History Of Thrombosis Research Articles

Abstract 14932: Prediction of Pulmonary Embolism Using Random Forest Algorithm: A Study on 917 Patients Over a Period of 1 Year in a New York City Public Hospital

Introduction: Pulmonary Embolism (PE) can be challenging to diagnose. Artificial intelligence (AI)-generated models can help improve the diagnostic accuracy of detecting PE. Aim: Establish the diagnostic accuracy of AI-generated models in predicting PE as compared to routinely used diagnostic predictive tools (Well’s score, YEARS score, and revised Geneva score). Methods: We conducted a single-center retrospective review of patients who underwent computed tomography pulmonary angiography (CTPA) for diagnosing PE over a one-year period. Twenty-five parameters including age, sex, race, BMI, history of deep vein thrombosis or PE, malignancy, hypertension, COPD, CKD, presenting symptoms like chest pain, dyspnea, cough, palpitations, dizziness, lightheadedness/syncope, hemoptysis, fever, pain on palpation of the lower extremity, vitals including heart rate, respiratory rate, oxygen saturation, findings of lower extremity venous duplex, presence of right ventricular dysfunction on echocardiogram, elevated troponin and pro-brain natriuretic peptide were utilized to train the AI model. Random forest algorithms were trained for predicting PE in 80% of the dataset, while the remaining 20% was used to test the AI model. Subsequently, the accuracy of the model was matched with the accuracy of four alternative modalities: clinical judgment of PE being equally or more likely, Well’s score >4, YEARS score ≥1, and revised Geneva score ≥11. CTPA results were used as the gold standard. Analysis was performed using STATA BE/17 and Python 3.8. Results: 917 patients were included in the analysis (median age: 57 years (IQR: 41-68); female: 59%). The AI model correctly classified patients with 84.6% diagnostic accuracy, outperforming every other modality (Figure 1). Conclusion: AI-generated prediction models can be useful in predicting PE with considerable accuracy. Further, large-scale studies are required to validate these results externally.

Abstract 12644: FlowTriever Percutaneous Aspiration Thrombectomy: A Promising Approach to Catch a (Throm)Bus In-Transit

Introduction: Clot-in-transit (CIT) is a life-threatening emergency that occurs in about 25,000 patients annually and is associated with high mortality due to rapid cardiopulmonary collapse. This is a case of right atrial (RA) CIT extending from existing IVC filter in a patient with pulmonary embolism (PE) who underwent successful FlowTriever® catheter-based thrombectomy. Description of Case: A 60-year-old male presented with progressively worsening dyspnea on exertion, generalized weakness and fatigue, intermittent chest pain, and right leg pain with immobility for several weeks. He had a history of deep vein thrombosis (DVT), PE in 2008 treated with 18-month of warfarin. IVC filter was placed at that time for unclear indication. His initial labs showed elevated troponin-I of 34 ng/mL and NT pro-BNP of 3542 pg/mL, atrial flutter with 2:1 conduction, incomplete right bundle branch block, and old inferior infarct on ECG. Imaging revealed an extensive bilateral PE with right ventricle (RV) to left ventricle (LV) ratio of 2.3. Transthoracic echocardiogram (TTE) showed global LV dysfunction with ejection fraction of 44%, RV strain, dilated IVC, and an 8.7-cm mobile CIT in IVC extending into RA. Despite being treated with Heparin infusion, patient remained persistently tachycardic and dyspneic. Given his clinical stagnation due to CIT and submassive PE, he underwent an invasive TTE-guided percutaneous IVC and pulmonary arterial thrombectomy using Inari FlowTriever® catheter. Repeated TTE showed complete resolution of atrial thrombus. There was improvement in pulmonary arterial pressure and symptoms immediately post thrombectomy, but atrial flutter persisted. He was eventually discharged the following day with betablocker and life-long duration of anticoagulation. At follow up, he had complete resolution of symptoms and normal sinus rhythm on ECG. Discussion: Although surgical embolectomy is considered first-line therapy, percutaneous thrombectomy should be considered early for CIT to prevent of cardiopulmonary deterioration and shorter hospital course. FlowTriever® is the first device not requiring a cardiopulmonary bypass circuit to be FDA cleared for RA CIT, particularly benefiting patients who are poor surgical candidates.

Abstract 15274: STEMI as Initial Manifestation of Essential Thrombocythemia

Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm of myeloid cell expansion, mainly excessive platelet production, associated with thrombotic complications. Myocardial infarction (MI) in the setting of ET can result from thrombosis in the absence of coronary atherosclerosis. Here we present a case of ST elevation MI in the setting of previously undiagnosed ET. Case Report: A 59-year-old male with hypertension presented to the ED with left upper extremity weakness which started upon waking. On exam, he was in acute distress and diaphoretic. EKG revealed sinus rhythm with ST elevation in II, III, aVF, V5, and V6 suggesting inferolateral STEMI (Figure 1A). Labs were notable for Hgb 8.5g/dL, white blood cell count 33k/μL, and platelets 1.9million/μL. Decision Making: He was loaded with aspirin and clopidogrel (dual antiplatelet therapy-DAPT) and taken for coronary angiogram which revealed 80-90% thrombotic occlusion of the left circumflex artery (Figure 1b). Thrombectomy was performed and a drug-eluting stent was placed. A bone marrow biopsy showed JAK2 positive ET with myelofibrosis. He was immediately started on hydroxyurea. Platelets remained elevated, thus pegylated IFN alpha-2a was started which normalized platelet count. He remained on DAPT through discharge with no recurrent ischemic events or in-stent thrombosis during the 45-day hospitalization post stent placement. Conclusion: Patients with ET are at high risk for arterial thrombosis regardless of the presence of traditional atherosclerotic risk factors. High-risk patients, which includes those age over 60 with JAK2 mutation or history of arterial thrombosis, should be treated prophylactically with aspirin and hydroxyurea for cytoreduction. MI may be the first clinical manifestation of ET, even in patients without atherosclerotic risk factors. Initial management in patients with ET presenting with STEMI includes PCI with DAPT and early cytoreductive therapy.

