BACKGROUND Lipoprotein(a) [Lp(a)] is a causal risk factor for coronary artery disease (CAD), with proposed prothrombotic properties besides proatherogenic effects. However, the association between Lp(a) and coagulation remains controversial so far. OBJECTIVE This study examined this relationship in subjects with or without angiographically documented CAD. METHODS Plasma levels of Lp(a) and coagulation biomarkers were assessed in clinically stable subjects undergoing elective coronary angiography. Subjects taking any anticoagulant therapy were excluded. The coagulation panel included coagulant activities of factors II, V, VII, VIII, IX, X, XI, and XII, von Willebrand factor antigen (vWF:Ag), thrombin generation assay (TGA), total tissue factor pathway inhibitor (TFPI), and activated factor VII-antithrombin (FVIIa-AT) complex. Lp(a) threshold values were defined according to the European Atherosclerosis Society consensus statement: normal <30 mg/dL, intermediate 30 to 50 mg/dL, and high >50 mg/dL. RESULTS Complete laboratory data were available for 383 subjects (males 75.3%; mean age 68.2 ± 9.7 years): 65 subjects had normal coronary arteries, 51 subjects had coronary stenosis <50%, and 267 subjects had coronary stenosis ≥50%. A modest yet significant increase in FV coagulant activity (FV:C) from low to high Lp(a) plasma levels was found and confirmed after adjustment for potential confounding factors. No differences were observed for all the other coagulant activities, vWF:Ag, total TFPI, FVIIa-AT levels, or TGA parameters. CONCLUSION In this pilot study, no major contribution of Lp(a) plasma levels was observed in modulating coagulation phenotype, as evaluated by multiple biomarkers. High Lp(a) plasma levels were associated with only a mild increase in FV:C.

Background: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with the risk of several chronic and acute diseases. However, updated data on vitamin D status in Mediterranean countries, including Italy, remain limited, hindering effective public health strategies. Objective: To assess serum 25(OH)D levels and their seasonal variation in healthy blood donors aged 18–65 years living in Northern Italy and not taking vitamin D supplements. Given the latitude and high levels of environmental pollution, cutaneous vitamin D synthesis may be impaired in this population. Recent Italian guidelines on supplementation highlight the need for updated data on hypovitaminosis D prevalence and seasonal synthesis capacity. Methods: In this exploratory cross-sectional study, 534 blood donors (268 men and 266 women) attending the Transfusion Medicine Unit of Verona University Hospital were enrolled between April 2016 and May 2018. Serum 25(OH)D concentrations were analysed according to season. Clinical, lifestyle, pharmacological and dietary characteristics were also collected. Results: Among healthy, normal-weight individuals, the prevalence of vitamin D insufficiency (25(OH)D<50 nmol/L) was low and limited to one-two months per year. Overweight and obesity significantly reduced the likelihood of achieving adequate 25(OH)D levels through cutaneous synthesis for several months. Mean 25(OH)D concentrations were higher than those previously reported in the same area, while seasonal variation remained preserved. Conclusions: Despite persistent environmental pollution, seasonal vitamin D synthesis is not impaired in this Northern Italy population. Updated data show higher 25(OH)D levels compared to past studies, supporting current recommendations against routine supplementation in healthy normal-weight individuals under 70 years

Background and Clinical Significance: Disorders caused by platelet-activating antibodies targeting platelet factor 4 (PF4) are recognized as the cause of severe thrombotic events and are not restricted to heparin-induced thrombocytopenia (HIT). Case Presentation: We report a 67-year-old man with thrombocytopenia and extensive portal-splenic-mesenteric vein thrombosis complicated by intestinal ischemia. Despite intravenous unfractionated heparin (UFH), his condition worsened toward pulmonary embolism, septic shock, and multi-organ failure. Thrombolysis with alteplase was also ineffective. Both thrombophilia testing and autoimmune panels were negative, including those for antiphospholipid syndrome. An anti-PF4 immune thrombotic disorder was hypothesized. Therefore, argatroban was initiated instead of UFH therapy and intravenous immune globulin (IVIG) was administered. The platelet count increased and the patient’s clinical condition progressively improved. An anti-PF4/heparin assay on a blood sample collected before IVIG was highly positive. Platelet activation assays did not demonstrate an increased activation after the addition of heparin (the Heparin-Induced Platelet Activation [HIPA] assay was negative) though increased activation was observed with the addition of PF4 (the PF4-Induced Platelet Activation [PIPA] assay was positive), thus defining a VITT-like syndrome. Conclusions: This case report highlights the crucial function of having adequate laboratory facilities available to disentangle different anti-PF4 disorders for an accurate definition of a specific diagnosis, such as VITT-like syndrome, thereby allowing for the most appropriate therapeutic management of these complex pathological conditions. The clinical suspicion of an anti-PF4 immune disorder should be considered in cases of severe, otherwise unexplained, thrombotic events associated with thrombocytopenia. Specific tests like HIPA and PIPA are essential for definitive diagnosis.

