Vascular Thrombotic Events Research Articles

Protein C Pretreatment Protects Endothelial Cells from SARS-CoV-2-Induced Activation.

SARS-CoV-2 can induce vascular dysfunction and thrombotic events in patients with severe COVID-19; however, the cellular and molecular mechanisms behind these effects remain largely unknown. In this study, we used a combination of experimental and in silico approaches to investigate the role of PC in vascular and thrombotic events in COVID-19. Single-cell RNA-sequencing data from patients with COVID-19 and healthy subjects were obtained from the publicly available Gene Expression Omnibus (GEO) repository. In addition, HUVECs were treated with inactive protein C before exposure to SARS-CoV-2 infection or a severe COVID-19 serum. An RT-qPCR array containing 84 related genes was used, and the candidate genes obtained were evaluated. Activated protein C levels were measured using an ELISA kit. We identified at the single-cell level the expression of several pro-inflammatory and pro-coagulation genes in endothelial cells from the patients with COVID-19. Furthermore, we demonstrated that exposure to SARS-CoV-2 promoted transcriptional changes in HUVECs that were partly reversed by the activated protein C pretreatment. We also observed that the serum of severe COVID-19 had a significant amount of activated protein C that could protect endothelial cells from serum-induced activation. In conclusion, activated protein C protects endothelial cells from pro-inflammatory and pro-coagulant effects during exposure to the SARS-CoV-2 virus.

Pulmonary embolism versus pulmonary vasculitis in Hughes-Stovin syndrome: Characteristic computed tomography pulmonary angiographic findings and diagnostic and therapeutic implications. HSS International Study Group

Background and aimHughes-Stovin syndrome (HSS) is a rare systemic vasculitis with widespread venous/arterial thrombosis and pulmonary vasculitis. Distinguishing between pulmonary embolism (PE) and in-situ thrombosis in the early stages of HSS is challenging. The aim of the study is to compare clinical, laboratory, and computed tomography pulmonary angiography (CTPA) characteristics in patients diagnosed with PE versus those with HSS. MethodsThis retrospective study included 40 HSS patients with complete CTPA studies available, previously published by the HSS study group, and 50 patients diagnosed with PE from a single center. Demographics, clinical and laboratory findings, vascular thrombotic events, were compared between both groups. The CTPA findings were reviewed, with emphasis on the distribution, adherence to the mural wall, pulmonary infarction, ground glass opacification, and intra-alveolar hemorrhage. Pulmonary artery aneurysms (PAAs) in HSS were assessed and classified. ResultsThe mean age of HSS patients was 35 ± 12.3 years, in PE 58.4 ± 17 (p < 0.0001). Among PE 39(78 %) had co-morbidities, among HSS none. In contrast to PE, in HSS both major venous and arterial thrombotic events are seen.. Various patterns of PAAs were observed in the HSS group, which were entirely absent in PE. Parenchymal hemorrhage was also more frequent in HSS compared to PE (P < 0.001). ConclusionMajor vascular thrombosis with arterial aneurysms formation are characteristic of HSS. PE typically appear loosely-adherent and mobile whereas “in-situ thrombosis” seen in HSS is tightly-adherent to the mural wall. Mural wall enhancement and PAAs are distinctive pulmonary findings in HSS. The latter findings have significant therapeutic ramifications.

Vascular complications in craniopharyngioma-resected paediatric patients: a single-center experience.

Craniopharyngioma (CP), although slow growing and histologically benign, has high morbidity, mostly related to hypothalamus-pituitary dysfunction and electrolyte imbalance. Increased risk of vascular complications has been described. However, data are still poor, especially in the paediatric population. The aim of our study was to evaluate the occurrence, timing, and predisposing factors of deep venous thrombosis (DVT) and other vascular alterations in neurosurgical paediatric CP patients. In a single-centre, retrospective study, we investigated 19 CP patients (11 males, 8 females, mean age 10.5 ± 4.3 years), who underwent neurosurgery between December 2016 and August 2022, referred to Meyer Children's Hospital IRCCS in Florence. Five patients (26.3%) presented vascular events, which all occurred in connection with sodium imbalances. Three DVT (two with associated pulmonary embolism, in one case leading to death) developed in the post-operative period, most frequently at 7-10 days. Elevated D-dimers, a reduced partial activated thrombin time and a prolonged C-reactive protein increase were highly related to thrombotic vascular events. One case of posterior cerebral artery pseudoaneurysm was described soon after neurosurgery, requiring vascular stenting. Superficial vein thrombophlebitis was a late complication in one patient with other predisposing factors. CP patients undergoing neurosurgery are at risk of developing DVT and vascular alterations, thus careful follow-up is mandatory. In our study, we found that the phase of transition from central diabetes insipidus to a syndrome of inappropriate antidiuretic hormone secretion may be a period of significant risk for DVT occurrence. Careful vascular follow-up is mandatory in CP-operated patients.

