Perfluorocarbons cause thrombocytopenia, changes in RBC morphology and death in a baboon model of systemic inflammation.

A perfluorocarbon (PFC) investigated for treatment of traumatic brain injury (TBI) delivers oxygen to support brain function, but causes transient thrombocytopenia. TBI can cause acute inflammation with resulting thrombocytopenia; an interaction between the PFC effects and TBI inflammation might exacerbate thrombocytopenia. Therefore, PFC effects on platelet (PLT) function and hemostasis in a lipopolysaccharide (LPS) model of inflammation in the baboon were studied. Animals were randomized to receive saline ±LPS, and ± one of two doses of PFC. PLT count, transmission electron microscopy, and microparticle populations were quantified at baseline (BL) and at 2, 24, 48, 72, and 96 hours; hemostatic parameters for aggregometry and for blood clotting were measured at baseline (BL) and days 3 and 4. Injection of vehicle and LPS caused thrombocytopenia within hours; PFCs caused delayed thrombocytopenia beginning 48 hours post-infusion. LPS+PFC produced a more prolonged PLT decline and decreased clot strength. LPS+PFC increased ADP-stimulated aggregation, but PFC alone did not. Microparticle abundance was greatest in the LPS+PFC groups. LPS+PFC caused diffuse microvascular hemorrhage and death in 2 of 5 baboons in the low dose LPS-PFC group and 2 of 2 in the high dose LPS-PFC group. Necropsy and histology suggested death was caused by shock associated with hemorrhage in multiple organs. Abnormal morphology of platelets and red blood cells were notable for PFC inclusions. In summary, PFC infusion caused clinically significant thrombocytopenia and exacerbated LPS-induced platelet activation. The interaction between these effects resulted in decreased hemostatic capacity, diffuse bleeding, shock and death.

Evidence of vaccinia dissemination despite lack of major reaction following smallpox vaccination.

Following vaccinia vaccination, vesicle formation at the site occurs in 95% of primary vaccinees and is thought to indicate virus replication and vaccine efficacy. Little is known about virus replication and immune response in those who do not develop a vesicle. We used PCR to detect vaccinia in various sites following receipt of the smallpox vaccine in those with and without vesicle formation. Among 80 participants, 74 developed and 6 failed to develop a vesicle. Vaccinia DNA was detected in the blood, in the oropharynx, on the dressing, and on the hands of 5%, 11%, 4%, and 0% of those with vesicle formation and of 33%, 17%, 0%, and 17% of those without vesicle formation, respectively (p > 0.05 for each site). The detection of systemic vaccinia DNA in vaccinees without vesicle formation challenges the current understanding that lack of vesicle formation indicates lack of virus replication, the prerequisite to immune response.

Similar hemostatic responses to hypovolemia induced by hemorrhage and lower body negative pressure reveal a hyperfibrinolytic subset of non-human primates.

BACKGROUND: To study central hypovolemia in humans, lower body negative pressure (LBNP) is a recognized alternative to blood removal (HEM). While LBNP mimics the cardiovascular responses of HEM in baboons, similarities in hemostatic responses to LBNP and HEM remain unknown in this species. METHODS: Thirteen anesthetized baboons were exposed to progressive hypovolemia by HEM and, four weeks later, by LBNP. Hemostatic activity was evaluated by plasma markers, thromboelastography (TEG), flow cytometry, and platelet aggregometry at baseline (BL), during and after hypovolemia. RESULTS: BL values were indistinguishable for most parameters although platelet count, maximal clot strength (MA), protein C, thrombin anti-thrombin complex (TAT), thrombin activatable fibrinolysis inhibitor (TAFI) activity significantly differed between HEM and LBNP. Central hypovolemia induced by either method activated coagulation; TEG R-time decreased and MA increased during and after hypovolemia compared to BL. Platelets displayed activation by flow cytometry; platelet count and functional aggregometry were unchanged. TAFI activity and protein, Factors V and VIII, vWF, Proteins C and S all demonstrated hemodilution during HEM and hemoconcentration during LBNP, whereas tissue plasminogen activator (tPA), plasmin/anti-plasmin complex, and plasminogen activator inhibitor-1 did not. Fibrinolysis (TEG LY30) was unchanged by either method; however, at BL, fibrinolysis varied greatly. Post-hoc analysis separated baboons into low-lysis (LY30 <2%) or high-lysis (LY30 >2%) whose fibrinolytic state matched at both HEM and LBNP BL. In high-lysis, BL tPA and LY30 correlated strongly (r = 0.95; P<0.001), but this was absent in low-lysis. In low-lysis, BL TAFI activity and tPA correlated (r = 0.88; P<0.050), but this was absent in high-lysis. CONCLUSIONS: Central hypovolemia induced by either LBNP or HEM resulted in activation of coagulation; thus, LBNP is an adjunct to study hemorrhage-induced pro-coagulation in baboons. Furthermore, this study revealed a subset of baboons with baseline hyperfibrinolysis, which was strongly coupled to tPA and uncoupled from TAFI activity.

