Biomarkers Of Hypercoagulability Research Articles

Edoxaban for the treatment of hypercoagulability and cerebral thromboembolism associated with cancer: A randomized clinical trial of biomarker targets.

This study aimed compare efficacy of edoxaban and enoxaparin upon biomarkers of hypercoagulability in patients with cancer-related embolic stroke of undetermined source (ESUS). In this open-label, randomized, pilot trial, patients with cancer-related ESUS within 30 days of diagnosis were randomly assigned (1:1) to receive edoxaban (60 mg once daily) or enoxaparin (1 mg/kg twice daily) for 90 days. The primary endpoint was interval change of serum D-dimer level between days 0 and 7. The secondary endpoints were microembolic signals detected by transcranial Doppler at 7 and 90 days, the modified Rankin scale score, and stroke recurrence during 90 days. Safety outcomes included major bleeding and all-cause death at 90 days. Of 303 patients with ischemic stroke and cancer, 40 fully met enrollment criteria and were randomized. Baseline D-dimer levels were numerically higher in the edoxaban group (22.9 ± 15.9 μg/mL vs 16.9 ± 16.9 μg/mL). D-dimer level change (%) between days 0 and 7 was similar in the two groups (53.2 ± 25.7 vs 52.2 ± 52.0; P = 0.11). Microembolic signals were detected in 41.1% and 43.8% at baseline, 41.2% and 42.9% at day 7, and 25.0% and 28.6% at day 90 in the edoxaban and enoxaparin groups, respectively. Non-significantly higher major bleeding (35.0% vs 10.0%, P = 0.06) and 90-day mortality (40.0% vs 25.0%, P = 0.31) were noted in the edoxaban group. Edoxaban and enoxaparin were comparable with respect to the biomarkers of hypercoagulability and cerebral thromboembolism. Larger trials are warranted to compare effects of edoxaban and enoxaparin upon recurrent stroke and major bleeding in patients with cancer-related ESUS. clinicaltrials.gov Identifier: NCT03570281 (https://clinicaltrials.gov/ct2/show/NCT03570281).

Leukemia Inhibitory Factor, Tissue Factor, Thrombomodulin, P-Selectine, D-Dimer, Thrombin Generation and Procoagulant Phospholipid Dependent Clotting Time Are Predictive for in Vitro Fertilization Outcome. the Prospective Roadmap-IVF Study

Background The link between blood hypercoagulability, endothelial cell activation and infertility or in vitro fertilization (IVF) failure is a puzzling issue. Activation of platelets, endothelial cells and blood coagulation, proinflammatory and angiogenetic potential play important role in implantation and early embryonic development. Biomarkers of cellular hypercoagulability are associated with high risk of IVF failure. Soluble Leukemia Inhibitory Factor (LIF), an interleukin 6 class cytokine expressed in the trophectoderm of the developing embryo is an important regulator in the establishment of pregnancy. Endoglin (Eng), a co-receptor for TGF-β1 and TGF-β3 is implicated in vascular complications of pregnancy and particularly in preeclampsia. Aim: The prospective longitudinal monocentric observational cohort study ROADMAP-IVF, evaluated the synergistic prognostic value of LIF and Eng with the biomarkers of cellular hypercoagulability in predicting the endometrial receptivity of fresh IVF cycles. Materials and Methods. The ROADMAP-IVF enrolled 40 women eligible for IVF with normal blood count, PT, aPTT, Fg, renal and liver function. The control group (CG) consisted of 30 healthy women with history of uncomplicated pregnancies. Exclusion criteria: Use of anticoagulant or antiplatelet agents during the last 30 days before inclusion. Known cardiovascular disease, active cancer. Active corticosteroid treatment. Primary end-point: Echographically documented pregnancy at 7 weeks from implantation. Blood was collected on day 2 (D2) from the natural cycle and 6 days after hormone treatment initiation corresponding to D8 of the cycle. Procoagulant phospholipid-dependent clotting time (PPL-ct), tissue factor (TF), thrombomodulin (TM), von Willebrand factor (vWF) and D-Dimers (DDi) were measured with assays from Diagnostica Stago (Asnieres, France). P- and E-Selectin, LIF and Eng were measured with ELISA. Thrombin generation (TG) with the TF 5 pM PPP-Reagent ® was assessed on Calibrated Automated Thrombogram (Stago, France). The cut-off values for studied biomarkers have been selected on the basis of ROC analysis. Univariate and multivariate logistic regression analysis examined the associations between the biomarkers and the study outcome. Results: 40 women were enrolled in the study. In 11 women pregnancy was confirmed with ultrasound and in 23 women no pregnancy was echographically documented. Age was not significantly different between the IVF (41 ys; range 22 - 48 ys) and the control group (40 ys; range 20 - 46 ys). At D2 and D8 the DDi and LIF were significantly higher in IVFG as compared to the CG. At D2 most of the patients had PPL-ct, DDi and MRI of TG higher than the upper normal limit (UNL). At D8 only TF was significantly increased as compared to the CG. Analytical data are presented in Table 1. Age did not correlate with the levels of the studied biomarkers. Significant correlations (p<0.05) were found between DDi and ETP (r=0.35); TM, TF and P-Selectin (r=0.4) at D2; TF, LIF and Eng (r=0.5) at D2 and D8; P-Selectin and PPL-ct (r=-0.4) at D2; P-Selectin and TM (r=0.4), E-Selectin (r=0.5), LIF (0.4) at D2; E-Selectin and P-Selectin (r=0.5), TF (r=0.3), and LIF (r=0.4) at D2. The ROC analysis showed that IVF failure was associate with DDi increase at D2 (AUC = 0.64); P-Selectin increase at D2(AUC = 0.57) and D8 (AUC = 0.61); TM increase at D8 (AUC = 0.61); TF increase at D8 (AUC = 0.57); LIF increase at D8 (AUC = 0.59); ETP increase at D2 (AUC = 0.67) and D8 (AUC = 0.67); Peak increase at D2 (AUC = 0.64) and D8 (AUC = 0.61). Prolongation of PPL-ct on D8 was predictive for positive pregnancy outcome(AUC 0.64). Conclusion The ROADMAP-IVF study showed that at least one out of four women eligible for IVF present biological evidence of activation of platelets, endothelial cells, blood coagulation or LIF upregulation. Hormone treatment administration does not significantly alter the proinflammatory or the hypercoagulable state. Among the studied biomarkers the levels of LIF, DDi, P-Selectine, TM and TF as well as the status of thrombin generation and PPL-ct showed a significant predictive value for the IVF outcome, particularly when measured at 6 days after hormone treatment administration. These findings will lead to the elaboration of an risk assessment model for IVF failure combining the selected biomarkers of hypercoagulability with LIF.

