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1.  Risk of venous thromboembolism occurrence among adults with selected autoimmune diseases: A study among a U.S. cohort of commercial insurance enrollees☆ 
Thrombosis research  2014;135(1):50-57.
This study assessed the risk of venous thromboembolism (VTE) among privately insured adults in the U.S. with one or more of the following autoimmune diseases: autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE).
Materials and Methods
Using the Truven Health MarketScan® Databases, patients 18–64 years of age with a diagnosis of AIHA, ITP, RA, or SLE in 2007 and a sex and age-group matched comparison group of enrollees were followed up through 2010 to identify VTE events. Survival curve and Cox proportional hazards analyses were conducted to assess differences between groups.
Among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases, the risk of at least one VTE event was 19.74, 7.72, 4.90, 9.89, and 13.35 per 1,000 person-years, respectively; among the comparison group, the risk was 1.91 per 1,000 person-years. The adjusted hazard ratios (aHRs) for VTE among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases (when compared with the comparison group) tended to decline over follow-up time; at 1 year, the aHRs were 6.30 (95% confidence interval [CI]: 4.44–8.94), 2.95 (95% CI: 2.18–4.00), 2.13 (95% CI: 1.89–2.40), 4.68 (95% CI: 4.10–5.33), and 5.11 (95% CI: 4.26–6.14), respectively.
Having AIHA, ITP, RA, or SLE, or >1 of these diseases was associated with an increased likelihood of a VTE event. More research is necessary to develop better understanding of VTE occurrence among people with autoimmune diseases.
PMCID: PMC4480419  PMID: 25456001
Autoimmune diseases; Autoimmune hemolytic anemia; Immune thrombocytopenic purpura; Rheumatoid arthritis; Systemic lupus erythematosus; Venous thromboembolism
2.  Risk of venous thromboembolism among hospitalizations of adults with selected autoimmune diseases 
Previous research has suggested autoimmune diseases are risk factors for developing venous thromboembolism (VTE). We assessed whether having diagnoses of selected autoimmune diseases associated with anti-phospholipid antibodies—autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE)—were associated with having a VTE diagnosis among US adult hospitalizations. A cross-sectional study was conducted using the 2010 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. VTE and autoimmune diseases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification coded diagnoses information. The percentages of hospitalizations with a VTE diagnosis among all non-maternal adult hospitalizations without any of the four autoimmune diseases of interest and among those with AIHA, ITP, RA, and SLE diagnoses were 2.28, 4.46, 3.35, 2.65 and 2.77 %, respectively. The adjusted odds ratios (OR) for having a diagnosis of VTE among non-maternal adult hospitalizations with diagnoses of AIHA, ITP, RA, and SLE were 1.25 [95 % confidence interval (CI) 1.05–1.49], 1.20 (95 % CI 1.07–1.34), 1.17 (95 % CI 1.13–1.21), and 1.23 (95 % CI 1.15–1.32), respectively, when compared to those without the corresponding conditions. The adjusted OR for a diagnosis of VTE associated with a diagnosis of any of the four autoimmune diseases was 1.20 (95 % CI 1.16–1.24). The presence of a diagnosis of AIHA, ITP, RA, and SLE was associated with an increased likelihood of having a VTE diagnosis among the group of all non-maternal adult hospitalizations.
PMCID: PMC4477705  PMID: 24464552
Autoimmune diseases; Autoimmune hemolytic anemia; Immune thrombocytopenic purpura; Rheumatoid arthritis; Systemic lupus erythematosus; Venous thromboembolism
3.  Thromboprophylaxis with fondaparinux in high-risk postoperative patients with renal insufficiency 
Thrombosis research  2013;133(4):629-633.
