Publications by authors named "Chris E Holmes"

24 Publications

  • Page 1 of 1

Safety of apixaban for venous thromboembolic primary prophylaxis in patients with newly diagnosed malignant glioma.

J Thromb Thrombolysis 2021 Aug 4. Epub 2021 Aug 4.

Division of Hematology/Oncology, Department of Medicine, University of Vermont Larner College of Medicine, Burlington, VT, USA.

The cumulative incidence of symptomatic venous thromboembolism (VTE) among patients with malignant gliomas (MG) is estimated to be as high as 36% during the course of therapy. Development of VTE is associated with an increased risk of hospitalization, delays in cancer treatment, and an increased risk of complications including intracranial hemorrhage as well as VTE specific symptoms. Despite the high risk of VTE and associated morbidity, there is no standard recommendations regarding long term outpatient VTE prophylaxis in patients with MG due to the lack of clinical trial evidence in this patient population. In this study, we treated ten patients with newly diagnosed MG with apixaban, 2.5 mg twice daily beginning 2-21 days after craniotomy and continuing for up to 6 months. Unacceptable toxicity was defined by ≥ grade 2 CNS or non-CNS hemorrhage, a thromboembolic event (i.e. stroke) or cardiovascular event requiring anticoagulation or anti-platelet therapy. There were no unacceptable toxicities to report and no treatment-related adverse events. None of the patients on the study were diagnosed with a VTE while receiving apixaban. We conclude that apixaban can be given safely to patients with primary MG shortly after craniotomy and should be considered for VTE prevention in these high-risk patients.
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http://dx.doi.org/10.1007/s11239-021-02537-wDOI Listing
August 2021

Pregnancy outcomes in female carriers of haemophilia B Leyden.

Br J Haematol 2020 08 20;190(4):e261-e264. Epub 2020 Jun 20.

Department of Hematology and Oncology, Larner College of Medicine at University of Vermont, Burlington, Vermont, USA.

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http://dx.doi.org/10.1111/bjh.16887DOI Listing
August 2020

Successful Model for Guideline Implementation to Prevent Cancer-Associated Thrombosis: Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic.

JCO Oncol Pract 2020 09 8;16(9):e868-e874. Epub 2020 Apr 8.

Data Management Office, University of Vermont Health Network, Burlington, VT.

Purpose: Guidelines recommend venous thromboembolism (VTE) risk assessment in outpatients with cancer and pharmacologic thromboprophylaxis in selected patients at high risk for VTE. Although validated risk stratification tools are available, < 10% of oncologists use a risk assessment tool, and rates of VTE prophylaxis in high-risk patients are low in practice. We hypothesized that implementation of a systems-based program that uses the electronic health record (EHR) and offers personalized VTE prophylaxis recommendations would increase VTE risk assessment rates in patients initiating outpatient chemotherapy.

Patients And Methods: Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) was a multidisciplinary program implemented by nurses, oncologists, pharmacists, hematologists, advanced practice providers, and quality partners. We prospectively identified high-risk patients using the Khorana and Protecht scores (≥ 3 points) via an EHR-based risk assessment tool. Patients with a predicted high risk of VTE during treatment were offered a hematology consultation to consider VTE prophylaxis. Results of the consultation were communicated to the treating oncologist, and clinical outcomes were tracked.

Results: A total of 918 outpatients with cancer initiating cancer-directed therapy were evaluated. VTE monthly education rates increased from < 5% before VTEPACC to 81.6% (standard deviation [SD], 11.9; range, 63.6%-97.7%) during the implementation phase and 94.7% (SD, 4.9; range, 82.1%-100%) for the full 2-year postimplementation phase. In the postimplementation phase, 213 patients (23.2%) were identified as being at high risk for developing a VTE. Referrals to hematology were offered to 151 patients (71%), with 141 patients (93%) being assessed and 93.8% receiving VTE prophylaxis.

Conclusion: VTEPACC is a successful model for guideline implementation to provide VTE risk assessment and prophylaxis to prevent cancer-associated thrombosis in outpatients. Methods applied can readily translate into practice and overcome the current implementation gaps between guidelines and clinical practice.
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http://dx.doi.org/10.1200/JOP.19.00697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489490PMC
September 2020

Prospective evaluation of drug-drug interactions in ambulatory cancer patients initiated on prophylactic anticoagulation.

J Oncol Pharm Pract 2020 Oct 11;26(7):1637-1642. Epub 2020 Feb 11.

Hematology and Oncology Division, University of Vermont Cancer Center, Burlington, VT, USA.

Introduction: Drug options for VTE prophylaxis are increasing for ambulatory cancer patients and data regarding anticoagulant-drug interactions and their relationship to VTE and bleeding are needed to improve care.

Methods: Over one year, 108 cancer patients with high VTE risk were prospectively identified. Potential anticoagulant-drug interactions were ascertained by chart review and graded on need for intervention. Providers selected anticoagulant prophylaxis based on potential drug interactions and patient-provider discussion. A cross-sectional analysis was performed thereafter to evaluate VTE and bleeding endpoints within one year of anticoagulant initiation.

