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- Concomitant a novel ALAS2 mutation and GATA1 mutation in a newborn: a case report and review of the literature. [Journal Article]
- Am J Blood Res 2014; 4(1):41-5.
GATA-1, an X-linked gene, encodes a transcription factor that plays a role in erythropoiesis and megakaryopoiesis. GATA-1 mutations have been associated with various diseases, such as X-linked thrombocytopenia. ALAS2 is an X-linked erythroid-specific isoenzyme expressed during erythropoiesis. Mutations of ALAS2 were associated with X-linked sideroblastic anemia. We report a case of newborn twin boy with anemia and thrombocytopenia at birth. A bone marrow biopsy at 4 months of age showed marked dyserythropoiesis, dysmegakaryopoiesis, and rare ringed sideroblasts. Gene sequencing study showed a previously reported mutation in GATA-1 at c.622G>A location (G208R) and a novel ALAS2 mutation at c.1436G>A location (R479Q).
- Splenic TFH expansion participates in B cell differentiation and antiplatelet antibody production via CD40L and IL-21 during adult immune thrombocytopenia. [JOURNAL ARTICLE]
- Blood 2014 Sep 16.
Antiplatelet-antibody-producing B cells play a key role in ITP pathogenesis, however little is known about T cell dysregulations that support B cell differentiation. During the past decade, T follicular helper cells (TFH) have been characterized as the main T cell subset within secondary lymphoid organs that promotes B cell differentiation leading to antibody class-switch recombination and secretion. Herein, we characterized TFH within the spleen of 8 controls and 13 ITP patients. We show that human splenic TFH are the main producers of interleukin (IL)-21, express CD40L (CD154) and are located within the germinal center of secondary follicles. Compared to controls, splenic TFH frequency is higher in ITP patients and correlates with germinal center and plasma cell percentages that are also increased. In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients. Overall, these results point out the involvement of TFH in ITP pathophysiology and the potential interest of IL-21 and CD40 as therapeutic targets in ITP.
- Complex pattern of interleukin-11-induced inflammation revealed by mathematically modeling the dynamics of C-reactive protein. [JOURNAL ARTICLE]
- J Pharmacokinet Pharmacodyn 2014 Sep 18.
Inflammation underlies many diseases and is an undesired effect of several therapy modalities. Biomathematical modeling can help unravel the complex inflammatory processes and the mechanisms triggering their emergence. We developed a model for induction of C-reactive protein (CRP), a clinically reliable marker of inflammation, by interleukin (IL)-11, an approved cytokine for treatment of chemotherapy-induced thrombocytopenia. Due to paucity of information on the mechanisms underlying inflammation-induced CRP dynamics, our model was developed by systematically evaluating several models for their ability to retrieve variable CRP profiles observed in IL-11-treated breast cancer patients. The preliminary semi-mechanistic models were designed by non-linear mixed-effects modeling, and were evaluated by various performance criteria, which test goodness-of-fit, parsimony and uniqueness. The best-performing model, a robust population model with minimal inter-individual variability, uncovers new aspects of inflammation dynamics. It shows that CRP clearance is a nonlinear self-controlled process, indicating an adaptive anti-inflammatory reaction in humans. The model also reveals a dual IL-11 effect on CRP elevation, whereby the drug has not only a potent immediate influence on CRP incline, but also a long-term influence inducing elevated CRP levels for several months. Consistent with this, model simulations suggest that periodic IL-11 therapy may result in prolonged low-grade (chronic) inflammation post treatment. Future application of the model can therefore help design improved IL-11 regimens with minimized long-term CRP toxicity. Our study illuminates the dynamics of inflammation and its control, and provides a prototype for progressive modeling of complex biological processes in the medical realm and beyond.
