Platelet dysfunction in critically ill patients.

: Thrombelastography Platelet Mapping (TEG-PM) allows for measurement of maximal potential clot strength (MA) and strength from stimulation of arachidonic acid (MA-AA) and adenosine disphosphate (MA-ADP) receptors. This study was conducted to assess degree of platelet dysfunction in critically ill adult patients. A retrospective study of critically ill, adult, nontrauma patients in a medical/surgical ICU was conducted from August 2013 to September 2014. All patients who underwent TEG-PM were enrolled. Patients with intracerebral hemorrhage, following cardiac surgery, or without an APACHE II score were excluded. Patients were divided into those with and without aspirin use. Demographics, APACHE II score, and laboratory results were abstracted. Student t test was used to test significance. A total of 79 patients were enrolled (61% male). Average age and APACHE II score were 61 ±â€Š16 years and 18 ±â€Š9, respectively. Factor-associated coagulation measures and MA were normal in all groups but MA-AA and MA-ADP were significantly reduced irrespective of anticoagulant use. Compared to the nonanticoagulated cohort, MA-AA was significantly reduced in those on aspirin. There was no difference in mortality or length of stay in any cohort. Inhibition of the AA and ADP pathways is common in critically ill patients. Clinical correlation with propensity for bleeding and need for transfusion requires further assessment.

Inhibition of platelet function is common following even minor injury.

BACKGROUND: Hemorrhage remains the leading cause of preventable death following injury. Whereas significant attention has been paid to the coagulation cascade, there are fewer studies evaluating platelet dysfunction following injury. Thrombelastogram platelet mapping (TEG-PM) allows for the measurement of maximal potential clot strength and clot strength selectively caused by arachidonic acid and adenosine disphosphate receptors on the platelet. The purpose of this study was to determine the incidence and magnitude of receptor-specific platelet dysfunction following injury in patients who are not otherwise pharmacologically anticoagulated. METHODS: A retrospective study of adult trauma patients evaluated at a Level I trauma center from August 2013 to September 2014 was conducted. Platelet function was assessed using TEG-PM. Patients on any anticoagulant or antiplatelet medication were excluded. Patients were divided into those with and without radiographically evident traumatic brain injury (TBI). Demographic variables, Injury Severity Score (ISS), injury pattern, laboratory test results, and mortality were abstracted. Statistical comparisons were made using the Student's t test or Mann-Whitney U-test. RESULTS: The study includes 459 patients, 92% following blunt injury. Median ISS was 5. Patients with TBI (n = 102) were significantly older (median age, 54 years vs. 35 years), were more severely injured (median ISS, 10 vs. 4), had a longer stay and higher mortality (9% vs. 0.3%). Maximal potential clot strength was normal in all cohorts, but the arachidonic acid and adenosine diphosphate pathways were significantly inhibited (30% ± 26% and 58% ± 27%, respectively). There was no correlation between TEG-PM values and ISS, length of stay, or mortality. There was no difference in the TBI cohort. There were no significant differences in TEG-PM parameters in those with an ISS greater than 14. There was no significant change in TEG-PM following platelet transfusion. CONCLUSION: Marked platelet inhibition is common following minor injury. Whereas the clinical significance of this finding remains unknown, the results of this study should be factored in the overall resuscitative strategy. LEVEL OF EVIDENCE: Prognostic/epidemiogic study, level III.

Whole blood platelet aggregation and release reaction testing in uremic patients.

BACKGROUND: Platelet function analysis utilizing platelet-rich plasma and optical density based aggregometry fails to identify patients at risk for uremia associated complications. METHODS: We employed whole blood platelet aggregation analysis based on impedance as well as determination of ATP release from platelet granules detected by a chemiluminescence method. Ten chronic kidney disease (CKD) stage 4 or 5 predialysis patients underwent platelet evaluation. Our study aims to evaluate this platform in this patient population to determine if abnormalities could be detected. RESULTS: Analysis revealed normal aggregation and ATP release to collagen, ADP, and high-dose ristocetin. ATP release had a low response to arachidonic acid (0.37 ± 0.26 nmoles, reference range: 0.6-1.4 nmoles). Platelet aggregation to low-dose ristocetin revealed an exaggerated response (20.9 ± 18.7 ohms, reference range: 0-5 ohms). CONCLUSIONS: Whole blood platelet analysis detected platelet dysfunction which may be associated with bleeding and thrombotic risks in uremia. Diminished ATP release to arachidonic acid (an aspirin-like defect) in uremic patients may result in platelet associated bleeding. An increased aggregation response to low-dose ristocetin (a type IIb von Willebrand disease-like defect) is associated with thrombus formation. This platelet hyperreactivity may be associated with a thrombotic diathesis as seen in some uremic patients.

Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1.

