Identifying Hemostatic Thresholds in Cancer Patients Undergoing Coronary Angiography Based on Platelet Count and Thromboelastography.

Objectives: To evaluate the role of platelet count and thromboelastogram (TEG) in the treatment of thrombocytopenic cancer patients with suspected coronary artery disease (CAD). Background: Cancer patients with CAD and thrombocytopenia are often treated non-invasively (i.e., without coronary angiography when clinically indicated) due to perceived high risk of bleeding. We sought to evaluate coagulability based on TEG and determine if platelet count and TEG could predict bleeding risk/mortality among cancer patients undergoing coronary angiography (CA). Methods: Baseline demographics, platelet count, and TEG parameters were recorded among cancer patients that underwent CA and had a concomitant TEG. Logistic regression and univariate proportional hazards regression analysis were performed to determine the impact of platelet count and coagulability on 24-month overall survival (OS). Results: All patients with platelet count <20,000/mm3 and nearly all patients with platelet count 20,000-49,000/mm3 were hypocoagulable based on TEG results. In contrast, nearly all patients with platelet counts of 50,000-99,999/mm3 had normal TEG results and OS similar to those with platelet counts of ≥100,000/mm3. Coagulability based on TEG was not associated with OS. However, a platelet count of <50,000/mm3 was associated with worse 24-month OS (hazard ratio = 2.76; p = 0.0072) when compared with a platelet count of ≥100,000/mm3. No major bleeding complications were observed in all groups. Conclusion: The majority of cancer patients with platelet counts of <50,000/mm3 were hypocoagulable based on TEG and had worse OS at 24 months. The relatively normal TEGs in the >50,000/mm3 groups, as well as the improved survival, suggest that with appropriate clinical indication and risk/benefit assessment, a cut-off of 50,000/mm3 platelets can be considered for CA in cancer patients.

Composite Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and T-Prolymphocytic Leukemia Presenting with Lymphocytosis, Skin Lesions, and Generalized Lymphadenopathy.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries with an incidence of 3-5 cases per 100,000 persons. Most patients follow an indolent clinical course with eventual progression and need for therapy. In contrast, T-prolymphocytic leukemia (T-PLL) is a rare type of T-cell leukemia with most patients having an aggressive clinical course and a dismal prognosis. Therapies are limited for T-PLL patients and there is a high relapse rate. Morphologically, the cells of CLL and T-PLL can show overlapping features. Here, we report the case of a 61-year-old man who presented with a clinically indolent CLL and T-PLL, initially diagnosed solely and followed as CLL, despite the presence of an associated but unrecognized aberrant T-cell population in blood. After 2 years, the T-PLL component became more apparent with cutaneous and hematologic manifestations and the diagnosis was confirmed by immunophenotypic and cytogenetic analysis. Fluorescence in situ hybridization demonstrated an ATM deletion in both CLL and T-PLL components. Retrospective testing demonstrated that composite CLL and T-PLL were both present in skin and lymph nodes as well as in blood and bone marrow since initial presentation. This case is also unique because it highlights that a subset of T-PLL patients can present with clinically indolent disease. The concomitant detection of ATM mutation in CLL and T-PLL components raises the possibility of a common pathogenic mechanism.

Novel hematological parameters for the evaluation of patients with myeloproliferative neoplasms: the immature platelet and reticulocyte fractions.

New automated hematology analyzers have led to the availability of novel hematological parameters, including the immature platelet fraction (IPF) and the immature reticulocyte fraction (IRF), both of potential interest in patients with myeloproliferative neoplasms (MPNs). We performed a prospective analysis of 217 patients with MPN, including 32 (15%) with essential thrombocythemia (ET), 43 (20%) with polycythemia vera (PV), and 142 (65%) with myelofibrosis (MF); the IPF and IRF were measured by the Sysmex XN analyzer. As compared to patients with ET, both a higher IPF and IRF were observed among patients with PV and MF. Factors associated with high IPF among patients with PV/ET were male sex, thrombocytopenia, and diagnosis of PV; among patients with MF, they were elevated peripheral blasts, low platelet count, JAK2 V617F mutation, and previous therapy. Factors associated with high IRF among patients with PV/ET were low hemoglobin, high reticulocyte count, and PV diagnosis; among patients with MF, they were peripheral blasts and elevated reticulocytes. The IPF and IRF represent novel parameters in patients with MPN with potential relevant clinical implications. Comparison with healthy subjects and those with secondary polycythemia is needed to confirm our preliminary findings.

