Occurrence Of Thrombotic Events Research Articles

#280 Effectiveness and safety of direct oral anticoagulants vs VKA in patients on chronic dialysis: a target trial emulation using nationwide registry data

Abstract Background and Aims The mortality and morbidity rates among patients on dialysis remain high and cardiovascular disease is the leading cause of death in this population. In chronic kidney disease (CKD), a major thromboembolic risk is paradoxically associated with a major haemorrhagic risk. Hence, the prescription of oral anticoagulants in CKD patients is challenging. Clinical trials of direct oral anticoagulants (DOAC) are scarce and inconclusive in patients who are receiving dialysis, for whom DOAC are not labelled in Europe. In an exhaustive French nationwide registry of patients undergoing chronic dialysis, we compared the effectiveness and safety of off-label DOAC use versus approved vitamin K antagonist (VKA). Method Data on patients on dialysis were extracted from the French Renal Epidemiology and Information Network (REIN) registry and merged with data from the French national healthcare system database (Système National des Données de Santé, SNDS). Patients on dialysis who had initiated treatment with an oral anticoagulant between January 1st, 2012, and December 31st, 2020, were eligible for inclusion. The primary safety outcome was the occurrence of major bleeding events and the primary effectiveness outcome was the occurrence of thrombotic events. Using target trial emulation design, we compared the safety and effectiveness outcomes for DOAC and VKA using propensity-score-weighted cause-specific Cox regression. Results 8 954 patients received an oral anticoagulant (483 DOAC and 8 471 VKA) for the first time after the initiation of dialysis. Over a median [interquartile range] follow-up period of 1.7 [0.8-3.2] years, 2 567 patients presented a first thromboembolic event and 1 254 patients had a bleeding event. After propensity score adjustment, the risk of a thromboembolic event was significantly lower in patients treated with a DOAC than in patients treated with a VKA (weighted hazard ratio (HR) [95% confidence interval (CI)]: 0.66 [0.46; 0.94] (Figure). A non-significant trend toward lower risk of major bleeding events was found in patients treated with a DOAC compared to patients treated with a VKA (weighted HR [95% CI]: 0.68 [0.41; 1.12]) (Figure). Sensitivity analyses showed the same trends. Conclusion The fact that patients on dialysis are excluded from large, cardiovascular-disease-focused randomized controlled trials (such as those with DOACs) significantly limits the evidence needed to make clinical decisions. Most of the retrospective cohort studies comparing these two drug classes were performed in the USA, where, in contrast to Europe, apixaban has been approved for the treatment of non-valvular fibrillation in patients on haemodialysis. Our real-world study of patients on dialysis is one of the first of its type to have assessed the effectiveness and safety of off-label DOAC prescription (relative to VKA prescription) in Europe. In a large group of dialysis patients initiating oral anticoagulation, the off-label use of DOACs was associated with a statistically significant lower risk of thromboembolic events, and a non-significant trend toward lower risk of bleeding relative to VKA use. These results are reassuring with regard to the off-label use of DOACs and might facilitate the establishment of an expert consensus and guidelines on antithrombotic therapy in patients with ESKD.

Biochemical risk factors and outcomes of acute promyelocytic leukemia patients with thrombotic events: a matched pair analysis.

Acute promyelocytic leukemia (APL) stands out as a distinctive form of acute leukemia, exhibiting a higher occurrence of thrombotic events when contrasted with other leukemia subtypes. Since thrombosis is a relatively rare but unfavorable condition with poor prognostic implications, it is crucial to determine the risk factors for thrombotic events in APL(thrombosis in large venous or arterial from onset to differentiation therapy in 30d). We performed a retrospective study involving 950 APL patients between January 2000 and October 2022, from which 123 were excluded by younger than 16years of age, 95 were excluded by incomplete data, and 6 were excluded by thrombosis related to CVC or PICC. A total of 23 APL patients with thrombosis for inclusion in our analysis were performed a 1:5 ratio matching based on sex (perfect match) and age (within 5years) to patients without thrombosis. These patients were continuously monitored in the outpatient department over a period of 5years. We meticulously examined clinical and laboratory data to pinpoint the risk factors related to thrombotic events in APL. Our primary clinical endpoints were all-cause mortality and achieving complete remission, while secondary clinical outcomes included APL relapse. Thrombotic events were observed in 2.4% (23/950) of APL patients. Compared to patients without thrombosis, patients with thrombosis had higher lactate dehydrogenase (LDH) [313 (223, 486) vs. 233 (188, 367) U/L, p = 0.020], higher indirect bilirubin [11.2 (7.4, 18.6) vs.8.3 (6.0, 10.7) umol/L, p = 0.004], higher creatinine [72 (62, 85) vs. 63 (54, 74) umol/L, p = 0.026], higher CD2 expression (65.2 vs. 15.2%, p < 0.001), higher CD15 expression (60.9 vs. 24.3%, p = 0.001), and PML/RARαisoforms (p < 0.001). Multivariate-logistic-regression analysis revealed several factors that were markedly related to thrombosis, including LDH (OR≈1.003, CIs≈1.000-1.006, p = 0.021), indirect bilirubin (OR≈1.084, CIs≈1.000-1.188, p = 0.043), CD2 expression positive (OR≈16.629, CIs≈4.001-62.832, p < 0.001), and CD15 expression positive (OR≈7.747, CIs≈2.005-29.941, p = 0.003). The S-type (OR≈0.012, CIs≈0.000-0.310, p = 0.008) and L-type (OR≈0.033, CIs≈0.002-0.609, p = 0.022) PML/RARα isoforms were negatively associated with thrombosis. Kaplan-Meier curves indicated that the survival rates were remarkably varied between APL patients with and without thrombosis (HR:21.34, p < 0.001). LDH and indirect bilirubin are variables significantly associated with thrombosis in APL, S-type and L-type PML/RARαisoforms exhibit a negative association with thrombotic events. The thrombotic events of APL can predict the subsequent survival of thrombosis. The findings of our study have the potential to facilitate early detection of thrombosis and enhance the prognosis for individuals with APL who develop thrombosis. Further validation of our findings will be essential through future prospective or multicenter studies.