Fondaparinux is an antithrombin-dependent factor Xa inhibitor that is used for thromboprophylaxis of patients undergoing hip fracture surgery, hip or knee replacement, or abdominal surgery. It is cleared by the kidney and should be used with caution in patients with renal impairment and avoided in patients with severe renal insufficiency. Recently, several studies have demonstrated that a lower dose of fondaparinux in patients with moderate renal impairment appears to be safe and effective. The purpose of this study was to obtain pharmacokinetic and clinical data on the use of prophylactic fondaparinux inpatients with renal insufficiency undergoing major abdominal surgery for cancer (n=8) or orthopedic surgery (n=1). Anti-factor Xa levels were obtained, and a published population pharmacokinetic model for fondaparinux was fit to the data. The data were analyzed using NONMEM software. Fondaparinux did not appear to accumulate in these patients, even when the drug was administered for up to twelve days. Pharmacokinetic analysis revealed thatthe apparent clearance in this population, who were primarily undergoing cancer surgery, was similar to prior studies in orthopedic surgery patients. In contrast, lower estimates were obtained for volume of distribution and absorption rate constant parameters.None of the patients sustained a hemorrhagic complication attributable to fondaparinux. One patient developed hypoxia in the setting of transient atrial fibrillation and clinical suspicion for pulmonary embolism, but this was not confirmed radiographically. These results support the use of 1.5 mg of fondaparinux every 24 hours for thromboprophylaxis in patients with renal insufficiency undergoing high-risk surgical procedures.
PMCID: PMC4156854  PMID: 24508189
thromboprophylaxis; renal failure; fondaparinux
4.  Characteristics of abdominal vein thrombosis in children and adults 
Thrombosis and haemostasis  2013;109(4):625-632.
The demographic and clinical characteristics of adults and children with lower extremity deep-vein thrombosis and/or pulmonary embolism (LE DVT/PE) may differ from those with abdominal vein thrombosis (abdominal VT). Abdominal VT can be a presenting sign of an underlying prothrombotic state, and its presence in the setting of known disease might have prognostic implications different from LE DVT/PE. This study describes clinical presentations of abdominal VT compared to LE DVT/PE in adults and children. We analysed prospectively-collected data from consecutive consenting patients enrolled in one of seven Centers for Disease Control and Prevention (CDC) funded Thrombosis and Hemostasis Network Centers from August 2003 to April 2011 to compare the demographic and clinical characteristics of adults and children with abdominal VT. Both adults and children with abdominal VT tended to be younger and have a lower body mass index (BMI) than those with LE DVT/PE. Of patients with abdominal VT, children were more likely to have inferior vena cava (IVC) thrombosis than adults. For adults with venous thromboembolism (VTE), relatively more women had abdominal VT than LE DVT/PE, while the proportions with LE DVT/PE and abdominal VT by sex were similar in children. Children with abdominal VT were more likely to have diagnosed inherited thrombophilia, while trauma was more common in children with LE DVT/PE. In conclusion, both children and adults with abdominal VT were younger with a lower BMI than those with LE DVT/PE. Significant differences exist between children and adults in respect to abdominal VT compared to LE DVT/PE.
PMCID: PMC3963260  PMID: 23407670
Venous thromboembolism; deep venous thrombosis; paediatrics; abdominal vein thrombosis
5.  Differences in Thrombotic Risk Factors in Black and White Women with Adverse Pregnancy Outcome☆ 
Thrombosis research  2013;133(1):108-111.
Black women have an increased risk of adverse pregnancy outcomes and the characteristics of thrombotic risk factors in this population are unknown. The objective of this study was to examine the racial differences in thrombotic risk factors among women with adverse pregnancy outcomes.
Uniform data were collected in women with adverse pregnancy outcomes (pregnancy losses, intrauterine growth restriction (IUGR), prematurity, placental abruption and preeclampsia) referred to Thrombosis Network Centers funded by the Centers for Disease Control and Prevention (CDC).
Among 343 white and 66 black women seen for adverse pregnancy outcomes, protein S and antithrombin deficiencies were more common in black women. The prevalence of diagnosed thrombophilia was higher among whites compared to blacks largely due to Factor V Leiden mutation. The prevalence of a personal history of venous thromboembolism (VTE) did not differ significantly by race. A family history of VTE, thrombophilia, and stroke or myocardial infarction (MI) was higher among whites. Black women had a higher body mass index, and a higher prevalence of hypertension, while the prevalence of sickle cell disease was approximately 27 fold higher compared to the general US black population.
Thrombotic risk factors differ significantly in white and black women with adverse pregnancy outcomes. Such differences highlight the importance of considering race separately when assessing thrombotic risk factors for adverse pregnancy outcomes.
