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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., Competing Interests: A.S.: Honoraria for lectures, manuscript writing, and/or participation on advisory board from Daiichi Sankyo, Bayer, Pfizer, Bristol-Myers Squibb, Sanofi, Werfen, Alexion, and Roche. D.P.: Honoraria for a webinar from Daiichi Sankyo. D.B.: Honoraria for lectures from Aspen and Werfen. A.C.: Honoraria for lectures from Bayer. E.G.: Honoraria for lectures from Sanofi and Italfarmaco, and for participation on advisory board from Roche, Sanofi Genzyme, and Novo Nordisk. C.M.: None. M.M.: Honoraria for lectures and manuscript writing from Daiichi-Sankyo. V.T.: Honoraria for lectures from Bayer and Novo Nordisk. A.T.: Honoraria for lectures from Werfen, Stago, and Roche; support for attending meetings from Novo Nordisk; honoraria for participation on advisory board from Bayer and Novo Nordisk. S.T.: Honoraria for lectures and for participation on advisory board from Werfen, Stago, Italfarmaco, Pfizer, Bristol-Myers Squibb, and Sanofi., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Venous thromboembolism (VTE) is the third most common cardiovascular disease. Interleukins (ILs) and micro-ribonucleic acids (miRNAs) have been proposed as molecules able to modulate endothelial inflammation and platelet hyperactivity. At present, no early biomarkers are available to predict the outcome of VTE. We investigated in a pilot study a selected number of miRNAs and ILs as prognostic VTE biomarkers and reviewed literature in this setting. Twenty-three patients (aged 18-65) with a new diagnosis of non-oncological VTE and free from chronic inflammatory diseases were enrolled. Twenty-three age- and sex-matched healthy blood donors were evaluated as control subjects. Serum miRNAs (MiRNA 126, 155, 17.92, 195), inflammatory cytokines (IL-6, tumor necrosis factor-α, IL-8), and lymphocyte subsets were evaluated in patients at enrolment (T0) and in controls. In VTE patients, clinical and instrumental follow-up were performed assessing residual vein obstruction, miRNA and ILs evaluation at 3 months' follow-up (T1). At T0, IL-8, activated T lymphocytes, Treg lymphocytes, and monocytes were higher in patients compared with healthy controls, as were miRNA 126 levels. Moreover, miRNA 126 and IL-6 were significantly increased at T0 compared with T1 evaluation in VTE patients. Higher levels of MiR126 at T0 correlated with a significant overall thrombotic residual at follow-up. In recent years an increasing number of studies (case-control studies, in vivo studies in animal models, in vitro studies) have suggested the potential role of miRNAs in modulating the cellular and biohumoral responses involved in VTE. In the frame of epidemiological evidence, this pilot study with a novel observational approach supports the notion that miRNA can be diagnostic biomarkers of VTE and first identifies miRNA 126 as a predictor of outcome, being associated with poor early recanalization., Competing Interests: None declared., (Thieme. All rights reserved.)

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. The recent spreadout of the COVID-19 pandemic requires a re-organization of Anticoagulation Clinics to prevent person-to-person viral diffusion and continue to offer the highest possible quality of assistance to patients. In this paper, based on the Italian Federation of Anticoagulation Clinics statements, we offer some advice aimed at improving patient care during COVID-19 pandemic, with particular regard to the lockdown and reopening periods. We give practical guidance regarding the following points: (1) re-thinking the AC organization, (2) managing patients on anticoagulants when they become infected by the virus, (3) managing anticoagulation surveillance in non-infected patients during the lockdown period, and (4) organizing the activities during the reopening phases.

Although direct oral anticoagulants (DOAC) do not require dose-adjustment on the basis of laboratory test results, the measurement of their anticoagulant effect is useful in special situations. This position paper issued by the Italian Scientific Societies that are mainly involved in the management of patients on DOAC is aimed at providing guidance to care-givers on which tests should be used and the situations in which testing is useful. The guidance is based on the data from the literature so far available and/or on consensus among experts.

