Cristina Legnani

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-β(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.

Warfarin withdrawal. Pharmacokinetic-pharmacodynamic considerations.

SummaryWarfarin, like all the 4-hydroxycoumarin compounds, has an asymmetric carbon atom. The clinically available warfarin preparations consist of a racemic mixture of equal amounts of 2 distinct S and R isomers, the former being 4-times more potent as anticoagulant and more susceptible to drug interaction. Warfarin is highly water soluble and rapidly absorbed from the stomach and the upper gastrointestinal tract; its plasma concentrations peak 60 to 90 minutes after oral administration. Warfarin binds to the enzyme vitamin K 2,3-epoxide reductase in liver microsomes, stopping the cycle of vitamin K and reducing γ-carboxylation of the precursors of vitamin D-dependent pro- and anticoagulant factors. A variable fraction of the binding with the target enzyme, albeit small, can be reversed by competitive displacers, such as dithiol-reducing agent activity. Differences in dithiol-reducing activity have been suggested as a contributing factor to the wide interindividual differences in sensitivity to oral anticoagulants. The anticoagulant effect is caused by a small fraction of the drug, since most (97 to 99%) is protein bound (mainly to albumin) and ineffective. Drugs that can displace the albumin binding will increase the action of warfarin, even though this effect is counteracted by a more rapid elimination of the drug. The elimination half-life of warfarin varies greatly among individuals, ranging from 35 to 45 hours; the S isomer has, however, an average half-life shorter than the R isomer.The plasma levels of vitamin K-dependent proteins are determined by a dynamic equilibrium between their synthesis and half-life times. The delay before warfarin takes effect reflects the half-life of the clotting proteins; the levels of factor VII and protein C (with shorter half-lives) are reduced earlier, reaching steady inhibited levels in about 1 day, whereas factor II takes more than 10 days.Oral anticoagulant therapy (OAT) with warfarin or other coumarin derivatives is increasingly administered to patients for primary or secondary prevention of various arterial or venous thromboembolic diseases. If in some clinical conditions OAT is given indefinitely, in others — such as venous thromboembolism or after tissue heart valve replacement — anticoagulants are usually given only for the high risk period of thrombotic complication. A recent large prospective study performed by the Italian Federation of Anticoagulation Clinics showed that about 30% of the patients who began OAT for various clinical indications stopped treatment at different times, confirming that withdrawal from OAT is an occurrence that affects a large number of patients. The expression ‘rebound phenomenon’ was adopted to indicate a hypercoagulant condition occurring after warfarin withdrawal. A possible more frequent recurrence of thromboembolism after cessation of anticoagulation became a matter of controversy and many clinical studies, mostly observational and noncontrolled, reported on the issue with inconsistent results. Most authoritative commentators agreed that rebound phenomenon, though possible, was not clinically relevant and did not differ in frequency and intensity according to mode of withdrawal. Scientific interest in the topic waned until more sensitive methods for investigating blood hypercoagulability became available.In recent years, many studies (reviewed in the text) have investigated the levels of different markers of hypercoagulability [fibrinopeptide A, activated factor VII, prothrombin fragments F1+2, thrombin-antithrombin complexes, D-dimers (DD)], consistently finding an increase in their values after cessation of anticoagulation. Changes in the levels of markers of activated blood coagulation were prospectively investigated by our group in 32 patients with venous thromboembolism who were randomly withdrawn abruptly or gradually from warfarin treatment. Our results indicate that interruption of anticoagulant treatment frequently elicits low grade activation of the haemostatic system, usually not detectable during steady-state anticoagulation. This phenomenon seems to be earlier and more intense after abrupt interruption, but also seems to occur after stepwise withdrawal. Although the activation of coagulation appears to be of limited extent and transient in most cases, it may in a few patients reach higher levels. It seems reasonable to suppose that these patients are at higher risk of thrombotic complications. We and others have suggested that gradual anticoagulant withdrawal would prevent and/or blunt the rebound phenomenon. However, the need to taper the anticoagulant dosage is still uncertain, since no convincing clinical evidence is as yet available. Specifically designed clinical trials are required to solve the issue.

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.

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.

D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis

We assessed the predictive value of D-dimer levels in combination with residual venous obstruction (RVO) for recurrent venous thromboembolism (VTE) in a prospective cohort of outpatients after oral anticoagulant therapy (OAT) suspension for a first episode of idiopathic proximal deep vein thrombosis of the lower limbs during a 2-year follow-up. Patients (n=400) were enrolled on the day of OAT suspension when RVO was determined by compression ultrasonography (present in 48.6% of patients). D-dimer (cut-off value: 500 ng/mL) was measured 30+/-10 days afterwards (abnormal in 56.4% of patients). The overall recurrence rate was 16.7% (67/400; 95% confidence intervals - CI -: 13-21 %). The multivariate hazard ratio (HR) for recurrence was 3.32 (95% CI: 1.78-6.75; p<0.0001) for abnormal D-dimer compared to normal D-dimer and 1.2 (95% CI:0.72-2.07; p>0.05) for RVO compared to absent RVO. The recurrence rate was 5.7% (95% CI:2-13%) and 10.4% (95% CI:6-18%), respectively, for normal D-dimer either without or with RVO, 22.9% (95% CI: 14-33%) and 25.9% (95% CI: 18-35%), respectively, for abnormal D-dimer, either without or with RVO. When compared with normal D-dimer without RVO, the multivariate HR for recurrence was similar for abnormal D-dimer either with RVO (4.76 - 95% CI:1.78-12.8) or without RVO (4.3-95%:1.56-11.88). Abnormal D-dimer at one month after OAT withdrawal is an independent risk factor for recurrent VTE, while RVO at the time of OAT withdrawal, either with normal or abnormal D-dimer after one month, does not influence the risk of recurrence.

