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1.  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
2.  Sleep duration and weight change in midlife women: The SWAN Sleep Study 
Obesity (Silver Spring, Md.)  2013;21(1):77-84.
Short sleep duration has been associated with higher current body mass index (BMI) and subsequent weight gain. However, most prior longitudinal studies are limited by reliance on self-reported sleep duration, and none accounted for the potential confounding effect of sleep-disordered breathing. The associations of sleep duration with current BMI and BMI change were examined among 310 midlife women in the Study of Women’s Health Across the Nation (SWAN) Sleep Study (2003–2005). Sleep duration was assessed for approximately one month with concurrent wrist actigraphy and sleep diaries. The presence and severity of sleep-disordered breathing was quantified using the apnea-hypopnea index (AHI) based on in-home polysomnography. BMI was assessed annually through core SWAN visit 10 (2006 and 2008). Mean BMI increased from 29.6 (SD=7.8) kg/m2 to 30.0 (SD=8.0) kg/m2 over an average of 4.6 years (SD=1.0) of follow up. In cross-sectional analyses controlling for AHI, demographic variables, and several potential confounding variables, actigraphy (estimate=−1.22, 95%C.I.: −2.03, −.42) and diary (estimate=−.86, 95%C.I. −1.62, −.09) measures of sleep duration were inversely associated with BMI. Each hour of less sleep was associated with 1.22 kg/m2 greater BMI for actigraphy sleep duration, and a 0.86 kg/m2 greater BMI for diary sleep duration. Longitudinal associations between sleep duration and annual BMI change were non-significant in unadjusted and fully-adjusted models. In this cohort of midlife women, cross-sectional associations between sleep duration and current BMI were independent of sleep-disordered breathing, but sleep duration was not prospectively associated with weight change.
PMCID: PMC3484178  PMID: 23505171
3.  Effect of sex on outcome after recurrent stroke in African Americans 
Sex-related disparities in stroke have been previously reported. However, the influence of sex on the outcome of recurrent stroke in blacks is less clear. Our objective is to investigate the effect of sex on the outcome of recurrent non-fatal stroke in the African American Antiplatelet Stroke Prevention Study (AAASPS)
The AAASPS is a double-blind, randomized, controlled trial of recurrent stroke. Participants -967 black women and 842 black men- with non-cardioembolic ischemic stroke were assigned to receive ticlopidine or aspirin and followed for up to two years. The NIH Stroke Scale (NIHSS), modified Barthel score (mBS), and the Glasgow Outcome Scale (GOS) were determined at enrollment, at pre-specified times thereafter and at the time of recurrent stroke. Survival analysis was used to test for a significant difference in the time to recurrent stroke between women and men.
Of the total 1,809 subjects enrolled in AAASPS, 186 subjects (89 women and 97 men) suffered recurrent non-fatal stroke. At enrollment, the NIHSS (2.87 for women and 3.00 for men; p=0.73), the mBS (18.26 for women and 18.52 for men; p=0.47) and the GOS (1.49 for women and 1.51 for men; p=0.86) were not significantly different. In follow-up and at the time of stroke recurrence, the NIHSS, mBS, and GOS were similar for both groups, except for the mBS at the 6-month visit, which was lower in women (18.49) than in men (19.37) (p=0.02). In the survival analysis, no significant difference in the time to recurrent stroke was found between women and men (p=0.69).
Although sex-related stroke disparities have been reported, in the AAASPS cohort outcomes for recurrent non-fatal non-cardioembolic ischemic stroke for women were not significantly different than for men. Differences in study populations and methodologies may explain discrepancies in results from the various studies.
PMCID: PMC2900416  PMID: 20444625
African Americans; Ischemic stroke; Advances in Stroke; Database; Gender; Sex
4.  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
5.  Vitamin D is associated with atheroprotective high-density lipoprotein profile in postmenopausal women 
Journal of Clinical Lipidology  2010;4(2):113-119.
Low vitamin D has been associated with low levels of high-density lipoprotein (HDL) cholesterol, a marker of coronary risk. Whether atheroprotective HDL particle composition accounts for this association and whether fat affects this association is not known.
To explore the association between HDL particle composition and 25-hydroxy vitamin D (25[OH]D) in post-menopausal women.
Vitamin D levels and lipoprotein composition were assessed in fasting blood samples of apparently healthy women from a diverse Chicago community. Visceral (VAT) and subcutaneous (SAT) abdominal fat area were assessed using computed tomography. Total body fat mass was measured by dual-energy X-ray absorptiometry.
We enrolled 78 women (50% black; 50% white), age 48 to 64 years, all of whom were participants in a longitudinal study of fat patterning. They had a mean 25[OH]D of 31 ± 15 µg/L, HDL cholesterol 57 ± 11 mg/dL, and large HDL particle subclass 8.6 ± 3.4 µmol/L. In a multivariable-adjusted regression model, each 5 µg/L higher 25[OH]D predicted 0.57 µmol/L (95%CI 0.20–0.95) higher large HDL particles, independent of race, season, and total HDL particle concentration. This association was only partially confounded by total body fat mass (0.49, 95%CI 0.10–0.89), SAT (0.50, 95%CI 0.11–0.90), or VAT (0.37, 95%CI 0.01–0.74). Age did not significantly influence the strength of associations.
Higher 25[OH]D levels are associated with large HDL particles. This association is stronger than that of HDL cholesterol and only partially confounded by body fat. Theoretically, vitamin D may protect against cardiovascular risk by promoting formation of large HDL particles, affecting reverse cholesterol transport.
PMCID: PMC3390416  PMID: 21122638
6.  Depressive Symptoms are Related to Progression of Coronary Calcium in Midlife Women: The Study of Women’s Health Across the Nation (SWAN) Heart Study 
American heart journal  2011;161(6):1186-1191.e1.
Major depression and depressive symptoms are associated with cardiovascular disease (CVD), but the impact of depression on early atherogenesis is less well known, particularly in women and minorities. This study examined whether depressive symptoms are associated with progression of coronary artery calcification (CAC) among women at mid-life.
The Study of Women’s Health Across the Nation (SWAN) is a longitudinal, multi-site study assessing health and psychological factors in mid-life women. An ancillary study (SWAN Heart) evaluated subclinical atherosclerosis in women who reported no history of CVD or diabetes. In 346 women, CAC was measured twice by electron beam computed tomography, an average of 2.3 years apart. Progression, defined as an increase by 10 Agatston units or more, was analyzed using relative risk regression. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression (CES-D) Scale.
Progression of CAC was observed in 67 women (19.1%). Each 1–SD higher CES-D score at baseline related to a 25% increased risk of CAC progression [RR 1.25, CI 1.06–1.47, p=0.007], adjusting for age, time between scans, ethnicity, education, menopausal status, and known CVD risk factors. This risk was similar to the risk induced by BMI [RR 1.31, CI 1.11–1.54, p=0.001] and systolic blood pressure [RR 1.28, CI 1.06–1.55, p=0.01].
Depressive symptoms were independently associated with progression of CAC in this cohort of midlife women. Depressive symptoms may represent a risk factor that is potentially modifiable for early prevention of CVD in women.
PMCID: PMC3140211  PMID: 21641367
atherosclerosis; coronary calcium; women; depression; epidemiology
7.  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

Results 1-7 (7)