AF-React study: Prevalence of thrombotic events in patients with atrial fibrillation receiving NOACs - real-world data analysis from northern Portugal primary healthcare.

Anticoagulation is recommended for stroke prevention in patients with atrial fibrillation (AF). The guidelines suggest non-vitamin K antagonist anticoagulants (NOACs) as the primary therapy for anticoagulation in AF. Several patient-related factors increase the risk of thrombotic events: elderly individuals, a previous history of stroke, and chronic kidney disease. This study aims to determine the association between NOACs and other patient variables in AF and the occurrence of thrombotic events. The database included all adults with the code K78 (ICPC-2 code for AF) who received clinical care in Northern Portugal's Primary Health Care between January 2016 and December 2018 and were dispensed the same NOAC at the pharmacy. The results indicate that 10.2% of AF patients on NOAC anticoagulation experienced a stroke. Furthermore, patients treated with apixaban and dabigatran had higher odds of experiencing a stroke compared to those treated with rivaroxaban. Among patients with the same age, gender, and CHA2DS2Vasc Score, apixaban was significantly associated with a higher likelihood of thrombotic events than rivaroxaban. These results have not been previously reported in studies with real-world data; therefore, a more detailed analysis should be conducted to enhance the validity of these findings.

Insight into antiphospholipid syndrome: the role and clinical utility of neutrophils extracellular traps formation

Antiphospholipid syndrome (APLS) is a systemic immune dysregulation distinguished by repetitive complications and pregnancy loss in the absence of definite etiology. Most research focuses on the laboratory detection and clinical features of APLS, but its precise etiology remains to be deeply explored. NETosis is a newly developed theory in the pathophysiology of APLS which may serve as the missing bridge between coagulation and inflammation reaching the disease progression and severity. We aimed in this study to navigate the prognostic role of NETosis in thrombotic APLS. Our study included 49 newly diagnosed APLS patients (both 1ry and 2ry) who met clinical and laboratory criteria as per the international consensus statement on the update of the classification criteria for definite APLS and were sub-classified according to the occurrence of thrombotic events in thrombotic and non-thrombotic types. In addition, 20 sex and age-matched reactive subjects and 20 sex and age-matched healthy volunteer controls were enrolled. NETosis formation was assessed by measuring serum Myeloperoxidase (MPO) and Histones level using the enzyme-linked immunosorbent assay (ELISA) technique. Both MPO and Histones levels were able to discriminate among APLS cases from normal controls, showing significant cutoffs of > 2.09 ng/ml for MPO and > 1.45 ng/ml for Histones (AUC values were 0.987and 1.000, respectively). These values can be used as predictors for NETosis pathophysiology in APLS patients. Additionally, these markers demonstrated a significant association with several prognostic indicators, including thrombosis, higher PT and INR, and lower hemoglobin (Hb) levels which are supposed to be ameliorated by using NETs inhibitors. In conclusion, we suggest that measuring NETosis markers, MPO, and Histones, in the early course of APLS using proposed cutoff values will facilitate the timely initiation of anti-NETosis therapy and improve the overall prognosis, particularly for patients with thrombotic APLS.

The role of leukocytes in myeloproliferative neoplasm thromboinflammation.

Classic myeloproliferative neoplasms lacking the Philadelphia chromosome are stem cell disorders characterized by the proliferation of myeloid cells in the bone marrow and increased counts of peripheral blood cells. The occurrence of thrombotic events is a common complication in myeloproliferative neoplasms. The heightened levels of cytokines play a substantial role in the morbidity and mortality of these patients, establishing a persistent proinflammatory condition that culminates in thrombosis. The etiology of thrombosis remains intricate and multifaceted, involving blood cells and endothelial dysfunction, the inflammatory state, and the coagulation cascade, leading to hypercoagulability. Leukocytes play a pivotal role in the thromboinflammatory process of myeloproliferative neoplasms by releasing various proinflammatory and prothrombotic factors as well as interacting with other cells, which contributes to the amplification of the clotting cascade and subsequent thrombosis. The correlation between increased leukocyte counts and thrombotic risk has been established. However, there is a need for an accurate biomarker to assess leukocyte activation. Lastly, tailored treatments to address the thrombotic risk in myeloproliferative neoplasms are needed. Therefore, this review aims to summarize the potential mechanisms of leukocyte involvement in myeloproliferative neoplasm thromboinflammation, propose potential biomarkers for leukocyte activation, and discuss promising treatment options for controlling myeloproliferative neoplasm thromboinflammation.