Thrombosis in Young Women on Ocps Likely Is Caused By an Unmasking Effect of Estrogens on Underlying Thrombophilias

Background: Estrogen-containing oral contraceptives (OCPs) increase the risk for thrombosis 3-4 fold in otherwise healthy young women, although the absolute thrombosis rate in young OCP users is only 0.05% per year (Trenor CC, Pediatrics. 2011;127: 347). In our prospective cohort database 70% of lower extremity venous thromboembolism in adolescent girls were associated with OCP use, usually of recent onset (<6months). OCPs are associated with acquired resistance to activated protein C (APC), an important thrombin regulatory pathway, with an increase in fibrinolysis (Douxfils J, Contraception, 2020;102:396). A causative role for estrogens in thrombus formation in young women is not completely understood. Aims: This study evaluated thrombin generation, thrombin reduction by APC (activated protein C resistance, APCR), fibrinolysis and thrombophilia in healthy young males, healthy young females who were using or not using estrogen hormone therapy (i.e. oral contraceptive pills/OCPs) and young females with thrombosis who were using or not using OCPs at the time of thrombus presentation. The goal of this study was to measure the effects of OCPs on laboratory assays of coagulation and fibrinolysis to reveal potential mechanisms in increased thrombosis risk. Methods: This was an analysis of a consented, prospective cohort study (Thrombo-PICS). Healthy controls included men and women with no personal or family history of bleeding or clotting who were using or not using OCPs and on no other relevant medications. Study groups included females who presented with thrombosis with no OCP use, or OCP use for less than six months versus six or more months. All participants with a history of thrombosis were studied three or more months following the onset of thrombosis and no longer on OCPs. Laboratory assays performed included calibrated automated thrombography (CAT) with and without thrombomodulin (CAT TM) to determine thrombin generation (endogenous thrombin potential, ETP) and thrombin reduction with APC (% ETP reduction, APCR) respectively, and the euglobulin clot lysis time (ELT) to model fibrinolysis. Factors known to cause APCR and to be associated with thrombosis were also assayed, including factor V Leiden (FVL), the prothrombin gene mutation (PTM), protein C, protein S, lipoprotein(a), and the lupus anticoagulant (LA). Overall results were presented using descriptive statistics. Chi-Squared tests and paired t-tests were used to make paired comparisons. Parametric and non-parametric paired comparisons were used to evaluate group differences in ETP, % ETP reduction, ELT and presence thrombophilic traits relative to estrogen use and history of thrombosis. Results: Table 1 and Figure 1 display results. All groups of females with a history of thrombosis had decreased mean %ETP reduction compared to healthy females not on OCPs (p=0.02), with the lowest values occurring in females with thrombosis following less than six months of OCP use. There was also a lower prevalence of abnormal CAT TM values amongst healthy controls not on OCPs as compared to thrombosis patients not on OCPs (19 vs 51%, p=0.005).Healthy females on OCPs showed an increased ETP (p=0.002) and a marked reduction in ELT (p<0.001) as compared to all other groups. Females with a history of thrombosis, whether associated with OCPs or not, were similar to healthy females not using OCPs in regard to ETP and ELT. Furthermore, females who developed thrombosis on OCPs were more likely to have a thrombophilic trait than healthy controls on OCPs (48 vs 4%, p<0.001). Healthy men were found to have a greater %ETP reduction than healthy women (p=0.04), while having a lower ETP than healthy women (p=0.007). There were no differences in ELTs between healthy male and female controls (p=0.39). Discussion: OCPs were associated with increased thrombin generation, increased APCR and accelerated fibrinolysis in healthy female controls. The lower ELT in healthy controls using OCPs suggests that increased fibrinolysis may partially balance acquired APCR from estrogen use. We were unable to test fibrinolysis in females on OCPs prior to the onset of thrombosis. Females with thrombosis onset within six months of starting OCPs showed the highest prevalence of thrombophilic traits known to cause APCR. These data suggest that the APCR effect of OCPs potentially augments the prothrombotic effect of underlying thrombophilias in the promotion of clinical thrombosis.

Low Thrombosis Risk CALR Mutations Confer Higher Risk of Essential Thrombocythemia Progression

Background: Patients (pts) with essential thrombocythemia (ET) face increased risk of thrombosis and the prospect of progression to myelofibrosis (MF) or acute leukemia. ET treatment recommendations from ELN 1 and NCCN 2 are largely governed by the revised IPSET-thrombosis score that identifies 4 risk categories from “very low” to “high” based on age, thrombosis history, and the presence of a JAK2 V617F mutation 3. Pts with CALR-mutated ET are known to have a lower risk of thrombosis than those with a JAK2 mutation, and for this reason, are often considered to have lower risk ET. Yet previous study of pts with clinically diagnosed ET found that CALR mutations may negatively impact progression risk 4. For this reason, we evaluated the impact of driver mutations on the risks of thromboembolic events, disease progression, and overall mortality for a cohort of pts with rigorously defined WHO ET treated at our institution. Methods: Medical records were queried for pts with the diagnosis (dx) of ET, as per ICD, code versions 9-10. The dx of ET and dx date were confirmed by manual review. All pts met the 2022 WHO criteria for ET, including a diagnostic marrow in all cases. Confounding diagnoses, including pre-fibrotic MF, polycythemia vera, or presumed ET in pts lacking a marrow biopsy, were strictly excluded by thorough review of the rich data available. Structured query language supplemented by manual review was used to extract clinical, laboratory, molecular, and marrow findings and treatment course. Overall (OS), MF-free (MFS), and thrombosis-free (TFS) survival were estimated using Kaplan-Meier methods. Univariable and multivariable analysis of post-ET MF (PETMF), thrombosis and mortality risk were performed using Cox proportional-hazards models using IPSET-survival 5 and revised IPSET-thrombosis variables as covariates. Results: The query returned 751 pts but only 338 met our strict criteria for ET with diagnostic marrows and had annotated driver mutations. Of these, 216 (64%) were positive for JAK2 V617F, 85 (25%) CALR, 19 (6%) MPL, and 18 (5%) triple negative (TN). We identified no significant differences among the driver mutation cohorts in dx age, sex, or median follow up duration. Semi-quantitative features of the diagnostic marrow biopsies, including age-adjusted cellularity and reticulin fibrosis score, were not significantly different among the groups. Red cell parameters at dx were mildly higher in the JAK2 pts (HCT, HGB, RBC all with p<0.001), WBC count was highest in TN pts ( p=0.012), and PLT count was not significantly different ( p=0.064). 20-year TFS for JAK2 was 71%, CALR 100%, MPL 90% and TN 83% ( p=0.0027, Figure 1); 20-year MFS for JAK2 was 87%, CALR 48%, MPL 65% and TN 94% ( p=0.00053, Figure 2); 20-year OS for JAK2 was 76%, CALR 86%, MPL 89% and TN 90% ( p=0.66). Multivariable analysis showed that CALR was associated with a significantly higher risk of PETMF as compared to JAK2 (HR 11.52, CI 1.88-70.51, p=0.008), independent of age, sex, WBC, and thrombosis history. Conversely, CALR was associated with a lower risk of thrombosis (HR 0.08, CI 0.01-0.58, p=0.013) when adjusting for sex and revised-IPSET thrombosis parameters. Discussion: We found that although pts with CALR-mutated ET have lower thrombosis risk, they experience higher risk of progression to MF. Current risk models for thrombosis yield treatment recommendations well suited to reducing thrombosis risk 3. With this success, pts are expected to live with ET for decades, thereby exposing them to other ET risks, most notably that of malignant disease progression. These risks are of particular concern for younger pts who suffer the greatest relative risk 6. It is important that thrombosis risk and fibrosis risk are not conflated as our data suggest that pts with low or very low risk CALR-mutated ET can be at higher risk of progression. Our findings reinforce the need for long-term data to guide therapy for ET based not only on the near-term thrombotic risk, but also on the long-term risk of progression.

