[Show abstract][Hide abstract] ABSTRACT: Background
Venous thromboembolism (VTE) treatment in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low molecular weight heparin (LMWH) for at least 3-6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting LMWH treatment beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE.Methods
Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6, and 7-12.FindingsOf 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy. 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. 116 patients died, four due to recurrent VTE and two due to bleeding.InterpretationMajor bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 03/2015; 13(6). DOI:10.1111/jth.12923 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The utility of screening for venous thromboembolism (VTE) in cancer patients is unknown. We evaluated this in a prospective cohort study of cancer patients initiating a new chemotherapy regimen and deemed high-risk (score ≥ 3) based on a validated Risk Score.
Patients were evaluated with baseline and Q4 (± 1) week serial ultrasonography for up to 16 weeks; additionally, computed tomography scans for restaging were also evaluated for VTE.
The study population comprised 35 patients. Pancreatic and gastro-esophageal cancers were the most common diagnoses. Of these, 8 (23%) developed a VTE. This included 5 patients with DVT alone (14%), 1 patient with PE alone (3%) and 2 (6%) with both. Ultrasound examinations identified asymptomatic DVT in 9.3% of patients at baseline; 0% at weeks 4 and 8 and 5.6% at week 12. Restaging CT scans identified asymptomatic PE in one patient at week 6 and in one patient at week 9 with subsequent DVT at week 10.
Screening for asymptomatic VTE has not been previously used as a clinical strategy in ambulatory cancer patients. We report that one-tenth of patients at baseline had occult DVT and in this high-risk population, screening at baseline may be of value.
Thrombosis Research 09/2014; 134(6). DOI:10.1016/j.thromres.2014.09.016 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Platelets have a newly appreciated and important role in many cancer related processes including tumor growth and metastases, angiogenesis, and promotion of a hypercoagulable state. Cancer patients commonly experience venous thromboembolism (VTE), a leading cause of mortality and a source of considerable morbidity and cost. The role of platelets in arterial thrombosis is well-established, but emerging evidence supports the concept that platelets are also involved in initiation of VTE. This is particularly true in cancer-associated thrombosis as extensive new evidence shows that thrombocytosis and platelet activation are predictive biomarkers of VTE. The role of therapeutic anti-platelet agents has been proven effective at preventing VTE in non-cancer patients, and there is early data suggesting benefit in cancer patients as well. This review summarizes platelet-related predictive biomarkers of cancer-associated thrombosis, platelet mediated mechanisms for VTE promotion in cancer patients, and antiplatelet agents in prevention of VTE.
Seminars in Oncology 06/2014; 41(3). DOI:10.1053/j.seminoncol.2014.04.009 · 3.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancer-associated thrombosis accounts for almost one-fifth of all cases of venous thromboembolism (VTE) and is a leading cause of death, morbidity, delays in care, and increased costs. Our understanding of risk factors for cancer-associated thrombosis has expanded in recent years, and investigators have begun to use biomarkers and clinical prediction models to identify those cancer patients at greatest risk for VTE. The Khorana Risk Model, which is based on easily obtained biomarkers and clinical factors, has now been validated in several studies. Recent clinical trials of prophylaxis and treatment of VTE in cancer patients are reviewed here. In addition, consensus guidelines and expert opinion regarding management of VTE in specific challenging situations are presented.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
Using the previously described clinical risk score for venous thromboembolism (VTE) (Khorana et a, Blood 2008) to identify high risk patients, this study evaluates the utility of screening for thrombosis in a prospective cohort of initially asymptomatic cancer patients initiating outpatient chemotherapy.
METHOD AND MATERIALS
Asymptomatic cancer patients initiating a new chemotherapy regimen & found to be high-risk for VTE based on a predictive risk model (score ≥3) were enrolled on an ongoing prospective cohort study with informed consent. Patients were evaluated with a baseline & an every 4 (± 1) week serial US study for up to 16 weeks. Additionally, CT scans obtained for restaging purposes were also evaluated for VTE.
Of the 35 high-risk patients enrolled, 8 (23%) were found to have VTE, 5 patients w/ DVT alone (14%), 1 w/ PE alone (3%) & 2 (6%) w/ both. 32 patients underwent a baseline US & 3 asymptomatic DVTs were identified (9%), w/ 1 patient also having an asymptomatic PE detected on staging CT. Subsequent US were performed in 23 patients at week 4 (0DVT), 21 patients at week 8 (0DVT) &18 patients at week 12 (1 DVT, 6%). An additional 2 patients developed symptomatic DVT between screens. Restaging CT scans identified an asymptomatic PE in a patient at week 6 & an asymptomatic PE in a patient at week 9. Of the patients w/ isolated DVT, 2 had isolated unilateral calf clot, 2 had unilateral calf & thigh clot, &1 had unilateral upper extremity clot.
