interleukin-8 and Thrombocytopenia

Heparin-induced thrombocytopenia remains a topical subject for at least two reasons. The first reason is the increasing prescription of low molecular weight heparins (LMWH) rather than unfractionated heparins, with limited laboratory surveillance, raising the question concerning the need for twice-weekly platelet counts, according to the recommendations of the Vidal drug directory. The second reason is the recent release onto the market of two products, danaparoid (Orgaran) and lepirudin (Refludin) for this precise indication of heparin-induced thrombocytopenia. These products greatly facilitate the management of this complication. Many basic research teams are trying to optimize the detection of heparin-dependent antibodies and to more clearly elucidate the mechanism of this particular thrombocytopenia, which carries a risk of very severe thrombotic complications when the diagnosis is delayed.

Topics: Antibodies; Anticoagulants; beta-Thromboglobulin; Chondroitin Sulfates; Dermatan Sulfate; Drug Monitoring; Drug Utilization; Enzyme-Linked Immunosorbent Assay; Heparin; Heparitin Sulfate; Hirudins; Humans; Interleukin-8; Peptides; Platelet Count; Platelet Factor 4; Recombinant Proteins; Risk Factors; Thrombocytopenia; Time Factors

Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Carcinoma, Renal Cell; Cytokines; Drug Eruptions; Exanthema; Fatigue; Female; Fever; Humans; Injections, Subcutaneous; Interferon-gamma; Interleukin-10; Interleukin-4; Interleukin-8; Kidney Neoplasms; Male; Melanoma; Middle Aged; Neoplasms; Polyethylene Glycols; Recombinant Proteins; Thrombocytopenia; Transforming Growth Factor beta; Uveal Neoplasms; Young Adult

Late-onset sepsis in the NICU is a major problem associated with high morbidity and mortality.. To determine if clinical characteristics, hematological parameters and serial measurements of serum IL-6 and IL-8 can detect late-onset sepsis in premature neonates prior to positive blood cultures.. The study was done in 2 phases. The first phase (S1) was a retrospective evaluation of clinical signs and timing of blood culture positivity in all neonates with late-onset cultures proven sepsis from 1991-1998. The second phase (S2) was a prospective study that enrolled infants > or = 72 hours old, suspected of sepsis based on the presence of criteria identified in S1. At that time (day 0), blood was drawn for a CBC with differential, blood culture, IL-6 and IL-8 levels; cytokine levels were repeated on day 1. Infants with positive cultures were diagnosed as confirmed sepsis; those with negative cultures, as no sepsis.. S1: Of the 48 episodes of culture proven, late-onset sepsis, 54% of the blood cultures were positive by 24 hours and 90% by 48 hours. The most common presenting signs were desaturations (50%) and increased gastric residuals (33%); I/T ratio > 0.16 differentiated between gram-positive, negative and fungal infections (p = 0.007). S2: 27 infants were enrolled. Eight (mean [SEM] gestational age of 28.2 [0.94] weeks; birth weight of 1.15 [0.11] kg) had positive blood cultures; 19 (gestational age of 27.7 [0.9] weeks; birth weight of 1.06 [0.13] kg) had no sepsis. Infants with sepsis were more likely to have apnea/bradycardia (p = 0.002); no differences in hematological profile, as compared to those with no sepsis. Seven (88%) infants had positive blood cultures by 48 hours. Median values of IL-6 (pg/ml) were higher in infants with sepsis vs. those with no sepsis on days 0 [40 vs. 13] (p = 0.03) and 1 [24 vs. 9] (p < 0.001). IL-8 levels were not significantly different.. In both S1 and S2, a majority of the blood cultures were positive by 48 hours. IL-6 levels on days 0 and 1 were significantly higher in infants with confirmed sepsis, prior to the blood culture being positive. IL-6 levels may be useful in the initiation as well as early termination of antibiotic therapy in late-onset neonatal sepsis.