In the original publication [...].

Background Inferior vena cava agenesis (IVCA) is a rare vascular abnormality characterised by the absence of one or more segments of the inferior vena cava and represents an underestimated cause of deep vein thrombosis (DVT). Given the very low prevalence of this condition and the lack of clinical trials, there is no consensus about the optimal anticoagulation strategy in IVCA-associated DVT. Objectives To investigate efficacy and safety of direct oral anticoagulants (DOACs) in IVCA-associated DVT. Methods We described three patients with IVCA-associated DVT followed at our Institution and treated with DOACs. Then, we performed a systematic review of the literature for ICVA-associated DVT treated with DOACs. Results In addition to our 3 cases, we found data from 19 publications for a total of 30 patients with IVCA-associated DVT treated with DOACs (24 subjects treated with rivaroxaban, 8 with apixaban, and one with dabigatran). Most patients were males (72.7 %) with a median age at DVT onset of 26.0 years (min–max range 13–64 years). The majority of DVT events were unprovoked (76.0 %). The standard thrombophilia tests were mainly negative. The median follow-up period during DOAC therapy was 1.0 years (min–max range 0–10 years), with one recurrent splanchnic vein thrombosis reported and no haemorrhagic events. Conclusions IVCA is a rare cause of DVT, which should be suspected in young adults with unprovoked DVT. Although future studies are needed, available data may support the use of DOACs in IVCA-associated DVT, with a reassuring profile of both efficacy and safety.

BACKGROUND:Hypertension is a major global health issue. Aldosterone synthase inhibitors (ASIs) have emerged as a promising therapeutic strategy for blood pressure control. METHODS:A thorough search of the MEDLINE and Embase databases up to March 30, 2024, identified randomized trials comparing ASIs with a placebo for hypertension treatment. Data extraction was done independently by 2 authors. Both random-effects (Restricted maximum likelihood) and fixed-effects meta-analyses were conducted to account for diversity and study size, respectively. Risk ratios for binary outcomes and mean differences for continuous outcomes were calculated. RESULTS:Seven randomized controlled trials involving 1440 patients (mean age, 60 years; 39% women) were included. The analysis showed that ASIs reduced office systolic blood pressure by 6.3 mm Hg ([95% CI, -8.8 to -3.8]; P<0.0001) and diastolic blood pressure by 2.2 mm Hg ([95% CI, -4.2 to -0.2]; P=0.03). The risk ratio for adverse events was 1.1 ([95% CI, 0.9-1.2]; P=0.3), with a similar trend for serious adverse events (risk ratio, 1.0 [95% CI, 0.5-2.3]; P=0.95). No treatment-related deaths occurred. However, the risk of hyperkalemia was higher with ASIs (risk ratio, 2.5 [95% CI, [1.2-5.4]; P<0.02). CONCLUSIONS:ASIs effectively reduce systolic and diastolic blood pressure in hypertensive patients and have a tolerable safety profile. The increased risk of hyperkalemia requires careful monitoring. These findings suggest ASIs are a potential treatment option for hypertension, pending further research in larger studies.

