Prospects for PLD Inhibition in Cancer and Thrombotic Disease

2019 ◽  
pp. 79-88 ◽  
Author(s):  
Christian Salazar ◽  
Michael A. Frohman
Keyword(s):  
Thrombotic Disease

Anticoagulant Activity of Hirulog™, a Direct Thrombin Inhibitor, in Humans

1993 ◽  
Vol 69 (02) ◽  
pp. 157-163 ◽  
Author(s):  
Irving Fox ◽  
Adrian Dawson ◽  
Peter Loynds ◽  
Jane Eisner ◽  
Kathleen Findlen ◽  
...  
Keyword(s):  
Rational Design ◽  
Therapeutic Potential ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
Direct Thrombin Inhibitor ◽  
Controlled Study ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Thrombotic Disease ◽  
Dose Dependent

SummaryHirulog™ (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095–101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers.In a randomized, placebo-controlled study (n = 54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 1 kg−1 h−1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p <0.001) and subcutaneous administration (r = 0.7, p = 0.002).To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide’s activity. At the administered dose of 0.6 mg kg−1 h−1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.The final phase of the study examined the activity and tolerability of hirulog in ten subjects during prolonged intravenous infusions for up to 24 h. The peptide (0.3 mg kg−1 h−1) exhibited sustained anticoagulant activity with no evidence for a cumulative effect. During hirulog infusion, APTT was prolonged from 210 to 250% baseline.In all phases of the study, hirulog administration was generally well-tolerated.Our observations show that hirulog is an active antithrombin agent with excellent tolerability in humans. As a direct thrombin inhibitor, hirulog provides a novel approach for the management of thrombotic disease.

Prophylaxis of Venous Thromboembolism Following Orthopedic Surgery: Mechanical and Pharmacological Approaches and the Need for Extended Prophylaxis

1999 ◽  
Vol 82 (08) ◽  
pp. 918-924 ◽  
Author(s):  
R.D. Hull ◽  
G.F Pineo
Keyword(s):  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Orthopedic Surgery ◽  
Total Joint Replacement ◽  
Case Series ◽  
Pharmacological Agents ◽  
Thrombotic Disease ◽  
Vein Thrombosis ◽  
Major Orthopedic Surgery ◽  
Mechanical Devices

IntroductionMajor orthopedic surgery, particularly total joint replacement or hip fracture, represents a high risk of future development of postoperative venous thromboembolism and warrants the routine use of prophylaxis with either mechanical devices or pharmacological agents. The aim of prophylaxis is to prevent fatal pulmonary embolism (PE) and the morbidity of deep vein thrombosis (DVT), particularly the development of post-thrombotic syndrome. Patterns of clinical practice, with respect to the prevention of venous thromboembolism and the appropriate use of anticoagulants for the treatment of thrombotic disease, have been strongly influenced by recent consensus conferences.1,2 Rules of evidence for assessing the literature have been applied to all recommendations regarding the prevention and treatment of thrombotic disease. These results were extrapolated using evidence gleaned from major clinical disorders and are based only on nonrandomized clinical trials or case series.1-3 Data from a large number of Level I clinical trials in patients undergoing orthopedic surgery have provided answers to many of the questions regarding prophylaxis of venous thromboembolism. In this review, we will discuss the prevention of venous thromboembolism following orthopedic surgery and discuss some of the controversial issues where further studies are required.

Carotid intimal sarcoma causing stroke and intracranial metastasis via tumor embolization

Neurology ◽  
2020 ◽  
Vol 94 (11) ◽  
pp. e1122-e1125
Author(s):  
Shashank Agarwal ◽  
Anna Derman ◽  
Eytan Raz ◽  
Syed T. Hoda ◽  
Karthikeyan Arcot ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Tumor Thrombus ◽  
Poor Response ◽  
Atheromatous Plaque ◽  
Left Internal Carotid Artery ◽  
Intracranial Metastasis ◽  
Tissue Mass ◽  
Thrombotic Disease ◽  
Intimal Sarcoma ◽  
Tumor Embolization