Background: Center-specific TTR (c-TTR) is a measure reporting the mean patient TTR within an anticoagulation clinic describing the quality of anticoagulant monitoring offered by that clinic. c-TTR has a considerable between-center variation, but its determinants are poorly understood., Objectives: We aimed at evaluating which clinical, procedural or laboratory factors could be associated with c-TTR variability in a multicenter, observational cross-sectional study over a five-year period., Patients/methods: Data from 832,204 individual patients followed for VKA therapy in 292 Centers affiliated with the Italian Federation of Anticoagulation Clinics (FCSA) were analyzed. c-TTR was computed based on the TTR of patients followed at each Center, and a mixed linear regression model was used for a predefined set of explanatory variables., Results: The Center next-visit interval ratio (the mean number of days after a visit with an INR outside the therapeutic range, divided by the days after a visit with an INR within the therapeutic range), the Center mean patient INR and the Center laboratory performance at EQA proficiency testing were the only variables that were independently associated with c-TTR (β-coefficients -17.32, 9.67, and -0.11, respectively; r2 = 0.635)., Conclusions: These findings suggest that c-TTR associates with proactive strategies aimed at keeping patients very close to their target INR with a prompt re-evaluation of those patients with under- or over-therapeutic INR.

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.

Dabigatran 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.

Introduction: Hormone replacement therapy is known to increase the risk of thromboembolic events. We compared the effects of HRT and raloxifene on some haemostasis variables., Materials and Methods: In a multicenter, double-blind study, 54 healthy postmenopausal women were randomized to receive either continuous treatment with 2 mg 17beta-estradiol plus 1 mg norethisterone acetate (n=30) or 60 mg raloxifene (n=24) daily for 12 months. Blood samples were collected at baseline and at 3, 6 and 12 months to evaluate therapy effects on some haemostasis variables (factor VII, factor VIII, prothrombin fragments 1 and 2, protein C, protein C activity, protein S, thrombin-antithrombin complex, D-dimer, antithrombin, fibrinogen and plasminogen activator inhibitor)., Results: Both raloxifene and continuous combined hormone therapy modified the haemostasis variables toward a more prothrombotic profile. Factor VIII (p<0.01) and fibrinogen (p<0.05) plasma levels significantly increased at 6 months, prothrombin fragments 1 and 2 (p<0.05) significantly increased at 12 months, whereas protein C activity (p<0.001) and antithrombin (p<0.01) significantly decreased at 12 months in both groups., Conclusions: Our results demonstrate that raloxifene and continuous combined hormone therapy exhibit the same prothrombotic profile. Both treatments induced an increase in procoagulant parameters at 6 months and a decrease in anticoagulant parameters at 12 months.

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.

Objective: To establish whether asymptomatic normotensive pregnant women with an abnormal uterine Doppler velocimetry, have haematological changes characteristic of congenital or acquired thrombophilia, and whether this information improve predict in pregnancy complications., Study Design: A prospective study involved the enrolment of 30 healthy normotensive pregnant women between the 23rd and 27th week of gestation, subdivided into group A (normal uterine Doppler velocimetry) and group B (abnormal uterine Doppler velocimetry). Besides uterine velocimetry (resistence index and presence/absence of notch), at enrolment in the study the PI of the umbilical artery and of the middle cerebral artery were measured, in addition to the usual foetal biometric parameters (biparietal diameter and abdominal circumference). Contemporaneously, a 20 ml blood sample was taken for the dosage of protein C, protein S, antithrombin III, activated protein C resistance, antiphospholipid antibodies and platelet functionality. Subsequently, for all the remaining period of the pregnancy, data were collected relating to the onset of any materno-foetal complications and modality of delivery, as well as neonatal data up to the first 20 days of life., Results: The incidence of adverse perinatal outcomes (pre-eclampsia, gestational hypertension, abruptio placentae, endouterine foetal death, preterm birth, caesarean section because of maternal or foetal problems, APGAR score lower than 7 at the 5th minute of life, small for gestational age) resulted as being 75% in group B versus 11% in group A (P<0.001). The mean gestational age at delivery was 34 weeks (range 27-41) in group A versus 39 weeks (range 37-42) in group B (P<0.001). No difference emerged as to either the mean activity in the plasma levels of the coagulation protein studied in patients with normal and abnormal uterine velocimetry. The same consideration is also true if the population is analysed in relation to the lesser or greater seriousness of the Doppler velocimetry abnormalities. Subdividing the patients in relation to the absence and to the presence of unfavourable perinatal outcomes, the thrombophilic indices appear to be substantially comparable., Conclusion: Uterine Doppler velocimetry, carried out between the 24th and the 26th week of pregnancy, proves its validity by identifying a population at high risk of adverse perinatal outcomes. In contrast, the investigations carried out on the haematological abnormalities characteristic of thrombophilia do not reveal any significant differences, either between patients with normal and those with abnormal velocimetry, or between patients with adverse perinatal outcomes and those without. It is thus unlikely that these preliminary data will lead to an improvement in the clinical reliability of uterine velocimetry.

