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July 1978 - present
January 1982 - December 2012
Education
September 1972 - June 1975
September 1967 - June 1972
Publications
Publications (338)
Considerable progress has been made in elucidating genetic and biologic risk factors for venous thromboembolism (VTE). Despite being able to identify heritable defects in a substantial proportion of patients with VTE, testing has not, in general, proven useful in management. Despite efforts to reduce inappropriate testing, it often falls to the hem...
Disclaimer
In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final versi...
Background:
Aspirin is commonly used as the only pharmacologic agent for prevention of venous thromboembolism (VTE) after joint replacement surgery in the United States. Despite this, prospective studies investigating VTE events after aspirin-only thromboprophylaxis in joint replacement surgery are lacking in the real-world setting.
Objectives:...
Introduction
Increased thromboembolism (TE) has been reported in ALK+ and ROS1+ non-small cell lung cancer (NSCLC).
Materials and Methods
Odds ratios (OR) and hazard ratios (HR) of TE were calculated from meta-analysis and time-to-event analysis respectively for either ALK+ or ROS1+ NSCLC patients.
Results
We identified 8 studies (766 ALK+, 143 R...
Background:
Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19).
Objective:
To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival.
Design:
In a...
Although anticoagulation remains the mainstay of treatment of acute venous thromboembolism (VTE), the use of thrombolytic agents or thrombectomy is required to immediately restore blood flow to thrombosed vessels. Nevertheless, systemic thrombolysis has not clearly been shown to improve outcomes in patients with large clot burdens in the lung or le...
Multiple risk-assessment models (RAMs) for venous thromboembolism (VTE) in hospitalized medical patients have been developed. To inform the 2018 American Society of Hematology (ASH) guidelines on VTE, we conducted an overview of systematic reviews to identify and summarize evidence related to RAMs for VTE and bleeding in medical inpatients. We sear...
Coronavirus Disease-2019 (COVID-19) is associated with a prothrombotic state with a high incidence of thrombotic events during hospitalization; however there are limited data examining rates of thrombosis after discharge. We conducted a retrospective observational cohort study of discharged patients with confirmed COVID-19 not receiving anticoagula...
Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and...
Background
Coronavirus Disease‐2019 (COVID‐19) is a recognized prothrombotic state. Patients hospitalized with active cancer are predisposed to thrombosis but whether active cancer further amplifies thrombotic risk with COVID‐19 is not known.
Objectives
To evaluate cumulative incidences of thrombotic and hemorrhagic events in hospitalized COVID‐19...
Hospitalized patients with cancer are at an increased risk of developing venous thromboembolism (VTE). The recommendation for routine pharmacologic thromboprophylaxis in hospitalized patients with cancer to prevent VTE is based on extrapolation of results from noncancer cohorts. There are limited data to support the efficacy and safety of fixed-dos...
Background:
Optimal management of acute pulmonary embolism requires expertise offered by multiple subspecialties. As such, pulmonary embolism response teams (PERT) have increased in prevalence, but the institutional consequences of a PERT are unclear.
Methods:
We compared all patients that presented to our institution with an acute pulmonary emb...
Venous thromboembolism (VTE) is a relatively frequent complication in hospitalized patients, especially in those with risk factors. The benefit of using direct oral anticoagulants (DOACs) for prevention is controversial. This systematic review was performed as part of the American Society of Hematology (ASH) guidelines on VTE, developed in partners...
Venous thromboembolism (VTE), which includes both deep venous thrombosis and pulmonary embolism, is a common and potentially fatal condition. Medical inpatients are at high risk for VTE because of immobility as well as acute and chronic illness. Several randomized trials demonstrated that chemoprophylaxis, or low-dose anticoagulation, prevents VTE...
The introduction of the direct oral anticoagulants for stroke prevention in atrial fibrillation and the management of thromboembolism has transformed the care of patients with these disorders.¹ These drugs, which selectively and reversibly inhibit factor Xa or thrombin in the common pathway of the coagulation cascade, have a wide therapeutic window...
