High Incidence Of Thrombosis Research Articles

COVID-19 Vaccine and Potentially Related Thromboembolic Events: Case Series

The advent of multiple COVID vaccinations over the past year through an accelerated vaccine development process has led to concerns over its safety. The United States approved for emergency use the BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), ChAdOx1 nCoV-19 (Oxford-AstraZeneca), and the Ad26.COV2.S (Janssen/Johnson & Johnson) vaccines. Although these vaccines have had a high safety profile, rare but serious adverse events have been reported including pulmonary embolism (PE) and cerebrovascular thrombosis. In this case series, we identified three patients admitted to Beaumont Hospital with new onset of pulmonary thromboembolism shortly after receiving the Pfizer-BioNTech vaccine. Clinical and laboratory data were obtained and reviewed from the Epic charting system. The three patients included two male and one female patient. All were older than the age of 40, obese with a BMI > 30 kg/m2, and had underlying vascular disorders including hypertension, coronary artery disease, and/or a history of a cerebrovascular accident. One patient was a current cigarette smoker, one had quit over 27 years ago, and the third patient never smoked. Two patients developed pulmonary embolism after the second dose of the Pfizer-BioNTech vaccine, while the third patient developed pulmonary embolism after the first dose. This case series illustrates a possible association between the Pfizer-BioNTech vaccine and the potential development of pulmonary thromboembolism, particularly in middle-aged, obese adults with underlying vascular disease. This is not surprising as recent research has seen higher incidence of thrombosis with other COVID-19 vaccinations including Moderna, Oxford-AstraZeneca, and Janssen/Johnson & Johnson. Identifying this possible association is crucial in early diagnosis and patient management, but more importantly in educating higher risk adults to avoid modifiable risk factors for venous thromboembolism including immobility, certain medications, and possibly postponing elective surgeries. Further prospective or retrospective cohort studies are warranted to assess this association.

Comparison of FXII Activation in Human Plasma By Extracellular Vesicles from Cancer Cells Versus Non-Transformed Cells

Introduction:Cancer-associated thrombosis (CAT) is a significant cause of morbidity and mortality in cancer patients. Several mechanisms underlying the development of thrombosis in cancer patients have been described. An underappreciated role for the contact activation pathway in pathologic thrombosis has become apparent in recent years, though its role in thrombosis induced by malignant disease has not been defined. It has been suggested that one mechanism for activation of the contact pathway may involve activation of factor XII (FXII) to FXIIa by extracellular vesicles (EV). To further explore this mechanism, we have isolated EV from several cancer cell lines and assessed their ability to cause FXII activation in normal human plasma.Methods:EV were isolated using a multistep ultrafiltration and ultracentrifugation method from HT29 (colorectal), U87 (glioblastoma), and PL45 (pancreatic) cell lines, as well as from primary cultures of human umbilical vein-derived fibroblasts, used as a control. EV were quantified by measuring protein concentration, and equal amounts of EV, as judged by protein content, were added to citrated human plasma (Fig. 1 A, B, C). FXIIa generation was quantified colorimetrically using the substrate H-D-Prolyl-L-phenylalanyl-Larginine-p-nitroaniline dihydrochloride (S-2302). Dextran sulfate was used as a positive control to induce FXII activation. Briefly, EV (one microgram by protein content) and S-2302 were added simultaneously to 40 microliters of normal human plasma, after which A405 was recorded.Results:We observed that all EV tested caused activation of FXII. However, the initial rate of FXII activation, as determined by comparison of the A405 at 1 minute, was between 80-300% higher in the presence of EV derived from cancer cell lines compared to that observed in the presence of fibroblast EV. Moreover, consistent with clinical observations suggesting that pancreatic cancer is associated with a particularly high incidence of thrombosis, we observed that EV from the PL45 cell line was the most potent in inducing FXII activation, in which the initial rate is about 120% or 300% higher than that of other cancer cell lines or fibroblast, respectively (Fig. 1D). To assess the specificity of the FXII substrate used in these studies, we performed parallel experiments using FXII deficient plasma, observing essentially no substrate conversion over the initial one minute assay period.Conclusion:These studies demonstrate that EV derived from both primary, non-transformed cells, which have generally been omitted from prior studies assessing the prothrombotic activity of EV, as well as cancer cell lines directly activate FXII in human plasma, though EV from cancer cell lines do so more potently and in accordance with the predicted thrombosis risk associated with the parental cancer cell type. Results with FXII-deficient plasma demonstrate that substrate activation is due to FXIIa rather than kallikrein. Current studies are focused on measuring the ability of EV isolated from patients with and without malignancy to activate FXII, and on defining the mechanisms of FXII activation, particularly the role of polyphosphate. Inhibition of contact pathway activation may be a new approach to treatment and prevention of CAT, particularly since patients with cancer are at higher risk for bleeding than normal individuals while on anticoagulation. [Display omitted] DisclosuresKhorana:Sanofi: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding; Leo: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

