High Risk For Thrombotic Events Research Articles

Association of D-dimer level with thrombotic events, bleeding, and mortality in Japanese patients with solid tumors: a Cancer-VTE Registry subanalysis

BackgroundThe D-dimer test is a simple test frequently used in routine clinical screening for venous thromboembolism (VTE). The Cancer-VTE Registry was a large-scale, multicenter, prospective, observational study in Japanese patients with cancer. This study aimed to clarify the relationship between D-dimer level at cancer diagnosis (baseline) and the incidence of events during cancer treatment (1-year follow-up period).MethodsThis was a post hoc sub-analysis of patients from the Cancer-VTE Registry whose D-dimer levels were measured at baseline. The incidence of events during the 1-year follow-up period was evaluated stratified by baseline D-dimer level. Adjusted hazard ratios for D-dimer level and events during the follow-up period were evaluated.ResultsAmong the total enrolled patients, baseline D-dimer level was measured in 9020 patients. The mean ± standard deviation baseline D-dimer level was 1.57 ± 3.94 µg/mL. During the follow-up period, the incidence of VTE, cerebral infarction/transient ischemic attack (TIA)/systemic embolic events (SEE), bleeding, and all-cause death increased with increasing baseline D-dimer level. The incidence of all-cause death increased with increasing D-dimer level regardless of cancer stage. The adjusted hazard ratio of all-cause death was 1.03 (95% confidence interval: 1.02–1.03) per 1.0-µg/mL increase in baseline D-dimer level.ConclusionsIncreases in D-dimer levels were associated with a higher risk of thrombotic events, such as VTE and cerebral infarction/TIA/SEE, during cancer treatment. Furthermore, higher D-dimer levels at cancer diagnosis were associated with a higher mortality rate, regardless of cancer stage.

Evaluation of viscoelastic coagulation monitoring parameters and fibrinogen concentrations in healthy dogs undergoing stifle arthroscopy and tibial plateau leveling osteotomy.

Evaluation of viscoelastic parameters along with Hct percentages, platelet numbers, and fibrinogen concentrations in healthy dogs undergoing elective stifle arthroscopy and tibial plateau leveling osteotomy (TPLO). These results determine if dogs are in a normal, hypocoagulable, or hypercoagulable state at 4 different time points. Prospective study of 37 client-owned dogs enrolled between February 2, 2022, and November 10, 2022. All dogs received a standardized anesthetic protocol. Patients enrolled in the study underwent stifle arthroscopy using a 3-portal technique with a TPLO performed by board-certified surgeons. Viscoelastic testing, Hct percentage, fibrinogen concentration, and platelet numbers were measured preoperatively, immediately postoperatively, 24 hours postoperatively, and 14 days postoperatively. Stifle arthroscopy and TPLO surgery was not associated with significant effects on viscoelastic coagulation monitoring and fibrinogen concentrations in healthy dogs when comparing the time points. Humans have a high risk of thrombotic events when undergoing elective orthopedic surgery and are often placed on prophylactic antithrombotic medication prior to surgery. Viscoelastic coagulation monitoring in dogs undergoing similar orthopedic procedures has been evaluated in veterinary medicine, but the effects on platelets and fibrinogen concentrations from similar orthopedic procedures and uniform anesthesia protocols have not been documented. Cranial cruciate ligament insufficiency is the most common orthopedic injury in dogs. Treatment requires elective surgical correction for the best results and improved long-term prognosis. The findings of this study suggest that similar preoperative prophylactic antithrombotic intervention is not needed for canine patients.

Increased risk of new‐onset cardiovascular disease after COVID‐19: A systematic review and meta‐analysis of 14 cohorts

