Chiara Ticozzi

(1) Background: The presence of metastatic disease significantly increases the risk of venous thromboembolism (VTE) in breast cancer, particularly during chemotherapy. Although not categorized as a highly thrombogenic malignancy, the elevated global prevalence of this cancer places a substantial number of patients at risk of thrombosis, which cannot yet be accurately predicted by validated risk assessment models (RAMs), highlighting the need for a dedicated model. (2) Aim: This study aims to develop a RAM for VTE in newly diagnosed metastatic breast cancer patients enrolled in a prospective, observational, and multicenter study. (3) Methods: A cohort of 189 patients beginning antitumor therapy were enrolled and prospectively monitored for VTE and mortality. Blood samples collected at enrollment were tested for D-dimer, fibrinogen, FVIII, prothrombin fragment 1 + 2 (F1 + 2), and thrombin generation (TG). Competing risk analyses were performed to identify significant predictors. (4) Results: Within one year, the cumulative incidences of VTE and mortality were 7.0% and 12%, respectively. Univariable analysis identified high Ki-67, D-dimer, FVIII, fibrinogen, and TG levels, along with low hemoglobin levels, as independent predictors of VTE. Only Ki-67, fibrinogen, FVIII, and hemoglobin were retained as significant predictors in multivariable analysis. These variables were further examined by multiple linear regression, which revealed Ki-67 and fibrinogen as the most significant parameters. A continuous RAM was then developed based on Ki-67 and fibrinogen (c-statistics 0.78), categorizing patients into low-risk and high-risk groups for VTE (2% vs. 13%; SHR 3.6, p = 0.018). This stratification could not be achieved using currently validated models for VTE risk. (5) Conclusions: We developed an accurate RAM for VTE that enables the identification of metastatic breast cancer patients at high risk for VTE, which supports clinicians in personalized thromboprophylaxis strategies if externally validated.

(1) Background: The hemostatic system and tumor biology display a tight and reciprocal interaction where clotting products enhance tumor growth and dissemination, and the tumor, in turn, triggers a hypercoagulable and inflammatory state. Evaluating circulating biomarkers related to thrombo-inflammatory may provide a promising tool for predicting tumor outcomes, especially in non-small cell lung cancer (NSCLC) characterized by unfavorable outcomes. (2) Aim: In a prospective cohort of NSCLC patients, we evaluated whether thromboinflammatory biomarkers could predict early disease progression (DP) during the first 6 months of first-line anticancer treatment. (3) Methods: 719 newly diagnosed advanced-stage NSCLC patients were included. Complete blood cell count, high-sensitivity C-reactive protein (hs-CRP), FVIII, fibrinogen, D-dimer, thrombin-antithrombin (TAT) complexes, and prothrombin fragment1+2(F1+2) were tested in blood samples collected before starting chemotherapy. DP was gathered during follow-up. (4) Results: The 6-month cumulative incidence rate for DP was 49%. Univariable Cox regression analysis identified metastatic status, BMI, hemoglobin, leukocytes, hs-CRP, FVIII, fibrinogen, TAT, and D-dimer as significant predictors of DP. In a multivariable analysis that included all previously significant variables, only hs-CRP and D-Dimer levels remained strongly associated with DP. The two variables were used to establish a risk stratification model that significantly identified patients at high risk of DP at 6 months (HR 2.9; 95% CI, 2.3–3.7), which can be applied to 3, 9, and 12 months. (5) Conclusions: Our model easily and precisely estimates early DP during chemotherapy. If externally validated, this model can significantly enhance the allocation of medical resources in managing advanced NSCLC, ensuring that patients receive the most effective care possible.

(1) Background: Venous thromboembolism (VTE) is a frequent complication in ambulatory lung cancer patients during chemotherapy and is associated with increased mortality. (2) Methods: We analyzed 568 newly diagnosed metastatic lung cancer patients prospectively enrolled in the HYPERCAN study. Blood samples collected before chemotherapy were tested for thrombin generation (TG) and a panel of hemostatic biomarkers. The Khorana risk score (KRS), new-Vienna CATS, PROTECHT, and CONKO risk assessment models (RAMs) were applied. (3) Results: Within 6 months, the cumulative incidences of VTE and mortality were 12% and 29%, respectively. Patients with VTE showed significantly increased levels of D-dimer, FVIII, prothrombin fragment 1 + 2, and TG. D-dimer and ECOG performance status were identified as independent risk factors for VTE and mortality by multivariable analysis and utilized to generate a risk score that provided a cumulative incidence of VTE of 6% vs. 25%, death of 19% vs. 55%, and in the low- vs. high-risk group, respectively (p < 0.001). While all published RAMs significantly stratified patients for risk of death, only the CATS and CONKO were able to stratify patients for VTE. (4) Conclusions: A new prediction model was generated to stratify lung cancer patients for VTE and mortality risk, where other published RAMs failed.

Introduction Coronavirus disease is a clinical challenge for patients with autoimmune conditions. Patients affected by immune thrombotic thrombocytopenic purpura (iTTP) are particularly vulnerable to SARS-CoV-2 infection. Protecting these patients with vaccination is therefore mandatory, although concerns may exist on a possible increased thrombotic risk or risk of disease relapse after vaccine exposure. So far, there is no information on serological response and hemostatic activation in iTTP patients after SARS-CoV-2 vaccination. Materials and Methods In this study, in April 2021, we enrolled iTTP patients in clinical remission and on regular outpatient follow-up to receive the first and second dose BNT162b2 vaccine as a part of a prospective trial aimed at monitoring for 6 months after vaccination the occurrence of subclinical laboratory signs of clotting activation, as well as overt thrombotic complications or disease relapse. The seroconversion response was monitored in parallel. The results were compared with those of control non-iTTP subjects. Results A moderate decrease of ADAMTS-13 activity was recorded at 3 and 6 months in five patients with normal values at baseline, while an ADAMTS-13 relapse occurred at 6 months in one patient. Abnormalities in the endothelium activation biomarkers postvaccination were observed in iTTP patients compared with controls. The immunological response to vaccine was overall positive. No clinical iTTP relapses or thrombotic events manifested in the 6 month-follow-up after vaccination. Conclusion The results of this study are in favor of efficacy and safety of mRNA vaccines in patients with iTTP, and highlight the importance of long-term monitoring of iTTP patients.