Patients with Non-Transfusion-Dependent Thalassemia May Evolve to Transfusion-Dependent Thalassemia in Adulthood

Introduction: Non-transfusion-dependent thalassemia (NTDT) describes a prevalent and clinically heterogeneous group of patients in the United States. Adults with significant forms of NTDT display progressive age-related complications due to chronic anemia and ineffective erythropoiesis. While the importance of early diagnosis and close monitoring in pediatric patients with NTDT is well-established, the characteristics and complications of adults with NTDT in the United States is poorly described. Many adult patients with NTDT are managed by community providers who often have limited experience with this condition.This single-center observational study describes the clinical characteristics of patients with NTDT during their initial presentation to an adult thalassemia treatment center and identifies intervenable complications related to NTDT. Methods: We evaluated patients referred to the Penn Comprehensive Adult Thalassemia Program between 2013 and 2023 who carried a diagnosis of NTDT (defined as alpha or beta thalassemia and requiring fewer than 8 units of red cells in the 12 months preceding their initial visit). Data was collected via manual chart review. Clinical complications were defined as symptoms at presentation, history of splenectomy, hepatosplenomegaly, paraspinal masses, pulmonary hypertension, cardiac arrhythmia, endocrine complications (hypothyroidism, hypogonadism, diabetes, decreased bone mineral density), thrombotic events, and iron overload requiring chelation. Laboratory markers of disease severity included hemoglobin (Hgb), markers of hemolysis, nucleated red blood cells, serum ferritin and MRI quantitation of liver and cardiac iron. Results: Of the 94 patients with thalassemia referred to the Penn Comprehensive Adult Thalassemia Program, 34 carried a diagnosis of NTDT. Of these, 13 had α- thalassemia (deletional and non-deletional HbH), 19 had β-thalassemia variants (homozygous or double heterozygous β-globin gene mutations), and 2 had hemoglobin E/β-thalassemia. The median age at referral was 37.5 years (range 20-74); 71% were female. In general, patients with β-thalassemia had a larger number of significant complications than those with α-thalassemia. Overall, 11 patients (32%, all with β-thalassemia) had a history of splenectomy, 21 (62%) had evidence of extramedullary hematopoiesis with hepatosplenomegaly, and 7 (21%) had paraspinal masses. Pulmonary hypertension was seen in 5 of 21 patients with β-thalassemia and hemoglobin E/β-thalassemia (24%) while 4 patients overall (11%) had a history of thrombosis. The most common endocrinopathy was decreased bone mineral density (32%). Mean Hgb was 9.1 g/dL, however, 53% had a Hgb < 9 g/dL. Seven patients had an increase in nucleated red blood cells (range 161-1522 %) as a marker of ineffective erythropoiesis. Serum ferritin exceeded international NTDT guidelines for tissue evaluation (> 800 ng/mL) in 32% of patients; the mean ferritin for all patients was 897 ng/mL (range 45-7601 ng/mL). A liver MRI was obtained in 56% of patients with mean iron content of 25 mg/g dry weight (range 1.5 - 41.2 mg/g dry weight). No patients had evidence of cardiac iron overload. Of the 34 patients referred for NTDT, 14 (41%) met criteria to initiate a chronic transfusion regimen to maintain a pre-transfusion Hgb > 9.5 g/dL per established guidelines. Criteria included fatigue (all patients), extramedullary hematopoiesis (32%), Hgb < 7 g/dL (8%), and pulmonary hypertension (15%). Several patients had more than one indication for chronic transfusion. Conclusions: This is the first report of patients with NTDT in the United States that highlights clinically significant complications that accumulate in adults. Our results demonstrate a previously unknown high prevalence of conditions that warrant close monitoring, screening and intervention. Clinically, 41% of adult NTDT patients referred to our comprehensive adult thalassemia program met criteria to initiate a chronic transfusion program, a number that is significantly higher than previously published rates outside of the USA. These findings indicate a critical need for thalassemia education of adult providers that emphasizes the importance of monitoring for early complications of NTDT, as well as criteria for initiating a chronic transfusion program to mitigate complications and provide meaningful impacts in clinical outcomes.