- Glycoprotein Ibα clustering induces macrophage-mediated platelet clearance in the liver. [JOURNAL ARTICLE]
- Thromb Haemost 2014 Sep 18; 112(6)
Many immune thrombocytopenia (ITP) patients, particularly patients with anti-glycoprotein (GP) Ib-IX autoantibodies, do not respond to the conventional treatments such as splenectomy. However, the underlying mechanism remains unclear. Here we found that anti-GPIbα N-terminus antibody AN51, but not other anti-GPIbα antibodies (AK2, HIP1, VM16d, or WM23), induced GPIbα clustering that led to integrin αbβ3-dependent platelet aggregation. After intravenous injection, AN51 dose-dependently induced thrombocytopenia in guinea pigs, and the platelets were mainly removed by macrophages in the liver. N-acetyl-D-glucosamine, previously shown to inhibit integrin αMβ2 mediated phagocytosis of refrigerated platelets, dose-dependently inhibited AN51-induced platelet clearance. Furthermore, AN51 but not VM16d, induced rapid platelet clearance in the liver of cynomolgus macaques. Five of 22 chronic ITP patients had anti-GPIbα autoantibodies, and the autoantibodies from four of the five patients competed with AN51 for binding to platelets. These data indicate that GPIbα clustering induced by anti-GPIbα N-terminus antibody causes integrin αbβ3-dependent platelet aggregation, phagocytosis, and rapid platelet clearance in the liver. Our findings reveal a novel Fc-independent mechanism underlying the pathogenesis of ITP, and suggest new therapeutic strategies for ITP patients with anti-GPIbα autoantibodies.
- [Pharmacological thromboprophylaxis in gynecology and obstetrics.] [JOURNAL ARTICLE]
- Hamostaseologie 2014 Sep 18; 34(4)
Venous thromboembolism (VTE) is associated with high morbidity and mortality. Therefore, effective methods for safe thromboprophylaxis remain an ongoing challenge in daily clinical practice. This is especially true for pregnant women and patients with gynaecological malignancies. Low-molecular weight heparins continue to be agents of choice for pharmacological thromboprophylaxis postoperatively, in pregnant patients at risk, and during the puerperium. However, these drugs can cause bleeds or heparin-induced thrombocytopenia (type II). Based on recent revisions of corresponding guidelines, this article provides an overview of the current state of pharmacological thromboprophylaxis and discusses prevailing problems and unresolved issues.
- The pharmacology and clinical application of thrombopoietin receptor agonists. [JOURNAL ARTICLE]
- Int J Hematol 2014 Sep 18.
The discovery and application of thrombopoietin (TPO) and thrombopoietin receptor (TPOR) agonists have changed the clinical treatment of thrombocytopenia. These compounds exert favorable clinical effects without the adverse events caused by traditional treatments (e.g., corticosteroids, immunoglobulins, monoclonal antibodies and splenectomy). This review provides a synopsis of new agents that boost platelet production, especially the TPOR agonists, and highlights their pharmacological characteristics and clinical applications.
- Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg). [JOURNAL ARTICLE]
- Target Oncol 2014 Sep 19.
The aim of this study was to explore the efficacy and toxicities of a combined regimen of bevacizumab plus immunotherapy and chemotherapy (BIC) and the circulating T regulatory cells (Treg) in metastatic renal cell cancer (mRCC). Nephrectomized mRCC patients were enrolled into a multicenter single-arm dose-finding study with five escalated dose levels of chemotherapy with intravenous gemcitabine and 5-fluorouracil associated with fixed intravenous doses of bevacizumab, subcutaneous low doses of interleukin-2, and interferon-α-2a. An expanded cohort (phase II study) was treated at the recommended dose for additional safety and efficacy information according to minimax Simon two-stage design. Blood samples for Treg were collected and evaluated by fluorescence-activated cell sorting (FACS) analysis on cycle 1. Fifty-one patients were entered to receive one of five dose levels. Median age was 58 years (male 67 %, pretreated 49 %): 15 patients were low risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, while 27 and nine were respectively intermediate- and high-risk patients. More frequent grade 3 and 4 toxicities included nonfebrile neutropenia, thrombocytopenia, and fever. Among patients evaluable for response (49), 29.5 % had partial response and 37 % stable disease. Overall median time to progression and median overall survival were 8.8 and 22.67 months, respectively. We observed a rapid increase in the percentage of Treg after immunotherapy and a reduction after bevacizumab only in patient who obtained a partial response or stable disease. The BIC was feasible, well tolerated, and shown interesting activity. Further studies are needed to explore if Treg could have a role in clinical response in mRCC treated with bevacizumab.