Incidence of thrombotic complications in COVID-19

A high incidence of thrombosis in hospitalised patients with COVID-19 was identified early during the pandemic. Accurately quantifying thrombotic risk may assist prognosis and guide appropriate thromboprophylaxis. Observational studies have estimated the rate of thrombosis in both hospitalised and non-hospitalised patients with COVID-19, and how this corresponds to the severity of illness. In this review, we provide an overview of the incidence and prevalence of arterial and venous thrombotic events in patients with COVID-19 and highlight the limitations in the studies to date. Asymptomatic individuals with COVID-19 and those with mild symptoms are at very low risk of thrombotic complications. However, rates of thrombosis are substantially increased in hospitalised patients, and are strikingly high in those patients who are critically-ill requiring treatment on the intensive care unit and especially those requiring extracorporeal membrane oxygenation. Clinicians managing such patients need to be aware of these risks and take appropriate steps with respect to thromboprophylaxis and heightened clinical vigilance. Large prospective observational studies will more accurately quantify thrombotic rate, and randomized controlled trials are currently investigating optimal thromboprophylactic strategies.

Abstract PS13-24: CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in real world practice

Abstract Background: Cyclin dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapy are an integral therapy for advanced hormone receptor positive breast cancer. Rates of venous thromboembolic events (VTE) were between 1-5% in clinical trials leading to CDK 4/6 inhibitor approval. Abemaciclib currently carries an FDA warning for VTE risk. However, rates of thrombosis in real world practice remain poorly described. We aim to better define the thrombotic risk associated with CDK 4/6 inhibitors, expanding to evaluate venous and arterial events. Additionally, factors that predispose to thrombosis while on CDK 4/6 inhibitors are unclear. We hypothesize the Khorana thrombosis risk score may predict which patients will experience thrombosis on CDK 4/6 therapy. Methods: We conducted a retrospective analysis of breast cancer patients aged ≥18 years who were prescribed a CDK 4/6 inhibitor (palbociclib, ribociclib, abemiciclib) at the Knight Cancer Institute and affiliated clinics between February 2015 and March 2020. Venous and arterial thrombosis occurring during treatment or within 30 days of discontinuation were included. We collected data including pre-treatment lab values, age, BMI, prior thrombosis, and smoking status and calculated a Khorana risk score for each patient. Utilizing univariate and multivariate logistic regression we compared these variables in patients who developed thrombosis and those who did not. We calculated overall survival of the two groups. Results: There were 270 patients included in the analysis and 29 patients (10.7%) developed a thrombotic event. Of these, 66% were venous, 28% were arterial, and 10% experienced >1 clot. Ribociclib had the highest incidence of thrombosis; 17%, followed by palbociclib; 9% and abemaciclib; 5% (Table 1). Multivariate analysis evaluating risk factors for thrombosis did not find any statistically significant predictors of thrombosis (Table 2). Khorana scores did not predict which patients experienced thrombosis. Median overall survival did not significantly differ between those who developed thrombosis and those who did not (23 months vs 17.5 months respectively, p value = 0.37). Discussion: Incidence of thrombosis in our institutional analysis is higher than reported in clinical trials. Interestingly, we found arterial thrombosis comprised over one-third of events. Patients on ribociclib experienced the highest incidence of thrombosis, suggesting the FDA thrombosis warning may need to be expanded to the drug class. Khorna scores were not predictive of thrombosis risk in our population, however only 1% of study patients had a high risk score over 2. Larger, real world studies are needed to define the risk of thrombosis with CDK 4/6 inhibitors. The role of prophylactic anticoagulation is yet to be defined in this patient population. TABLE 1: Incidence of thrombosisCumulative Incidence:Total CDK 4/6 inhibitor populationn = 270Number of thrombotic events29 (11%)Total arterial8 (28%)Total venous19 (66%)Total arterial + venous2 (6.9%)Incidence by CDK4/6 inhibitorAbemaciclib (n = 20)1 (5%)Palbociclib (n = 233)22 (9.4%)Ribociclib (n = 17)3 (17.6%)Site of eventFirst thrombotic eventn = 26CVA2 (6.9%)CVA + DVT1 (3.5%)CVA + MI1 (3.5%)DVT10 (34.5%)MI1 (3.5%)PE4 (13.8%)PE + DVT2 (7%)Line associated DVT1 (3.5%)Retinal vein thrombosis1 (3.5%)TIA3 (10.3%)Second thrombotic eventn = 3DVT1 (3.5%)PE + MI1 (3.5%)TIA1 (3.5%) TABLE 2 Predictors of thrombosisCharacteristicOR95% CIP-ValueAge1.020.98 - 1.060.28BMI1.040.98 - 1.10.24Hemoglobin0.830.69 - 1.000.06History of thrombosis1.910.72 - 5.090.20Platelet1.00.99 - 1.010.86Smoking2.610.75 - 9.110.13WBC0.970.84 - 1.110.64 Citation Format: Malinda West, Claire Smith, Tia Kohs, Ramin Amirsoltani, Jessica Ribkoff, Joshua Choung, Alison Palumbo, Joseph Shatzel. CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in real world practice [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-24.

Biodegradable Extremely-Small-Diameter Vascular Graft Made of Silk Fibroin can be Implanted in Mice.