In this prospective observational study, 23% of cancer outpatients deemed high-risk for VTE developed clot at a rate much higher than found in both normal & acutely ill hospitalized populations (0.5 & 6% respectively). This study confirms the validity of the previously described risk score developed by Khorana et al & makes this model highly predictive of identifying patients at risk for VTE. In addition, these findings suggest that screening US for asymptomatic clot should be considered in high-risk patients based on this risk score. This study highlights the importance of VTE screening in the calf, w/ 50% of patients w/ VTE having calf clot & 25% having isolated unilateral calf clot, indicating that this region should be included in the assessment of DVT.
Screening ultrasonography for asymptomatic thrombosis should be considered in high-risk patients based on this risk score with the goal of reducing the morbidity and mortality assocated with VTE.
Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
[Show abstract][Hide abstract] ABSTRACT: Stored red blood cells (RBCs) release hemoglobin (Hb) that leads to oxidative damage, which may contribute to thrombosis in susceptible transfusion recipients. Oxidative stress stimulates the generation of a new class of lipid mediators called F2 -isoprostanes (F2 -IsoPs) and isofurans (IsoFs) that influence cellular behavior. This study investigated RBC-derived F2 -IsoPs and IsoFs during storage and their influence on human platelets (PLTs).
F2 -IsoP and IsoF levels in RBC supernatants were measured by mass spectrometry during storage and after washing. The effects of stored supernatants, cell-free Hb, or a key F2 -IsoP, 8-iso-prostaglandin F2α (PGF2α ), on PLT function were examined in vitro.
F2 -IsoPs, IsoFs, and Hb accumulated in stored RBC supernatants. Prestorage leukoreduction reduced supernatant F2 -IsoPs and IsoFs levels, which increased again over storage time. Stored RBC supernatants and 8-iso-PGF2α induced PLT activation marker CD62P (P-selectin) expression and prothrombotic thromboxane A2 release. Cell-free Hb did not alter PLT mediator release, but did inhibit PLT spreading. Poststorage RBC washing reduced F2 -IsoP and IsoF levels up to 24 hours.
F2 -IsoPs and IsoFs are produced by stored RBCs and induce adverse effects on PLT function in vitro, supporting a potential novel role for bioactive lipids in adverse transfusion outcomes. F2 -IsoP and IsoF levels could be useful biomarkers for determining the suitability of blood components for transfusion. A novel finding is that cell-free Hb inhibits PLT spreading and could adversely influence wound healing. Poststorage RBC washing minimizes harmful lipid mediators, and its use could potentially reduce transfusion complications.
[Show abstract][Hide abstract] ABSTRACT: It is unclear what proportion of VTE events in lung cancer patients are incidentally discovered and whether incidental events affect mortality.
We conducted a retrospective cohort study of lung cancer patients seen at the University of Rochester between January 1, 2006 and December 31, 2008 with the goal of quantifying and characterizing VTE events. Multiple clinical variables and mortality outcomes were compared using Kaplan-Meier survival analysis and multivariate Cox proportional hazards.
The study population consisted of 207 subjects with lung cancer. The median age was 66 years and 55% were female (n = 115). Thirty-one patients (14.9%) experienced at least 1 VTE event with 32.2% (10/31) of these incidentally discovered. Incidental events comprised 29.4% (n = 5) of pulmonary embolisms, 11.1% (n = 2) of deep vein thrombosis, and 100% (n = 3) of visceral events. The median survival for patients with incidental VTE was 23.4 months (95% confidence interval [CI], 4.8-32.1) compared with 45.8 months (95% CI, 34.1-56.8) in patients without VTE (HR 2.4; 95% CI, 1.2-4.9; P = .01), but in a subgroup analysis of stage IV patients overall survival was not significantly different (HR, 0.94; P = .33). Patients with clinically suspected VTE had the lowest median survival at 13.1 months (95% CI, 6.4-18.9) which was significantly lower than patients without VTE (HR, 2.7; 95% CI, 1.6-4.5; P = .002), but not significantly different from patients with incidental VTE (HR, 1.2; 95% CI, 0.4-2.0; P = .7). In multivariate analysis, occurrence of VTE (HR, 2.3; 95% CI, 1.3-3.8; P = .002) was significantly associated with mortality when adjusting for age, stage, and histology.
One-third of VTE events in lung cancer patients are incidentally discovered and VTE has negative clinical effect in lung cancer patients.
Clinical Lung Cancer 07/2013; 14(6). DOI:10.1016/j.cllc.2013.06.003 · 3.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To provide current recommendations about the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer.
