What evaluation and care is offered to women after unexplained recurrent pregnancy loss (RPL) or intra-uterine foetal death (IUFD) and what are the reproductive outcomes? Women are assessed for thrombophilia and often treated with low-molecular weight heparin (LMWH) and/or low-dose aspirin (ASA). Randomized controlled trials (RCTs) on possible efficacy of heparins and/or aspirin have been inconclusive due to limited power to detect a difference and patient heterogeneity. Prospective multicentre cohort study performed in 12 hospitals in three countries between 2012 and 2019. All consecutive pregnant women with recurrent PL (≥3 losses or 2 losses in the presence of at least one euploid foetal karyotype) or at least one IUFD. Eligible women may have undergone thrombophilia testing before conception, at the discretion of local providers. The possible assignment of women to treatments (such as LMWH) was not decided a priori but was determined based on the responsible provider’s current practice. Aims of the study were: (i) to evaluate factors associated with pregnancy outcome; (ii) to compare clinical management strategies in women with and without a subsequent successful pregnancy; and (iii) to evaluate characteristics of women who may benefit from antithrombotic therapy. A propensity score matching method was used to balance the differences in baseline characteristics. A matched sample of 265 pregnant women was analysed, with all undergoing thrombophilia screening; 103 out of 119 (86.6%) with and 98/146 (67.1%) without thrombophilia were prescribed with LMWH and/or ASA. Overall, live-births were recorded in 204 cases (77%), PL or IUFD in 61 (23%) pregnancies. Logistic regression showed a significant interaction between thrombophilia and treatment with LMWH (P = 0.03). Findings from sensitivity analysis showed odds ratio (OR) for pregnancy loss in women with inherited or acquired thrombophilia in absence of any treatment was 2.9 (95% CI, 1.4–6.1); the administration of LMWH (with or without ASA) was associated with higher odds of live-birth (OR, 10.6; 95% CI, 5.0–22.3). Furthermore, in women without thrombophilia, the odds of live-birth was significantly and independently associated with LMWH prophylaxis (alone or in association with ASA) (OR, 3.6; 95% CI, 1.7–7.9). While the propensity score matching allows us to balance the differences in baseline characteristics, it does not eliminate all confounding. Antithrombotic prophylaxis during pregnancy may be effective in women with otherwise unexplained PL or IUFD, and even more useful in those with thrombophilia. The study was funded by Italian Ministry of Health (Ricerca Corrente 2018-2020). Dr G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr E.G. has received consultant fees from Italfarmaco and Sanofi. All other authors declare that they have no conflict of interest. NCT02385461.

This narrative review summarizes the available literature on the association between In Vitro Fertilization (IVF) treatments and thrombosis, focusing on epidemiology and pathophysiology. Thrombosis is a rare IVF-related complication, with an incidence of approximately 0.2%, dramatically increased by ovarian hyperstimulation syndrome (OHSS). Arterial thrombosis, primarily associated with OHSS, is a rare and early event, while venous thrombosis, although more common, remains a rare complication of IVF. Venous thrombosis often affects the upper body. The thrombotic risk is higher during the first trimester of pregnancy obtained through IVF. This review discusses the impact of risk factors such as OHSS, thrombophilia, obesity, advanced maternal age, and polycystic ovarian syndrome, which predispose women to thromboembolic events during and after IVF stimulation.

Background: Endothelial dysfunction, coupled with inflammation, induces thrombo-inflammation. In COVID-19, this process is believed to be associated with clinical severity. Von Willebrand factor (VWF), and a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS-13), are strong markers of endothelial dysfunction. We evaluated the impact of the VWF/ADAMTS-13 fraction on COVID-19 severity and prognosis. Materials and methods: A cohort study including 74 COVID-19 patients, with 22 admitted to the intensive care unit (ICU) and 52 to the medical ward (MW), was carried out. We also evaluated, in a group of 54 patients who were prospectively observed, whether variations in VWF/ADAMTS-13 correlated with the degree of severity and routine blood parameters. Results: A VWF:RCo/ADAMTS-13 fraction above 6.5 predicted in-hospital mortality in the entire cohort. At admission, a VWF:RCo/ADAMTS-13 fraction above 5.7 predicted admission to the ICU. Furthermore, the VWF:RCo/ADAMTS-13 fraction directly correlated with C-reactive protein (CRP) (Spearman r: 0.51, p < 0.0001) and D-dimer (Spearman r: 0.26, p = 0.03). In the prospective cohort, dynamic changes in VWF:RCo/ADAMTS-13 and the CRP concentration were directly correlated (Spearman r, p = 0.0014). This relationship was significant in both groups (ICU: p = 0.006; MW: p = 0.02).Conclusions: The present findings show that in COVID-19, the VWF/ADAMTS-13 fraction predicts in-hospital mortality. The VWF/ADAMTS-13 fraction may be a helpful tool to monitor COVID-19 patients throughout hospitalization.

