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Identifying adherence to direct oral anticoagulants (DOACs) plays a major role in treatment efficacy and safety. The DOAC Dipstick can detect DOACs in urine samples of acutely diseased patients at plasma thresholds of about 30 ng/mL. A prospective observational consecutive cohort study was performed on outpatients taking DOACs. The presence of direct oral factor Xa inhibitors (DXIs) in patient urine samples were independently evaluated by visual interpretation of the DOAC Dipstick pad colors. DOAC plasma concentration was assessed using STA®-Liquid Anti-Xa and STA®-Liquid Anti-IIa chromogenic substrate assays. Positive DOAC Dipstick results were compared with a threshold plasma of DOAC concentration ≥30 ng/mL. Of 120 patients (age 55.4 + 16.1 years, female n = 63), 77 were on rivaroxaban and 43 on apixaban. Plasma concentrations were 129 ± 118 ng/mL for rivaroxaban, and 163 ± 130 ng/mL for apixaban, DOAC Dipstick test has a sensitivity of 97.2% and a positive predictive value of 89.5% at 30 ng/mL. No differences occurred between DXIs. Specificity and negative predictive value could not be determined due to the low number of true negative values. There were no differences in the interpretation of rivaroxaban and apixaban pad colors between observers (Kappa 1.0). Results show that DOAC Dipstick may be a useful tool for identifying DXIs in urine samples in an outpatient setting at a plasma threshold ≥ 30 ng/mL. Further studies should include patients treated with dabigatran, vitamin K antagonists, or other anticoagulants.

Introduction Antiphospholipid syndrome (APS) is an autoimmune disease characterised by thrombosis (arterial, venous or small vessel) or obstetrical events and persistent antiphospholipid antibodies (aPL), according to the Sydney classification criteria. Many studies have performed cluster analyses among patients with primary APS and associated autoimmune disease, but none has focused solely on primary APS. We aimed to perform a cluster analysis among patients with primary APS and asymptomatic aPL carriers without any autoimmune disease, to assess prognostic value.Methods In this multicentre French cohort study, we included all patients with persistent APS antibodies (Sydney criteria) measured between January 2012 and January 2019. We excluded all patients with systemic lupus erythematosus or other systemic autoimmune diseases. We performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with baseline patient characteristics to generate clusters.Results We identified four clusters: cluster 1, comprising ‘asymptomatic aPL carriers’, with low risk of events during follow-up; cluster 2, the ‘male thrombotic phenotype’, with older patients and more venous thromboembolic events; cluster 3, the ‘female obstetrical phenotype’, with obstetrical and thrombotic events; and cluster 4, ‘high-risk APS’, which included younger patients with more frequent triple positivity, antinuclear antibodies, non-criteria manifestations and arterial events. Regarding survival analyses, asymptomatic aPL carriers relapsed less frequently than the others, but no other differences in terms of relapse rates or deaths were found between clusters.Conclusions We identified four clusters among patients with primary APS, one of which was ‘high-risk APS’. Clustering-based treatment strategies should be explored in future prospective studies.

Objective Antiphospholipid syndrome (APS) is defined by the association of thromboembolic and/or obstetrical clinical manifestations and the presence of antiphospholipid antibodies. The objective of our study was to evaluate the impact of the triple-positive profile in a cohort of 204 APS patients.Methods We conducted a retrospective study, including patients with primary or secondary APS, meeting the Sydney criteria with at least one thrombotic and/or obstetrical complication. Clinical characteristics and the risk of relapse (defined by the occurrence of a new thrombotic event and/or a new adverse obstetrical event) between triple-positive and non-triple-positive APS patients were compared.Results 204 patients were included in our study, 68 were triple-positive and 136 were single or double positive. 122 patients (59.8%) had primary APS. 67 patients (32.8%) had obstetrical APS, with a higher rate among triple-positive patients (45.6% vs 26.5%, p=0.010), and 170 patients (83.3%) had thrombotic APS, without difference between triple-positive and others. Thrombotic events were more often venous (56.4%) than arterial (37.7%). Triple-positive patients had more placental complications than others (17.6% vs 2.9%, p=0.001) and more non-criteria events (48.5% vs 25.7%, p=0.002). Among non-criteria events, there was a higher frequency of Sneddon syndrome in triple-positive patients (7.4% vs 0.7%, p=0.028). The relapse rate was higher in triple-positive patients than in others (63.2% vs 39,7%, p=0002). In multivariate analysis, the triple-positive profile was associated with a higher risk of relapse (HR 1.63; 95% CI 1.04 to 2.55; p=0.031).Conclusion The triple-positivity is associated with a higher risk of relapse and obstetrical complications.

