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The management of anticoagulant therapy in pregnant women with mechanical heart valves (MHVs) is difficult and often challenging even for clinicians experienced in the field. These pregnancies, indeed, are burdened with higher rates of complications for both the mother and the fetus, compared to those in women without MHVs. The maternal need for an optimal anticoagulation as provided by vitamin K antagonists is counterbalanced by their teratogen effect on the embryo and fetus. On the other hand, several concerns have been raised about the efficacy of heparins in pregnant women with MHVs, considering the high risk of thrombotic complications in these patients. Therefore, numerous clinical issues about the management of pregnant women with MHVs remain unanswered, such as the selection of the best anticoagulant agent, the optimal anticoagulation levels to be achieved and maintained, and the evaluation of long-term effects for both the mother and the fetus. Based on a comprehensive review of the current literature, the Italian Federation of the Centers for the Diagnosis and the Surveillance of the Antithrombotic Therapies (FCSA) proposes experience-based suggestions and expert opinions. Particularly, this consensus document aims at providing practical guidance for clinicians dealing with pregnant women with MHVs, to optimize maternal and fetal outcomes while guaranteeing adequate anticoagulation. Finally, FCSA highlights the need for the creation of multidisciplinary teams experienced in the management of pregnant women with MHVs during pregnancy, delivery, and postpartum , in order to better deal with such complex clinical issues and provide a comprehensive counseling to these patients., Competing Interests: A.S. received honoraria for lectures, manuscript writing, and/or participation on advisory board from Daiichi Sankyo, Bayer, Pfizer, Bristol-Myers Squibb, Novartis, Viatris, Sanofi, Werfen, Boehringer-Ingelheim, Alexion, and Roche. All other authors have nothing to declare., (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/).)