Background: the tight and reciprocal interaction between cancer and hemostasis has stimulated investigations on the possible role of hemostatic biomarkers in predicting specific cancer outcomes, such as disease progression (DP) and overall survival (OS). In a prospective cohort of newly diagnosed metastatic gastrointestinal (GI) cancer patients from the HYPERCAN study, we aimed to assess whether the hemostatic biomarker levels measured before starting any anticancer therapy may specifically predict for 6-months DP (6m-DP) and for 1-year OS (1y OS). Methods: plasma samples were collected and tested for thrombin generation (TG) as global hemostatic assay, and for D-dimer, fibrinogen, and prothrombin fragment 1 + 2 as hypercoagulation biomarkers. DP and mortality were monitored during follow-up. Results: A prospective cohort of 462 colorectal and 164 gastric cancer patients was available for analysis. After 6 months, DP occurred in 148 patients, providing a cumulative incidence of 24.8% (21.4–28.4). D-dimer and TG endogenous thrombin potential (ETP) were identified as independent risk factors for 6m-DP by multivariate Fine–Gray proportional hazard regression model corrected for age, cancer site, and >1 metastatic site. After 1 year, we observed an OS of 75.7% (71.9–79.0). Multivariate Cox regression analysis corrected for age, site of cancer, and performance status identified D-dimer and ETP as independent risk factors for 1y OS. Patients with one or both hemostatic parameters above the dichotomizing threshold were at higher risk for both 6m-DP and 1-year mortality. Conclusion.: in newly diagnosed metastatic GI cancer patients, pretreatment ETP and D-dimer appear promising candidate biomarkers for predicting 6m-DP and 1y OS. In this setting, for the first time, the role of TG as a prognostic biomarker emerges in a large prospective cohort.

Introduction: Patients (pts) with immune thrombotic thrombocytopenic purpura (iTTP) are at high risk of severe COVID-19, therefore protection from SARS-CoV-2 by vaccination is particularly relevant in this setting, although concerns may exist on possible adverse reactions or disease relapse after vaccination. In this study, in a group of iTTP pts who received in-hospital COVID-19 vaccination in a special program for 'fragile patients', we prospectively evaluated over time the antibody response, the clinical and laboratory disease parameters and hemostatic biomarker levels. Methods: Twelve iTTP pts in clinical remission and regularly followed-up in our Center were enrolled in April 2021, all of them received 2 doses of BNT162b2 vaccine (Pfizer-BioNTech) over 21 days, and were followed-up for clinical and laboratory testing for 60 days. Blood samples were collected at enrollment (day 0, D0) before the 1 ^st vaccine dose; on day 21 (D21) before the 2 ^nd dose; and on day 60 (D60) after the 1 ^st dose. Blood cell counts, anti-Spike receptor-binding-domain protein (anti-S/RBD) IgG, ADAMTS-13 activity, and anti-ADAMTS-13 IgG (chromogenic assay and ELISA), were measured at each time point. Additionally, an extensive study of hemostatic markers (i.e. FVIII, von Willebrand Factor (vWF) antigen and activity, fibrinogen, D-dimer, tPA, PAI, and F1+2) was performed. Follow up is currently continuing. Results: Median age of our cohort was 65 years with M/F ratio of 4/8. Median time since last acute iTTP episode was 40 months, median follow up of the cohort was 71 months (95% CI 30-126). All pts were in clinical remission, except one patient (P1) who had an iTTP relapse after contracting SARS-CoV-2 infection, in Dec 2020, and was on low-dose steroids on D0. One patient (P2) had an ADAMTS-13 relapse in Jan 2021, and received pre-emptive rituximab. No other pts were on immunosuppressive therapy. Concerning the status of ADAMTS-13 activity on D0, 6 pts showed normal levels (>50%), while 5 had a moderate (50-20%) and 1 a complete (15 U/ml, despite clinical remission. Overall, a significant increase in anti-S/RBD IgG level was observed on D21 (p = 0.0005) and D60 (p = 0.0005). Remarkably, only P2 did not show an increase in anti-S/RBD IgG titer after both doses of BNT162b2. Median levels of FVIII and vWF antigen did not significantly change during follow up, while increased vWF activity was seen on D60 (p = 0.05). Fibrinogen levels were stable, and an increase in D-dimer (>1000 ng/mL both on D21 and D60) was seen in P3. There were no changes in the other hemostatic parameters, and no thromboses were observed. Conclusions: In our cohort of iTTP pts, COVID-19 was associated with 1 clinical and 1 ADAMTS-13 relapse. Our data show that SARS-CoV-2 vaccination was effective in inducing an antibody response in all but one patient who received rituximab within 3 months before vaccination, confirming recent findings. Overall, vaccination had no relevant impact on the hemostatic profile of our pts, and did not appear to be a driver of iTTP relapses. However, anti-SARS-CoV-2 antibodies monitoring in iTTP pts may be useful after vaccination, as currently it is unknown how long the antibody titer may persist. Although small, this study is in favor of efficacy and safety of mRNA vaccines in pts with iTTP.