The Procoagulant Phospholipid Dependent Clotting Time and the Initiation Phase of Thrombin Generation Test Are Mandatory for the Evaluation of the Risk for Severe Early Onset Preeclampsia

Bakground: Preeclampsia occurs in up to 7% of pregnancies in Western Countries and is a leading cause of maternal and fetal morbidity and mortality. Classification of preeclampsia is based on the timing of symptoms' onset and the severity of the clinical status. Accordingly, early and late preeclampsia are characterized by symptom onset before or after 32-34 weeks of gestation respectively. Pathogenesis of preeclampsia is characterized by abnormal placental vascular development with impaired invasion of the uterine spiral arteries by trophoblasts, resulting in fetal complications and maternal endothelial dysfunction. Intact antithrombotic properties of the endothelial cells and efficient regulation of thrombin generation and platelet activation at the microenvironment of the uterus are necessary conditions for successful trophoblast invasion and development of feto-maternal circulation during normal pregnancy. , Prompt identification of pregnant women at risk of preeclampsia worsening could help to anticipated therapeutic intervention and improvement of the clinical outcome. Aim: The ROADMAP-Early Onset Preeclampsia study (ROADMAP-EOP) aiming to respond to this unmet need assessed the clinical relevance of biomarkers of hypercoagulability and endothelial activation for prompt identification of pregnant women at high risk of preeclampsia. Materials and Methods: An observational single center retrospective case-control study was conducted in pregnant women diagnosed with preeclampsia from July 2020 to July 2021. Pregnant women were retrospectively enrolled upon EOP diagnosis and stratified in mild EOP group (n=34) and severe EOP group (n=15 according to the criteria of the International Society for the Study of Hypertension in Pregnancy ). Eligible women were included in the study before initiation of any treatment for preeclampsia. The control group (n=35) consisted of women with uncomplicated pregnancy. All women were assessed with thromboelastometry, Calibrated Automated Thrombo-gram®, tissue factor activity (TFa), Procoagulant phospholipid dependent clotting time (Procoag-PPL), Proteins S, TFPI, D-dimer, antithrombin, thrombomodulin, fibrinogen prothrombin time and activated partial thromboplastin time. Primary and secondary end points were severe EOP and EOP respectively. Principal component analysis (PCA) was performed to check for associations among the biomarkers and the clinical out-come. Results: There were no significant differences regarding age, gravidity, gestational age and the body mass index (BMI) between EOP groups and normal pregnancy as well as within the EOP groups. Platelet counts were similar in healthy pregnant women, and mild EOP group, and significantly lower in severe EOP (p<0.05). No other statistically significant differences were found between-groups. The PCA showed that the repartition of data allowed to discriminate the patients with EOP from healthy pregnant women as well as patients with mild EPO from those with severe EOP. When biomarkers of hypercoagulability were considered according to the severity of EOP in PCA analysis the lag-time and PPL clotting time were independently associated with the risk of severe EOP (Table 1and Figure 1)). The increase of the lag-time by 1 min was associated with a 20.2-fold increase of the risk of severe EOP. The marginal effects curve shows that for a lag-time longer than 2.6 min, the probability of severe EOP was higher than 50% .Longer Procoag-PPL clotting time was associated with lower risk of severe EOP. The marginal effects curve, showed that for Procoag-PPL clotting time longer than 58.75 sec the probability of severe EOP decreased by 50%. These data suggest that a biological score composed of the Procoag-PPL® clotting time and thrombin generation (Throbmogram-Thrombinoscope® PPP-reagent 1 pM-TF as-say) could be a useful tool to identify pregnant women with high probability of EOP Conclusion: the Procoag-PPL® clotting time and thrombin generation assay reflect cellular derived hypercoagulability and allow accurate screening of pregnant women for the prompt identification of those at risk of EOP and the evaluation of its severity. This concept has to be validated in a large prospective cohort trial. . An external validation of the proposed methodology needs to be performed in a large prospective observational study.

Relationship Among Clinically Obtained Biomarkers of Inflammation, Hypercoagulability, and Macrophage Activation, and Delirium in Critically Ill Patients With COVID-19.

Retrospective, observational cohort study. ICUs at two large, urban, academic referral hospitals. All consecutive adult patients admitted to the ICU from March 1, 2020, to June 7, 2020, with COVID-19 with clinical biomarkers and delirium assessments performed. None. Daily concentrations of CRP, d-dimer, and ferritin were obtained. Coma (assessed by Richmond Agitation-Sedation Scale) and delirium (assessed by Confusion Assessment Method for the ICU/Confusion Assessment Method for the ICU-7) were measured bid. A cohort of 197 ICU patients with COVID-19 were included. Higher d-dimer (odds ratio [OR], 1.57; 95% CI, 1.17-2.12; p < 0.01) and ferritin quartiles (OR, 1.36; 95% CI, 1.02-1.81; p < 0.01) were associated with greater odds of the composite outcome of delirium/coma next day. d-dimer was associated with greater odds of next day delirium (OR, 1.49; 95% CI, 1.14-1.94; p < 0.01) and coma independently (OR, 1.52; 95% CI, 1.08-2.14; p = 0.017). Higher ferritin quartiles were associated with greater odds of next day delirium (OR, 1.33; 95% CI, 1.04-1.70; p = 0.026) and coma independently (OR, 1.59; 95% CI, 1.14-2.23; p < 0.01). Higher CRP quartiles were associated with coma (OR, 1.36; 95% CI, 1.03-1.79; p = 0.030) and delirium severity the next day (β = 0.30; se, 0.07; p ≤ 0.01). Our hypothesis-generating study found d-dimer and ferritin were associated with delirium/coma the following day, as well as delirium and coma independently. CRP was associated with next day coma and delirium severity. Larger studies to validate these results are needed.