- CHANGES IN THE INCIDENCE OF SEVERE THROMBOCYTOPENIA AND ITS PREDISPOSING CONDITIONS IN HIV-INFECTED PATIENTS SINCE THE INTRODUCTION OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY. [JOURNAL ARTICLE]
- J Acquir Immune Defic Syndr 2014 Sep 16.
Severe thrombocytopenia (platelets <50x10/L) is relatively frequent during HIV infection and is associated with bleeding risk and disease progression. We investigated the changes in the incidence of severe thrombocytopenia and its predisposing conditions in a cohort of HIV-positive subjects.The incidence and predictors of platelet counts <50x10/L were investigated in all patients enrolled at our Institution between 1985 and 2012. Three different periods were considered on the basis of the available antiretroviral regimens: P1 (1985-1989), P2 (1990-1996) and P3 (1997-2012). Incidence rates were assessed using Poisson regression models, and the predictors by means of Cox regression.The study involved 5,137 patients with platelet counts >50x10/L at enrolment. Severe thrombocytopenia occurred in 597 subjects, and its incidence decreased overtime. The incidence decreased in patients with opportunistic diseases and malignancies, but increased in patients with chronic liver disease; thrombocytopenia unrelated to any cause other than HIV infection remained stable. Multivariate analysis showed that injected drug use, a diagnosis of AIDS, low CD4+ cell counts, increased serum alanine aminotransferase levels and an earlier year of enrolment were predictors of an increased risk of severe thrombocytopenia, whereas the use of highly active antiretroviral therapy (HAART) was associated with a reduced risk.A considerable reduction in the incidence of severe thrombocytopenia after the introduction of HAART was found, probably due to its ability to limit bone marrow damage induced by uncontrolled HIV replication and opportunistic infections. On the contrary, HAART may have a reduced impact on thrombocytopenia related to chronic liver disease.
- Deep vein thrombosis after arthroscopic anterior cruciate ligament reconstruction in a patient with primary thrombocytopenia. [JOURNAL ARTICLE]
- Acta Orthop Traumatol Turc 2014; 48(4):455-458.
Deep vein thrombosis is a rare complication after arthroscopic anterior cruciate ligament reconstruction. We present a patient with primary thrombocytopenia who had deep vein thrombosis after arthroscopic anterior cruciate ligament reconstruction. The patient recovered well at a 2-year follow-up. The purpose of this study was to enhance the awareness on venous thrombosis, a rare complication after arthroscopic anterior cruciate ligament reconstruction.
- Coexistence of congenital syphilis and cytomegalovirus infection: a case report. [Journal Article]
- Acta Dermatovenerol Croat 2014 Sep; 22(3):215-7.