Tyrosine kinase inhibitors induce mesenchymal stem cell-mediated resistance in BCR-ABL+ acute lymphoblastic leukemia.

Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL(+) acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. In this study, we identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and prosurvival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to IL-7R/Janus kinase signaling to survive in the MSC milieu. Our findings illustrate a novel perspective in the evolution of TKI resistance and provide insights for advancing the treatment of BCR-ABL(+) ALL.

Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is characterized by the fusion of retinoic acid receptor alpha (RARA) with promyelocytic leukemia (PML) or, rarely, other gene partners. This report presents a patient with APL with a novel fusion between RARA and the interferon regulatory factor 2 binding protein 2 (IRF2BP2) genes. A bone marrow examination in a 19-year-old woman who presented with ecchymoses and epistaxis showed morphologic and immunophenotypic features consistent with APL. PML oncogenic domain antibody was positive. Results of fluorescence in situ hybridization, conventional cytogenetics, reverse transcription-polymerase chain reaction (RT-PCR), and oligonucleotide microarray for PML-RARA and common APL variant translocations were negative. Next-generation RNA-sequencing analysis followed by RT-PCR and direct sequencing revealed distinct breakpoints within IRF2BP2 exon 2 and RARA intron 2. The patient received all-trans retinoic acid, arsenic, and gemtuzumab ozogamicin, and achieved complete remission. However, the disease relapsed 10 months later, 2 months after consolidation therapy. This is the first report showing involvement of IRF2BP2 in APL, and it expands the list of novel RARA partners identified in APL.

Critically ill cancer patients are not consistently hypercoagulable after craniotomy.

INTRODUCTION: Recent reports using thrombelastography have suggested that neurosurgical patients develop a hypercoagulable state in the postoperative period. Since venous thromboembolism is a potentially life threatening complication in these patients, we studied a similar population in our institution. METHODS: We conducted a prospective pilot study to evaluate postoperative coagulation changes in critically ill cancer patients after craniotomy. Data collected included demographics, diagnoses, severity of illness, all hematological information (coagulation tests included conventional and TEG), therapies, and complications. Analysis included descriptive statistics, and multivariate regression analysis. RESULTS: Eleven patients were included in the study. Mean age was 52 +/- 17 years, BMI 28 +/- 6.5, APACHE II and SOFA scores were 11.18 +/- 5.0 and 3.82 +/- 1.6 respectively. The Coagulation Index (CI), which is derived from the measured values of R, K, MA, and alpha angle was 1.22 +/- 3.5, R 4.2 +/- 1.6, K 2.0 +/- 2.1, MA 60.78 +/- 5.97, and alpha angle 66.88 +/- 14.9; while the Thrombodynamic Potential Index (TPI), which is derived from the measured values of K and MA only was 32.48 +/- 21. The CI correlated significantly with R, K, alpha angle, MA, TMA, TPI, PMA, E, A30 and A60 but not with the PTT, INR, or SOFA and APACHE II scores. One patient was hypocoagulable by CI and TPI values; in contrast, nine patients were hypercoagulable by TPI but only one by CI. There were no cases of VTE. CONCLUSIONS: Hypercoagulability as defined by the CI was not a common finding in this study. Although the TPI indicated hypercoagulability in a large number of patients, we do not believe it is a good tool to assess the patient's clotting status or predictor of thrombosis because in contrast to the CI, it does not take into account the enzymatic portions of the clotting cascade. A larger TEG study is warranted to determine the clinical significance of these changes in this and other populations.