study (#NCT03803579) venous blood was collected 15-30 days after DOAC initiation in AF patients who were then followed for one year to record the occurrence of major and clinically relevant non-major bleeding. DOAC plasma levels were measured in one laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients [957 (57.7%) and 700 treated with standard and low-dose, respectively]. Fifty bleeding events were recorded during 1606 years of follow-up (3.11% pt/yrs). Fifteen bleeding events (4.97% pt/yrs) occurred in patients with C-trough standardized values in the highest activity class (> 0.50); whereas 35 events (2.69% pt/yrs) occurred in those with values in the two lower classes ( 0.50, p= 0.0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first three months of treatment. 19% of patients receiving low doses had standardized activity values in the highest class. More bleeding occurred in patients treated with low (4.3% pt/yrs) than standard (2.2% pt/yrs; p= 0.0160) dose DOAC. Early measurement of DOAC levels in AF patients identified many subjects with high activity levels despite the low doses use and had more bleeding risk during the first 3 months of treatment.

Thrombotic events associated with low baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study.

ABSTRACT: Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment efficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-specific mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class (-1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study.

Persistent antiphospholipid (aPL) antibodies are occasionally found in subjects without prior history of thromboembolic events (TEs), raising the dilemma of whether to initiate or not a primary thromboprophylaxis. A first TE is considered rare in aPL carriers, but previous studies did not consider the aPL profile nor was the test positivity confirmed in a reference laboratory. In this study, 104 subjects with high-risk aPL profile (positive lupus anticoagulant, anticardiolipin, and anti-ß(2)-glycoprotein I antibodies, triple positivity) confirmed in a reference laboratory, were followed up for a mean of 4.5 years. There were 25 first TEs (5.3% per year): the cumulative incidence after 10 years was 37.1% (95% confidence interval [CI], 19.9%-54.3%). On multivariate analysis, male sex (hazard ratio = 4.4; 95% CI, 1.5-13.1, P = .007) and risk factors for venous thromboembolism (hazard ratio = 3.3; 95% CI, 1.3-8.5, P = .01) were independent predictors for TEs. Aspirin did not significantly affect the incidence of TE. In conclusion, the occurrence of a first TE in carriers of high-risk aPL profile is considerable; it is more frequent among male subjects and in the presence of additional risk factors for venous TE. These data can help in the decision to initiate primary thromboprophylaxis in these subjects.

D-Dimers in diagnosis and prevention of venous thrombosis: recent advances and their practical implications.

D­Dimers derive from degradation of cross­linked fibrin by plasmin, and thus their level is a marker of coagulation and fibrinolytic system activation. Guidelines recommend that D­dimers are determined if the pretest probability (PTP) is low or intermediate, to exclude venous thromboembolism (VTE), either deep vein thrombosis or pulmonary embolism, and to avoid imaging tests. If the PTP is high or D­dimer level is above the suggested thresholds, imaging is recommended. D­Dimer assays offer high sensitivity and low specificity, as D­dimer levels can be above the threshold in several other conditions than thrombosis, and they increase with age. As a result, there have been several proposals to improve the diagnostic accuracy of D­dimer levels by adjusting the cutoffs according to patient characteristics, such as age, PTP, pregnancy, renal function, or cancer. D­Dimer levels can also predict clinical severity of COVID­19, and escalated anticoagulation based on D­dimer levels can be associated with a lower risk of mortality in patients with severe COVID­19. Finally, D­dimer levels have been incorporated in prediction models for recurrent VTE to help identify patients who may benefit from prolonged anticoagulation.

Incidence and clinical outcomes of heparin-induced thrombocytopenia: 11 year experience in a tertiary care university hospital.