Atrial Fibrillation in Patients with Myelofibrosis

Background: Atrial fibrillation (AF) is the most common arrythmia (1-2% of the general population) and is associated with high risk of arterial thrombotic events. AF is not well characterized in the context of myeloproliferative neoplasms (MPN). Recent studies imply that thrombotic risk stratification among MPN AF patients may be suboptimal using the standard CHA2DS2VASC score, and true predictor of thrombotic risk may be presence of myelofibrosis instead. Clinical context in which AF occurs in myelofibrosis patients had not been investigated so far, but such analysis is needed to better understand why is the presence of myelofibrosis in particular the main predictor of thrombotic events among AF MPN patients. We aimed to evaluate prevalence and clinical associations of AF among patients with myelofibrosis. Methods: We retrospectively investigated a cohort of 154 patients with overt myelofibrosis treated in 6 Croatian hematology centers in period 2004-2022. Diagnoses were reassessed according to the 2016 WHO criteria for primary myelofibrosis (PMF) and the 2008 IWGMRT criteria for secondary myelofibrosis (SMF). Presence of AF documented in medical records and clinical correlations of AF status with main disease related characteristics were analyzed. Results: Among a total of 154 patients, 86 had PMF, 35 had post polycythemia vera (PV) and 33 had post essential thrombocythemia (ET) SMF. Median age was 69 years. There were 91 (59%) males, 111 (75%) patients were JAK2, 9 (7.3%) CALR and 4 (3.3%) MPL mutated. AF was present in 15 (9.7%) patients with myelofibrosis which was significantly more frequent than anticipated in the general population of similar age (P<0.001). There were no significant associations of AF with neither etiology of myelofibrosis, age, sex, mutational status, degree of bone marrow fibrosis, spleen size, history of thrombosis, estimated glomerular filtration rate, hemoglobin, WBC nor platelet count (P>0.05 for all analyses). DIPSS score did not differ between AF and non-AF PMF patients, but MYSEC-PM score was significantly higher among AF SMF patients (P=0.029). AF in comparison to non-AF patients more frequently had constitutional symptoms (87% vs 54%, P=0.015), positive bleeding history (27% vs 6%, P=0.004), heart failure (47% vs 12%, P<0.001), obesity (21% vs 4%, P=0.010), lower MCHC (313 vs 318 g/L, P=0.031), higher urea (median 8.5 vs 6.8 g/L, P=0.009) and higher CHA2DS2VASC score (4 vs 3 points, P=0.003). AF more frequently received anticoagulants and diuretics than non-AF patients (P<0.05), whereas similar rates of cytoreductive therapy and aspirin were utilized. Despite all myelofibrosis patients with AF patients having CHA2DS2VASC score ≥2 points, only 60% of them received anticoagulant therapy, 27% received aspirin and 73% received cytoreductive therapy. No significant difference in survival and thrombosis was observed between AF and non-AF myelofibrosis patients (P>0.05 for all analyses) although study may be underpowered for these analyses. Summary/Conclusion: AF is frequent in patients with myelofibrosis and might be associated with higher frequency of constitutional symptoms, particular cardiovascular comorbidities and consistently high predetermined CHAD2DS2VASC risk. Nevertheless, unexpectedly low proportion of patients receives anticoagulant therapy, possibly due to anticipated risk of bleeding and cytopenias common in myelofibrosis patients. It remains a question whether suboptimal treatment or presence myelofibrosis itself might be a risk factor for unfavorable outcomes among AF MPN patients.

Right Ventricular Thrombus on Echocardiography

Right ventricular thrombi (RVTs) have been almost exclusively studied in patients with pulmonary embolism (PE). The implications of an isolated RVT, a finding typically encountered on transthoracic echocardiography (TTE), are lacking. In this study, we sought to identify the echocardiographic and clinical features associated with the presence of RVTs. Between 1998 and 2023, 138 patients with RVT documented on TTE were retrospectively identified. Demographic data, presence of intracardiac devices, hypercoagulable conditions, history of deep vein thrombosis (DVT), PE, and/or left ventricular thrombus were abstracted from electronic chart review. Measurements of right and left ventricular size, and function were performed on TTE. Of the total population of patients with RVT, <1/2 had intracardiac devices, 29% had a documented hypercoagulable state (e.g., cancer or a clotting disorder). Most patients had dilated (77%) and dysfunctional (72%) right ventricles. Approximately 50% of RVTs were discovered in nonstandard imaging planes, suggesting that the presence of RVT is likely underestimated in clinical practice. Of those evaluated for PE, 80% had PE. Of those evaluated for DVT, 53% had DVT. In conclusion, further investigations are warranted to better guide when to investigate the right ventricle for RVTs on TTE and the impact of RVTs on patient outcomes.

Cardiovascular Risk Factors Are Common in Myeloproliferative Neoplasms and Portend Worse Survival and Thrombotic Outcomes