PMCID: PMC4405792  PMID: 24246297
Thrombotic risk factors; thrombophilia; adverse pregnancy outcomes; racial disparities
6.  Whole Blood Gene Expression Analyses in Patients With Single Versus Recurrent Venous Thromboembolism 
Thrombosis research  2011;128(6):536-540.
Venous thromboembolism may recur in up to 30% of patients with a spontaneous venous thromboembolism after a standard course of anticoagulation. Identification of patients at risk for recurrent venous thromboembolism would facilitate decisions concerning the duration of anticoagulant therapy.
In this exploratory study, we investigated whether whole blood gene expression data could distinguish subjects with single venous thromboembolism from subjects with recurrent venous thromboembolism.
40 adults with venous thromboembolism (23 with single event and 17 with recurrent events) on warfarin were recruited. Individuals with antiphospholipid syndrome or cancer were excluded. Plasma and serum samples were collected for biomarker testing, and PAXgene tubes were used to collect whole blood RNA samples.
D-dimer levels were significantly higher in patients with recurrent venous thromboembolism, but P-selectin and thrombin-antithrombin complex levels were similar in the two groups. Comparison of gene expression data from the two groups provided us with a 50 gene probe model that distinguished these two groups with good receiver operating curve characteristics (AUC 0.75). This model includes genes involved in mRNA splicing and platelet aggregation. Pathway analysis between subjects with single and recurrent venous thromboembolism revealed that the Akt pathway was up-regulated in the recurrent venous thromboembolism group compared to the single venous thromboembolism group.
In this exploratory study, gene expression profiles of whole blood appear to be a useful strategy to distinguish subjects with single venous thromboembolism from those with recurrent venous thromboembolism. Prospective studies with additional patients are needed to validate these results.
PMCID: PMC3726737  PMID: 21737128
genomics; risk factors; deep vein thrombosis
7.  Effect of Escitalopram on Mental Stress-Induced Myocardial Ischemia: The Results of the REMIT Trial 
JAMA  2013;309(20):2139-2149.
Mental-stress-induced myocardial ischemia (MSIMI) is an intermediate surrogate endpoint representing the pathophysiological link between psychosocial risk factors and adverse outcomes of coronary heart disease (CHD). However, pharmacological interventions aimed at reducing MSIMI have not been well studied.
To examine the effects of 6 weeks of escitalopram treatment vs. placebo on MSIMI and other psychological stress-related biophysiological and emotional parameters.
Design, Setting, and Participants
The REMIT study is a randomized, double-blind, placebo-controlled trial of patients with clinically stable CHD and laboratory MSIMI. Enrollment occurred from 7/24/2007–8/24/2011 at a tertiary medical center.
Eligible participants were randomized 1:1 to receive escitalopram (dose began at 5 mg with titration to 20 mg/day in 3 weeks) or placebo over 6 weeks.
Main Outcome Measure
Occurrence of MSIMI, defined as (1) development or worsening of regional wall motion abnormality; (2) left ventricular ejection fraction reduction ≥8%; and/or (3) horizontal or downsloping ST-segment depression ≥1mm in ≥2 leads lasting for ≥3 consecutive beats during ≥1 of 3 mental tasks.
127 participants were randomized to escitalopram (n=64) or placebo (n=63); 112 (96.1%) completed endpoint assessments (n=56 in each arm). At the end of 6 weeks, more patients taking escitalopram (34.2% [95% CI, 25.4 to 43.0]) had absence of MSIMI during the 3 mental stressors compared with patients taking placebo (17.5% [95% CI, 10.4 to 24.5]) based on unadjusted multiple imputation model for intention-to-treat analysis. A significant difference favoring escitalopram was observed (OR=2.62 [95% CI, 1.06 to 6.44]). Rates of exercise-induced ischemia were slightly lower at 6 weeks in the escitalopram group (45.8% [95% CI, 36.6 to 55.0]) than in patients receiving placebo (52.5% [95% CI, 43.3 to 61.7]), compared with baseline escitalopram (49.2% [95% CI, 39.9 to 58.5]) vs placebo (56.7% [95% CI, 47.5 to 65.9]), but this difference was not statistically significant.
Conclusion and relevance
Among patients with stable CHD and baseline MSIMI, 6 weeks of escitalopram versus placebo resulted in lower prevalence of MSIMI. There was no difference in exercise-induced ischemia.