While we are now able to diagnose inherited thrombophilias in a substantial number of patients with venous thromboembolism (VTE), the initial hope that their presence would inform recurrence risk and thus decisions on anticoagulation duration has largely been disappointing. Indeed, the presence or absence of transient provoking risk factors has pro...
Purpose:
To describe a case of unfractionated heparin (UFH) unresponsiveness in the operating room secondary to reversal of rivaroxaban with coagulation factor Xa (recombinant) inactivated-zhzo (andexanet alfa).
Summary:
A 70 year old man with a known 4.5 to 5.0 centimeter abdominal aortic aneurysm and atrial fibrillation managed with rivaroxaba...
Background
The long‐tem risk of recurrence in patients with a first unprovoked venous thromboembolism (VTE) who have negative D‐dimer results is uncertain.
Objectives
To determine this risk, including in subgroups based on sex.
Patients and Methods
ln a prospective interventional cohort study of 410 patients with a first unprovoked VTE, anticoagu...
Background
Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain.
Methods
In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scor...
Background:
Protein disulfide isomerase (PDI) is a thiol isomerase secreted by vascular cells that is required for thrombus formation. Quercetin flavonoids inhibit PDI activity and block platelet accumulation and fibrin generation at the site of a vascular injury in mouse models, but the clinical effect of targeting extracellular PDI in humans has...
Reasons that some people tend to form venous thromboembolism (VTE) more than others are examined. Only a few years ago, it was held that laboratory testing for congenital thrombophilia would prove highly decisive; however, currently it is felt that the role of such thrombophilia testing is greatly outweighed by clinical factors as this power overwh...
Background:
Venous thromboembolism (VTE) is the third most common vascular disease. Medical inpatients, long-term care residents, persons with minor injuries, and long-distance travelers are at increased risk.
Objective:
These evidence-based guidelines from the American Society of Hematology (ASH) intend to support patients, clinicians, and othe...
Key Points
The same type of APA on 2 occasions or >1 type of APA on the same or different occasions is associated with recurrent VTE. APA and D-dimer levels seem to be independently associated with recurrence after a first unprovoked VTE.
In this issue of Blood, Heit et al provide epidemiologic data that the near-universal provision of prophylaxis for venous thromboembolism (VTE) to patients in acute care hospitals has not significantly reduced its overall incidence.
Pulmonary embolism (PE) can result in rapid clinical decompensation in many patients. With increasing patient complexity and advanced treatment options for PE, multidisciplinary, rapid response teams can optimize risk stratification and expedite management strategies. The Massive And Submassive Clot On-call Team (MASCOT) was created at our institut...
Objectives:
Anticoagulant and antiplatelet medications are known to increase the risk and severity of traumatic intracranial hemorrhage (tICH), even with minor head trauma. Most studies on bleeding propensity with head trauma are retrospective, are based on trauma registries, or include heterogeneous mechanisms of injury. The goal of this study wa...
Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. Despite full anticoagulation during pregnancy and the postpartum period, women with AT deficiency may still be vulnerable to developing venous thromboembolism (VTE), including fatal events. There is limited guidance on the management of AT deficiency in pregnancy, inclu...
Objective:
To review insights gained in the past several years about hereditary antithrombin (AT) deficiency and to outline approaches to the management of patients with AT deficiency in the acute and chronic settings.
Data sources:
An extensive literature search of Scopus (January 2008-April 2016) was performed for the terms congenital antithro...
Background:
The rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS).
Objectives:
To determine whether quantitative D-dimer levels using a low threshold...
Thrombophilias are hereditary and/or acquired conditions that predispose patients to thrombosis. Testing for thrombophilia is commonly performed in patients with venous thrombosis and their relatives; however such testing usually does not provide information that impacts management and may result in harm. This manuscript, initiated by the Anticoagu...
Background
The International Society on Thrombosis and Haemostasis (ISTH) identified the need for an international core curriculum on thrombosis and haemostasis for its Society members and the larger thrombosis and haemostasis community.AimsThe current research sought consensus on the core competencies required by medical doctors who are ready to p...
Four direct oral anticoagulants have been approved for use in many countries. These drugs are valuable alternatives to vitamin K antagonists, such as warfarin, for many patients requiring anticoagulation to prevent stroke due to nonvalvular atrial fibrillation and to treat and prevent venous thromboembolism. The mechanism of these agents is to sele...