Incorporating Prior Data in Quantitative Benefit-Risk Assessments: Case Study of a Bayesian Method.

Multiple criteria decision analysis (MCDA) and stochastic multi-criteria acceptability analysis (SMAA) in their current implementation cannot incorporate prior or external information on benefits and risks. We demonstrate how to incorporate prior data using a Bayesian mixture model approach while conducting quantitative benefit-risk assessments (qBRA) for medical products. We implemented MCDA and SMAA in a Bayesian framework. To incorporate information from a prior study, we use mixture priors on each benefit and risk attribute that mixes information from a previous study with a vague prior distribution. The degree of borrowing is varied using a mixing proportion parameter. A demonstration case study for qBRA using the supplementary New Drug Application (sNDA) filing for Rivaroxaban for the indication of reduction in the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD) was used to illustrate the method. Net utility scores, obtained from the randomized controlled trial data to support the sNDA, from the MCDA for Rivaraxoban and comparator were 0.48 and 0.56, respectively, with Rivaroxaban being the preferred alternative only 33% of the time. We show that with only 30% borrowing from a previous RCT, the MCDA and SMAA results are favorable for Rivaroxaban, accounting for the seemingly aberrant results on all-cause death in the trial data used to support the sNDA. Our method to formally incorporate prior data in MCDA and SMAA is easy to use and interpret. Software in the form of an RShiny App is available here: https://sai-dharmarajan.shinyapps.io/BayesianMCDA_SMAA/ .

Hyperhomocysteinemia in Adult Patients: A Treatable Metabolic Condition.

Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for various significant medical conditions, yet controversy persists around its assessment and management. The diagnosis of disorders afffecting homocysteine (Hcy) metabolism faces delays due to insufficient awareness of its clinical presentation and unique biochemical characteristics. In cases of arterial or venous thrombotic vascular events, particularly with other comorbidities, it is crucial to consider moderate to severe HHcy. A nutritional approach to HHcy management involves implementing dietary strategies and targeted supplementation, emphasizing key nutrients like vitamin B6, B12, and folate that are crucial for Hcy conversion. Adequate intake of these vitamins, along with betaine supplementation, supports Hcy remethylation. Lifestyle modifications, such as smoking cessation and regular physical activity, complement the nutritional approach to enhance Hcy metabolism. For individuals with HHcy, maintaining a plasma Hcy concentration below 50 μmol/L consistently is vital to lowering the risk of vascular events. Collaboration with healthcare professionals and dietitians is essential for developing personalized dietary plans addressing the specific needs and underlying health conditions. This integrated approach aims to optimize metabolic processes and reduce the associated health risks.

Abstract 14222: Annual Vascular and Bleeding Outcomes in East Asian Poststenting Patients With Acute Coronary Syndrome: The BRIC-ACS II Trial

