Giant Cell Arteritis Presenting as Small Bowel Infarction

Giant cell arteritis predominantly affects cranial arteries and rarely involves other sites. We report a patient who presented with small bowel obstruction because of infarction from mesenteric giant cell arteritis. She had an unusual cause of her obstruction and a rare manifestation of giant cell arteritis. In spite of aggressive therapy with steroids, she died a month later because of multiple complications. We discuss the diagnosis and management of small bowel obstruction and differential diagnosis of vasculitis of the gastrointestinal tract. We were able to find 11 cases of bowel involvement with giant cell arteritis in the English literature. This case report illustrates that giant cell arteritis can be a cause of small bowel obstruction and bowel infarction. In the proper clinical setting, vasculitides need to be considered early in the differential diagnosis when therapy may be most effective

Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid Antibodies (aPL)-mediated inhibition of endometrial angiogenesis

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies (aPL). Different pathogenic mechanisms for aPL-mediated pregnancy failure have been proposed. In particular a direct effect of aPL on both maternal and fetal side of the placental tissue has been reported, since their reactivity with \u3b22-glycoprotein I (\u3b22GPI) makes them adhere to trophoblast and human endometrial endothelial cell (HEEC) membranes. \u3b22GPI can be recognized by aPL that, once bound, interfere with both trophoblast functions and with the HEEC differentiation.APS patients can be successfully treated with Low Molecular Weight Heparin (LMWH). Recent reports suggest that LMWH acts through mechanisms alternative to its well known anticoagulant effect, because of its ability to bind \u3b22GPI. In our previous studies, we showed that LMWH is able to reduce the aPL binding to trophoblasts and restore cell invasiveness and differentiation. So far, however, no study has described its effects on endometrial angiogenesis.The aim of our research was to evaluate whether two LMWHs, tinzaparin and enoxaparin, have an effect on the aPL-inhibited endometrial angiogenesis. This prompted us to investigate: (i) in vitro HEEC angiogenesis through a Matrigel assay; (ii) VEGF secretion by ELISA; (iii) matrix metalloproteinase-2 (MMP-2) activity by gelatin zymography; (iv) Nuclear Factor-\u3baB (NF-\u3baB) DNA binding activity by colorimetric assay; (v) STAT-3 activation by a sandwich-ELISA kit. Furthermore, using an in vivo murine model we investigated the LMWHs effects on angiogenesis.We demonstrated that the addition of LMWHs prevents aPL-inhibited HEEC angiogenesis, both in vitro and in vivo, and is able to restore the aPL inhibited NF-\u3baB and/or STAT-3 activity, the VEGF secretion and the MMPs activity.The demonstration of a beneficial role for LMWHs on the aPL-inhibited HEEC angiogenesis might provide additional mechanisms whereby this treatment protects early pregnancy in AP

Pleural effusions in Hematologic malignancies

Nearly all hematologic malignancies can occasionally present with or develop pleural effusions during the clinical course of disease. Among the most common disorders are Hodgkin and non-Hodgkin lymphomas, with a frequency of 20 to 30%, especially if mediastinal involvement is present. Acute and chronic leukemias, myelodysplastic syndromes, are rarely accompanied by pleural involvement. Furthermore, 10 to 30% of patients receiving bone marrow transplantation develop pleural effusions. In cases of hematologic pleural effusions, drug toxicity, underlying infectious, secondary malignant or rarely autoimmune causes should be carefully sought. In most cases, the pleural fluid responds to treatment of the primary disease, whereas resistant or relapsing cases may necessitate pleurodesis

The relation between bone marrow angiogenesis and the proliferation index Ki-67 in multiple myeloma

Aim: Angiogenesis correlates with disease progression in various haematological malignancies. This study investigated the association between microvascular density (MVD) and the Ki-67 proliferation index (Ki-67 PI), bone marrow infiltration, and C reactive protein (CRP) in patients with multiple myeloma. Methods: Bone marrow MVD was examined in 44 biopsies at diagnosis and 15 in plateau phase by immunostaining the endothelial cells with a monoclonal antibody to CD34. The Ki-67 PI was evaluated by a double immunostaining technique using the monoclonal antibodies MIB-1 and CD38. Results: MVD, Ki-67 PI, bone marrow infiltration, and CRP were significantly higher in pretreatment patients than in controls and decreased in patients achieving plateau phase. MVD significantly correlated with Ki-67 PI and infiltration, and Ki-67 correlated with infiltration. Conclusion: In multiple myeloma, apart from being a marker of proliferative activity, Ki-67 is also associated with bone marrow angiogenesis and tumour burden

Serum evaluation of angiogenic cytokines basic fibroblast growth factor, hepatocyte growth factor and TNF-alpha in patients with myelodysplastic syndromes: Correlation with bone marrow microvascular density