Persisting Endothelial Cell Activation and Hypercoagulability after Recovering from COVID-19: The Roadmap-Post COVID-19 Study

Background: In patients with severe COVID-19, activation of blood coagulation and endothelial cells orchestrated with complement activation and cytokine storm leads to disease worsening and death. Hypercoagulable state and endothelial cell activation and fibrinolytic unbalance are common alterations in patients with COVID-19 hospitalized either at the conventional medical ward or at the intensive care unit (ICU). Two systematic reviews highlight that D-dimer values are higher in non survivors as well as in patients with severe COVID-19 than in those with mild disease, showing the association between D-dimer levels and disease severity or death. Nevertheless, there are limited data in small series of patient, on the persistence of hypercoagulability and endothelial cell activation following recovery from COVID-19. Aims: To investigate the persistence of endothelial cell activation and hypercoagulability after recovery from COVID-19. Patients/Methods. COVID-19 survivors (n = 208) and 30 healthy individuals were enrolled in this study. Methods: In ,total, 208 COVID-19 survivors were included in the study; 125 males (60%) and 83 females (40%) with a median age of 50 years (IQR = 20, range 18 to 78 years). Biomarkers of hypercoagulability and endothelial cell activation: The procoagulant phospholipid-dependent clotting time (PPL-ct) was measured using a factor Xa-based clotting assay STA®-Procoag-PPL. Free-TFPI levels were measured with the ELISA Free TFPI, Asserachrom®; D-dimer and fibrin monomers (FM) were measured by STA Liatest D-Di and STA Liatest FM; soluble thrombomodulin (sTM) was measured by Asserachrom® TM. All assays were from Diagnostica Stago, Asnières, France. Heparanase-levels were measured with ELISA kits R&D. Systems (Lille France). Detection of anti-SARS-CoV2 antibodies: IgG and IgA anti-SARS-CoV-2 antibodies were detected in the sera of the survivors using a semi-quantitative commercial ELISA methodology (Euroimmun Medizinische Labordiagnostika AG, Lubeck, Germany) Results: The median interval between symptom onset and screening for SARS-CoV-2 antibodies was 62 days (IQR = 22 days). Antibodies against SARS-CoV-2 were detected in all survivors enrolled in the study. The median level of IgG and IgA antibodies was 5.68 U (IQR = 6.19) and 3.62 U (IQR = 5.36), respectively. In 112 survivors with known blood group, 48 (43%) were group O, 44 (39%) were group A, 14 (13%) were group B, and 6 (5.4%) were group AB. Survivors showed significantly higher levels of D-Dimers, FM, TFPI, and heparanase as compared to that of the control group. Survivors had significantly shorter PPL-ct . One out of four of COVID-19 survivors showed increase at least one biomarker of endothelial cell activation or hypercoagulability (Table1). Elevated D-dimer was associated with older age. Elevated FM was associated with female gender. Elevated heparanase was independently associated with male gender. Decreased Procoag-PPL clotting time was associated with female gender. Univariate and multivariate logistic regression analysis examining predictors of hypercoagulability in study cohort of COVID-19 survivors are reported in table 2 . The interval between COVID-19 diagnosis and assessment was not associated with the changes of the studied biomarkers. Conclusion: The ROADMAP-postCOVID-19 study offers an analysis of a large panel of biomarkers of endothelial cell activation and hypercoagulability in survivors of COVID-19. The study documents that two months after symptoms' onset, activation of endothelial cells, in vivo thrombin generation, and fibrin lysis are frequent phenomena up to two months from COVID-19 symptom onset. The data presented herein allow to propose that evaluation of blood hypercoagulability (using D-dimer for instance) and endothelial cell activation could offer the possibility of prompt identification of COVID-19 survivors at risk of post-COVID-19 vascular complications. The findings of the present study underline the need for a thorough evaluation of a potential correlation between the sustained hypercoagulability and endothelial cell activation with the symptomatology of long-COVID-19 to apply anticipated diagnostic and therapeutic strategies. The clinical relevance of the identified biomarkers of endothelial activation and hypercoagulability in the assessment of the risk of long COVID-19 must be investigated in a prospective study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sex Hormone Levels, Biomarkers of Hypercoagulability and Endothelial Cell Activation Are Determinants of Severity of COVID-19 in Women and Men. the Roadmap-COVID-19 Prospective Study

Background: Patients with COVID 19 disease have haemostatic dysfunction and are at higher risk of thrombotic complications. Although age and sex are a major risk factor for outcome. Even though the incidence of COVID 19 seems to be similar in both genders, men are at a higher risk of a worse outcome, with the odds up to 2.8 times higher than those for women. It is not known whether sex hormones contribute to this preposition. The real impact of sex hormone levels on the severity of COVID 19 remains to be demonstrated. Objectives: We aimed to investigate the impact of variations in sex hormone levels on the hypercoagulability and severity of COVID 19 in women and men according to age. Methods: 186 patients with symptomatic newly diagnosed Covid 19 were enrolled in the study. Specially we included postmenaupausal women (>50 years) and age matched men. Participants were divided into two groups: moderate Covid-19 (ARDS) and severe Covid-19. The control group consisted of 60 healthy individuals, with the same age as patients. Biomarkers of hypercoagulability and endothelial cell activation: Procoagulant phospholipid (PPL) TFPI, D-Dimer, Soluble thrombomodulin , Tissue factor activity, Thrombin generation (TG) with the Calibrated Automated Thrombogram (CAT) were all measured with assays were from Diagnostica Stago, Asnières, France. Total testosterone, estradiol, and progesterone were measured by ELISA method (Abcam, France). IL-6, Complement C3a and C5a by Human IL-6 ELISA kit, ThermoFisher (Scientific Asnieres-sur-Seine, France). The Upper Normal Limit (UNL) and the Lower Normal Limit (LNL) for each studied biomarker were defined in the control group as follows: UNL= mean + 2 standard deviation (SD), and LNL: = mean - 2 SD. Results: The levels of biomarkers of hypercoagulability, endothelial cell activation and inflammation in patients and controls are reported in Table 1. Thrombogram was marked by significantly prolonged lag time, prolonged time to peak and decreased ETP compared to the control group. The comparison between females and males showed that the lag-time was over the UNL in 18% of men over 50 years versus 8% in men under 50 years, and in 10% and 0% of women respectively. ETP values were below the LNL in 82% of men over 50 years versus 63% for men under 50 years and in 54% and 92% for women respectively. In the same way, the peak of thrombin was over the UNL in 39% and 15% for men over 50 and men under 50 versus 12% and 0% for women respectively. The TFPI were over the UNL in 99% of men over 50 years and in 84% of men under 50 years versus 91% and 87% for women respectively. D-Di increased in 88% of patients under or over 50 years independently of the group. The PPL were shorter than the LNL in 90 % and 80% of men over and under 50 years respectively, and for women in 86% and 77% respectively. The levels of TM were significantly lower in women for the 2 groups in comparison with men over or under 50 years. The levels of C3a, were above the UNL in 86%, and 63% for men over and under 50 years respectively and in 55% and 87% of women over and under 50 years respectively. The testosterone levels in males both younger and older than 50 years were significatively below the lower limit of the normal range of each age group. The estradiol levels were in normal range for women but significantly increased men (Table2). Stratification by the severity of COVID-19 showed that the testosterone levels were significantly lower in men who developed ARDS or severe COVID-19 than in those who did not (p>0.05). In men, the estradiol levels were significantly increased but the difference was not significant between those with severe or mild COVID-19. Males who developed severe COVID-19 had a lower progesterone level. No statistically significant difference in testosterone or progesterone levels were found in the women compared to normal range, the estradiol level was lower in females with ARDS (Table 3.)Relationship analysis of sex hormones with markers of immune activation, testosterone levels and estradiol/testosterone were correlated with, IL-6, fibrinogen, and D-Di. Conclusion: Our study highlights that disturbance in circulating sex hormone levels is a hallmark of critical COVID-19 in males and reinforces the concept that determination of testosterone and E2/T ratio in association with biomarkers of hypercoagulability upon diagnosis might lead to an a accurate risk assessment tool for prompt identification of patients at high risk of COVID-19 worsening. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches.