N-Acetylcysteine To Reduce Mortality For Patients Requiring Cardiac Catheterization or Cardiac Surgery: A Systematic Review And Meta-Analysis.

Multimers of von Willebrand factor (VWF) play a critical role in various processes inducing morbidity and mortality in cardiovascular risk patients. With the ability to reduce VWF multimers, N-acetylcysteine (NAC) could reduce mortality in patients undergoing coronary catheterization or cardiac surgery. However, its impact in perioperative period has never been studied so far in regard of its potential cardiovascular benefits. Then, four databases were searched for randomized controlled trials that compared in-hospital mortality between an experimental group, with NAC, and a control group without NAC, in patients undergoing coronary catheterization or cardiac surgery. The primary efficacy outcome was in-hospital mortality. Secondary outcomes were the occurrence of thrombotic events, major cardiovascular events, myocardial infarction, and contrast induced nephropathy. The safety outcome was occurrence of hemorrhagic events. Nineteen studies totaling 3718 patients were included. Pooled analysis demonstrated a reduction of in-hospital mortality associated with NAC: Odds Ratio (OR), 0.60; 95% CI, 0.39-0.92; P=0.02. The occurrence of secondary outcomes was not significantly reduced with NAC except for contrast-induced nephropathy. No difference was reported for hemorrhagic events. Subgroup analyses revealed a life-saving effect of NAC in a dose-dependent manner with reduction of in-hospital mortality for the NAC high-dose group, but not for the NAC standard-dose (<3500 mg) group. In conclusion, without being able to conclude on the nature of the mechanism involved, our review suggests a benefit of NAC in cardiovascular risk patients in perioperative period in terms of mortality and supports prospective confirmatory studies.

Thrombosis Tendency After Splenectomy in a Danish Family With Hemoglobin Volga, and a Literature Review

Hemoglobin (Hb) Volga is a rare, unstable β-chain hemoglobin variant (β27 Ala→Asp), causing chronic hemolytic anemia. This study presents two members of a Danish family, splenectomized due to Hb Volga at and with multiple thrombotic events. The proband was diagnosed with Hb Volga 9 years old and splenectomy was performed as a part of treatment. Throughout his life, he experienced multiple superficial thrombophlebitis, two episodes of distal deep venous thrombosis (DVT) on lower extremities (age 32 and 33) and a transient ischemic attack (TIA) presented as amaurosis fugax (age 51). Thrombophilia investigation was normal. The proband’s son was diagnosed with Hb Volga and underwent splenectomy at the age of 6. Despite anticoagulation therapy, he suffered from multiple venous thromboembolic events in his youth and died of chronic pulmonary embolism (PE)/pulmonary hypertension combined with infection. Given the observed propensity for multiple thromboses in these two patients, a literature review was conducted investigating reported occurrence of thrombotic events in individuals with Hb Volga. Currently 25 cases of Hb Volga are reported worldwide. The clinical symptoms primarily described are related to hemolytic anemia. Splenectomy is reported in 15 patients. Thromboses have previously been reported in only three patients who were also splenectomized. These cases involved DVT and PE, myocardial infarction, and an unspecified thrombotic event. The proband represents the first reported Hb Volga case with both venous and arterial thrombotic disorders. The exact mechanism underlying thrombotic tendency in patients with Hb Volga remains unknown, but it is probably associated with splenectomy.

Factores asociados con el diagnóstico de síndrome antifosfolípido: ¿cuándo debemos solicitar los estudios?

IntroductionIn clinical practice, there is no established guidance on the timing of sample collection when suspicion of antiphospholipid syndrome (APS) arises. Instead, only a list of risk factors for APS exists, without adequate quantification of the significance of each factor. Materials and methodsAnalytical observational case-control study, nested in a retrospective cohort of patients with venous or arterial thrombosis in whom APS was suspected. Patients with a confirmed diagnosis of APS according to the Sapporo criteria or triple positive initial result (cases) were compared with patients negative for APS (controls). The aim was to assess the association between the diagnosis of APS and various clinical and paraclinical factors. Results68 patients were included (72% women, 41.2% with deep venous thromboembolism and 29.4% with pulmonary embolism). In 18 patients APS was confirmed. There were no significant differences in age in patients with and without confirmation of the diagnosis (44.0±17.9 vs. 51.2±14.9, P=.069). In the multivariate analysis, a significant and independent association was found between having APS and rheumatic disease (OR: 12.1, P=.02), PTT prolongation (OR: 17.6, P=.014), platelet count <150,000 (OR: 18.6, P=.008), and a history of previous thrombosis events (OR: 6.1 for each event, P=.027). ConclusionsIn patients with arterial or venous thrombosis, there is a greater possibility of confirming APS if there is a history of rheumatic disease, prolongation of PTT to more than 5seconds, thrombocytopenia, and previous events of thrombotic disease. In these patients, it is advisable to screen for APS, to prevent the further occurrence of thrombotic events.

Effectiveness and safety of direct oral anticoagulants versus vitamin K antagonists in patients on chronic dialysis: a nationwide registry study.

