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Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. About a quarter of the anticoagulated patients require temporary cessation of direct oral anticoagulants (DOACs) or vitamin K antagonists for a planned intervention within 2 years from anticoagulation inception. Several clinical issues about DOAC interruption remain unanswered: many questions are tentatively addressed daily by thousands of physicians worldwide through an experience-based balancing of thrombotic and bleeding risks. Among possible valuable answers, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) proposes some experience-based suggestions and expert opinions. In particular, FCSA provides practical guidance on the following issues: (1) multiparametric assessment of thrombotic and bleeding risks based on patients' individual and surgical risk factor, (2) testing of prothrombin time, activated partial thromboplastin time, and DOAC plasma levels before surgery or invasive procedure, (3) use of heparin, (4) restarting of full-dose DOAC after high risk bleeding surgery, (5) practical nonpharmacological suggestions to manage patients perioperatively. Finally, FCSA suggests creating a multidisciplinary “anticoagulation team” with the aim to define the optimal perioperative management of anticoagulation.

At variance with vitamin K antagonists, the new oral anticoagulants (NOAs) can be prescribed at fixed dosage without adjustment by laboratory testing. However, this does not necessarily mean that the laboratory does not play a role for their management. This position paper represents the consensus document of three Italian scientific societies dealing with laboratory issues in thrombosis and hemostasis. It is aimed at reviewing: 1) which test(s) should be used to evaluate the anticoagulant effect of each of the NOAs presently available (i.e., dabigatran, rivaroxaban and apixaban); 2) the patients to be investigated; and 3) the timing of investigation.

Summary Background Bleeding is the most serious complication of the use of oral anticoagulation in the prevention and treatment of thromoboembolic complications. We studied the frequency of bleeding complications in outpatients treated routinely in anticoagulation clinics. Methods In a prospective cohort from thirty-four Italian anticoagulation clinics, 2745 consecutive patients were studied from the start of their oral anticoagulation (warfarin in 64%, acenocourmarol in the rest). The target anticoagulation-intensity was low (international normalised ratio [INR] ≤2·8) in 71% of the patients and high (> 2·8) in the remainder. We recorded demographic details and the main indication for treatment and, every 3·4 months, INR and outcome events. Such events included all complications (bleeding, thrombosis, other), although only bleeding events are reported here, and deaths. We divided bleeding into major and minor categories. Findings 43% of the patients were women. Nearly three-fifths of the patients were aged 60·79; 8% were over 80. The main indication for treatment was venous thrombolism (33%), followed by non-ischaemic heart disease (17%). Mean follow-up was 267 days. Over 2011 patient-years of follow-up, 153 bleeding complications occurred (7·6 per 100 patient-years). 5 were fatal (all cerebral haemorrhages, 0·25 per 100 patient-years), 23 were major (1·1), and 125 were minor (6·2). The rate of events was similar between sexes, coumarin type, size of enrolling centre, and target INR. The rate was higher in older patients: 10·5 per 100 patient-years in those aged 70 or over, 6·0 In those aged under 70 (relative risk 1·75, 95% CI 1·29–2·39, p vs 6·0 per 100 patient-years) (1·80, 12–2·7, p vs 6·3, 1·75, 1·27–2·44, p 4 5, 7·91, 5·44–11·5, p Interpretation We saw fewer bleeding events than those recorded in other observational and experimental studies. Oral anticoagulation has become safer in recent years, especially if monitored in anticoagulation clinics. Caution is required in elderly patients and anticoagulation intensity should be closely monitored to reduce periods of overdosing.

Hemorrhagic and thrombotic diseases are highly heterogeneous disorders that may affect a large proportion of the population, as in the case of patients taking antithrombotic drugs. The appropriate management of such conditions requires the availability of specific diagnostic assays, together with knowledge of the possible clinical syndromes and of their appropriate treatment. This can only be achieved through second-level specialized laboratories supervised by trained personnel. Such diagnostic and therapeutic organization is not widely available in Italy except in a very limited number of those large hospitals that are centers of excellence on a national scale. Increasing the availability of such resources would be of great benefit to patients, and could also be cost-effective for the national healthcare system. This document is promoted by the Italian Society for the Study on Hemostasis and Thrombosis (SISET) and by the main Italian scientific societies involved in the field during the years 2011-2012. It aims to identify the level of scientific and professional training required to define a physician as a Hemostasis and Thrombosis Expert, graded according to the levels of skill required for different clinical settings.