Trial Registration Identifier: NCT00574847
PMCID: PMC4378823  PMID: 23695483
8.  Depressive Symptoms and Mental Stress Induced Myocardial Ischemia in Patients with Coronary Heart Disease 
Psychosomatic medicine  2013;75(9):822-831.
The primary focus of this study was to examine associations between depressive symptoms and mental stress induced myocardial ischemia (MSIMI) in patients with coronary heart disease (CHD).
Adult patients with documented CHD were recruited for baseline mental stress and exercise stress screening testing as a part of the enrollment process of the REMIT trial. Patients were administered the Beck Depression Inventory II (BDI-II) and the Center for Epidemiologic Studies Depression Scale (CESD). Following a 24-48-hour Beta-blocker withdrawal, consented patients completed three mental stress tests followed by a treadmill exercise test. Ischemia was defined as 1) any development or worsening of any wall motion abnormality (WMA), 2) reduction of left ventricular ejection fraction (LVEF) ≥ 8% by transthoracic echocardiography, and/or ischemic ST-segment change by electrocardiography during stress testing. MSIMI was considered present when ischemia occurred in at least one mental test. Data were analyzed using logistic regression adjusting for age, gender, and resting left ventricular ejection fraction.
One hundred twenty five (44.2 %) of 283 patients were found to have MSIMI and 93 (32.9%) had ESIMI. Unadjusted analysis showed that BDI-II scores were positively associated with the probability of MSIMI (OR = .1.30: 95% CI 1.06 – 1.60, p = .013) and number of MSIMI positive tasks (all p < .005). These associations were still significant after adjustment for covariates (ps ≤ .05).
In CHD patients, depressive symptoms were associated with a higher probability of MSIMI. These observations may enhance our understanding of the mechanisms contributing to the association of depressive symptoms to future cardiovascular events.
PMCID: PMC4378828  PMID: 24163385
Mental stress induced myocardial ischemia; exercise induced myocardial ischemia; depressive symptoms; coronary heart disease
9.  Aspirin Exposure Reveals Novel Genes Associated with Platelet Function and Cardiovascular Events 
To develop RNA profiles that could serve as novel biomarkers for the response to aspirin.
Aspirin reduces death and myocardial infarction (MI) suggesting that aspirin interacts with biological pathways that may underlie these events.
We administered aspirin, followed by whole blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1,n=50), and two validation cohorts of volunteers (HV2,n=53) or outpatient cardiology patients (OPC, n=25). Platelet function was assessed by platelet function score (PFS; HV1/HV2) or VerifyNow Aspirin (OPC). Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for association with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death/MI in two patient cohorts (n=587, total) from RNA samples collected at cardiac catheterization.
A set of 60 co-expressed genes named the “aspirin response signature” (ARS) was associated with PFS in HV1 (r = −0.31, p = 0.03), HV2 (r = −0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for 17 ARS genes were identified in the platelet proteome, of which, six were associated with PFS. The ARS was associated with death/MI in both patient cohorts (odds ratio = 1.2, p = 0.01 and hazard ratio = 1.5, p = 0.001), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31 - 37%, p ≤ 0.0002) was improved by including the ARS or one of its genes, ITGA2B.
RNA profiles of platelet-specific genes are novel biomarkers for identifying those do not response adequately to aspirin and who are at risk for death/MI.
PMCID: PMC3786046  PMID: 23831034
aspirin; platelets; genes; myocardial infarction; biomarkers
10.  Heparin-Induced Thrombocytopenia 
Annual review of medicine  2010;61:77-90.
Heparin-induced thrombocytopenia (HIT) is an immune-mediated hypercoagulable disorder caused by antibodies to platelet factor 4 (PF4) and heparin. HIT develops in temporal association with heparin therapy and manifests either as an unexplained thrombocytopenia or thrombocytopenia complicated by thrombosis. The propensity for thrombosis distinguishes HIT from other common drug-induced thrombocytopenias. Diagnosing HIT in hospitalized patients is often challenging because of the frequency of heparin use, occurrence of thrombocytopenia from other causes, and development of asymptomatic PF4/heparin antibodies in patients treated with heparin. This review summarizes our current understanding of the pathogenesis, clinical features, diagnostic criteria, and management approaches in HIT.