Background and Objectives: We carried out a prospective, randomized trial to test whether a computer-based decision support system to initiate and maintain oral anticoagulant (OA) treatment can improve the laboratory quality of therapy., Design and Methods: Two separate sets of patients on oral anticoagulants, in five Italian anticoagulant clinics, were studied: 335 patients in the first three months of treatment (stabilization phase), 916 patients (775 patient-years) beyond the third month of treatment (maintenance phase). Patients were randomized to a computerized system, which included algorithms able to suggest OA dosing and to schedule appointments (computer-aided dosing) or to an arm in which OA were prescribed by the same teams of expert physicians without such algorithms (control group). Primary outcomes were: A) the percentage of patients reaching a stable state of anticoagulation during each of the first three months of treatment; B) the percentage of time individuals spent within the aimed therapeutic range (maintenance phase)., Results: Patients in the computer-aided dosing group achieved a stable state significantly faster (p<0.01) and they spent more time within the therapeutic range during maintenance (p<0.001) than controls. The favorable effect of computer-aided dosing was mainly due to a reduction of the time spent below the therapeutic range and was associated with an increase of mean INR value, of anticoagulant drug dosage, and with a reduction of the number of appointments per patient (all changes significant: p<0.001)., Interpretation and Conclusions: The computer decision-aided support improves the laboratory quality of anticoagulant treatment, both during long-term maintenance and in the early, highly unstable phase of treatment, and it also significantly reduces the number of scheduled laboratory controls.

The 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 <0.01; RR 6.2 (95% CI 1.95-19.4). There was a trend towards a higher rate of thrombotic complications in cancer patients (6.8% vs. 2.5%; p = 0.058; RR 2.5 [CI 0.96-6.5]) but this did not achieve statistical significance. In the group of patients with cancer, the bleeding rate was high across the different INR categories and was independent of the temporally associated International Normalized Ratio (INR). In contrast, the bleeding rate was increased only with INR values greater than 4.5 in the group of patients without cancer. The rate of thrombotic events was significantly higher in both cohorts when the INR was less than 2.0. 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.

Background: Whether elderly patients are at increased risk of complications during oral anticoagulant treatment (OAT) is still a matter of debate., Method: 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., Results: 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., Conclusions: 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.

The in vitro and ex vivo antiplatelet effects of 2-amino-1,2-benzisothiazolin-3-one (1) are compared with those of its parent compound 1,2-benzisothiazolin-3-one (2) and with acetylsalicylic acid (ASA) against different agonists. 2-Amino-1,2-benzisothiazolin-3-one inhibits adenosine diphosphate (ADP)-, arachidonic acid (AA)- and collagen-induced human platelet aggregation in vitro, with IC50 values of 8.90 x 10(-5), 1.50 x 10(-6) and 5.11 x 10(-8) mol/l, respectively. The strong inhibitory activity is significant not only for collagen but also for AA-induced aggregation. The same compound inhibits ex vivo collagen- and particularly AA-induced rabbit platelet aggregation at the tested dose of 10 mg/kg i.m. In view of the potential use of 2-amino-1,2-benzisothiazolin-3-one as antithrombotic agent, the log P values for both 1,2-benzisothiazolin-3-one derivatives 1 and 2 are determined, to gain an understanding of the significance of the 2-amino group in the 1,2-benzisothiazolin-3-one moiety with respect to the biological activity under study.

