Charles Knupp

A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

BackgroundPlatelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study.MethodsThe primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients.ResultsThere were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events.ConclusionsDespite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.

Sleep disorders in adult sickle cell patients.

STUDY OBJECTIVES While sleep apnea has been studied in children with sickle cell disease (SCD), little is known about sleep disorders in adult sickle cell patients. The objective of this study was to evaluate sleep disordered breathing and its polysomnographic characteristics in adult patients with sickle cell disease. METHODS The analysis cohort included 32 consecutive adult SCD patients who underwent a comprehensive sleep evaluation and overnight polysomnography in an accredited sleep center after reporting symptoms suggesting disordered sleep or an Epworth Sleepiness Scale score ≥ 10. Epworth score, sleep parameters, comorbid conditions, and narcotic use were reviewed and compared in patients with and without sleep disordered breathing. SCD complication rates in the two groups also were compared. RESULTS In adult SCD patients who underwent overnight polysomnography, we report a high prevalence (44%) of sleep disordered breathing. Disease severity was mild to moderate (mean apnea-hypopnea index = 17/h (95% CI: 10-24/h). Concomitant sleep disorders, including insomnia complaints (57%) and delayed sleep-phase syndrome (57%), also were common in this population. In this limited cohort, we did not find increased SCD complications associated with sleep disordered breathing in adult patients with sickle cell disease. CONCLUSIONS A high burden of sleep disordered breathing and other sleep-related complaints were identified in the adult sickle cell population. Our results provide important information on this unique population.

Outbreak of Mycobacterium mucogenicum bloodstream infections among patients with sickle cell disease in an outpatient setting.

OBJECTIVE To study an outbreak of Mycobacterium mucogenicum bloodstream infections in an outpatient setting. DESIGN Outbreak investigation and retrospective chart review. SETTING University outpatient clinic. Patients. Patients whose blood cultures tested positive for M. mucogenicum in May or June 2008. METHODS An outbreak investigation and a review of infection control practices were conducted. During the process, environmental culture samples were obtained. Isolates from patients and the environment were genotyped with the DiversiLab typing system to identify the source. Chart reviews were conducted to study the management and outcomes of the patients. RESULTS Four patients with sickle cell disease and implanted ports followed in the same hematology outpatient clinic developed blood cultures positive for M. mucogenicum. A nurse in the clinic had prepared intravenous port flushes on the sink counter, using a saline bag that was hanging over the sink throughout the shift. None of the environmental cultures grew M. mucogenicum except for the tap water from 2 rooms, 1 of which had a faucet aerator. The 4 patient isolates and the tap water isolate from the room with the aerator were found to have greater than 98.5% similarity. The subcutaneous ports were removed, and patients cleared their infections after a course of antibiotic therapy. CONCLUSION The source of the M. mucogenicum bacteremia outbreak was identified by genotyping analysis as the clinic tap water supply. The preparation of intravenous medications near the sink was likely an important factor in transmission, along with the presence of a faucet aerator.

Effect of thrombin inhibitors on thrombin-induced platelet release and aggregation.

Thrombin-induced platelet activation was interrupted with hirudin or Dansylarginine N-(3-ethyl-1-5-pentanediyl) amide (DAPA) to study the time requirement for receptor occupancy by thrombin in promoting platelet responses at low (0.25 U/ml), intermediate (0.5 U/ml) and high (1 U/ml) thrombin concentrations. Each of these thrombin inhibitors suppressed adenosine triphosphate (ATP) release and aggregation by thrombin when added either before or simultaneously with thrombin or within seconds of the initiation of these responses by thrombin. If the inhibitors were added later, yet before aggregation or release was complete, no effect was present. The period of time for which active thrombin was required in order to promote these reactions had the following characteristics: (i) it is thrombin concentration dependent for a given response; (ii) it is longer for aggregation than for ATP secretion at each thrombin concentration; (iii) it is increased in platelets modified by chymotrypsin or platelets partially inhibited by antimycin A and 2-deoxy-D-glucose, which have prolonged aggregation and ATP release responses. In direct comparison studies, the inhibitory effects of hirudin and DAPA were identical on aggregation and ATP release. Thrombin binding, under similar experimental conditions identical to those used to measure platelet activation, was prevented by hirudin, but not by DAPA. Therefore, the effect of DAPA on thrombin must be at the proteolytic site region and not at the hirudin-inhibitable platelet binding region. It is concluded from these studies that the tight coupling requirements for thrombin to induce platelet dense granule release and aggregation are directly dependent upon both the thrombin concentration and the rate of the individual platelet responses. Catalytic site integrity is required for the duration of this period of receptor occupancy.

