Brianne L. Dunn

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.

Ticlopidine-associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (SONAR)

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder. The classic TTP ‘pentad’ is thrombocytopenia, microangiopathic hemolytic anemia (MAHA), renal impairment, neurological symptoms, and fever (Amorosi & Ultmann, 1966). Laboratory studies identified deficiency of plasma ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13) activity (ADAMTS13:AC) among some TTP patients (Furlan et al, 1998; Tsai & Lian, 1998). ADAMTS13 cleaves the peptide bond between Thy1605 and Met1606 in the A2 domain of von Willebrand factor (VWF) subunit. VWF is released into the plasma as unusually large VWF multimers (UL-VWFMs), which are degraded into smaller size VWF multimers by ADAMTS13. In the late 1990s, studies in the United States identified 117 cases of TTP that developed after initiation of the thienopyridine, ticlopidine; although at that time, ADAMTS13 activity levels were not widely available (Bennett et al, 1999; Steinhubl et al, 1999). A study of seven patients in the United States with ticlopidine-associated TTP found that all seven had severe deficiency of ADAMTS13 activity and five had detectable antibodies to ADAMTS13 activity (Tsai et al, 2000). We now report on 22 individuals from Japan with ticlopidine-induced TTP and compare these findings to those from the United States. Ticlopidine was the primary anti-platelet agent in Japan from 1989 to 2006. Since 1998, our laboratory at Nara Medical University has been a nationwide referral centre in Japan for thrombotic microangiopathies (TMAs), including TTP (Fujimura & Matsumoto, 2010). The study protocol was approved by the Ethics Committee of Nara Medical University Hospital. TTP diagnostic criteria were: microangiopathic haemolytic anaemia (haemoglobin ≤ 120 g/l), Coombs test negative, undetectable serum haptoglobin (<1 μmol/l), more than 2 fragmented red cells (schistocytes) in a microscopic field with 9100 magnification, increased serum lactate dehydrogenase (LDH) above institutional baseline, thrombocytopenia (platelet count ≤ 100 × 109/l), absence of evidence for disseminated intravascular coagulation and no other identifiable cause of TTP. Additional information on fever ≥37°C; and central nervous system and renal function data were abstracted. Patients were included if, in addition to criteria for idiopathic TTP, the patient had received ticlopidine prior to TTP onset. Before therapeutic plasma exchange or plasma infusion was initiated, whole blood samples (five ml) were withdrawn from each patient and placed into plastic tubes containing 1/10 volume of 3.2% sodium citrate. Plasma was separated by centrifugation at 3000 g for 15 min at 4°C, kept in aliquots at −80°C until testing, and sent to our laboratory with clinical information. Until March 2005, ADAMTS13:AC was determined by classic VWF multimer (VWFM) assay with a detection limit of 3% of the normal control (Furlan et al, 1996; Kinoshita et al, 2001). Thereafter, a chromogenic ADAMTS13-act-enzyme-linked immunosorbent assay (ELISA) with a detection limit of 0-5% of the normal control was developed, and replaced the VWFM assay. Plasma ADAMTS13 inhibitor (ADAMTS13:INH) titres were analysed either by classic VWFM assay or chromogenic ADAMTS13-act-ELISA using heat-inactivated plasmas at 56°C for 30 min. A total of 22 ticlopidine-associated TTP patients fulfilled the inclusion criteria (Table I). Age at diagnosis ranged from 41 to 89 years, with the median age of onset of 69 years. Females accounted for 45.5% of the cohort. Ticlopidine had been administered for a median of 27-5 d (range, 14–35 d) but was discontinued after a clinical diagnosis of TTP was made. Median values for hemoglobin were 83 (60–146) g/l, platelets 9–5 (3.57) × 109/l, and serum creatinine 132.6 (35–380) μmol/l. Abnormal neurological findings were noted in 63.6%. All of the patients had 4 BU/ml. Both ticlopidine-associated TTP deaths did not receive therapeutic plasma exchange. Table I Characteristics of ticlopidine-associated thrombotic thrombocytopenic purpura in Japan and United States. To our knowledge, this is the first study to report detailed characteristics of ticlopidine-associated TTP among patients outside of the United States. Our findings, from a cohort of ticlopidine-associated TTP patients in Japan, identified severe ADAMTS13 deficiency and antibodies to ADAMTS13 in 100% of these 22 individuals. A decade earlier, severe ADAMTS13 deficiency was reported in 100% of seven patients with ticlopidine-associated TTP in the United States and antibodies to ADAMTS13 in five of these patients (Bennett et al, 1999; Tsai et al, 2000). While ticlopidine-induced TTP is undoubtedly a rare disease, it is reassuring that the original observations reported from the United States have been independently replicated in Japan (Bennett et al, 1999; Steinhubl et al, 1999). Limitations of our study should be identified. Follow-up ended at the time of hospital discharge, which prevented us from reporting on relapse rates. Ticlopidine is rarely used today, having been replaced by clopidogrel in 1999 because of safety concerns. Our research has shown that clopidogrel, unlike ticlopidine, does not lead to ADAMTS13 antibody formation and deficiency of ADAMTS13 activity and the rare cases of clopidogrel-associated TTP are not responsive to therapeutic plasma exchange. Also, very little is known about TTP associated with prasugrel (the newest thienopyridine), despite 14 cases of prasugrel-associated TTP having been reported to the Food and Drug Administration in 2009 and 2010 (Jacob et al, 2012). Careful pharmacovigilance to identify severe adverse drug reactions developing among small numbers of persons can serve as important warning signals for potentially serious adverse drug events internationally.