AbstractCardiovascular diseases (CVD) are common in long COVID, yet the associated risk remains uncertain. We aimed to quantify the risk of new‐onset cardiovascular diseases after COVID‐19. We searched PubMed, Embase, and Web of Science from inception up to October 2022. Cohort studies that provided information on the number, proportion, or relative risks (RR) of cardiovascular diseases after COVID‐19 were included. Paired reviewers independently screened studies, extracted data, and assessed the risk of bias. We performed random‐effects models meta‐analyses to calculate RR and corresponding 95% confidence interval (95%CI), and conducted subgroup analyses and meta‐regression to explore the potential risk factors. Absolute effects were calculated to facilitate interpretation. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess the certainty of evidence. Outcomes of interest were any CVD, major adverse cardiovascular events (MACE), arrhythmias, heart failure, myocarditis, and thrombotic events. Fourteen cohort studies with over 25.37 million participants were included. The results showed a 2.42 times higher risk of any CVD (RR = 2.42, 95% CI: 1.24–4.71; 51 more per 1000), a 95% higher risk of MACE (RR = 1.95, 95% CI: 1.59–2.40; 4 more per 1000), a 61% higher risk of arrhythmias (RR = 1.61, 95% CI: 1.42–1.83; 12 more per 1000), a 71% higher risk of heart failure (RR = 1.71, 95% CI: 1.33–2.21; 2 more per 1000), a 5 times higher risk of myocarditis (RR = 5.06, 95% CI: 3.78–6.77; 4 more per 1000), and a 2.49 times higher risk of thrombotic events (RR = 2.49, 95% CI: 1.22–5.06; 6 more per 1000) associated with COVID‐19. Besides, for thrombotic events, a statistically significant subgroup effect was observed in male participants compared to females (Pinteraction = 0.008). The certainty of evidence was high for myocarditis, but low or very low for other outcomes. The results clearly showed varying degrees of elevated new‐onset CVD risk in post‐COVID‐19 individuals. Additionally, our findings suggest that male patients face a higher risk of thrombotic events. However, the differences in pooled results between studies, and the over‐precision due to the large sample size of the included studies resulted in high heterogeneity of exceeding 90% in most outcomes, which led to low certainty of evidence.

Risk-based and individualised management of bleeding and thrombotic events in adults with primary immune thrombocytopenia (ITP).

Although bleeding is one of the main symptoms of primary immune thrombocytopenia (ITP), risk factors for bleeding have yet to be fully established. Low platelet count (PC; <20-30 × 109 /L) is generally indicative of increased risk of bleeding. However, PC and bleeding events cannot be fully correlated; many other patient- and disease-related factors are thought to contribute to increased bleeding risk. Furthermore, even though ITP patients have thrombocytopenia and are at increased risk of bleeding, ITP also carries higher risk of thrombotic events. Factors like older age and certain ITP treatments are associated with increased thrombotic risk. Women's health in ITP requires particular attention concerning haemorrhagic and thrombotic complications. Management of bleeding/thrombotic risk, and eventually antithrombotic therapies in ITP patients, should be based on individual risk profiles, using a tailored, patient-centric approach. Currently, evidence-based recommendations and validated tools are lacking to support decision-making and help clinicians weigh risk of bleeding against thrombosis. Moreover, evidence is lacking about optimal PC for achieving haemostasis in invasive procedures settings. Further research is needed to fully define risk factors for each event, enabling development of comprehensive risk stratification approaches. This review discusses risk-based and individualised management of bleeding and thrombosis risk in adults with primary ITP.

Erythrophagocytosis Mediated By Circulating Monocytes Is Induced By Distinct Mechanisms Depending on the Disease

Stress erythropoiesis (SE) occurs when the steady state erythropoiesis is no longer sufficient to sustain the number of healthy red blood cells (RBC) needed in the circulation. There is an extension of this activity to extramedullary sites, contributing to the increase in cell production in the erythroblastic island (EBI) niche, and altered or damaged RBCs are then cleared by macrophages. Some diseases have a state of chronic SE. Sickle cell anemia (SCA) affects multiple aspects of RBCs, leading to recurrent vaso-occlusive crisis, hemolytic anemia, and inflammation. Polycythemia Vera (PV), an acquired neoplastic disease with mutations in JAK2 kinase, is characterized by the overproduction of RBCs, increasing blood viscosity, and resulting in a higher risk of thrombotic events. We previously showed that circulating monocytes (MC) of both diseases have a phenotype similar to the EBIs macrophages, with higher expression of CD169, CD163, CD206 and VCAM-1, and also participate in the phagocytosis of RBCs, function typically carried out by macrophages. Therefore, the aim of this study was to determine whether the increased phagocytic activity found in these patients was due to the alterations on the MCs phenotype or if it was an influence of the RBCs, as well as investigate the consequences to the iron metabolism after phagocytosis. MCs from peripheral blood were isolated and incubated for 2 hours with previously stained RBCs, to allow the phagocytosis to happen. After this period, the remaining RBC were lysed and the antibodies anti-intracellular heme-oxigenase-1 (HO-1) and anti-membrane ferroportin (FPN) were used for flow cytometry analysis. The statistical analysis was done by paired t-student test (P&amp;lt;0.05). When exposed to SCA RBCs, MCs from SCA patients and healthy controls (HC) show higher phagocytic capability, than when exposed to HC RBCs (MC HC 22.9±8 vs 9.4±1.1, **P=0,0099; MC SCA 33.6±11.4 vs 16.4±11, **P=0,0054; respectively). The same happens to PV and HC MCs: when exposed to PV RBCs: they show higher phagocytosis compared to the presence of HC RBCs (MC HC 9.3±4.4 vs 2.8±4.7, **P=0.0065; MC PV 21.3±6.1 vs 11±6.8, *P=0.0146; respectively). Investigating the role of MCs in this activity, we compared SCA, PV and HC MCs in the presence of patients RBCs. SCA MCs internalized RBCs similarly to HC MCs (P=0.0699); on the other hand, PV MCs presented higher phagocytic capability when compared to HC MCs (**P=0.0022). In all groups, the expressions of both HO-1 and FPN were higher in those MCs that participated in the phagocytosis than in those that didn't contribute to this function (HO-1: MC SCA 91.9±4 vs 65.9±16.8, **P=0.0098, MC PV 92.1±5.5 vs 61.7±15.5, ***P=0.0007; FPN: MC SCA 81.8±13.8 vs 66.5±15.7, ***P=0.0003, MC PV 70.9±17 vs 53.2±16.5, **P=0.0013 respectively). This indicates an increase in the ability to degrade heme and export iron post-phagocytosis. The results suggest that RBCs from patients with SCA are the ones responsible for the increase in the phagocytic activity by MCs, indicating that RBCs clearance is not an innate function of SCA MCs, even though they are active participants in the circulation. For PV, both RBCs and MCs seem to contribute to the increase of this process in the circulation of patients. The higher expression of molecules related to the iron metabolism suggests a participation of circulating MCs to the iron disponibility, helping with the maintenance of stock for the erythrocytic production. Even though SCA and PV have different pathophysiology, they both present SE and the circulating MCs from both groups show an important participation in the clearance of RBCs, either by an intrinsic function of MCs or a direct influence of changes in the RBCs, suggesting the important contribution of MCs to avoid oxidative stress and help with iron disponibility for erythropoiesis during the course of SE.