DISCUSSION Myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) are characterized by increased risk of arterial and venous thrombosis. Cardiovascular risk factors (CV RFs) including hypertension, hyperlipidemia, diabetes, smoking, and obesity likely contribute to thrombotic risk, but the exact incidence of these risk factors and the impact of CV RF modification in MPNs is less clear. The purpose of this study was to determine the prevalence of baseline CV RFs in MPN patients, investigate their association with genomic profiles, and evaluate their effect on long-term outcomes. We retrospectively analyzed patients who received targeted gene sequencing at Massachusetts General Brigham / Dana Farber Cancer Institute (N=977) from 2014-2023, and met WHO 2016 criteria for PV, ET, MF, or pre-fibrotic MF. CV RFs were identified through ICD-9 or 10 codes present prior to MPN diagnosis, and defined as hypertension, hyperlipidemia, diabetes, current smoking status, or BMI&amp;gt;30. Patient and treatment characteristics were described with summary statistics. Genomic profiles were compared between ET, PV, and MF patients with vs without a CV RF. Primary outcome was overall death. Secondary outcomes were venous thromboembolism, arterial thrombosis (including myocardial infarction and stroke), and transformation to MF or acute myeloid leukemia (AML). We calculated cumulative incidence functions of arterial/venous thrombosis as well as overall survival in patients with or without a CV RF. Hazard ratios (HR) were estimated for outcomes using Cox proportional hazards regression. Our cohort contained 399 (39.6%) ET, 312 (31.0%) PV, and 237 (23.5%) MF or pre-fibrotic MF patients. The median age at diagnosis was 58.5 years, and 47.9% of patients were male. The overall prevalence of hyperlipidemia, hypertension, and diabetes at MPN diagnosis was 16%, 20%, and 8%. The average BMI at diagnosis in all MPNs was 27.28, with 64% and 23% of patients having a BMI of &amp;gt;25 and &amp;gt;30. Six percent of MPN patients were current smokers at time of diagnosis, compared to 39% former smokers and 56% never smokers. ET and PV patients with ≥1 CV RF at MPN (N = 234, 32.9%) diagnosis were older (mean age 61.1 vs 52.1 years, p&amp;lt;0.001), and more likely to be male (50.9% vs 41.3%, p=0.02), non-White (12.4% vs 7.6%, p=0.015), and have a prior history of atherosclerotic disease (16.2% vs 4.4%, p&amp;lt;0.001), thrombosis (13.7% vs 5.0%, p&amp;lt;0.001), and heart failure (2.1% vs 0.4%, p=0.042). MF patients with ≥1 CV RF (N = 120, 50.6%) were also more likely to be older (mean age 67.5 vs 60.4 years, p&amp;lt;0.001), male (66.7% vs 53.9%, p=0.047), and have a prior history of atherosclerotic disease (19.2% vs 6.0%, p=0.003) (Table). Results of targeted gene sequencing closest to MPN diagnosis were analyzed. A similar proportion of driver ( JAK2, CALR, MPL) and concomitant ( TET2, ASXL1, DNMT3A, SRSF2, SF3B1, U2AF1, ZRSR2) mutations were seen in MPN patients with or without a CV RF. However, patients with ET or PV with ≥1 CV RF had a lower variant allele fraction (VAF) of their driver mutation (mean 41.0% vs 48.1%, p = 0.004), which was primarily driven by JAK2 (mean 43.5% vs 52.0%, p=0.003). In ET and PV, after adjusting for variables significant on univariate analysis, the presence of ≥1 CV RF was associated with higher risk of death from any cause (HR 1.73, 95% CI 1.08-2.76) and arterial thrombosis (HR 2.33, 95% CI 1.22-4.42). Among patients with MF, the presence of ≥1 CV RF was not associated with increased risk of death when adjusted for age, sex, and prior thrombosis (HR 1.36, 95% CI 0.84 - 2.20). MPN patients with ≥1 CV RF did not have increased rates of MF or leukemia progression (Fig). In our study, CV RFs are common among patients with MPN. CV RFs were associated with adverse outcomes, including death and thrombosis among patients with ET or PV. We found no differences in the molecular profiles in MPN patients with or without CV RFs, although a lower JAK2 VAF was seen in patients without CV RFs, which will need to be explored further. MPN patients with a CV RF had significantly worse overall survival and cumulative arterial thrombosis rates, although the presence of CV RFs does not impact MF or leukemia progression. However, our results highlight the importance of addressing CV RFs in MPN care to improve morbidity and mortality.

Hemoglobin F and Incidence of Thrombotic Event in Sickle Cell Disease

Introduction Characterized by abnormally sickle-shaped erythrocytes disrupting blood flow in small vessels, Sickle Cell Disease (SCD) continues to be the most common hemoglobinopathy in the United States, affecting approximately 100,000 people (Onimoe &amp; Rotz, 2020). A 2017 cohort study of SCD patients found that there is an increased risk and earlier incidence of venous thromboembolisms compared to their matched controls (Brunson et al., 2017). Fetal hemoglobin (HbF) is the best characterized modifier of disease severity in SCD, and historically, patients with low HbF percentages are at a higher risk of developing vaso-occlusive complications, organ damage, and early death (Agrawal et al., 2014). We hypothesize that having a higher hemoglobin F (unaffected by sickle cell mutation), would confer some protection from hemolysis and would be inversely related to the incidence of thrombosis in sickle cell disease patients. Methods This study uses a descriptive and cross-sectional design to analyze existing, secondary medical record data of 496 SCD patients that received care from the Center for Blood Disorders in Augusta, Georgia. Data abstraction included history of thrombotic event (TE) and HbF values closest to the TE, along with, presence of SCD clinical complications, use of blood thinning medications, specific lab values, hemoglobin electrophoresis, and history of COVID-19. For those without a history of TE, the most recent data in these categories was collected. To test the association of HbF with a categorical variable such as medical history of thrombosis, we used a two-sample t-test. To test the association of HbF with a continuous variable such as D-dimer, we computed Pearson's correlation coefficient and used Fisher's z-test. Patients with SCD who developed thrombosis were further divided into quantiles based on HbF levels [Table 1]. We collected mean age at thrombosis and mean D-dimer for these quantiles and ANOVA was used for statistical analysis. All analyses were performed using R version 4.2.3. Results Of the 496 charts reviewed, 131 patients had a history of TE and 27 of those patients have more than one recorded TE (total=189). Twenty patients did not have HbF data close to TE and were not included in this analysis. The mean HbF for patients without history of TE was 8.89 (SD 10.0), whereas the mean HbF for patients with history of TE was 10.1 (SD 10.3). A two-sample t-test comparing these two groups produced a p-value of 0.2126. Mean age of thrombosis in each quantile were 31.6 (SD 14.6), 28.7 (SD 10.5), 34.8 (SD 11.7), and 37.1 (SD 11.9), respectively, with ANOVA producing a p-value of 0.008059. Mean D-dimer in each quantile were 1017 (SD 1408), 1417 (SD 1415), 1404 (SD 1493), and 2921 (SD 8898), respectively, with ANOVA producing a p-value of .6645. Conclusions While there is no significant relationship between mean HbF levels and development of thrombosis in this cohort of 496 SCD patients, the mean age of development of thrombosis was significantly higher in higher quantiles of HbF, compared to lower quantiles, suggesting that patients with higher HbF are protected longer from thrombosis. There was no relationship between mean D-dimer level and development of thrombosis in the patients we analyzed. In SCD patients with thrombosis, D-dimer was not significantly associated with thrombosis even between different quantiles of HbF. To our knowledge, this is the first study evaluating association between HbF level, D-dimer, and development of thrombosis in SCD patients. Current therapies for SCD focus on symptom management and disease modification. While the mechanism is still not completely understood, Hydroxyurea increases the number of red blood cells (RBCs) with detectable HbF, protecting RBCs from sickle hemoglobin polymerization, thus interrupting the natural disease pathophysiology (Steinberg, 2020). Some gene therapy for sickle cell disease aims at increasing HbF in SCD patients (Abraham &amp; Tisdale, 2021). Would such therapy be protective against increased risk of thrombosis associated with SCD, remains to be determined. One limitation of this project is the restricted sample size of SCD patients with thromboembolism, and larger data size of sickle cell patients may better elucidate a relationship between Hemoglobin F and thrombosis in SCD patients.