Musculoskeletal Safety Outcomes of Patients Receiving Daptomycin with HMG-CoA Reductase Inhibitors

ABSTRACT Daptomycin, a cyclic lipopeptide antibiotic, and 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly administered in the inpatient setting and are associated with creatine phosphokinase (CPK) elevations, myalgias, and muscle weakness. Safety data for coadministration of daptomycin with statins are limited. To determine the safety of coadministration of daptomycin with statin therapy, a multicenter, retrospective, observational study was performed at 13 institutions in the Southeastern United States. Forty-nine adult patients receiving statins concurrently with daptomycin were compared with 171 patients receiving daptomycin without statin therapy. Detailed information, including treatment indication and duration, infecting pathogen, baseline and subsequent CPK levels, and presence of myalgias or muscle complaints, was collected. Myalgias were noted in 3/49 (6.1%) patients receiving combination therapy compared with 5/171 (2.9%) of patients receiving daptomycin alone (P = 0.38). CPK elevations of >1,000 U/liter occurred in 5/49 (10.2%) patients receiving combination therapy compared to 9/171 (5.3%) patients receiving daptomycin alone (P = 0.32). Two of five patients experiencing CPK elevations of >1,000 U/liter in the combination group had symptoms of myopathy. Three patients (6.1%) discontinued therapy due to CPK elevations with concurrent myalgias in the combination group versus 6 patients (3.5%) in the daptomycin-alone group (P = 0.42). CPK levels and myalgias reversed upon discontinuation of daptomycin therapy. Overall musculoskeletal toxicity was numerically higher in the combination group but this result was not statistically significant. Further prospective study is warranted in a larger population.

Incorporating Standardized Colleague Simulations in a Clinical Assessment Course and Evaluating the Impact on Interprofessional Communication

Objective. To determine the impact of incorporating standardized colleague simulations on pharmacy students’ confidence and interprofessional communication skills. Design. Four simulations using standardized colleagues portraying attending physicians in inpatient and outpatient settings were integrated into a required course. Pharmacy students interacted with the standardized colleagues using the Situation, Background, Assessment, Request/Recommendation (SBAR) communication technique and were evaluated on providing recommendations while on simulated inpatient rounds and in an outpatient clinic. Additionally, changes in student attitudes and confidence toward interprofessional communication were assessed with a survey before and after the standardized colleague simulations. Assessment. One hundred seventy-one pharmacy students participated in the simulations. Student interprofessional communication skills improved after each simulation. Student confidence with interprofessional communication in both inpatient and outpatient settings significantly improved. Conclusion. Incorporation of simulations using standardized colleagues improves interprofessional communication skills and self-confidence of pharmacy students.