Hemophilia is characterized by genetic mutations resulting in the deficiency of factors critical to the normal process of coagulation, sometimes resulting in spontaneous bleeding into soft tissue, joints, and internal organs. The 2 most common subtypes are hemophilia A, or factor VIII deficiency, and hemophilia B, or factor IX deficiency. Hemophili...
Normal d-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment.
To determine whether patients with a first unprovoked VTE and negative d-dimer test result who stop anticoagulant therapy have a low risk for r...
Thromboembolic events associated with human plasma‐derived C1 esterase inhibitor (C1-INH) use in patients with hereditary angioedema (HAE) have been reported in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database. The purpose of this article is
to review and assess the strength of available evidence regarding the thr...
A previously healthy 41-year-old man presents with left leg pain and shortness of breath. He has a 20-pack-year history of smoking but quit 2 years ago. An ultrasound of the left leg shows thrombosis of the superficial femoral and popliteal veins. On chest computed tomography (CT) angiogram, there is a large right hilar mass and enlarged mediastina...
The availability of new oral anticoagulants (NOACs) targeting either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban and apixaban) for the prevention and treatment of thrombosis has been highly anticipated. NOACs have major pharmacologic advantages over vitamin K antagonists (eg, warfarin), including rapid onset/offset of action, few drug...
Atrial fibrillation (AF) is a common and morbid cardiac arrhythmia that increases in prevalence with advancing age. The risk of ischemic stroke, a primary and disabling hazard of AF, also increases with advancing age. The aging of the population is anticipated to contribute to a rising burden of AF-related morbidity and economic costs, given the cl...
Atrial fibrillation (AF) is the most common cardiac dysrhythmia, and its prevalence is growing. The care of patients with AF is complex and involves multiple specialties and venues of care. Guideline recommendations are available for AF therapy; however, their implementation can be challenging. The Society of Cardiovascular Patient Care has develop...
For >50 years, vitamin K antagonists (eg, warfarin) were the only available oral anticoagulants. Warfarin, however, is associated with >10-fold interindividual variation in dose to achieve therapeutic anticoagulation. The pharmacokinetics and pharmacodynamics of warfarin are influenced by genetic polymorphisms (CYP 2C9 and VKORC1), dietary vitamin...
The aims of the study reported here were to provide data from six pregnant subjects who were enrolled in a clinical trial of antithrombin (AT) concentrate, discuss other published case series and case reports, and provide general guidance for the use of AT concentrate for inherited AT deficiency in pregnancy.
In the late 1980s, 31 AT-deficient subj...
Elevated levels of circulating tissue factor-bearing microparticles (TFMP) have been associated with an increased risk of developing venous thromboembolism (VTE) in cancer patients. We performed a randomized phase II study to evaluate the cumulative incidence of VTE in advanced cancer patients with lower levels of TFMP not receiving thromboprophyla...
To evaluate the risk of venous thromboembolic events associated with the use of progestin-only contraception and whether that risk differs with the mode of drug delivery (oral, intrauterine, or depot injection).
Systematic review and meta-analysis of randomised controlled trials and observational studies.
Pubmed, Embase, Cochrane Library, and refer...
Anticoagulants are the mainstay of therapy for thromboembolic diseases. In addition to the more traditional agents, new oral anticoagulants, including dabigatran etexilate, rivaroxaban, and apixaban, have been shown to be effective across several indications. Bleeding is a serious complication associated with any anticoagulant, but many of the trad...
3344
Background
Combined oral contraceptives (COC) containing estrogens and progestins are associated with a 2 to 4-fold increased risk of venous thromboembolic events. Progestin-only contraceptives are commonly prescribed to women with a higher risk for thrombosis, although a lower thrombotic risk than COC has not been clearly established. We per...
While parenteral anticoagulants such as unfractionated and low molecular weight heparins and the oral vitamin K antagonists are effective for the prevention and treatment of thrombosis, they have a number of limitations. Up until recently, vitamin K antagonists (e.g. warfarin) have been the only available oral anticoagulants. These drugs have a del...
