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1.  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.
doi:10.1016/j.thromres.2013.11.019
PMCID: PMC4156854  PMID: 24508189
thromboprophylaxis; renal failure; fondaparinux
2.  Characteristics of abdominal vein thrombosis in children and adults 
Thrombosis and haemostasis  2013;109(4):625-632.
Summary
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.
doi:10.1160/TH12-08-0568
PMCID: PMC3963260  PMID: 23407670
Venous thromboembolism; deep venous thrombosis; paediatrics; abdominal vein thrombosis
3.  Aspirin Exposure Reveals Novel Genes Associated with Platelet Function and Cardiovascular Events 
Objectives
To develop RNA profiles that could serve as novel biomarkers for the response to aspirin.
Background
Aspirin reduces death and myocardial infarction (MI) suggesting that aspirin interacts with biological pathways that may underlie these events.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jacc.2013.05.073
PMCID: PMC3786046  PMID: 23831034
aspirin; platelets; genes; myocardial infarction; biomarkers
4.  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.
doi:10.1146/annurev.med.042808.171814
PMCID: PMC4153429  PMID: 20059332
platelet factor 4; heparin; thrombosis; immunoassays; direct thrombin inhibitors; immune thrombocytopenia; immune-mediated thrombosis
5.  Whole Blood Gene Expression Analyses in Patients With Single Versus Recurrent Venous Thromboembolism 
Thrombosis research  2011;128(6):536-540.
Introduction
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.
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.thromres.2011.06.003
PMCID: PMC3726737  PMID: 21737128
genomics; risk factors; deep vein thrombosis
6.  A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing 
The New England journal of medicine  2013;369(24):2283-2293.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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 ClinicalTrials.gov number, NCT00839657.)
doi:10.1056/NEJMoa1310669
PMCID: PMC3942158  PMID: 24251361
7.  Prevalence and Clinical Characteristics of Mental Stress–Induced Myocardial Ischemia in Patients With Coronary Heart Disease 
Objectives
The goal of this study was to evaluate the prevalence and clinical characteristics of mental stress–induced myocardial ischemia.
Background
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.
Methods
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.
Results
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).
Conclusions
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)
doi:10.1016/j.jacc.2012.11.037
PMCID: PMC3913125  PMID: 23410543
mental and exercise stress; myocardial ischemia
8.  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.
Summary
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.
doi:10.1160/TH12-03-0202
PMCID: PMC3582386  PMID: 23223800
Platelets; platelet activity; serotonin; epinephrine; transporter
9.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.thromres.2009.11.017
PMCID: PMC3834257  PMID: 20659762
10.  Characterization of the Hypercoagulable State in Patients with Sickle Cell Disease 
Thrombosis research  2012;130(5):e241-e245.
SUMMARY
Background
The pathophysiology of sickle cell disease (SCD) is complex, with increasing evidence of a pronounced prothrombotic state.
Objective
We investigated thrombin generation in SCD utilizing calibrated automated thrombography (CAT) and Ddimer, with subsequent correlation to clinical disease.
Patient/Methods
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.
Results
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.
Conclusion
Hypercoagulable markers distinguish between patients with SCD during and between VOC, but do not correlate with specific clinical phenotypes.
doi:10.1016/j.thromres.2012.08.307
PMCID: PMC3474885  PMID: 22959127
sickle cell disease; thrombin; hypercoagulable state
11.  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.
doi:10.1055/s-0032-1328894
PMCID: PMC3804561  PMID: 23111862
thrombotic thrombocytopenic purpura; ticlopidine; clopidogrel; prasugrel; adverse event
13.  Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy 
Objectives
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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s11239-012-0683-0
PMCID: PMC3337886  PMID: 22294277
aspirin; platelets; light transmittance aggregometry; PFA100; principal components analysis
15.  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.
Background
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.
Method
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.
Conclusion
The REMIT study examines the effect of SSRI on MSIMI in vulnerable CHD patients and probes some potential underlying mechanisms.
doi:10.1016/j.ahj.2011.09.018
PMCID: PMC3254211  PMID: 22172432
16.  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.
doi:10.1038/ki.2008.613
PMCID: PMC3500614  PMID: 19180126
drug-associated TTP; epidemiology; ADAMTS13
17.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
Objectives
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jacc.2007.04.093
PMCID: PMC3167088  PMID: 17868804
18.  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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/PSY.0b013e3181d2f104
PMCID: PMC2869533  PMID: 20190126
C-reactive protein; Interleukin-6; Anger Recall; Depressive Symptoms; Hostility; Gender
19.  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.
doi:10.1200/JCO.2009.22.4584
PMCID: PMC2799059  PMID: 19738120
20.  Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage 
The New England journal of medicine  2010;362(7):600-613.
BACKGROUND
We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia.
METHODS
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).
RESULTS
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).
CONCLUSIONS
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. (ClinicalTrials.gov number, NCT00128713.)
doi:10.1056/NEJMoa0904084
PMCID: PMC2951321  PMID: 20164484
21.  Anti-Heparin/Platelet Factor 4 Antibody Optical Density Values and the Confirmatory Procedure in the Diagnosis of Heparin Induced Thrombocytopenia 
Thrombosis and haemostasis  2008;100(4):678-684.
Summary
Background
Laboratory testing for heparin-induced thrombocytopenia (HIT) includes the highly sensitive, though less specific, heparin/platelet factor 4 (PF4) ELISA. A confirmatory test with excess heparin is routinely performed on positive ELISA results to improve test specificity; the significance of a negative confirmatory result is unknown.
Objectives
1. Evaluate the clinical utility of the PF4 ELISA confirmatory assay. 2. Examine the relationship between ELISA OD value and clinical diagnosis of HIT. 3. Assess current practice at a tertiary care medical center regarding patients with anti-heparin/PF4 antibodies.
Patients/Methods
Patients with anti-heparin/PF4 antibodies detected by commercial ELISA during 2005 were identified. A confirmatory test was performed on positive ELISA results. Patients were labeled confirmatory positive (confirm+) or confirmatory negative (confirm-). Patients were classified as HIT+ (met criteria for HIT), HIT? (HIT possible), and HIT- (did not meet criteria for HIT) utilizing ACCP guidelines.
Results
115 patients with anti-heparin/PF4 antibodies were identified. 98 patients were confirm+; 17 were confirm-. The majority of confirm+ patients were HIT+ or HIT?(72%); the majority of confirm- patients were HIT-(81%). Patients who were HIT+/confirm+ had higher ELISA OD values than patients who were HIT?/confirm+ or HIT-/confirm+ (p=0.031, p=0.001). Two confirm- patients were HIT+, one was HIT?; all had high ELISA OD values.
Conclusions
Although confirm+ status correlated with clinical HIT, the confirmatory procedure misclassified some patients by yielding a confirm- result despite clinical HIT with high ELISA OD values. Future studies should compare higher ELISA OD values with the confirmatory procedure as strategies to improve ELISA diagnostic specificity for HIT.
PMCID: PMC2575642  PMID: 18841292

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