Implementing a Multidisciplinary Approach to Enhance Compliance With Guideline-Recommended Prechemotherapy Pneumococcal Vaccination in a Military-Based Medical Oncology Practice.

PURPOSE: Patients with cancer are at increased risk for invasive pneumococcal disease, including community-acquired pneumonia. Current Advisory Committee on Immunization Practices and National Cancer Comprehensive Network guidelines recommend pneumococcal vaccination for immunocompromised patients, including patients with cancer. METHODS: We conducted a quality improvement (QI) project to enhance compliance with pneumococcal vaccination in patients before their chemotherapy. Baseline pneumococcal vaccination rates were gathered from July 2013 to June 2014. We reviewed the current guidelines for pneumococcal vaccinations in patients with cancer with physicians and encouraged them to prescribe the pneumococcal vaccination to patients before therapy. We also recruited our clinic nurse practitioner, who meets all patients for chemotherapy teaching, to prescribe the vaccine to patients younger than 65 years of age. RESULTS: During the baseline period, of the 110 patients younger than 65 years who received chemotherapy, seven (6.4%) received the pneumococcal vaccine. Of the 90 patients (median age, 60 years; range, 20 to 86 years) who received chemotherapy during the study period, 58 were younger than 65 years, of whom three patients were already vaccinated before their diagnosis. Twenty-five (45.5%) patients were vaccinated through our QI project. We have improved our compliance with pneumococcal vaccination by 39% ( P < .001). CONCLUSION: We have improved compliance with pneumococcal vaccination in patients with cancer receiving chemotherapy in our clinic through a QI project. We found that screening is best accomplished by a single person who is able to screen all patients. This practice is now a standard of care in our clinic.

Novel Brentuximab Vedotin Combination Therapies Show Promising Activity in Highly Refractory CD30+ Non-Hodgkin Lymphoma: A Case Series and Review of the Literature.

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of hematologic malignancies which typically respond to standard first-line chemoimmunotherapy regimens. Unfortunately, patients with refractory NHL face a poor prognosis and represent an unmet need for improved therapeutics. We present two cases of refractory CD30+ NHL who responded to novel brentuximab vedotin- (BV-) based regimens. The first is a patient with stage IV anaplastic large cell lymphoma (ALCL) with cranial nerve involvement who failed front-line treatment with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) and second line cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate (MTX), and cytarabine (hyperCVAD) with intrathecal- (IT-) MTX and IT-cytarabine, but responded when BV was substituted for vincristine (hyperCBAD). The second patient was a man with stage IV diffuse large B-cell lymphoma (DLBCL) with leptomeningeal involvement whose disease progressed during first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and progressed despite salvage therapy with rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) in whom addition of BV to topotecan resulted in a significant response. This report describes the first successful salvage treatments of highly aggressive, double refractory CD30+ NHL using two unreported BV-based chemoimmunotherapy regimens. Both regimens appear effective and have manageable toxicities. Further clinical trials assessing novel BV combinations are warranted.