Thrombophilic conditions are associated with an increased risk of venous thromboembolic events (VTE) during pregnancy. Thrombophilic disorders are either acquired, as in antiphospholipid syndrome, or inherited, as in factor V Leiden. Both are associated with VTE but acquired disorders can also increase the risk of arterial events. However, there is...
Numerous randomized clinical trials have compared various durations of anticoagulant therapy with a vitamin K antagonist (ie, warfarin) for an initial episode of venous thromboembolism (VTE). Despite major advances in understanding the pathophysiology of thrombosis and its genetic basis, clinical risk factors at presentation have emerged as the pri...
Venous thromboembolism is the most frequent preventable cause of death in hospitalized patients. Currently available anticoagulants have limitations that restrict their widespread use, particularly in long-term indications. Vitamin K antagonists require frequent monitoring and dose adjustment, and have a narrow therapeutic window with the risk of b...
Despite an improved understanding of the risk factors underlying venous thromboembolism (VTE), extensive clinical investigation, and detailed clinical guidelines, the decision to extend anticoagulation indefinitely for an individual patient with VTE is often problematic. Patients with VTE in association with major surgery, trauma, immobilization, o...
Evidence for the associations of single nucleotide polymorphisms (SNPs) in the F7 gene and factor (F)VII levels and with risk of coronary heart disease (CHD) is inconsistent. We examined whether F7 tagging SNPs (tSNPs) and haplotypes were associated with FVII levels, coagulation activation markers (CAMs) and CHD risk in two cohorts of UK men.
Genot...
To assess platelet function and safety following single-dose administration of a novel formulation of intravenous (IV) diclofenac sodium (Dyloject) 37.5 mg versus oral diclofenac 50 mg, IV ketorolac 30 mg, and oral acetylsalicylic acid (ASA) 325 mg.
Open-label, randomized, single-dose, 4-treatment crossover study.
Clinical research unit.
30 healthy...
Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.
We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration,...
Polymorphic configurations of the coagulation factor VII gene (F7) are associated with plasma levels of FVII antigen (FVII:Ag) and FVII coagulant activity (FVII:C). Our aim was to determine whether F7 polymorphisms influence risk of ischemic stroke in young adults. One hundred and fifty survivors of ischemic stroke before the age of 45 and an equal...
Arterial and venous thrombosis are serious health threats. Patients with atrial fibrillation (AF), acute coronary syndromes (ACS), and venous thromboembolism (VTE) can reduce their risk of thrombosis through proper anticoagulation. Multiple evidence-based guidelines exist regarding the proper use of antithrombotic therapy, yet previous studies have...
Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances.
We meta-analysed individual records of 160 309 people...
489
The management of recurrent pregnancy loss is uncertain. Some cohort studies have identified an association between inherited thrombophilias and recurrent or late-nonrecurrent pregnancy loss which has prompted investigators to evaluate the benefit of low molecular weight heparin to achieve live birth. A similar benefit for low molecular weight...
Context Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified.
Objective To assess major lipids and apolipoproteins in vascular risk.
Design, Setting, and Participants Individual records were supplied on 302 430 people without initial vascular disease from 68 long-term prospective studi...
The management of recurrent pregnancy loss is uncertain. Some cohort studies have identified an association between inherited thrombophilias and recurrent or late non-recurrent pregnancy loss, which has prompted investigators to evaluate the benefit of low molecular weight heparin (LWMH) to achieve live birth. A similar benefit for LMWH has also be...
Despite the strong association between malignant disease and thromboembolic disorders, the molecular and cellular basis of this relationship remains uncertain. We evaluated the hypothesis that tumor-derived tissue factor-bearing microparticles in plasma contribute to cancer-associated thrombosis.
We developed impedance-based flow cytometry to detec...
Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke.
To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.
Long-term prospective studies that recorded Lp(...
The purpose of this study was to determine the effect of a variant in EPCR (Ser219Gly), previously shown to affect EPCR shedding, on plasma FVII, FVIIa, and downstream markers of activated coagulation.