Objective: To determine the incidence of bleeding and thrombotic vascular events in the "real-world"acute coronary syndromes (ACS) Chinese patients over 1-year following stent implantation. Background: The balance between vascular and bleeding outcomes during dual antiplatelet therapy (DAPT) is a matter of considerable controversy, especially in Asian populations. In contrast to Europeans, Chinese patients experience more bleeding but less thrombotic events over aggressive DAPT with ticagrelor than after conventional clopidogrel. Methods and Results: From November 2017 till April 2020 we enrolled post-stenting ACS patients (n=5,515) from 30 tertiary hospitals with the strict 1-year follow-up (n=5.150). Only few 153(3.0%) patients developed MACE (a composite of all-cause death, myocardial infarction, ischemic stroke, or urgent coronary revascularization). The cumulative incidence of annual bleeding (BARC ≥2) was 5.8% (298/5150) among patients who completed 1year follow-up.The BARC ≥2 bleeding was almost twice higher 298 (5.8%) and was not associated with worsened MACE [CI:0.37 -1.67; P =0.52). Patients treated with ticagrelor (n=1620, 6.0%) had a significantly increased risk of bleeding than those treated with clopidogrel (n=2331; 4.1%) (HR=1.486; 95% CI:1.12-1.97; P=0.006), but similar risk of vascular MACE (2.7% vs 2.8%; HR= 0.94; 95% CI:0.64-1.38; P = 0.747).The factors independently associated with the comprehensive risk of BARC ≥2 bleeding and MACE , including female gender, renal insufficiency, peptic ulcer, atrial fibrillation, continuous use of ticagrelor and non-continuous DAPT. The discrimination of the nomogram model was further tested by the ROC curve (AUC value:0.610 (95% CI, 0.577-0.642 )). Conclusions: The annual incidence of BARC≥2 bleeding in ACS patients treated with PCI in China was almost twice higher (5.8%) than MACE (3.0%). DAPT with ticagrelor increased the bleeding rates with no trend towards MACE reduction. The trial was registered at the clinnicaltrials.org as NCT03402711.This study was sponsored by Sanofi.

Paracentral Acute Middle Maculopathy After COVID-19 Disease: Multimodal Evaluation.

To report the case and multimodal imaging findings of a healthy young woman who developed paracentral acute middle maculopathy (PAMM) 9 weeks after COVID-19 disease. Case report. Ultra-widefield fundus photography, macular spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and OCT-angiography (OCT-A) were performed. A 36-year-old woman who developed PAMM 9 weeks after SARS-CoV-2 infection. A 36-year-old woman went to the emergency department (ED) with sudden, painless, left eye (LE) vision loss. The only relevant past medical history was COVID-19 disease 9 weeks before. Best corrected visual acuity (BCVA) was 20/200, a LE relative afferent pupillary defect (RAPD) was present and superficial hemorrhages throughout the macular area and peripheral retina were found. Nearly four hours after admission, LE BCVA recovered to 20/20 without RAPD. Five days after presentation in the ED, the patient returned with recurrent LE vision loss, with spontaneous recovery within 12 hours. Macular SD-OCT revealed hyperreflectivity of the inner plexiform and inner nuclear layers and the diagnosis of PAMM was established. The patient started oral acetylsalicylic acid and oral prednisolone. The patient did not report any new episodes of vision loss and there was a progressive resolution of abnormal fundus findings. SARS-CoV-2 infection increases the risk of vascular thrombotic events with possible involvement of the retinal circulation, and PAMM may present as a possible complication. Ophthalmologists should be able to recognize it promptly through multimodal imaging findings.

Abdominal aortic calcification in patients newly diagnosed with essential thrombocythemia.

Although atherosclerosis is likely to be involved in the development of arterial thrombotic events in patients with essential thrombocythemia (ET), abdominal aortic calcification (AAC) has rarely been investigated. We evaluated the prevalence and clinical relevance of AAC at the time of ET diagnosis. This retrospective study included patients newly diagnosed with ET who underwent abdominal computed tomography (CT) at the time of diagnosis between January 2002 and December 2021 at Chungnam National University Hospital, Daejeon, Korea. CT images were reviewed and an aortic calcification score was assigned. Of the 94 patients (median age, 62 yr; range, 18‒90 yr), AAC was detected in 62 (66.0%). AAC was most commonly mild (33.0%), followed by moderate (22.7%) and severe (5.3%). Old age [odds ratio (OR), 34.37; 95% confidence interval (CI), 12.32‒95.91; P＜0.001] was an independent risk factor for AAC. The patients with AAC had a higher WBC count (11.8±4.7 vs. 9.7±2.9×109/L, P=0.017), higher neutrophil-to-lymphocyte ratio (4.3±2.7 vs. 3.1±1.5, P=0.039), and higher JAK2V617F positivity (81.5% vs. 58.8%, P=0.020) compared to those without AAC. AAC was an independent risk factor for arterial thrombotic vascular events that occurred before or at diagnosis of ET (OR, 4.12; 95% CI, 1.11‒15.85; P=0.034). AAC is common in patients with ET and is associated with arterial thrombotic events.