BACKGROUND:Activated factor VII-antithrombin complex (FVIIa-AT) is an indirect plasma biomarker of the interaction between tissue factor (TF) and FVIIa. High FVIIa-AT levels have been associated with an increased risk of mortality. METHODS:We investigated the genetic determinants of FVIIa-AT plasma levels by a candidate gene approach in a cohort of 610 subjects with (n = 478) or without (n = 132) angiographically-demonstrated coronary artery disease (CAD). RESULTS:Plasma concentration of FVIIa-AT did not differ between CAD and CAD-free subjects, but predicted the mortality risk in CAD during a median follow-up of 64-months. Among 7 polymorphisms in 4 candidate genes, codifying for FVII, TF, Endothelial Protein C Receptor (EPCR), and Low-density lipoprotein receptor-Related Protein 1 (LRP1), none was associated with CAD. Three of them were independently associated with FVIIa-AT plasma concentration. F3 -603 A > G polymorphism predicted mortality in CAD consistent with the influence on FVIIa-AT levels, with the G allele-carriers having both higher FVIIa-AT concentration (86.4 with 95 %CI 82.4-90.5 versus 76.7 with 95 %CI 71.0-82.8 pM) and higher mortality risk (HR 1.92 with 95 %CI 1.08-3.41) as compared with AA homozygotes. Conversely, the F7 -323 A1/A2, the strongest genetic predictor of FVIIa-AT variability, and EPCR Ser219Gly polymorphisms were associated with FVIIa-AT levels but were not predictive of mortality. CONCLUSIONS:Our results indicate that FVIIa-AT plasma levels are influenced by distinct genetic determinants linked to either TF or FVII expression. The heterogeneous association of FVIIa-AT-related polymorphisms with mortality risk in CAD suggests a predominant role of TF expression rather than FVII levels in the setting of secondary cardiovascular prevention.

Background/Objectives: Fatty acids (FAs) play crucial roles in human physiology, and their levels have been associated with hypertension, although with inconsistent findings. Primary Aldosteronism (PA), a common, often underdiagnosed form of secondary hypertension, carries a higher risk of organ damage compared to essential hypertension (EH). This study aimed to compare plasma FA profiles of patients with unilateral PA and EH and explore the impact of therapies. Methods: Participants were recruited at the Hypertension Unit of Verona University Hospital. PA diagnosis/subtype was confirmed according to guidelines. Blood samples were collected at enrollment and at follow-up (after treatment with a mineralocorticoid receptor antagonist (MRA) and adrenalectomy). Plasma long- and very-long-chain FAs were extracted and analyzed using gas chromatography. Results: Each sample was assessed for a panel of 19 selected FA species. Compared to EH (n = 60), PA patients (n = 22) exhibited lower plasma levels of behenic acid (p = 0.03), total monounsaturated fatty acids (p = 0.02), specifically palmitoleic (p = 0.005) and erucic acids (p = 0.02), and higher levels of ω6 polyunsaturated fatty acids (PUFAs, p = 0.02). Longitudinal analysis in PA patients showed that MRAs decreased total saturated FAs (pADJ = 0.01) and increased total PUFAs (pADJ = 0.006), and these changes were largely maintained even after adrenalectomy. Conclusions: This pilot study reveals significant alterations in the plasma FA profiles of PA patients compared to EH, suggesting a more prominent inflammatory state in PA. Both pharmacological and surgical interventions induced a positive shift in the FA profile of PA patients. These findings highlight the potential of FAs as biomarkers for PA risk stratification and may offer novel therapeutic opportunities.

