Risk of subclinical atherosclerosis in primary Sjogren's syndrome: A systematic review and meta-analysis.

BACKGROUND: Currently, the guidelines for prevention and management of atherosclerosis in patients with Sjogren's syndrome (SS) do not differentiate from those concerning the general population. OBJECTIVES: The present systematic review aimed to summarize evidence from primary studies assessing the risk of subclinical atherosclerosis in patients with primary SS (pSS). METHODS AND RESULTS: Literature was searched until June 2023. Eligible records were randomized controlled trials and observational studies comparing subclinical atherosclerosis markers between pSS patients and healthy controls. DerSimonian-Laird random effects models were used to calculate overall effect estimates. Totally, 19 observational studies comprising 1625 participants were included. Compared to healthy controls, pSS patients had significantly higher values of carotid-femoral intima-media thickness (cfIMT) (MD= 0.07 mm; 95 % CI= [0.04, 0.11]; p <0.001) and were more frequently diagnosed with atherosclerotic plaques (OR= 1.9; 95 % CI= [1.32, 2.74]; p <0.001). Moreover, pSS patients showed a decreased flow and nitrate-mediated dilation (MD = -2.48 %; 95 % CI= [-4.57, -0.39]; p = 0.02, MD= -2.11 %; 95 % CI= [-3.22, -1.01]; p <0.001, respectively). Similar results were observed for the pulse-wave velocity (MD= 0.7 m/s; 95 % CI= [0.36, 1.05]; p <0.001) and the ankle-brachial index (OR= 5.78; 95 % CI= [2.23, 14.99]; p = 0.003). Based on meta-regression analyses, only the disease duration and erythrocyte sedimentation rate were positively and significantly associated with higher cfIMT values. CONCLUSION: Patients with pSS have an increased risk of subclinical atherosclerosis compared to healthy population and thus possibly require early and disease-specific intervention. Further research is warranted for more accurate cardiovascular risk management in SS.

Accelerated Atherosclerosis and Management of Cardiovascular Risk in Autoimmune Rheumatic Diseases: An Updated Review.

Even though diagnosis and management pathways have been substantially improved over the last years, autoimmune rheumatic diseases (AIRDs) such as rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren's syndrome, and systemic vasculitides have been linked to elevated rates of cardiovascular morbidity and mortality, primarily secondary to accelerated atherosclerosis. This phenomenon can be partially attributed to the presence of established cardiovascular risk factors but may also be a result of other inflammatory and autoimmune mechanisms that are enhanced in AIRDs. According to the current guidelines, the recommendations regarding cardiovascular disease prevention in patients with AIRDs are not significantly different from those applied to the general population. Herein, we present a review of the current literature on the risk of accelerated atherosclerosis in AIRDs and provide a summary of available recommendations for the management of cardiovascular risk in rheumatic diseases.

Perioperative Coagulation Profile in Major Liver Resection for Cancer: A Prospective Observational Study.

Hepatectomy-induced coagulation disturbances have been well studied over the past decade. Cumulative evidence supports the superiority of global coagulation analysis compared with conventional coagulation tests (i.e., prothrombin time or activated partial thromboplastin time) for clinical decision making. Cancer, however, represents an acquired prothrombotic state and liver resection for cancer deserves a more thorough investigation. This prospective observational study was conducted to assess the perioperative coagulation status of patients undergoing major hepatectomies for primary or metastatic hepatic malignancy. Patients were followed up to the 10th post-operative day by serial measurements of conventional coagulation tests, plasma levels of coagulation factors, and thrombin generation assay parameters. An abnormal coagulation profile was detected at presentation and included elevated FVIII levels, decreased levels of antithrombin, and lag time prolongation in thrombin generation. Serial hematological data demonstrated increased Von Willebrand factor, FVIII, D-dimer, fibrinogen and decreased levels of natural anticoagulant proteins in the early post-operative period predisposing to a hyper-coagulable state. The ratio of the anticoagulant protein C to the procoagulant FVIII was low at baseline and further declined post-operatively, indicating a prothrombotic state. Though no bleeding complications were reported, one patient experienced pulmonary embolism while under thromboprophylaxis. Overall, patients with hepatic carcinoma presenting for elective major hepatectomy may have baseline malignancy-associated coagulation disturbances, aggravating the hyper-coagulable state documented in the early post-operative period.