Risks factors for highly unstable response to oral anticoagulation: a case-control study

The factors associated with persistent instability of oral anticoagulant treatment (OAT) were investigated in a case‐control study. The most unstable patients from 35 Italian anticoagulation clinics were matched with stable controls, for gender, age and OAT indication. Socio‐demographic data, medical history, dietary and life habits, cytochrome P450 CYP2C9 variants, blood cell count, liver and renal functions were investigated. An ‘Abbreviated Mental Test’ (AMT) and a questionnaire to assess patient compliance to, and comprehension of, OAT indications and mechanisms were administered. An International Normalized Ratio (INR) above 4·5 was more frequently found in cases (n = 77) than controls (n = 80) (12·3% vs. 0·4%; P < 0·0001). The odds ratio for instability was significantly higher for: people who worked versus pensioners, acenocoumarol versus warfarin, and an insufficient score in the AMT and/or in the questionnaire. Cytochrome P450 CYP2C9 variants *1/*3 or *2/*3 or *3/*3 were more frequent among cases than controls (29·9% vs.15·0%; P = 0·042). No differences were observed as regards the other variables. In conclusion, we found that high intra‐individual variability in OAT control was multifactorial, but poor OAT comprehension was prevalent.

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 (patients 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.

Evolution of untreated calf deep-vein thrombosis in high risk symptomatic outpatients: the blind, prospective CALTHRO study.

The natural history of calf deep-vein thrombosis (DVT) is still uncertain and it is debated whether it warrants to be diagnosed and treated. We aimed to investigate the complication rate of untreated isolated calf DVT (ICDVT). Symptomatic outpatients were prospectively managed with serial compression ultrasonography (SCUS). Those without proximal DVT and with likely pre-test clinical probability (PCP) or altered D-dimer received immediate subsequent complete examination of calf deep veins (CCUS) by a different operator. The result of CCUS was kept blind both to the managing doctor and the patient and disclosed after three months. Primary outcome was the rate of venous thromboembolism at three months. We examined 431 subjects (196 males; median age 68.0 years) in whom five outcomes were recorded (1.2%; 95% confidence intervals [CI]: 0.4-2.7). If CCUS results had been available, outcomes would have been recorded in 3/424 patients (0.7%; 95% CI: 0.2-2.1) with two events in subjects negative at both serial and complete CUS. ICDVT was diagnosed in 65 subjects (15.3%; 95% CI: 12-19); of whom 59 remained uneventful (one was lost to follow-up). A significant higher rate of outcomes was recorded in subjects with than without ICDVT (5/64; 7.8%; 95% CI: 3-17 vs. 3/351; 0.8%; 95% CI: 0-2; p=0.003). However, after excluding two events picked at serial CUS in subjects with ICDVT, the difference became barely significant (3/64; 4.7%; 95% CI: 1-13; p=0.049). Thrombotic evolution of untreated ICDVT in high-risk subjects may be relevant. Larger studies are needed to address this issue.

Acute effects of defibrotide, an experimental antithrombotic agent, on fibrinolysis and blood prostanoids in man

SummaryDefibrotide is a polynucleotide extracted from mammalian lung, which shows antithrombotic and anti-ischaemic activity in animals, probably related to stimulation of fibrinolysis and/or enhancement of prostacyclin production. The effect of a single infusion of defibrotide on fibrinolysis and the levels of certain prostanoids in man has been investigated in a cross-over double-blind placebo-controlled study.Evaluation of changes in fibrinolysis was difficult because of the spontaneous activation observed after placebo. However, the fast-acting plasminogen activator inhibitor was decreased only at end of the defibrotide infusion, suggesting a moderate profibrinolytic effect superimposed on the spontaneous activation.There was a marked and prolonged elevation of the plasma level of 6-keto-PGF1α, the stable metabolite of prostacylcin. In collagen stimulated whole blood, both 6-keto-PGF1α and prostaglandin E2 production were also greatly increased, with no consistent indication of inhibition of thromboxane B2. It is suggested that defibrotide stimulates prostacyclin and prostaglandin E2 production by leucocytes or via platelet/leukocyte interactions. The effects observed here should be useful in guiding subsequent clinical trials.

Comparison between different D-Dimer cutoff values to assess the individual risk of recurrent venous thromboembolism: analysis of results obtained in the DULCIS study

D‐dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event of venous thromboembolism (VTE).