Topics: Biomarkers; Cytokines; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature, Diseases; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Neutrophils; Prospective Studies; Retrospective Studies; Sepsis; Thrombocytopenia; Time

Topics: Adult; Aged; Blood Platelets; Decitabine; Down-Regulation; Female; Humans; Interleukin-8; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Thrombocytopenia; Treatment Outcome

The purpose of the study is to evaluate the incidence, association with serum cytokine profile, and prognostic value of thrombocytopenia, in critically ill patients with severe sepsis/septic shock.. A cohort of 105 consecutive patients admitted in intensive care unit was included in our analysis. Serum levels of intercellular adhesion molecule, vascular cell adhesion molecule, interferon γ, interleukin 8, and soluble form of the urokinase-type plasminogen activator receptor (suPAR) were measured.. Thrombocytopenia was observed in 53% of patients at the time of admission. Platelet counts showed a statistically significant negative correlation with serum levels of intercellular adhesion molecule, suPAR, and interleukin 8 (P < .0001). In multivariate analysis, high Acute Physiological and Chronic Health Evaluation II score, high serum suPAR, and low platelet counts were associated with increased mortality, and receiver operating characteristic curve analysis was used to determine the best cutoff value for mortality prediction. Each variable with a value above or below the predefined cutoff levels were given 1 point. Patients were categorized in risk groups based on total point score. High-risk (2-3), intermediate-risk (1), and low-risk (0 points) groups consisted of 43%, 22%, and 35% and 28-day mortality was observed in 69%, 26%, and 3% of the patients in each group, respectively.. Thrombocytopenia is associated with poor prognosis and a distinct serum cytokine profile.

Topics: Adult; Aged; Biomarkers; Critical Care; Critical Illness; Cytokines; Female; Greece; Hospital Mortality; Humans; Incidence; Interleukin-8; Male; Middle Aged; Prognosis; Prospective Studies; Receptors, Urokinase Plasminogen Activator; ROC Curve; Sepsis; Thrombocytopenia

Hemolytic uremic syndrome (HUS), a vascular disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure, is caused by enterohemorrhagic Shiga toxin (Stx)-producing bacteria, which mainly affect children. Besides Stx, the inflammatory response mediated by neutrophils (PMN) is essential to HUS evolution. PMN can release neutrophil extracellular traps (NET) composed of DNA, histones, and other proteins. Since NET are involved in infectious and inflammatory diseases, the aim of this work was to investigate the contribution of NET to HUS. Plasma from HUS patients contained increased levels of circulating free-DNA and nucleosomes in comparison to plasma from healthy children. Neutrophils from HUS patients exhibited a greater capacity to undergo spontaneous NETosis. NET activated human glomerular endothelial cells, stimulating secretion of the proinflammatory cytokines IL-6 and IL-8. Stx induced PMN activation as judged by its ability to trigger reactive oxygen species production, increase CD11b and CD66b expression, and induce NETosis in PMN from healthy donors. During HUS, NET can contribute to the inflammatory response and thrombosis in the microvasculature and thus to renal failure. Intervention strategies to inhibit inflammatory mechanisms mediated by PMN, such as NETosis, could have a potential therapeutic impact towards amelioration of the severity of HUS.

Topics: Acute Kidney Injury; Anemia, Hemolytic; Apoptosis; Bacterial Infections; Cells, Cultured; Child; Endothelial Cells; Extracellular Traps; Hemolytic-Uremic Syndrome; Humans; Interleukin-6; Interleukin-8; Kidney; Neutrophil Activation; Neutrophils; Reactive Oxygen Species; Shiga Toxin; Thrombocytopenia