Position Paper on the Management of Pregnancy-Associated Superficial Venous Thrombosis. Balkan Working Group for Prevention and Treatment of Venous Thromboembolism.

Venous thromboembolism (VTE) is a multifactorial disease that can possibly affect any part of venous circulation. The risk of VTE increases by about 2 fold in pregnant women and VTE is one of the major causes of maternal morbidity and mortality. For decades superficial vein thrombosis (SVT) has been considered as benign, self-limiting condition, primarily local event consequently being out of scope of well conducted epidemiological and clinical studies. Recently, the approach on SVT has significantly changed considering that prevalence of lower limb SVT is twice higher than both deep vein thrombosis (DVT) and pulmonary embolism (PE). The clinical severity of SVT largely depends on the localization of thrombosis, when it concerns the major superficial vein vessels of the lower limb and particularly the great saphenous vein. If untreated or inadequately treated, SVT can potentially cause DVT or PE. The purpose of this review is to discuss the complex interconnection between SVT and risk factors in pregnancy and to provide evidence-based considerations, suggestions, and recommendations for the diagnosis and treatment of this precarious and delicate clinical entity.

Pravastatin plus L-arginine prevents adverse pregnancy outcomes in women with uteroplacental vascular dysfunction.

BACKGROUND: Uteroplacental vascular dysfunction, characterized by diminished uterine artery (UtA) blood flow in the second trimester is a clinically useful predictor of the further development of preeclampsia, fetal growth restriction and stillbirth. Efforts to develop effective treatments to protect pregnancies with abnormal UtA Dopplers would be of significant clinical benefit for mothers and their fetuses. OBJECTIVE: The aim of this pilot non randomized control study was to use pravastatin +L-arginine to improve uteroplacental haemodynamics and prevent adverse maternal and neonatal outcomes in women with abnormal Dopplers and high risk for developing adverse pregnancy outcomes. STUDY DESIGN: This study was performed between 2015 and 2018. All women received primary care at OB/GYN Polyclinic Jurisic and Narodni Front University Hospital, University of Belgrade Medical School, Serbia. Approval for investigational drug use was obtained and all women gave informed consent. 10 pregnant women with a poor obstetric history that developed uteroplacental dysfunction (UtA pulsatility index (PI) above the 95th percentile and notching) at 20.5 weeks IQR [17.7-22] gave consent to be treated daily with pravastatin (40 mg) and L-arginine (1.5 g) to improve placental blood flow and pregnancy outcomes. 5 women remained untreated after diagnosis at 21 weeks [20-22] (control group). Due to presence of risk factors for pregnancy complications, close maternal and fetal monitoring was undertaken in all patients. Doppler examinations were performed to monitor changes in placental vascular resistance and fetal well-being and growth. RESULTS: PRAV+L-arginine improved uteroplacental haemodynamics, increased fetal growth and prevented early onset preeclampsia leading to delivery close to term (delivery date: median 38 weeks, IQR[36.5-39]) and appropriate weight for gestational age compared to controls, in which placental blood flow did not improve and 2 women developed severe early onset preeclampsia. Neonates from the control group were born preterm (25 weeks IQR[23.5-25]), growth restricted and spent several months at NICU. Two neonates died due to prematurity-associated complications. PRAV+L-arginine treatment prolonged pregnancies for 4.1 months, compared to 26 days in the untreated group, preventing neonatal complications associated with prematurity. The infants are now 1-3 years old and show normal growth and development. CONCLUSION: This study describes the successful management with pravastatin+L-arginine of 10 pregnant patients with uteroplacental vascular dysfunction and high risk of adverse maternal and fetal outcomes. A larger study is being organized to confirm these observations.

Prospective Assessment of Biomarkers of Hypercoagulability for the Identification of Patients With Severe Coronary Artery Disease. The ROADMAP-CAD Study.