HDAC Inhibitor CS014 Attenuates Thrombosis Alone and in Combination with Rivaroxaban without Increased Risk of Bleeding

Introduction: Targeting the human platelet for prevention of occlusive thrombotic events remains an active area of research due to the high incidence of myocardial infarction and stroke due to platelet-rich thrombotic clots. While, many patients taking FXa anticoagulant therapy require further inhibition of thrombosis, dual therapy including anticoagulant plus antiplatelet drugs result in an increased risk for bleeding. The current study sought to determine if a histone deacetylase (HDAC) inhibitor, either alone or in combination with the FXa inhibitor rivaroxaban, is able to effectively inhibit platelet and fibrin formation at the site of vascular injury without causing a significant increase in the bleeding risk in mice. Methods and Results: Thrombosis and bleeding models in the mouse were assessed in the presence of the HDAC inhibitors valproic acid (VPA) or the newly developed HDAC inhibitor, CS014. Both CS014 and VPA significantly, dose-dependently inhibit platelet accumulation and fibrin formation at the site of a vascular injury using the laser-induced cremaster thrombosis assay model. Further, to determine if CS014 has the potential to be used in conditions where an anticoagulant is already on board, mice were dosed for 5 days with rivaroxaban alone or in combination with CS014 and were assessed for prevention of laser-induced thrombosis in the cremaster arteriole. Both rivaroxaban and CS014 alone cause significant attenuation of clot formation. To determine if the combination results in an increased risk for bleeding, blood from mice treated with CS014 or rivaroxaban alone, or in combination was assessed for coagulation activity and clot strength using thromboelestography (TEG). Rivaroxaban was found to significantly delay onset of clotting in TEG whereas CS014 did not show any delay in coagulation or clotting with TEG. In combination CS014 was not observed to cause any additional delay in clotting time or decrease in maximal clot strength compared to rivaroxaban alone. Finally, a tail vein bleeding assay was conducted to determine if CS014 alone or in combination with rivaroxaban result in an increased risk for bleeding. Neither CS014 alone, rivaroxaban alone, or the combination of CS014 plus rivaroxaban resulted in increased bleeding time in the resected tail experiment. Conclusions: The data presented here suggests that while CS014 and rivaroxaban are each effective antithrombotic agents, they work well together to minimize clot formation without altering coagulation or clotting compared to rivaroxaban alone. Hence, CS014 has the potential to enrich the toolbox of anticoagulant therapies in patients with a high risk of thrombotic events.

Navigating the Course of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: A Review of Guided Approaches.