ObjectiveTo present the clinical, radiologic, and pathologic findings of a patient with carotid intimal sarcoma.MethodsDetailed medical interview, neurologic examination, and diagnostic evaluation including CT angiography head and neck, MRI brain and neck, digital subtraction angiography, and biopsy of the mass were performed.ResultsWe report a patient who presented with symptoms of multifocal, bilateral strokes over weeks caused by an enlarging tumor thrombus associated with an intimal sarcoma of the carotid artery. The presence of a carotid space mass encasing the left internal carotid artery was initially not recognized on imaging and was mistakenly attributed to soft atheromatous plaque rather than tumor thrombus. Rapid disease progression resulted in multiple intracranial metastases from tumor embolization.ConclusionClinical and radiologic findings of intimal sarcoma may be similar to those of thrombotic disease. However, patients with sarcoma may show an associated perivascular soft tissue mass and an unusual distribution of vessel stenosis. Reevaluation of imaging should be considered in patients presenting with initial imaging findings suggestive of rapidly progressive thrombotic disease who have a poor response to antithrombotic therapy and do not follow an expected clinical course.

Diagnosis and Initial Treatment of Venous Thromboembolism in Patients With Cancer

2009 ◽  
Vol 27 (29) ◽  
pp. 4889-4894 ◽  
Author(s):  
Michael B. Streiff
Keyword(s):  
Venous Thromboembolism ◽  
Initial Treatment ◽  
Vena Cava ◽  
Initial Therapy ◽  
Primary Objective ◽  
Thrombotic Disease ◽  
Venous Stenting ◽  
Patients With Cancer ◽  
Vena Cava Filters ◽  
Increased Risk

Purpose Venous thromboembolism (VTE) is a common complication of cancer and its therapy. The purpose of this article is to review the diagnosis and initial treatment of VTE in the patient with cancer. Methods I conducted a survey of the English-language literature on topics relevant to the diagnosis and initial treatment of VTE in patients with cancer. Results Patients with cancer are at increased risk for VTE because of the presence of multiple risk factors for thrombotic disease. The most common signs and symptoms of VTE as well as the utility of clinical prediction rules and D-dimer testing in the diagnosis of VTE in the patient with cancer are reviewed. Duplex ultrasound and computer tomography angiography are the primary objective diagnostic modalities for VTE. Low molecular weight heparin is the preferred initial therapy for VTE. Until further data emerge, thrombolysis and vena cava filters should be reserved for patients in whom anticoagulation is insufficient or contraindicated. Outpatient management is feasible for carefully selected patients with cancer with deep vein thrombosis (DVT) and low-risk pulmonary embolism. Anticoagulation is the preferred initial therapy for cancer patients with central venous catheter–associated DVT, calf DVT, and unsuspected VTE. Conclusion Optimal initial management of VTE in patients with cancer entails maintaining a high index of suspicion for thrombotic disease, confirming diagnostic suspicions with objective testing and evidence-based use of anticoagulation, and adjunctive therapeutic modalities (thrombolysis, vena cava interruption, venous stenting). Further investigation of initial diagnostic and treatment strategies for VTE focusing on patients with cancer are warranted.

Haemostatic Genetic Risk Factors in Arterial Thrombosis

2001 ◽  
Vol 86 (07) ◽  
pp. 374-385 ◽  
Author(s):  
Rachel Simmonds ◽  
José Hermida ◽  
Suely Rezende ◽  
David Lane
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Genetic Polymorphism ◽  
Genetic Risk ◽  
Arterial Thrombosis ◽  
Membrane Glycoprotein ◽  
Thrombotic Disease ◽  
Integral Role ◽  
Technical Simplicity ◽  
Digital Nature

SummaryHaemostasis plays an integral role in arterial thrombotic disease. However, establishing which of the factors are risk factors has proven surprisingly difficult. Because of its technical simplicity and digital nature, the study of haemostatic polymorphisms as risk factors has grown in popularity. Once established as a risk factor, a genetic polymorphism has the potential to aid selective prophylaxis and therapy of disease. Numerous reports have now been published on polymorphisms of coagulation and fibrinolytic factors, of coagulation and fibrinolytic inhibitory proteins, and of platelet membrane glycoprotein receptors. This article describes the polymorphisms and evaluates the results of these studies using the premises of consistency of within-report genotype/phenotype/disease relationships and consistency of outcome between studies. Many studies have been only of association between polymorphisms and disease, a type of study that is prone to error. Furthermore, the collective outcome of these studies has primarily been inconsistent. It is concluded that despite the early promise of polymorphisms as risk factors, fresh approaches differing in scale and design are now required to clarify their possible importance.