PubMed and the Cochrane Library were searched for randomized controlled trials, systematic reviews, meta-analyses, and clinical practice guidelines from November 2012 through July 2014. An update committee reviewed the identified abstracts.
Of the 53 publications identified and reviewed, none prompted a change in the 2013 recommendations.
Most hospitalized patients with active cancer require thromboprophylaxis throughout hospitalization. Routine thromboprophylaxis is not recommended for patients with cancer in the outpatient setting. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low-molecular weight heparin (LMWH) or low-dose aspirin. Patients undergoing major surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered in those undergoing major abdominal or pelvic surgery with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term secondary prophylaxis (at least 6 months). Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer. Anticoagulation should not be used to extend survival of patients with cancer in the absence of other indications. Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should educate patients about the signs and symptoms of VTE.
[Show abstract][Hide abstract] ABSTRACT: An increasing number of academic senior physicians are approaching their potential retirement in good health with accumulated clinical and research experience that can be a valuable asset to an academic institution. Considering the need to let the next generation ascend to leadership roles, when and how should a medical career be brought to a close? We explore the roles for academic medical faculty as they move into their senior years and approach various retirement options. The individual and institutional considerations require a frank dialogue among the interested parties to optimize the benefits while minimizing the risks for both. In the United States there is no fixed age for retirement as there is in Europe, but European physicians are initiating changes. What is certain is that careful planning, innovative thinking, and the incorporation of new patterns of medical practice are all part of this complex transition and timing of senior academic physicians into retirement.
[Show abstract][Hide abstract] ABSTRACT: Venous thromboembolism (VTE) is a serious risk after major orthopedic surgery (MOS) including total knee replacement, total hip replacement and hip fracture surgery. This risk can be reduced with several pharmacologic and mechanical prophylactic approaches, and the choice among them depends on their ability to reduce VTE with an acceptable increase in adverse events, especially major bleeding complications. Improvements in medical and surgical care have led to a progressive decrease in the risk of VTE after MOS with an estimated baseline risk with contemporary practice of approximately 4.3 % up to day 39 after surgery. Low-molecular-weight heparin is the most thoroughly studied thromboprophylactic agent following MOS and demonstrates good effectiveness with an acceptable rate of bleeding complications. Warfarin, rivaroxaban, dabigatran, and apixaban have all been studied in large trials in comparison with low-molecular-weight heparin and also show an acceptable benefit: risk ratio. Mechanical approaches including graduated compression stockings, intermittent pneumatic compression and venous foot pump also offer protection against VTE, but there is less evidence is available regarding their effectiveness and risks. Combination therapy consisting of an antithrombotic agent and mechanical device is probably more effective than either alone. The appropriate use of thromboprophylaxis after MOS results in reduced VTE with acceptable bleeding risks.
Journal of Thrombosis and Thrombolysis 02/2013; 35(3). DOI:10.1007/s11239-013-0889-9 · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: ABO-mismatched platelets (PLTs) are commonly transfused despite reported complications. We hypothesized that because PLTs possess A and B antigens on their surface, ABO-mismatched transfused or recipient PLTs could become activated and/or dysfunctional after exposure to anti-A or -B in the transfused or recipient plasma. We present here in vitro modeling data on the functional effects of exposure of PLTs to ABO antibodies.
STUDY DESIGN AND METHODS: PLT functions of normal PLTs of all ABO types were assessed before and after incubation with normal saline, ABO-identical plasma samples, or O plasma samples with varying titers of anti-A and anti-B (anti-A/B). Assays used for this assessment include PLT aggregation, clot kinetics, thrombin generation, PLT cytoskeletal function, and mediator release.
RESULTS: Exposure of antigen-bearing PLTs to O plasma with moderate to high titers of anti-A/B significantly inhibits aggregation, prolongs PFA-100 epinephrine closure time, disrupts clot formation kinetics, accelerates thrombin generation, reduces total thrombin production, alters PLT cytoskeletal function, and influences proinflammatory and prothrombotic mediator release.
CONCLUSIONS: Our findings demonstrate a wide range of effects that anti-A/B have on PLT function, clot formation, thrombin generation, PLT cytoskeletal function, and mediator release. These data provide potential explanations for clinical observations of increased red blood cell utilization in trauma and surgical patients receiving ABO-nonidentical blood products. Impaired hemostasis caused by anti-A/B interacting with A and B antigens on PLTs, soluble proteins, and perhaps even endothelial cells is a potential contributing factor to hemorrhage in patients receiving larger volumes of ABO-nonidentical transfusions.
[Show abstract][Hide abstract] ABSTRACT: VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT.
The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.
In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B).
Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.
[Show abstract][Hide abstract] ABSTRACT: 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.