Dual antiplatelet therapy (DAPT) is the standard approach to prevent thrombotic events in patients undergoing percutaneous coronary intervention and presenting with chronic or acute coronary syndromes. However, a sizeable proportion of patients presents with an impaired or unwarranted response to DAPT depending on genetic polymorphisms or variability in platelet response. Therefore, the concept of changing the type or dose of antiplatelet drugs based on the result of platelet function or genotype tests (ie, guided DAPT) has been introduced. The goal of guided DAPT is to intensify the antiplatelet potency in patients at high risk of thrombotic events (ie, escalation) and to decrease the antiplatelet potency in patients at high risk of bleeding (ie, de-escalation). This review aims to present an up-to-date and comprehensive overview of the latest research findings on DAPT modulation guided by either platelet function or genetic testing, discussing its current indications and future directions.

PI3KC2α inhibition is antithrombotic in blood from hypercholesterolemic mice

BackgroundCurrent antiplatelet agents exhibit reduced antithrombotic efficacy in high-risk populations such as populations with hypercholesterolemia. The class II PI3-kinase, PI3KC2α, is a recently discovered target for novel antiplatelet therapy. PI3KC2α inhibition is antithrombotic in healthy mouse models, but whether this is preserved in hypercholesterolemia remains unknown. ObjectivesThis study aimed to examine whether genetic deficiency or pharmacologic inhibition of PI3KC2α provides antithrombotic effects in blood from hypercholesterolemic mice. MethodsHypercholesterolemic PI3KC2α-deficient mice were generated by breeding into an ApoE−/− background. Thrombosis was examined using an ex vivo whole blood thrombosis assay. The effect of pharmacologic inhibition of PI3KC2α was examined in whole blood from ApoE−/− mice treated with the PI3KC2α inhibitor MIPS-21335. ResultsApoE−/− mice exhibited the anticipated prothrombotic effect of hypercholesterolemia, with a 1.5-fold increase in thrombus volume in blood from ApoE−/− vs wild-type mice. This prothrombotic phenotype in blood from hypercholesterolemic mice was significantly reduced with PI3KC2α deficiency. Acute pharmacologic inhibition of PI3KC2α with MIPS-21335 similarly reduced thrombosis in blood from ApoE−/− mice. ConclusionThese findings demonstrate that targeting PI3KC2α results in a potent antithrombotic effect in hypercholesterolemic mice and suggest that PI3KC2α is a promising target for antithrombotic therapy in patients with hypercholesterolemia at a high risk of thrombotic events.

Real-World Clinical Characterisation of Polycythaemia Vera Patients from a Prospective Registry in Portugal: Is Resistance to Hydroxyurea a Reality?

Patients with polycythaemia vera (PV) are at increased risk of thrombosis and haemorrhages. Although hydroxyurea (HU) has been the frontline therapy for patients at high risk of vascular complications, about 25% of patients develop resistance/intolerance to this therapy. The aim of this non-interventional, multicentre cohort study was to understand the clinical characteristics and HU treatment response of Portuguese PV patients. HU resistance/intolerance was defined according to adjusted European LeukemiaNet (ELN) criteria. In total, 134 PV patients with a mean (SD) disease duration of 4.8 (5.0) years were included and followed up for 2 years. At baseline, most patients were ≥60 years old (83.2%), at high risk for thrombotic events (87.2%), and receiving HU therapy (79.1%). A total of 10 thrombotic events and 8 haemorrhagic events were reported, resulting in a 5-year probability of thrombo-haemorrhagic events of 17.2%. Haematocrit (p = 0.007), haemoglobin (p = 0.012) and MPN10 symptom score (12.0 (11.6) vs. 10.3 (9.1); p = 0.041) decreased significantly at the 24-month visit compared to baseline. Overall, 75.9% of patients met at least one of the adjusted ELN criteria for HU resistance, and 14.4% of patients remained on HU throughout the study. The results from this real-world study may help identify the subset of patients at higher risk for disease sequelae who may benefit from earlier second-line treatment.

Factors determining the prognosis after elective myocardial revascularization in patients with coronary artery disease with multifocal atherosclerosis

Aim. To identify factors determining the prognosis after elective myocardial revascularization in patients with coronary artery disease (CAD) with multifocal atherosclerosis (MFA).Material and methods. The study is based on the prospective registry REGATA-1, ClinicalTrials NCT04347200 (1500 patients with stable coronary artery disease; men, 78,6%, age, 65±8,7 years). We selected 238 patients with MFA, the criteria of which were multivessel CAD (at least 2 arteries) in combination with stenosis ≥50% of at least one of the peripheral vascular system. The selection criteria was elective myocardial revascularization followed by dual antiplatelet therapy for at least 6-12 months. Unfavorable outcomes were analyzed, namely thrombotic events (TEs) in any vascular system and bleeding (BARC type 2-5).Results. The median follow-up was 859 days (interquartile range [523;1665]). Thrombosis dominated in the structure of events: the total incidence of TEs was 18,5% (including fatal — 4,2%), and the total incidence of bleeding was 7,5% (including BARC type 3 — 1,7%). Predictors of TE were smoking (hazard ratio (HR)=2,18), myocardial infarction (HR=2,6) and ischemic stroke/transient ischemic attack (HR=2,81) more than a year ago, as well as revascularization with percutaneous coronary intervention (PCI) versus coronary artery bypass grafting. For PCI, the prognosis was worse in case of incomplete revascularization, as well as when the intervention was limited to ≤2 arterial segments and the total length of stents &lt;26 mm. Among all predictors of poor prognosis, the most significant was high-risk PCI in combination with dual antiplatelet therapy for &lt;12 months (HR=6,7).Conclusion. For the first time, TE predictors in patients with CAD and MFA have been identified, which will improve secondary prevention in a category of patients with an extremely high risk of TEs.