PMCID: PMC4153429  PMID: 20059332
platelet factor 4; heparin; thrombosis; immunoassays; direct thrombin inhibitors; immune thrombocytopenia; immune-mediated thrombosis
11.  A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing 
The New England journal of medicine  2013;369(24):2283-2293.
The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.
We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy.
At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.
Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG number, NCT00839657.)
PMCID: PMC3942158  PMID: 24251361
12.  Prevalence and Clinical Characteristics of Mental Stress–Induced Myocardial Ischemia in Patients With Coronary Heart Disease 
The goal of this study was to evaluate the prevalence and clinical characteristics of mental stress–induced myocardial ischemia.
Mental stress–induced myocardial ischemia is prevalent and a risk factor for poor prognosis in patients with coronary heart disease, but past studies mainly studied patients with exercise-induced myocardial ischemia.
Eligible patients with clinically stable coronary heart disease, regardless of exercise stress testing status, underwent a battery of 3 mental stress tests followed by a treadmill test. Stress-induced ischemia, assessed by echocardiography and electrocardiography, was defined as: 1) development or worsening of regional wall motion abnormality; 2) left ventricular ejection fraction reduction ≥8%; and/or 3) horizontal or downsloping ST-segment depression ≥1 mm in 2 or more leads lasting for ≥3 consecutive beats during at least 1 mental test or during the exercise test.
Mental stress–induced ischemia occurred in 43.45%, whereas exercise-induced ischemia occurred in 33.79% (p = 0.002) of the study population (N = 310). Women (odds ratio [OR]: 1.88), patients who were not married (OR: 1.99), and patients who lived alone (OR: 2.24) were more likely to have mental stress–induced ischemia (all p < 0.05). Multivariate analysis showed that compared with married men or men living with someone, unmarried men (OR: 2.57) and married women (OR: 3.18), or living alone (male OR: 2.25 and female OR: 2.72, respectively) had higher risk for mental stress-induced ischemia (all p < 0.05).
Mental stress-induced ischemia is more common than exercise-induced ischemia in patients with clinically stable coronary heart disease. Women, unmarried men, and individuals living alone are at higher risk for mental stress-induced ischemia. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847)
PMCID: PMC3913125  PMID: 23410543
mental and exercise stress; myocardial ischemia
13.  Hyperreactive platelet phenotypes: Relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation 
Thrombosis and haemostasis  2012;109(1):85-92.
The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics to platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modeling. Stimulation with submaximal (2 μM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.
PMCID: PMC3582386  PMID: 23223800
Platelets; platelet activity; serotonin; epinephrine; transporter
14.  The Effect of Aspirin on Endothelial Progenitor Cell Biology: Preliminary Investigation of Novel Properties 
Thrombosis research  2010;126(3):10.1016/j.thromres.2009.11.017.
Atherosclerosis develops in an environment of endothelial injury and inflammation. Circulating endothelial progenitor cells (EPCs) are required for vascular repair and restoration of normal endothelial function. We tested the hypothesis that the nonselective cyclooxygenase (COX) inhibitor aspirin exerts an effect on circulating EPCs.
As part of a larger study evaluating the effect of aspirin dose in primary and secondary prevention, subjects (n=32) were assigned randomly to either 81mg or 325mg aspirin daily for two months, and circulating mononuclear cells were enumerated at the beginning of the study and after 2 months using fluorescent antibodies against CD34 and CD133 as well as based on aldehyde dehydrogenase (ALDH) activity. Brachial artery endothelial function via flow-mediated dilation (BAFMD) and light transmittance platelet aggregometry in response to physiologic agonists was also determined.
Subjects taking aspirin at the time of study entry had a lower numbers of CD133+/34+ cells compared to those not previously exposed (0.01% vs. 0.05% of MNCs, P<0.03). After 2 months, subjects randomized to 81 vs. 325 mg of ASA had no significant differences in the median numbers of EPCs, although mean numbers trended lower in the high dose group. Patients on chronic ASA therapy continued to have lower numbers of EPCs. Similar effects were observed in CD34 and CD 133 single-positive cells, as well as ALDHbr cells. BAFMD did not differ nor change significantly over time between aspirin dose groups. All patients had decreased ex vivo platelet aggregation in response to arachidonic acid and ADP stimulation.
