Anne Bradshaw

Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure

Thromboembolism is an important complication of heart failure. To test the hypothesis that heart failure may be associated with hemostatic dysfunction, we studied hemostatic function in 21 patients with stable chronic heart failure and related these measures to the severity of heart failure as assessed by clinical evaluation, neuroendocrine activation, radionuclide ventriculography, and cardiopulmonary exercise testing. Plasma and blood viscosity were elevated; all patients showed evidence of platelet activation, and many had elevated plasma concentrations of fibrinopeptide A, D-dimer, and von Willebrand factor. The plasma concentrations of these variables were poorly interrelated and related poorly to the severity of heart failure. Plasma concentrations of angiotensin II and endothelin were correlated, and the latter was also correlated with the plasma concentration of von Willebrand factor. Patients with chronic heart failure have hemostatic abnormalities that may predispose them to thromboembolic events and may be in part due to neuroendocrine activation.

Trends and usage in a London National Health Service Sperm Bank for cancer patients.

Abstract Sperm cryopreservation is the only method currently available that offers men with cancer insurance against sterilising iatrogenic treatments. We carried out two cohort and cross-sectional audits to identify trends with sperm cryopreservation referral rates and sample usage rates for men diagnosed with cancer and who banked sperm at The Andrology Laboratory, Hammersmith Hospital, Imperial College NHS Trust. These retrospective audits revealed that a total of 4362 men with cancer successfully banked sperm between 1976 and 2013. Truncating the dataset to 2009 to allow for lag times between storage and use, the overall sample usage rate for cancer patients was 6.0% with 75 live births. Increased median age at referral influences the cancer profile of men seen at the bank, which is highlighted by a disproportionate rise in the number of men with prostate cancer. Among men who use banked sperm, a large rise in the use of intracytoplasmic sperm injection has occurred over time. The number of patients requiring the service is sharply increasing year on year as are the number of patients who go on to use their sample in assisted conception. The historical use rates of frozen sperm are likely to be significant underestimations of future use.

BKV-specific T cells in the treatment of severe refractory haemorrhagic cystitis after HLA-haploidentical haematopoietic cell transplantation

Haemorrhagic cystitis caused by BK virus (BKV) is a known complication of allogeneic haematopoietic cell transplantation (HCT) and is relatively common following HLA‐haploidentical transplantation. Adoptive immunotransfer of virus‐specific T cells from the donor is a promising therapeutic approach, although production of these cells is challenging, particularly when dealing with low‐frequency T cells such as BKV‐specific T cells.

Hemostatic studies in patients with infective endocarditis: a report on nine consecutive cases with evidence of coagulopathy

SummaryLocal and generalized changes in coagulation may be important in the genesis of vegetations and embolism in infective endocarditis. To characterize such alterations, serial hematological investigations were performed on nine consecutive patients who satisfied the inclusion criteria. Platelet survival was measured by Indium111 labeling. Acute and convalescent samples were analyzed for fibrinogen, factor VIIIc, antithrombin III (AT III), fibrin/fibrinogen degradation products (FDPs), and platelet aggregation. The results suggest that in the active stage of the disease: (1) hypercoagulability may be caused by a rise in acute phase reactants, (2) an acceleration of coagulation and fibrinolysis may supervene, and (3) in some cases there is a reduction in platelet aggregation, possibly as a result of continued circulation of previously activated “exhausted” platelets.

Analysis of hematopoietic recovery after autologous transplantation as method of quality control for long-term progenitor cell cryopreservation