Multiple myeloma (MM) is characterized by the malignant expansion of differentiated plasma cells. Although many chemotherapeutic agents display cytotoxic activity toward MM cells, patients inevitably succumb to their disease because the tumor cells become resistant to the anticancer drugs. The cancer stem cell hypothesis postulates that a small subpopulation of chemotherapy-resistant cancer cells is responsible for propagation of the tumor. Herein we report that efflux of the pluripotent stem cell dye CDy1 identifies a subpopulation in MM cell lines characterized by increased expression of P-glycoprotein, a member of the ABC (ATP-binding cassette) superfamily of transporters encoded by ABCB1. We also demonstrate that ABCB1-overexpressing MM cells are resistant to the second-generation proteasome inhibitor carfilzomib that recently received accelerated approval for the treatment of therapy-refractive MM by the U.S. Food and Drug Administration. Moreover, increased resistance to carfilzomib in sensitive MM cells following drug selection was associated with upregulation of ABCB1 cell-surface expression which correlated with increased transporter activity as measured by CDy1 efflux. We further show that chemosensitization of MM cells to carfilzomib could be achieved in vitro by cotreatment with vismodegib, a hedgehog pathway antagonist which is currently in MM clinical trials. CDy1 efflux may therefore be a useful assay to determine whether high expression of ABCB1 is predictive of poor clinical responses in MM patients treated with carfilzomib. Our data also suggest that inclusion of vismodegib might be a potential strategy to reverse ABCB1-mediated drug resistance should it occur.

Relapsed acute myelogenous leukemia of brachial plexus after marrow transplant.

We present a detailed description of brachial plexus infiltration by acute myelogenous leukemia (AML) in the setting of a remission bone marrow biopsy, without evidence of leukemia by flow cytometric analysis. This case illustrates the possibility of dormant leukemic cells in the peripheral nervous system (PNS) in a patient in apparent clinical remission. In patients with an unexplained brachial plexopathy and a history of AML, leukemic infiltrate of the PNS must be considered.

PET/CT imaging in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is the classical immune-complex disease. Involvement of vital organs, particularly the kidneys and brain, accounts for significant morbidity and mortality. A number of imaging tools are currently available for evaluation of inflammatory conditions. By targeting the increased glucose uptake of infiltrating granulocytes and tissue macrophages, positron emission tomography with fluorine-18 fluorodeoxyglucose ([(18) F]FDG PET/CT) has been shown to delineate inflammation with high sensitivity. Because activated lymphocytes have increased glucose metabolism, [(18) F]FDG PET has been successfully used to visualize large concentrations of these cells in lymphoid organs where antigen presentation and lymphocyte activation occur. Widespread increased FDG uptake in lymph nodes of patients with active SLE, as well as increased thymic uptake, has been described. The most prevalent and dramatic PET/CT finding in neuropsychiatric SLE (NP-SLE) patients is parieto-occipital hypometabolism. In conclusion, PET/CT has become an excellent ancillary tool to assess disease activity and prognosis in SLE patients.

An indolent case of T-prolymphocytic leukemia with t(3;22)(q21;q11.2) and elevated serum beta2-microglobulin.

We report a novel case of T-prolymphocytic leukemia, small cell variant, associated with complex cytogenetic findings including t(3;22)(q21;11.2) and elevated serum beta2-microglobulin. The diagnosis is based on morphologic, immunophenotypic, cytogenetic, and molecular analysis of peripheral blood and bone marrow. In contrast to most reported cases of T-prolymphocytic leukemia, this patient did not present with lymphadenopathy or organomegaly. Moreover, only a moderate leukocytosis (25.3 x 10(3)/microL) was evident at presentation. In the absence of any specific treatment, the patient is doing well, with a stable white blood cell count 12 months following presentation. Further investigation may be warranted to determine whether the unusual cytogenetic findings and elevated serum beta2-microglobulin are associated with the indolent clinical course in this patient.

Comparison of relative value of bone marrow aspirates and bone marrow trephine biopsies in the diagnosis of solid tumor metastasis and Hodgkin lymphoma: institutional experience and literature review.

CONTEXT: Bone marrow aspirates as well as bone marrow trephine biopsies are frequently performed to assess whether there is marrow involvement by a malignancy. Numerous reports differ in the relative value of these 2 procedures and fail to provide concise guidelines that can help choose the appropriate technique in this clinical situation. OBJECTIVE: To compare the relative value of aspirates and trephine biopsies in the diagnosis of solid tumor metastasis and Hodgkin lymphoma. In addition, we correlate our findings with those of the literature to provide a concise practice guideline. DESIGN: Sixty-six cases showing bone marrow involvement by solid tumor and Hodgkin lymphoma in bone marrow aspirates, bone marrow trephine biopsies, or both were included in the study. The diagnosis and findings made on aspirates were compared with those made on trephine biopsies in each case. RESULTS: In those cases where both aspirate and trephine biopsy were available for evaluation, there was a 22% positive correlation in the findings on aspirates and trephine biopsies. The correlation between aspirates and trephine biopsies was highest in cases of small cell carcinoma of the lung (3/11, or 36.3%) followed by breast carcinoma (7/20, or 35%), prostate carcinoma (1/9, or 11.1%), and Hodgkin lymphoma (1/20, or 5%). Two of 5 cases from the miscellaneous category demonstrated simultaneous involvement of aspirate and trephine biopsy by a gastric carcinoma as well as an adrenal gland carcinoma. CONCLUSIONS: Bone marrow aspirate and bone marrow trephine biopsy should both be performed in patients with proven or suspected malignancies where staging may affect management. However, bone marrow aspirate has only a minimal role, if any, in detecting bone marrow involvement by Hodgkin lymphoma. In cases of breast carcinoma, small cell carcinoma of lung, and prostate carcinoma, aspirate evaluation may confirm trephine biopsy results or, more rarely, provide the sole confirmation of the malignancy.