Results: The average number of potential drug interactions per patient was higher for warfarin than others (3.04 vs. 1.28 (apixaban), 1.02 (rivaroxaban), and 0.98 (LMWH)). The severity of the interactions based on grade was, for apixaban: 1.6% grade X, 50.8% grade D, and 47.5% grade C; for rivaroxaban: 2.1% grade X, 64.9% grade D, 33.0% grade C; for LMWH, 0% grade X, 66.7% grade D, 33.3% grade C; and for warfarin, 0% grade X, 29.4% grade D, 70.6% grade C. At the end of the investigational period, 11 bleeds and 7 VTEs were reported. Drug combinations significantly associated with an increased bleeding risk were crizotinib with apixaban or rivaroxaban and PPIs with warfarin. The use of sulfamethoxazole-trimethoprim with warfarin was associated with an increased VTE risk.

Conclusions: DOACs had fewer DDIs than warfarin, although interaction severity differed between anticoagulants. Some anticoagulant-drug interactions were associated with bleeding or VTE. Although not powered for analysis, DDI severity did not affect bleeding rates and inversely correlated with VTE risk.
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http://dx.doi.org/10.1177/1078155220901569DOI Listing
October 2020

Risk factors for cancer-associated venous thromboembolism: The venous thromboembolism prevention in the ambulatory cancer clinic (VTE-PACC) study.

J Thromb Haemost 2019 12 22;17(12):2152-2159. Epub 2019 Sep 22.

Departments of Medicine and Pathology & Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.

Background: The Khorana Score is a validated risk score for predicting 6-month incidence of cancer-associated venous thromboembolism (CAT) among patients starting chemotherapy. Venous thromboembolism (VTE) risk factors important in the general population, including age, sex, prior VTE, and hospitalization, are not included in this score, their association with VTE in cancer patients is unknown.

Objective: To examine risk factors for CAT and the impact of incorporating longitudinal hospitalization into risk assessment.

Methods: Risk factors were recorded among patients starting chemotherapy at a single institution from 2012-14. Hospitalization and time-periods after hospitalization were assessed as time-varying covariates. Logistic regression was used to determine factors related to 6-month CAT risk (the Khorana Score endpoint). Proportional hazard models were used for risk factor identification throughout the 3-year observation period.

Results: Among 1,583 patients starting chemotherapy (mean age 60, 48% male), 187 developed CAT (11.8%) with 129 (69%) cases occurring within 6 months of starting chemotherapy. In the 6-month analysis, no additional risk factors were associated with CAT. In the 3-year analysis, male sex (HR 1.57, 95%CI 1.21, 2.07), prior VTE (HR 2.12, 95%CI 1.41, 3.18), and hospitalization (HR 2.69, 95%CI 1.92, 3.75) were associated with increased hazard of CAT, adjusting for risk factors in the Khorana score.

Conclusions: When time-to-event data were incorporated into CAT risk assessment, male sex, prior VTE, and hospitalization were important risk factors. These data highlight the need to consider dynamic methods for assessing VTE risk in cancer patients, with particular attention to the period around hospitalizations.
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http://dx.doi.org/10.1111/jth.14614DOI Listing
December 2019

Successful management of refractory bleeding in liver failure with tranexamic acid: Case report and literature review.

Res Pract Thromb Haemost 2019 Jul 26;3(3):424-428. Epub 2019 Apr 26.

Division of Hematology Oncology, Department of Medicine Larner College of Medicine at the University of Vermont Burlington Vermont.

A 50-year-old woman with advanced cirrhosis presented with spontaneous subdural hematoma. She had a worsening clinical course following craniotomy despite administration of multiple blood products. With elevation in D-dimer, persistently low fibrinogen and poor response to factor/fibrinogen replacement therapies, we had a suspicion for uncontrolled fibrinolysis. A literature review was conducted on treatment of hyperfibrinolysis in cirrhosis, finding 4 reports in which antifibrinolytics were used to control bleeding with different outcomes. The dose of tranexamic acid used in our patient was employed from previous experience in trauma patients. We transitioned from intravenous to oral administration based on expected pharmacokinetics. Our patient had a successful outcome with resolution of bleeding.
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http://dx.doi.org/10.1002/rth2.12203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611358PMC
July 2019

Regional variation and cost implications of prescribed extended half-life factor concentrates among U.S. Haemophilia Treatment Centres for patients with moderate and severe haemophilia.

Haemophilia 2019 Jul 17;25(4):668-675. Epub 2019 Apr 17.

St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Extended half-life (EHL) factor VIII (FVIII) and IX (FIX) products are intended to decrease the burden of prophylaxis for patients with haemophilia A or B. Whether these newer concentrates have led to meaningful clinical practice change remains vague.