Evaluation of an Explainable Tree-Based AI Model for Thrombophilia Diagnosis and Thrombosis Risk Stratification

Background: Thrombophilia diagnosis can often be a convoluted process involving collection and analysis of clinical data, specialized laboratory testing, and high-level decision-making. This is inherently subjective due to differences in the clinical practice philosophy of each individual practitioner and can vary depending on institutional guidelines and available resources. Patient care and clinical outcomes may be affected as a result, which in turn provides a potential opportunity for optimization of thrombophilia diagnosis using AI. Methods: This retrospective study evaluated the utility and effectiveness of an AI-powered algorithm (XGBoost) programmed to replicate the process of thrombophilia diagnosis. A total of 256 patients were referred by their clinician for thrombophilia evaluation at our ambulatory coagulation clinic between November 2019 and February 2023 and clinical and laboratory data were collected from the electronic medical record. Thrombophilia diagnosis was established (or ruled out) on the basis of the patients' personal and family history of thrombosis as well as according to the results of thrombophilia testing including established acquired and inherited thrombophilia risk factors. The XGBoost, a gradient boosting algorithm for supervised learning, was used to perform a randomized search over a predefined set of tree parameters and to find a well-performing configuration on the data using cross-validation. The dataset contained 12 clinical data parameters and 26 laboratory data parameters. The target variable was two-dimensional, consisting of the thrombophilia probability score and thrombophilia risk factors. Thrombophilia probability scores were calculated based on clinical data from the following criteria: one point assigned each for a) spontaneous thrombotic event; b) mild risk situation; c) recurrent thrombosis; d) atypical thrombosis localization; e) age &amp;lt;50 years at the time of first thrombosis; f) family history of thrombosis and/or first degree relative with an established thrombophilia diagnosis. A probability score of 0 points corresponded to “unlikely thrombophilia”; 1-2 points “thrombophilia cannot be excluded”; 3 points “likely thrombophilia”; and 4+ points “most likely thrombophilia”. Thrombophilia risk factors were categorized by a scale of 0-3 indicating no risk (0), low risk (1), intermediate risk (2), and high risk (3). Results: Six patients were excluded from analysis due to lack of availability of sufficient clinical data. Clinical and laboratory data from the remaining 250 patients were thus included in the XGBoost analysis. The resulting trees and associated feature importance rankings revealed decisive factors for the detection of thrombophilia and suggested modified thresholds (e.g. age at the first occurrence of thrombosis increased from 50 years to 51.5 years) for an objective and standardized diagnostic procedure. The relative contribution of each clinical and laboratory feature to overall performance of the algorithm is shown in the Figure. The dataset was divided into three subsets: 200 train data, 25 validation data, and 25 test data, ensuring a representative distribution across the evaluation process. The model ultimately showed a sensitivity of 100% and a specificity of 100% for the thrombophilia probability score, and a sensitivity of 75% and specificity of 98% for the thrombophilia risk factors (Table). Conclusion: These results highlight the utility of tree-based AI models to support the objective and complex diagnosis of thrombophilia and thrombosis risk stratification. Furthermore, medical professionals can gain helpful insights from this AI-powered decision-making process due to the explainable nature of the model. We expect that the algorithm will show a higher sensitivity and specificity for the thrombophilia risk factors when we repeat the tests with a larger data set, which is currently ongoing.

Real-World Experience of Ropeginterferon-Alfa Treatment of PV and ET - Two Centers Experience

BACKGROUND AND AIM: Interferon alpha is an effective treatment for Polycythemia Vera (PV) and Essential Thrombocythemia (ET) and is the only treatment known to induce sustained molecular responses by decreasing JAK2 mutation allelic burden. Long-acting pegylated interferons are better tolerated. Ropeginterferon-alfa is a monopegylated interferon with a longer half-life and is the first interferon to be FDA-approved for the treatment of PV. It is not yet approved for ET, but clinical trials are ongoing. Given the similar disease biology between PV and ET and the efficacy of pegylated interferon-alfa in both PV and ET, this study aims to look at a real-world experience of treating PV and ET with ropeginterferon-alfa since its approval. METHODS: We conducted a retrospective chart review of all our PV and ET patients treated with ropeginterferon-alfa at Huntsman Cancer Institute, University of Utah (SLC cohort), and at the University of North Carolina at Chapel Hill (UNC cohort), since the drug's approval for PV from November 2021 through June 2023. The complete hematologic response (CHR) was defined as the normalization of blood counts within the reference range of the local lab standards. Prior to ropeginterferon-alfa, the participants were managed with therapeutic phlebotomies, or cytoreduced with either hydroxyurea, pegylated interferon-alpha 2a ( Pegasys), JAK2 inhibitors, or were newly diagnosed and previously untreated. RESULTS: A total of 120 patients (76 in SLC cohort and 44 in UNC cohort) were included in this study. Of those, 75 (62.5%) were diagnosed with PV, 37 (31%) with ET, and 1 with congenital polycythemia due to germline JAK2 mutation. Twenty-three (19%) patients had a prior history of thrombosis. JAK2 mutation was present in 100 (83%) patients, while 9 (7.5%) were CALR mutated, 1 with MPL mutation, and 1 with triple-negative ET. Extended myeloid gene panel sequencing was available in 64 (53.3%) patients and 35 of them (54.6%) patients had additional somatic mutations. Most common somatic mutations include TET2 (11 patients) and DNMT3A (8 patients) and CBL (3 patients), among others. Of the cohort, 15 (12%) patients discontinued ropeginterferon-alfa due to various adverse events, which included: fatigue, joint aches, skin rash, and increased anxiety and depression. Of the 105 patients who are on ropeginterferon-alfa, 9 patients were previously untreated patients while 96 (91.4%) were pretreated with other therapies and switched to ropeginterferon-alfa. In many patients, the switch to ropeginterferon-alfa was done because of the increased frequency and aggressivity of squamous cell skin cancers while on hydroxyurea treatment. All of them started ropeginterferon-alfa at a dose of either 50 mcg or 100 mcg every two weeks and were increased at an increment of 50 mcg to achieve a goal of CHR. As most of the patients were switching from prior therapies, 51 (49%) were already in CHR at the time of initiating ropeginterferon-alfa. The median ropeginterferon-alfa dose to maintain CHR was 50mcg in the SLC cohort and 100mcg in the UNC cohort. (See table for more details). We have 6 patients with DNMT3A mutation, 4 (66.6%) have achieved CHR at a median ropeginterferon-alfa dose of 100 mcg (range 50 mcg - 150 mcg), and 2 patients are undergoing dose titration. Of the 11 patients with TET2 mutation, 7 (63.3%) achieved CHR at a median ropeginterferon-alfa dose of 150 mcg (range 50 mcg - 500 mcg). The analysis of JAK2 V617F and CALR allelic burden, transcripts of inflammatory, prothrombotic, and hypoxia-regulated (HIFs) genes, and evaluation of females for reversal of clonal to polyclonal myelopoiesis is ongoing. CONCLUSION: Ropeginterferon-alfa is effective in PV and ET, however, the dose that achieves CHR is highly individualized, necessitating an incremental titration approach. The patients already in CHR from prior therapy needed relatively lower doses of ropeginterferon-alfa to maintain CHR. Clinical trials are ongoing with an alternate accelerated dosing scheme and results are awaited.