Aim: Synthetic vascular grafts are widely used in surgical revascularization, mainly for medium- to large-sized vessels. However, synthetic grafts smaller than 6 mm in diameter are associated with a high incidence of thrombosis. In this study, we evaluated silk fibroin, a major protein of silk, with high biocompatibility and biodegradability, as a useful material for extremely-small-diameter vascular grafts.Methods: A small-sized (0.9 mm inner diameter) graft was braided from a silk fibroin thread. The right carotid arteries of 8- to 14-week-old male C57BL/6 mice were cut at the midpoint, and fibroin grafts (5- to 7-mm in length) were transplanted using a cuff technique with polyimide cuffs. The grafts were harvested at different time points and analyzed histologically.Results: CD31+ endothelial cells had already started to proliferate at 2 weeks after implantation. At 4 weeks, neointima had formed with α-smooth muscle actin+ cells, and the luminal surface was covered with CD31+ endothelial cells. Mac3+ macrophages were accumulated in the grafts. Graft patency was confirmed at up to 6 months after implantation.Conclusion: This mouse model of arterial graft implantation enables us to analyze the remodeling process and biocompatibility of extremely-small-diameter vascular grafts. Biodegradable silk fibroin might be applicable for further researches using genetically modified mice.

High risk of thrombosis in patients with advanced lung cancer harboring rearrangements in ROS1.

Based on the high incidence of thromboembolic events (TEs) observed in lung adenocarcinomas with ALK translocations and taking into account the biological proximity of ROS1 and ALK, we conducted a retrospective analysis of patients with advanced lung carcinoma carrying rearrangements in ROS1 from 23 centres in Spain and one centre in Portugal. The main objective of the study was to analyse the incidence of TE in this population, looking for predictive risk factors, and its impact on overall survival. A total of 58 patients were included. The incidence of TEs throughout the disease was 46.6% (n=27) with a median follow-up of 19 months (range: 1-78 months) and a median overall survival of 52 months in the total population and 50 months for the patients presenting TEs, with a hazards ratio of 1.12 (95% confidence interval: 0.47-2.65) p=0.78. The majority of the events were venous (n=24; 89%) and occurred in the ambulatory setting (n=18; 67%). Almost half of the patients (n=13; 48%) presented the TE in the peri-diagnostic period. The high incidence of thrombosis, especially during the cancer diagnosis process, requires special attention from a clinician. Despite the limitations of such a small descriptive study, its results are in accordance with previously reported data. It would be important to design prospective studies of antithrombotic prophylaxis in this population because of their possible impact in reducing the risk of TEs.

Impact of Blood Group Type on Severity of Disease in COVID-19 Patients

BackgroundThe virus SARS-CoV-2, which causes COVID-19 has rapidly spread into a global pandemic. In critically ill patients with the disease, common symptoms include sepsis, severe pneumonia with acute respiratory distress syndrome (ARDS), and complications such as coagulopathy and thrombosis. Many patients with COVID-19 have sequelae such as venous thromboembolism (VTE) including pulmonary embolism (PE) and deep vein thrombosis (DVT) as well as arterial thromboembolism (ATE) including stroke. COVID-19 induced inflammation can induce a prothrombotic state by activating the coagulation cascade; coupled with the immobility of severe and critically ill patients in ICU, making thrombosis common in this patient population. Different blood types in patients include A, B, AB, and O. ABO carbohydrate moieties are genetically inherited and have been linked to predisposing patients to cardiovascular diseases, cancers, and even susceptibility of COVID-19. Blood type positivity and negativity are determined by the Rhesus (Rh) factor, which is a protein found on the surface of red blood cells and is also genetically inherited and linked to higher incidence of certain diseases such as diabetes. Studies have shown a relationship between blood types and increased severity of infection from COVID-19 including increased risk of thrombosis. Blood type A has been shown to have higher severity of disease with O blood type having a lower risk of infection or mortality. This study was done to evaluate if patients with different blood types have increased risk for thrombosis or higher mortality rates with COVID-19 infection.MethodsA retrospective analysis was performed on COVID-19 positive hospitalized patients between March 1, 2020 and June 26, 2020 at our institution with reported blood typing. Patients who had a thromboembolism (VTE, DVT, PE, ATE, or stroke) verified by imaging were extracted from this cohort and included in the analysis. The prevalence of different blood types in COVID-19 patients was compared to the general population without COVID-19. The incidence of thrombosis and mortality rate based on blood type was analyzed to understand severity of COVID-19 disease. Statistical analysis was performed using chi-squared testing.ResultsAmong 1265 COVID-19 positive patients during our time frame, 138 patients were identified to have a thrombosis. Of those, 102 patients with thrombosis and 402 without thrombosis had reported blood types that were used for analysis. There was no significant difference in prevalence of blood types in COVID-19 patients (A 34.3%, AB 2.9%, B 16.7%, O 46.1%) to the general nonCOVID-19 population (A32.7%, AB 4.2%, B 14.9%, O 48.1%) (p=0.8572). There was no significant difference in incidence of thrombosis between blood types: A (23.3%), AB (15%), B (20.7%), and O (18.7%) (p=0.6513). When stratifying by Rh factor, there was also no significant difference in incidence of thrombosis by blood types: A- (11.1%), A+ (24.1%), AB- (0%), AB+ (15.8%), B- (25%), B+ (20.3%), O- (18.2%), O+ (18.7%) (p=0.9054). There was also no significant difference in mortality rate between COVID-19 patients based on blood types in our cohort: A (20.7%), AB (15%), B (13.4%), and O (21.8%) (p=0.3747).ConclusionOur study demonstrates that there is no increased prevalence of one blood type over another between COVID-19 patients compared to the general population, showing that patients are not at higher risk for COVID-19 infection based on blood type. There was also no difference between blood types based on incidence of thrombosis. When further stratifying with Rh factor, there was also no difference in incidence of thrombosis based on blood types. This shows that regardless of Rh positivity or negativity, there is no increased risk for thrombosis in COVID-19 patients based on blood type. There is also no difference in mortality in COVID-19 patients based on blood type. Since COVID-19 patients who are critically ill and have more severe disease have higher incidence of thrombosis and higher mortality rates, our study suggests that patients are not at higher risk for severe COVID-19 disease based on blood type. However, this study is also limited due to small sample size, and prospective studies are needed to better understand the relationship between blood type and severity of disease in COVID-19+ patients.DisclosuresNo relevant conflicts of interest to declare.