Oncological Skull Base Reconstruction with Microvascular Tissue Transplantation in Advanced Relapsed Cases

Introduction: Tumors involving the skull base are real challenges to reconstructive surgeons. Many articles have been published about these reconstructions, especially in primary cases. In tumor relapses after previous surgeries or irradiation, the surgical options for reconstruction are extremely narrowed and is our opinion that microvascular autologous tissue transplantation is specially indicated in those patients, even though it requires a technically demanding procedure. Materials and Methods: We analyzed retrospectively all patients treated at our institution between March 2014 and December 2018 and that met all the inclusion criteria: 1) oncological surgery for a tumor involving the skull base; 2) previous surgical treatment for that tumor; 3) cranial base bone resection; 4) dural exposure or defect; 5) reconstruction done with a free flap. The patient's age, comorbidities, number of previous surgeries and/or irradiation, oncological excisional procedures, type of defect, type of reconstruction, postoperative complications and mortality were reviewed. Results: Fifteen flaps were used in the 14 patients that met all the inclusion criteria. The used flaps were: Anterolateral Thigh (ALT) perforator or chimeric ALT/Vastus Lateralis (VL) (n=6), profunda artery perforator (n=3), muscular Rectus Abdominis (n=2), Vertical Rectus Abdominis Myocutaneous (VRAM) (n=2), chimeric osteomuscular scapular tip/Latissimus Dorsi (LD) (n=1) and radial forearm (n=1). Dural defects were reconstructed with Pericranial or fascia Lata grafts in 7 patients. No total flap failures or vascular thrombotic events were noted and just one case of partial flap necrosis was registered (treated conservatively). There was one case of cerebrospinal fluid leakage, one diffuse cerebral edema and one donor site wound dehiscence, all successfully treated with conservative measures. The only complication that required a second operation was a cranioplasty prosthetic exposure that required a second free flap. One patient had a tracheostomy bleeding followed by a pneumothorax and died 8 weeks postoperatively with a nosocomial pneumonia. In the follow-up period, one patient died 19 months postoperatively with a local relapse and another with a metastatic disease (at month 15). Conclusion: Secondary or multiple relapsed cases in the skull base require reconstructions that are technically demanding and the defects are often extensive. The surgical options are extremely reduced by previous treatments and if the basic concepts of cranial base reconstruction were strictly respected, the microsurgical free flaps can offer the best chance to avoid severe complications. However, it is not without some postoperative complications and mortality can be significant in the follow-up because of the advanced stage of the oncologic disease.

Real-World Incidence of Adverse Clinical Outcomes Among People With Coronary Artery Disease and/or Peripheral Artery Disease in Relation to Vascular Risk in the United States

Presence of polyvascular disease, diabetes, heart failure, or renal insufficiency in patients with chronic coronary artery disease (CAD) and peripheral artery disease (PAD) are associated with increased risks of adverse events, including major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs). In this retrospective observational study using administrative claims data from Optum's deidentified Clinformatics Data Mart Database from January 2016 to September 2021, we described the incidence rates of MACEs, MALEs, and major thrombotic vascular events in patients with CAD or PAD stratified by the presence of risk factors (i.e., polyvascular disease, diabetes, heart failure, or renal insufficiency). A total of 1,435,241 patients (77% CAD and 34% PAD) met the inclusion and exclusion criteria. Patients with 0 risk factors were deemed the low-risk group (47%; n=681,333) and patients with ≥1 risk factor were deemed the high-risk group (53%; n=753,908). The mean age was 71.8 and 73.6years, and 42% and 44% were female in the low- and high-risk groups, respectively. Compared with the low-risk group, the high-risk group had a 72% higher hazard of developing MACEs (adjusted hazard ratio 1.72, 95% confidence interval 1.70 to 1.74), 82% higher hazard of developing major thrombotic vascular events (1.82, 1.80 to 1.84), and 146% higher hazard of developing MALEs (2.46, 2.39 to 2.53) (all p <0.001). In conclusion, in patients with CAD or PAD, the presence of 1 or more risk factors was associated with higher risks of MACEs, MALEs, and major thrombotic vascular events, underscoring the need to improve management of underlying diseases in this population.