The 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 < or =90 days vs. >90 = 20.6, C.I. 12.7-33.5; p <0.0001). The risk was higher in patients aged > or =70 y (1.62, C.I. 1.0-2.61; p <0.05), and when indication for anticoagulant treatment was peripheral/cerebral arterial disease (1.84, C.I. 1.01-3.36; p <0.05). The frequency of thrombotic events was 17.5% when international normalised ratio (INR) levels were < 1.5, decreasing to 2.3% for INRs within the 2-2.99 category (relative risk of INRs <2.0 vs. > or =2 = 1.88, C.I. 1.16-3.07; p <0.05). 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 <2.0 INR, in patients > 70 years and in those with cerebrovascular/peripheral arterial disease.

The synthesis of a new compound, 2-amino-1,2-benzisothiazolin-3-one, is described and its antiplatelet activity was studied. A good platelet aggregation inhibitory activity of the tested drug was clearly demonstrated both in vitro and ex vivo, presumably through an effect on arachidonic acid cascade or directly on thromboxane A2 (TXA2) receptors. An early and long lasting effect on bleeding time has also been observed. The results suggest that 2-amino-1,2-benzisothiazolin-3-one could be a potential antithrombotic agent.

Background: To assess the incidence of bleeding complications during oral anticoagulant therapy (OAT) in a population of patients representative of daily practice in Italian anticoagulation clinics., Design: prospective, inception-cohort, multicentre., Setting: Thirty-four anticoagulation clinics federated in the Italian Federation of Anticoagulation Clinics., Patients: 2745 consecutive patients, included from beginning of their first OAT course. Most patients were aged between 60 and 79 y (57.8%), with 8% being > or = 80 y. Venous thromboembolism was the most frequent indication for OAT (one third of all the patients), followed by non ischemic heart disease which mainly included atrial fibrillation (16.8% of patients). Warfarin (in 63.8% of patients) and acenocoumarol were the only anticoagulant drugs used. The targeted anticoagulation intensity was low (INR < or = 2.8) in 71% of patients and high (INR > 2.8) in the remainder., Outcomes: Fatal, major and minor bleeding events. Thrombotic events were also recorded, though not analyzed in the present report., Findings: During the 2011 patient-years (pt-y) of follow-up, 153 bleeding complications (7.6% pt-y) were recorded--5 fatal (all cerebral haemorrhages, 0.25% pt-y), 23 major (1.1% pt-y) and 125 minor (6.2% pt-y). The rate of events did not vary according to sex, coumarin type, size of enrolling centre or targeted therapeutic range; it was higher in older patients (10.5% pt-y in those aged > or = 70 y, relative risk--RR--1.75, p < 0.001), in cases where indication for anti-coagulant treatment was peripheral and/or cerebrovascular disease (12.5% pt-y; RR 1.80, p < 0.01) and during the first 90 days of treatment (11% pt-y, RR 1.75, p < 0.001). One fifth of bleeding events occurred at a very low anticoagulation intensity (INR < 2; the category rate being 7.7% pt-y); the rate was 4.8% pt-y in the 2.0-2.9 INR category, reaching 9.5% pt-y, 40.5% pt-y and 200% pt-y in the 3-4.4, 4.5-6.9 and > or = 7 INR categories respectively (RR for INR levels > 4.5 = 7.91, p < 0.0001)., Conclusions: The overall rate of bleeding events recorded in the present study was much lower than that recorded in other (including recent) observational and experimental studies. The risk of bleeding increased in the following cases: age > 70 y; arterial vascular disease as indication for OAT; first 3 months of treatment; INR values > or = 4.5. OAT has become safer in recent years, particularly if monitored in special anticoagulation clinics. Caution should be exercised when prescribing OAT in elderly patients and the intensity anticoagulation levels should be closely monitored to minimize incidental periods of overanticoagulation.