There is paucity of data on the transfusion need and its impact on the overall mortality in patients with COVID-19. We explored mortality in hospitalized patients with COVID-19 who required transfusions. Information on clinical variables and in-hospital mortality were obtained from medical records of 422 patients admitted to medical wards or the Intensive Care Unit (ICU). In-hospital mortality occurred in 147 (34.8%) patients, 94 (63.9%) of whom were admitted to the ICU. The median fatalities age was 77 years (IQR 14). Overall, 100 patients (60 males) received transfusion during hospitalization. The overall mortality was significantly and independently associated with age, ICU admission, Chronic Kidney Disease (CKD), and the number of transfused Red Blood Cell (RBC) units. Specifically, CKD was associated with mortality in patients admitted to medical wards, whereas the number of transfused RBC units predicted mortality in those admitted to the ICU. Transfusion strongly interacted with the admission to ICU (OR: 9.9; 95% CI: 2.5–40.0). In patients with COVID-19, age is one of the strongest risk factors in predicting mortality independently of the disease’s severity. CKD confers a higher risk of mortality in patients admitted to medical wards. In those admitted to the ICU, the more RBC units are transfused, the more mortality increases.

Context: The role of inflammation in shaping death risk in diabetes is still unclear. Objective: To study whether inflammation is associated with and helps predict mortality risk in patients with type 2 diabetes. To explore the intertwined link between inflammation and tryptophan metabolism on death risk. Methods: There were 2 prospective cohorts: the aggregate Gargano Mortality Study (1731 individuals; 872 all-cause deaths) as the discovery sample, and the Foggia Mortality Study (490 individuals; 256 deaths) as validation sample. Twenty-seven inflammatory markers were measured. Causal mediation analysis and in vitro studies were carried out to explore the link between inflammatory markers and the kynurenine to tryptophan ratio (KTR) in shaping mortality risk. Results: Using multivariable stepwise Cox regression analysis, interleukin (IL)-4, IL-6, IL-8, IL-13, RANTES, and interferon gamma–induced protein-10 (IP-10) were independently associated with death. An inflammation score (I score) comprising these 6 molecules is strongly associated with death in both the discovery and the validation cohorts HR (95% CI) 2.13 (1.91-2.37) and 2.20 (1.79-2.72), respectively. The I score improved discrimination and reclassification measures (all P < .01) of 2 mortality prediction models based on clinical variables. The causal mediation analysis showed that 28% of the KTR effect on mortality was mediated by IP-10. Studies in cultured endothelial cells showed that 5-methoxy-tryptophan, an anti-inflammatory metabolite derived from tryptophan, reduces the expression of IP-10, thus providing a functional basis for the observed causal mediation. Conclusion: Adding the I score to clinical prediction models may help identify individuals who are at greater risk of death. Deeply addressing the intertwined relationship between low-grade inflammation and imbalanced tryptophan metabolism in shaping mortality risk may help discover new therapies targeting patients characterized by these abnormalities.

Background: Elevated high-sensitivity C-reactive protein (hsCRP) levels are associated with poor cardiovascular outcomes, particularly in patients with advanced peripheral arterial disease (PAD). This study aimed to assess the impact of hsCRP on clinical characteristics and long-term outcomes in a cohort of PAD patients. Methods: A total of 346 patients with advanced PAD were enrolled and stratified into two groups based on their median hsCRP level (Group 1: 0.32 mg/dL). The patients were followed for a mean of 102.70 ± 44.13 months. Their clinical characteristics, comorbidities, and long-term cardiovascular events, including myocardial and/or peripheral revascularization, ischemia, and death, were analyzed. This study evaluated two composite endpoints: major adverse cardiovascular events (MACEs) and major adverse peripheral events (MAPEs). MACEs comprised fatal cardiovascular events, cerebral ischemia, cardiac infarction, myocardial revascularization, acute peripheral arterial occlusion, and peripheral reperfusion. MAPEs included carotid reperfusion, acute peripheral arterial occlusion, and lower limb revascularization. Results: The patients in Group 2 had a higher body mass index, waist circumference, and waist–hip ratio compared to those in Group 1 (all p < 0.05). Inflammatory markers, including fibrinogen and the erythrocyte sedimentation rate, were significantly elevated in Group 2 (both p < 0.01). While the overall incidence of peripheral revascularization was similar between groups, these interventions occurred significantly earlier in Group 2 (28.24 ± 38.87 months vs. 67.04 ± 49.97 months, p = 0.004; HR: 2.015, 95% CI: 1.134–3.580, p = 0.017). The MAPEs were comparable in number, but occurred earlier in Group 2 (36.60 ± 37.35 months vs. 66.19 ± 48.18 months, p < 0.01; HR: 1.99, 95% CI: 1.238–3.181, p = 0.004). Similarly, the MACEs had an earlier onset in Group 2 (40.31 ± 38.95 months vs. 55.89 ± 46.33 months, p = 0.04; HR: 1.62, 95% CI: 0.983–1.987, p = 0.062). A total of 169 deaths were recorded during the follow-up. Group 2 exhibited a significantly higher mortality rate (56% vs. 42%, p < 0.01) and an earlier trend in mortality (76.58 ± 43.53 months vs. 84.86 ± 5.18 months), although this difference did not reach statistical significance (p = 0.22). Conclusions: Elevated hsCRP levels (>0.32 mg/dL) are associated with a worse clinical profile and earlier adverse events in patients with advanced PAD. Group 2 experienced significantly earlier peripheral revascularization, MACEs, and MAPEs. The mortality rates were also significantly higher, highlighting the prognostic value of hsCRP in this population.