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.

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.

Abstract Background From this retrospective study, we aimed to (1) describe the prevalence and characteristics of non-criteria features in primary antiphospholipid syndrome (p-APS) and (2) determine their prognostic value. Methods This retrospective French multicenter cohort study included all patients diagnosed with p-APS (Sydney criteria) between January 2012 and January 2019. We used Kaplan-Meier and adjusted Cox proportional hazards models to compare the incidence of relapse in p-APS with and without non-criteria manifestations. Results One hundred and seventy-nine patients with p-APS were included during the study time, with a median age of 52.50 years [39.0; 65.25] and mainly women (n = 112; 62.6%). Among them, forty-three patients (24.0%) presented at least one non-criteria manifestation during the follow-up: autoimmune cytopenias (n = 17; 39.5%), Libman Sachs endocarditis (n = 5; 11.6%), APS nephropathy (n = 4; 9.3%), livedo reticularis (n = 8; 18.6%), and neurological manifestations (n = 12; 27.9%). In comparison to p-APS without any non-criteria manifestations (n = 136), p-APS with non-criteria features had more arterial thrombosis (n = 24; 55.8% vs n = 48; 35.3%; p = 0.027) and more frequent pre-eclampsia (n = 6; 14.3% vs n = 4; 3.1%; p = 0.02). The prevalence of triple positivity was significantly increased in patients with non-criteria features (n = 20; 47.6% vs n = 25; 19.8%; p = 0.001). Patients with p-APS and non-criteria manifestations (n = 43) received significantly more additional therapies combined with vitamin K antagonists and/or antiaggregants. Catastrophic APS (CAPS) tended to be more frequent in p-APS with non-criteria features (n = 2; 5.1% vs none; p = 0.074). The p-APS with non-criteria manifestations had significantly increased rates of relapse (n = 20; 58.8% vs 33; 33.7%; p = 0.018) in bivariate analysis, but in survival analyses, the hazard ratio (HR) of relapse was not significantly different between the two groups (HR at 1.34 [0.67; 2.68]; p = 0.40). Conclusions The presence of non-criteria features is important to consider, as they are associated with particular clinical and laboratory profiles, increased risk of relapse, and need for additional therapies. Prospective studies are necessary to better stratify the prognosis and the management of p-APS.

Background. Hypercoagulable state and endothelial cell activation are common alterations in patients with COVID-19. Nevertheless, the hypothesis of persistent hypercoagulability and endothelial cell activation following recovery from COVID-19 remains an unresolved issue. Objectives. 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. The following biomarkers were measured: procoagulant phospholipid-dependent clotting time (PPL-ct), D-Dimer, fibrin monomers (FM), free Tissue factor pathway inhibitor (free-TFP)I, heparinase, and soluble thrombomodulin (sTM). Antibodies against SARS-CoV-2 (IgG and IgA) were also measured. Results. The median interval between symptom onset and screening for SARS-CoV-2 antibodies was 62 days (IQR = 22 days). 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. 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. One out of four of COVID-19 survivors showed increase at least one biomarker of endothelial cell activation or hypercoagulability. Conclusions. Two months after onset of COVID-19, a significant activation of endothelial cells and in vivo thrombin generation persists in at least one out of four survivors of COVID-19. The clinical relevance of these biomarkers in the diagnosis and follow-up of patients with long COVID-19 merits to be evaluated in a prospective clinical study.

It has long been recognized a crucial role played by platelets in thrombosis and hemostasis. Along with that, laboratory and clinical data suggest that platelets contribute to tumor progression and metastasis through a variety of interactions with cancer cells. During oncological process, the platelet function becomes modulated via their activation and increased aggregation being one of the risk factors for developing thrombosis in cancer patients. The platelets per se enhance tumor cell dissemination, activate endothelial cells, and attract immune cells to the primary and metastatic tumor sites. In this review, we summarize the current knowledge about the complex interactions between platelets and tumor cells, as well as cells of the microenvironment, and discuss the development of new antitumor agents aimed at various arms in platelet functioning.

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.