Abstract Background: lipoprotein(a) [Lp(a)] is an established risk factor for cardiovascular disease. Among the molecular mechanisms underlying this association, beyond proatherogenic and proinflammatory properties, a prothrombotic diathesis has also been proposed, usually related to the homology between apolipoprotein(a) and plasminogen which supports a potential antifibrinolytic role. Moreover, other Lp(a)-related mechanisms of haemostatic imbalance have been advocated, from platelet activation to tissue factor (TF) expression. However, the link between Lp(a) and coagulation remains controversial so far. Aims: the aim of this study was to investigate the relationship of Lp(a) plasma levels with coagulation phenotype, evaluated by the assessment of both individual coagulation factors and global coagulation test such as thrombin generation assay (TGA), in a cardiovascular cohort of subjects with angiographic documentation of coronary artery vessels. Material and methods: plasma levels of Lp(a) and a large panel of coagulation biomarkers were assessed in clinically stable subjects undergoing elective coronary angiography. Subjects taking any anticoagulant therapy were excluded from this analysis. The coagulation panel included coagulant activities of factors II, V, VII, VIII, IX, X, XI and XII, as well as TGA, which explores the individual’s overall plasma propensity to form a blood clot when triggered by TF exposure ex-vivo, and activated factor VII-antithrombin (FVIIa-AT) complex, which is considered an indirect marker of TF expression. Lp(a) threshold values were defined according to the European Atherosclerosis Society consensus statement: normal <30 mg/dL, intermediate 30-50 mg/dL, and high >50 mg/dL. Results: laboratory data were available for 384 subjects (males 75.3%; mean age 68.2±9.7 years): 65 subjects had normal coronary arteries (CAD-free), 52 subjects had coronary lesions with stenosis <50% (CAD-borderline), and 267 subjects had coronary lesions with stenosis ≥50% (CAD). Most of patients (87.0%) were taking lipid-lowering therapies. Subjects with intermediate-high Lp(a) plasma levels were more represented in CAD than in CAD-free (12.0%-24.0% versus 7.7%-18.5%, respectively). As regards the correlation with coagulation biomarkers, in the whole study population a progressive and mild increase in coagulant activity of FV (FV:C) from low to high Lp(a) plasma levels was found (84.3±18.7%, 88.8±18.3%, and 90.1±18.7%, P=0.010), while there was no difference for the other individual coagulant activities. No difference was detected for either FVIIa-AT plasma levels or TGA parameters. The association of Lp(a) levels with FV:C was confirmed by multiple linear regression models after adjustment for sex, age, CAD diagnosis, and renal function (standardized beta coefficient=0.101, P=0.047), plasma lipids, including LDL cholesterol and apolipoprotein B (standardized beta coefficient=0.107, P=0.046), and the other coagulant activities (standardized beta coefficient=0.133, P=0.004). Conclusions: in this pilot analysis within a cohort of cardiovascular patients we did not find a major contribution of Lp(a) plasma levels in modulating coagulation phenotype, which was assessed by means of different laboratory biomarkers. High Lp(a) plasma levels were associated only with a mild increase of FV:C. This association appears independent of some potential confounding factors but deserves further validation and elucidation by both larger epidemiological/clinical studies and more in-depth biological/biochemical investigations.

BACKGROUND:Altered blood flow, which characterizes aortic stenosis (AS), influences von Willebrand factor (VWF) conformation and enhances ADAMTS13 cleavage, potentially influencing factor VIII (FVIII) clearance and plasma levels. AIM:To investigate whether ABO blood group and genetic variants of cellular receptors involved in VWF/FVIII clearance may interact with AS in determining genotype-driven FVIII levels. PATIENTS/METHODS:FVIII:c levels were analyzed in patients with severe AS (SAS, n = 115), with coronary artery disease and without valvular heart disease (CAD, n = 300), and healthy subjects (HS, n = 172), clustered according to ABO and receptor genotypes. Variants with functional association with receptor mRNA and/or FVIII levels, localized in 5 receptors (LDLR, STAB2, SCARA5, ASGR2, CLEC4M) with different VWF/FVIII binding properties, were selected. RESULTS:In SAS group, a significant interaction between ABO and receptor genotypes in modulating FVIII:c levels was observed with positive B values for lectins (ASGR2 and CLEC4M) and negative for LDLR and STAB2. The lectin variants, as well as their combinations, showed significantly lower FVIII levels in the non-O group with high glycan expression and potentially improved FVIII binding and increased clearance. Differently, the non-lectin LDLR and STAB2 variants, and their combinations, were associated with genotype-driven high FVIII levels, particularly in the O group. All these patterns were not observed in CAD or HS groups. CONCLUSION:These observations suggest that differential interaction between genotypes of specific cellular receptors and ABO blood group may contribute to high/low FVIII:c levels in O/non-O blood group subjects, respectively, and to the large inter-individual variability of FVIII levels in SAS.

Background: Tissue factor (TF), the main initiator of the coagulation cascade, plays a role in cancer progression and prognosis. Activated factor VII-antithrombin complex (FVIIa-AT) is considered an indirect marker of TF exposure by reflecting TF-FVIIa interaction. Objectives: To assess the link between FVIIa-AT plasma levels, TF messenger RNA (mRNA) expression, and survival in cancer. Methods: TF pathway-related coagulation biomarkers were assessed in 136 patients with cancer (52 with hepatocellular carcinoma, 41 with cholangiocarcinoma, and 43 with colon cancer) undergoing surgical intervention with curative intent. TF mRNA expression analysis in neoplastic vs nonneoplastic liver tissues was evaluated in a subgroup of 91 patients with primary liver cancer. Results: FVIIa-AT levels were higher in patients with cancer than in 136 sex- and agematched cancer -free controls. In patients with cancer, high levels of FVIIa-AT and total TF pathway inhibitor were associated with an increased mortality risk after adjustment for confounders, but only FVIIa-AT remained a predictor of mortality by including both FVIIa-AT and total TF pathway inhibitor in Cox regression (hazard ratio, 2.80; 95% CI, 1.23-6.39; the highest vs the lowest quartile). This association remained significant even after adjustment for extracellular vesicle-associated TF-dependent procoagulant activity. In the subgroup of patients with primary liver cancer, patients with high TF mRNA levels had an increased mortality risk compared with that for those with low TF mRNA levels (hazard ratio, 1.92; 95% CI, 1.03-3.57), and there was a consistent correlation among high FVIIa-AT levels, high TF mRNA levels, and increased risk of mortality. Conclusion: High FVIIa-AT levels may allow the identification of patients with cancer involving high TF expression and predict a higher mortality risk in liver cancer.