SARS-CoV-2–infected individuals may suffer a multi–organ system disorder known as “long COVID” or post-acute sequelae of SARS-CoV-2 infection (PASC). There are no standard treatments, the pathophysiology is unknown, and incidence varies by clinical phenotype. Acute COVID-19 correlates with biomarkers of systemic inflammation, hypercoagulability, and comorbidities that are less prominent in PASC. Macrovessel thrombosis, a hallmark of acute COVID-19, is less frequent in PASC. Female sex at birth is associated with reduced risk for acute COVID-19 progression, but with increased risk of PASC. Persistent microvascular endotheliopathy associated with cryptic SARS-CoV-2 tissue reservoirs has been implicated in PASC pathology. Autoantibodies, localized inflammation, and reactivation of latent pathogens may also be involved, potentially leading to microvascular thrombosis, as documented in multiple PASC tissues. Diagnostic assays illuminating possible therapeutic targets are discussed.

P1683: PERSISTENT HYPERCOAGULABILITY, ENDOTHELIOPATHY AND INFLAMMATION IN COVID-19 PATIENTS APPROXIMATING 1 YEAR AFTER RECOVERY.

Background: Sustained hypercoagulability and endotheliopathy has been demonstrated in convalescent COVID-19 patients for up to 4 months from recovery in previous studies. Aims: We performed a prospective, observational study assessing for hypercoagulability, endotheliopathy and inflammation in recovered COVID-19 patients beyond 6 months of recovery. Methods: The haemostatic (coagulation tests, global haemostatic tests), endothelial function and inflammatory profiles of recovered COVID-19 patients were evaluated at least 6 months after diagnosis of COVID-19. 39 patients were reviewed at a mean of 12.7±3.6 months following recovery from SARS-CoV-2 infection. These values were compared with a control group of healthy volunteers (n=124) who did not have COVID-19. Results: Among the 39 patients (71.8% males, median age 43 years, 11 having asymptomatic COVID-19, 19 having mild to moderate COVID-19, 2 having severe COVID-19 and 7 having critical COVID-19 requiring ICU care), 2 patients had pulmonary embolism during acute SARS-CoV-2 infection, and 1 patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. COVID-19 patients had significantly higher biomarkers of hypercoagulability, endothelial dysfunction and inflammation as compared to controls (Figure 1). Elevated D-dimer and Factor VIII levels above the normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of COVID-19 patients respectively, with a higher median D-dimer 0.34 μg/mL (IQR 0.28, 0.46) (p < 0.001) and Factor VIII 150% (IQR 171, 203) (p=0.004), compared to controls. Thrombin generation (Thromboscreen) also showed higher median endogenous thrombin potential (ETP) 1352nM*min (IQR 1152, 1490)(p=0.002), peak height 221.4nM (IQR 170.2, 280.4)(p=0.01) and a delayed lag time 2.4min (1.42-2.97)(p=0.0002) compared to controls. Raised endothelial biomarkers such as von Willebrand factor antigen (VWF:Ag) and ICAM-1 were observed in 17.9% (7/39) and 7.7% (3/39) of COVID-19 patients respectively, with a higher median VWF:Ag 117%(IQR 86, 154)(p=0.02) and ICAM-1 54.1%(IQR 43.8, 64.1)(p=0.004) than controls. Interleukin-6 (IL-6) was noted to be raised in 35.9% (14/39) of recovered COVID-19 patients, with a higher median IL-6 of 1.5pg/ml (IQR 0.6, 3.0) compared to controls. Subgroup analysis stratifying COVID-19 patients by age (≥50 years old), COVID-19 mRNA vaccination before acquiring SARS-CoV-2 infection, or pre-existing cardiovascular risk factors did not show any statistically significant differences across haemostatic, endothelial or inflammatory parameters. Patients who had experienced mild or asymptomatic COVID-19 compared with moderate to severe COVID-19 also demonstrated raised markers of hypercoagulability, endothelial dysfunction and inflammation. Image:Summary/Conclusion: Persistent hypercoagulability, endotheliopathy and inflammation is still detectable approximately 1 year from recovery in COVID-19 patients, with prior COVID-19 mRNA vaccination not appearing to reduce this risk.

Fibrinolytic Proteins and Factor XIII as Predictors of Thrombotic and Hemorrhagic Complications in Hospitalized COVID-19 Patients.

IntroductionIn a prospective cohort of hospitalized COVID-19 patients, an extensive characterization of hemostatic alterations by both global and specific assays was performed to clarify mechanisms underlying the coagulopathy and identify predictive factors for thrombotic and hemorrhagic events during hospitalization.Materials and MethodsIntensive care unit (ICU; n = 46) and non-ICU (n = 55) patients were enrolled, and the occurrence of thrombotic and hemorrhagic events was prospectively monitored. At study inclusion, thromboelastometry together with the measurement of specific coagulation proteins and hypercoagulation markers was performed.ResultsPatients (median age 67 years) showed significantly shorter clot formation time together with greater maximum clot firmness by thromboelastometry, increased levels of F1 + 2 and D-dimer, as biomarkers of hypercoagulability, and of procoagulant factors V, VIII, IX, XI, and fibrinogen, while FXIII was significantly reduced. The concentration of fibrinolytic proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were elevated in the overall cohort of patients. Many of these hemostatic alterations were significantly greater in ICU compared to non-ICU subjects and, furthermore, they were associated with inflammatory biomarker elevation [i.e., interleukin 6 (IL-6), C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), and procalcitonin]. After enrollment, 7 thrombosis and 14 major bleedings occurred. Analysis of clinical and biological data identified increased t-PA, PAI-1, and NLR values as independent predictive factors for thrombosis, while lower FXIII levels were associated with bleeding.ConclusionThis study demonstrates alterations in all different hemostatic compartments analyzed, particularly in severe COVID-19 conditions, that strongly correlated with the inflammatory status. A potential role of fibrinolytic proteins together with NLR and of FXIII as predictors of thrombotic and hemorrhagic complications, respectively, is highlighted.