The Evolution of COVID-19 Associated Vascular Complications from 2020 to 2022

Vascular thrombotic events are prominent in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A meta-analysis of 64,503 hospitalized SARS-CoV-2 patients showed deep vein thrombosis in 11.2% and pulmonary embolism 7.8%. One study screening for venous thromboembolism reported a 25% incidence. Vascular thrombosis was reported as an independent risk factor for mortality in SARS-CoV-2. Acute limb ischemia was reported in 0.3% to 1.0% of hospitalized patients, predominantly male, and 18% of these patients suffered limb loss. We observed vascular complications in SARS-CoV-2 has changed from 2020. This study compared venous and arterial thromboembolism during the early stages of the pandemic to the present. Patients with confirmed SARS-CoV-2 between December 2019 and April 2022 and treated with an arterial/venous thromboembolic event at a major metropolitan hospital were reviewed retrospectively. We found 68 patients found to have either venous thromboembolism or an arterial thromboembolism, 45 in 2020 and 23 after 2020. Mean age of all patients 60.8 ± 4.2 years (range, 32-92 years). Mean age in 2020 was 62.8 ± 16.3 years (range, 36-92 years) and the mean age of those after 2020 was 56.9 ± 13.4 years (range, 32-87 years). Overall, 38 patients were male and 30 female. In 2020, there were 31 males and 14 females. After 2020, we identified 7 males and 16 females. Overall, 56 vessels involved were in lower extremity and 12 in upper extremity. In 2020, 34 vessels involved were in lower extremity and 11 in upper extremity. After 2020, 22 vessels involved were in lower extremity and 1 in upper extremity. Overall, 31 thrombosis were venous and 37 were arterial. In 2020, 9 were venous and 36 arterial thrombosis. After 2020, 22 were venous and 1 arterial thrombosis. Overall, 39 required surgical interventions. In 2020, 29 underwent surgical interventions. After 2020, 10 underwent surgical interventions (all venous). Overall, 59 patients were discharged and 9 expired. In 2020, 36 were discharged and 9 expired. After 2020, all 23 were discharged. Vascular complications are a common manifestation of SARS-CoV-2 infection. Early in the pandemic, most vascular complications were acute, occurred primarily in arteries, required major emergency interventions and amputations, and were associated with high mortality. As the pandemic evolved, observed vascular complications were less acute, more indolent, and less catastrophic, affected mostly veins, required less urgent interventions, or treated with just observation, and associated with low mortality. The vascular complications associated with SARS-CoV-2 infection have changed from the early pandemic to present. The long-term vascular effects of SARS-CoV-2 is unknown.

Post-COVID recurrent dyspnoea

Rationale: Post-COVID symptoms need aggressive evaluation. Patient’s Concern: A 29-year-old male patient who had suffered from COVID-19 eight weeks earlier, presented with an acute onset of breathlessness and right-sided chest pain due to pneumothorax. Emergency tube thoracostomy was performed. However, it failed to improve hypoxia. Diagnosis: High-resolution computed tomography of the thorax with computed tomography pulmonary angiography revealed pulmonary arterial thrombosis, ground-glass opacities, and bilateral pneumatoceles. Interventions: Hospital admission and treatment with low molecular weight heparin at a dose of 1.5 mg/kg every 24 h. Outcomes: The large pneumatocele showed significant resolution after three months of follow-ups. Lessons: Being increasingly reported after having a SARS-CoV-2 infection, pneumatocele formation, due to post-COVID lung scarring and late vascular thrombotic events, is a peculiar sequela and can present as acute dyspnoea. Long-term preventive anticoagulants after recovery from COVID-19 are necessary. Breathing exercises during recovery should be done with caution.

Vascular thrombosis after single dose Ad26.COV2.S vaccine in healthcare workers in South Africa: open label, single arm, phase 3B study (Sisonke study)

ObjectiveTo assess the rates of vascular thrombotic adverse events in the first 35 days after one dose of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in healthcare workers in South Africa...