Aim: To characterize the longitudinal use of standard (SHL) and EHL factor concentrates at haemophilia treatment centres (HTCs), using the ATHNdataset, a US database of 138 ATHN-affiliated HTCs.

Methods: Factor concentrate use among moderate and severe haemophilia A and B patients without inhibitors was analysed at three time points over 18 months.

Results: Use of EHL concentrates rose from 10% of patients to 22% during this study. EHL FVIII prophylaxis is prescribed to the minority of patients, 28%; EHL FIX now predominates for prophylaxis, 52%. Rates of prescribed EHL products varied significantly by age group and HTC region. Median prescribed prophylaxis for SHL compared to EHL products was FVIII 6240 and 5200 and FIX 6968 and FIX 3900 IU/kg/y, respectively. On-demand EHL use has grown but has minimal contribution to overall usage (2%).

Conclusion: Haemophilia treatment centre region and patient age impact the rate of adoption of EHL products; however, EHL prescribing continues to rise nationally, particularly for EHL FIX. Careful attention to annual cost of prophylaxis is imperative as the decrease in median EHL prophylaxis consumption is not offset by the higher unit cost of these products. It is unclear how further growth in use of EHLs will be impacted by emerging non-factor replacement and gene therapies.
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http://dx.doi.org/10.1111/hae.13758DOI Listing
July 2019

Characterization of purine-rich element binding protein B as a novel biomarker in acute myelogenous leukemia prognostication.

J Cell Biochem 2018 02 18;119(2):2073-2083. Epub 2017 Oct 18.

Division of Hematology/Oncology, Department of Medicine, University of Vermont, Robert Larner, M. D. College of Medicine, Burlington, Vermont.

Acute myelogenous leukemia (AML) is an aggressive hematologic cancer characterized by infiltration of proliferative, clonal, abnormally differentiated cells of myeloid lineage in the bone marrow and blood. Malignant cells in AML often exhibit chromosomal and other genetic or epigenetic abnormalities that are useful in prognostic risk assessment. In this study, the relative expression and novel single-stranded DNA (ssDNA) binding function of purine-rich element binding proteins A and B (Purα and Purβ) were systematically evaluated in established leukemia cell lines and in lineage committed myeloid cells isolated from patients diagnosed with a hematologic malignancy. Western blotting revealed that Purα and Purβ are markedly elevated in CD33 /CD66b cells from AML patients compared to healthy subjects and to patients with other types of myeloid cell disorders. Results of in silico database analysis of PURA and PURB mRNA expression during hematopoiesis in conjunction with the quantitative immunoassay of the ssDNA-binding activities of Purα and Purβ in transformed leukocyte cell lines pointed to Purβ as the more distinguishing biomarker of myeloid cell differentiation status. Purβ ssDNA-binding activity was significantly increased in myeloid cells from AML patients but not from individuals with other myeloid-related diseases. The highest levels of Purβ activity were detected in myeloid cells from primary AML patients and from AML patients displaying other risk factors forecasting a poor prognosis. Collectively, these findings suggest that the enhanced ssDNA-binding activity of Purβ in transformed myeloid cells may serve as a unique and measurable phenotypic trait for improving prognostic risk stratification in AML.
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http://dx.doi.org/10.1002/jcb.26369DOI Listing
February 2018

A multidisciplinary quality improvement program increases the inferior vena cava filter retrieval rate.

Vasc Med 2017 02 3;22(1):51-56. Epub 2016 Nov 3.

1 Thrombosis and Hemostasis Program, Division of Hematology - Oncology, Department of Medicine, and Cardiovascular Research Institute of Vermont, Larner College of Medicine, University of Vermont, Burlington, VT, USA.

Published reports indicate low retrieval rates for retrievable inferior vena cava (IVC) filters. We performed a historic-controlled study of a 5-year intervention (March 2007 to February 2012) to improve IVC filter retrieval rates at a university medical center serving a rural area. All adults with a retrievable filter placed were included, except those with a life expectancy <6 months. The intervention included initial verbal counseling and printed educational materials, correspondence after discharge, and a hematology consultation. The control group included patients with retrievable filters placed in the 15 months preceding study initiation. In the control group, 116 filters were placed and 27 (23%) were removed, compared to 378 filters placed and 169 (45%) removed during the intervention. Adjusting for patient characteristics, the odds ratio of retrieval during the intervention was 3.03 (95% CI 1.85-4.27) compared to the control period. An intervention including patient education and hematology follow-up appeared to significantly improve IVC filter retrieval rates.
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http://dx.doi.org/10.1177/1358863X16676658DOI Listing
February 2017

Platelet phenotype changes associated with breast cancer and its treatment.

Platelets 2016 Nov 2;27(7):703-711. Epub 2016 May 2.

e University of North Carolina Lineberger Comprehensive Cancer Center , Chapel Hill , NC , USA.