A Simple Prognostic Score for Critical COVID-19 Derived from Patients without Comorbidities Performs Well in Unselected Patients.

We aimed to search for laboratory predictors of critical COVID-19 in consecutive adults admitted in an academic center between 16 September 2020–20 December 2021. Patients were uniformly treated with low-molecular-weight heparin, and dexamethasone plus remdesivir when SpO2 < 94%. Among consecutive unvaccinated patients without underlying medical conditions (n = 241, 49 year-old median, 71% males), 22 (9.1%) developed critical disease and 2 died (0.8%). White-blood-cell counts, neutrophils, neutrophil-to-lymphocyte ratio, CRP, fibrinogen, ferritin, LDH and γ-GT at admission were each univariably associated with critical disease. ROC-defined cutoffs revealed that CRP > 61.8 mg/L, fibrinogen > 616.5 mg/dL and LDH > 380.5 U/L were each associated with critical disease development, independently of age, sex and days from symptom-onset. A score combining higher-than-cutoff CRP (0/2), LDH (0/1) and fibrinogen (0/1) predicted critical disease (AUC: 0.873, 95% CI: 0.820–0.926). This score performed well in an unselected patient cohort (n = 1228, 100% unvaccinated) predominantly infected by the alpha variant (AUC: 0.718, 95% CI: 0.683–0.753), as well as in a mixed cohort (n = 527, 65% unvaccinated) predominantly infected by the delta variant (AUC: 0.708, 95% CI: 0.656–0.760). Therefore, we propose that a combination of standard biomarkers of acute inflammatory response, cell death and hypercoagulability reflects the severity of COVID-19 per se independently of comorbidities, age and sex, being of value for risk stratification in unselected patients.

The COMPASS-COVID-19-ICU Study: Identification of Factors to Predict the Risk of Intubation and Mortality in Patients with Severe COVID-19

In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation is an urgent need. Objectives. To derive a prognostic score for the risk of intubation or death in patients with COVID-19 admitted in intensive care unit (ICU), by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes. Design, Setting and Participants. A prospective, observational study enrolled 118 patients with COVID-19 admitted in the ICU. On the first day of ICU admission, all patients were assessed for biomarkers (protein C, protein S, antithrombin, D-Dimer, fibrin monomers, FVIIa, FV, FXII, FXII, FVIII, FvW antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing TF, IL-6, complement C3a, C5a, thrombin generation, PT, aPTT, hemogram, platelet count) and clinical predictors. Main Outcomes and Measures. The clinical outcomes were intubation and mortality during hospitalization in ICU. Results: The intubation and mortality rates were 70% and 18%, respectively. The COMPASS-COVID-19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively). Conclusions and Relevance. COVID-19 is related to severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID-19-ICU risk assessment model is accurate for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The COMPASS-COVID-19-ICU score is feasible in tertiary hospitals and could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention.

Treatment Resistance Risk in Patients with Newly Diagnosed Multiple Myeloma Is Associated with Blood Hypercoagulability: The ROADMAP-MM Study

Biomarkers of hypercoagulability are potential candidates for the evaluation of risk for primary treatment resistance in patients with newly diagnosed multiple myeloma (NDMM). This study aimed to identify the most clinically relevant biomarkers for the evaluation of treatment-resistance risk. NDMM patients (n = 144) were enrolled prior to treatment initiation. Response to treatment was assessed at 3 months. STA-Procoag-PPL®, factor VIIa factor V, antithrombin, fibrin monomers, soluble thrombomodulin (TM), free TFPI, D-Dimer, P-selectin, heparanase, and thrombin generation (Calibrated Automated Thrombogram® and PPP-Reagent®) were measured. In total, 23% (n = 33) of the patients showed a poor response/resistance to treatment (defined as stable disease, minor response, progressive disease). Poor response/treatment resistance was associated with longer Procoag-PPL® clotting time, higher Peak of thrombin, and higher D-Dimer levels. These biomarkers were included in a prognostic model derived via multivariate analysis. The model had 84% sensitivity and 59% specificity to identify patients at high risk of treatment resistance. The AUC of the ROC analysis for the model was 0.75. In conclusion, Procoag-PPL®, D-Dimer, and Peak of thrombin generation are clinically relevant for the identification of NDMM patients at risk for poor response to antimyeloma treatment. A prospective multicenter study is necessary for the validation of this new approach.

Endothelial Cell Activation and Thrombin Generation Assessment for the Risk of Severe Early Onset Preeclampsia. the ROADMAP-EOP Study

Background The ROADMAP-EOP study aimed to identify clinically relevant biomarkers of hypercoagulability for the identification of pregnant women at risk of early onset preeclampsia worsening. Methods The ROADMAP-EOP observational single center retrospective case–control study was conducted in Greece (Centre for Human Reproduction, Genesis Athens Clinic, Athens, Greece) from July 2020 to July and enrolled pregnant women diagnosed with EOP stratified in mild EOP group (n = 34) and severe EOP group (n = 15) as well as women with uncomplicated pregnancy (control group; n = 35). All women were assessed with thromboelastometry (ROTEM®), Calibrated Automated Thrombogram®, tissue factor activity (TFa), procoagulant phospholipid dependentclotting time (Procoag-PPL®), Proteins S (PS), TFPI, D-dimer, antithrombin (AT), thrombomodulin (TM), fibrinogen, prothrombin time (PT) and activated partial thromboplastin time (aPTT). The primary study end-point was severe earlyonset preeclampsia. Principal component analysis (PCA) was performed. Results The PCA analysis showed that a score composed of the lag-time, ttPeak and Procoag-PPL accurately predicted severe EOP (sensitivity 71.4%, specificity 61.8%, and AUC of the ROC analysis 0.953). Conclusion The pilot ROADMAP-EOP shows that activation of endothelial cells and blood hypercoagulability are driven events in the worsening of EOP. Among a large panel of biomarkers and coagulation assays, thrombingeneration test and procoagulant phospholipid dependent clotting time emerged as clinically relevant for the evaluation of the risk of severe EOP. This methodology for the development of a new clinic-biological risk assessment model for prompt identification of pregnant women at risk of severe EOP must be validated in a large multi-centerprospective study.