Background Nephrotic syndrome (NS) is associated with an increased risk of thromboembolic events (TEs), due to hemostatic derangements. The use of direct oral anticoagulants (DOACs) in the prevention of TE has not been studied intensively in patients suffering from NS. Methods The method included retrospective analysis of consecutive incident patients with NS due to glomerular disease, receiving apixaban for thromboprophylaxis. It is an uncontrolled, single-center study. Results We identified 27 patients treated with apixaban for the prevention of TEs, in the context of NS. During follow-up, apixaban minimal blood concentration (trough level; Cmin) and maximum blood concentration (Cmax) levels were measured. The mean duration of the anticoagulant treatment was 153 days (±132). Patients were followed for a mean of 14.7 months (±8.4) since the introduction of apixaban. Three patients had a TE at the time of NS diagnosis. Two patients had pulmonary embolism (PE) and one patient presented a stroke in a lupus membranous nephropathy context. One patient developed PE approximately 2 months after the introduction of apixaban treatment. No minor or major bleeding events were noticed. Conclusion The present study shows that patients, suffering from severe NS under anticoagulant therapy with apixaban had a reduced risk of venous and arterial TEs compared with patients previously described in the literature, without increased risk of bleeding.

In cancer patients, thrombocytopenia can result from bone marrow infiltration or from anticancer medications and represents an important limitation for the use of antithrombotic treatments, including anticoagulant, antiplatelet, and fibrinolytic agents. These drugs are often required for prevention or treatment of cancer-associated thrombosis or for cardioembolic prevention in atrial fibrillation in an increasingly older cancer population. Data indicate that cancer remains an independent risk factor for thrombosis even in case of thrombocytopenia, since mild-to-moderate thrombocytopenia does not protect against arterial or venous thrombosis. In addition, cancer patients are at increased risk of antithrombotic drug-associated bleeding, further complicated by thrombocytopenia and acquired hemostatic defects. Furthermore, some anticancer treatments are associated with increased thrombotic risk and may generate interactions affecting the effectiveness or safety of antithrombotic drugs. In this complex scenario, the European Hematology Association in collaboration with the European Society of Cardiology has produced this scientific document to provide a clinical practice guideline to help clinicians in the management of patients with cancer and thrombocytopenia. The Guidelines focus on adult patients with active cancer and a clear indication for anticoagulation, single or dual antiplatelet therapy, their combination, or reperfusion therapy, who have concurrent thrombocytopenia because of either malignancy or anticancer medications. The level of evidence and the strength of the recommendations were discussed according to a Delphi procedure and graded according to the Oxford Centre for Evidence-Based Medicine.

Thrombotic and hemorrhagic complications are related to a significant rate of morbidity and mortality in patients with myeloproliferative neoplasms (MPNs), they are therefore called “thrombohemorrhagic” syndromes. Several clinical factors, such as age and presence of cardiovascular comorbidities are responsible for thrombotic complications. High blood counts, platelet alterations, presence of JAK2 mutation and possibly of other CHIP mutations such as TET2, DNMT3A, and ASXL1, procoagulant microparticles, NETs formation, endothelial activation and neo-angiogenesis are some of the parameters accounting for hypercoagulability in patients with myeloproliferative neoplasms. Bleeding complications emerge as a result of platelet exhaustion. They can be also linked to a functional deficiency of von Willebrand factor, when platelet counts rise above 1000G/L. The mainstay of management consists on preventing hemostatic complications, by antiplatelet and/or anticoagulant treatment and myelosuppressive agents in high-risk patients.Circumstances related to a high thrombohemorrhagic risk, such as pregnancy and the perioperative period, prompt for specific management with regards to anticoagulation and myelosuppression treatment type. In order to apply a patient-specific treatment strategy, there is a need for a risk score assessment tool encompassing clinical parameters and hemostasis biomarkers.

Cancer patients exhibit an increased risk of venous thromboembolism (VTE), with VTE being the second leading cause of morbidity and mortality in these patients. The implementation of lockdowns following the COVID-19 pandemic has resulted in decreased mobility and delayed access to care, thus further increasing the susceptibility to VTE. Cancer patients may also be at a higher risk of SARS-CoV-2 infection and have been shown to be more likely to experience severe COVID-19 disease compared to patients without cancer. Given that both cancer and COVID-19 exhibit a hypercoagulable state, stasis of blood flow, and endothelial injury, cancer patients with COVID-19 constitute a vulnerable population with a high risk of thrombosis and bleeding. However, to date there are limited studies evaluating whether cancer patients infected with SARS-CoV-2 have a higher VTE incidence than COVID-19 patients without cancer, how to assess the risk of VTE, prophylaxis and treatment in this special population. Herein, we highlight the urgent need for studies in cancer patients with COVID-19 to ensure appropriate patient care and improve clinical outcomes.