Platelets and their granular contents influence both angiogenesis and breast cancer progression. This study was performed to assess the effect of breast cancer and its treatment on platelet biology and the response to inhibition of the platelet P2Y12 receptor. Receptor-specific platelet activation and inhibition was studied for three platelet-associated proteins important in cancer angiogenesis and progression, vascular endothelial growth factor (VEGF), thrombospondin1 (TSP1), and transforming growth factor beta 1 (TGF-β1). Twenty-four women with active breast cancer and 10 healthy controls not receiving antiplatelet therapy participated in the study. Ex vivo activation of platelets in whole blood was accomplished using PAR1AP, PAR4AP, convulxin, and ADP. Platelet inhibition was accomplished using the P2Y12 receptor antagonist cangrelor (the in vitro equivalent of clopidogrel). VEGF, TSP1, and TGF-β1 were measured using standard ELISA. Platelet activation by ADP, PAR1, PAR4, and collagen receptors increased VEGF, TSP1, and TGF-β1 secretion in patients with breast cancer. Agonist-induced release of VEGF was greater in cancer patients as compared to healthy controls (p = 0.02 for ADP, p < 0.001 for PAR1AP, PAR4AP, and convulxin) despite a decrease in the efficiency of VEGF secretion in patients with breast cancer. These differences were not observed for TSP1 and TGF-β1 secretion. P2Y12 receptor inhibition decreased VEGF, TSP1, and TGF-β1 secretion. In patients with cancer, cangrelor inhibited TSP1 release to a greater extent than VEGF and TGF-β1 release. In patients with breast cancer, the magnitude of platelet inhibition achieved by cangrelor was greater than that achieved with healthy controls for all agonists and platelet proteins studied. While platelets are known to influence progression of breast cancer, our results show that breast cancer and its treatment influence the platelet phenotype by increasing the secretion of pro-angiogenic proteins following platelet activation, modulating the efficiency of platelet protein release as well as increasing the response to antiplatelet therapy.
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http://dx.doi.org/10.3109/09537104.2016.1171302DOI Listing
November 2016

Spinal Cord Infarction in a Patient with Hereditary Spherocytosis: A Case Report and Discussion.

Case Rep Neurol Med 2016 14;2016:7024120. Epub 2016 Mar 14.

Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT 05401, USA.

The etiology of spinal cord infarcts (SCIs), besides being related to aortic perioperative events, in large subset of SCIs, remains cryptogenic. We present a first case of SCI in a patient with hereditary spherocytosis and discuss the potential pathophysiologic considerations for vascular compromise. A 43-year-old woman with a history of hereditary spherocytosis, post splenectomy status, presented with chest, back, and shoulder pain with subsequent myelopathic picture; SCI extending from C4-T2 was confirmed by MRI. Despite aggressive treatment her stroke progressed leading to her demise. Her autopsy confirmed the SCI and revealed some incidental findings, but the cause of SCI remained unidentified. Exclusion of the known etiologies of SCI by extensive negative workup including autopsy evaluation suggested that SCI in our case was related to her history of hereditary spherocytosis. Both venous and arterial adverse vascular events, at a higher rate, have been associated in patients with hereditary spherocytosis who had their spleens removed compared to nonsplenectomized patients. Postsplenectomy increases in the platelet, red blood cell count, leukocyte count, and cholesterol concentrations are postulated to contribute to increased thrombotic risk. Additional prothrombotic factors include continuous platelet activation and adhesion as well as abnormalities of the red blood cell membrane.
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http://dx.doi.org/10.1155/2016/7024120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808664PMC
April 2016

Efficacy of a short course of complex lymphedema therapy or graduated compression stocking therapy in the treatment of post-thrombotic syndrome.

Vasc Med 2014 Feb;19(1):42-8

Department of Medicine, University of Vermont, Burlington, VT, USA.

Treatment options for established post-thrombotic syndrome (PTS) are limited. Complex lymphedema therapy (CLT), a non-invasive treatment that improves lymphatic flow, may have the potential to improve PTS. We conducted a single-center, investigator-blind, randomized controlled trial of 31 patients with a clinically established diagnosis of PTS and compared the efficacy of graduated compression stockings alone (30-40 mmHg) with CLT, a treatment that includes compression stockings, exercise, patient education, skin care and lymphatic drainage. Primary outcomes were the 1- and 3-month changes in PTS severity by the Villalta score and disease-specific quality of life using the VEINES-QOL (Venous Insufficiency Epidemiological and Economic Study Quality of Life) questionnaire. Analysis was by intent-to-treat. We found from a baseline average score of 9.9 points, CLT reduced mean PTS severity scores by -2.4 points (p=0.02) at the 1-month and -2.3 points (p=0.05) at the 3-month follow-up. Score reductions with stockings only were similar at -2.1 (p=0.03) and -3.3 points (p=0.03) at 1 and 3 months. The differences in score between treatments were not significant. Neither treatment significantly changed the VEINES-QOL score except in patients with severe disease. Patients with moderate to severe PTS derived the greatest benefit from either therapy and the two therapies differentially impacted PTS signs and symptoms. We found a short course of lymphedema therapy and compression stockings offer similar benefit in patients with PTS; however, larger studies are needed to further explore the potential use of CLT in PTS, particularly in patients with more severe disease. ClinicalTrials.gov Identifier: NCT00633971.
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http://dx.doi.org/10.1177/1358863X14521883DOI Listing
February 2014

Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer.