Background: Rheumatic heart disease (RHD) with mechanical heart valve (MHV) replacement is common in Africa. However, MHV requires lifelong anticoagulation that could have a particular impact in women in reproductive age., Methods: We report data of a prospective observational cohort study conducted between August 2018 and September 2019 in MHV patients in the Salam Centre for Cardiac Surgery built in Khartoum by Emergency, an Italian Non-Governmental Organization, to evaluate bleeding risk, its associated determinants, and the impact of lifelong anticoagulation in fertile women., Results: We studied 3647 patients (median age 25.1 years; 53.9% female). During follow-up [median time 1.1 (0.1-1.2) years], we recorded 85 major bleedings (rate 2.16 × 100 pt-years), Major bleedings occurred more frequently among women (64/85 cases, 75.3%; rate 3.0 × 100 pt-years), compared to men (21/85 cases, 24.7%; rate 1.16 × 100 pt-years) (RR 2.6; 95% CI 1.6-4.5; p = 0.0001). Multivariate analysis was performed to identify variables associated with major bleeding, and female sex was the only risk factor significantly associated, whereas aspirin treatment and higher INR target showed a non-significant trend for higher bleeding risk. Thirty-two/85 (37.6%) of major bleedings were metrorrhagias. When we calculate the incidence of major bleedings after the exclusion of gynecological events, no sex differences in the bleeding risk were found (HR 1.3, 95% CI 0.8-2.3; p = 0.3)., Conclusions: Bleeding risk of young MHV patients on oral anticoagulant therapy is higher among women, mainly due to metrorrhagia. Women in the reproductive life are at high risk for gynecological bleeding when treated with anticoagulants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Rheumatic heart disease with mechanical heart valve (MHV) replacement is common in Africa. However, MHV requires long-life anticoagulation and managing this can be challenging., Methods and Results: We report data of a prospective observational study conducted between August 2018 and September 2019 in MHV patients in the Salam Centre for Cardiac Surgery built in Khartoum, by Emergency, an Italian Non-Governmental Organization, to evaluate the quality of anticoagulation control and the risk of thrombotic complications., Results: We studied 3647 patients (median age 25.1 years; 53.9 % female). Median Time in Therapeutic Range (TTR) was 53 % (interquartile range 37 % to 67 %) and 70 thrombotic events (rate 1.8 × 100 pt-years [95 % CI 1.38-2.23]) were recorded. Among patients in the first quartile of TTR (≤37 %), we recorded 34/70 (48.6 %) of all thrombotic events (rate 3.7 × 100 pt-years [95 % CI 2.5-5.1]), with a high mortality rate (2.2 × 100 pt-years [95 % CI 1.3-3.3]). In patients with guideline-recommended TTR (≥65 %) the event rate was 0.8 × 100 pt-years for thrombotic events [95 % CI 0.3-1.5] and 0.4 × 100 pt-years for mortality [95 % CI 0.1-0.9]. Multivariable analysis showed that having a TTR in the lowest quartile (≤37 %) and being noncompliant are significantly associated with increased thrombotic risk. Aspirin use or different valve type did not influence the thrombotic risk. Almost 40 % of all thromboembolic complications could have been potentially prevented by further improving VKA management to obtain a TTR > 37 %., Conclusion: The thrombotic risk of MHV patients on VKAs living in a low-income country like Sudan is associated with low quality of anticoagulation control. Efforts should be made to decrease the number of non-compliant patients and to reach a guideline-recommended TTR of ≥65 %., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pregnancy and childbirth on anticoagulants after mechanical heart valve replacement present a high risk of complications for both mother and baby. On top of pregnancy worsening the mother's cardiac function, anticoagulant therapy itself is a crucial problem. A safe and effective anticoagulation regimen for both mother and fetus is not possible. The most effective drugs for preventing valve thrombosis are VKAs, whose dosage needs to be adjusted with frequent INR checks. Moreover, VKAs can have embryopathic and teratogenic action. Patients in follow-up and anticoagulant treatment at the Salam Centre for Cardiac Surgery in Sudan live spread out over a large area where transport to the Center is generally difficult; pregnancy treatment has, therefore, been adapted to the limitations of reality. Pregnancy is discouraged and contraception and therapeutic abortion are recommended, but this guidance frequently goes unheeded. Here we describe maternal and fetal outcomes in 307 consecutive pregnancies recorded by staff at the oral anticoagulant clinic (OAC) from April 2017 to November 2021. Out of 307 pregnancies, there were 15 maternal deaths (4.9%), 24 thrombotic events (7.8%) and 22 major bleedings (7.2%). Fifty pregnancies (16.3%) were terminated by therapeutic abortion. Only 47.6% of pregnancies had good maternal and neonatal outcomes. Data clearly show that, due to the complexity of pregnancy in women with mechanical heart valves and the scarcity of tertiary healthcare services in the area where patients live, maternal mortality is at an unacceptable level and requires a structured, multi-disciplinary intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Erba, Gatti, Hassan, Langer, Chatenoud, Portella and Baiocchi.)

Rheumatic heart disease is endemic in Sub-Saharan Africa and while efforts are under way to boost prophylaxis and early diagnosis, access to cardiac surgery is rarely affordable. In this article, we report on a humanitarian project by the NGO EMERGENCY, to build and run the Salam Centre for Cardiac Surgery in Sudan. This hospital is a center of excellence offering free-of-charge, high-quality treatment to patients needing open-heart surgery for advanced rheumatic and congenital heart disease. Since it opened in 2007, more than 8,000 patients have undergone surgery there; most of them Sudanese, but ~20% were admitted from other countries, an example of inter-African cooperation. The program is not limited to surgical procedures. It guarantees long-term follow-up and anticoagulant treatment, where necessary. By way of example, we report clinical features and outcome data for the pediatric cohort: 1,318 children under the age of 15, operated on for advanced rheumatic heart disease between 2007 and 2019. The overall 5-year survival rate was 85.0% (95% CI 82.7-87.3). The outcomes for patients with mitral valves repaired and with mitral valves replaced are not statistically different. Nevertheless, observing the trend of patients undergoing valve repair, a better outcome for this category might be assumed. RHD in children is an indicator of poor socio-economic conditions and an inadequate health system, which clearly will not be cured by cardiac surgery alone. Nevertheless, the results achieved by EMERGENCY, with the crucial involvement and participation of the Sudanese government over the years, show that building a hospital, introducing free cardiac surgery, and offering long-term post-operative care may help spread belief in positive change in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Miccio, Quattrociocchi, Valgoi, Chatenoud, Lentini, Giovanella, Rolla, Erba, Gatti, Rocchi, Saad, Salvati, Langer, Portella and Strada.)