An analysis of risk factors for venous thromboembolism in primary versus revision total joint arthroplasty

BackgroundOne of the most serious complications after primary or revision lower extremity total joint arthroplasty (TJA) is venous thromboembolism disease (VTE). Identifying patients at high risk for VTE allows tailoring of prophylactic anticoagulation regimens to those most vulnerable. This study aimed to identify risk factors for VTE in primary and revision lower extremity TJA. MethodsThe Electronic Medical Record was queried from a single academic institution for all patients who underwent a lower extremity TJA between 2007 and 2020. Demographics, comorbid conditions, perioperative characteristics, and postoperative complications were identified. An Elastic Net Multiple Logistic Regression Model was used to assess 49 covariates and predict those associated with a significant risk of VTE. ResultsWe identified 4900 primary and revision total knee arthroplasty (TKA) and total hip arthroplasty (THA) patients. There was no significant difference between primary and revision THA. Primary TKA had a higher rate of VTE than revision TKA. Significant risk factors identified for VTE in THA patients include histories of deep vein thrombosis (DVT), pulmonary embolism (PE), metastatic tumors, hemiplegia, and Hispanic ethnicity. Risk factors for VTE in TKA patients include histories of DVT, PE, metastatic tumors, and postoperative warfarin and heparin use. In all patients, age was a significant predictor of VTE risk. ConclusionOur work identifies many risk factors for VTE following TJA. While the increased rate of VTE in some populations may represent selection bias, it also highlights the incomplete understanding of the etiology and prevention of this complication in the joint arthroplasty population and requires further study.

Do sleeve gastrectomy and Roux-en-Y gastric bypass have different venous thromboembolism risk factors? Creation of 30-day Bariatric Hypercoagulation Score.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality after bariatric surgery, most often occurring after discharge within 30 days after surgery. To determine the risk factors associated with VTE after either sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) and to develop a Bariatric Hypercoagulation Score (BHS) to predict 30-day adverse postoperative outcomes. University hospital. Using 2015-2018 data from the Metabolic and Bariatric Surgery Quality Improvement Program, a BHS was created by performing a logistic regression of "venous thromboembolism." The variables with the highest odds ratio (OR) were selected for the SG and RYGB groups. Then, the 30-day outcomes of low-risk (0-1), average-risk (2-3), and high-risk (≥4) BHS were compared. Similar risk factors for VTE were found in both the SG and RYGB groups; the highest OR was shown by history of deep vein thrombosis (SG: 3.54, RYGB: 3.05). Other related factors in both groups were history of pulmonary embolism, prolonged length of stay, Black race, and male sex. Conversely, unique risk factors such as dialysis (OR 1.81) was found in the SG group; meanwhile, prolonged operative time (OR 1.50) and age >60 years (OR 1.28) were for the RYGB group. When comparing the 30-day outcomes, BHS ≥4 had a significantly higher rate of complications (P < .001). SG and RYGB have some risk factors in common for VTE; however, dialysis was associated only with SG, and prolonged operative time and age >60 years were associated only with RYGB. BHS ≥4 showed higher 30-day adverse outcomes. The VTE-correlated variables require special consideration when assessing patients undergoing SG and RYGB.

Proton Therapy in the Treatment of Men with Breast Cancer

PurposeMale breast cancer treatment involves multimodality therapy, including radiation therapy; nevertheless, few men have received proton therapy (PT) for it. Further, heart disease is an established leading cause of death in men, and radiation therapy heart dose correlates with cardiac toxicity, highlighting the need for cardiac-sparing radiation techniques. Thus, we provide a descriptive analysis of PT in a male breast cancer cohort. Patients and MethodsMen who received PT for localized breast cancer between 2012 and 2022 were identified from a prospective database. Toxicities were prospectively recorded by using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. ResultsFive male patients were identified. All had estrogen receptor (ER)–positive, Her2neu-negative disease and received adjuvant endocrine therapy. One had genetic testing positive for BRCA2, one had a variant of unknown significance (VUS) in the APC gene, and one had a VUS in MSH2. Median age was 73 years (range, 41–80). Baseline comorbidities included obesity (n = 1), diabetes (n = 1), hypertension (n = 4), history of deep vein thrombosis (n = 1), personal history of myocardial infarction (n = 3; 1 with a pacemaker), and a history of lung cancer (n = 1). All received PT to the left chest wall and comprehensive regional lymphatics. One received passive-scattering PT, and 4 received pencil beam scanning. One patient received a boost to the mastectomy incision via electrons. Median heart dose was 1 GyRBE (range, 0–1.0), median 0.1-cm3 dose to the left anterior descending artery was 7.5 GyRBE (range, 0–14.2), and median follow-up was 2 years (range, 0.75–6.5); no patient experienced a new cardiac event, and all remain free from breast cancer recurrence and progression. ConclusionIn a small case series for a rare diagnosis, PT to the chest wall and regional lymphatics, including internal mammary nodes, resulted in low cardiac exposure, high local regional disease control rates, and minimal toxicity. Proton therapy should be considered for treating men with breast cancer to achieve cardiac sparing.

Scleromyxedema associated with macular edema and retinal hemorrhage.