A 22-year-old pregnant woman with an intravenous drug abuse habit delivered a girl in the 26th gestational week with a fetal length and weight of 38 cm/990 g (pc. 75-91). She did not participate in prenatal care that included screening for congenital diseases, syphilis, and human immunodeficiency virus (HIV) infection during the pregnancy. Laboratory examinations revealed positive rapid plasma reagin (RPR) (1:128), Treponema pallidum particle agglutination assay (TPPA) and TpELISA results. Immediately before delivery, labial herpes simplex virus-1 (HSV-1), Streptococcus agalactiae, and genital yeast infections were detected. Hepatitis B surface antigen (HbsAG), HIV, and hepatitis C virus (HCV) serology remained negative. The preterm and immature newborn girl had mild jaundice, minimal edema, and gluteal hematomas with petechiae. The liver and spleen were extremely enlarged (reaching the plevic bones). Increased muscle tone and rigid elbow, knee, and hip joints were found (Figures 1, 2). Additionally, X-ray examination detected multiple jejunal atresia. Brainstem evoked response audiometry ruled out hearing loss. In laboratory investigations anisocytosis, thrombocytopenia, elevated liver enzymes (ASAT: 3850 U/L, ALAT: 558 U/L, GGT: 292 U/L, ALP: 436 U/L), elevated lactate dehydrogenase (LDH) (38180 mmol/L), and creatinine kinase (CK) (7.1 U/L) with elevated bilirubin levels (87.9 μmol/L) were found. In microbiology investigations a high CMV virus number was detected using a quantitative real-time polymerase chain reaction (PCR) method from the urine and blood. Syphilis serology was positive (RPR: 1:16 positive, TPPA, TpELISA, and T. pallidum IgM immunoblot positive). HSV PCR (in the oral mucosa, conjunctiva, and blood) remained negative. Intravenous penicillin-G (100.000 IU/kg/dose for 10 days) therapy was administered. Intravenous ganciclovir was started, but was discontinued after 2 weeks because of progressive thrombocytopenia and elevating liver enzymes. The newborn underwent transfusion due to anemia and extreme thrombocytopenia. Blue light therapy was administered for 3 days because of jaundice. The multiple jejunal atresia was treated by operation (terminoterminal jejuno-jejunostomia and ileal stricturaplastica) in the Semmelweis University Pediatrics Clinic. At the time of writing this report, the girl was 2 months old, growing and developing; her intestinal passage is satisfactory, but the liver enzymes are extremely high due to the CMV infection. Congenital syphilis and congenital CMV are preventable diseases, but they are still the most common causes of perinatal mortality and morbidity worldwide (4,5). Intravenous drug users and mothers of low socioeconomic status belong to the highest risk groups for vertical transmission of infections. Congenital syphilis may induce jaundice, hepatosplenomegaly, wrinkled skin, thrombocytopenia, and anemia, with symptoms that are clinically similar to congenital CMV infection, making the differential diagnosis difficult (1,5,6). Although syphilis screening tests are mandatory in the first trimester of pregnancy in Hungary, at least one congenital syphilis case was observed yearly since the mid-nineties. Therefore, a second syphilis test is strongly recommended after the 28th gestational week or before delivery, particularly in high risk groups (7). The prenatal diagnosis of fetal CMV infection is based on amniocentesis in the 21st gestational week, which is a risky and non-standard method. The widely used ultrasonography examination often yields a uncertain diagnosis (8). Intravenous penicilline-G is effective treatment for congenital syphilis, but there is no gold standard therapy for CMV infection. Treatment with ganciclovir may prevent hearing loss later in life, but it has several severe side effects (neutropenia, anemia, thrombocytopenia, elevated liver enzymes) (9). Furthermore, studies on the effect of prolonged valganciclovir therapy are still ongoing (10). Prevention is the most effective method of reducing the prevalence of congenital CMV: pregnant women should avoid contact with the saliva of young children. In our case, the mother of the newborn belonged to a high risk group and did not participate in the prenatal caring system; mandatory screening tests were not done, so congenital infections were diagnosed only at delivery. The treatment for congenital syphilis was effective, and resulted in decrease of RPR titers. Most of the clinical symptoms did not improve, and the liver enzymes were continuously increased, indicating that CMV infection was a major contributor in clinical manifestation. Further follow up is needed to evaluate the radiological findings of long bones. Our case draws attention to the importance of early and effective prenatal diagnosis, adequate treatment of prenatal infectious diseases, and the necessity of a multidisciplinary approach to congenital infections.