Multiple myeloma (MM) is a hematologic neoplasm characterized by plasma tumor cell proliferation in the bone marrow. It's a rare malignancy before a 40-year-old and it is extremely uncommon during pregnancy. We report the case of a 37-year-old woman with a newly diagnosed IgG λ MM (Durie-Salmon stage IIIA, International Staging System II and good prognosis cytogenetic) at the 27th week of her pregnancy. Our management during pregnancy, the delivery, and initiation of anti-myeloma treatment with bortezomib, lenalidomide, and dexamethasone are published. There are a few reviews reporting the most common features and management of MM during pregnancy. We perform a comprehensive review of all 32 cases reported between 1965 and 2014 in which a MM was diagnosed during pregnancy including score, cytogenetic results, labor characteristics, and response to therapy. About 53% of pregnant women did not start treatment before partum. Cesarean section was the most common form of delivery (82%). About 88% of newborns were healthy, although most of them were premature (73%). Management of a MM diagnosed during pregnancy should be based on the presence of myeloma-related organ damage to secure survival of the mother without fetal adverse effects related to treatment. Serial fetal ultrasound may be helpful in order to avoid complications. The cesarean section may be preferred depending on maternal and fetus prognosis. Whole-body diffusion-weighted imaging minimal response could be an appropriate technique to discard plasmacytomas during pregnancy in critical situations such as the appearance of symptoms of spinal cord compression. Therapeutic choices should be agreed with the pregnant after a thorough discussion of the prognostic factors of the disease and the potential risk for the fetus and the patient. While awaiting partum, dexamethasone is a non-toxic treatment. Triple therapy including a proteasome inhibitor should be started quickly after delivery. Copyright © 2014 John Wiley & Sons, Ltd.

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Aim: In the present work we have studied the role of platelets and microvesicles in patients with severe hemophilia A (HA) treated under the regimen of prophylaxis. We have analyzed whether the administration of coagulation factor FVIII modifies this hemorrhagic phenotype in a cohort of 16 patients with diagnosis of severe HA, who were on prophylactic treatment with recombinant FVIII. Methods: Blood tests were performed before (72h without FVIII, baseline sample) and after 15 minutes of FVIII infusion. As a control group, 15 healthy subjects were studied. Platelet aggregation was determined by closure time, optical aggregation, impedance aggregation and flow cytometry. We also studied the expression of the platelet activation markers P-selectin, CD63, platelet-tissue factor, formation of platelet-leukocyte aggregates and tissue factor exposure. The total number of platelet and endothelial microvesicles were also analyzed by flow cytometry, as well as platelet cytosolic Ca2+ mobilization. Results: We found no significant differences in platelet function in patients with severe HA in prophylactic treatment before and after FVIII infusion. After FVIII administration, patients presented fewer endothelial microvesicles, indicating that the treatment does not increase one of the possible thrombotic risk markers of these patients. The total amount of plasma microvesicles and the platelet microvesicles were decreased in patients with HA compared to the control group. Conclusions: Our results do not support any effect of FVIII on platelet function in patients with severe HA treated under the regime of prophylaxis.

We found no significant differences in platelet function in patients with severe HA in prophylactic treatment before and after FVIII infusion. After FVIII administration, patients presented fewer endothelial microvesicles, indicating that the treatment does not increase one of the possible thrombotic risk markers of these patients.

INTRODUCTION Hemophilia A (HA) is a rare inherited genetic disorder linked to the X chromosome, characterized by joint bleeding in patients with severe disease with <1% of factor VIII (FVIII)(White et al. Thromb Haemost 2001). However, there are cases of severe HA with less bleeding than usual and it has been postulated that there must be other contributors to the hemorrhagic phenotype, including a platelet dysfunction (Van Bladel et al. Haematologica 2011). In this study we analyzed platelet reactivity in a cohort of 16 male patients with severe HA in prophylactic treatment by flow cytometry. The control group was 15 healthy male subjects. METHODS A longitudinal prospective observational study cohort was conducted. The study was performed according to the Declaration of Helsinki of 1975 (revised 1983), and was approved by the Ethics Committee of our Institution. Sixteen HA male patients without FVIII inhibitor aged 9-39 years (mean 22,75 years, SD 11,428) and 15 adult male healthy volunteers aged 26-48 years (mean 36,4 years, SD 6,6) were included. All subjects had normal platelet counts (150-450x103/µl). The blood was collected by antecubital venipuncture and avoiding the use of tourniquet to minimize the spontaneous activation of platelets during extraction. For HA patients blood samples were taken immediately before FVIII infusion (basal sample, 72h without FVIII) and 15 minutes after the infusion of FVIII. Levels of factor FVIII in plasma were determined using a chromogenic method. We analyzed platelet responsiveness, using the thrombin receptor activator peptide-6 (TRAP-6) as agonist, measuring the expression of CD62P and CD63 by flow cytometry. For microparticles analysis, percentages and number of events positive for CD62P and CD41 were gated for Annexin-V+ subpopulation. Endothelial cell-derived microparticles were identified as CD144+CD41-. To calculate the absolute count we considered the final volumes of each tube and it was expressed in events/µL for each subpopulation (Annexin-V +, CD41+, CD144+ and CD62P+). For the analysis of cytoplasmic free calcium release, whole blood was labelled with PerCP-Cy5.5-human anti-CD61 and the calcium sensitive dye Fluo-4-AM for 15 min at room temperature. Following adjustment of the basal fluorescence, samples were stimulated with the agonists TRAP-6 or adenine-5«-diphosphate sodium salt (ADP) and analyzed for 5 min by flow cytometer. Ionophore A23187 was used as a positive control for calcium mobilization. Afterwards mean fluorescence intensity values were analysed with the Kaluza flow cytometry analysis software (Beckman Coulter). RESULTS Statistical analysis was carried out using SPSS statistical software version 19.0.All values were expressed as mean ± SD for each experimental group.To compare the results in HA patients before and after administration of FVIII we used the t-Student test for means related, to compare HA patients and the control group we used the t-student test for independent samples. Data of calcium were analyzed by one-way analysis of variance followed by Tukey-Kramer for multiple comparisons. The minimum acceptable level of significance wasp<0.05. Basal levels of FVIII in plasma were4,58 ± 6,4%. The mean fluorescence intensity for CD62P after stimulation with TRAP was significantly lower in HA patients after infusion of FVIII compared to basal levels (p<0,05)(Table 1). Regarding microparticles (MPs), we detected higher expression of CD41+ MPs in HA patients after infusion of FVIII compared to basal expression, but not for CD41+CD62P+ MPs. Also, percentage of CD144+ MPs were significantly lower in HA patients after FVIII infusion (Table 2). Moreover, we did not find statistically significant differences comparing the release of calcium between the different groups (Table 3). CONCLUSION In this study severe HA patients in prophylactic treatment displayed normal platelet activation and microparticles plasmatic levels. However, the platelet activation marker CD62P after TRAP agonist and the endothelial cell origin microparticles expression were lower 15 minutes after the infusion factor VIII. Acknowledgments We wish to thank to Pfizer providing economic support to this project. Disclosures Melero-Amor: Pfizer: Research Funding. García Candel:Pfizer: Research Funding. García:Pfizer: Research Funding. Romecin:Pfizer: Research Funding. Iyu:Pfizer: Research Funding. Cabañas-Perianes:Pfizer: Research Funding. Pérez:Pfizer: Research Funding. O´Connor:Pfizer: Research Funding. Moraleda:Pfizer: Research Funding. Marín:Pfizer: Research Funding. Blanquer Blanquer:Pfizer: Research Funding.