Clonal hematopoiesis of indeterminate potential (CHIP), marked by the accumulation of somatic mutations in hematopoietic stem cells, significantly elevates the risk of all-cause mortality, mainly due to cardiovascular events. Therefore, investigating this pathophysiological phenomenon is crucial for understanding cardiovascular aging and enhancing both health span and lifespan. In the present study, we examined samples of subjects enrolled within the angiographically controlled Verona Heart Study (VHS), which provides a robust model for cardiovascular aging, particularly regarding coronary artery disease (CAD). We analyzed 44 older subjects diagnosed with coronary artery disease (CAD) and 42 healthy, sex- and age-matched controls (CAD-FREE). Employing deep sequencing and an amplicon-based approach, we focused on 11 key genetic regions in ASXL1, DNMT3A, IDH1, IDH2, JAK2, PPM1D, SF3B1, SRSF2, TET2, TP53, and U2AF1 genes to investigate clonal hematopoiesis. Subjects in the CAD group exhibited a significantly higher variant burden than those in the CAD-FREE group, both in terms of the total number of somatic variants and disruptive variants affecting protein function. This increased mutational load was notably influenced by six specific genetic regions: ASXL1, DNMT3A, IDH2, JAK2, TET2, and U2AF1, which displayed elevated variant rates in the CAD subjects. Moreover, ASXL1, DNMT3A, IDH2, JAK2, SF3B1, TET2, and TP53 exhibited substantially higher levels of disruptive variants in the CAD group. In summary, our findings highlight a correlation between clonal hematopoiesis and the accumulation of disruptive variants in specific genomic regions in the VHS cohort, thereby shedding light on their potential role in cardiovascular aging.

Background: The role of human plasma fatty acid (FA) composition in coagulation cascade has received limited attention so far, despite evidence that the coagulation is deeply influenced by lipid binding. Aims: To assess the relationships between plasma FAs and thrombin generation parameters in a single-center, angiographically-controlled, cohort of subjects with or without coronary artery disease (CAD). Methods: Plasma FA concentrations were measured by a gas-chromatographic method in clinically stable subjects undergoing to elective coronary angiography who were also characterized for thrombin generation assay. Thrombin generation was studied using the Calibrated Automated Thrombogram assay (CAT®, Diagnostica Stago, France) The following parameters of thrombogram were analyzed: the lag-time of thrombin generation, the time to reach the peak of thrombin (ttPeak), the thrombin peak (Peak), the endogenous thrombin potential (ETP) that reflects the total amount of thrombin activity. Subjects with any acute illness, including acute coronary syndrome, in the month before blood collection and coronary angiography were excluded from this study. Results: The plasma FA profile was available for 245 subjects (males 73.9%; mean age 68.1±10.3 years): 54 with normal coronary arteries (CAD-free group) and 191 with coronary lesions with stenosis ≥50% (CAD group), of whom 51 with history of previous myocardial infarction (MI). Thirty-nine subjects taking oral anticoagulant therapies were excluded from further analysis on thrombin generation. In the 206 subjects not taking oral anticoagulants the saturated FAs 20:0, 22:0, and 24:0 were inversely correlated with peak of thrombin (R=-0.200 with P=0.004, R=-0.151 with P=0.031, and R=-0.182 with P=0.009, respectively) and endogenous thrombin potential (R=-0.217 with P=0.002, R=-0.170 with P=0.015, and R=-0.202 with P=0.004, respectively), while the saturated FA 26:0 correlated inversely with peak of thrombin (R=-0.208, P=0.003) and directly with time-to-peak (R=0.190, P=0.006). Defining very long-chain saturated FAs (VLSFAs) as those with 20 carbons or more, the sum of their levels remained inversely associated with both peak of thrombin and endogenous thrombin potential after adjustment for gender, age, CAD diagnosis, renal function and other traditional cardiovascular risk factors by linear regression analysis (standardized beta coefficient=-0.465 with P<0.001 and standardized beta coefficient=-0.400 with P=0.001, respectively). In the whole study population subjects with CAD with or without MI had lower levels of VLSFAs than CAD-free subjects (1.43±0.34, 1.58±0.40, and 1.68±0.43 g/100g, respectively, P=0.005 by ANOVA). Stratifying the study population on the basis of FA levels in CAD-free subjects, the prevalence of subjects within the highest VLSFA quartile (≥2.06 g/100g) decreased progressively from CAD-free to CAD without MI and CAD with MI (24.1%, 11.4%, and 3.9%, respectively, P=0.003). Conclusions: This preliminary analysis showed an inverse correlation between VLSFA and thrombin generation, thereby indicating a potential antithrombotic effect of high VLSFA levels. Additionally, high VLSFA levels were linked to a lower prevalence of CAD and MI, consistently with the recent studies indicating that elevated VLSFA concentrations are associated with favourable cardiovascular outcomes.