Our preliminary studies suggest that aspirin exerts a time-dependent effect on circulating EPCs. Short-term exposure to differing doses of ASA had indeterminate effects on EPCs levels, suggesting that time of ASA exposure may play a more important role than dose. Determining the responsible mechanism(s) and the overall clinical relevance of these findings will require further investigation.
PMCID: PMC3834257  PMID: 20659762
15.  Characterization of the Hypercoagulable State in Patients with Sickle Cell Disease 
Thrombosis research  2012;130(5):e241-e245.
The pathophysiology of sickle cell disease (SCD) is complex, with increasing evidence of a pronounced prothrombotic state.
We investigated thrombin generation in SCD utilizing calibrated automated thrombography (CAT) and Ddimer, with subsequent correlation to clinical disease.
The study included 51 patients homozygous for hemoglobin S, either admitted for vaso-occlusive crisis (VOC) (n=34) or while in steady state and being seen in outpatient clinic (n=37). Twenty patients had blood drawn during both VOC and steady state. Mean values for CAT and D-dimer were compared between groups. Mean values for patients with and without clinical complications such as avascular necrosis and stroke were also compared. Linear regression was used to evaluate correlation to number of hospitalizations and for all pediatric patients, transcranial doppler (TCD) velocities.
The mean D-dimer during VOC (2743 ± 3118 ng/ml) was significantly higher than during steady state (1151 ± 802, p<0.0001). Comparison of crisis and steady state by CAT also revealed a significant difference in all phases of thrombin generation, including mean endogenous thrombin potential (1381 ± 295 nM vs 923 ± 316, p<0.0001) and peak thrombin generated (284 ± 9 vs 223 ± 18, p=0.0002). There were no significant differences in mean values for the clinical outcomes examined in adults. In pediatric patients, however, increased TCD velocities correlated with steady state Ddimer (r2=0.32, p=0.02) and thrombin-antithrombin complex (r2=0.28, p=0.04.
Hypercoagulable markers distinguish between patients with SCD during and between VOC, but do not correlate with specific clinical phenotypes.
PMCID: PMC3474885  PMID: 22959127
sickle cell disease; thrombin; hypercoagulable state
16.  Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A 20-Year Review from the Southern Network on Adverse Reactions (SONAR) 
Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.
PMCID: PMC3804561  PMID: 23111862
thrombotic thrombocytopenic purpura; ticlopidine; clopidogrel; prasugrel; adverse event
18.  Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy 
To develop an integrated metric of non COX-1 dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics.
NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established.
We administered 325mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures.
The PFS strongly correlated with each measure of NCDPF in each cohort. After two or four weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, p<0.0001) and was higher (p < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final - Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = −0.45), HV2 (r = −0.54), DM (r = −0.68), p<0.0001 for all. AAA remained suppressed during aspirin therapy.
The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time.
PMCID: PMC3337886  PMID: 22294277
aspirin; platelets; light transmittance aggregometry; PFA100; principal components analysis
20.  Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment: Background, Design, and Method for the REMIT Trial 
American Heart Journal  2011;163(1):20-26.
Mental stress induced myocardial ischemia (MSIMI) is common in patients with clinically stable coronary heart disease (CHD) and is associated with poor outcomes. Depression is a risk factor of MSIMI. The Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment (REMIT) trial investigates whether selective serotonin reuptake inhibitor (SSRI) treatment can improve MSIMI. The rationale and outline of the study are described.
In this single center randomized clinical trial, adult patients with clinically stable CHD are recruited for baseline mental and exercise stress testing assessed by echocardiography. Additionally, psychometric questionnaires are administered and blood samples are collected for platelet activity analysis. Patients who demonstrate MSIMI, defined by new abnormal wall motion, ejection fraction reduction ≥8%, and/or development of ischemic ST change in electrocardiogram during mental stress testing, are randomized at a 1:1 ratio to escitalopram or placebo for 6 weeks. Approximately 120 patients with MSIMI are enrolled in the trial. The stress testing, platelet activity assessment and psychometric questionnaires are repeated at the end of the 6-week intervention. The hypothesis of the study is that SSRI treatment improves MSIMI via mood regulation and modification of platelet activity.