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., (Copyright ©ERS 2016.)

Objective: To evaluate the risk of recurrent intracranial hemorrhage (ICH) in patients on vitamin K antagonists (VKAs) after a first episode of ICH., Methods: The Cerebral Haemorrhage in patients Restarting Oral Anticoagulant Therapy (CHIRONE) Study collected data of patients eligible for the study from the database of 27 centers affiliated with the Italian Federation of Anticoagulation Clinics., Results: We enrolled 267 patients (163 male, median age 73.9 years) who had received VKA anticoagulation after an ICH event. During the total period of follow-up (778 patient-years), ICH recurred in 20 patients (7.5%; rate 2.56 × 100 patient-years) at a median time of 16.5 months, and was fatal in 5 patients (25%; rate 0.4 × 100 patient-years). Male sex, hypertension, prosthetic valves, previous ischemic stroke, renal failure, cancer, and spontaneous events were associated with the risk of recurrence, though none of them in isolation reached statistical significance. More than one-third of spontaneous recurrences occurred in patients with a posttraumatic index event., Conclusions: Our results show that patients with a history of ICH carry a significant risk of recurrent ICH when treated with VKA anticoagulation. The risk is also present, though to a lower degree, in patients with previous posttraumatic events. All patients with a history of ICH require a careful evaluation of their thromboembolic risk to estimate the net clinical benefit of (re)starting anticoagulation with VKAs.

The Prolong study shows that continuing vitamin K antagonists (VKA) in patients with abnormal D-dimer (evaluated by a qualitative assay, Clearview Simplify D-dimer) results in a significant reduction of venous thromboembolism (VTE) recurrence. The present study retrospectively analyzes a subgroup of patients enrolled in the Prolong study with a view to calculate cut-off values for six quantitative D-dimer methods to predict the risk of VTE recurrence. We measured D-dimer levels by VIDAS D-dimer Exclusion (bioMerieux), STA Liatest D-dimer (DiagnosticaStago), HemosIL D-dimer and HemosIL D-dimer HS (Instrumentation Laboratory), Innovance D-dimer (Siemens) and AutoDimer (Trinity Biotech) in frozen plasma aliquots sampled 30 ± 10 days after VKA cessation in 390 patients enrolled in the Prolong study. During follow-up (562.7 years), 28 patients had recurrent VTE (7.2%, 5.0% person-years). Since D-dimer levels are positively correlated with age and significantly lower in men, we calculated method-specific cut-off values according to age and gender. The HRs for VTE recurrence calculated using method-specific cut-off values based on age and gender are higher than those using cut-off values indicated by the manufacturers for VTE exclusion in symptomatic outpatients. These data suggest that method-specific cut-off values calculated according to patient age and gender can be more accurate in identifying patients at a higher risk for VTE recurrence. These method-specific cut-off values are being evaluated in the ongoing prospective management multicenter DULCIS study.

Migraine, particularly migraine with aura (MA), may be a risk factor for ischemic stroke (IS). The reasons for this association are unknown. We investigated the presence of genetic abnormalities of the protein C system in 83 MA patients, 31 IS patients, and 124 healthy controls, all aged under 45 years. We found an increased frequency of activated protein C resistance due to Arg506Gln factor V mutation, and of protein S deficiency in both disorders, with figures higher than those reported in the general population and significantly different from those found in controls. These prothrombotic genetic abnormalities may be shared risk factors in IS and MA, and may play a role in increasing the risk of cerebrovascular disease in migraineurs.

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.

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.