The sodium chloride cotransporter (NCC) is essential for electrolyte balance, blood pressure regulation, and pathophysiology of hypertension as it mediates the reabsorption of ultrafiltered sodium in the renal distal convoluted tubule. Given its pivotal role in the maintenance of extracellular fluid volume, the NCC is regulated by a complex network of cellular pathways, which eventually results in either its phosphorylation, enhancing sodium and chloride ion absorption from urines, or dephosphorylation and ubiquitination, which conversely decrease NCC activity. Several factors could influence NCC function, including genetic alterations, hormonal stimuli, and pharmacological treatments. The NCC’s central role is also highlighted by several abnormalities resulting from genetic mutations in its gene and consequently in its structure, leading to dysregulation of blood pressure control. In the last decade, among other improvements, the acquisition of knowledge on the NCC and other renal ion channels has been favored by studies on extracellular vesicles (EVs). Dietary sodium and potassium intake are also implicated in the tuning of NCC activity. In this narrative review, we present the main cornerstones and recent evidence related to NCC control, focusing on the context of blood pressure pathophysiology, and promising new therapeutical approaches.

Descriviamo un raro caso di angina in un paziente con origine anomala dell’arteria coronaria circonflessa dal seno di Valsalva destro, con decorso retroaortico e doppio ponte miocardico dell’arteria discendente anteriore. Durante l’ecocardiografia transtoracica, in una sezione 4 camere modificata, è stato riscontrato il cosiddetto “RAC sign”. Di solito, la diagnosi di questa anomalia congenita della circolazione coronarica viene sospettata durante l’ecocardiogramma. Nel nostro caso, la diagnosi è stata sospettata durante la coronarografia e, successivamente, confermata dall’ecocardiografia e dall’angio-tomografia computerizzata coronarica.

Cancer patients have an increased risk of venous thromboembolism, which is their second cause of death after disease progression itself. Several thrombotic risk factors coexist in cancer patients, including the ability of both cancer and tumoral microenvironment's cells to directly or indirectly activate platelets and the enzymes of the coagulation cascade, resulting in a hypercoagulable state of blood. This narrative review gives an overview of the main mechanisms leading to venous thromboembolism in cancer patients, including the role that platelets and the clotting proteins may have in tumor growth and metastasis. Of note, the hemostatic balance is altered in cancer patients who may, next to a thrombosis tendency, also have an increased risk of bleeding. To highlight the complexity and the precariousness of the hemostatic balance of these patients, we discuss 2 specific gastrointestinal malignancies: hepatocellular carcinoma, which is frequently associated with liver cirrhosis, a condition that causes profound alterations of hemostasis, and colorectal cancer, which is characterized by a fragile mucosa that is prone to bleeding. Understanding the molecular mechanisms of cancer-associated thrombosis may give a unique opportunity to develop new innovative drugs, acting differently on distinct pathways and potentially allowing to reduce the risk of bleeding related to antithrombotic therapies. SIGNIFICANCE STATEMENT: The topic is significant because understanding the molecular mechanisms leading to cancer-associated thrombosis and bleeding, focusing on gastrointestinal malignancies, enables the development of more rationale and innovative antithrombotic strategies for cancer-associated thrombosis. Eventually, this will support an improved and patient-tailored antithrombotic management in vulnerable oncologic patients.