Using Clinical and Echocardiographic Characteristics to Characterize the Risk of Ischemic Stroke in Patients with COVID-19

BackgroundCOVID-19 has been associated with an increased incidence of ischemic stroke. The use echocardiography to characterize the risk of ischemic stroke in patients hospitalized with COVID-19 has not been explored. MethodsWe conducted a retrospective study of 368 patients hospitalized between 3/1/2020 and 5/31/2020 who had laboratory-confirmed infection with SARS-CoV-2 and underwent transthoracic echocardiography during hospitalization. Patients were categorized according to the presence of ischemic stroke on cerebrovascular imaging following echocardiography. Ischemic stroke was identified in 49 patients (13.3%). We characterized the risk of ischemic stroke using a novel composite risk score of clinical and echocardiographic variables: age <55, systolic blood pressure >140 mmHg, anticoagulation prior to admission, left atrial dilation and left ventricular thrombus. ResultsPatients with ischemic stroke had no difference in biomarkers of inflammation and hypercoagulability compared to those without ischemic stroke. Patients with ischemic stroke had significantly more left atrial dilation and left ventricular thrombus (48.3% vs 27.9%, p = 0.04; 4.2% vs 0.7%, p = 0.03). The unadjusted odds ratio of the composite novel COVID-19 Ischemic Stroke Risk Score for the likelihood of ischemic stroke was 4.1 (95% confidence interval 1.4-16.1). The AUC for the risk score was 0.70. ConclusionsThe COVID-19 Ischemic Stroke Risk Score utilizes clinical and echocardiographic parameters to robustly estimate the risk of ischemic stroke in patients hospitalized with COVID-19 and supports the use of echocardiography to characterize the risk of ischemic stroke in patients hospitalized with COVID-19.

Prospective Assessment of Biomarkers of Hypercoagulability in Oncological Patients and Healthcare Workers Following Vaccination Against Sars-Cov-2 with the mRNA Vaccine. the Roadmap-COVID-19-Vaccin Study

Background: COVID-19 has been associated with hypercoagulability, endothelial cell injury and frequent thrombotic complications resulting both from direct effects of the virus on the endothelium and from the ‘cytokine storm’ resulting from the host's immune response. Since the COVID-19 vaccines have been shown to effectively prevent symptomatic infection including hospital admissions and severe disease, the risk of COVID-19-related thrombosis should be expected to (almost) disappear in vaccinated individuals. However, some rare cases of venous thrombosis have been reported in individuals vaccinated with mRNA vaccines. Thus, there is a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and on the rare thrombotic events observed after the vaccination with these vaccines. This phenomenon raised some scepticism of even some fear about the safety of these vaccines which could compromise the adhesion of the citizens in the vaccination program.Aims: We conducted a prospective observational study, to explore the impact of vaccination with the BNT162b2 (Pfizer/BioNTech) on blood hypercoagulability and endothelial cell activation and to investigate if this is modified by the presence of active cancer.Methods: In total 229 subjects were prospectively included in the study from April to June 2021. Subjects were stratified in three predefined groups: 127 vaccinated patients with active cancer (VOnco group), 72 vaccinated health care workers (VHcw group) and 30 non vaccinated health individuals (Control group). Blood samples were obtained 2 days after the administration of the first dose of BNT162b2 vaccine and collected in Vacutainer® tubes (0.109 mol/L trisodium citrate). Platelet poor plasma (PPP) was prepared by double centrifugation at 2000 g for 20 minutes at room temperature and plasma aliquots were stored at -80°C until assayed. Samples of PPP were assessed for thrombin generation (TG) with PPP-Reagent® (Thrombogram-Thrombinoscope assay with PPP-Reagent®TF 5pM), E-selectin, D-dimers, (D-Di), Tissue Factor (TFa), procoagulant phospholipid-dependent clotting time (Procag-PPL) and von Willebrand factor (vWF), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), and platelet factor 4 (PF4). All assays were from Diagnostica Stago (France). The upper and lower normal limits (UNL and LNL) for each biomarker were calculated by the mean±2SD for the control group.Results: All vaccinated subjects showed significantly increased levels of PF4 (71% >UNL, p<0.001), D-Dimers (74% >UNL, p<0.01), vWF (60% >UNL, p<0.01), FVIII (62% >UNL, p<0.01) and shorter Procoag-PPL clotting time (96% <LNL, p<0.001), as compared to controls. Thrombin generation showed significantly higher Peak (60% >UNL, p<0.01), ETP (38% >UNL, p<0.01) and MRI (66% >UNL, p<0.01) but no differences in lag-time in vaccinated subjects as compared to the control group. Vaccinated subjects did not show any increase at the levels of TFa, TFPI, TM and E-selectin in comparison with the control group. The studied biomarkers were not significantly different between the VOnco and VHcw groups.Conclusion: The ROADMAP-COVID-19-Vaccine study shows that administration of the first dose of the BNT162b2 vaccine induced significant platelet activation documented by shorter Procoag-PPL associated with increased levels of PF4. Plasma hypercoagulability was less frequent in vaccinated individuals whereas there was no evidence of significant endothelial cells activation after vaccination. Interestingly, the presence of active cancer was not associated with an enhancement of platelet activation, hypercoagulability, or endothelial cell activation after the vaccination. Probably, the generated antibodies against the spike protein or lead to platelet activation in a FcyRIIa dependent manner that results in PF4 release. The implication of the mild inflammatory reaction triggered by the vaccination could be another possible pathway leading to platelet activation. Nevertheless, vaccination does not provoke endothelial activation even in patients with cancer. The findings of the ROADMAP-COVID-19-Vaccine study support the concept administration of mRNA based vaccines does not directly cause a systematic hypercoagulability. DisclosuresGligorov: Roche-Genentech: Research Funding; Novartis: Research Funding; Onxeo: Research Funding; Daichi: Research Funding; MSD: Research Funding; Eisai: Research Funding; Genomic Heatlh: Research Funding; Ipsen: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding. Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria.