The Pediatric Sepsis Biomarker Risk Model (PERSEVERE), a pediatric sepsis risk model, uses biomarkers to estimate baseline mortality risk for pediatric septic shock. It is unknown how PERSEVERE performs within distinct septic shock phenotypes. We tested PERSEVERE in children with septic shock and thrombocytopenia-associated multiple organ failure (TAMOF), and in those without new onset thrombocytopenia but with multiple organ failure (MOF).. PERSEVERE-based mortality risk was generated for each study subject (n = 660). A priori, we determined that if PERSEVERE did not perform well in both the TAMOF and the MOF cohorts, we would revise PERSEVERE to incorporate admission platelet counts.. Multiple PICUs in the United States.. Standard care.. PERSEVERE performed well in the TAMOF cohort (areas under the receiver operating characteristic curves [AUC], 0.84 [95% CI, 0.77-0.90]), but less well in the MOF cohort (AUC, 0.71 [0.61-0.80]). PERSEVERE was revised using 424 subjects previously reported in the derivation phase. PERSEVERE-II had an AUC of 0.89 (0.85-0.93) and performed equally well across TAMOF and MOF cohorts. PERSEVERE-II performed well when tested in 236 newly enrolled subjects. Sample size calculations for a clinical trial testing the efficacy of plasma exchange for children with septic shock and TAMOF indicated PERSEVERE-II-based stratification could substantially reduce the number of patients necessary, when compared with no stratification.. Testing PERSEVERE in the context of septic shock phenotypes prompted a revision incorporating platelet count. PERSEVERE-II performs well upon testing, independent of TAMOF or MOF status. PERSEVERE-II could potentially serve as a prognostic enrichment tool.

Topics: Biomarkers; Chemokine CCL3; Child; Child, Preschool; Female; Granzymes; HSP70 Heat-Shock Proteins; Humans; Infant; Intensive Care Units, Pediatric; Interleukin-8; Male; Matrix Metalloproteinase 8; Models, Statistical; Multiple Organ Failure; Platelet Count; Prognosis; Risk Assessment; Shock, Septic; Thrombocytopenia; United States

In some patients, the anticoagulant heparin elicits formation of antibodies that can cause the life and/or limb-threatening syndrome known as heparin-induced thrombocytopenia (HIT). HIT antibodies target complexes formed at specific molar ratios of heparin and platelet factor 4 (PF4). The unpredictable occurrence and the mechanism of this atypical immune response to PF4:heparin complexes are poorly understood.. We investigated whether complexes formed at specific PF4:heparin ratios (PHRs) might resemble molecular patterns associated with host defense responses.. We used an in vitro cytokine release assay to determine whether defined PHRs caused cytokine release from human whole blood. Lipopolysaccharide (LPS) was used as a positive assay control, and some experiments included antibodies to block Toll-like receptor 4 (TLR4).. PF4:heparin complexes caused release of the biomarker interleukin 8 in whole blood, and the level of response varied with the stoichiometric ratio of PF4 to heparin. The profile of response to LPS and to PF4:heparin complexes varied among blood donors, and the interleukin 8 response to both LPS and PF4:heparin was inhibited by TLR4-blocking antibodies.. Specific PF4-heparin complexes can elicit a TLR4-mediated response, suggesting that these complexes can mimic a pathogen-associated molecular pattern, and supporting the suggestion that the HIT immune response represents a misdirected host defense mechanism.

Topics: Dose-Response Relationship, Drug; Heparin; Humans; Interleukin-8; Lipopolysaccharides; Platelet Factor 4; Signal Transduction; Thrombocytopenia; Toll-Like Receptor 4

Dengue is the most prevalent human arbovirus disease in the world. Dengue infection has a large spectrum of clinical manifestations, from self-limited febrile illness to severe syndromes accompanied by bleeding and shock. Thrombocytopenia and vascular leak with altered cytokine profiles in plasma are features of severe dengue. Although monocytes have been recognized as important sources of cytokines in dengue, the contributions of platelet-monocyte interactions to inflammatory responses in dengue have not been addressed. Patients with dengue were investigated for platelet-monocyte aggregate formation. Platelet-induced cytokine responses by monocytes and underlying mechanisms were also investigated in vitro. We observed increased levels of platelet-monocyte aggregates in blood samples from patients with dengue, especially patients with thrombocytopenia and increased vascular permeability. Moreover, the exposure of monocytes from healthy volunteers to platelets from patients with dengue induced the secretion of the cytokines IL-1β, IL-8, IL-10 and MCP-1, whereas exposure to platelets from healthy volunteers only induced the secretion of MCP-1. In addition to the well-established modulation of monocyte cytokine responses by activated platelets through P-selectin binding, we found that interaction of monocytes with apoptotic platelets mediate IL-10 secretion through phosphatidylserine recognition in platelet-monocyte aggregates. Moreover, IL-10 secretion required platelet-monocyte contact but not phagocytosis. Together, our results demonstrate that activated and apoptotic platelets aggregate with monocytes during dengue infection and signal specific cytokine responses that may contribute to the pathogenesis of dengue.