The Impact of Different Prophylactic Anticoagulation Doses on the Outcomes of Patients with COVID-19

IntroductionAs the COVID-19 pandemic spread throughout the world, it was seen that patients who presented with critical disease had a higher incidence of thrombotic complications, associated with a poor prognosis. Currently prophylactic anticoagulation is recommended for all patients with COVID-19 who require hospitalization as part of the supportive management. However, since a higher incidence of thrombosis despite prophylactic anticoagulation has been reported, some recommendations indicate that an increase to intermediate or therapeutic dosing should be considered. The full spectrum of complications and outcomes related to this strategy are still unknown.MethodsWe conducted a cross-sectional study using the COVID-19 registry of the ARMII study group, based in Centro Medico ABC, a private hospital in Mexico City. We included all patients admitted from March 12 to July 31, 2020, who received prophylactic anticoagulation at standard (enoxaparin 40mg QD), intermediate (0.5 mg/kg QD or 40 mg BID), or therapeutic doses (1mg/kg BID), a decision taken by the attending physician based on clinical and laboratory criteria. Patients with previous or presenting with thrombosis were excluded.We compared the three groups to identify baseline characteristics and conducted multivariable logistic regressions to measure the association of anticoagulation profiles and adverse outcomes.ResultsOut of total 322 patients, we identified 81 (25%) who received standard dose, 164 (51%) who received intermediate and 77 (24%) on therapeutic doses. Age and sex were distribuited similarly among groups; patients with intermediate and therapeutic doses were more overweight and obese, but this was not significant (p=0.052). On admission, patients who received intermediate and therapeutic doses had lower oximetry registry when compared with standard doses (89%, 88% and 92% respectively, p=0.008). Three severity scales, NEWS, MULBSTA and CALL, were higher in patients with intermediate and therapeutic doses (p=0.01, p=0.02 and p=0.005, respectively). Regarding laboratory values, patients on therapeutic doses had higher leucocytes on admission (median 6 x 109L, 6 and 8, p=0.05) but lower lymphocyte absolute counts (median 1240 cells/mm3, 935 and 920, p<0.001). Patients who were given higher doses of anticoagulation had higher levels of C-reactive protein, DHL, and ferritin (p<0.001) and higher levels of IL-6 (p=0.02). Levels of D-dimer were also higher in this group (p<0.001). Patients with therapeutic doses of anticoagulation were more likely to present major bleeding when compared to intermediate or standard prophylactic doses (9% vs 1% vs 0%, p=0.0006) and clinically relevant bleeding (12% vs 2% vs 5%, p=0.01).(Table 1)The incidence of pulmonary embolism (PE) in the entire cohort was 5%, while the incidence of major bleeding was 2.5%. There were no differences between the different doses of anticoagulation; no patients presented deep venous thrombosis.During follow-up, a total of 21 patients died, representing 6.5% of the study population. Independent factors that predicted death included age, CRP and D-dimer levels on admission, history of hypertension and requirement of mechanical invasive ventilation. When adjusting for these confounders, therapeutic anticoagulation was associated with a lower risk of death (OR 0.079 95% CI 0.008-0.76).When restricting the analysis for patients who required mechanical ventilation, anticoagulation was also associated with a lower risk of death (OR 0.031 95% CI 0.002-0.54) but not for intermediate doses (OR 0.10 95% CI 0.01-1.06).(Figure 1)ConclusionsAnticoagulation might not play a causal role in the risk of requiring mechanical ventilation, but the decision to increase doses might reflect patients who present with more severe disease. In our cohort, the majority of the patients were receiving intermediate prophylactic doses and the incidence of PE is lower than in worldwide reports. Therapeutic doses of anticoagulation were not associated with a lower risk of PE, but were associated with lower risk of death. However, therapeutic doses were also associated with a higher risk of major and clinically significant bleeding. Randomized-controlled clinical trials are needed to understand the role of higher doses of prophylactic anticoagulation in COVID-19.DisclosuresNo relevant conflicts of interest to declare.