In patients with stable coronary artery disease (CAD) blood hypercoagulability figures among factors leading to thrombosis. Tissue factor (TF) exposure at ruptured plaque initiates blood coagulation and hypercoagulability is responsible for thrombus formation. Early identification of patients eligible for angiography is a challenging issue for effective prevention of ACS. This pilot study aimed to identify biomarkers of hypercoagulability that can be prospectively used in risk assessment tools for the evaluation of CAD severity. Biomarkers of hypercoagulability could be a used for the evaluation of CAD severity. Platelet-poor plasma from 66 patients who were referred to coronary angiography was assessed for thrombin generation, phospholipid-dependent clotting time (Procoag-PPL ® ) and D-Dimers, and evaluated against atherosclerotic burden. Patients with CAD, as compared to controls, showed attenuated thrombin generation lag time: 4.7 (3.8-5.4) min versus 2.5 (2.1-2.9) min; p < 0.0001, shorter Procoag-PPL® clotting time 55.0(32-66) s versus 62.8 (42-85) s; p = 0.001), and higher D-Dimer levels 0.509 (0.27-2.58) µg/ml versus 0.309 (0.23-0.39) µg/ml; p = 0.038. Multivariate logistic regression model showed excellent discriminatory value in predicting CAD severity. The ROADMAP-CAD study showed that the Procoag-PPL® clotting time and thrombin Peak are informative for the the burden of the coronary atherosclerotic disease. The clinical relevance of this observation in the development of a new clinic-biological risk assessment model for early diagnosis of severe CAD has to be examined in a prospective study.

Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine.

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism.

OBJECTIVES: A previous pilot study showed that pravastatin supplementation improved pregnancy outcomes in women with obstetric antiphospholipid syndrome (OAPS) that developed placental insufficiency despite standard of care treatment low molecular weight heparin plus low dose aspirin (LMWH + LDA). In this study we investigated the mechanism behind the beneficial effects of the triple therapy LMWH + LDA + pravastatin in improving uteroplacental vascular function and reducing pregnancy complications in OAPS. We hypothesized that nitric oxide (NO) is involved in the vasculoprotective effects of the triple therapy. A mouse model of OAPS that resembles the clinical scenario was used to test this hypothesis. METHODS: Eleven women with OAPS that developed preeclampsia (PE) and/or intrauterine growth restriction (IUGR) associated with uteroplacental vascular dysfunction despite treatment with LMWH + LDA participated in this study after given informed written consent. Seven women were supplemented with pravastatin at the time abnormal uterine artery Dopplers were detected and 4 remained on LMWH + LDA treatment only. Wire myography was used to identify the mechanisms underpinning the protective effects of the triple therapy in the mouse model of OAPS. RESULTS: The triple therapy increased serum NO levels, diminished uteroplacental vessels resistance improving placental function and prolonged pregnancies compared to conventional treatment LMWH + LDA, leading to live births in women with OAPS. Comparable to the observations in women, the triple therapy protected pregnancies in OAPS-mice, increasing placental perfusion and pregnancy outcomes. A synergistic vasculoprotective effect of the triple therapy on uterine arteries and aorta was demonstrated in OAPS-mice. LMWH + LDA showed a partial protection on endothelial function. Addition of pravastatin increase eNOS synthesis, expression and activity/signaling leading to a significant increment in nitric oxide (NO) generation, resulting in improved placental vascular function and total protection of pregnancies. CONCLUSION: LMWH + LDA + PRAV increased serum NO levels and significantly improved placental haemodynamics and maternal and neonatal outcomes in women and mice with OAPS. A role for eNOS/NO in mediating the placental vasculoprotective effects in OAPS-mice was demonstrated, strengthening the concept that impaired NO production is a crucial mediator in the pathogenesis of OAPS and a potential target for pharmacological interventions. The efficacy of pravastatin supplementation should be confirmed in a larger clinical trial.

Overview of risk assessment models for venous thromboembolism in ambulatory patients with cancer.