Direct oral anticoagulants vs. vitamin K antagonists in patients with antiphospholipid syndrome: a systematic review and meta-analysis.

MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials comparing efficacy and safety of VKAs and DOACs inhibitors in patients with APS. Recurrent thrombosis, all-cause mortality, stroke, adverse reactions, and bleeding were among outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95% CIs. The analysis included 625 patients from four randomized controlled trials and one post hoc analysis. Meta-analysis showed statistically non-significant difference between DOACs inhibitors and VKAs in the recurrent thrombosis risk (arterial or venous) [RR 2.77 (95%, CI 0.79, 9.65); P=0.11, I2=50%]. Consistent results were revealed among patients with the previous history of arterial thrombosis [RR 2.76 (95% CI 0.93, 8.16); P=0.75, I2=0%], venous thrombosis [RR 1.71 (95% CI 0.60, 4.84); P=0.31, I2=15%] and patients who were triple antiphospholipid positive [RR 4.12 (95% CI 0.46, 37.10); P=0.21, I2=58%]. DOACs inhibitors were significantly associated with increased risk of stroke [RR 8.51 (95% CI 2.35, 3.82); P=0.47, I2=0%]. DOACs exhibited increased risk of stroke among patients with APS. In addition, although not significant, the higher RRs among patients on DOACs may indicate higher risk of thrombotic events associated with DOACs.

Intraindividual variability over time of thrombin generation in patients with cirrhosis

BackgroundPatients with cirrhosis are at high risk of thrombotic events, including portal vein thrombosis and venous thromboembolism. In such patients, hypercoagulability is not detected by conventional coagulation tests, but only by the thrombin generation assay (TGA) that integrates the role of pro- and anticoagulant factors. However, TGA use to predict clinical events depends on thrombin generation variability over time. ObjectivesThe aim of this study was to compare TGA intraindividual variability over time in patients with cirrhosis and in healthy controls. MethodsBlood samples were prospectively collected from 34 healthy controls and 52 patients with cirrhosis at week 0 (inclusion), 6, and 12. TGA was performed with the calibrated automated thrombogram method, tissue factor (5 pM), phospholipids, and with and without thrombomodulin (4 nM) or activated protein C (1 nM). ResultsWhen TGA was performed with thrombomodulin, endogenous thrombin potential in patients with cirrhosis was higher compared with controls and increased with cirrhosis severity. Stability over time of all thrombin generation parameters was excellent in healthy controls, good in Child-Turcotte-Pugh (CTP)-A patients, and poor in CTP-B/C patients (severe cirrhosis). In CTP-B/C patients, the phenotype was more variable because one-third of patients switched to normal or hypercoagulability during the 3-month follow-up. ConclusionA study with longer monitoring is needed to correlate the hypercoagulable phenotype of patients with cirrhosis with the occurrence of thrombotic events.

Monoclonal Gammopathy of Thrombotic Significance.

The current review provides an overview of the thrombotic risk observed in patients with MG who do not otherwise require treatment. We discuss clinical and biomarker studies that highlight the heterogenous hemostatic profile observed in these patients and how knowledge has evolved over the past 20 years. Biomarker studies suggest shared biologic features between multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS), which involves both hypercoagulability and platelet activation. Hemostatic abnormalities identified in MGUS patients cannot be translated into clinical practice as they lack correlation to clinical events. The prothrombotic phenotype of MGUS patients has not been ascertained yet, but novel data on coagulation markers are promising. We also review rare conditions associated with the thrombogenic properties of the monoclonal protein that predispose to arterial, venous or microthrombotic events and demonstrate that the M-protein can be linked to clinically significant thrombotic events. Cryoglobulinemia, cryofibrinogenemia, cryo-crystaloglobulinemia and MG-related antiphospholipid syndrome are reviewed. We propose the new umbrella term "monoclonal gammopathy of thrombotic significance" (MGTS) to refer to significant, recurrent thrombotic events in patients with MGUS that provide a rationale for targeting the underlying plasma cell clone. Identifying MGUS patients at high risk for thrombotic events is currently a challenge.

