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Background: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients., Objectives: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission., Methods: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, Vermont) between 2010 and 2019, and the validation cohorts included people admitted to Hennepin County Medical Center (Minneapolis, Minnesota), University of Michigan Medical Center (Ann Arbor, Michigan), and Harris Health Systems (Houston, Texas). Individuals with VTE at admission, aged <18 years, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to select candidate HA-VTE risk factors for final inclusion in the RAM., Results: The development cohort included 60 633 admissions and 227 HA-VTE, and the validation cohorts included 111 269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t statistics ≥1.5 were included in the RAM: history of VTE, low hemoglobin level, elevated creatinine level, active cancer, hyponatremia, increased red cell distribution width, and malnutrition. The areas under the receiver operating characteristic curve and calibration slope were 0.72 and 1.10, respectively. The areas under the receiver operating characteristic curve and calibration slope were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems, respectively. The RAM performed well stratified by age, sex, and race., Conclusion: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. All rights reserved.)

Background: We previously determined good agreement and high specificity of the International Society on Thrombosis and Haemostasis (ISTH) definition of pulmonary embolism (PE)-related death among an expert central adjudication committee (CAC). CACs are often composed of experts in the corresponding research field. Involving physician trainees in CACs would allow investigators to divide the workload and foster trainees' research experience., Objective: To evaluate the accuracy of the ISTH definition of PE-related death for PE- versus non-PE-related deaths as confirmed by autopsy and its interrater agreement among physician trainees., Methods: This retrospective autopsy cohort included all patients with PE-related deaths between January 2010 and July 2019 as well as patients who died in 2018 from a cause other than PE at the New York-Presbyterian Hospital. Based on premortem clinical summaries, two physician trainees independently determined the cause of death using the ISTH definition of PE-related death. We calculated the sensitivity and specificity of the ISTH definition to identify autopsy-confirmed PE-related death and its interrater agreement., Results: Overall, 126 death events were adjudicated (median age, 68 years; 60 [48%] women), of which 29 (23%) were due to PE, as confirmed by autopsy. Sensitivity and specificity of the ISTH definition for autopsy-confirmed PE-related death was 48% (95% CI, 29-67) and 100% (95% CI, 96-100), respectively. Interrater reliability for PE-related death was good (percentage agreement, 93%; 95% CI, 87-96, Cohen's Kappa, 0.67; 95% CI, 44-85)., Conclusion: Our findings are consistent with our previous validation study. They further support the use of the ISTH definition of PE-related death and revealed high agreement between adjudicators with varied experience., Competing Interests: Declaration of competing interests There are no competing interests to disclose. Funding information S.R. Kahn, A. Delluc, N. Langlois, G. Le Gal, and T. Tritschler are members of the Canadian Venous Thromboembolism Research Network (CanVECTOR); the Network received grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT-142654). S.R. Kahn holds a Tier 1 Canada Research Chair in venous thromboembolism. A. Delluc is recipient of a University of Ottawa Department of Medicine Research Salary Award. G. Le Gal holds a mid-career clinician scientist award from the Heart and Stroke Foundation of Ontario, and the Chair on the Diagnosis of Venous Thromboembolism, Department of Medicine, University of Ottawa., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Purpose: Venous thromboembolism (VTE), especially pulmonary embolism (PE) and lower extremity deep vein thrombosis (LE-DVT), is a serious and potentially preventable complication for patients with cancer undergoing systemic therapy., Methods: Using retrospective data from patients diagnosed with incident cancer from 2011-2020, we derived a parsimonious risk assessment model (RAM) using least absolute shrinkage and selection operator regression from the Harris Health System (HHS, n = 9,769) and externally validated it using the Veterans Affairs (VA) health care system (n = 79,517). Bootstrapped c statistics and calibration curves were used to assess external model discrimination and fit. Dichotomized risk strata using integer scores were created and compared against the Khorana score (KS)., Results: Incident VTE and PE/LE-DVT at 6 months occurred in 590 (6.2%) and 437 (4.6%) patients in HHS and 4,027 (5.1%) and 3,331 (4.2%) patients in the VA health care system. Assessed at the time of systemic therapy initiation, the new RAM included components of the KS with the modified cancer subtype, cancer staging, systemic therapy class, history of VTE, history of paralysis/immobility, recent hospitalization, and Asian/Pacific Islander race. The c statistic was 0.71 in HHS and 0.68 in the VA health care system (compared with 0.65 and 0.60, respectively, for KS). Furthermore, the new RAM appropriately reclassified 28% of patients and increased the proportion of VTEs in the high-risk group from 37% to 68% in the validation data set., Conclusion: The novel RAM stratified patients with cancer into a high-risk group with 8%-10% cumulative incidence of VTE and 7% PE/LE-DVT at 6 months ( v 3% and 2%, respectively, in the low-risk group). The model had improved performance over the original KS and doubled the number of VTE events in the high-risk stratum. We encourage additional external validation from prospective studies.[Media: see text].