J Cell Physiol 2014 Aug;229(8):1005-15

Department of Medicine, University of Vermont, Burlington, Vermont.

While platelets are well known to play a central role in hemostasis and thrombosis, there is emerging experimental evidence to suggest that they also mediate tumor cell growth, dissemination, and angiogenesis. An increase in platelet number (thrombocytosis) and activity is seen in patients with a wide spectrum of malignancies, and the former is correlated with a decrease in overall survival and poorer prognosis. Preclinical data suggest that circulating tumor cell partnerships with platelets in the blood facilitate tumor metastases through direct interactions and secreted bioactive proteins. Platelets form aggregates with tumor cells, thereby protecting them from host immune surveillance through physical shielding and induction of "platelet mimicry." There is also laboratory evidence to suggest that activated platelets interact with cancer cells within the tumor microenvironment through paracrine signaling and direct contact, thereby promoting tumor cell growth and survival. For example, platelets release mediators of both tumor angiogenesis and osteoclast resorption. The interplay between platelets and tumor cells is complex and bidirectional with involvement of multiple other components within the tumor microenvironment, including immune cells, endothelial cells, and the extracellular matrix. We review the role of platelets in tumor progression, emphasizing the opportunity these interactions afford to target platelets and platelet function to improve patient outcomes in the cancer prevention and treatment setting.
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http://dx.doi.org/10.1002/jcp.24539DOI Listing
August 2014

Initiation of aspirin therapy modulates angiogenic protein levels in women with breast cancer receiving tamoxifen therapy.

Clin Transl Sci 2013 Oct 15;6(5):386-90. Epub 2013 May 15.

Department of Medicine, University of Vermont, Burlington, Vermont, USA.

Aspirin has a range of antineoplastic properties linked to inhibition of cyclooxygenase enzymes in tumor cells, platelet inhibition and to inhibition of angiogenesis. We undertook a prospective study to determine the influence of a 45-day course of aspirin therapy on circulating and intraplatelet levels of selected proangiogenic (vascular endothelial growth factor [VEGF]) and antiangiogenic (thrombospondin-1 [TSP-1]) proteins, and platelet protein release in women diagnosed with breast cancer who were receiving tamoxifen therapy. Initiation of aspirin therapy increases serum and intraplatelet levels of TSP-1 without a corresponding increase in VEGF levels. Following aspirin therapy, VEGF levels decreased (relative to pretreatment levels) while TSP-1 returned to pretreatment levels. Plasma TSP-1 and VEGF levels did not change on aspirin therapy. Aspirin use also decreased thrombin receptor mediated release of TSP-1 and VEGF from platelets. The selective impact on platelet angiogenic protein content and release supports one mechanism by which aspirin can modify the angiogenic balance in women receiving tamoxifen therapy. Aspirin therapy appears to favor an overall antiangiogenic balance in women with breast cancer who are receiving tamoxifen therapy.
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http://dx.doi.org/10.1111/cts.12070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350889PMC
October 2013

Platelets, coagulation and fibrinolysis in breast cancer progression.

Breast Cancer Res 2013 ;15(4):207

The progression of breast cancer from early-stage to metastatic disease results from a series of events during which malignant cells invade and travel within the bloodstream to distant sites, leading to a clonogenic accumulation of tumor cells in non-breast tissue. While mechanistically complex, an emerging literature supports hemostatic elements as an important patient factor that facilitates the metastatic potential of breast cancer. Hemostatic elements involved include platelets, coagulation, and fibrinolysis. Key steps in breast tumor progression, including cellular transformation, proliferation, tumor cell survival, and angiogenesis, can be mediated by components of the hemostatic system. Thus, the hemostatic system provides potential targets for novel therapeutic approaches to breast cancer therapy with drugs in current use and in development. The present article provides a comprehensive overview of the evidence and mechanisms supporting the roles played by platelets, coagulation activation, and the fibrinolytic system in breast cancer progression.
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http://dx.doi.org/10.1186/bcr3425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979075PMC
December 2014

An association between anti-platelet drug use and reduced cancer prevalence in diabetic patients: results from the Vermont Diabetes Information System Study.

BMC Cancer 2010 Jun 15;10:289. Epub 2010 Jun 15.

Hematology and Oncology, University of Vermont, Given Building Second Floor, Burlington, VT 05401, USA.