A B S T R A C T Important progress has been made in the development of risk assessment models (RAM) for the identification of outpatients on anticancer treatment at risk of venous thromboembolism (VTE). Since the breakthrough publication of the original Khorana risk score (KRS) more than 10 years ago, a new generation of KRS-based scores have been developed, including the Vienna Cancer and Thrombosis Study, PROTECHT, CONKO, ONCOTEV, TicOnco and the CATS/MICA score. Among these the CATS/MICA score showed that a simplified score composed of only two calibrated predictors, the type of cancer and the D-dimer levels, offers a user-friendly tool for the evaluation of cancer-associated thrombosis (CAT) risk. The COMPASS-CAT score is the first that introduced a more synthetic approach of risk evaluation by combining cancer-related predictors with patient comorbidity in a score which is designed for the types of cancer frequently seen in the community (i.e. breast, lung colon or ovarian cancers) and has been externally validated in independent studies. The Throly score is registered as part of the same group as it has a similar structure to the COMPASS-CAT score and is applicable in patients with lymphoma. The incorporation of specific biomarkers of hypercoagulability to the RAM for CAT offers the possibility to perform a precision medicine approach in the prevention of CAT. The improvement of RAM for CAT with artificial intelligence methodologies and deep learning techniques is the challenge in the near future.

Immunomodulatory Effects of Vitamin D in Pregnancy and Beyond.

In addition to its role in calcium homeostasis and bone formation, a modulatory role of the active form of vitamin D on cells of the immune system, particularly T lymphocytes, has been described. The effects of vitamin D on the production and action of several cytokines has been intensively investigated in recent years. In this connection, deficiency of vitamin D has been associated with several autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Hashimoto Thyroiditis (HT), and multiple sclerosis (MS). In a successful pregnancy, the maternal immune response needs to adapt to accommodate the semiallogeneic fetus. Disturbances in maternal tolerance are implicated in infertility and pregnancy complications such as miscarriages (RM) and preeclampsia (PE). It is well-known that a subset of T lymphocytes, regulatory T cells (Tregs) exhibit potent suppressive activity, and have a crucial role in curtailing the destructive response of the immune system during pregnancy, and preventing autoimmune diseases. Interestingly, vitamin D deficiency is common in pregnant women, despite the widespread use of prenatal vitamins, and adverse pregnancy outcomes such as RM, PE, intrauterine growth restriction have been linked to hypovitaminosis D during pregnancy. Research has shown that autoimmune diseases have a significant prevalence within the female population, and women with autoimmune disorders are at higher risk for adverse pregnancy outcomes. Provocatively, dysregulation of T cells plays a crucial role in the pathogenesis of autoimmunity, and adverse pregnancy outcomes where these pathologies are also associated with vitamin D deficiency. This article reviews the immunomodulatory role of vitamin D in autoimmune diseases and pregnancy. In particular, we will describe the role of vitamin D from conception until delivery, including the health of the offspring. This review highlights an observational study where hypovitaminosis D was correlated with decreased fertility, increased disease activity, placental insufficiency, and preeclampsia in women with APS.

Pravastatin and-L-arginine combination improves umbilical artery blood flow and neonatal outcomes in dichorionic twin pregnancies through an nitric oxide-dependent vasorelaxant effect.