Severe coronavirus disease-19 (COVID-19) has been associated with fibrin-mediated hypercoagulability and thromboembolic complications. To evaluate potential biomarkers of coagulopathy and disease severity in COVID-19, we measured plasma levels of eight biomarkers potentially associated with coagulation, fibrinolysis, and platelet function in 43 controls and 63 COVID-19 patients, including 47 patients admitted to the intensive care unit (ICU) and 16 non-ICU patients. COVID-19 patients showed significantly elevated levels of fibrinogen, tissue plasminogen activator (t-PA), and its inhibitor plasminogen activation inhibitor 1 (PAI-1), as well as ST2 (the receptor for interleukin-33) and von Willebrand factor (vWF) compared to the control group. We found that higher levels of t-PA, ST2, and vWF at the time of admission were associated with lower survival rates, and that thrombotic events were more frequent in patients with initial higher levels of vWF. These results support a predictive role of specific biomarkers such as t-PA and vWF in the pathophysiology of COVID-19. The data provide support for the case that hypercoagulability in COVID-19 is fibrin-mediated, but also highlights the important role that vWF may play in the genesis of thromboses in the pathophysiology of COVID-19. Interventions designed to enhance fibrinolysis might prove to be useful adjuncts in the treatment of coagulopathy in a subset of COVID-19 patients., (© 2022. Japanese Society of Hematology.)