Anticoagulant interventions in hospitalized patients with COVID‐19: A scoping review of randomized controlled trials and call for international collaboration

IntroductionCoronavirus disease (COVID‐19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID‐19 and consequently, immediate answers from high‐quality randomized trials are needed. MethodsThe World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID‐19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate. ResultsA total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi‐arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D‐dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All‐cause mortality is part of the primary outcome in 14 trials. DiscussionSeveral trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID‐19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly.

The differences of atrial thrombus locations and variable response to anticoagulation in nonvalvular atrial fibrillation with ventricular cardiomyopathy.

ObjectivesThis study aims to research the clinical features of atrial thrombi in patients with nonvalvular atrial fibrillation (AF).METHODSThis study included 191 patients of AF who had atrial thrombi. One hundred and twenty‐eight of them were assigned into nonventricular cardiomyopathy group (non‐VCM), and the remaining 63 into ventricular cardiomyopathy group (VCM). After atrial thrombi diagnosed, all patients had taken oral anticoagulant therapy. The resolution rates of thrombi within 12 months were compared between the two groups, as well as the locations of thrombi.ResultsOf all 191 patients, 161 had thrombi only detected in left atrial appendage (LAA), 20 in both left atrium (LA) and LAA, six in LA only, and four in right atrium only. More patients had thrombi out of LAA in the VCM group than in the non‐VCM group (30.2% vs 8.6%, P < .001). After propensity score matching, the atrial thrombi were resolved faster in the non‐VCM group than in the VCM group (mean time length: 22 ± 2 weeks vs 30 ± 3 weeks, P = .038), and the resolution rate within 12 months was higher in the non‐VCM group than in the VCM group (88.7% vs 61.4%, Log‐rank, P = .038). In Cox proportional hazards model, absence of ventricular cardiomyopathy was an independent predictor for the resolution of atrial thrombus (hazard ratio: 1.76; P = .035).ConclusionsThe patients of atrial fibrillation with ventricular cardiomyopathies have higher incidence of thrombosis in the body of left atrium or right atrium. And the resolution rate was lower in these patients.

Utility of the 4Ts score in excluding heparin-induced thrombocytopenia in lung transplant recipients.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic complication following heparin exposure. Data is limited on the incidence of HIT and validity of 4Ts score in the solid organ transplant population. This retrospective observational cohort included patients who underwent lung transplant between August 2015 and June 2018 and had a clinical suspicion of HIT with heparin-PF4 testing. The 4Ts score was correlated with the heparin-PF4 antibody and serotonin release assay (SRA) results, with positive SRA considered confirmed HIT. Of 146 patients evaluated, the overall incidence of HIT was low (2(1%)). Fifty-one patients had heparin-PF4 testing and were included in the cohort; 5 (10%) had positive heparin-PF4 and 1 (2%) had confirmed HIT. The median 4Ts score was 3 (3-4). Thirty (59%), 17 (33%), and 4 (8%) patients had low, intermediate, and high risk, respectively. The intermediate/high risk group compared to the low risk group had a higher use of alternative non-heparin anticoagulation [13 (62%) vs 7 (23%); p = 0.0086)] and a higher incidence of thrombosis [13 (62%) vs 1 (3%); p < 0.0001]. No patient with a low 4Ts score had confirmed HIT, supporting the utility of low 4Ts score to exclude HIT diagnosis in lung transplant recipients.

Searching for the Best Way to Assess the Risk of Thrombosis in Aesthetic Plastic Surgery; The Role of the Caprini/Pannucci Score.

There is concern regarding the high incidence of thrombosis in plastic surgery patients. For this reason, we wanted to compare the results of the Caprini/Pannucci score in patients with and without a past history of thrombosis admitted for aesthetic plastic surgery. This was a case-control study of 152 patients undergoing aesthetic plastic surgery procedures. We formed two groups: Group I had 70 patients who had thrombosis after aesthetic plastic surgery and group II had 82 patients without thrombosis. We studied the considered risk factors for thrombosis. We weighted the factors according to the OR and linear regressions. We then related them to the Caprini/Pannucci score. Patients in group I had a score of 5.68 versus 3.45 in group II (p < 0.001). There was a 9.86% increase in thrombosis for each increased point in the rating. A higher effectiveness of the Caprini score was found in the high-score group; the greatest flaw was in the low-scoring group. The sensitivity was 75.71%, and the specificity was 70.73%. The factors with the greatest impact were the infiltration of fat in the buttocks, degree of obesity and time of surgery. There was an increased risk of thrombosis in patients with gluteal fat injections, varicose veins, obesity and immune disorders as well as those who had previously given birth. To increase the effectiveness of the score and to use the score as a basis on which to decide upon prophylactic care, it is necessary to modify the score and add some factors. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