Abstract Background Venous thromboembolism (VTE) accounts for an estimated 900,000 cases per year in the US alone and constitutes a considerable burden on healthcare systems across the globe. Objective To understand why the burden is so high, qualitative and quantitative research was carried out to gain insights from experts, guidelines and published studies on the unmet clinical needs and therapeutic strategies in VTE prevention and treatment in three populations identified as being at increased risk of VTE and in whom VTE prevention and treatment were regarded as suboptimal: pregnant women, the elderly and obese patients. Methodology A gap analysis methodology was created to highlight unmet needs in VTE management and to discover the patient populations considered most at risk. A questionnaire was devised to guide qualitative interviews with 44 thrombosis and haemostasis experts, and a review of the literature on VTE in the specific patient groups from 2015 to 2017 was completed. This was followed by a Think Tank meeting where the results from the research were discussed. Results This review highlights the insights gained and examines in detail the unmet needs with regard to VTE risk-assessment tools, biomarkers, patient stratification methods, and anticoagulant and dosing regimens in pregnant women, the elderly and obese patients. Conclusions Specifically, in pregnant women at high risk of VTE, low-molecular-weight heparin (LMWH) is the therapy of choice, but it remains unclear how to use anticoagulants when VTE risk is intermediate. In elderly patients, evaluation of the benefit of VTE prophylaxis against the bleeding risk is particularly important, and a head-to-head comparison of efficacy and safety of LMWH versus direct oral anticoagulants is needed. Finally, in obese patients, lack of guidance on anticoagulant dose adjustment to body weight has emerged as a major obstacle in effective prophylaxis and treatment of VTE.

Patients with cancer are at a high risk of symptomatic venous thromboembolism (VTE), which is a common cause of morbidity and mortality in this patient population. Increased risk of recurrent VTE and bleeding complications are two major challenges associated with therapeutic anticoagulation in these patients. Long-term therapy with low-molecular-weight heparins (LMWHs) has been the standard of care for the treatment of cancer-associated VTE given its favorable risk–benefit ratio in comparison with vitamin K antagonists. Direct oral anticoagulants (DOACs), which offer the convenience of oral administration and have a rapid onset of action, have recently emerged as a new treatment option for patients with cancer-associated thrombosis (CT). Randomized clinical trial data with head-to-head comparisons between DOACs and LMWHs showed that overall, DOACs have a similar efficacy profile but a higher risk of bleeding was observed in some of these studies. This review aims to identify unmet needs in the treatment of CT. We discuss important considerations for clinicians tailoring anticoagulation (1) drug–drug interactions, (2) risk of bleeding (e.g., gastrointestinal bleeding), (3) thrombocytopenia, hematological malignancies, (4) metastatic or primary brain tumors, and (5) renal impairment. Additional research is warranted in several clinical scenarios to help clinicians on the best therapeutic approach.

The DOAC Dipstick accurately detects the presence or absence of factor Xa (DXI) and thrombin inhibitor (DTI) classes of direct oral anticoagulants (DOACs) in patients' urine samples on DOAC treatment. The aim of the study was to systematically review the literature and compare the performance of prototype and commercial test strips with a meta-analysis. A systematic literature search of electronic databases PubMed (MEDLINE) and Cochrane Library was performed. Heterogeneity between studies was calculated using the Chi-squared test and the I2 index. A random effects model was used to pool data to compare the performance of prototype and commercial test strips. Using PRISMA reporting guidelines, four of 1,081 publications were eligible for inclusion in the meta-analysis: three reporting on prototype (DXI n = 658, DTI n = 586) and one on commercial test strips (DXI n = 451, DTI n = 429). Sensitivity and specificity of DXI and DTI detection did not differ significantly between the prototype and commercial test strips. Odds ratios were 0.718 and 0.365 for sensitivity and 1.211 and 1.072 for specificity of DXI and DTI (p-values between 0.3334 and 1.000), respectively. The pooled sensitivity and specificity values for DXI were 0.968 (p = 0.1290, I2 47.1%) and 0.979 (p = 0.1965, I2 35.9%), and for DTI 0.993 (p = 0.1870, I2 37.5%) and 0.993 (p = 0.7380, I2 0%), respectively. Prototype and commercial DOAC test strips did not differ in their ability to detect DXI and DTI in patient urine samples. This supports the confidence in use of the DOAC Dipstick test, although it needs to be validated in specific patient populations.