Edmonton symptom assessment system for outpatient symptom monitoring of sickle cell disease

Objectives Although the extension of palliative care methodology to sickle cell disease (SCD) care has been proposed, there is no current standard for symptom assessment. Our goal was to assess the feasibility of integrating the Edmonton Symptom Assessment System (ESAS) into the outpatient management of SCD. Methods Seventy-five adult patients presenting for outpatient visits at a comprehensive SCD center were enrolled. Patients completed the ESAS (self-report of 10 symptoms during the last 24 hours) and a survey regarding their opinion of the ESAS at enrollment and follow-up. Results Pain (P = 0.0272) was the only symptom score that changed significantly between the initial and follow-up visits. In patients with a self-reported pain crisis, pain (P < 0.0001), fatigue (P = 0.0025), depression (P = 0.0458), nausea (P = 0.0384), and symptom distress scores (P = 0.0019) were significantly higher than for patients without a pain crisis. On the initial visit, 92% of all patients agreed or strongly agreed that the ESAS was easy to complete; 83% were satisfied or very satisfied with the ESAS as a way to report symptoms. Conclusions Our data suggest that the ESAS is well received and can be successfully included as part of the longitudinal symptom management strategy for SCD.

Pulmonary artery occlusion pressure may overdiagnose pulmonary artery hypertension in sickle cell disease.

A high prevalence of Pulmonary Hypertension (PH) in sickle cell disease (SCD) has been reported in several studies. However, few studies that describe the hemodynamics have actually measured pulmonary artery occlusive pressure (PAOP). Furthermore, even PAOP has been shown to be unreliable in discriminating pulmonary artery hypertension from pulmonary venous hypertension. We prospectively examined the accuracy of PAOP using simultaneous left ventricular end diastolic pressure (LVEDP) measurement as the gold standard.

Pulse Infusion Interleukin-2 with Famotidine and Cyclophosphamide Has Activity in Previously Treated Metastatic Melanoma

There is no established systemic therapy for patients with stage IV melanoma refractory to prior systemic treatment. Interleukin-2 (IL-2) is capable of inducing T-lymphocyte cytotoxicity against melanoma in vitro and in vivo. Famotidine may enhance the activity of T-cells further by allowing for increased IL-2 internalization by the IL-2 receptor on lymphocytes. Cyclophosphamide may decrease the immunosuppressive effects of regulatory T-cells. Daily short intravenous (i.v.) infusions (pulses) of IL-2 were used to treat 14 patients with metastatic melanoma, all of whom had experienced disease progression despite prior systemic therapy. The patients received 21.6 million IU/m(2) of pulse IL-2 i.v. for 15-30 minutes, preceded by 20 mg of famotidine i.v. (13) patients received 350 mg/m(2) of cyclophosphamide i.v. on day 1 (1 patient did not). Eight (8) patients were treated in an oncology inpatient unit while, most recently, 6 patients have received therapy on an outpatient basis. The cycles were repeated every 3 weeks until disease progression occurred. The patients included 10 males with a median age of 56 (range 31-87) with an Eastern Cooperative Oncology Group performance status of -1 (range 0 - -1). Common metastatice sites included lymph nodes (13), lungs (8), liver (4), and subcutaneous (4). Prior systemic therapy included IL-2 (11), interferon (7), and chemotherapy (7). The median number of cycles the patients underwent was 3 with a range of 1-7. The most common toxic reactions were fever, rigors, nausea/emesis, hypomagnesemia, and hypophosphatemia. One complete response and four partial responses were observed (response rate, 36%; 95% confidence interval: 14%-64%). Responses occurred in the lungs, liver, lymph nodes, and subcutaneous sites. The median response duration was 3.4 months, with a median survival of 8.3 months for the entire group. Six (6) patients remain alive with a median survival of 10.3 months. Pulse IL-2 with famotidine and cyclophosphamide produced activity in previously treated patients with melanoma and may be given on an outpatient basis to selected individuals.

Opioid Induced Sleep Disordered Breathing in Sickle Cell Patient

Opioid Induced Sleep Disordered Breathing in Sickle Cell Patient Chronic opioid use is a risk factor for sleep disordered breathing (SDB) like obstructive sleep apnea (OSA), Biot’s or ataxic breathing, central sleep apnea and sleep related hypoventilation. Withdrawal of opioids may be the optimal management but it is not always feasible. Continuous positive airway pressure (CPAP) therapy, which is effective treatment for OSA, may not resolve central events. Opioid induced sleep disordered breathing has been described mostly in patients with chronic back pain on narcotics. We present a case of sickle cell disease who is a 37 year old male on short and long acting Morphine presenting with excessive daytime sleepiness, fatigue and memory loss. Baseline nocturnal polysomnography (NPSG) showed central sleep apnea (Biot’s breathing) with AHI of 27. After initial failure of CPAP, ASV at IPAPmax/ EPAPmin (inspiratory and expiratory positive airway pressures) of 25/7 cm of H2O with a pressure support setting of 0-15 and auto back-up rate was applied with complete resolution of Biot’s breathing and symptoms. This case highlights the increased risk of central sleep apnea induced by opioids in a population with improving life expectancy and chronic use of narcotics. It also adds to the small but growing body of evidence suggesting the beneficial role of ASV in opioid induced sleep disordered breathing where narcotics /opioids cannot be discontinued.