Hematopoietic precursor cells (HPC) are able to restore hematopoiesis after high-dose chemotherapy and their cryopreservation is routinely employed prior to the autologous hematopoietic cell transplantation (AHCT). Although previous studies showed feasibility of long-term HPC storage, concerns remain about possible negative effects on their potency. To study the effects of long-term cryopreservation, we compared time to neutrophil and platelet recovery in 50 patients receiving two AHCT for multiple myeloma at least 2 years apart between 2006 and 2016, using HPC obtained from one mobilization and collection attempt before the first transplant. This product was divided into equivalent fractions allowing a minimum of 2 × 106 CD34+ cells/kg recipient’s weight. One fraction was used for the first transplant after median storage of 60 days (range, 17–165) and another fraction was used after median storage of 1448 days (range, 849–3510) at the second AHCT. Neutrophil recovery occurred at 14 days (median; range, 11–21) after the first and 13 days (10–20) after the second AHCT. Platelets recovered at a median of 16 days after both procedures. Considering other factors, such as disease status, conditioning and HPC dose, this single institution data demonstrated no reduction in the potency of HPC after long-term storage.

Mesenchymal stromal stem cell (MSC) immunotherapy for experimental septic shock: systematic review and meta-analysis with trial sequential analysis of mortality

Introduction: The majority of patients treated for hematological malignancies with a stem-cell-graft and postponed donor-lymphocyte-infusion (DLI) from an unrelated-donor (URD) are 10/10 HLA-matched with the donor, frequently resulting in a mismatch for HLA-DP. Under non-inflammatory conditions, expression of HLA-DP is restricted to hematopoietic cells. Therefore, an HLA-DP-mismatch can give rise to a specific Graft-versus-Leukemia (GvL) effect. However, in specific cases, patients receiving HLA-DP-mismatched T-cells suffer from coinciding GvHD mediated by a profound alloHLA-DP-specific immune response. Adoptive transfer of invitro selected allo-HLA-DP-restricted donor T-cells directed against antigens specifically expressed on hematopoietic cells may be an elegant strategy to induce a specific GvL-effect without coinciding GvHD. Material (or patients) and methods: To induce allo-HLA-DPdirected T-cell responses, HLA-DP mismatched (10/10 matched) donor/patient pairs were selected. Donor PBMC were co-cultured with patient mature-monocyte-derivedDCs for 14 days. After re-stimulation, reactive CD4-T-cells were clonally isolated based on expression of the activation marker CD137, and expanded. Growing T-cell clones were analyzed for allo-HLA-DP-restriction, hematopoiesisand cell-lineage-specificity using hematopoietic cells (monocytes, DCs, EBV-LCL) of donor and patient-origin, leukemic cell samples and non-hematopoietic (interferon-gammapretreated, HLA-class-II-expressing, skin-derived-fibroblasts) target cells. Results: 80% of the reactive CD4-T-cell clones were found to be allo-HLA-DP-restricted as defined by recognition of patient, but not donor-derived target cells, and confirmed by recognition of third-party target cells expressing the mismatched, patient-specific HLA-DP allele. Within the alloHLA-DP-reactivity we found different tissue-and lineagespecificities. As expected, we found many T-cell clones that produced IFNγ, GM-CSF and/or IL-4 when tested against hematopoietic cells as well as non-hematopoietic cells expressing the target HLA-DP allele. The majority of these clones also exerted cytotoxic activity against these target cells. Interestingly, we found 30-40% of the allo-HLA-DPrestricted T-cell clones to specifically produce cytokines when tested against hematopoietic cells but not against nonhematopoietic cells expressing the target HLA-DP allele. In accordance, these clones showed cytotoxic activity against the hematopoietic targets, but did not lyse fibroblasts despite interferon-induced proper expression of the target HLA-DP allele. Moreover, from these hematopoiesis-restricted T-cell clones one third showed a myeloid-lineage-specificity illustrated by recognition of monocytes and DCs, but not EBV-LCL. These allo-HLA-DP-restricted, myeloid-reactive T-cell clones showed also reactivity against primary AML blasts and CD34 progenitor cells expressing the target HLA-DP molecule. Conclusion: These results indicate that hematopoiesisrestricted, and even cell-lineage-specific T cells are an elementary component of the allo-HLA-DP-specific T-cell repertoire. In-vitro generation of allo-HLA-DP-restricted, hematopoiesisand cell-lineage-specific T-cells may allow safe and effective therapeutic application of HLA-DP-immunity. Disclosure of Interest: None declared.