Objectives: The authors present a novel technique to detect and characterize LAA thrombus in humans using combined positron emission tomography (PET)/cardiac magnetic resonance (CMR) of a fibrin-binding radiotracer, [ 64 Cu]FBP8., Background: The detection of thrombus in the left atrial appendage (LAA) is vital in the prevention of stroke and is currently performed using transesophageal echocardiography (TEE)., Methods: The metabolism and pharmacokinetics of [ 64 Cu]FBP8 were studied in 8 healthy volunteers. Patients with atrial fibrillation and recent TEEs of the LAA (positive n = 12, negative n = 12) were injected with [ 64 Cu]FBP8 and imaged with PET/CMR, including mapping the longitudinal magnetic relaxation time (T 1 ) in the LAA., Results: [ 64 Cu]FBP8 was stable to metabolism and was rapidly eliminated. The maximum standardized uptake value (SUV Max ) in the LAA was significantly higher in the TEE-positive than TEE-negative subjects (median of 4.0 [interquartile range (IQR): 3.0-6.0] vs 2.3 [IQR: 2.1-2.5]; P < 0.001), with an area under the receiver-operating characteristic curve of 0.97. An SUV Max threshold of 2.6 provided a sensitivity of 100% and specificity of 84%. The minimum T 1 (T 1Min ) in the LAA was 970 ms (IQR: 780-1,080 ms) vs 1,380 ms (IQR: 1,120-1,620 ms) (TEE positive vs TEE negative; P < 0.05), with some overlap between the groups. Logistic regression using SUV Max and T 1Min allowed all TEE-positive and TEE-negative subjects to be classified with 100% accuracy., Conclusions: PET/CMR of [ 64 Cu]FBP8 is able to detect acute as well as older platelet-poor thrombi with excellent accuracy. Furthermore, the integrated PET/CMR approach provides useful information on the biological properties of thrombus such as fibrin and methemoglobin content. (Imaging of LAA Thrombosis; NCT03830320)., Competing Interests: Funding Support and Author Disclosures Support for this study was provided in part by the following grants from the National Institutes of Health: R01HL109448 (to Drs Caravan and Sosnovik), R01HL141563 (to Dr Sosnovik), R01HL131907 (to Dr Caravan), R01HL131635 (to Dr Mekkaoui), and R01CA218187 (to Dr Catana); and the following grants to the A. A. Martinos Center for Biomedical Imaging: S10RR022976, S10RR019933, P41EB015896. Dr Caravan is an inventor of [64Cu]FBP8, which is patented by Massachusetts General Hospital. Dr Caravan is a founder of and has financial interests in Collagen Medical, LLC, and Factor 1A, LLC, which are developing fibrin-targeted imaging probes. Factor 1A, LLC has a license to the patent covering the probe [64Cu]FBP8 that used in this study. Dr Caravan’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Anti-β-2 glycoprotein I antibodies (anti-B2GPI) are often cited as the major pathogenically relevant antibody in antiphospholipid syndrome (APS), but it is unclear if there is clinical evidence to support this theory. We performed a systematic review to determine if immunoglobulin G anti-B2GPI positivity was independently associated with thrombotic and/or obstetric manifestations of APS. We searched MEDLINE, EMBASE, The Cochrane Library, and clinicaltrials.gov electronic databases through April 2020 for prospective studies that met prespecified design criteria. Of 4758 articles identified through computer-assisted search, 4 studies examining obstetric outcomes and 2 studies examining thrombotic outcomes were included for qualitative assessment. The presence of anti-B2GPI had only a weak independent association with thrombosis and was, at best, inconsistently associated with obstetric complications. A quantitative assessment could not be performed because of study heterogeneity. The overall quality of the evidence was very low. Although anti-B2GPI are commonly thought to mediate APS manifestations, clinical evidence is lacking with very low-quality data to support a weak association with thrombosis., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The International Society on Thrombosis and Haemostasis (ISTH)'s Scientific and Standardization Committee (SSC) recently proposed a definition of pulmonary embolism (PE)-related death., Objectives: To evaluate the accuracy and interrater reliability of the ISTH definition of PE-related death in an autopsy cohort., Methods: We reviewed reports of 1064 consecutive adult autopsies that were performed at the NewYork-Presbyterian Hospital from January 2010 until July 2019. We included all patients with autopsy-confirmed PE-related death (cases) during that time frame, combined with patients who died in 2018 from a cause other than PE (controls). Based on clinical summaries, two adjudicators independently adjudicated the cause of death in each patient using the ISTH classification for the cause of death, blinded to the case/control status and ratio. The primary outcome was autopsy-confirmed PE-related death. We determined the sensitivity and specificity of the ISTH definition to identify autopsy-confirmed PE-related death, and its interrater reliability using the percentage agreement and Cohen's kappa., Results: A total of 126 patients who underwent autopsy were included in the analysis (median age, 68 years [range, 21-94], 60 [48%] women), of which 29 (23%) had died from PE as confirmed by autopsy. The ISTH definition's sensitivity and specificity for autopsy-confirmed PE-related death were 45% (95% CI, 26-64) and 99% (95% CI, 94-100), respectively. Interrater reliability for PE-related death was substantial (percentage agreement, 94% [95% CI, 89-97]; kappa, 0.73 [95% CI, 0.55-0.97])., Conclusion: Adjudication of the cause of death using the ISTH definition resulted in very high specificity, moderate sensitivity, and good interrater reliability for PE-related death., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Patients with antiphospholipid antibodies (aPL) and thromboembolism (TE) are at risk for recurrent TE. Few studies, however, distinguish patients based on the initial event., Objectives: We performed a systematic review and meta-analysis to investigate patients with aPL and venous TE (VTE), provoked or unprovoked, and patients with arterial TE (ATE)., Patients/methods: We conducted searches in PubMed, CINAHL, Cochrane, and EMBASE. Inclusion criteria were prospective trials or cohort studies investigating patients with aPL and ATE or VTE. Excluded studies did not provide estimated recurrence rates, did not specify whether the incident event was ATE or VTE, included patients with multiple events, or included <10 patients. Two-year summary proportions were estimated using a random effects model., Results: Ten studies described patients with VTE, 2 with ATE, and 5 with VTE or ATE. The 2-year proportion for recurrent TE in patients with VTE who were taking anticoagulant therapy was 0.054 (95% confidence interval [CI], 0.037-0.079); the 2-year proportion for patients not taking anticoagulant therapy was 0.178 (95% CI, 0.150-0.209). Most studies did not distinguish whether VTE were provoked or unprovoked. The 2-year proportion for recurrent TE in patients with ATE who were taking anticoagulant therapy was 0.220 (95% CI, 0.149-0.311); the 2-year proportion for patients taking antiplatelet therapy was 0.216 (95% CI, 0.177-0.261)., Conclusions: Patients with aPL and ATE may benefit from a different antithrombotic approach than patients with aPL and VTE. Prospective studies with well-defined cohorts with aPL and TE are necessary to determine optimal antithrombotic strategies., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Randomized controlled trials (RCTs) have demonstrated that low-dose direct oral anticoagulants (DOACs), including rivaroxaban and apixaban, may help reduce the incidence of cancer-associated venous thromboembolism (VTE)., Methods: A cost-utility analysis was performed from the health sector perspective using a Markov state-transition model in patients with cancer who are at intermediate-to-high risk for VTE. Transition probability, relative risk, cost, and utility inputs were obtained from a meta-analysis of the RCTs and relevant epidemiology studies. Differences in cost, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) per patient were calculated over a lifetime horizon. One-way, probabilistic, and scenario sensitivity analyses were conducted., Results: In patients with cancer at intermediate-to-high risk for VTE, treatment with low-dose DOAC thromboprophylaxis for 6 months, compared with placebo, was associated with 32 per 1000 fewer VTE and 11 per 1000 more major bleeding episodes over a lifetime. The incremental cost and QALY increases were $1445 and 0.12, respectively, with an ICER of $11,947 per QALY gained. Key drivers of ICER variations included the relative risks of VTE and bleeding as well as drug cost. This strategy was 94% cost effective at the threshold of $50,000 per QALY. The selection of patients with Khorana scores ≥3 yielded the greatest value, with an ICER of $5794 per QALY gained., Conclusions: Low-dose DOAC thromboprophylaxis for 6 months appears to be cost-effective in patients with cancer who are at intermediate-to-high risk for VTE. The implementation of this strategy in patients with Khorana scores ≥3 may lead to the highest cost-benefit ratio., (© 2020 American Cancer Society.)