Clinical trials of direct oral anticoagulants (DOAC) are scarce and inconclusive in patients who are receiving dialysis, for whom DOAC are not labelled in Europe. In a French nationwide registry study of patients on chronic dialysis, we compared the effectiveness and safety of off-label DOAC use vs. approved vitamin K antagonist (VKA). Data on patients on dialysis were extracted from the French Renal Epidemiology and Information Network (REIN) registry and merged with data from the French national healthcare system database (Système National des Données de Santé, SNDS). Patients on dialysis who had initiated treatment with an oral anticoagulant between January 1st, 2012, and December 31st, 2020, were eligible for inclusion. The primary safety outcome was the occurrence of major bleeding events and the primary effectiveness outcome was the occurrence of thrombotic events. Using propensity-score-weighted cause-specific Cox regression, we compared the safety and effectiveness outcomes for DOAC and VKA. 8,954 patients received an oral anticoagulant (483 DOAC and 8,471 VKA) for the first time after the initiation of dialysis. Over a median [interquartile range] follow-up period of 1.7 [0.8-3.2] years, 2,567 patients presented a first thromboembolic event and 1,254 patients had a bleeding event. After propensity score adjustment, the risk of a thromboembolic event was significantly lower in patients treated with a DOAC than in patients treated with a VKA (weighted hazard ratio (wHR) [95% confidence interval (CI)]: 0.66 [0.46; 0.94]. A non-significant trend toward a lower risk of major bleeding events was found in DOAC-treated patients, relative to VKA-treated patients (wHR [95%CI]: 0.68 [0.41; 1.12]). The results were consistent across subgroups and in sensitivity analyses. In a large group of dialysis patients initiating an oral anticoagulant, the off-label use of DOACs was associated with a significantly lower risk of thromboembolic events and a non-significantly lower risk of bleeding, relative to VKA use. This provides reassurance regarding the off-label use of DOACs in people on dialysis.

COVID-19: Not a thrombotic disease but a thromboinflammatory disease.

While Coronavirus Disease in 2019 (COVID-19) may no longer be classified as a global public health emergency, it still poses a significant risk at least due to its association with thrombotic events. This study aims to reaffirm our previous hypothesis that COVID-19 is fundamentally a thrombotic disease. To accomplish this, we have undertaken an extensive literature review focused on assessing the comprehensive impact of COVID-19 on the entire hemostatic system. Our analysis revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection significantly enhances the initiation of thrombin generation. However, it is noteworthy that the thrombin generation may be modulated by specific anticoagulants present in patients' plasma. Consequently, higher levels of fibrinogen appear to play a more pivotal role in promoting coagulation in COVID-19, as opposed to thrombin generation. Furthermore, the viral infection can stimulate platelet activation either through widespread dissemination from the lungs to other organs or localized effects on platelets themselves. An imbalance between Von Willebrand Factor (VWF) and ADAMTS-13 also contributes to an exaggerated platelet response in this disease, in addition to elevated D-dimer levels, coupled with a significant increase in fibrin viscoelasticity. This paradoxical phenotype has been identified as 'fibrinolysis shutdown'. To clarify the pathogenesis underlying these hemostatic disorders in COVID-19, we also examined published data, tracing the reaction process of relevant proteins and cells, from ACE2-dependent viral invasion, through induced tissue inflammation, endothelial injury, and innate immune responses, to occurrence of thrombotic events. We therefrom understand that COVID-19 should no longer be viewed as a thrombotic disease solely based on abnormalities in fibrin clot formation and proteolysis. Instead, it should be regarded as a thromboinflammatory disorder, incorporating both classical elements of cellular inflammation and their intricate interactions with the specific coagulopathy.

Hemostatic Efficacy and Safety of Weight-Based Versus Fixed-Dose 4F-PCC for Vitamin K Antagonist Reversal.

Background: Four-factor prothrombin complex concentrate (4F-PCC) is indicated for vitamin K antagonist (VKA) reversal but is associated with thrombotic events (TE). In 2018, the institution revised 4F-PCC dosing for VKA reversal from INR and weight-based dosing to a fixed-dose of 1500 units. Objective: The purpose of this study was to compare hemostatic efficacy and TE rate of fixed-dose 4PCC to weight-based dosing. Methods: This was a retrospective, single-center, quasi-experimental study of adult patients who received 4F-PCC for VKA reversal from January 2014 through May 2016 (INR and weight-based dosing) or April through October 2018 (fixed-dosing). The primary endpoint was hemostatic efficacy, defined by achieving an INR of ≤1.4, or an INR of ≤1.7 with evidence of hemostasis. The key secondary endpoint was TE within 14 days of 4F-PCC administration. Data were analyzed using descriptive statistics, chi-squared for nominal data and Mann-Whitney U for ordinal and continuous data. Results: The study included 163 patients who received weight-based dosing and 45 who received fixed-dose 4F-PCC. Hemostatic efficacy was 76.9% of patients in the weight-based group and 77.4% of patients in the fixed-dose group (P = .229). TE occurred in 13.5% of the weight-based vs 6.7% of the fixed-dose group (P = .181). Conclusion: This study found no difference in hemostatic efficacy with fixed-dose 4F-PCC for VKA reversal compared to INR and weight-based dosing. The occurrence of TE was reduced by 50% with the 4F-PCC fixed-dose strategy; however, this difference was not statistically significant. Further randomized studies are needed to confirm these results.