The Compass-COVID19-ICU Study: Identification of Factors to Predict the Risk of Intubation and Mortality in Patients with Severe COVID-19

Background: In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation or death is un unmet need.Objective: To derive a prognostic score for the risk of intubation or death in patients with critical COVID-19 by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes.Methods: We conducted a prospective, observational monocentric study enrolling 118 patients with COVID-19 admitted in the intensive care unit. At the 1st day of ICU admission all patients were assessed for the following biomarkers : protein C, protein S, antithrombin, D-Dimer, fibrin monomers, factors VIIa, V, XII, XII, VIII, von Willebrand antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing tissue factor, IL-6, complement C3a, C5a, thrombin generation, prothrombin time, activated partial thromboplastin time, hemogram, platelet count) and clinical predictors. The clinical outcomes were intubation and mortality during hospitalization in ICU.Results: The intubation and mortality rate were 70 % and 18% respectively. Multivariate analysis led to the derivation of the COMPASS- COVID19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization. The score predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively).Conclusions and Relevance: Critical COVID-19 is related with severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID19-ICU score is an accurate predictive model for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The assessment with the COMPASS- COVID-19-ICU score is feasible in tertiary hospitals. In this context it could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention. DisclosuresTerpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria.

Procoagulant Phospholipid Dependent Clotting Time: A New Tool for the Identification of Multiple Myeloma Patients at Risk Poor Treatment Response

Background: Research has long focused on the implications of platelet, endothelial cell and blood coagulation activation in the risk of venous thromboembolism in patients with multiple myeloma (MM). Given the pivotal role of the malignant cell in coagulation activation we studied the association between biomarkers of hypercoagulability and cancer cell activity.Aim: Using data from the prospective, longitudinal observational study ROADMAP-MM CAT (PROspective Risk Assessment anD bioMArkers of hyPercoagulability for the identification of patients with Multiple Myeloma at risk for Cancer Associated Thrombosis) we aimed to identify biomarkers of cellular and plasma hypercoagulability that play a role in determining response to the anti-myeloma treatment.Methods: Newly diagnosed patients with MM were enrolled. Patients on anticoagulant treatment were excluded. A standardized clinical research form (CRF) was completed at enrollment (T0) and at 3 months post treatment initiation (T1). Blood samples were collected at the same time points. Procoagulant phospholipid-dependent clotting time (Procoag-PPL®), tissue factor activity (TFa), thrombomodulin activity (TMa), factor VIIa, factor V (FV), antithrombin (AT), fibrin monomers (FM) and D-Dimers were measured with respective assays from Diagnostica Stago (Asnieres, France) on a STA-R® analyzer (Diagnostica Stago). Plasma levels of P-Selectin and heparanase were measured with ELISA Kits from Cusabio Biotech (from CliniSciencies, France) and R&D Systems (Lille France), respectively. Samples of platelet-poor plasma (PPP) were assessed for thrombin generation (TG) with the TF 5pMPPP-Reagent® on Calibrated Automated Thrombogram (Stago, France). The control group (CG) consisted of 30 healthy age and sex-matched individuals.Results. A total of 100 treatment naïve MM patients were enrolled. Median age was 66.5±12.0 (37-88) years and 54% of the population was male. Disease stage was distributed as follows: 24.3% ISS-I, 20.4% ISS II and 55.3% ISS-III. Bortezomib-based therapy was given to 64.1% of the patients, thalidomide based in 6.8% and lenalidomide-based in 24.3%. Median time to follow up was 11.5 months. There were 16 deaths overall and mortality rate was 162/1000 person-years (median time of death since diagnosis 4.5 months, range 1-9 months). At T1, patients with stable disease (n=8) and progressive disease (n=14) were classified as non-responders. A total of 78 patients achieved at least a partial response and were classified as responders. Compared to controls at T0, MM patients showed significantly increased levels of TFa, D-Dimers and FM and significantly shorter Procoag-PPL clotting time. P-selectin levels were significantly decreased and heparanase levels significantly increased. FVIIa, FV and AT were not significantly different between patients and controls. MM patients showed significantly increased lag-time and ttPeak and significantly lower Peak, ETP and MRI as compared to the control group. TFa and D-dimer levels decreased significantly 3 months post treatment initiation (T1) whereas TMa and AT significantly decreased. At T1 thrombin generation was further attenuated (lower ETP and Peak, prolongation of ttPeak and lower MRI). Univariate analysis demonstrated that among the studied biomarkers only short PPL-ct was associated with a significantly increased risk of no response to treatment. The area under the curve (AUC) in a plot of PPL-ct against no response to treatment (receiver operator curve analysis) was 0.7 (p=0.01).Conclusion. The prospective ROADMAP-CAT multiple myeloma study demonstrates for the first time that among a large number of hypercoagulability biomarkers assessed in newly diagnosed treatment-naïve MM patients, PPL-ct, that reflects the amount of procoagulant microparticles present in plasma, is a significant predictor of poor treatment response. A prospective trial is required to evaluate the potential role of this biomarker in anti-myeloma treatment optimization. [Display omitted] DisclosuresTerpos:Amgen: Honoraria, Other: SC member, Research Funding; Takeda: Honoraria, Other: SC member, Research Funding; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Abbvie: Honoraria; GSK: Honoraria. Garderet:Takeda: Honoraria; Amgen: Honoraria.

Longitudinal Haemostatic Biomarker Trajectories Predict Cancer-Associated Venous Thromboembolism