Introduction: While trials have demonstrated non-inferiority of direct oral anticoagulant drugs (DOAC) to low-molecular-weight heparins (LMWH) for the treatment of cancer associated thrombosis (CAT), it is unclear if the newer intervention is cost-effective., Methods: We performed a cost-utility analysis using a Markov state-transition model over a time horizon of 60 months in a hypothetical cohort of 65-year-old patients with active malignancy and first acute symptomatic CAT who were eligible to receive either rivaroxaban/edoxaban or dalteparin. We obtained transition probability, relative risk, cost, and utility inputs from the literature. We estimated the differential impact on costs and quality-adjusted life years (QALYs) per patient and performed one-way and probabilistic sensitivity analyses to test the robustness of results., Results: Using the base-case analysis over 60 months, DOAC versus dalteparin was associated with an incremental cost reduction of $24,129 with an incremental QALY reduction of 0.04. In the one-way sensitivity analysis, the cost of dalteparin contributed the most to the incremental cost difference; relative risk of death related to underlying cancer contributed the most of the incremental QALY difference. The probabilistic sensitivity analysis confirmed the base-case analysis, with a large reduction in cost but small reduction in QALYs., Conclusion: Rivaroxaban or edoxaban as compared to dalteparin is cost saving from a payer's perspective for the treatment of CAT. Professional organizations and healthcare systems may want to consider this analysis in future practice recommendations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: It is unclear if direct oral anticoagulants (DOACs) are effective and safe alternatives to low-molecular-weight heparin (LMWHs) for the treatment of cancer-associated venous thromboembolism (VTE). We aim to synthesize existing literature that compared DOACs versus LMWHs in this high-risk population., Materials and Methods: We conducted a systematic review using EMBASE, MEDLINE and CENTRAL for all observational studies and randomized controlled trials (RCTs) (PROSPERO: CRD42017080898). Two authors independently reviewed study eligibility, extracted data, and assessed bias. Primary outcomes included 6-month recurrent VTE and major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB) and mortality., Results: We screened 426 articles, reviewed 25 in full-text, and selected 13 and 2 for qualitative and quantitative synthesis, respectively. Based on a meta-analysis of the 2 RCTs, DOACs had lower 6-month recurrent VTE (42/725) when compared to LMWH (64/727) (RR: 0.65 (0.42-1.01)). However, DOACs had higher major bleeding (40/725) when compared to LMWH (23/727) (RR 1.74 (1.05-2.88)). Similarly, CRNMB was higher (RR 2.31 (0.85-6.28)) for patients receiving DOACs. There was no difference in mortality (RR 1.03 (0.85-1.26)). Observational studies were heterogeneous with high risks of bias but showed recurrent VTE rates consistent with the meta-analysis., Conclusions: DOACs were more effective than LMWHs to prevent recurrent VTE but were associated with a significantly increased risk of major bleeding as well as a trend toward more CRNMB. The absolute risk differences were small (2-3%) for both primary outcomes and may reflect better compliance with DOACs than LMWHs., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Tenth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, on September 22 and 23, 2017. This scientific program was developed by clinicians for clinicians and was promoted by two major clinical research institutes-the Brazilian Clinical Research Institute and the Duke Clinical Research Institute of the Duke University School of Medicine. Comprising academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Ninth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, on October 15, 2016. This scientific program was developed by clinicians for clinicians and was promoted by two major clinical research institutes-the Brazilian Clinical Research Institute and the Duke Clinical Research Institute of the Duke University School of Medicine. Comprising academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