Transferrin and Erythropoietin Increased Levels Correlate with Thrombosis at High Altitude

Living at high altitude involves great interest because of the challenging multiple adaptive responses to a hypoxic environment. Native Bolivian Andeans have lived at an altitude of 4000 m in The Andes mountains for about 14,000 years exposed to a low atmospheric pressure (453 mmHg) and low oxygen concentration (12,7%). It was described Andeans adaptation to high altitude is mainly related to cardiovascular issues (PMID: 29100088), with a low significantly genetic selection in HIF pathway components responsible of erythropoiesis regulation (PMID: 36980912), so that they have adapted to exist with increased hemoglobin concentrations. Thus, Andeans can be prevalent to undergone hematological and thromboembolic disorders. Thrombotic events have been reported to be increased at high altitude, and this recently associated to increased transferrin (Tf) (PMID: 36040436), likewise to increased erythropoietin (Epo) (Amaru, RevMed 2022). Increased Tf were described to be induced by both iron deficiency and hypoxia via HIF (PMID: 9242677). In addition, iron deficiency was postulated to inhibit the function of prolyl hydroxylase 2 (PHD2) in the hydroxylation of HIF-2, necessary for recognition and degradation by VHL (PMID:22304911). Under normal conditions, Tf is bound to fibrinogen at a molar ratio of 4:1, leading to plasma Tf sequestration by fibrinogen and leaving little Tf free in the circulation. While at hypoxia conditions, abnormally upregulated Tf potentiates thrombin, factor XIIa and inhibits antithrombin, inducing hypercoagulability (PMID:36040436). Similarly, increased HIF1a at high altitude increases Tf promoting the transferrin gene expression, which contains HIF-1α binding sites in its enhancer region (PMID:36844187). HIF is a DNA-binding transcription factor for activating expression of Epo gene (PMID:32561149). Epo, in turn, is increased due to the hyperegulation of HIF as expected at low atmospheric pressure environments. Epo activates the hypoxia-inducible factor that leads to Epo synthesis to stimulate red blood cell production, which also increases the demand for iron to synthesize hemoglobin (PMID:21078592). This, added to a decreased iron and increased HIF 1a, gives rise to a hyperregulation of Tf. Epo has been described to have prothrombotic properties and be related to thrombotic events (PMID:10779449; Amaru, RevMed 2022). In this sense, to further observe a correlation of transferrin and erythropoietin increased levels with the risk of thrombotic events at high altitude, we studied patients with erythrocytosis, anemia and polycythemia vera. We analyzed clinical, lab tests and epidemiological data of 920 patients with Chronic Mountain Sickness erythrocytosis (CMS-e) (n=560), anemia (n=372), and Polycythemia Vera (PV) (n=20), all Bolivian Andeans born and residing at 4000 m. Considering at this altitude normal hemoglobin concentrations vary from 14-17 g/dl in women and 15-18 g/dl in men, erythrocytosis condition comprises Hb levels &amp;gt;18 g/dl in women and &amp;gt;19 g/dl in men (Amaru et al, Rev Hematol Mex, 2016); similarly, it embraces Hb &amp;lt;12 g/dl for women and &amp;lt;13 g/dl for men in anemias (PMID: 23317073). Positive JAK F617V tests were corroborated in PV patients. Iron deficiency correlation considered serum ferritin &amp;lt;30 ug/L and MCV &amp;lt;80 fL (Clark et al, Nutrition, 2008). Eco-doppler study records confirmed the occurrence of thrombotic events. Data analysis was performed through Excel 16.29.1 and SPSS program, Chi-squared, Fishers and Pearson tests were done. We observed significative increased Tf levels in erythrocytosis, anemia, and PV patients mainly on those presenting iron levels deficiency. Epo was highly increased in erythrocytosis patients with iron deficiency. These results correlated with the incidence of thrombotic events in erythrocytosis (CMS-e) and anemia patients with iron deficiency. Age was also relevant in both groups. (Table 1). The increase of Epo levels correlated with thrombosis in erythrocytosis and PV patients with iron deficiency (Table 1). Transferrin and Erythropoietin increased levels at high altitude correlated with thrombosis in Chronic Mountain Sickness erythrocytosis and iron deficiency anemia patients. However, Increased Tf did not correlate with thrombosis in PV patients at high altitude. Our data confirm that increased Tf and Epo have prothrombogenic properties in CMS-e, iron deficiency anemia patients at high altitude.