Platelet Indices: Is it a Reliable Biomarker in Viral Infections?

Platelets are non-nucleated blood cells that are essential for maintaining hemostasis. While platelet activation and increased platelet numbers (thrombocytosis) are associated with a higher risk of thrombotic events, low platelet counts (thrombocytopenia) and a variety of platelet function abnormalities are associated with a higher risk of bleeding. Platelets and their activation state have been proven in recent years to influence innate and adaptive immune responses, and low platelet counts have been identified as a surrogate indicator for poor prognosis in septic patients. Platelet activation frequently occurs in conjunction with viral infections. Viruses, on the other hand, can interact directly with platelets and megakaryocytes, modulating their function. All these factors contribute to platelet activation, which leads to increased platelet consumption and elimination, as well as thrombocytopenia, which is common during viral infection Platelets and their secreted products have been demonstrated to suppress infection and aid virus persistence in the presence of certain viruses, making platelets a double-edged sword during viral infections. In this review we have highlighted about what is currently known about platelet interactions with various types of viruses, virus effects on platelet activation, as well as platelet-mediated regulation of innate and adaptive immune responses.

A massive stroke in a pregnant woman following COVID-19 infection: A case report

Background and aims: COVID-19 infection increases the risk of pathological thrombotic events in venous and arterial circulation. COVID-19 patients are reported, a wide range of neurovascular symptoms is highlighted, such as cerebral vascular accidence. This study aimed to report a massive stroke in a pregnant woman with COVID-19 infection. Case Report: We report a 41-year-old pregnant woman, gravid 5 para 2 living 2 abortion 2 at gestational age 22 weeks and 4 days with Covid-19 infection, which developed into a massive stroke in the Basilar artery despite receiving a therapeutic dosage of Enoxaparin Sodium. Conclusion: The possibility of thrombosis should be considered in COVID-19 patients with symptoms indicating an increase in intracranial pressure (ICP) such as decreased consciousness, strabismus, and agitation. Considering the higher risk of thrombotic events in COVID-19 patients, cerebral venous sinus thrombosis (CVST) could be a possible consequence. Thus, the precise observation of neurologic manifestations in covid-19 patients, especially in pregnant women, is recommended.

Assessing the Relationship between Thrombosis and Immune-Related Adverse Events in Patients with Lung Cancer Treated with Immune Checkpoint Inhibitors

Introduction: Venous thromboembolisms (VTE) frequently occur in cancer patients, and the role of immune checkpoint inhibitors on thrombotic risk has been a rising concern for clinicians. Identifying pro-thrombotic risk factors could guide primary prophylaxis strategies in patients receiving immunotherapy. Immune checkpoint blockade can induce inflammatory side effects known as immune-related Adverse Events (irAE). Inflammatory states are known to be associated with a hypercoagulable state. It is not established whether patients treated with immunotherapy experience a higher risk of thrombotic events during periods of increased inflammation surrounding irAE occurrence. Similarly, while immune checkpoint inhibitors have been shown to be associated with increased bleeding events, it is not clear whether irAE occurrence affects incidence of hemorrhage. Our primary objective was to determine the association between irAE and thrombosis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors in order to better elucidate potential risk factors for thrombosis in patients on immunotherapy. Our secondary objective was to evaluate the association between irAE and clinically significant bleeding events. Methods: We identified all patients with non-small cell lung cancer treated with pembrolizumab at an academic medical center between 2016 and 2021. Outcomes of interest were VTE and clinically relevant bleeding (a composite of major bleeding and clinically-relevant non-major bleeds). We collected information regarding concurrent chemotherapy use with immunotherapy, frequency and type of irAE, steroid use for treatment for irAE, and use of anticoagulation or antiplatelet agents. We used logistic regression to calculate the odds ratios (OR) and 95% confidence intervals (CI) of VTE and clinically-relevant bleeding among patients who had an irAE prior to the outcome of interest compared to those who did not. We calculated the odds of VTE associated with use of concurrent chemotherapy (vs. no concurrent chemotherapy). Results: Of 102 patients included, 46.1% were female, and average age at diagnosis was 66.8 ± 10.5 years. Thirty-four patients were treated with pembrolizumab alone, with the remainder receiving concurrent chemotherapy and/or targeted therapy with pembrolizumab. Overall, 21 patients experienced thrombotic events (20.6%), 7 (6.9%) experienced clinically-relevant bleeding events, and 28 (27%) experienced an irAE. (Table 1). Overall, occurrence of irAE was not associated with increased odds of VTE (OR: 1.07, 95% CI: 0.37-3.11, P=0.90). (Figure 1). Similarly, among those with an irAE, steroid treatment was not associated with increased odds of VTE (OR: 1.14, 95% CI: 0.17-7.69, P=0.89). The combination of chemotherapy with pembrolizumab did not result in a statistically significant increase in odds of VTE (OR: 1.37, 95% CI: 0.52-3.60, P=0.53). The odds of clinically-relevant bleeding was not statistically higher among those with an irAE (OR: 2.10, 95% CI: 0.44-10.0, P=0.35). Conclusions: The development of irAE in patients with NSCLC treated with pembrolizumab does not appear to predict the development of VTE. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Values and Preferences Towards Antithrombotic Therapy in Patients with Myeloproliferative Neoplasms: A Qualitative Study