Heparin-induced thrombocytopenia (HIT) is a rare immuno-mediated adverse reaction with high thrombotic and mortality risk. To evaluate incidence and outcomes of HIT cases diagnosed at a tertiary care hospital from 2007 to 2018. A retrospective study was conducted. Patients with suspected HIT underwent 4Ts score assessment and anti-heparin PF4 IgG antibodies ELISA screening test. If the latter was positive, platelet aggregation test (PAT) was performed. If the latter was positive, any form of heparin was stopped, alternative anticoagulants were started and then overlapped with warfarin. HIT incidence was calculated by dividing HIT cases by the mean yearly number of admitted patients over 11 years. Follow-up was 90 days. Among 2125 screening tests, 96 (4.5%) were positive with confirmatory PAT in 82/90 (3.8% for missing data in 6). Median age was 75; 39 patients were surgical and 51 medical. The median 4Ts score was 5. Unfractionated heparin was employed in 34 (37%). HIT incidence was 0.16/1000/patient/years (95% CI: 0.12-0.23) in surgical and 0.15/1000/patient/years (95%: 0.12-0.20) in medical patients. HIT with thrombosis (HIT-T) was observed in 31 patients (0.05/1000/patient/years 95% CI: 0.04-0.1), with venous thromboses in 25 (80%). HIT without thrombosis was observed in 59 patients (0.1/1000 patient/years; 95% CI: 0.08-0.13, twofold vs HIT-T). All cause mortality was 25.5% (95% CI: 17.6-35.4), major bleeding 7.7% (95% CI:3.2-15.3), and thromboembolic complications 3.3% (95% CI:1.1-9.3). HIT is a rare event with high mortality, despite the use of non heparin anticoagulants.

Venous Thromboembolism in Women of Childbearing Age: Insights from the START Registry.

BACKGROUND: Women of childbearing age are exposed to venous thromboembolic risk mainly for pregnancy and use of oral contraceptives. The impact of risk factors (RF) on venous thromboembolism (VTE) in these circumstances is still unclear. AIM: In the context of START registry, we aimed to investigate the weight of a series of RF on the occurrence of pregnancy- or combined oral contraceptive (COC)-associated VTE. MATERIALS AND METHODS: We selected all women included in the START for VTE occurred between 18-42 years and compared those with a first or recurrent pregnancy/postpartum- (group A) or COC-VTE (group B) with those who had VTE outside these circumstances (group C). Final analysis included a cohort of 532 women. Follow-up data showed that there were no significant differences between the groups in terms of thrombotic and haemorrhagic complications. As for pregnancy-associated VTE, the overall outcome was good in terms of both maternal and fetal prognosis. RESULTS: In a binary model of logistic regression, correcting for potential confounders, VTE family history conferred a significant and independent higher risk of COC-VTE compared with group C. Similarly, comparison between group A and C documented that family history significantly affected the risk of pregnancy-associated VTE. VTE in the group C was significantly associated with older age. Lastly, smoke was a significant risk factor for pregnancy/postpartum VTE when group A and group B were compared. CONCLUSION: Present data suggest that in the setting of fertile women, family history of VTE has a greater role in predicting COC- and pregnancy/postpartum- VTE than outside these circumstances.

Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study.

The PROLONG randomized trial showed that a normal D-dimer (D-d) 1 month after anticoagulation suspension for unprovoked venous thromboembolism (VTE) was associated with a low risk of late recurrences (4.4% patient years). However, it is unknown whether D-d changes subsequently. The aim of this prospective multicenter study was to assess D-d time course and its relation with late recurrences in patients with normal D-d 1 month after anticoagulation suspension for a first episode of unprovoked VTE. D-d was measured with a qualitative method (Clearview Simplify D-dimer; Inverness Medical Professional Diagnostics). Patients with a normal D-d 1 month after stopping anticoagulation repeated D-d testing every 2 months for 1 year. D-d was normal in 68% (243/355) of patients 1 month after anticoagulation suspension. Patients in whom D-d became abnormal at the third month and remained abnormal afterward had a higher risk of recurrence (7/31; 27% patient years; 95% confidence interval [CI]: 12-48) than patients in whom D-d remained normal at the third month and afterward (4/149; 2.9% patient years; 95% CI: 1-7; adjusted hazard ratio: 7.9; 95% CI: 2.1-30; P = .002). Repeated D-d testing after anticoagulation suspension for a first episode of unprovoked VTE could help tailor the duration of treatment. This trial is registered at http://clinicaltrials.gov as NCT00266045.

Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded.