The Food and Drug Administration approval of ruxolitinib for treatment of myelofibrosis and polycythemia vera has changed the management of patients with myeloproliferative neoplasms. Yet the impact of this therapy on risk of thrombosis, a major cause of morbidity and mortality among these patients, remains unknown. The aim of this study was to evaluate the impact of ruxolitinib on the risk of thrombosis among patients with polycythemia vera or myelofibrosis. Following identification of randomized controlled trials comparing ruxolitinib to standard care or placebo, rates of thrombosis, including venous and arterial thrombosis, were analyzed using fixed effects models. Rates of thrombosis were significantly lower among patients treated with ruxolitinib [risk ratio 0.45, 95% confidence interval (CI) 0.23-0.88]. Subgroup analysis of venous and arterial thrombosis demonstrated similar risk ratios, which did not reach statistical significance (risk ratio 0.46, 95% CI 0.14-1.48 and RR 0.42, 95% CI 0.18-1.01, respectively). In conclusion, our analysis suggests that JAK2 inhibition with ruxolitinib decreases the risk of arterial and/or venous thrombosis in patients with polycythemia vera or myelofibrosis. These findings will require confirmation in a prospective study.

To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fifth International Symposium of Thrombosis and Anticoagulation was held in Belo Horizonte, Minas Gerais, Brazil, on October 18-19, 2012. This scientific program was developed by clinicians for clinicians and was promoted by three major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, and Hospital do Coração Research Institute. Comprising 2 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fourth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, from October 20-21, 2011. This scientific program was developed by clinicians for clinicians and was promoted by three major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, and Hospital do Coração Research Institute. Comprising 2 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

This article provides the rationale for the approach to making recommendations primarily used in four articles of the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines: orthopedic surgery, nonorthopedic surgery, nonsurgical patients, and stroke. Some of the early clinical trials of antithrombotic prophylaxis with a placebo or no treatment group used symptomatic VTE and fatal PE to measure efficacy of the treatment. These trials suggest a benefit of thromboprophylaxis in reducing fatal PE. In contrast, most of the recent clinical trials comparing the efficacy of alternative anticoagulants used a surrogate outcome, asymptomatic DVT detected at mandatory venography. This outcome is fundamentally unsatisfactory because it does not allow a trade-off with serious bleeding; that trade-off requires knowledge of the number of symptomatic events that thromboprophylaxis prevents. In this article, we review the merits and limitations of four approaches to estimating reduction in symptomatic thrombosis: (1) direct measurement of symptomatic thrombosis, (2) use of asymptomatic events for relative risks and symptomatic events from randomized controlled trials for baseline risk, (3) use of baseline risk estimates from studies that did not perform surveillance and relative effect from asymptomatic events in randomized controlled trials, and (4) use of available data to estimate the proportion of asymptomatic events that will become symptomatic. All approaches have their limitations. The optimal choice of approach depends on the nature of the evidence available.

To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in São Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

Venous thromboembolic events are common in patients with malignancy, producing both morbidity and mortality. Although the underlying mechanisms by which cancer might promote a procoagulant state are multifaceted and incompletely understood, recent translational research has significantly advanced our understanding of the relationship between cancer and thrombosis. The occurrence of a thromboembolic event in a patient with an active malignancy should be regarded as a life-threatening complication, and decisions regarding prevention and treatment are usually complex. Outcomes may be improved by an evidence-based approach to management with consideration of practice guidelines., (Copyright 2010 Elsevier Inc. All rights reserved.)