We discuss a case of macular edema and retinal hemorrhage associated with scleromyxedema. A case report is presented. A 64-year-old male with history of deep vein thrombosis and pulmonary embolism presented with new onset rash in the setting of switching anticoagulation treatments. He developed blurred vision was found to have macular edema and dot blot retinal hemorrhages which improved with systemic and topical corticosteroids. Systemic autoimmune conditions including scleromyxedema should be considered in the workup of occult cystoid macular edema.

Plasma level of ADAMTS-13 in maintenance hemodialysis patients and its relation to arteriovenous fistula thrombosis

Background: End-stage renal disease is the final stage of chronic kidney disease in which irreversible deterioration in renal function occur and the body fails to maintain fluid and electrolyte balance, this need regular hemodialysis (HD) a process that removes accumulated solute from a patient with near-total renal function loss. Arteriovenous fistula (AVF) is the vascular access of choice for patients who require hemodialysis. AVF thrombosis is a major issue in hemodialysis patients, which increase their morbidity and lessen HD efficiency.&#x0D; Objective: To assess plasma level of ADAMTS-13 in HD patients and its association with AVF thrombosis, and to correlate the plasma level of ADAMTS-13 with age, duration of dialysis, certain hematological parameters and estimated GFR.&#x0D; Patients and Methods:This Cross_sectional study done on 60 patients with ESRD on regular HD sessions, 20 healthy persons were included as a control . The patients subdivided into two subgroups with and without AVF thrombosis. Plasma samples were freezed until the test for the level of ADAMTS-13 was done.&#x0D; Results: The plasma ADAMTS-13 level was significantly lower in HD patients compared to control group (P &lt; 0.001), and was a significantly lower in patients with a history of AVF thrombosis than HD patients without a history of AVF thrombosis. HD patients with AVF thrombosis had significantly lower eGFR compared to patients without a history of AVF thrombosis. There was a positive correlation of plasma ADAMTS-13 level with the mean of eGFR , platelet count and negative correlation with MPV.&#x0D; Conclusion: Significant differences between HD patients and control regarding eGFR and hematological parameters . Plasma ADAMTS-13 level was significantly lower in patients compared to controls and significantly lower in patients group with AVF thrombosis than HD group without thrombosis.

Plasma level of ADAMTS-13 in maintenance hemodialysis patients and its relation to arteriovenous fistula thrombosis

Background: End-stage renal disease is the final stage of chronic kidney disease in which irreversible deterioration in renal function occur and the body fails to maintain fluid and electrolyte balance, this need regular hemodialysis (HD) a process that removes accumulated solute from a patient with near-total renal function loss. Arteriovenous fistula (AVF) is the vascular access of choice for patients who require hemodialysis. AVF thrombosis is a major issue in hemodialysis patients, which increase their morbidity and lessen HD efficiency. Objective: To assess plasma level of ADAMTS-13 in HD patients and its association with AVF thrombosis, and to correlate the plasma level of ADAMTS-13 with age, duration of dialysis, certain hematological parameters and estimated GFR. Patients and Methods:This Cross_sectional study done on 60 patients with ESRD on regular HD sessions, 20 healthy persons were included as a control . The patients subdivided into two subgroups with and without AVF thrombosis. Plasma samples were freezed until the test for the level of ADAMTS-13 was done. Results: The plasma ADAMTS-13 level was significantly lower in HD patients compared to control group (P &lt; 0.001), and was a significantly lower in patients with a history of AVF thrombosis than HD patients without a history of AVF thrombosis. HD patients with AVF thrombosis had significantly lower eGFR compared to patients without a history of AVF thrombosis. There was a positive correlation of plasma ADAMTS-13 level with the mean of eGFR , platelet count and negative correlation with MPV. Conclusion: Significant differences between HD patients and control regarding eGFR and hematological parameters . Plasma ADAMTS-13 level was significantly lower in patients compared to controls and significantly lower in patients group with AVF thrombosis than HD group without thrombosis. Keywords: ADAMTS-13, Arteriovenous fistula, Hemodialysis, Thrombosis

Diagnostic screening for risk of cerebral venous thrombosis in young patients taking oral contraceptives

Cerebral venous thrombosis is rarely diagnosed in young patients, approximately 3–4 cases per a million people in the general population. This is probably due to the fact that the clinical manifestations of CVT are nonspecific and vary from isolated headaches to individual neurological symptoms. On the other hand, the detection of this pathology is difficult due to the lack of awareness of physicians about the diagnostic screening of risk factors. In recent years, risk factors associated with disorders in the blood coagulation system (genetically determined and acquired coagulopathy) and changes in the vascular wall have come to the fore, especially in female patients using oral contraceptives. However, the prescription of this group of drugs does not take into account the risk of developing vascular complications, such as cerebral vein thrombosis, so the concept of primary vigilance in adolescents with menstrual irregularities and women of reproductive age when prescribing hormonal drugs should be based on careful screening for changes in the coagulation system. organism. The concept of primary vigilance in the appointment of hormonal drugs should be based on careful screening for congenital or acquired changes in the coagulation system of the body. Significant genetic mutations for diagnosis are Leiden and F2-prothrombin G20210A, methylenetetrohydrophosphate reductase (MTHFR), plasminogen activator inhibitor (PAI-I), factor VII, glycoprotein (GP IIIa), deficiency of proteins C, S, and antithrombin. It is advisable to include the determination of vitamins B in screening. In non-pregnant women, folate deficiency can only be detected in erythrocytes, while normal in plasma. If any mutation is found in a patient, it is necessary to examine his next of kin to clarify their genetic profile and timely use of preventive measures against thrombosis, it is recommended to replace oral contraceptives with other methods of contraception. If a history of thrombosis has previously occurred, lifelong treatment with anticoagulants is indicated.

Widespread Bilateral Pulmonary Embolism: A Case Report

We present a 45-year-old man with a personal pathological history of deep vein thrombosis of the lower limbs without current medical management. It begins suddenly with respiratory difficulty, decreased oxygen saturation, and dyspnea. Upon arrival at the emergency department, chest angio tomography was performed, highlighting bilateral filling defects, from main branches to segmental branches, so admission to the hemodynamics room for right heart catheterization was decided. Thrombectomy, bilateral ultrasound rheolysis and targeted fibrinolysis were performed, with improvement in mean pulmonary artery pressure (mPAP) to 19 mmHg compared to the previous one.