Statistical analysis was undertaken in approximately 2000 healthy middle aged men (NPHSII). Higher soluble EPCR levels were confirmed for Gly allele...
Prophylaxis for venous thromboembolism is recommended for at least 10 days after total knee arthroplasty; oral regimens could enable shorter hospital stays. We aimed to test the efficacy and safety of oral rivaroxaban for the prevention of venous thromboembolism after total knee arthroplasty.
In a randomised, double-blind, phase III study, 3148 pat...
We recently reported the association between the Malmö sequence variant in F9 (rs6048) and deep vein thrombosis.
We aimed to study whether the association between F9 Malmö and deep vein thrombosis is explained by linkage disequilibrium with nearby single-nucleotide polymorphisms, and whether the association is explained biologically by F9 Malmö aff...
Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive...
Ligneous gingivitis is a rare condition characterized by inflammation and nodular gingival enlargement secondary to fibrin deposits in the gingival that results from plasminogen deficiency. Several therapeutic approaches have been used with limited success. We report a case of a patient with homozygous plasminogen deficiency and ligneous gingivitis...
Elderly patients with idiopathic pulmonary embolism (PE) are at high risk for recurrent venous thromboembolic disease and might benefit from long-term anticoagulant therapy. But they are also at higher risk for bleeding complications. Because there have been no clinical trials addressing PE treatment in elderly patients, the balance of therapeutic...
Cancer cells shed procoagulant vesicles containing tissue factor, and these tissue factor-bearing microparticles (TFMP) may play a role in thrombus formation in vivo. Using impedance-based flow cytometry to quantify microparticles and a high affinity monoclonal antibody specific for tissue factor, we previously demonstrated the presence of tissue f...
The RECORD program comprised four pivotal phase III trials comparing the oral direct Factor Xa inhibitor, rivaroxaban, with subcutaneous enoxaparin for the prevention of venous thromboembolism (VTE) after total hip and knee replacement (THR and TKR). A total of 12,729 patients were randomized to receive rivaroxaban 10 mg once daily (od) starting 6–...
Rivaroxaban is an oral, direct Factor Xa inhibitor that has been evaluated in the RECORD phase III clinical trial program for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. RECORD3 (Lassen M, et al. N Engl J Med2008;358:2776–2786) showed that oral rivaroxaban 10 mg once daily (od) given post-operatively significantly r...
Although current anticoagulants such as unfractionated and low-molecular-weight heparins and the vitamin K antagonists are effective for the prevention and treatment of thrombosis, they have several limitations. The vitamin K antagonists, the only approved oral anticoagulants, have a narrow therapeutic window, thereby requiring regular laboratory m...
This chapter describes the pharmacology of approved parenteral anticoagulants, including 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 t...
To determine whether activation of coagulation increases in parallel with inflammation and whether coagulation activation markers (CAMs) are independently associated with coronary heart disease (CHD), in the prospective study, NPHSII.
Surveillance of 2997 men between 50 and 63 years yielded 314 first CHD events during 36507 person-years of observat...
Background:
There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and phar...
The appropriate time to restart anticoagulation in the postpartum period is not known. The purpose of the present study was to determine whether the timing of postpartum enoxaparin influences hemorrhagic outcomes. A total of 95 women were treated with peripartum enoxaparin and compared with 303 consecutive deliveries where anticoagulation was not a...
Medicine is gradually adapting to the challenges presented by a rapidly aging society. Although “aging” itself is not a disease, older people are more likely to have illnesses, and these are more likely to be chronic and debilitating. Geriatric medicine, the discipline responsive to the special
The benefit of combined mechanical and pharmacologic methods for venous thromboembolism prevention after abdominal surgery has not been clearly established.
To compare the efficacy and safety of fondaparinux in conjunction with intermittent pneumatic compression vs. intermittent pneumatic compression alone in this context.
This was a randomized, do...
The plasma kallikrein-kinin system (PKKS) has been implicated in cardiovascular disease, but activation of the PKKS has not been directly probed in individuals at risk of coronary heart disease (CHD) or stroke.
To determine the involvement of the PKKS, including factor XI, in cardiovascular disease occurring in a nested case-control study from the...