AN OBSERVATIONAL STUDY TO ASSESS THE SEVERITY AND OUTCOME OF COVID 19 AND NON COVID 19 STROKE PATIENT IN TERTIARY CARE CENTER AND ITS ASSOCIATED HOSPITAL

Background: Covid-19 might be more likely to cause thrombotic vascular events, including stroke, than other coronavirus &amp; seasonal infectious diseases. The proposed mechanisms for these cerebrovascular events include a hypercoagulable state from systemic inammation &amp; cytokine storm; postinfectious immune-mediated responses. 40 COVID-19-infected patients with Stroke and 40 Non COVID-19 infected in age group 25-100 years admitted in our 500 bedded covid dedicated hospitals associated with Maharaja Yashwantrao hospital, Indore, were observed for their clinical prole, complications, laboratory parameters, inammatory markers, radiological parameters and outcome etc. Patients were divided into two study groups i.e. Covid-19 Stroke group and Non Covid-19 Stroke group. Clinical, laboratory and radiological parameters were observed in both groups and found out to be worse in covid-19 stroke group.

The impact of partial and complete lockdown during the COVID-19 pandemic on acute surgical services: a retrospective cohort study

PurposeThe burden of the coronavirus disease of 2019 (COVID-19) pandemic on the healthcare sector has been overwhelming, leading to drastic changes in access to healthcare for the public. We aimed to establish the impact of implemented government partial and complete lockdown policies on the volume of surgical patient admissions at a tertiary referral center during the pandemic.MethodsA database was retrospectively created from records of patients admitted to the surgical ward through the emergency department. Three 6-week periods were examined: The complete lockdown period (CLP), which included a ban on the use of cars with the exception of health service providers and essential sector workers; A pre-COVID period (PCP) 1 year earlier (no lockdown); and a partial lockdown period (PLP) that involved a comprehensive curfew and implementing social distancing regulations and wear of personal protective equipment (e.g., masks) in public places.ResultsThe number of patients admitted to the surgery ward was significantly higher in the PCP cohort compared to the CLP and PLP cohorts (p = 0.009), with a 42.1% and 37% decline in patients’ admissions, respectively. Admission rates for patients with biliary pathologies and vascular thrombotic events increased. 30-day mortality rates did not differ significantly between the three periods (p = 0.378).ConclusionsWhile COVID-19 lockdown regulations had a significant impact on patient admission rates, surgical outcomes were not affected and the standards of care were maintained. Future protocols should strive to improve access to healthcare to avoid complications caused by delayed diagnosis and treatment.

Rivaroxaban in patients with symptomatic peripheral artery disease after lower extremity bypass surgery with venous and prosthetic conduits

BackgroundPatients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) have a high risk of adverse limb and cardiovascular events. The results from the VOYAGER PAD (efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities) trial have demonstrated that rivaroxaban significantly reduced this risk with an overall favorable net benefit for patients undergoing surgical revascularization. However, the efficacy and safety for those treated by surgical bypass, including stratification by bypass conduit (venous or prosthetic), has not yet been described. MethodsIn the VOYAGER PAD trial, patients who had undergone surgical and endovascular infrainguinal LER to treat PAD were randomized to rivaroxaban 2.5 mg twice daily or placebo on top of background antiplatelet therapy (aspirin 100 mg to be used in all and clopidogrel in some at the treating physician’s discretion) and followed up for a median of 28 months. The primary end point was a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, and cardiovascular death. The principal safety outcome was major bleeding using the TIMI (thrombolysis in myocardial infarction) scale. The index procedure details, including conduit type (venous vs prosthetic), were collected at baseline. ResultsAmong 6564 randomized patients, 2185 (33%) had undergone surgical LER. Of these 2185 patients, surgical bypass had been performed for 1448 (66%), using a prosthetic conduit for 773 patients (53%) and venous conduit for 646 patients (45%). Adjusting for the baseline differences and anatomic factors, the risk of unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving a prosthetic conduit vs a venous conduit (adjusted hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.65-3.90; P < .001), and the risk of acute limb ischemia was three times greater (adjusted HR, 3.07; 95% CI, 1.84-5.11; P < .001). The use of rivaroxaban reduced the primary outcome for the patients treated with bypass surgery (HR, 0.78; 95% CI, 0.62-0.98), with consistent benefits for those receiving venous (HR, 0.66; 95% CI, 0.49-0.96) and prosthetic (HR, 0.87; 95% CI, 0.66-1.15) conduits (Pinteraction = .254). In the overall trial, major bleeding using the TIMI scale was increased with rivaroxaban. However, the numbers for those treated with bypass surgery were low (five with rivaroxaban vs nine with placebo; HR, 0.55; 95% CI, 0.18-1.65) and not powered to show statistical significance. ConclusionsSurgical bypass with a prosthetic conduit was associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjustment for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduced this risk, with an increase in the bleeding risk, but had a favorable benefit risk for patients treated with bypass surgery, regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain.