PF687 RISK OF THROMBOSIS IN PATIENTS WITH POLYCYTHEMIA VERA AND ESSENTIAL THROMBOCYTHEMIA ACCORDING TO THE JAK2 V617F ALLELE BURDEN

Background: Thrombosis is one of the major causes of morbidity and mortality in patients with chronic phase myeloproliferative neoplasms (MPN) comprising polycythemia vera (PV) and essential thrombocythemia (ET). The JAK2 V617F mutation is the most common driver mutation in BCR-ABL1 negative MPNs and the presence of JAK2 V617F is an independent risk factor of thrombotic events in patients with ET. Aims: In this study, we analyzed whether the JAK2 V617F allele burden is associated with the incidence of thrombosis in JAK2 V617F-positive patients with PV or ET. Methods: This was a retrospective study that assessed the impact of JAK2 V617F allele burden on clinical and laboratory characteristics in JAK2 V617F-positive patients with PV or ET. Patients with a diagnosis of PV or ET according to the WHO criteria at Daegu Catholic University Hospital between 2008 and 2018 were included in this study. JAK2 V617F allele burden were measured by pyrosequencing. Results: A total of 127 patents, median age 68 years, with PV (n = 61) or ET (n = 66) were included in our analyses. The JAK2 V617F allele burden in the entire population of patients was 45.0 ± 25.9%. A higher V617F allele burden was associated with higher white blood cell counts, higher hemoglobin values, lower platelet counts and higher LDH level (p < 0.001, p < 0.001, p = 0.001, and p = 0.001, respectively). There was a statistically significant difference in the JAK2 V617F allele burden between PV and ET (p < 0.001). The median V617F allele burden in PV patients was 58%, and ET was 30%. Thrombotic events were observed in 27.8% and 51.5% in patients with PV and ET, respectively. Multivariate logistic regression analysis revealed that older age (odds ratio, 1.07; 95% CI 1.01–1.18) was associated with higher incidence of thrombosis in patients with PV. In patients with ET, multivariate logistic regression analysis revealed that older age (odds ratio, 1.36; 95% CI 1.14–1.72), higher hemoglobin (odds ratio, 1.26; 95% CI 1.09–1.54), and V617F allele burden≥30% (odds ratio, 1.03; 95% CI 1.00–1.08) was elucidated as risk factors for thrombotic complications. Summary/Conclusion: JAK2 V617F allele burden can represent the disease phenotype. The incidence of thrombotic complications in ET patients with high JAK2 V617F allele burden is significantly higher than patients with low JAK2 V617F allele burden. There was no significant difference of the rate of thrombosis in PV patients according to the JAK2 V617F allele burden.

Clinical Analysis of 208 Patiets with BCR/ABL Negative Myeloproliferative Neoplasms

To analyze the incidence, hemogram, genetics, clinical manifestations, therapeutic efficacy and outcome of patients with myeloproliferative neoplasms(MPN) so as to provide much more therapeutic basis for clinically studying the pathogenesis, diagnosis, and treatment as well as evaluating the prognosis of MPN patients. The clinical data and related laboratory test results in 208 cases of BCR/ABL fusion gene regative MPN were collected and analyzed retrospectively. The MPN could occur at any age, but the highest incidence was observed in patients aged 40-79. Among 208 patients with MPN, the patients with essential thrombocythemia(ET) accounted for 48.56%(101/208), the patients with polycythemia vera(PV) accounted for 25.96%(54/208), and the patients with primary myelofibrosis(PMF) accounted for 25.48(53/208). The clinical manifestation of MPN varied, the first manifestations was no-specific, onset of disease presented slow. The JAK2V617F gene mutation existed in 130 out of 208 patients with MPN, total mutation rate was 62.5%;JAK2V617F mutation rate in PV patients was 81.5%(44/54), while that in ET and PMF patients was 58.4%(59/101) and 50.9%(27/53) respectively, the detected rate of this mutation in PV patients was significantly higher than that in ET and PMF patients (P<0.05), while there was no significant difference between ET and PMF patients(P>0.05). In PV group, the WBC count of JAK2V617F positive patients was significantly enhanced (P<0.01), while there were no statistical differences of hemoglobin level and platelet count (P>0.05); in ET and PMF groups, the JAK2V617F positive patients had a higher WBC count and hemoglobin level(P<0.05), while the difference of platelet count was no significant(P>0.05). The most common vascular event in patients with MPN was ischemic cerebrovascular disease. The JAK2V617F mutation related with risk of thrombosis (OR=2.222, 95% CI=1.101 to 4.486). The difference in the incidence of vascular event between ET and PV patients was no statistically significant (P>0.05), but the incidence of vascular event in ET and PV patients was higher than that in PMF patients(P<0.05). The disease conversion much more easily happened in JAK2V617F positive patients. After treatment, the MPN could be controlled, yet the maintained treatment is needed. The MPN can occur almost at any age, but more commonly occures in middle-aged and elderly persons. The onset of MPN varies, the clinical manifestation was similar, a high detected rate of JAK2V617F mutation is observed in MPN patients and relates closely with onset of MPN; moreover, JAK2V617F mutation rate relates with type of MPN. The MPN patients with JAK2V617F mutation have higher WBC count and higher incidence of thrombosis. After treatment, the MPN can be better controlled, and need maintenance treatment. So as to avoid the reccurence of disease, control the complications and obtain the longterm survival.