SummaryTo evaluate the role of low-molecular weight heparin (LMWH) as an alternative to oral anticoagulants in the prevention of recurrent venous thromboembolism, we compared in a randomized trial conventional warfarin treatment with a three-month course of enoxaparin 4000 anti-Xa units once a day subcutaneously. 187 patients with symptomatic deep-vein thrombosis (DVT), diagnosed by strain-gauge plethysmography plus D-dimer latex assay and confirmed by venography in most cases, were treated with full-dose subcutaneous heparin for ten days and then randomized to secondary prophylaxis. During the 3-month treatment period, 6 of the 93 patients who received LMWH (6%) and 4 of the 94 patients on warfarin (4%) had symptomatic recurrence of venous thromboembolism confirmed by objective testing (p = 0.5; 95% confidence interval [Cl] for the difference, -3% to 7%). Four patients in the LMWH group had bleeding complications as compared with 12 in the warfarin group (p = 0.04; 95% Cl for the difference, 4% to 14%). In the 9-month follow-up period, during which 34 patients on warfarin prolonged treatment for other 3 months and 14 up to one year, 10 patients in the enoxaparin group and 4 patients in the warfarin group suffered a documented recurrence of venous thromboembolism. Of these 14 late recurrences, just one occurred in patients with postoperative DVT. After one year there were 16 recurrences (17%) in the LMWH group and 8 (9%) in the warfarin group (p = 0.07; 95% Cl for the difference, 1% to 16%).These results confirm the potential of LMWH as an alternative to oral anticoagulants in this setting, and suggest to evaluate in a prospective study a slightly higher dose of enoxaparin in patients with postoperative DVT.

SummaryDabigatran and other new oral anticoagulants (OAC) represent a step forward in stroke prevention in patients with atrial fibrillation (AF). They indeed have been shown to be an alternative to vitamin K antagonists (VKAs) without the burden of laboratory control. However, these new drugs compete with an effective and well-established therapy, thus bringing about a series of questions and doubts. In this report members of the board of the Italian Federation of Thrombosis Centers (FCSA) answer some questions every clinician might be confronted with.

The diagnostic value of a latex D-dimer test combined with strain-gauge plethysmography (SGP) was assessed in 425 patients referred to our vascular laboratory because of clinically suspected deep-vein thrombosis (DVT) of lower limbs, using venography as the reference standard. The inpatient/outpatient ratio was 236 189 . Adequate venograms were obtained in 401 patients and a DVT was diagnosed in 195 (49%). SGP results were borderline in 38 patients. In the 363 unequivocal cases, sensitivity of SGP was 88% and specificity 90%. The sensitivity of D-dimer latex test was 78% and the specificity 88%. Out of the 363 unequivocal cases, D-dimer test results were discordant with SGP in 88 cases, of whom 60% had DVT and 40% had not, and concordant in 275. The sensitivity of concordant results was 98% ( 124 127 ) and specificity 97% ( 143 148 ). Compared with strain-gauge plethysmography (plus venography in case of borderline results), the combined approach reduced the diagnostic errors (false positive plus false negative results) from 10% ( 40 401 ; 95% confidence interval, 7–13%) to 2% ( 8 401 ; 95% CI, 0.6–3.4%) albeit requiring a greater number of venographies, from 9% ( 38 401 ; 95% CI, 7–12%) to 31% ( 126 401 ; 95% CI, 27–36%). Most calf DVT (94%) were identified. We conclude that this test combination is valuable in the diagnosis of DVT in symptomatic patients, because of the high accuracy of concordant test results. Venography is required in case of borderline or discordant results.

The antithrombotic activity of a series of benzopyranopyrimidine derivatives was investigated in platelet-dependent and independent pulmonary thromboembolism in mice. Intraperitoneal subacute treatment with 2-morpholino derivative 3c significantly prevented paralysis due to collagen plus epinephrine-induced pulmonary thrombosis while 2-piperidino substituted derivative 3h significantly protected mice from paralysis caused by thrombin-induced intravascular fibrin formation at dosage not affecting bleeding time. These compounds, previously proved to be effective as antiplatelet agents in vitro, were in vivo more potent as antithrombotics than lysine acetylsalicylate and possessed lower prohemorrhagic activity than the reference drug. Although their ineffectiveness on clotting times, PT and APTT, allows the involvement of coagulation pathways to be ruled out, the mechanisms underlying the favourable benefit risk ratio for these two compounds remain to be further clarified.

To assess the natural history and risk factors for thrombosis in a large cohort of unselected patients with antiphospholipid antibodies.Three hundred sixty consecutive patients (118 males, 242 females, median age 39 years [range 2 to 78]) fulfilling the currently accepted criteria for diagnosis of lupus anticoagulant (LAC) (n = 326) and/or raised immunoglobulin G anticardiolipin antibodies (IgG ACA) (n = 185) were collected from 16 Italian institutions and prospectively observed for a median of 3.9 years (range 0.5 to 5). Main endpoints were the occurrence of arterial or venous thrombosis, the outcome of pregnancies, and any severe complications leading to hospitalization or death.Thirty-four patients developed a thrombotic complication, with a total incidence of 2.5% patient-years. Multivariate logistic regression analysis identified two independent risk factors for thrombotic events: a previous thrombosis (RR 4.9; 95% CI, 1.76 to 13.7; P0.005) and IgG ACA titer above 40 units (RR 3.66; 95% CI, 1.24 to 10.8; P0.01). A total of 28 pregnancies were observed in 25 women and 11 (39%) were abortive. Adverse pregnancy outcomes were significantly more frequent in women with a history of miscarriage or vascular occlusion (9/16, 56%) than in asymptomatic women (2/12, 17%) (P = 0.035). Four patients developed non-Hodgkin's lymphoma during the follow-up. Eighteen patients died. Vascular events and hematological malignancies represented the most frequent causes of death (n = 5 for each).The present study shows that: (a) previous thrombosis and ACA titer40 U are independent predictors of thrombosis; (b) history of miscarriage or vascular disease is significantly associated with adverse pregnancy outcome; (c) hematological malignancies can develop during follow-up in patients with antiphospholipid antibodies.