Topics: Adult; Apoptosis; Blood Platelets; Capillary Permeability; Chemokine CCL2; Dengue; Dengue Virus; Female; Humans; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-8; Male; Monocytes; P-Selectin; Phagocytosis; Phosphatidylserines; Platelet Activation; Thrombocytopenia

We describe a novel type of human thrombocytopenia characterized by the appearance of giant platelets and variable neutropenia. Searching for the molecular defect, we found that neutrophils had strongly reduced sialyl-Lewis X and increased Lewis X surface expression, pointing to a deficiency in sialylation. We show that the glycosylation defect is restricted to α2,3-sialylation and can be detected in platelets, neutrophils, and monocytes. Platelets exhibited a distorted structure of the open canalicular system, indicating defective platelet generation. Importantly, patient platelets, but not normal platelets, bound to the asialoglycoprotein receptor (ASGP-R), a liver cell-surface protein that removes desialylated thrombocytes from the circulation in mice. Taken together, this is the first type of human thrombocytopenia in which a specific defect of α2,3-sialylation and an induction of platelet binding to the liver ASGP-R could be detected.

Topics: Animals; Asialoglycoprotein Receptor; Blood Platelets; Child; Female; Granulocytes; Humans; Interleukin-8; Liver; Mice; Mutation; N-Acetylneuraminic Acid; Neutropenia; Nucleotide Transport Proteins; Oligosaccharides; Phenotype; Protein Binding; Selectins; Sialyl Lewis X Antigen; Thrombocytopenia

Platelet factor 4 heparin enzyme immunoassay, platelet aggregation test, and serotonin release assay are commonly used to diagnose and confirm heparin-induced thrombocytopenia. We describe a case of recurrent thrombocytopenia appearing in a few hours after each heparin administration and who tested negative for the three assays. Further analysis revealed anti-interleukin (IL)-8 antibodies and IL-8-dependent platelet activation facilitated by heparin, which may explain this unusual case of heparin-induced thrombocytopenia.

Topics: Anticoagulants; Antiphospholipid Syndrome; Female; Heparin; Humans; Immunoenzyme Techniques; Interleukin-8; Middle Aged; Platelet Activation; Platelet Count; Thrombocytopenia

Some cases of heparin-induced thrombocytopenia (HIT) have been reported to be associated with antibodies against interleukin-8 (IL-8), a chemokine related to platelet factor 4. We found that sera from 5 HIT patients containing immunoglobulin G (IgG) or IgM antibodies to IL-8, as evidenced using surface plasmon resonance spectroscopy, were able to trigger IL-8-dependent activation of washed platelets, leading to procoagulant activity. This activation occurred at IL-8 concentrations achievable in vivo and was facilitated by heparin (0.1 U/mL). Activation was also induced by affinity-purified anti-IL-8 IgG and involved FcgammaRIIa. In the 2 patients who could be followed up, antibodies were no longer detectable 4 months after heparin withdrawal. One additional patient with paraneoplastic recurrent thrombosis without thrombocytopenia was found to have platelet-activating anti-IL-8 IgM, but in this case heparin was inhibitory. This is another example of potentially pathogenic platelet activation by antibodies.