Obesity Paradox in Patients With Deep Venous Thrombosis.

We aimed to investigate the association between obesity and deep venous thrombosis (DVT) in a country with a high prevalence of obesity. This is a retrospective cohort study of patients who presented with DVT between 2008 and 2012. Data were analyzed and compared based on body mass index (BMI), and patients were classified into normal (<25), overweight (≥25 to <30), obese I (30 to <35), obese II (35 to <40), and obese III (≥40). Among 662 patients with DVT, 28% were overweight and 49% were obese. The mean age was 50.3 (16.5) years, and 51% were females. Diabetes mellitus and prior venous thromboembolism were significantly higher among obese patients. History of malignancy was more common in nonobese patients. Protein S and antithrombin III deficiency and hyperhomocysteinemia were more prevalent among morbid obese patients. Also, obese patients had higher incidence of thrombosis in the distal veins ( P = .03). Warfarin use and long-term therapy were more frequent in obese than nonobese. Postthrombotic syndrome was comparable in obese and nonobese groups. Recurrent DVT was higher in obese I ( P < .01), whereas mortality rates were greater in nonobese groups ( P = .001). Malignancy, diabetes mellitus, and common femoral vein involvement were predictors of mortality, whereas BMI ≥30 was the predictor of survival. Cox regression models showed that after adjusting for age, sex, pulmonary embolism, and duration of warfarin treatment, BMI ≥40 had better survival (hazard ratio: 0.177, 95% confidence interval: 0.045-0.691, P = .013). There is a significant association between obesity and DVT. Obese patients have characteristic risk factors and better survival. This obesity paradox needs further studies to assess its clinical and pharmacotherapeutic implications.

Efficacy of aspirin in preventing peripherally inserted central venous catheter-related thrombosis: a systematic review

Objective To evaluate the effect of aspirin in preventing peripherally inserted central venous catheter (PICC) -related thrombosis by Cochrane systematic review method. Methods The relevant randomized controlled trials, quasi-randomized controlled trials and case-control study were searched in the Wang Fang Databases, VIP, CNKI, CINAHL, Elsevier, Cochrane Database of Systematic Reviews, EBSCO and Pub Med. The studies were selected according to the inclusion and exclusion criteria by two reviewers, and the quality of included studies was evaluated according to Cochrane Handbook 5.1.0 and Newscastle-Ottawa scale. Meta-analysis was conducted by using RevMan5.0. Results A total of 9 articles included three randomized controlled trials, five quasi-randomized controlled trials and one case-control study involving 3 064 patients. The results of Meta-analysis showed that the control group had a significantly higher incidence of thrombosis than experimental group (OR=3.66, 95%CI=0.42-0.77, P=0.000 2) ; control group had a significantly higher incidence of thrombosis within one week than experimental group (OR=2.99, 95%CI=0.14-0.67, P=0.003) ; control group had a significantly higher incidence of unplanned removal than experimental group (OR=2.63, 95%CI=0.04-0.63, P=0.008) . Control group had a significantly higher incidence of phlebitis than experimental group (OR=4.47, 95%CI=0.16-0.49, P<0.05) . Conclusions Aspirin can be used as an efficient way to prevent PICC associated thrombosis, while the side effect should be closely observed. Key words: Aspirin; Thrombosis; Peripherally inserted central venous catheters; Meta-analysis

EL-16 - Management of cancer-associated thrombosis

The development of VTE has been known to be one of cautious complications and associated with a worse QOL and survival outcome in cancer patients. Cancer patients have a 4∼7 fold increased risk of VTE compared with general population. Around 10% of the patients with unprovoked VTE have been reported to have hidden cancer. The high incidence of thrombosis is reported in patients with pancreas, ovary, lung, and brain tumor. On the other hand, relatively low risks are seen in patients with mammary or prostate cancer. While the mechanisms on development of VTE associated with cancer progression are actively studied recently, it remains unsolved. One of most attractive molecules is tumor-derived tissue factor-bearing microparticles (TMP) which are produced by cancer cells and spread out in circulating blood. TMP may attach to surface membrane of vascular endothelial cells and leukocytes via the interaction of adhesion molecules, and then blood coagulation system is activated and induces the formation of thrombosis on the phospholipid cell surface membrane. In cancer patients, VTE delays in surgery and administration of chemotherapy and increased risk of bleeding due to anticoagulation, and then results in worse QOL and increased mortality. Therefore, the prediction and adequate prevention of VTE should be essential. In 2008 Khorana et al proposed the predictive model for VTE in cancer patients, which included type of cancer, platelet count ( = >350,000/ml), Hb <10g/dl, WBC >11000/ml and BMI = >35. Recently, D-dimer is indicated to be predictive biomarkers of thrombosis. Several guidelines for prophylaxis and treatment of VTE in cancer patients are presented. Prophylaxis against VTE is generally accepted in cancer patients with high risk Khorana score for DVT. Low molecular weight heparin is mostly used as first line therapy, although it is not currently approved in Japan. The clinical usefulness of direct oral anticoagulants (DOACs) has not yet been concluded.