Effect of Factor VIII and Von Willebrand Factor Activities on Number of Bleeding Events in Previously Treated Patients with Von Willebrand Disease on Regular Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate

Background: von Willebrand disease (VWD) is characterized by a deficiency or reduction of activity in von Willebrand factor (VWF). As VWF has a role in stabilizing coagulation factor VIII (FVIII), VWD patients often suffer from secondary FVIII deficiency. Current guidelines recommend that VWD patients with a history of severe and frequent bleeds should use long-term prophylaxis with factor replacement therapy. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII concentrate containing VWF and FVIII in a 1:1 activity ratio (pdVWF/FVIII; wilate ®) in adults and children with VWD. The primary endpoint was met, showing a decrease of 84% in the mean total annualized bleeding rate (ABR). As elevated levels of FVIII are associated with an increased risk for thrombosis, it is important to determine whether repeated dosing with pdVWF/FVIII leads to accumulation of FVIII over time. Aims: To investigate the activity levels of VWF and FVIII in patients with VWD receiving regular prophylaxis with pdVWF/FVIII. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years old with VWD type 1 (VWF:RCo &amp;lt;30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a pdVWF/FVIII concentrate during a 6-month, prospective, observational, run-in study (WIL-29). Patients in WIL-31 received regular pdVWF/FVIII prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. VWF activity (VWF:RCo) and FVIII activity (measured by the chromogenic [Chr] and one-stage [OS] assays) were performed at baseline and throughout the study. Full pharmacokinetic (PK) analyses were performed in all patients aged 6-16 years, a single dose of 60 ± 10 IU/kg pdVWF/FVIII was administered. Samples were collected at up to 1 hour prior to injection and then at multiple time points post-injection (1-72 hours). Safety, including the occurrence of thrombotic events, was monitored throughout the study. Results: The overall study population included 33 patients, with a median age of 18 years consisting of 9 (27.3%) patients aged 6-11 years, 6 (18.2%) patients aged 12-16 years, and 18 (54.5%) patients aged ≥17 years. Six (18.2%) patients had severe type 1 VWD, 5 (15.2%) patients had type 2, and 22 (66.7%) patients had type 3. Baseline FVIII and VWF activities in WIL-31 were similar regardless of age group, and as expected were lower in patients with type 3 VWD compared with severe type 1 and type 2 (Figure 1). There was a negative correlation of baseline FVIII and VWF activity with the number of spontaneous bleeding episodes (BEs) during prophylaxis. Patients who had no spontaneous BEs during prophylaxis had higher baseline FVIII and VWF levels compared with those who had spontaneous BEs. Mean peak and trough FVIII and VWF activity levels remained consistent during the study and there was no accumulation of either factor over the 12-month prophylaxis period (Figure 2). Full PK assessments were performed according to protocol in 13 patients aged 6-16 years. The mean ± standard deviation in vivo half-life was 16.1±6.7, 16.2±7.7, and 9.8±7.7 hours, for FVIII Chr, FVIII OS, and VWF:RCo, respectively. No thrombotic events were observed. Conclusion: No accumulation of FVIII or VWF in the plasma was reported in 33 patients who received regular prophylaxis with pdVWF/FVIII for 12 months, regardless of VWD type and age.

Efficacy and Safety of Activated Prothrombin Complex Concentrate for Reversal of the Anticoagulant Effect of Apixaban and Rivaroxaban in Patients with Major Bleeding.

The use of activated prothrombin complex concentrate (aPCC) to treat direct oral anticoagulant (DOAC)-associated bleeding is off-label and clinical experience is limited. We aimed to assess the efficacy and safety of aPCC in reversing the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding. A retrospective cohort study of adult non-randomized patients was conducted at a tertiary referral medical center in the United States (US) to investigate the use of aPCC for the reversal of the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding. The primary outcome was achieving clinical hemostasis according to prespecified criteria. Safety outcomes included the occurrence of thrombotic events during hospitalization. A total of 217 patients were included in the study. Intracranial hemorrhage (ICH) was the most common site of bleeding (n = 100, 46.1%), followed by gastrointestinal bleed (n = 87, 40.1%). Clinical hemostasis was achieved in 170 patients (78.3%), and the risk of not achieving hemostasis with ICH-related bleeding was significantly higher than that of non-ICH-related bleeding (2.5, 95% confidence interval [CI] 1.44-4.34; p < 0.001). Eight patients not achieving hemostasis died during hospitalization, all of whom were suffering from ICH, and mortality associated with non-ICH-related bleeding was significantly lower compared with ICH-related bleeding (0.91, 95% CI 0.86-0.97; p < 0.001). Thromboembolic events during hospitalization occurred in one patient (0.5%). The use of aPCC for the management of apixaban- or rivaroxaban-related major bleeding is effective in most cases and is associated with a low risk of thromboembolism.

Anticoagulation strategies in COVID-19 infected patients receiving ECMO support.