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] < or = 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% Cl 1.29-2.39, p < 0.001). The rate was also higher when the indication was peripheral and/or cerebrovascular disease than venous thromboembolism plus other indications (12.5 vs 6.0 per 100 patient-years) (1.80, 1.2-2.7, p < 0.01), and during the first 90 days of treatment compared with later (11.0 vs 6.3, 1.75, 1.27-2.44, p < 0.001). A fifth of the bleeding events occurred at low anticoagulation intensity (INR < 2, rate 7.7 per 100 patient-years of follow-up). The rates were 4.8, 9.5, 40.5, and 200 at INRs 2.0-2.9, 3-4.4, 4.5-6.9, and over 7, respectively (relative risks for INR > 4.5, 7.91, 5.44-11.5, p < 0.0001)., 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.

To assess the risk of thromboembolism in women using oral contraceptives (OCs), we identified through computer search in the hospitals of the province of Parma, Italy, all women aged 15-44 who were resident in the province and had a documented thromboembolic event in the years 1989-93. The number of users and nonusers of OCs was estimated by the drug sale data for the province and by the demographic statistics. In cases with venous thromboembolism (VT) the prevalence of concomitant deficiency of antithrombin III, protein C, protein S, and of factor V gene mutation Arg506GIn was evaluated. The incidence rate of VT was 37/59,603 woman-years in users (0.62 per 1000) and 13/303,954 woman-years in nonusers (0.042 per 1000), for a relative risk (RR) of 14.5 (95% confidence interval: 7.8-27.1; P < 0.001); the rate of stroke per 1000 woman-years was 0.17 in users and 0.036 in nonusers (RR = 4.6; 2.9-10.7; P < 0.01). A congenital thrombophilia involving the protein C anticoagulant system was documented in about 25% of young women developing venous thromboembolism while on OCs.

Purpose: To assess the natural history and risk factors for thrombosis in a large cohort of unselected patients with antiphospholipid antibodies., Patients and Methods: 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., Results: 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; P < 0.005) and IgG ACA titer above 40 units (RR 3.66; 95% CI, 1.24 to 10.8; P < 0.01). 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)., Conclusions: The present study shows that: (a) previous thrombosis and ACA titer > 40 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.

The International Sensitivity Index (ISI) of thromboplastins is determined by calibration using fresh plasmas from 60 patients stabilized on oral anticoagulants and 20 healthy subjects. This procedure is demanding, particularly for those who have no easy access to patients. The alternative use of a smaller number of lyophilized plasmas has already been considered, but one important issue, the number of repeated measurements to be carried out, has never been addressed. Two commercial rabbit thromboplastins, A and B, were calibrated in 3 laboratories against CRM 149R. On each of 10 working days, prothrombin times were measured for a different set of 8 fresh plasmas and for the same set of 8 lyophilized plasmas. The ISI values for both thromboplastins were estimated by orthogonal regression on fresh and lyophilized plasmas. The between- and within-laboratory CV values of the estimated ISI were taken as measures of precision of the calibration. In addition, ISI and CV were calculated daily on cumulative results obtained with lyophilized plasmas from day 1 to day 10. The ISI values for both thromboplastins calculated with lyophilized plasmas were not significantly different from those with fresh plasmas (mean of 3 laboratories: 1.42 vs 1.48 for A and 1.22 vs 1.20 for B). The between-laboratory precision of the calibration with lyophilized plasmas was not considerably different from that with fresh plasmas (CV for 3 labs: 5.2% vs 6.8% for A and 0.9% vs 2.2% for B). The ISI estimated with lyophilized plasmas on results of day 1 were not different from those of days 2 through 10. Good within-laboratory precision of the calibration (CV around 2%) was already achieved on day 3. In conclusion, this study shows that lyophilized plasmas pooled from normals and patients on oral anticoagulants can be used as substitutes for individual fresh plasmas to simplify the existing procedure for thromboplastin calibration.