Background: Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocythemia (ET), confer a high risk for thrombotic events. The primary and secondary prevention of thrombotic events is managed with antithrombotic therapy, which is complicated by a high frequency of bleeding in Ph- MPN patients. When making shared decisions about antithrombotic therapy, physicians and patients must weigh thrombotic and bleeding risks and their consequences. However, little is known about the preferences and perceptions of patients with MPNs regarding antithrombotic therapy. The objectives of this study were therefore to identify: 1) patient-important factors and 2) barriers and facilitators to the use of antithrombotic therapy as thromboprophylaxis among patients with MPNs. Methods: In this qualitative study, semi-structured focus groups (FGs) were conducted with people diagnosed with PV and ET recruited via email from Canadian MPN Patient Support Groups. Focus groups were stratified based on previous history of a bleed requiring medical attention, previous history of thrombosis, or no history of bleeding or thrombosis. Open-ended questions and probes were used to guide FG discussions and FGs concluded with a polling exercise in which participants selected the most important facilitators and barriers to antithrombotic medication use. Data were analyzed using thematic analysis and the techniques of the Framework Method (Gale et al., 2013). Two team members independently reviewed and coded FG audio transcripts using NVivo to develop a coding framework. Coding comparison queries were run to assess agreement, discussion was used to resolve discrepancies, and the coding framework was iteratively refined. Data were reviewed by two members of the study team and preliminary themes were identified, guided by the research objectives. Results: We present preliminary results of our analysis. Four FGs were conducted with a total of 18 participants (range 3-6 participants). The average age of participants was 59 years, 13 (72%) were female and 10 (56%) had ET. Participants were taking aspirin (16/18, 89%), warfarin (1/18, 5%), and apixaban (1/18, 5%). Three participants (17%) had a prior thrombotic event, (ischemic stroke, myocardial infarction, and splanchnic vein thrombosis), and 3 (17%) had a prior bleeding event (epistaxis, gastrointestinal [GI] bleeding). The most important factors identified for taking antithrombotic therapy were preventing thrombotic events (94%) and a physician's recommendation (83%). Many participants perceived there was no choice when it came to the decision to use antithrombotic therapy; rather it was a physician-prescribed, necessary treatment to prevent thrombosis. Perceived downsides to antithrombotic therapy included the higher risk of bleeding, prolonged bleeding, and bruising, with specific concern about the visibility of bruises. Several participants also voiced concerns about the impact of long-term aspirin use on GI health and the potential for ulcer formation. A few participants reported lowering their dose of aspirin, as per physician recommendations or by self-adjusting the dose based on concerns about GI bleed risk. However, some participants did not perceive any downsides to using antithrombotic therapy or considered that the benefits outweighed the risks, while others were less certain. Additional analyses are underway. Conclusion: Patients with MPNs accept antithrombotic therapy use, motivated by trust in their physician's recommendations and the desire to prevent a stroke or myocardial infarction. While these values and preferences align with PV and ET treatment guidelines, it is important to recognize the influence that physician recommendations have on patients' perceptions towards antithrombotic therapy in the shared decision-making process.