Hospitalized COVID-19 patients with hypoxemic respiratory failure may deteriorate despite invasive mechanical ventilation and thus require extracorporeal membrane oxygenation (ECMO) support. Unfractionated heparin (UFH) is the antithrombotic of choice, however, bivalirudin may offer more predictable pharmacokinetics resulting in consistent anticoagulant effects with lower bleeding and thrombotic occurrences. The aim of this study was to evaluate efficacy and safety outcomes in patients undergoing venovenous (VV) ECMO receiving bivalirudin or UFH-based anticoagulation. This retrospective, single-center, observational cohort study included patients with confirmed COVID-19 infection requiring VV ECMO support receiving anticoagulation with UFH or bivalirudin. Primary endpoints were time to reach therapeutic aPTT, percent time spent in aPTT range, and the occurrence of thrombotic events over the entire course of ECMO support. Secondary endpoints included the incidence of major/minor bleeding, the ability to wean off ECMO support, in-hospital mortality, and length of stay. Twenty-two patients were included in the study (n=10 UFH, n=12 bivalirudin). Time to therapeutic aPTT was achieved faster with UFH (10h vs. 20h). The percentage time spent within the goal aPTT range was similar between UFH and bivalirudin (50% vs. 52%). Thrombotic events were significantly higher in the UFH group (40% DVT, 40% PE, 80% oxygenator thrombus in ECMO machine, 10% ischemic stroke) versus bivalirudin (8% DVT, 17% PE, 33% oxygenator thrombus, no ischemic strokes) (CI 95%, p=0.04). The overall bleeding incidence was higher in the UFH arm (90% vs. 75%). The mortality rate was 90% in the UFH group and 58% in the bivalirudin group. The length of stay was similar between the two study arms. In hospitalized patients with COVID-19-associated acute respiratory distress syndrome (ARDS) on VV ECMO support, the use of bivalirudin showed to be a viable anticoagulation alternative in terms of efficacy compared to UFH and resulted in a favorable safety profile with lower rates of bleeding and thrombotic events.

Incidence, Risk Factors and Mortality Associated with Major Bleeding Events in Hospitalized COVID-19 Patients.

Thromboprophylaxis is a mainstay of treatment of hospitalized COVID-19 patients, due to the high occurrence of thrombotic events. This increases the risk of bleeding. However, data on bleeding events and associated risk factors are scarce. Thus, we aimed to investigate the incidence, predictors and clinical outcomes associated with major bleeding in hospitalized COVID-19 patients. We retrospectively evaluated a cohort of 4014 consecutively hospitalized COVID-19 patients treated in a tertiary-level institution in the period 3/2020-3/2021. Bleeding of any kind was documented in 322 (8%) and major bleeding in 129 (3.2%) patients. A total of 129 (40.1%) bleeding events were present at the time of hospital admission, and 193 (59.9%) occurred during hospitalization. In the multivariate logistic regression analysis, intensive-care-unit treatment (adjusted odds ratio (aOR) 6.55; p < 0.001), atrial fibrillation (aOR 2.55; p = 0.029), higher white-blood-cell count (WBC) (aOR 1.03; p = 0.021), lower hemoglobin (aOR 0.97; p = 0.002) and history of bleeding (aOR 17.39; p < 0.001) were recognized as mutually independent predictors of major bleeding. Major bleeding was significantly associated with increased in-hospital mortality compared to non-major-bleeding patients (59.7% vs. 34.8%, p < 0.001), especially if occurring during hospitalization. Median time from major bleeding to death was 5 days. Bleeding events are frequent in hospitalized COVID-19 patients, with a significant proportion of patients presenting at the time of hospital admission, and others almost universally exposed to anticoagulant and corticosteroid therapies. Major bleeding is associated with high mortality, especially if occurring during hospitalization. The recognition of patients at risk and implementation of timely interventions are of high clinical importance.

Does the use of tranexamic acid increase the risk of VTE in patients with hemoptysis?

The aim of this study was to create a predictive nomogram that can accurately identify the risk factors of venous thromboembolism (VTE) in hospitalized patients exhibiting hemoptysis. The present study gathered clinical and demographic data of 1,052 hospitalized patients with hemoptysis at Dongyang Hospital between January 2016 and January 2021 through the Lejiu database. The patients were categorized into two groups: the thrombotic event group (n=123) and the non-thrombotic event group (n=929), based on the presence of VTE before discharge. The study utilized univariable and multivariable logistic regression analyses to identify the independent risk factors for VTE, with the occurrence of thrombotic events serving as the dependent variable. Furthermore, a nomogram prediction model was formulated to verify the findings. In hospitalized patients with hemoptysis, the risk of VTE was found to be independently associated with the administration of tranexamic acid (TXA), the presence of D-dimer, and the Charlson Comorbidity Index (CCI) score (p<0.05). A nomogram model was constructed to evaluate the probability of VTE in patients hospitalized with hemoptysis. This model allows for the timely detection of early VTE warning signs, which may ultimately reduce its occurrence.

A Retrospective Analysis of Vitamin D Levels in Hospitalized COVID-19 Patients With Suspected Pulmonary Embolism.

Introduction Despite using anti-coagulation therapy in hospitalized coronavirus disease 2019 (COVID-19) patients, they have high rates of pulmonary embolism (PE) and deep vein thrombosis (DVT). The main objective of this study was to evaluate the association between vitamin D deficiency and thrombotic events (defined as the occurrence of a new PE or DVT) in hospitalized COVID-19 patients. Materials and Methods This was a retrospective, cross-sectional study of 208 hospitalized COVID-19 patients who received a computed tomographic pulmonary angiography (CTPA) based on clinical suspicion of PE between January 1, 2020, and February 5, 2021. A <20 ng/mL serum vitamin D level was used to categorize vitamin D deficiency. Nonparametric tests and multivariate binary logistic regression were used to evaluate the association between serum vitamin D levels and clinical outcomes. Results The mean vitamin D level was 26.7±13.0 ng/mL (n=208), and approximately one-third of patients were vitamin D deficient (n=68, 32.7%). No association was found between vitamin D deficiency and the occurrence of thrombotic events. The incidence of PE was 19.1% in vitamin D deficient patients compared to 11.4% in vitamin D sufficient patients (p=0.13). Vitamin D deficiency was positively associated with ICU admission (OR 3.047, 95%CI 1.57-5.91, p=0.001) and mortality (OR 3.76, 95%CI 1.29-11.01, p=0.016). Conclusions This study found no association between vitamin D deficiency and the occurrence of a new PE or DVT in hospitalized COVID-19 patients. Patients with vitamin D deficiency were more likely to be admitted to the ICU and had increased overall mortality.