The REMIT study examines the effect of SSRI on MSIMI in vulnerable CHD patients and probes some potential underlying mechanisms.
PMCID: PMC3254211  PMID: 22172432
21.  Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008) 
Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.
PMCID: PMC3500614  PMID: 19180126
drug-associated TTP; epidemiology; ADAMTS13
22.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
PMCID: PMC3167088  PMID: 17868804
23.  Associations of depressive symptoms, trait hostility, and gender with C-reactive protein and interleukin-6 response following emotion recall 
Psychosomatic medicine  2010;72(4):333-339.
Depressive symptoms moderate the effect of trait hostility on circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6). We extended these findings by examination of the effects of depressive symptoms and hostility on changes in CRP and IL-6 in response to an acute laboratory stressor.
The study included 307 men and 218 women, affording the opportunity to examine moderation by gender. Regression analyses were performed to examine depressive symptoms, hostility ratings, gender, and their interactions as predictors of CRP and IL-6 response to an emotion recall task. Analyses were adjusted for age, race, body mass index, and pre-recall task levels of either CRP or IL-6.
The product term for depressive symptoms × hostility × gender was not significantly related to CRP nor IL-6 response. However, depressive symptoms × hostility did interact to predict CRP response (p = .002); those with the combination of high symptoms of depression and hostility had the largest CRP response. The depressive symptoms × gender interaction was also a predictor of both CRP (p = .001) and IL-6 (p = .04) response; for each inflammatory marker depressive symptoms were significantly associated with higher CRP response in women, as compared to men. Hostility did not moderate depressive symptoms, nor gender for IL-6.
Our findings extend prior research by suggesting that, broadly speaking, depression is related to inflammatory markers, however this relation appears complex. Depression seems to be related to inflammation more strongly among hostile individuals, and more strongly among women than among men.
PMCID: PMC2869533  PMID: 20190126
C-reactive protein; Interleukin-6; Anger Recall; Depressive Symptoms; Hostility; Gender
24.  Impact of Venous Thromboembolism and Anticoagulation on Cancer and Cancer Survival 
Journal of Clinical Oncology  2009;27(29):4902-4911.
Changes in the hemostatic system and chronic hemostatic activation are frequently observed in patients with cancer, even in the absence of venous thromboembolism (VTE). VTE is a leading cause of death among patients with cancer and contributes to long-term mortality in patients with early as well as advanced-stage cancer. Mounting evidence suggests that components of the clotting cascade and associated vascular factors play an integral part in tumor progression, invasion, angiogenesis, and metastasis formation. Furthermore, there are intriguing in vitro and animal findings that anticoagulants, in particular the low molecular weight heparins (LMWHs), exert an antineoplastic effect through multiple mechanisms, including interference with tumor cell adhesion, invasion, metastasis formation, angiogenesis, and the immune system. Several relatively small randomized controlled clinical trials of anticoagulation as cancer therapy in patients without a VTE diagnosis have been completed. These comprise studies with LMWH, unfractionated heparin, and vitamin K antagonists, with overall encouraging but nonconclusive results and some limitations. Meta-analyses performed for the American Society of Clinical Oncology VTE Guidelines Committee and the Cochrane Collaboration suggest overall favorable effects of anticoagulation on survival of patients with cancer, mainly with LMWH. However, definitive clinical trials have been elusive and questions remain regarding the importance of tumor type and stage on treatment efficacy, the impact of fatal thromboembolic events, optimal anticoagulation therapy, and safety with differing chemotherapy regimens. Although the LMWHs and related agents hold promise for improving outcomes in patients with cancer, additional studies of their efficacy and safety in this setting are needed.
PMCID: PMC2799059  PMID: 19738120
25.  Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage 
The New England journal of medicine  2010;362(7):600-613.
We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia.
We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1×1011, 2.2×1011, or 4.4×1011 platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria).
In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25×1011) than in the medium-dose group (11.25×1011) or the high-dose group (19.63×1011) (P = 0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001).
Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1×1011 and 4.4×1011 platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. ( number, NCT00128713.)
PMCID: PMC2951321  PMID: 20164484

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