Long Term Results of Phase 2 Study of Pegylated Interferon in Patients with Essential Thrombocythemia and Polycythemia Vera: Median Follow-up of 15 Years

Introduction: Pegylated interferon alfa-2a [PEG-IFN] have been used for almost 3 decades in patients with polycythemia vera [PV] and essential thrombocythemia [ET], but long-term data from prospective studies are limited. Objective: We present results of our single center, prospective, phase II study of PEG-IFN in patients with ET and PV with a median follow up of 183 months (range, 6-198, at data lock June 2022; previous data lock was May 2015). Methods: The study enrolled patients with ET (n=40) or PV (n=43) over the age of 18, irrespectively of previous therapy (37% untreated). PEG-IFN dose modifications, monitoring, and response assessment were as published (Masarova et al, Lancet Haematology, 2017). Testing sensitivity for JAK2V167F mutation allele burden was 1% till 2018, and 0.1% since then. Molecular response [MR; assessed in patients with baseline JAK2 ≥20%] was defined as complete (CMR; undetectable), partial (PMR; decrease by ≥50% but detectable) and minor (mMR; decrease by 20-49%). Results: Among 83 enrolled patients (median age 53 years, 29 males), after median follow up of 183 months (range, 6-198), 11 patients (13%) continue on active therapy on study. Current doses range from 45 mcg every 9 weeks to 180 mcg weekly. Forty-six (55%), 18 (22%) and 6 (7%) patients were treated for ≥5, ≥10 and ≥15 years, respectively. The overall median exposure to PEG-IFN (n = 83) was 95 months (range, 3-191). Twenty-seven patients (41%) from the initial 66 hematologic responders [HR; 80%] were in HR at the time of their last follow-up, including 5 patients who lost but regained HR with longer therapy. Table 1 shows responses in patients who remained on study for 4+ years. Median duration of HR was 137 months (range, 2.2-189). Thirty-five (63%) of 55 JAK2 mutated patients with molecular sequencing achieved molecular response: 10 CMR (18%), 20 PMR (36%) and 5 mMR (9%). At the time of last follow-up on study, 24 patients remained in MR (67%). Only 17 treated patients underwent repeated molecular sequencing since the last study update; 3 of them experienced change: 1 lost PMR (JAK2: 38%->61%), 1 lost CMR (JAK2: 0%-6%) and 1 regained PMR (JAK2: 13%->7%). Median duration on study in months [range] was 127 [25-189], 91 [11-192], 15 [2-183] and 81.5 [6-187] for JAK2(+) patients who achieved CMR (n = 10), PMR & mMR (n = 25), without MR (n = 25) and in JAK2(-) (n = 23), respectively. Five patients with previous CMR had subsequent testing, 4 of them had detectable JAK2 allele in the range of 0.1%-0.5% using more sensitive assay. Median duration of MR was unreached in patients who achieved < 1% JAK2 and it was 96 months (range, 6-155) in patients with 20-99% JAK2 allele decrease. Reasons for therapy discontinuation included treatment-related toxicities in 20 patients (24%; 11/13 for grade ≥3), patient's decision in 19 (23%), ET/PV progression or lack of response in 12 (14%), other reasons in 10 (12%, e.g., motor vehicle accident), transformation to myelofibrosis or acute leukemia [MF/AML] in 7 (8%) and death in 4 patients (5%, all unrelated). Medical reasons for discontinuation after 10 years on study included 3 carcinomas: 1 head squamous cell, 1 pancreatic and 1 ovarian; and 2 adverse events: grade 3 Sjogren syndrome and grade 2 recurrent transaminitis. Annual discontinuation rates are shown in graph. There were no transformations to MF/AML on therapy since the last study update for a total number of cases of 7. No additional vascular thrombotic events occurred with overall incidence of 0.9 / 100 person-years. Five patients experienced new adverse events after 10 years on therapy: mild flu-like symptoms, fatigue or diarrhea (3); grade 2 transaminitis (1) and Sjogren syndrome (1). Twenty-five patients continued on active follow-up after PEG-IFN discontinuation until the current data lock with a median follow-up off therapy of 92 months (range, 8-132). Twenty patients are alive (on cytoreductive therapy in 11), 5 died (acute leukemia in 2, other medical condition, bleeding, stroke for 1 each). As of last follow-up, 25% (n = 21) of originally enrolled patients died. Median overall survival (n = 83) since enrollment was unreached. Conclusions: Our 15 years of follow-up of pegylated interferon in patients with ET and PV confirms durability of responses and disease control in patients who are able to tolerate long therapy and an acceptable safety profile. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Plasmin Inhibitor in Health and Diabetes: Role of the Protein as a Therapeutic Target.