BACKGROUND: D-dimer testing to rule out deep vein thrombosis is less useful in older patients because of a lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of older patients (>50 years) in whom pulmonary embolism could be excluded. We retrospectively validated the efficacy of this cut-off combined with clinical probability for the exclusion of deep vein thrombosis. DESIGN AND METHODS: Five management study cohorts of 2818 consecutive outpatients with suspected deep vein thrombosis were used. Patients with non-high or unlikely probability of deep vein thrombosis were included in the analysis; four different D-dimer tests were used. The proportion of patients with a normal D-dimer test and the failure rates were calculated using the conventional (500 µg/L) and the age-adjusted D-dimer cut-off (patient's age x 10 µg/L in patients >50 years). RESULTS: In 1672 patients with non-high probability, deep vein thrombosis could be excluded in 850 (51%) patients with the age-adjusted cut-off value versus 707 (42%) patients with the conventional cut-off value. The failure rates were 7 (0.8; 95% confidence interval 0.3-1.7%) for the age-adjusted cut-off value and 5 (0.7%, 0.2-1.6%) for the conventional cut-off value. The absolute increase in patients in whom deep vein thrombosis could be ruled out using the age-adjusted cut-off value was largest in patients >70 years: 19% among patients with non-high probability. CONCLUSIONS: The age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of older patients in whom deep vein thrombosis can be safely excluded.

A new warfarin dosing algorithm including VKORC1 3730 G > A polymorphism: comparison with results obtained by other published algorithms.

PURPOSE: Warfarin dosing is affected by clinical and genetic variants, but the contribution of the genotype associated with warfarin resistance in pharmacogenetic algorithms has not been well assessed yet. We developed a new dosing algorithm including polymorphisms associated both with warfarin sensitivity and resistance in the Italian population, and its performance was compared with those of eight previously published algorithms. METHODS: Clinical and genetic data (CYP2C9*2, CYP2C9*3, VKORC1 -1639 G > A, and VKORC1 3730 G > A) were used to elaborate the new algorithm. Derivation and validation groups comprised 55 (58.2% men, mean age 69 years) and 40 (57.5% men, mean age 70 years) patients, respectively, who were on stable anticoagulation therapy for at least 3 months with different oral anticoagulation therapy (OAT) indications. RESULTS: Performance of the new algorithm, evaluated with mean absolute error (MAE) defined as the absolute value of the difference between observed daily maintenance dose and predicted daily dose, correlation with the observed dose and R(2) value, was comparable with or slightly lower than that obtained using the other algorithms. The new algorithm could correctly assign 53.3%, 50.0%, and 57.1% of patients to the low (≤25 mg/week), intermediate (26-44 mg/week) and high (≥ 45 mg/week) dosing range, respectively. Our data showed a significant increase in predictive accuracy among patients requiring high warfarin dose compared with the other algorithms (ranging from 0% to 28.6%). CONCLUSIONS: The algorithm including VKORC1 3730 G > A, associated with warfarin resistance, allowed a more accurate identification of resistant patients who require higher warfarin dosage.

Thrombotic burden, D-dimer levels and complete compression ultrasound for diagnosis of acute symptomatic deep vein thrombosis of the lower limbs.

BACKGROUND: Diagnostic algorithms for deep vein thrombosis (DVT) include D-dimer for its high negative predictive value, thus reducing the need for imaging. Small thrombi may be associated with low D-dimer levels, increasing false negatives. AIM: To assess the sensitivity and thus the false negative rates of standard and age-adjusted D-dimer cut offs for isolated distal DVT (IDDVT) in outpatients. MATERIALS AND METHODS: We enrolled consecutive outpatients with suspected DVT of the lower limbs referring to our vascular emergency department from 2009 to 2018. Patients underwent D-dimer testing (STA, Stago, cut-off: 500 µg/L), pretest clinical probability (PTP) evaluation and complete compression ultrasonography. Follow-up was 3 months. RESULTS: Among 3948 patients (M:1554-39%, median age 69), 486 proximal DVTs (12.3%) and 348 IDDVTs (8.8%) were diagnosed. Median D-dimer was higher in proximal than IDDVT (3960 vs 1400 µgr/L; p = 0.001). The false negative rate of the standard D-dimer cut-off was 2% (95%CI: 0.8-3.2%) for proximal DVT and 14.7% (95% CI: 11-81%) for IDDVT. The false negative rate of the age-adjusted cut-off was 4.9% (3-7%) for proximal DVT and 19.5% (95% CI: 15.4-24.7%) for IDDVT. CONCLUSIONS: Small calf thrombi are associated with low D-dimer levels, and age-adjusted D-dimer may be below the cut-off more frequently in subjects with IDDVT than standard cut-off D-dimer, although such D-dimer levels might exclude IDDVT that require treatment.