Background: Venous thromboembolism is an important complication of cancer. Elevated biomarkers of hypercoagulability, such as D-Dimer and Prothrombin Fragment 1.2 (F1.2), are associated with an increased risk of cancer-associated VTE. However, the evolution of these biomarkers during the course of disease is incompletely understood. Moreover, it is unclear whether potential longitudinal changes in these biomarkers over time harbor additional prognostic information on VTE risk in the oncologic setting.Aim: To define the role of longitudinal haemostatic biomarker trajectories for personalized prediction of VTE risk in patients with cancer.Methods: In this prospective cohort study, 164 patients with active malignancy were enrolled at cancer diagnosis or at progression after complete or partial remission (median age: 62 years [51-69; female sex: n=79 (48%); tumor sites: lung n=58 (35%), brain n=48 (29%), pancreas n=33 (20%), colon n=22 (13%), stomach n=3 (2%); metastatic disease: n=72 (44%)). D-Dimer (median: 0.8 µg/mL [25th-75th percentile: 0.4-2.0]), F1.2 (227 pmol/L [166-332]), and others (to be presented at the meeting) were measured at study inclusion, as well as during 637 follow-up visits each 1 month apart, for a planned number of 7 total visits (median number of visits: 5 [4-7]). Primary endpoint of the study was a composite of symptomatic, objectively-confirmed, and independently-adjudicated deep vein thrombosis and/or pulmonary embolism (VTE) during the observation period of 250 days. Joint models of longitudinal and time-to-event data were implemented to study how the haemostatic biomarker trajectories associate with the risk of cancer-associated VTE.Results: The primary endpoint of VTE occurred in 18 patients, corresponding to a 250-day VTE risk of 12.1% (95% confidence interval (CI): 7.8-18.5). Graphical inspection of biomarker trajectories with a moving average suggested that levels of D-Dimer (Figure 1, Panel A) and F1.2 (Figure 1, Panel B) increased before the occurrence of VTE. Indeed, in linear mixed modeling, D-Dimer increased by 0.19 µg/mL/month (0.05-0.32, p=0.007) in patients who eventually developed VTE, but remained constant in patients who did not develop VTE (change per month=0.01 µg/mL, -0.09-0.9, p=0.97). Similarly, F1.2 increased by 9.8 pmol/L/month (0.2-19.5, p=0.045) in patients who developed VTE, while the corresponding increase in patients who did not develop VTE was smaller and not statistically significant (3.3 pmol/L/month, -1.2-7.9, p=0.155). In joint modeling, a doubling of the D-Dimer trajectory was associated with a 2.8-fold increase in the risk of VTE (Hazard ratio (HR)=2.79, 95%CI: 1.66-4.69, p<0.0001). A corresponding increase in F1.2 was associated with a 2.6-fold increase in VTE risk (HR=2.61, 1.02-6.74, p=0.046), respectively. While patients with metastatic cancer had higher levels of both D-Dimer (1.2 vs. 0.6 µg/mL, p<0.0001) and F1.2 (249 vs. 219 pmol/L, p=0.0003) than non-metastatic patients, the prognostic associations between the biomarker trajectories and VTE risk was highly comparable between these two patient groups (p for interaction=0.48, HR for D-Dimer trajectory in non-metastatic patients=3.16 (1.65-6.06, p=0.001), HR for D-Dimer trajectory in metastatic patients=2.51 (1.38-4.56, p=0.003); results for F1.2 not shown).Conclusions: D-Dimer and F1.2 increase before the onset of cancer-associated VTE, but remain relatively constant over time in patients with cancer who do not develop VTE. So-called joint models can successfully link these biomarker trajectories to the prospective risk of VTE. These findings apply similarly to patients with metastatic and non-metastatic cancers. We conclude that the assessment of haemostatic biomarker trajectories in patients with cancer is a novel concept that could substantially advance the personalized assessment of VTE risk in the oncologic setting. [Display omitted] DisclosuresPabinger:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Patients with Lung Adenocarcinoma at Risk for Cancer Associated Thrombosis. the Observational Roadmap-CAT Study

INTRODUCTION: The aim of this prospective longitudinal study was to identify the most clinically relevant hypercoagulability biomarkers in lung adenocarcinoma patients for elaboration of an improved risk assessment model (RAM) for venous thromboembolism (VTE).METHODS: 150 ambulatory patients with lung adenocarcinoma were prospectively enrolled as well as a control group comprised of 30 healthy age & sex-matched individuals. Thrombin generation parameters, procoagulant phospholipid-dependent clotting time (Procoag-PPL), tissue factor activity (TFa), factor VIIa (FVIIa), factor V (FV), antithrombin (AT), D-Dimers (DDi), P-selectin and heparanase levels were assessed in platelet-poor plasma (PPP) at inclusion (baseline) and at the end of the 3rd chemotherapy cycle (acute phase). Cox regression analysis was used to identify independent VTE predictors.RESULTS: At baseline, patients had significantly attenuated thrombin generation, shorter Procoag-PPL, higher levels of TFa, D-Dimers and heparanase, and lower levels of FVIIa and P-selectin, compared to controls. A significant increase in Procoag-PPL, FV and FVIIa and a decrease of P-selectin levels was observed between baseline and the acute phase. Hospitalization within the last 3 months prior to assessment, time since cancer diagnosis less than 6 months, mean rate index of thrombin generation (MRI) and Procoag-PPL were independently associated with symptomatic VTE. Accordingly, a prediction model including the above parameters had improved discriminating capacity (area under the curve/AUC: 0.84).CONCLUSIONS: Ambulatory patients with lung adenocarcinoma may display pronounced blood hypercoagulability due to decreased Procoag-PPL, increased endothelial cell activation and increased degradation of fibrin. Incorporation of Procoag-PPL and MRI of thrombin generation may improve the accuracy of a VTE RAM in the above setting. DisclosuresNo relevant conflicts of interest to declare.

The Vasculopathy of Juvenile Dermatomyositis: Endothelial Injury, Hypercoagulability, and Increased Arterial Stiffness.

Vasculopathy is considered central to the pathogenesis of juvenile dermatomyositis (DM) and is associated with severe extramuscular manifestations. We undertook this study to investigate the hypothesis that the vasculopathy of juvenile DM can be noninvasively tracked by examining biomarkers of endothelial injury, subclinical inflammation, hypercoagulability, and vascular arterial stiffness. The study population was a UK cohort of children with juvenile DM. Circulating endothelial cells (CECs) and microparticles (MPs) were identified using immunomagnetic bead extraction and flow cytometry, respectively. Plasma thrombin generation was determined using a fluorogenic assay. Cytokine and chemokine levels were measured by electrochemiluminescence. Arterial stiffness was assessed using pulse wave velocity (PWV). Results were expressed as the median and interquartile range (IQR), and statistical significance was assessed using nonparametric analyses. Ninety patients with juvenile DM and 79 healthy control subjects were included. The median age of the patients was 10.21 years (IQR 6.68-13.40), and the median disease duration was 1.63 years (IQR 0.28-4.66). CEC counts were higher in all patients with juvenile DM compared to controls (median 96 cells/ml [IQR (40-192] and 12 cells/ml [IQR 8-24], respectively; P < 0.0001). Circulating MP numbers were also significantly higher in patients with active juvenile DM compared to controls (median 204.7 × 103 /ml [IQR 87.9-412.6] and 44.3 × 103 /ml [IQR 15.0-249.1], respectively; P < 0.0001). MPs were predominantly of platelet and endothelial origin. Enhanced plasma thrombin generation was demonstrated in patients with active juvenile DM compared to those with inactive disease (P = 0.0003) and controls (P < 0.0001). Carotid-radial PWV adjusted for age was increased in patients with juvenile DM compared to controls (P = 0.003). We observed increased endothelial injury and increased levels of proinflammatory cytokines in patients with active juvenile DM. MP profiles reflected distinct disease activity status in juvenile DM and are markers of vascular pathology, platelet activation, and thrombotic propensity. Ongoing long-term vascular injury may result in increased arterial stiffness in patients with juvenile DM.