Real world data evidence (RWDE) on cancer patients' (pts) awareness and knowledge of cancer associated thrombosis (CAT) events.

e18774 Background: Cancer pts are mostly unaware of the higher than normal risk of developing a CAT event. A recently reported European survey, with 745 participants, showed that just above two-thirds (69%) of pts never received information and were not aware of the higher thrombotic risk associated with cancer diagnosis and its diverse treatments. Methods: A comprehensive survey was sent, during July-September 2022, to members of Belong.life, a social and professional international free application for cancer pts and their caregivers. Pts who registered within the diagnostic groups, received a 24 questions survey of demographic and specialized questions referring to their knowledge on the possible increased risk of associated thromboembolic events, as well as determine the available resources for pts education. 1200 adult pts with a variety of cancers, replied to the survey. Most pts were receiving active anticancer treatments. Independent demographic and clinical variables were analyzed. Results: 1200 cancer pts, Belong users from English speaking countries, completed the survey, most of them females (74%, 889/1200) and &gt; 50 years of age (85%,1014/1200). Commonest cancers were breast (29%,350/1200), gastrointestinal (15%,182/1200), lung (12%,144/1200) and gynecological (11%,142/1200). 80% (964/1200) never suffered thrombosis before their cancer diagnosis. Overall, at the time of answering the survey, 71% (861/1200) claimed not being aware of their CAT risks. 28% (339/1200) of the responders were aware of CAT at the time of replying to the survey, and of them only 17% (49/289) confirmed to be fully informed of CAT risks. Among all those that received information on CAT, 10% (120/1200) obtained it at the time of their first thrombotic event occurrence, while 14% (172/1200) were informed at the time of their cancer diagnosis and/or commencement of their planned treatments. Verbal information on CAT was mostly conveyed (51%) by the medical staff, in face to face meetings, while family and friends gave mostly internet and social media guidance (73%). Conclusions: The presence of a CAT impacts cancer pts clinical outcomes and quality of life. Available data on CAT education and awareness have been sparse. A recent European survey has shown important awareness gaps. Our RWDE survey, on 1200 Belong members with diverse geographical backgrounds and a variety of cancers, confirmed that 71% of the surveyed pts are not aware of their CAT risks before their diagnosis and/or treatment of cancer, indicating a major need for education on the known CAT risk factors, signs and symptoms, and available diagnostic imaging and treatment approaches. It is imperative that oncologists, together with allied medical professionals involved in cancer care, provide relevant CAT information, at the time of a patient’s cancer diagnosis, when individual treatments are planned, and along the pts’s cancer journey.

Lipoprotein(a) Does Not Predict Thrombotic Events and In-Hospital Outcomes in Patients with COVID-19.

The prothrombotic and proinflammatory properties of lipoprotein(a) (Lp(a)) have been hypothesized to play a role in the pathogenesis of severe COVID-19; however, the prognostic impact of Lp(a) on the clinical course of COVID-19 remains controversial. This study aimed to investigate whether Lp(a) may be associated with biomarkers of thrombo-inflammation and the occurrence of thrombotic events or adverse clinical outcomes in patients hospitalized for COVID-19. We consecutively enrolled a cohort of patients hospitalized for COVID-19 and collected blood samples for Lp(a) assessment at hospital admission. A prothrombotic state was evaluated through D-dimer levels, whereas a proinflammatory state was evaluated through C-reactive protein (CRP), procalcitonin, and white blood cell (WBC) levels. Thrombotic events were marked by the diagnosis of deep or superficial vein thrombosis (DVT or SVT), pulmonary embolism (PE), stroke, transient ischemic attack (TIA), acute coronary syndrome (ACS), and critical limb ischemia (CLI). The composite clinical end point of intensive care unit (ICU) admission/in-hospital death was used to evaluate adverse clinical outcomes. Among 564 patients (290 (51%) men, mean age of 74 ± 17 years) the median Lp(a) value at hospital admission was 13 (10-27) mg/dL. During hospitalization, 64 (11%) patients were diagnosed with at least one thrombotic event and 83 (15%) patients met the composite clinical end point. Lp(a), as either a continuous or categorical variable, was not associated with D-dimer, CRP, procalcitonin, and WBC levels (p > 0.05 for all correlation analyses). In addition, Lp(a) was not associated with a risk of thrombotic events (p > 0.05 for multi-adjusted odds ratios) nor with a risk of adverse clinical outcomes (p > 0.05 for multi-adjusted hazard ratios). In conclusion, Lp(a) does not influence biomarkers of plasma thrombotic activity and systemic inflammation nor has any impact on thrombotic events and adverse clinical outcomes in patients hospitalized for COVID-19.