Platelet transactivation by monocytes promotes thrombosis in heparin-induced thrombocytopenia

AbstractHeparin-induced thrombocytopenia (HIT) is characterized by a high incidence of thrombosis, unlike other antibody-mediated causes of thrombocytopenia. We have shown that monocytes complexed with surface-bound platelet factor 4 (PF4) activated by HIT antibodies contribute to the prothrombotic state in vivo, but the mechanism by which this occurs and the relationship to the requirement for platelet activation via fragment crystallizable (Fc)γRIIA is uncertain. Using a microfluidic model and human or murine blood, we confirmed that activation of monocytes contributes to the prothrombotic state in HIT and showed that HIT antibodies bind to monocyte FcγRIIA, which activates spleen tyrosine kinase and leads to the generation of tissue factor (TF) and thrombin. The combination of direct platelet activation by HIT immune complexes through FcγRIIA and transactivation by monocyte-derived thrombin markedly increases Annexin V and factor Xa binding to platelets, consistent with the formation of procoagulant coated platelets. These data provide a model of HIT wherein a combination of direct FcγRIIA-mediated platelet activation and monocyte-derived thrombin contributes to thrombosis in HIT and identifies potential new targets for lessening this risk.

Dysfunction of mechanical heart valve prosthesis: experience with surgical management in 48 patients.

Dysfunction of mechanical heart valve prostheses is an unusual but potentially lethal complication after mechanical prosthetic valve replacement. We seek to report our experience with mechanical valve dysfunction regarding etiology, surgical techniques and early outcomes. Clinical data of 48 patients with mechanical valve dysfunction surgically treated between October 1996 and June 2011 were analyzed. Mean age was 43.7±10.9 years and 34 were female (70.8%). The median interval from primary valve implantation to dysfunction was 44.5 months (range, 1 hour to 20 years). There were 21 emergent and 27 elective reoperations. The etiology was thrombosis in 19 cases (39.6%), pannus in 12 (25%), thrombosis and pannus in 11 (22.9%), improper disc orientation in 2 (4.1%), missing leaflet in 1 (2.1%), excessively long knot end in 1 (2.1%), endogenous factor in 1 (2.1%) and unidentified in 1 (2.1%). Surgical procedure was mechanical valve replacement in 37 cases (77.1%), bioprosthetic valve replacement in 7 (14.9%), disc rotation in 2 (4.2%) and excision of excessive knot end in 1 (2.1%). Early deaths occurred in 7 patients (14.6%), due to low cardiac output in 3 (6.3%), multi-organ failure in 2 (4.2%) and refractory ventricular fibrillation in 2 (4.2%). Complications occurred in 10 patients (20.8%). Surgical management of mechanical valve dysfunction is associated with significant mortality and morbidity. Earlier identification and prompt reoperation are vital to achieving better clinical outcomes. The high incidence of thrombosis in this series highlights the need for adequate anticoagulation and regular follow-up after mechanical valve replacement.

Genomic landscape in KIT D816V+ advanced systemic mastocytosis

Objective: Polycythemia Vera (PV) and Essential Thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPN) characterized by frequent thrombotic complication. Thus, the important goal of therapy is to prevent thrombosis. However, there are some JAK2V617F mutation-positive patients who show bone marrow features characteristic for PV but do not meet the World Health Organization (WHO) diagnostic criteria of PV. Recently, a new definition of masked PV is proposed; which is hypothesized as the initial manifestation of MPN. Masked PV is believed to have thrombosis more frequently than PV and ET. Here, we evaluated the outcome of patients who corresponded to masked PV. Design: We reviewed our patients retrospectively who were diagnosed as PV or ET in our institute. From medical records, we evaluated the incidence of thrombosis of patients who corresponded to masked PV. Patients: Eligible patients were JAK2V617F mutated PV or ET patients who were diagnosed in our hospital according to WHO criteria. They were classified as overt PV if hemoglobin level was >18.5g/dl in males and >16.5g/dl in females. When hemoglobin level of 16.018.4g/dl in males and 15.0-16.4 g/dl in females, they were classified as masked PV. The remaining patients with>45 10/mL of platelets were diagnosed as ET. Main Outcomes Measure: The incidence of thrombosis was 17% in masked PV and this was less frequently than in overt PV or ET. Results: Among 56 JAK2V617F-mutated patients, 6 patients (11%) were classified as masked PV and all of them were males. Their leucocyte counts was lower (11300 vs 10950/mL) and platelets counts was higher (51.6 vs 61.4 10/mL) than overt PV. Median age was 60 in overt PV, 68 in ET and 47.5 in masked PV. The incidence of thrombosis was 36%, 28% and 17%, respectively. In masked PV patients of our hospital, the incidence of thrombosis was less frequently. A possible reason for that is the treatment which maintained the Hematocrit (Hct) level below 50% in masked PV patients. Conclusion: In our patients the masked PV did not show high incidence of thrombosis, possibly because of the treatment that maintained the Hct level below 50%.