Background: Diabetes is associated with an increased risk of several malignancies. Both diabetic patients and patients with cancer have an increase in platelet reactivity and platelet activation has recently emerged as a potential mediator of cancer progression. Drug therapies, such as aspirin, that reduce platelet reactivity reduce both cardiovascular and cancer risk.

Methods: We performed a cross-sectional analysis to assess the association between history of cancer and current anti-platelet drug use in a primary care population of adults with diabetes enrolled in the Vermont Diabetes Information System.

Results: Self-reported characteristics, medical history, and a complete medication list were recorded on 1007 diabetic adults. Fifty percent of diabetic patients used an anti-platelet drug. In unadjusted analysis, no association was seen between anti-platelet drug use and cancer history (OR = 0.93; P = .70). Platelet inhibitor use was associated with a decreased patient-reported history of malignancy in a multivariate logistic regression adjusted for age, sex, body mass index, comorbidity, and number of medications (OR = 0.66; CI 0.44-0.99; P = .045). Similar odds of association were seen in both males and females, and for aspirin and non-aspirin platelet inhibitor therapy.

Conclusions: Our data suggest an association between anti-platelet drug use and reduced cancer prevalence in patients with diabetes. Given the potentially large implications of our observations in the diabetic population, further studies are required to determine if this association is causal.
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http://dx.doi.org/10.1186/1471-2407-10-289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893115PMC
June 2010

The effect of P2Y-mediated platelet activation on the release of VEGF and endostatin from platelets.

Platelets 2010 ;21(2):85-93

Department of Medicine, University of Vermont, Burlington, Vermont, USA.

Vascular endothelial growth factor (VEGF) and endostatin are key protein modulators of angiogenesis found within platelets. The platelet activation pathways that control angiogenic protein release are incompletely elucidated. The differential release of pro-angiogenic and anti-angiogenic proteins from the platelet has been demonstrated for proteinase activated receptors (PARs). Given the ability of tumors to secrete ADP and the availability of ADP receptor antagonists clinically, we determined the influence of adenosine diphosphate (ADP) and the ADP receptors, P2Y(1) and P2Y(12), on platelet release of the angiogenic stimulator protein, VEGF, and the angiogenic inhibitor protein, endostatin. Minimally altered whole blood (WB) and platelet rich plasma (PRP) from healthy volunteers was stimulated with ADP alone (12.5 uM), in combination with a P2Y(1) antagonist (MRS2179) or a P2Y(12) antagonist (cangrelor). VEGF and endostatin protein concentrations were assessed by an ELISA assay. We report that maximally stimulating concentrations of ADP significantly increased VEGF release from platelets in both PRP and WB by 36+/-12% 36+/-12% 54+/-18% 36 +/- 12% (p < 0.05) respectively as compared to control. Both P2Y(1) and P2Y(12) receptor antagonism inhibited this release. Conversely, endostatin levels did not change following ADP stimulation in PRP, while a 4.7% (p = 0.03) increase was observed in WB. As compared to thrombin receptor activation, ADP activation was a weaker stimulus for VEGF release. We found that activation of platelets by ADP results in an increase in soluble VEGF concentrations with minimal effects on endostatin concentrations, suggesting ADP release in the tumor microenvironment may be, on balance, proangiogenic. P2Y receptor antagonism abrogates ADP mediated proangiogenic protein release and thus may represent a potential pharmacologic strategy for regulating platelet mediated angiogenesis.
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http://dx.doi.org/10.3109/09537100903470298DOI Listing
May 2010

A novel association between a chronic subdural hematoma and a fibrinolytic pathway defect: case report.

Neurosurgery 2009 Jun;64(6):E1192; discussion E1192

Division of Neurosurgery, University of Vermont, Burlington, Vermont 05401, USA.

Objective: Chronic subdural hematoma (CSDH) is a common form of intracranial hemorrhage that is known to recur in up to one-fifth of treated patients. We present a patient with recurrent CSDH who was found to have a defect in the fibrinolytic pathway, which may be a novel explanation for recurrent CSDH. This defect, deficiency of plasminogen activator inhibitor type I (PAI-1), should be recognized as a possible cause of CSDH.

Clinical Presentation: A 49-year-old man presented with a CSDH, which recurred each time after 2 initially-effective craniotomies.

Intervention: A deficiency of PAI-1 was diagnosed after the second recurrence. We hypothesize that this defect in the fibrinolytic system contributed to the recurrent hematoma. Treatment with aminocaproic acid led to resolution of the CSDH.

Conclusion: PAI-1 deficiency should be considered in patients with recurrent CSDH that lack another compelling explanation, particularly in patients with a family history of bleeding diatheses. PAI-1 deficiency can be identified by measuring plasma levels and can be treated with an oral course of aminocaproic acid.
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http://dx.doi.org/10.1227/01.NEU.0000345650.60160.07DOI Listing
June 2009

Correlates of anemia in American blacks and whites: the REGARDS Renal Ancillary Study.

Am J Epidemiol 2009 Feb 9;169(3):355-64. Epub 2008 Dec 9.