Eight healthy volunteers (6 males, 2 females, mean age 31.6 yrs), were administered--on three separate days--200, 400 and 800 mg of a new low molecular weight Dermatan sulphate (Desmin), given as a single i.v. bolus (2 min.) injection. Before each administration and 10, 20, 30 min., 1, 2, 4, 8, 12, 24 hours after, blood samples were drawn and the following coagulative assays performed: aPTT (activated Partial Thromboplastin Time), TT (Thrombin Time), anti Xa (Xa Factor inhibition), Heptest, Stachrom D.S.. Furthermore, a kinetic analysis was performed on the activity curves calculated on the Heptest and Stachrom data. Plasma peak values and half lives of the parameters checked showed a clear dose-effect relationship. aPTT and TT showed very short-lasting variations and the inhibition of Factor Xa was moderate, but significant. The most evident and specific effects of Desmin were those on Heptest and Stachrom D.S.: both tests were influenced in a clear-cut and dose-dependent way, mainly as a consequence of the action of Desmin on HCII, with partially different kinetic patterns. A series of in vitro experiments proved an anti Xa effect of Desmin, mediated by antithrombin III, well above the possible interference of the small (< 1%) heparin contaminants in Desmin. An even more marked anti Xa activity was seen in the in vivo study, an observation so far unrecognized for this type of drug: some possible interpretations of this fact are discussed.

We report a new case of severe bleeding diathesis due to an acquired inhibitor of fibrin crosslinking. The patient, an 80-year-old woman, was admitted to the hospital for a massive subcutaneous hematoma, with severe anemia requiring red cell transfusion; a subsequent retroperitoneal hematoma developed 2 weeks later. Coagulation studies were normal except for a thromboelastographic pattern suggestive of FXIII deficiency. Clot solubility test was abnormal even after 1:1 mix with normal plasma. Immunochemical studies confirmed the presence of a monoclonal IgG lambda inhibitor directed against FXIII activity (type II FXIII inhibitor). The patient IgG fraction selectively inhibited FXIII transamidating activity but did not inhibit the thrombin-mediated activation of FXIII. The patient was treated with high doses of FXIII concentrate to overcome the inhibitor and immunosuppressive therapy with cyclophosphamide and discharged in good conditions. High doses of commercially available FXIII appear to be a safe and effective method of controlling acute episodes of bleeding in patients with acquired FXIII deficiency.

To 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 [CI] 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% CI 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% CI for the difference, 1% to 16%).(ABSTRACT TRUNCATED AT 250 WORDS)

In our Center for the Surveillance of Anticoagulant Treatment, most of the 1700 patients followed-up are traditionally treated with acenocoumarol, while warfarin is administered nowadays to an increasing proportion of patients. To assess if the difference in the pharmacokinetics of these two drugs may determine a different laboratory quality of treatment, a retrospective study was performed on the computerized files of all 142 patients on treatment with warfarin for more than 100 days and on a control group of 142 patients treated with acenocoumarol, matched for age, sex, disease state and duration of oral anticoagulant therapy (OAT). The study considered 7071 assays for a total of 432 patient-years of treatment. The overall quality of treatment was significantly better in patients treated with warfarin (72% of controls within the therapeutic range versus 67% on acenocoumarol, p < 0.001). Also the individual quality of therapy, which was assessed as the percentage of patients with 75% or more assays in range, was in favour of warfarin (50.7% vs 34.5%, p < 0.05). Warfarin therapy was more stable and fewer assays were required for treatment monitoring. Confounding factors possibly influencing the treatment stability, such as interfering drugs, diagnostic or therapeutical procedures requiring withdrawal of anticoagulation, were evaluated and no significant difference between the two groups was found. The difference in the laboratory quality of OAT was marked in patients treated for prevention of arterial thromboembolism, while it was negligible in patients with venous thromboembolic disease, whose mean duration of OAT was considerably shorter. Since there is no evidence that acenocoumarol is more efficacious or safer than warfarin, the latter seems to be preferable for patients who are candidate to very prolonged OAT.