scholarly journals The Role of Cysteine and Homocysteine in Venous and Arterial Thrombotic Disease

2001 ◽  
Vol 116 (1) ◽  
pp. 56-60 ◽  
Author(s):  
Rossella Marcucci ◽  
Tamara Brunelli ◽  
Betti Giusti ◽  
Sandra Fedi ◽  
Guglielmina Pepe ◽  
...  
Keyword(s):  
Thrombotic Disease

Association of the Platelet Glycoprotein Ia C807T Gene Polymorphism With Nonfatal Myocardial Infarction in Younger Patients

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2449-2453 ◽  
Author(s):  
S. Santoso ◽  
T.J. Kunicki ◽  
H. Kroll ◽  
W. Haberbosch ◽  
A. Gardemann
Keyword(s):  
Myocardial Infarction ◽  
Odds Ratio ◽  
Type I Collagen ◽  
Strong Association ◽  
Platelet Glycoprotein ◽  
Type I ◽  
Presumptive Diagnosis ◽  
Thrombotic Disease ◽  
Allele Specific ◽  
Artery Disease

Abstract Recently, we have shown that two alleles of the glycoprotein (GP) Ia gene, designated C807 and T807, are associated with low or high platelet GPIa-IIa density and consequently with slower or faster rate of platelet adhesion to type I collagen, respectively. This polymorphism could therefore present a genetic predisposition for the development of thrombotic disease and hemostasis. We investigated the relationship of the GPIa C807T dimorphism to the risk of coronary artery disease (CAD) and myocardial infarction (MI). An allele-specific polymerase chain reaction (PCR) was developed for genotyping of C807T polymorphism. DNA samples from 2237 male patients who underwent coronary angiography on account of coronary heart disease as verified illness or presumptive diagnosis were genotyped. The odds ratio was calculated as an estimate of the relative risk by multiple logistic regression. We found a strong association between the T allele and nonfatal MI among individuals younger than the mean age of 62 years (n = 1,057; odds ratio, 1.57; P = .004). The odds ratio of MI increased for T807 carriers with decreasing age. The highest odds ratio was detected within the youngest 10% of the study sample (&lt;49 years; n = 223; odds ratio, 2.61; P = .009). In contrast, no evidence of an association between C807T dimorphism with CAD was found. Our findings suggest that inherited platelet GP variations might have an important impact on acute thrombotic disease.

scholarly journals Identification of Two Novel Point Mutations in the Human Protein S Gene Associated With Familial Protein S Deficiency and Thrombosis

1996 ◽  
Vol 16 (12) ◽  
pp. 1407-1415 ◽  
Author(s):  
Muyao Li ◽  
George L. Long
Keyword(s):  
Genomic Dna ◽  
Mrna Level ◽  
Point Mutations ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
Cdna Sequencing ◽  
Thrombotic Disease ◽  
S Gene ◽  
S Deficiency

Individuals with thrombosis who were believed to possess associated familial protein S deficiency were analyzed for mutations in the protein S gene by a two-step process. First, the individuals were analyzed for protein S Pro 626 A/G dimorphism in both their genomic DNA and reverse-transcribed (RT) polymerase chain reaction (PCR)–amplified cDNA from peripheral blood cell mRNA. If a heterozygote expressed both alleles at the mRNA level at this site in genomic DNA, a search for point mutations was made by direct cDNA sequencing. RT-PCR amplification of exons 1-6 with mRNA from two twin sisters, each of whom has severe type I protein S deficiency, revealed both larger and smaller fragments in addition to the expected 504–base pair fragment in normal individuals. A donor splice-site mutation at position +4 of the 5′ end of intron A was subsequently identified in both sisters and their mother. This mutation would lead to incorrect precursor mRNA splicing and the observed cDNA products. Translation of the altered mRNAs would result in a truncated protein without biological activity. In a second family, cDNA sequencing revealed a T→G mutation at codon 603 (Ile→Ser) in exon 15 of the protein S gene in an individual with protein S deficiency (mixed type) and a history of thrombosis. The same mutation was also detected in the proband's mother and grandmother, both of whom also exhibit protein S deficiency and thrombotic disease. This mutation occurs within a disulfide loop of protein S that is believed to be responsible for binding to C4b binding protein and may result in greater affinity between protein S and C4b, consequently leading to thrombotic disease.

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