A significant decrease of plasma antithrombin III (AT III) levels, measured with four different biological and immunological methods, was found in 8 of 11 members of a Sicilian family (family DM) and in 3 of 14 members of a northern Italian family (family A). Different behaviour after oral anticoagulant treatment with acenocoumarin was seen in 2 long-term treated subjects. The propositus of family DM, who had had a long history of recurrent thrombosis, did not show any increase of AT III levels. A significant increase was, on the contrary, observed in the propositus of family A, who had suffered a recent thrombosis in a branch of the inferior mesenteric vein.

SummaryThe paper reports on rate and type of thrombotic events occurring during the observational, prospective, inception-cohort, multicenter ISCOAT study. 2,745 unselected, daily practice patients, consecutively referring to 34 Italian anticoagulation clinics to monitor the oral anticoagulant treatment, were included in the study from beginning of their first anticoagulant course. During a total follow-up of 2,011 patient-years of treatment 70 thrombotic events (3.5 per 100 patient years) were recorded in 67 patients: 20 fatal (1%), 39 major (1.9%) and 11 minor (0.6%). 34/70 events occurred within the first 90 days of treatment (relative risk - at multivariate analysis - of 90 = 20.6, C.I. 12.7-33.5; p 70 y (1.62, C.I. 1.0-2.61; p 2 = 1.88, C.1.1.16-3.07; p The recorded rate of thrombotic events was lower than that reported in the few available studies. A greater risk should be expected during the first 90 days of treatment, when anticoagulation levels are 70 years and in those with cerebrovascular/peripheral arterial disease.

SummaryThe optimal long-term treatment of acute venous thromboembolism (VTE) in patients with malignancy remains undefined. In particular, based on current evidence, it is uncertain whether secondary prophylaxis using standard intensity oral anticoagulant therapy is associated with higher risks of bleeding and recurrent thrombosis in patients with cancer than in those without cancer. This study compared the outcome of anticoagulation courses in 95 patients with malignancy with those of 733 patients without malignancy. All patients were participants in a large, nation-wide population study and were prospectively followed from the initiation of their oral anticoagulant therapy.Based on 744 patient-years of treatment and follow-up, the rates of major (5.4% vs 0.9%), minor (16.2% vs 3.6%) and total (21.6% vs 4.5%) bleeding were statistically significantly higher in cancer patients compared with patients without cancer. Bleeding was also a more frequent cause of early anticoagulation withdrawal in patients with malignancy (4.2% vs. 0.7%; p In conclusion, patients with malignancy treated with oral anticoagulants have a higher rate of bleeding and possibly an increased risk of recurrent thrombosis compared with patients without malignancy. Safer and more effective anticoagulant therapy is needed for this challenging group of patients.

Whether elderly patients are at increased risk of complications during oral anticoagulant treatment (OAT) is still a matter of debate.Bleeding and thrombotic events occurring during OAT in 461 patients, aged 75 years or older when they started OAT, and in 461 patients younger than 70 years, matched for sex, OAT indication, and treating center, were examined in a prospective, multicenter, inception-cohort study.Bleeding rate was 9.9% and 6.6% patient-years in elderly and young patients, respectively (P = .07), and 2.1% and 1.1% for major bleeding (P = .19); 6 and 1 events, respectively, were fatal (all intracranial, relative risk, 6.4; P = .05). In the elderly, bleeding rate was lower (4.5%) for international normalized ratios (INRs) between 2.0 and 2.9; it was higher during the first 90 treatment days (P = .05) and when arterial vascular disease was the indication for OAT (P = .03). Thrombosis rate was 4.2% and 2.5% patient-years in elderly and young patients, respectively (P = .10); however, 13 and 5 events were fatal (relative risk, 2.8; P = .04). Thrombosis rate was lower (1.5%) for INRs between 2.0 and 2.9; it was higher during the first 90 treatment days (P.001) and 6 of 7 venous events occurred at lower than 2.0 INRs.A nonsignificant trend was noted toward a higher rate of both bleeding and thrombotic complications in elderly vs matched younger patients. Intracranial bleeding and fatal thrombotic events were significantly more frequent in the elderly. Our results also indicate that lower than 2.0 INRs do not preclude bleeding in the elderly nor offer adequate protection from thrombotic events. Moderate anticoagulation (2.0-3.0 INRs) in elderly patients seems the safest and most effective.