Protein S antibody as an adjunct therapy for hemophilia B.

ABSTRACT: Hemophilia B (HB) is caused by an inherited deficiency of plasma coagulation factor IX (FIX). Approximately 60% of pediatric patients with HB possess a severe form of FIX deficiency (<1% FIX activity). Treatment typically requires replacement therapy through the administration of FIX. However, exogenous FIX has a limited functional half-life, and the natural anticoagulant protein S (PS) inhibits activated FIX (FIXa). PS ultimately limits thrombin formation, which limits plasma coagulation. This regulation of FIXa activity by PS led us to test whether inhibiting PS would extend the functional half-life of FIX and thereby prolong FIX-based HB therapy. We assayed clotting times and thrombin generation to measure the efficacy of a PS antibody for increasing FIX activity in commercially obtained plasma and plasma from pediatric patients with HB. We included 11 pediatric patients who lacked additional comorbidities and coagulopathies. In vivo, we assessed thrombus formation in HB mice in the presence of the FIXa ± PS antibody. We found an accelerated rate of clotting in the presence of PS antibody. Similarly, the peak thrombin formed was significantly greater in the presence of the PS antibody, even in plasma from patients with severe HB. Furthermore, HB mice injected with PS antibody and FIX had a 4.5-fold higher accumulation of fibrin at the thrombus induction site compared with mice injected with FIX alone. Our findings imply that a PS antibody would be a valuable adjunct to increase the effectiveness of FIX replacement therapy in pediatric patients who have mild, moderate, and severe HB.

Modulation of protein S and growth arrest specific 6 protein signaling inhibits pancreatic cancer cell survival and proliferation.

Thrombotic complications and hypercoagulopathies are commonly associated with the progression of pancreatic ductal adenocarcinoma (PDAC). Although the mechanistic link between the two phenomena is uncertain, there is evidently an increase in procoagulant proteins and a decrease in anticoagulants in PDAC patients. For example, the anticoagulant protein S (PS) is decreased during the progression of PDAC, a condition that possibly contributes to the hypercoagulopathies. PS is also an important signaling molecule that binds a family of tyrosine kinase receptors known as TAM (Tyro3, Axl and Mer) receptors; TAM receptors are often upregulated in different cancers. Growth Arrest Specific 6 or GAS6 protein, a homolog of PS, is also a TAM receptor family ligand. The downstream signaling pathways triggered by this ligand­receptor interaction perform diverse functions, such as cell survival, proliferation, efferocytosis, and apoptosis. Targeting the TAM receptors to treat cancer has had limited success; side effects are a significant obstacle due to the widespread numerous functions of TAM receptors. In the present study, it was revealed that PS­TAM interaction was pro­apoptotic, whereas GAS6­mediated TAM signaling promoted proliferation and survival in select PDAC cell lines. Furthermore, by regulating the balance between these two signaling pathways (by overexpressing PS or knocking down GAS6), the proliferative potential of the cells was decreased. Both long­term and short­term effects of natural PS overexpression were comparable to the treatment of the cells with the drug UNC2025, which inhibits the Mer­receptor. The present study lays the foundation for investigation of PS as a therapeutic agent to control cancer progression and to concurrently arrest thrombotic events.

Factor VIII in the setting of acute ischemic stroke among patients with suspected hypercoagulable state.

BACKGROUND: Elevation of factor VIII is associated with higher risk of large vessel arterial occlusions including stroke. METHODS: Factor VIII levels were examined in consecutive patients with acute ischemic stroke (AIS) presenting to a single center between July 2008 and May 2012. Factor VIII levels exceeding the laboratory reference range were considered elevated (>150%). RESULTS: Factor VIII level was elevated in 72.4% (84 of 116) of the patients. Elevated factor VIII level was more frequent in blacks, diabetics, and patients who were anemic. Patients with elevated factor VIII had higher median baseline National Institute of Health Stroke Scale (NIHSS; 5 vs 2, P = .0295) and twice the frequency of neuroworsening (21.4% vs 9.4%), but discharge NIHSS and modified Rankin Scale were similar in the groups. CONCLUSIONS: High factor VIII level was found in the majority of tested patients with AIS. Several baseline differences were found between patients with normal and high factor VIII levels, but no differences were identified in outcome.

Infections present on admission compared with hospital-acquired infections in acute ischemic stroke patients.

BACKGROUND: To date, few studies have assessed the influence of infections present on admission (POA) compared with hospital-acquired infections (HAIs) on neurologic deterioration (ND) and other outcome measures in acute ischemic stroke (AIS). METHODS: Patients admitted with AIS to our stroke center (July 2010 to December 2010) were retrospectively assessed. The following infections were assessed: urinary tract infection, pneumonia, and bacteremia. Additional chart review was performed to determine whether the infection was POA or HAI. We assessed the relationship between infections in ischemic stroke patients and several outcome measures including ND and poor functional outcome. A mediation analysis was performed to assess the indirect effects of HAI, ND, and poor functional outcome. RESULTS: Of the 334 patients included in this study, 77 had any type of infection (23 POA). After adjusting for age, National Institutes of Health Stroke Scale at baseline, glucose on admission, and intravenous tissue plasminogen activator, HAI remained a significant predictor of ND (odds ratio [OR]=8.8, 95% confidence interval [CI]: 4.2-18.7, P<.0001) and poor functional outcome (OR=41.7, 95% CI: 5.2-337.9, P=.005), whereas infections POA were no longer associated with ND or poor functional outcome. In an adjusted analysis, we found that 57% of the effect from HAI infections on poor functional outcome is because of mediation through ND (P<.0001). CONCLUSIONS: Our data suggests that HAI in AIS patients increases the odds of experiencing ND and subsequently increases the odds of being discharged with significant disability. This mediated effect suggests a preventable cause of ND that can thereby decrease the odds of poor functional outcomes after an AIS.

A comprehensive stroke center patient registry: advantages, limitations, and lessons learned.

INTRODUCTION: The use of a medical data registry allows institutions to effectively manage information for many different investigations related to the registry, as well as evaluate patient's trends over time, with the ultimate goal of recognizing trends that may improve outcomes in a particular patient population. METHODS: The purpose of this article is to illustrate our experience with a stroke patient registry at a comprehensive stroke center and highlight advantages, disadvantages, and lessons learned in the process of designing, implementing, and maintaining a stroke registry. We detail the process of stroke registry methodology, common data element (CDE) definitions, the generation of manuscripts from a registry, and the limitations. ADVANTAGES: The largest advantage of a registry is the ability to prospectively add patients, while allowing investigators to go back and collect information retrospectively if needed. The continuous addition of new patients increases the sample size of studies from year to year, and it also allows reflection on clinical practices from previous years and the ability to investigate trends in patient management over time. LIMITATIONS: The greatest limitation in this registry pertains to our single-entry technique where multiple sites of data entry and transfer may generate errors within the registry. LESSONS LEARNED: To reduce the potential for errors and maximize the accuracy and efficiency of the registry, we invest significant time in training competent registry users and project leaders. With effective training and transition of leadership positions, which are continuous and evolving processes, we have attempted to optimize our clinical research registry for knowledge gain and quality improvement at our center.