The interaction of thrombin with platelet protease nexin

Thrombin interacts with a platelet protein which is immunologically related to fibroblast protease nexin and has been termed platelet protease nexin I (PNI). Conflicting hypotheses about the relationship of the thrombin-PNI complex formation to platelet activation have been proposed. The studies presented here demonstrate that the platelet-associated and supernatant complexes with added 125I-thrombin are formed only under conditions which produce platelet activation in normal and chymotrypsin-modified platelets. The platelet-associated complex is formed prior to the appearance of complexes in supernatants. Appearance of the supernatant complex coincides with the appearance of thrombospondin in the reaction supernatants. Excess native thrombin, dansylarginine N-(3-ethyl-1,5-pentanediyl) amide or hirudin can prevent radiolabeled platelet-associated complex formation if added before 125I-thrombin. DAPA or hirudin can prevent or dissociate complex formation if added up to one minute after thrombin but not at later time points. The surface associated complex is accessible to trypsin although a portion remains with the cytoskeletal proteins when thrombin-activated platelets are solubilized with Triton X 100. The surface-associated complex formation parallels many aspects of the specific measurable thrombin binding, yet it does not appear to involve other identified surface glycoprotein thrombin receptors or substrates. Although the time course of appearance of the complexes in supernatants is consistent with other data which suggest that PNI may be released from platelet granules during platelet activation, other explanations for the appearance of PNI on the platelet surface and in supernatants during platelet activation are possible.

Daytime pulse oximetry measurements may not predict nocturnal desaturations in adult sickle cell patients

Dear Editor, Sickle cell disease (SCD) is an autosomal recessive genetic blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape [1]. In pediatric SCD, the frequency of transient 15–30-s duration episodes of hypoxia during sleep correlated with the frequency of painful sickle cell crisis [2]. Nocturnal desaturation has been described in pediatric patients with sickle cell disease, with a prevalence of up to 40 % in children and adolescents [3]. Whether nocturnal hypoxemia has similar prevalence and impact on an adult SCD population is not known. Up to 40 % of adults with sickle cell disease have sudden death events without any detectable cause found at autopsy [4]. Nocturnal hypoxemia may contribute to these events and contribute to this reduced survival either acutely or chronically. Prior studies have revealed that pulse oximetry is a reliable tool in assessing patients with and without sickle cell disease [5, 10]. The charts of all patients with SCD referred to the pulmonary clinic from the Adult Comprehensive Sickle Cell program at the Brody School of Medicine from March 2010 to April 2011 were reviewed. The study design was reviewed and approved by the IRB at East Carolina University. Patient’s oxygen saturations were measured by either overnight continuous pulse oximetry or with overnight polysomnography according to our standard protocol. Controls were 20 consecutive patients without SSD who had undergone sleep studies at our sleep center and who had resting oxygen saturations of ≥95 % with no underlying cardiopulmonary disease or obstructive sleep apnea (OSA). Medical charts from 43 consecutive adult SCD patients were analyzed. Eight patients were excluded because of incomplete data. The mean age was 38.9 years, and female-to-male ratio 2:1 with mean hemoglobin of 8.7 gm/dL. Of the total 35 patients with nocturnal pulse oximeter data, 16 were found to have nocturnal desaturation (45.7 %). Of the 25 patients with normal daytime oxygen saturation at rest (95 % or greater), nine (36 %) were found to have nocturnal desaturation compared to seven of ten patients (70 %) who had low daytime saturation (p=0.13) The control group (n=20) consisting of consecutive patients without SCD who had a resting daytime saturation of ≥95 % showed no nocturnal desaturations when compared with the SCD (0 vs 36 %) (p=0.0025). The mean age of control group was 45.7 years (SD, 13.2) with 13 women (65 %) with a mean BMI of 32.6. The group of SCD patients who demonstrated significant nocturnal oxygen desaturations was compared with the group without significant nocturnal oxygen desaturations. There were no statistically significant demographic or clinical differences (see Table 1) Out of the 35 patients, 31 patients had overnight polysomnography. The group which had nocturnal desaturations had a significantly higher apnea–hypopnea index compared to the group without nocturnal desaturations.(14 vs 4) (p=0.01).Clinical outcomes such as total and nighttime crises, pain medication use, insomnia, hospital admissions, and emergency department visits were not statistically different between these two groups Our study evaluated the relationship of day and night oxygen saturations in a cohort of adult SCD patients. Adult SCD patients referred to the pulmonary clinic had a high H. Mehta : J. T. Efird :R. A. Kadali : P. Boettger :D. Liles : C. Knupp Brody School of Medicine, East Carolina University, 3E-149, Brody medical sciences building, Greenville, NC 28590, USA