Abstract Background Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups. Objective To present current expert insights and evidence on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill. Methodology To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts. Results The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment. Conclusions Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug–drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, low-molecular weight heparins remain the first choice for prophylaxis in critically ill and cancer patients due to their safety and efficacy profile, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins. Herein we present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in patients with cancer and the critically ill.

The prevalence of thrombosis in lymphoma patients is reportedly high and ranges from 3-10%. Vascular malfunction and inflammatory processes further contribute to the thrombotic activation process in these patients. Andexanet alfa (AA) is an antidote for factor Xa inhibitors and its usage has been reported with thrombotic complications. This study was designed to compare the effect of AA on the thrombin generation (TG) potential. Blood samples from 78 patients with confirmed diagnosis of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and Chronic lymphocytic leukemia (CLL) were collected from the University of Belgrade Clinic, Serbia. Normal human plasma (NHP) was used for referencing purposes. Individual samples were supplemented with AA at 100 ug/ml. TG studies were carried out using a commercially available fluorogenic substrate method. TG parameters such as peak thrombin (PT), lag time (LT) and area under the curve (AUC) were compiled. Cumulatively, lymphoma patients showed an increase in LT compared to NHP which decreases with AA. The PT and AUC levels were decreased compared to NHP and increases with AA. Upon sub-grouping of lymphoma patients, PT levels for all sub-groups were increased with AA. The AUC values increased for HL and NHL and decreased for CLL with AA. Variations in lag time were noted in all 3 sub-groups. Lymphoma represents a heterogenous group of patients where both the hypercoagulable state and inflammatory responses simultaneously occur. Increased thrombin generation in post AA supplemented samples suggest that the use of this agent may potentially be associated with thrombotic complications.

Abstract 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 βHCG 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.

Introduction Hypercoagulability is a common blood alteration in newly diagnosed chemotherapy naïve patients with multiple myeloma. The identification of the procoagulant potential of cancer cells, which is principally related to tissue factor (TF) expression, attracts particular interest. The mechanisms by which myeloma plasma cells (MPCs) activate blood coagulation have been poorly investigated. Aim To identify the principal actors related with MPCs that boost thrombin generation (TG). Methods TF and annexin V expression by MPCs and MPC-derived microparticles (MPC-dMPs) was analyzed by flow cytometry. TF activity (TFa) and TF gene expression were also determined. TG in the presence of MPCs or MPC-dMPs was assessed with the calibrated automated thrombogram assay (CAT) in normal human PPP and in plasma depleted of factor VII or XII. TG was also assessed in plasma spiked with MPCs and MPC-dMPs. Results MPC-dMPs expressed approximately twofold higher levels of TF as compared with MPCs. The TFa expressed by MPC-dMPs was significantly higher compared with that expressed by MPCs. MPCs and MPC-dMPs enhanced TG of human plasma. TG was significantly higher with MPC-dMPs compared with MPCs. Conclusion MPCs indirectly induce blood-borne hypercoagulability through the release of MPC-dMPs rich in TF. Since MPCs, expressing low TFa, represent a weak procoagulant stimulus, the hypercoagulability at the microenvironment could be the resultant of MPC-dMPs rich in TF.

Reliable laboratory diagnosis of heparin-induced thrombocytopenia (HIT) remains a major clinical concern. Immunoassays are highly sensitive, while confirmatory functional tests (based on heparin-dependent platelet activation) lack standardization. We evaluated the diagnostic performance of a functional flow cytometric assay (FCA) based on the detection of heparin-dependent platelet activation with an anti-p-selectin. A total of 288 patients were included (131 HIT-positive and 157 HIT-negative) with a HIT diagnosis established by expert opinion adjudication (EOA) considering clinical data and local laboratory results. The FCA was centrally performed in a single laboratory on platelet-rich plasma, using a very simple four-color fluorometer. The results were standardized according to the Heparin Platelet Activation (HEPLA) index. The serotonin release assay (SRA) was performed in the four French reference laboratories. Based on the final HIT diagnosis established by EOA, the sensitivity and specificity of the FCA were 88 and 95%, respectively, values very similar to those of the SRA (88 and 97%, respectively). This study showed that the FCA, based on easily implementable technology, may be routinely used as a reliable confirmatory test for HIT diagnosis.