Rationale and Objectives: A few case reports have suggested a possible thrombogenic effect of nonionic contrast media. In vitro investigations have lead to conflicting results. The authors performed three ex vivo studies to evaluate the influence of an ionic, ioxaglate, and a nonionic, iopamidol, low-osmolality contrast medium on a series of clotting and fibrinolytic parameters, after intravenous or intra-arterial administration, during routine diagnostic procedures., Methods: In the first study, iopamidol was given to 20 consecutive patients through an arterial catheter for digital subtraction arteriography (DSA). In the second study, iopamidol was compared with ioxaglate. The media were randomly and blindly administered intravenously to 21 consecutive patients undergoing brain computed tomography (CT). Finally, ioxaglate was administered intra-arterially to 20 consecutive patients, in a situation comparable with that of the first study., Results: In the first study, a weak anticoagulant effect and an activation of fibrinolysis were found, associated with indirect markers of thrombin generation, such as increased plasma levels of fibrinopeptide A (FpA) and thrombin-antithrombin III complexes (TAT). In the second study, no significant changes were seen with either contrast medium, for thrombin or fibrinolysis activation parameters. In the third study, the intra-arterially administered contrast medium elicited a marked increase of FpA and TAT, together with an anticoagulant effect., Conclusion: Both ionic and nonionic contrast media are able to interfere with the clotting/fibrinolytic system in the general circulation when they are administered to patients at the usual dosages. Ioxaglate shows more marked anticoagulant and thrombin-generating effects than iopamidol. The procedure (ie, arterial catheter versus intravenous infusion) seems to be more important than the category of contrast medium in conditioning the magnitude of these effects.

In 107 asymptomatic and untreated patients with inherited syndromes associated with thrombophilia (antithrombin III, protein C and protein S deficiencies), we compared in parallel two plasma peptides which reflect activation of the common coagulation pathway: the prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA). Both F1 + 2 and FPA were measured with simple, commercially available ELISA methods. High levels of F1 + 2 or FPA were found in about one fourth of the patients as a whole. When patients were divided according to the type of inherited thrombophilic syndrome, it appeared that F1 + 2 was more frequently elevated in protein C and protein S deficiencies than in antithrombin deficiency; and that, in general, it was no more frequently elevated than FPA. Although our data confirm the existence of a procoagulant imbalance in inherited thrombophilic syndromes due to defects of natural anticoagulant proteins, they do not confirm that such imbalance can be more frequently diagnosed by measuring F1 + 2 levels, particularly in patients with antithrombin deficiency.

We evaluated the effects of heparan-sulphate administration on clotting times, thromboelastographic parameters and serum thromboxane B2 levels in hypercholesterolemic rabbits with aortic atherosclerotic lesions (sudanophilic areas). 24 New Zealand male rabbits were divided into three groups of 8 animals each. Group A and B were fed a rabbit chow diet containing 0.7% of cholesterol whereas Group C was fed a standard rabbit diet without cholesterol. Group A was treated by subcutaneous route with 6 mg/kg/day of heparan sulphate. At the beginning of the study and after 3 and 6 months of treatment, serum cholesterol and thromboxane B2 levels were tested. Furthermore, at the end of the experiment, we evaluated plasma fibrinogen, aPTT, PT and TT values. The administration of heparan-sulphate in cholesterol fed rabbits produced: a reduction of plasma fibrinogen levels, without modifying aPTT and TT; a protective effect vs the lengthening in PT values, likely induced by cholesterol rich diet; a reduction of plasma thrombophilic activities and of aortic atheromasic involvement induced by dietetic cholesterol intake. However, increased serum thromboxane B2 levels, likely through a proaggregant activity were observed. We suggest that heparan-sulphate administration, in cholesterol fed rabbits, has a favourable effect on clotting parameters, while contrasting effects were found on platelet activity.

This collaborative study, organized by the Hemostasis Subcommittee of C.I.S.M.E.L., evaluated the accuracy, precision, and comparability of the following six widely used fibrinogen assays: total clottable fibrinogen (Blombäck and Blombäck), clotting time (Von Clauss), turbidimetry (Ellis and Stransky), Chromotime System, prothrombin time (PT)-derived, and radial immunodiffusion (RID). The same frozen samples, with normal and high contents of fibrinogen, were examined in four laboratories. The methods were calibrated with an internal standard whose fibrinogen content was determined gravimetrically. Both the Von Clauss and the RID methods were reliable, accurate, and precise, if adequate calibration was used. The PT-derived method was highly reproducible, but had some problems with accuracy. We demonstrate that an adequate calibration procedure is indispensable for reliable fibrinogen measurements whatever method is used. Because neither the calibration procedures proposed by the manufacturers nor the use of lyophilized commercial plasmas is adequate for this purpose, we urge that an international standard for fibrinogen measurement be promptly established.