Department of Medicine, University of Vermont, Burlington, VT, USA.

For unclear reasons, anemia is more common in American blacks than whites. The authors evaluated anemia prevalence (using World Health Organization criteria) among 19,836 blacks and whites recruited in 2003-2007 for the REasons for Geographic And Racial Differences in Stroke Renal Ancillary study and characterized anemia by 3 anemia-associated conditions (chronic kidney disease, inflammation, and microcytosis). They used multivariable models to assess potential causes of race differences in anemia. Anemia was 3.3-fold more common in blacks than whites, with little attenuation after adjusting for demographic variables, socioeconomic factors, and comorbid conditions. Increasing age, residence in the US southeast, lower income, vascular disease, diabetes, hypertension, and never smoking were associated with anemia. Age, diabetes, and vascular disease were stronger correlates of anemia among whites than blacks (P < 0.05). Among those with anemia, chronic kidney disease was less common among blacks than whites (22% vs. 34%), whereas inflammation (18% vs. 14%) and microcytosis (22% vs. 11%) were more common. In this large, geographically diverse cohort, anemia was 3-fold more common in blacks than whites with different characteristics and correlates. Race differences in anemia prevalence were not explained by the factors studied. Future research into the causes and consequences of anemia in different racial groups is needed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720717PMC
http://dx.doi.org/10.1093/aje/kwn355DOI Listing
February 2009

The clinical diagnosis of heparin-induced thrombocytopenia in patients receiving continuous renal replacement therapy.

J Thromb Thrombolysis 2009 May 17;27(4):406-12. Epub 2008 May 17.

Department of Medicine, Division of Hematology & Oncology, University of Vermont College of Medicine, Burlington, VT 05401, USA.

Background: Thrombocytopenia is common in critically ill patients who receive continuous renal replacement therapy. Often, these patients receive heparin therapy and the diagnosis of heparin induced thrombocytopenia (HIT) is considered as a potential etiology. No data regarding the clinical diagnosis of HIT is available for patients receiving continuous renal replacement therapy.

Patients And Methods: We performed a retrospective study of 29 consecutive patients who received CRRT in a medical-surgical intensive care unit (ICU) and determined trends in platelet counts following CRRT and the frequency of meeting platelet based clinical criteria for consideration of a HIT diagnosis.

Results: For patient exposures to CRRT concurrent with heparin, 54% met at least one clinical threshold for consideration of the diagnosis of HIT. In 31% of exposures, both a platelet count <100,000/mm3 and a >50% decrease from baseline were seen. In contrast, the majority (73-85%) of patients receiving CRRT had a low pre-test probability of HIT using the "4T's" scoring system. Mean platelet counts while on CRRT concurrent with heparin were significantly lower than when patients received heparin alone (P < 0.02).

Conclusions: The clinical diagnosis of HIT in ICU patients initiating CRRT is challenging given the decrease in platelet counts seen following CRRT initiation in the majority of patients. A prospective study in this population is needed to optimize patient outcomes.
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http://dx.doi.org/10.1007/s11239-008-0228-8DOI Listing
May 2009

Tamoxifen and aromatase inhibitors differentially affect vascular endothelial growth factor and endostatin levels in women with breast cancer.

Clin Cancer Res 2008 May;14(10):3070-6

Department of Medicine, University of Vermont, Burlington, Vermont, USA.

Purpose: Circulating and cellular proangiogenic and antiangiogenic proteins such as vascular endothelial growth factor (VEGF) and endostatin contribute to the local angiogenic balance. We explored the effects of tamoxifen and aromatase inhibitors on concentrations of VEGF and endostatin in plasma, serum, and platelet releasate (induced by platelet activation).

Experimental Design: VEGF and endostatin concentrations were measured with a quantitative immunoassay before and after 1 to 5 weeks of treatment in 30 women with breast cancer treated with either tamoxifen (n = 14) or aromatase inhibitors (n = 16). Platelet activation was induced by a thrombin receptor agonist.

Results: Tamoxifen therapy resulted in an increase in platelet releasate concentrations of VEGF (P = 0.01) but no change in plasma VEGF. In contrast, aromatase inhibitor therapy did not affect serum, plasma, or platelet releasate VEGF. In univariate analysis, aspirin use attenuated the tamoxifen-associated increase in VEGF in the platelet releasate and decreased serum levels of VEGF (P = 0.03). Aromatase inhibitor therapy resulted in a decrease in serum endostatin concentrations (P = 0.04), whereas plasma concentrations of endostatin tended to be higher during treatment with aromatase inhibitors (P = 0.06). Tamoxifen therapy resulted in no change in serum or plasma endostatin concentrations. Platelet releasate concentrations of endostatin did not change with either treatment. Interindividual variability was noted among both aromatase inhibitor--and tamoxifen-treated patients.