The vascular obstructive thrombus is composed of a mesh of fibrin fibers with blood cells trapped in these networks. Enhanced fibrin clot formation and/or suppression of fibrinolysis are associated with an increased risk of vascular occlusive events. Inhibitors of coagulation factors and activators of plasminogen have been clinically used to limit fibrin network formation and enhance lysis. While these agents are effective at reducing vascular occlusion, they carry a significant risk of bleeding complications. Fibrin clot lysis, essential for normal hemostasis, is controlled by several factors including the incorporation of antifibrinolytic proteins into the clot. Plasmin inhibitor (PI), a key antifibrinolytic protein, is cross-linked into fibrin networks with higher concentrations of PI documented in fibrin clots and plasma from high vascular risk individuals. This review is focused on exploring PI as a target for the prevention and treatment of vascular occlusive disease. We first discuss the relationship between the PI structure and antifibrinolytic activity, followed by describing the function of the protein in normal physiology and its role in pathological vascular thrombosis. Subsequently, we describe in detail the potential use of PI as a therapeutic target, including the array of methods employed for the modulation of protein activity. Effective and safe inhibition of PI may prove to be an alternative and specific way to reduce vascular thrombotic events while keeping bleeding risk to a minimum. Key Points Plasmin inhibitor (PI) is a key protein that inhibits fibrinolysis and stabilizes the fibrin network.This review is focused on discussing mechanistic pathways for PI action, role of the molecule in disease states, and potential use as a therapeutic target.

Vascular thrombotic events in the era of modern myeloma therapy.

The treatment landscape in multiple myeloma (MM) has changed drastically in the past two decades with new treatment paradigms evolving. In this issue Sborov et al. provide the first study investigating the frequency, severity, onset of vascular thrombotic events (VTEs) and use of prophylactic therapies in a trial applying a contemporary myeloma treatment protocol and highlight that prevention of VTEs needs to be revisited in the era of modern myeloma treatment. Commentary on: Sborov et al. Daratumumab plus lenalidomide, bortezomib and dexamethasone in newly diagnosed multiple myeloma: Analysis of vascular thrombotic events in the GRIFFIN study. Br J Haematol. 2022;199:355-365.

The Diabetic Platelet

Patients with Diabetes Mellitus (DM) have accelerated atherosclerosis, which is the main essential factor contributing to the high risk of atherothrombotic events in these patients. Atherothrombotic complications are the principal cause of morbidity and mortality in patients with DM. Both atherosclerosis and the increased risk of thrombotic vascular events may result from dyslipidaemia, endothelial dysfunction, platelet hyperreactivity, an impaired fibrinolytic balance, and abnormal blood flow. Platelets of DM patients are characterised by dysregulation of several signalling pathways causing increased adhesion, activation and aggregation. Platelet function of patients with DM is complicated by several mechanisms, such as hyperglycaemia, insulin deficiency and resistance, associated metabolic conditions, and cellular abnormalities. The present manuscript purposes to provide a review on the up-to-date status of data on platelet abnormalities that characterise patients with DM.