The increase in fetal and neonatal morbidity and mortality associated with twin pregnancies correlates with an increased risk of preterm delivery, low birth weight, and intrauterine growth restriction (IUGR). Although the pathogenesis of IUGR is unclear and thus management remains a major challenge, feto-placental blood vessels are compromised, and altered umbilical blood flow is observed. In this pilot observational study we investigated the effects of pravastatin plus l-arginine on umbilical artery (umb art) blood flow. Between 2013 and 2016, five women received daily doses l-arginine and pravastatin when an umb art pulsatility index above limits for gestational age was observed and concerns about selective growth restrictions arose. All patients showed selective absent or reversed end-diastolic umbilical artery Doppler flow (AREDV) associated with increased perinatal mortality. Pravastatin (PRAV) plus l-arginine (l-Arg) treatment diminished umb art resistance significantly and allowed pregnancy to continue. No signs of acidosis or hypoxia, normal cardiotocography tracing, normal fetal movement and fetal weight gain were observed in the twins that showed abnormal umb art Dopplers. All neonates were born around 33 weeks (median 33 weeks, IQR [31.4-33.0]), thus diminishing substantially the chances for any prematurity-associated adverse neonatal outcomes. The infants now show normal growth and development. In in vitro studies, pravastatin induced relaxation of aortic rings. Murine studies identified were performed to investigate the mechanism behind PRAV+L-Arg beneficial effects. A nitric oxide (NO)-dependent synergistic vasorelaxant effect of PRAV+L-Arg was demonstrated using aortic rings. Increased levels of placental NO and increased synthesis of eNOS in placental endothelial cells were observed in mice treated with PRAV+L-Arg compared to untreated mice and mice treated with PRAV- or L-Arg alone. This study suggests that PRAV plus L-Arg might be a good therapeutic option to improve blood flow in umbilical arteries prolonging pregnancy and improving pregnancy outcomes in twins. A RCT should be organized to confirm these results.

Impact of blood hypercoagulability on in vitro fertilization outcomes: a prospective longitudinal observational study.

BACKGROUND: Blood coagulation plays a crucial role in the blastocyst implantation process and its alteration may be related to in vitro fertilization (IVF) failure. We conducted a prospective observational longitudinal study in women eligible for IVF to explore the association between alterations of coagulation with the IVF outcome and to identify the biomarkers of hypercoagulability which are related with this outcome. METHODS: Thirty-eight women eligible for IVF (IVF-group) and 30 healthy, age-matched women (control group) were included. In the IVF-group, blood was collected at baseline, 5-8 days after administration of gonadotropin-releasing hormone agonist (GnRH), before and two weeks after administration of human follicular stimulating hormone (FSH). Pregnancy was monitored by measurement of ßHCG performed 15 days after embryo transfer. Thrombin generation (TG), minimal tissue factor-triggered whole blood thromboelastometry (ROTEM®), procoagulant phospholipid clotting time (Procoag-PPL®), thrombomodulin (TMa), tissue factor activity (TFa), factor VIII (FVIII), factor von Willebrand (FvW), D-Dimers and fibrinogen were assessed at each time point. RESULTS: Positive IVF occurred in 15 women (40%). At baseline, the IVF-group showed significantly increased TG, TFa and TMa and significantly shorter Procoag-PPL versus the control group. After initiation of hormone treatment TG was significantly higher in the IVF-positive as compared to the IVF-negative group. At all studied points, the Procoag-PPL was significantly shorter and the levels of TFa were significantly higher in the IVF-negative group compared to the IVF-positive one. The D-Dimers were higher in the IVF negative as compared to IVF positive group. Multivariate analysis retained the Procoag-PPL and TG as predictors for the IVF outcome. CONCLUSIONS: Diagnosis of women with hypercoagulability and their stratification to risk of IVF failure using a model based on the Procoag-PPL and TG is a feasible strategy for the optimization of IVF efficiency that needs to be validated in prospective trials.

Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy.

BACKGROUND: Administration of conventional antithrombotic treatment (low-dose aspirin plus low-molecular weight heparin [LDA+LMWH]) for obstetric antiphospholipid syndrome (APS) does not prevent life-threatening placenta insufficiency-associated complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR) in 20% of patients. Statins have been linked to improved pregnancy outcomes in mouse models of PE and APS, possibly due to their protective effects on endothelium. Here, we investigated the use of pravastatin in LDA+LMWH-refractory APS in patients at an increased risk of adverse pregnancy outcomes. METHODS: We studied 21 pregnant women with APS who developed PE and/or IUGR during treatment with LDA+LMWH. A control group of 10 patients received only LDA+LMWH. Eleven patients received pravastatin (20 mg/d) in addition to LDA+LMWH at the onset of PE and/or IUGR. Uteroplacental blood hemodynamics, progression of PE features (hypertension and proteinuria), and fetal/neonatal outcomes were evaluated. RESULTS: In the control group, all deliveries occurred preterm and only 6 of 11 neonates survived. Of the 6 surviving neonates, 3 showed abnormal development. Patients who received both pravastatin and LDA+LMWH exhibited increased placental blood flow and improvements in PE features. These beneficial effects were observed as early as 10 days after pravastatin treatment onset. Pravastatin treatment combined with LDA+LMWH was also associated with live births that occurred close to full term in all patients. CONCLUSION: The present study suggests that pravastatin may improve pregnancy outcomes in women with refractory obstetric APS when taken at the onset of PE or IUGR until the end of pregnancy.