Conclusions: Tamoxifen and aromatase inhibitor therapy affect VEGF and endostatin levels and likely contribute to the angiogenic balance in breast cancer patients. Aspirin decreased the proangiogenic effects of tamoxifen, suggesting that antiplatelet and/or antiangiogenic therapy might improve the effectiveness of tamoxifen in women with breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-4640DOI Listing
May 2008

Influence of preparative procedures on assay of platelet function and apparent effects of antiplatelet agents.

Am J Cardiol 2007 Aug 26;100(4):722-7. Epub 2007 Jun 26.

Cardiology Unit, Department of Medicine, University of Vermont, Burlington, Vermont, USA.

Previous studies have shown that anticoagulants alter platelet reactivity and the apparent effects of antiplatelet agents. This study was conducted to identify the impact of methods of preparation of blood samples on an assay of platelet function and the effects of antiplatelet agents. The activation of platelets was identified with the use of flow cytometry in response to thrombin (1 and 10 nmol/L), adenosine diphosphate (0.2 and 1 micromol/L), platelet activating factor (1 nmol/L), and convulxin (1 and 10 ng/ml). Antiplatelet effects were assessed after the addition in vitro of tirofiban (50 ng/ml) and cangrelor (10 nmol/L). Results were compared in whole blood and platelet-rich plasma (PRP) anticoagulated with corn trypsin inhibitor (32 microg/ml, a specific inhibitor of factor XIIa). The fraction of young platelets was quantified with thiazole orange, which identifies ribonucleic acid. The activation of platelets was consistently less in PRP compared with whole blood. Activation in PRP was 23 +/- 15% that in whole blood for thrombin, 65 +/- 26% for adenosine diphosphate, 40 +/- 20% for platelet activating factor, and 49 +/- 25% for convulxin (p <0.01 for each comparison). The fraction of young platelets in PRP was 39 +/- 11% that in whole blood (p <0.001). The effects of antiplatelet agents varied with agonist and antiplatelet agent but were generally greater in PRP compared with whole blood (p <0.05). In conclusion, platelet reactivity is lower and the effects of antiplatelet agents are greater and potentially misleading in PRP compared with whole blood. The accuracy of platelet function testing may be improved by performance in whole blood.
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http://dx.doi.org/10.1016/j.amjcard.2007.03.091DOI Listing
August 2007

Contributions of young platelets and of previously activated platelets to platelet reactivity in patients with coronary artery disease.

Thromb Res 2008 1;121(4):455-62. Epub 2007 Aug 1.

Cardiology Unit, Department of Medicine, University of Vermont, Burlington, Vermont, USA.

Introduction: We sought to determine why some patients with coronary artery disease have more platelets that do not activate (express P-selectin on their surface) despite exposure in vitro to high concentrations of agonists and whether this finding is associated with altered platelet reactivity.

Methods: We assessed platelet activation and the proportion of young platelets with the use of flow cytometry in blood from 50 patients with coronary artery disease undergoing cardiac catheterization. Ultrastructural characteristics of platelets isolated with the use of a fluorescence activated cell sorter were assessed with the use of electron microscopy.

Results: Ultrastructural characteristics of platelets that did not exhibit surface expression of P-selectin in response to 50 nM thrombin delineated 2 groups; resting platelets devoid of glycogen stores and activated platelets. Because the activated platelets had shed their surface P-selectin we refer to them as 'previously activated' platelets. To estimate the proportion of 'previously activated' platelets we quantified the percentage of platelets that bound annexin-V but did not express P-selectin after exposure to 50 nM thrombin. The fraction of 'previously activated' platelets ranged from 0.3%-4.8% and correlated modestly though positively with the fraction of young platelets (r=0.41, p=0.003). Patients with more young platelets tended to have more 'previously activated' platelets and exhibited greater platelet reactivity.

Conclusions: A greater proportion of 'previously activated' platelets is associated with a greater fraction of young platelets and increased platelet reactivity. The presence of 'previously activated' platelets in circulating blood may be a marker of micro or macro thrombosis.
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http://dx.doi.org/10.1016/j.thromres.2007.06.004DOI Listing
April 2008

Diagnosis and treatment of breast cancer in the elderly.

CA Cancer J Clin 2003 Jul-Aug;53(4):227-44

Department of Medicine, University of Vermont, Burlington, VT, USA.

As the population of the United States ages, women over the age of 65 have become a prominent cohort in the breast cancer population, with approximately 50% of all new breast cancers occurring in women aged 65 years and older. Early studies in breast cancer often excluded women based on age or comorbidity, leaving physicians and patients with a growing number of diagnostic and treatment options, each of which often carry short-term morbidity risks for potential long-term gain. We review the current data available for diagnosis and treatment of elderly women with breast cancer in both the adjuvant and metastatic disease setting. In addition, the role of screening and new concepts in prevention are discussed with emphasis on the older patient.
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http://dx.doi.org/10.3322/canjclin.53.4.227DOI Listing
September 2003
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