Although venous thromboembolism is an important cause of morbidity and mortality within the hospital, a significant proportion of at-risk inpatients do not receive measures known to reduce the risk of deep vein thrombosis and pulmonary embolism. The objective of the present study was to determine whether a pharmacy-driven alert system would, compared to usual care, be associated with a higher rate of adequate venous thromboembolism prevention measures among at-risk inpatients on a general internal medicine service. The study was a prospective, controlled trial set at a university-based teaching hospital. The participants were adults who were admitted (Monday through Friday) to the general internal medicine inpatient service from 19 June to 21 September 2006. Their treatment included a pharmacist assessment of venous thromboembolism risk and a pharmacist-driven alert to the treating physician. The Proportion of at-risk patients receiving adequate thromboprophylaxis within 36 h of admission was recorded. Overall, 140 patients were at sufficient risk for venous thromboembolism to be included. In the usual care group, prophylactic measures were ordered for 49 (61%) of the 80 patients at moderate to high risk. In the pharmacist-alert group, 44 (73%) of the 60 moderate to high venous thromboembolism-risk patients received adequate thromboprophylaxis (P = 0.15). Although we did not observe a statistically significant difference between the groups, our results are consistent with previous reports suggesting that alert systems can increase the proportion of hospitalized patients who receive adequate measures to prevent venous thromboembolism.

The importance of thrombosis and anticoagulation in clinical practice is rooted firmly in several fundamental constructs that can be applied both broadly and globally. Awareness and the appropriate use of anticoagulant therapy remain the keys to prevention and treatment. However, to assure maximal efficacy and safety, the clinician must, according to the available evidence, choose the right drug, at the right dose, for the right patient, under the right indication, and for the right duration of time. The first International Symposium of Thrombosis and Anticoagulation in Internal Medicine was a scientific program developed by clinicians for clinicians. The primary objective of the meeting was to educate, motivate and inspire internists, cardiologists and hematologists by convening national and international visionaries, thought-leaders and dedicated clinician-scientists in Sao Paulo, Brazil. This article is a focused summary of the symposium proceedings.

Antiphospholipid antibodies including anticardiolipin antibodies, lupus anticoagulants, and anti-beta(2) glycoprotein-1-specific antibodies may identify patients at elevated risk of first or recurrent venous or arterial thromboembolism. Traditionally, published case series supplemented by anecdotal experience have formed the basis of management of patients with these autoantibodies. Over the past several years, studies have described the management of patients with key clinical manifestations of antiphospholipid antibodies, including patients with antiphospholipid antibody syndrome. As a result, evidence-based treatment recommendations are possible for selected patients with, or at risk of, thrombosis in the setting of antiphospholipid antibodies. Unfortunately, most patients encountered in clinical practice do not correspond directly with those enrolled in clinical trials. For such patients, treatment recommendations are based on experience, extrapolation, and less rigorous evidence. This article proposes 5 cases typical of those found in clinical practice and provides recommendations for therapy focused on a series of clinical questions. Whenever possible, the recommendations are based on evidence; however, in many cases, insufficient evidence exists, so the recommendation is experiential.

The optimal perioperative anticoagulation management in patients on warfarin therapy is poorly defined due to the lack of randomized trials. Because guidelines are heterogeneous, it was hypothesized that "treatment strategies are not uniform in clinical practice". Between February 2003 and May 2003, a questionnaire with 4 different clinical scenarios was distributed to physicians by e-mail, or direct contact was made by a survey monitor. Two scenarios described the cases of patients with a mechanical heart valve (MHV) in the mitral position, with additional risk factors for a systemic embolism; one undergoing major (scenario 1) and the other minor surgery (scenario 3). Two scenarios described patients with an aortic MHV; one undergoing major (scenario 2) and the other minor (scenario 4) surgery. Different preoperative and postoperative management options were offered. The treatment options for all scenarios were the same. Of the 90 questionnaires distributed, 52 (57.8%) were returned. Hospitalization for full-dose intravenous unfractionated heparin (IV UH) was the most commonly selected strategy in the preoperative phase for scenarios 1 (59%), 2 (42%) and 3 (44%). In scenario 4, 34% chose IV UH. Outpatient, full- dose, subcutaneous UH or low-molecular-weight heparin (LMWH) was the most selected option in the postoperative phase for all scenarios, with the exception of number 4 (52.9% in scenario 1, 34% in scenario 2, 32%, in scenario 3 and 28% in scenario 4). Even among expert clinicians, the management of perioperative anticoagulation is heterogeneous. In particular, the definition of risk categories and the optimal intensity of antithrombotic drugs need to be defined by well-designed prospective studies.