Rapid detection of D-Dimers with mLabs® whole blood method for venous thromboembolism exclusion. Comparison with Vidas® D-Dimers assay.

BACKGROUND: Easy to use point of care assays for D-Dimers measurement in whole blood from patients with clinical suspicion of venous thromboembolism (VTE) will facilitate the diagnostic strategy in the Emergency Department (ED) setting. We prospectively evaluated the diagnostic performance of the point-of-care mLabs® Whole Blood D-Dimers test and we compared it with the Vidas® D-Dimers assay. METHODS: As part of the diagnostic algorithm applied in patients with clinical suspicion of VTE, the VIDAS® D-Dimers Test was prescribed by the emergency physician in charge. The mLabs® Whole Blood D-Dimers Test was used on the same samples. All patients had undergone exploration with the recommended imaging techniques for VTE diagnosis. RESULTS: Both assays were performed, on 99 emergency patients (mean age was 65 years) with clinical suspicion of VTE. In 3% of patients, VTE was documented with a reference imaging technique. The Bland and Altman test showed significant agreement between the two methods. Both assays showed equal sensitivity and negative predictive value for VTE. CONCLUSIONS: The mLabs whole blood assay is a promising point of care method for measurement of D-Dimers and exclusion of VTE diagnosis in the emergency setting which should be validated in a larger prospective study.

Impact of breast cancer stage, time from diagnosis and chemotherapy on plasma and cellular biomarkers of hypercoagulability.

BACKGROUND: In breast cancer patients routine thromboprophylaxis is not recommended but individualized risk assessment is encouraged. The incorporation of hypercoagulability biomarkers could increase the sensitivity of risk assessment models (RAM) to identify patients at VTE risk. To this aim we investigated the impact of cancer-related characteristics on hypercoagulability biomarkers. METHODS: Thrombin generation (TG) assessed with the Thrombogramme-Thrombinoscope®, levels of platelet derived microparticles (Pd-MP) assessed with flow cytometry, procoagulant phospholid dependent clotting time (PPL-ct) measured with a clotting assay and D-Dimers (were assessed in a cohort of 62 women with breast cancer and in 30 age matched healthy women. RESULTS: Patients showed significantly higher TG, Pd-MP, D-Dimers levels and shortened PPL-ct compared to the controls. The PPL-ct was inversely correlated with the levels of Pd-MP, which were increased in 97% of patients. TG and D-Dimers were increased in 76% and 59% of patients respectively. In any stage of the disease TG was significantly increased as compared to the controls. There was no significant difference of TG in patients with local, regional of metastatic stage. There was no significant difference in Pd-MP or Pd-MP/PS+ between the subgroups of patients with local or regional stage of cancer. Patients with metastatic disease had significantly higher levels of Pd-MP and Pd-MP/PS+ compared to those with regional stage. The D-Dimers increased in patients with metastatic stage. In patients on chemotherapy with less than 6 months since diagnosis TG was significantly higher compared to those on chemotherapy who diagnosed in interval > 6 months. Patients with metastatic disease had significantly higher levels of Pd-MP and D-Dimers compared to those with non-metastatic disease. CONCLUSION: In breast cancer patients the stage, the time elapsed since the diagnosis and the administration of chemotherapy are determinants of cellular and plasma hypercoagulability. The levels and the procoagulant activity of Pd-MP are interconnected with the biological activity and the overall burden of cancer. TG reflects the procoagulant properties of both breast cancer and chemotherapy in the initial period of cancer diagnosis. Thus the weighted incorporation of the biomarkers of cellular and plasma hypercoagulabilty in RAM for VTE might improve their predictive value.