Topical thrombin preparations and their use in cardiac surgery

Coagulopathic bleeding may lead to increased morbidity and mortality after cardiac surgery. Topical bovine thrombin has been used to promote hemostasis after surgical procedures for over 60 years and is used frequently as a topical hemostatic agent in cardiac surgery. Recently, use of bovine thrombin has been reported to be associated with increased risk for anaphylaxis, thrombosis, and immune-mediated coagulopathy thought secondary to the production of antifactor V and antithrombin antibodies. In patients who develop bovine thrombin-induced immune-mediated coagulopathy, clinical manifestations may range from asymptomatic altera- tions in coagulation tests to severe hemorrhage and death. Patients undergoing cardiac surgical procedures may be at increased risk for development of antibodies to bovine thrombin products and associated complications. This adverse immunologic profile has led to the development of alternative preparations including a human and a recombinant thrombin which have been shown to be equally efficacious to bovine thrombin and have reduced antigenicity. However, the potential benefit associated with reduced antigenicity is not truly known secondary to the lack of long-term experience with these products. Given the potentially higher margin of safety and less stringent storage concerns compared to human thrombin, recombinant thrombin may be the most reasonable approach in cardiac surgery.

Perceived Motivating Factors and Barriers for the Completion of Postgraduate Training Among American Pharmacy Students Prior to Beginning Advanced Pharmacy Practice Experiences

Objective. To examine perceived motivating factors and barriers (MFB) to postgraduate training (PGT) pursuit among pharmacy students. Methods. Third-year pharmacy students at 13 schools of pharmacy provided demographics and their plan and perceived MFBs for pursuing PGT. Responses were characterized using descriptive statistics. Kruskal-Wallis equality-of-proportions rank tests determined if differences in perceived MFBs existed between students based on plan to pursue PGT. Results. Among 1218 (69.5%) respondents, 37.1% planned to pursue PGT (32.9% did not, 30% were undecided). Students introduced to PGT prior to beginning pharmacy school more frequently planned to pursue PGT. More students who planned to pursue PGT had hospital work experience. The primary PGT rationale was, “I desire to gain more knowledge and experience.” Student debt was the most commonly cited barrier. Conclusion. Introducing pharmacy students early to PGT options and establishing work experiences in the hospital setting may increase students’ desire to pursue PGT.

Examining collaborative leadership through interprofessional education: findings from a mixed methods study

ABSTRACT Collaborative leadership is essential as recent trends in healthcare service delivery necessitate interprofessional collaboration and care. Interprofessional education (IPE) efforts, therefore, have to prepare students for this type of leadership. The purpose of this study was to understand how students’ perceptions of leadership change as a result of embedding a collaborative leadership model, the Social Change Model (SCM) of leadership, in an IPE course. Data were collected from 30 students participating in an interprofessional course through two interprofessional course reflections, pre/post leadership posters and poster reflections, and a pre/post survey. Results from paired sample t-tests suggested students significantly improved in their perceptions of leadership efficacy. These data also indicated improvements to the three group-level values of the SCM: collaboration, common purpose, and controversy with civility. Findings from the qualitative data suggest that students learned to view leadership as more of a team effort than the actions of a single individual and as more of a process than a role. Findings also revealed the benefits and challenges of using a visual process of poster development as a way of examining students’ changes in perceptions of leadership over the course of the semester. Implications are discussed in relationship to the utility of the SCM in promoting students’ shifts in conceptualizations of leadership that emphasizes collaboration and helps prepare students to engage in these ways within interprofessional teams in their practice.

Evaluating the perceived impact of an interprofessional childhood obesity course on competencies for collaborative practice

ABSTRACT Interprofessional education (IPE) is needed to prepare health professional students to address the complexities of childhood obesity in practice. This mixed-method study sought to evaluate the perceived impact of a childhood obesity IPE intervention on health professional students’ collaborative competency development within two domains: roles/responsibilities and teams/teamwork. Fourteen health professional students participated in this mixed-methods study. Quantitative data were collected through pre/post surveys, while qualitative data were collected through reflection assignments. Survey findings indicated that students reported significant increases in growth within both interprofessional competency domains. Qualitative data elaborated on the types of learning students experienced relative to each domain. Implications of this study for research and practice related to IPE to address complex health issues, such as childhood obesity, are shared.

What are the latest recommendations for managing severe sepsis and septic shock

ABSTRACTSevere sepsis is a continuum of physiologic stages characterized by infection, systemic inflammation, and hypoperfusion leading to tissue injury and organ failure. The primary goal of sepsis treatment is to prevent morbidity and mortality. Crystalloids are now recommended over colloids for volume resuscitation, one of the key interventions for patients with sepsis.