After the introduction of warfarin, long-term oral anticoagulation treatment remained unchanged for more than 50 years. Most recently, with the development and approval of new oral anticoagulants, the treatment of medical conditions that require thrombosis prophylaxis and long-term anticoagulation has become more complex. In the case of venous thromboembolism (VTE) prevention after orthopedic surgery, the new oral agents will be less costly than the parenteral alternative. In other settings (such as atrial fibrillation or treatment of acute VTE), the new agents will offer additional convenience at higher cost, but the degree to which they will reduce clinically important events such as thrombosis or bleeding will be limited, especially for patients on optimally controlled warfarin. As the use of the new oral anticoagulants becomes more widespread, it will be important for all clinicians to have a basic understanding of their pharmacology, advantages, and limitations. Although the need to measure or reverse the effect of these drugs will arise infrequently, clinicians--especially hematologists--will desire evidence-based recommendations about how to manage such scenarios, which will require research studies. [ABSTRACT FROM AUTHOR]

The article focuses on a study on gastrointestinal tract bleeding (GIB). It aims to determine the incidence of thrombosis, recurrent GIB and death in patients 90 days after experiencing a GIB event. It uses Kaplan-Meier curves to estimate the survival function of thrombosis, recurrent GIB and death in patients who resumed warfarin therapy and those who did not. It concludes that the benefits for patients in resuming anticoagulant therapy outweigh the risks.

Study Objective. To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin. Design. Retrospective, matched cohort analysis. Setting. Centralized anticoagulation service in an integrated health care delivery system. Patients. A total of 2597 adult patients receiving warfarin from January 1998-December 2005; 1080 patients were in the low INR cohort and were matched to 1517 patients in the therapeutic INR cohort based on index INR date, indication for warfarin, and age. Measurements and Main Results. Stable, therapeutic anticoagulation was defined as two INR values, measured at least 2 weeks apart, within or above the therapeutic range. The low INR cohort included patients with a third INR value of 0.5 or more units below their therapeutic range. The therapeutic INR cohort included patients with a third therapeutic INR value and no INR value 0.2 or more units below their target INR range in the ensuing 90 days. The primary outcome was anticoagulation-related thromboembolism during the 90 days after the index INR. Secondary outcomes were times to the first occurrence of anticoagulation-related complications (bleeding, thromboembolism, or death) in the 90 days after the index INR. Four thromboembolic events (0.4%) occurred in the low INR cohort and one event (0.1%) in the therapeutic INR cohort (p=0.214). The differences in the proportions of thromboembolism, bleeding, or death were not significant between the cohorts (p>0.05). No significant differences were noted in the hazard of thromboembolism, bleeding, or death between the cohorts (p>0.05). Conclusion. Patients with stable INRs while receiving warfarin who experience a significant subtherapeutic INR value have a low risk of thromboembolism in the ensuing 90 days. The risk was similar to that observed in a matched control population in whom therapeutic anticoagulation was maintained. These findings do not support the practice of anticoagulant bridge therapy for patients stabilized on warfarin therapy to reduce their risk for thromboembolism during isolated periods of subtherapeutic anticoagulation. [ABSTRACT FROM AUTHOR]

Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) require indwelling central venous catheters. The comparative incidence, risk, and outcome of isolated catheter-related deep venous thrombosis (CR-DVT) versus pulmonary embolism/lower-extremity DVT (PE/LE-DVT) remains unclear. We conducted a retrospective cohort study for patients undergoing allo-HSCT from 2006 to 2019. CR-DVT and PE/LE-DVT outcomes were screened using ICD codes and radiology reports and confirmed by medical record reviews. Cox regression models were used to assess the association between thrombotic outcomes and pertinent baseline and time-varying covariates. The impact of thrombotic events within 1-year post-transplant (time-varying) on overall mortality was also assessed. Among 2879 patients, the cumulative incidence of isolated CR-DVT and PE/LE-DVT at 12 months was 4.2 % and 4.8 %, respectively. The strongest time-varying predictor for onset of CR-DVT and PE/LE-DVT was hospitalization inpatient status (HR 3.71 [95 % CI 2.16–6.37] and 3.99 [95 % CI 2.00–7.99], respectively). Other overlapping variables included lymphoma diagnosis and BMI > 35 kg/m2, whereas acute GVHD grades 2–4 were found to be significantly associated with risk of PE/LE-DVT but not CR-DVT. After adjusting for baseline variables and acute GVHD, the occurrences of CR-DVT and PE/LE-DVT were both independently associated with increased overall mortality (HR 1.58 [95 % CI 1.23–2.02] and HR 1.53 [95 % CI 1.19–1.97], respectively). We observed a high incidence of both CR-DVT and PE/LE-DVT with overlapping and unique risk factors. CR-DVT was also associated with increased mortality similar to PE/LE-DVT. Standardized strategies targeting high-risk hospitalization periods may help mitigate the development of thrombotic outcomes post-transplant. • Catheter related thrombosis is a common complication in stem cell transplant. • The 12-month cumulative incidence of catheter related thrombosis was 4.2 %. • Isolated catheter related thrombosis was associated with increased mortality. • Inpatient status, lymphoma, and body mass index were predictive of thrombosis. • Graft versus host disease was only predictive of non-catheter related thrombosis. [ABSTRACT FROM AUTHOR]

Abstract: Since its discovery during the first half of the 20th century by biochemists at the University of Wisconsin, warfarin (along with other vitamin K antagonists) has remained the only oral anticoagulant available to patients at risk for thromboembolism. After nearly 6 decades in clinical practice, we have learned much about warfarin. Although it is highly effective for most patients, warfarin has a number of undesirable attributes: significant inter- and intra-patient variability in dose-response, a narrow therapeutic index, a slow pharmacodynamic response, and numerous interactions with both diet as well as other medications. The negative characteristics associated with warfarin have inspired many clinicians, patients, and researchers to wonder if a better alternative can be discovered. To that end, at least three novel anticoagulant compounds are in the late stages of development and several others are progressing through earlier phases of investigation. This review will summarize the latest clinical trial data pertinent to several newer antithrombotic agents and discuss recent developments that impact the safety and challenges associated with warfarin and other vitamin K antagonists (VKA). [Copyright &y& Elsevier]

The article reports that below-knee elastic compression stockings reduced development of the postthrombotic syndrome (PTS) in proximal deep venous thrombosis (DVT). PTS is a complication of DVT and is characterized by swelling, pain, discoloration, and in some cases, venous ulcer formation. Patients with a first episode of proximal DVT were assigned to wear or not to wear elastic compression stockings for 12 years. This study, much like previous studies, is limited by the lack of a placebo control group.

Abstract: Introduction: This study tests the hypothesis that nonadherence with INR monitoring is associated with an increased risk for warfarin-related bleeding and thrombosis and describes patient characteristics associated with INR monitoring nonadherence. Materials and Methods: This was a retrospective, longitudinal, matched cohort study wherein patients were categorized into adherent and nonadherent cohorts; adherent patients were matched 2:1 to nonadherent patients. The primary study endpoint was the first occurrence of bleeding or thromboembolism. Multivariate logistic regression modeling identified patient characteristics associated with INR monitoring adherence or nonadherence. Results: A total of 4995 and 2544 patients contributed 10729 and 5385 patient-years of warfarin therapy in the adherent and nonadherent groups, respectively. The rate of thromboembolic events during follow up was higher in the nonadherent group than in the adherent group (0.95% vs. 0.62% per patient-year, respectively; p=0.019) and nonadherence to INR monitoring was associated with a moderately higher risk of thromboembolism (adjusted Hazard Ratio=1.51; 95% confidence interval=1.04 – 2.20). The difference in bleeding between the two groups was not statistically significant. Conclusions: Repeatedly missing INR tests is an easily identified clinical parameter that is associated with moderately increased risk for thromboembolism in patients taking chronic warfarin therapy. Clinicians should carefully consider the underlying thromboembolic risk and extent of nonadherence when weighing the benefits of continued warfarin therapy for a given patient. [Copyright &y& Elsevier]