Topics: Antibodies; Antigens, CD; Heparin; Humans; Immunoglobulin G; Immunoglobulin M; Interleukin-8; Platelet Activation; Platelet Factor 4; Receptors, IgG; Thrombocytopenia

The effects of intravenous administration of a first-generation adenoviral vector expressing beta-galactosidase were compared in two baboons receiving a high dose or lower dose of vector, 1.2 x 10(13) or 1.2 x 10(12) particles/kg, respectively. The high-dose baboon developed acute symptoms, decreased platelet counts, and increased liver enzymes, and became moribund at 48 hr after injection, while the lower-dose baboon developed no symptoms. Expression of the beta-galactosidase transgene was prominent in liver, spleen, and endothelium of the arterial vasculature in the high-dose baboon, but was much more limited and spared the endothelium in the lower-dose baboon. Injury to the vascular endothelium was the most prominent abnormality in the high-dose baboon. Extensive histological studies provide a detailed picture of the pathology associated with a lethal dose of first-generation adenoviral vector in a primate.

Topics: Adenoviridae; Animals; beta-Galactosidase; Endothelium, Vascular; Genetic Vectors; Infusions, Intravenous; Interleukin-6; Interleukin-8; Liver; Male; Mice; Mice, Inbred C57BL; Papio; Platelet Count; Thrombocytopenia; Tissue Distribution; Tumor Necrosis Factor-alpha

Thrombosis is a life-threatening complication that occurs in a subset of patients with heparin-induced thrombocytopenia (HITT). The pathogenic mechanisms underlying the variable occurrence of thrombosis in HITT is poorly understood. It was hypothesized that monocyte activation leading to tissue factor expression may play a role in promoting a thrombogenic state in HITT. This study demonstrates that a human platelet factor 4 (PF4)/heparin-specific murine monoclonal antibody (KKO) binds to peripheral blood-derived human monocytes in a PF4-dependent manner. KKO and antibodies from patients with HITT induce monocytes to synthesize and secrete interleukin-8 and induce cell-surface procoagulant activity, which is abrogated following treatment with antihuman tissue factor antibody. The findings suggest a novel mechanism by which PF4/heparin antibodies may promote a hypercoagulable state in patients with HITT. (Blood. 2001;98:1252-1254)

Topics: Antibodies, Monoclonal; Autoantibodies; Coagulants; Heparin; Humans; Interleukin-8; Monocytes; Platelet Factor 4; Thrombocytopenia; Thrombophilia; Thromboplastin; Thrombosis

Heparin-induced thrombocytopenia (HIT) is frequently associated with antibodies (Abs) to heparin-PF4 complexes (H-PF4). In order to investigate whether there are variations in specificity of Abs, we studied 63 samples from patients with suspected HIT. Two groups of samples were separated after comparing their reactivity against H-PF4 or recombinant PF4 (r-PF4) using ELISA. In group Ab1 (n = 46), Abs only or mainly bound to H-PF4 complexes and thus most of the epitopes recognized probably involved both heparin and PF4. In group Ab2 (n = 17), Abs exhibited similar reactivity to r-PF4 and H-PF4, and the antigens recognized were possibly neoepitopes mainly expressed by modified PF4 and by H-PF4 complexes. Platelet activation tests were positive with 56 samples containing high titres of Abs to H-PF4. Most samples (n = 59) contained IgG antibodies, often associated with IgA antibodies which were more frequently found in group Ab2, and/or IgM. With unfractionated heparin treatment, HIT was associated with Ab1 or Ab2 antibodies, whereas only Ab1 antibodies were detected after low-molecular-weight heparin (LMWH). Furthermore, cross-reactivity with danaparoid sodium was present only in group Ab1 and mainly involved LMWH-treated patients.

Topics: Adult; Aged; Aged, 80 and over; Antibodies; Antibody Specificity; beta-Thromboglobulin; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Female; Heparin; Heparitin Sulfate; Humans; Interleukin-8; Male; Middle Aged; Peptides; Platelet Activation; Platelet Factor 4; Thrombocytopenia