Variables associated with bleeding and thrombotic outcomes among patients admitted to the hospital with COVID-19 and elevated D-dimer: insights from the ACTION randomised clinical trial

Abstract Background In the ACTION trial, therapeutic anticoagulation did not show benefit on mortality, days of hospitalization and oxygens therapy at 30 days among patients with COVID19. However, this strategy was associated with higher rate of bleeding and a potential reduction in the rate of clinical thrombotic events. The current analysis evaluated which variables were independently associated with both outcomes in order to help the identification of the risk for thrombotic and hemorrhagic events among patients with COVID19. Methods A total of 615 patients hospitalized with COVID-19 and elevated D-dimer levels were randomly assigned to prophylactic anticoagulation (mainly in-hospital heparin) or a therapeutic strategy that used in-hospital rivaroxaban 20 mg daily for stable patients, or enoxaparin 1 mg/kg twice daily for unstable patients, followed by rivaroxaban through 30 days. One patient withdrew consent and was not included in the analysis. The current analysis tested baseline clinical characteristics and laboratorial exams one by one with independent logistic regressions for the composite of bleeding (major bleeding and clinically relevant nonmajor bleeding) and thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, and major adverse limb events). Significant variables (p&amp;lt;0.05) were selected to adjust several multiple logistic models. Final models were chosen based on Akaike information criterion and therapeutic anticoagulation was included in the final model based on the primary results of the trial. Results The model for bleeding events showed an accuracy of area under the curve (AUC) of 0.635 (table 1) while the model for thrombotic events had an AUC of 0.725 (table 2). Level of respiratory support (especially invasive ventilation) was associated with both outcomes in the multivariable analysis (tables 1 and 2). Beyond respiratory support, level of creatinine and history of coronary disease were also independently associated to the risk of thrombotic events. When the utilization of therapeutic anticoagulation (mainly with rivaroxaban) was included in the multivariable analysis, this variable was strongly associated with higher risk of bleeding (model AUC of 0.718) but was not associated with lower rate of thrombotic events (Tables 1 and 2). Conclusion Since the variables associated with higher risk of thrombotic events are similar to the variables associated to bleeding complications, the selection of patients with better balance of risk vs. benefit to use therapeutic anticoagulation in COVID-19 still a challenging decision. Coronary disease and creatine may help to identify patients at higher risk of thrombotic complications while the use of therapeutic dose of direct oral anticoagulant increased the risk of bleeding in almost 4 times among patients hospitalized due to COVID19. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Investigator initiated research with financial support of Bayer

A randomized, cross-over study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of milvexian with single and dual antiplatelet therapy in healthy participants

Abstract Background According to scientific evidence, modulation of Factor XI (FXI) function may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically relevant bleeding in a variety of conditions associated with a high risk of thrombotic events. Milvexian (BMS-986177/JNJ-70033093) is an oral small molecule that binds reversibly to and inhibits the active form of FXI (FXIa) with high affinity and selectivity. Depending on the patient population, milvexian is expected to provide benefit to patients as replacement or add on therapy to current guideline-recommended antithrombotic agents which include aspirin and/or clopidogrel. Purpose This DDI study aimed to investigate the safety and to identify possible pharmacokinetic (PK) or pharmacodynamic (PD) interaction of milvexian when co-administered with aspirin and/or clopidogrel. Methods The study consisted of 3 parts, each of which was a single DDI study using a randomized, 3-period, 3-treatment crossover design. Six unique treatment sequences were utilized in the study. Milvexian was placebo controlled and blinded when co-administered with aspirin and clopidogrel (Part 1), with clopidogrel (Part 2), or with aspirin (Part 3). In each case the subjects crossed over to milvexian monotherapy. Subjects were randomly assigned into 1 part of the study only. Results Overall, multiple dose milvexian 200 mg given BID for 5 days with and without dual antiplatelet therapy (clopidogrel given as 300 mg on Day 1 followed by 4 days of 75 mg clopidogrel, and aspirin 325 mg once daily given for 5 days) was safe and well tolerated. There were 8 mild bleeding adverse events (AEs) reported from 5 subjects in various treatment groups; no trend towards increased bleeding potential was observed when milvexian was co-administered with dual antiplatelet therapy or separately with aspirin or clopidogrel. After co-administration of aspirin and clopidogrel with milvexian, peak (Cmax) and total exposure [AUC(TAU)] of milvexian were reduced 17% and 15%, respectively, on Day, 1 but were not changed on Day 5, compared to milvexian administered alone. After co-administration of clopidogrel or aspirin separately with milvexian, peak and total exposures of milvexian were not changed, compared to milvexian administered alone. Exposure-dependent prolongation of activated partial thromboplastin time (aPTT) and reduction of Factor XI clotting activity (FXIc) were observed with milvexian administration. Effects were similar when milvexian was administered alone or in combination with aspirin and/or clopidogrel. Conclusion This Phase 1 study in healthy adults demonstrated administration of milvexian alone or in combination with aspirin and/or clopidogrel was not associated with a trend towards AE's including bleeding. Milvexian steady-state exposure and PD effects were similar when milvexian was administered alone or in combination with aspirin and/or clopidogrel. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bristol Myers Squibb and Janssen Pharmaceuticals

Prediction of thrombosis in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study on 1258 patients.

Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events.