Gabapentin, a structural analog of gamma-aminobutyric acid, is used to treat peripheral neuropathic pain. Here we report the first case of platelet function disorder associated with gabapentin ...treatment in a 44-year-old woman without a history of bleeding. She presented with mucocutaneous bleeding approximately 1 month after initiation of gabapentin and platelet function tests showed no aggregation to arachidonic acid and epinephrine, a defective response to ADP and a slightly decreased response to collagen. Gabapentin's imputability was supported by the fact that all platelet functions were normalized 6 days after drug discontinuation, with the simultaneous disappearance of bleedings.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Cardiopulmonary bypass (CPB) induces the release of platelet factor 4 (PF4) and patients are at risk of heparin‐induced thrombocytopenia (HIT). This study was aimed to determine whether an ...abnormal evolution in platelet count (PC) after CPB is predictive of the development of HIT antibodies. Two abnormal PC patterns were defined: pattern P1, characterized by a decrease in PC following previous correction of thrombocytopenia occurring during CPB, and pattern P2, defined as a persistent low PC in the days following CPB. PC was evaluated for 10 d in 305 consecutive patients before and after CPB. Serotonin release assay (SRA) was carried out between days 8 and 10 to detect pathogenic heparin‐dependent antibodies. Moreover, antibodies to heparin–PF4 (H–PF4) complexes were assayed by enzyme‐linked immunosorbent assay. PC evolution after CPB was normal in 300 patients although antibodies to H–PF4 were frequently present (53·4%). Changes in PC were abnormal in five patients with pattern P1 (n = 4) or P2 (n = 1). As SRA was positive in four of the five cases, the positive predictive value of abnormal PC pattern for pathogenic HIT antibodies was 80%. Careful follow‐up of PC after CPB makes it possible to predict with high specificity (99%) for those patients who develop pathogenic HIT antibodies.
1 Hematology Departments of Angers
2 Nantes
3 Tours
4 Grenoble
5 Nancy
6 Rennes
7 Dijon
8 Saint Etienne
9 LFB-Paris, France
Correspondence: Yves Gruel, Service dHématologie Hémostase, Hôpital ...Trousseau, 37044 Tours Cedex, France. E-mail: gruel{at}med.univ-tours.fr
Background: The effects of L-asparaginase on hemostasis during induction chemotherapy are less defined in adults than in children. We, therefore, studied the effects of L-asparaginase in adult patients.
Design and Methods: This was a retrospective analysis of 214 patients treated with L-asparaginase (7500 IU/m 2 x 6) for acute lymphoblastic leukemia or lymphoblastic lymphoma. Between day 1 of the induction course and discharge, clinical events, and biological and therapeutic modifications were reviewed.
Results: Antithrombin and fibrinogen levels were lower than 60% and 1 g/L in 71% and 73% of patients, respectively. Twenty thromboses occurred in 9.3% of the patients; these patients had a median antithrombin level of 53% (range, 21–111) at the time of the event. Forty-two episodes of bleeding occurred in 31 patients with a median fibrinogen level of 1.3 g/L. Infusions of L-asparaginase were reduced or delayed in 64% of patients due to low fibrinogen and/or antithrombin levels. Fresh-frozen plasma, antithrombin and fibrinogen were infused in 31%, 41% and 52% of patients, respectively. The mean antithrombin and fibrinogen levels increased from 61% to 88% and from 1 to 1.4 g/L after infusion of antithrombin or fibrinogen respectively, while both levels remained unchanged after the infusion of fresh-frozen plasma. In patients who received antithrombin concentrates L-asparaginase injections were less frequently omitted or delayed (53% vs. 72%, p =0.005), the rate of thrombosis was lower (4.8% vs . 12.2%, p =0.04) and the disease-free survival was also reduced ( p =0.05).
Conclusions: This retrospective study suggests that antithrombin concentrates may have a beneficial effect on the outcome of adults treated for acute lymphoblastic leukemia with L-asparaginase; prospective studies are essential to confirm this hypothesis.
Key words: L-asparaginase, acute lymphoblastic leukemia, antithrombin, fibrinogen.
Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, ...which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes.
The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs.
This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor).
The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study).
ClinicalTrials.gov Identifier: NCT02509468 , first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.
The pathogenesis of thrombosis in heparin-induced thrombocytopenia (HIT) was studied by investigating whether antibodies to heparin-platelet factor 4 (H-PF4) induced tissue factor (TF) synthesis by ...monocytes. Plasma from 5 patients with HIT containing IgG to H-PF4 was incubated with peripheral blood mononuclear cells without or with purified PF4 and heparin. Significant TF-dependent procoagulant activity (PCA) expressed by monocytes, measured with a factor Xa-based chromogenic assay, was induced after incubation of each HIT plasma sample. This monocyte PCA required the presence of PF4 and was inhibited by high concentrations of heparin. Furthermore, purified HIT IgG added to whole blood with PF4 and heparin also provoked significant synthesis of TF mRNA by monocytes, demonstrated by RT-PCR, and this effect was not observed with normal IgG. These findings strongly support the hypothesis that antibodies to PF4 developed in HIT trigger the production of tissue factor by monocytes, and this effect could account in vivo for hypercoagulability and thrombotic complications in affected patients.
This study was designed to investigate the changes in acoustic properties of whole blood during the coagulation process. High frequency (from 20 to 40 MHz) ultrasound parameters were measured both in ...double transmission (DT) and backscattering (BS) mode to assess sound velocity and backscatter coefficient, respectively. The integrated backscatter coefficient (IBC) and the effective scatterer size (ESS) were deducted from the backscatter coefficient. Measurements were performed on whole blood samples collected from 12 healthy volunteers. During the blood clotting process (2 h observation), acoustic parameters were measured with 15 s time resolution for the transmission parameter and 5 s (for the 5 first min) and 30 s (for the end of the observation time) for the backscattering parameters. The results obtained clearly showed that simultaneous measurements of parameters in DT and BS modes are able to identify several stages during the in vitro blood clotting process. In particular, red blood cell (RBC) aggregation can be described from the backscattering parameters and liquid-gel transition phase of blood from the sound velocity. Intra- and inter-individual dispersion of these parameters were also measured and discussed.
In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, ...and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1 to 2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cellbased Immune Therapies; and Gene Therapy.
Tissue Factor Pathway Inhibitor-2 (TFPI-2) is a potent inhibitor of plasmin which activates metalloproteinases (MMPs) involved in extracellular matrix (ECM) degradation. Its secretion in ECM makes ...TFPI-2 a potential inhibitor to regulate tumour invasion and metastasis. Moreover, TFPI-2 is frequently downregulated, particularly in aggressive cancers. In this study, we silenced TFPI-2 in the NCI-H460 non-small cell lung cancer cell line and evaluated the role of TFPI-2 in cell invasion and its impact on MMPs expression. As the effects of siRNA are transient, the consequences of both gene silencing and restoration to normal expression could be studied kinetically in the same cells. We showed that TFPI-2 expression by NCI-H460 cells was effectively downregulated using specific small interfering RNA and this silencing was associated with an increase in the invasive potential of tumour cells while migration was not affected. We also showed that mRNA levels and protein expression of MMP-2, -3, -9, -14 were not influenced by TFPI-2 silencing. Moreover, the gelatinase activity of MMP-2 and MMP-9 was unmodified. In contrast, MMP-1 mRNA levels and protein were significantly and similarly increased in cells transfected with TFPI-2 siRNA. In conclusion, this study confirms that TFPI-2 downregulation can contribute to tumour invasion of lung cancer cells.
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