A case of warfarin-induced dermatitis in a 79 year-old patient with Protein S deficiency is described. Both total Protein S antigen and free Protein S were moderately reduced (about 50%). The skin lesion did not progress to frank necrosis and it was associated with elevated creatin phosphokinase (CPK) levels in plasma and with thrombosis of the anterior tibial vein localized to the area of dermatitis (probably warfarin-induced deep venous thrombosis). After warfarin withdrawal and beginning of heparin therapy, serum CPK rapidly normalized and the skin lesion improved.

271 patients with acute symptomatic deep venous thrombosis of lower limbs, confirmed by strain-gauge plethysmography and/or venography, were randomly assigned to receive intermittent subcutaneous heparin calcium or heparin sodium by continuous intravenous infusion for 6-10 days. Heparin dosage was adjusted to maintain activated partial thromboplastin time values (Thrombofax reagent) at 1.3-1.9 times the basal ones. Strain-gauge plethysmography was repeated at the end of heparin treatment, and evaluation of therapy was performed by comparing the indexes of venous hemodynamics and by assessing the incidence of pulmonary embolism and of bleeding complications. In the intravenous group, Maximal Venous Outflow (MVO) increased from 20.8 +/- 12.8 to 28.4 +/- 17.5 ml/min per 100 ml of tissue and Venous Capacitance (VC) from 1.39 +/- 0.92 to 1.94 +/- 1.0 ml/100 ml of tissue (mean +/- SD). In the subcutaneous group, MVO increased from 21.0 +/- 12.7 to 27.5 +/- 18.1 and VC from 1.60 +/- 0.86 to 2.06 +/- 1.0. The median improvement of MVO and VC were 22% and 36% respectively in the IV group and 20% and 24% in the SC group. Clinical pulmonary embolism occurred in 2 patients in the intravenous group (1 fatal) and in 4 in the subcutaneous group (1 fatal). 9 major bleeding complications occurred in the intravenous group (1 fatal) and 5 in the subcutaneous group (1 fatal). The differences were not significant at the statistical analysis. The results suggest that subcutaneous intermittent heparin has a comparable efficacy to continuous intravenous heparin in the treatment of deep venous thrombosis. To the same conclusion points an overview of the seven randomized trials which compared these treatment modalities.

The results of a cooperative study on the quality of treatment of patients with prosthetic heart valves (PHV) on long-term oral anticoagulants (OA) are reported. The study was carried out on 695 patients bearing PHV (with an overall 8,340 checks carried out in 1988) through a computer-assisted system for monitoring the laboratory and treatment follow-up. The specifications of the software are described in detail in the text. The mean INR slightly differed in the two participating centers (Rome and Parma) (3.25 vs 3.19) as did the weekly mean dosage (18.2 vs 20.7 mg) of oral anticoagulant, which was always Acenocoumarol. More than 70% of the checks were within the range in both centers as evaluated by a check randomly chosen once a month for each single patient. Considering the whole bunch of data, about 80% of the patients had greater than 50% of their checks within the therapeutic range and more than 30% had greater than 75% of the checks within the range. This study demonstrates that the availability of a computerized program for monitoring oral anticoagulant therapy allows to perform multicenter studies and to obtain data which can improve the quality of treatment of patients on OA.

The effect of 1,4-bis-[3(3,4,,5-trimethoxybenzoyl-oxy)-propyl]-perhydro-1,4-diazepine (dilazep, Cormelian), a coronaroactive drug, was studied by various tests of hemostasis in vitro on human plasma. The antiplatelet action of the drug was clearly demonstrated: it inhibited, in appropriate concentrations, ADP, adrenaline and collagen induced aggregation platelet factor 3 (PF3) availability and clot retraction induced by ADP-reptilase. Conversely, coagulation tests as well as the lysis time of diluted whole blood were unaffected by the drug.