Recent studies have documented that angiogenesis plays a significant role in haematological malignancies, including mylodysplastic syndromes (MDS). Basic fibroblast growth factor (b-FGF), Hepatocyte growth factor (HGF) and Tumor necrosis factor-alpha (TNF-alpha) are multifunctional cytokines that potently stimulate angiogenesis. The aim of the present study was to evaluate the microvascular density (MVD) and the serum levels of these angiogenic factors in patients with myelodysplastic syndromes (MDS). In 61 patients with MDS, MVD was measured in bone marrow biopsies and b-FGF, HGF and TNF-alpha were determined in the serum of the same patients by enzyme-linked immunosorbent assay (ELISA). Serum levels of b-FGF, HGF and TNF-alpha as well as MVD in the bone marrow were increased in MDS patients compared to healthy controls (p < 0.0001). Levels of b-FGF, HGF and TNF-alpha were also significantly higher in high-risk for leukemic transformation MDS than in low-risk (p < 0.0001). Significant differences were also found regarding MVD in high and low risk patients (p < 0.001). Both b-FGF and HGF levels were significant predictors of survival (p < 0.0005, log-rank test). The present study showed that serum levels of b-FGF, HGF and TNF-alpha are significantly increased and dependent on the severity of MDS suggesting that the determination of these parameters may offer considerable information regarding disease progression and prognosis

Elevated serum concentration of hepatocyte growth factor in patients with multiple myeloma: Correlation with markers of disease activity

Hepatocyte growth factor (HGF) has been shown to be involved in angiogenesis, epithelial cell proliferation, and osteoclast activation. HGF and its receptor are expressed on myeloma cell lines and could be involved in the pathogenesis of bone destruction in multiple myeloma (MM). The aim of this study was to examine serum levels of HGF in untreated MM patients and its correlation with bone turnover indices and markers of disease activity. Forty-seven newly diagnosed MM patients and 25 controls were included: 12 patients were of stage I, 13 of stage II, and 22 of stage III (Durie-Salmon classification). Bone lesions were scored from 0 to 3, according to X-ray findings. Serum osteocalcin (OC), interleukin-6 (IL-6), TNF-alpha, beta(2)-microglobulin (beta(2)M), CRIP, calcium, and 24-hr urine N-telopeptide cross-links of collagen breakdown (NTx) were determined. HGF levels were significantly higher at stage III compared to stages II and I (medians: 1,990.4 vs. 1,743.8 and 1,432.4 pg/mL, respectively, P < 0.05). Similarly, NTx, IL-6, TNF-alpha, CRIP, beta(2)M, and calcium increased significantly with advancing stage (P < 0.01). OC was higher at stage I in comparison to stages 11 and III (P < 0.01). All parameters were significantly higher in patients than controls. HGF showed a strong correlation with IL-6 and TNF-alpha and less with beta(2)M, CRP, NTx, and OC. We conclude that serum HGF levels are increased in advanced stages of MM disease and extended bone lesions. HGF correlates with IL-6 and TNF-alpha, which are cytokines involved in osteoclast stimulation in MM. However, an independent association of HGF with bone turnover markers was not shown in this study, thus its role in MM bone disease needs to be further clarified. (C) 2003 Wiley-Liss, Inc

Levels of serum cytokines and acute phase proteins in patients with essential and cancer-related thrombocytosis

Essential thrombocytosis (ET) is a myeloproliferative disorder resulting in an increased production of abnormal platelets. Reactive thrombocytosis (RT) is occasionally observed in clinical situations including chronic inflammation and malignancy. The aim of the present study was to evaluate the discriminatory efficiency of various laboratory tests in patients with ET and cancer-related RT. Forty-five patients with ET, 52 patients with RT, and 25 age-matched normal individuals comprised the study population. Plasma interleukin-1 alpha (IL-1a), IL-2, IL-6, tumor necrosis factor alpha (TNF-a), platelets, hematocrit, hemoglobin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lactate dehydrogenase (LDH) and ferritin were determined. We found increased levels of territin, LDH, CRP, ESR, IL-1a, and IL-6 in RT compared with ET (p < 0.01 to p < 0.0005). Hemoglobin, hematocrit, and platelets were significantly lower in RT than in ET (p < 0.0005). Furthermore, ferritin and ESR were negatively correlated with Hct, hemoglobin, and TNF-a, whereas ferritin was positively correlated with ESR, IL-1a, IL-6, and CRP, and IL-1a was positively correlated with IL-6. We consider that the aforementioned parameters should be included in the investigation of unexplained thrombocytosis for the differentiation of essential from cancer related thrombocytosis

Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia/thrombosis (HIT) is a serious immune reaction to heparins, characterized by thrombocytopenia and often severe thrombosis with high morbidity and mortality. HIT is mediated by IgG antibodies against heparin/platelet factor 4 antigenic complexes. These complexes are thought to activate platelets leading to thrombocytopenia and thrombosis. Here we show that HIT immune complexes induce NETosis via interaction with FcγRIIa on neutrophils and through neutrophil-platelet association. HIT immune complexes induce formation of thrombi containing neutrophils, extracellular DNA, citrullinated histone H3 and platelets in a microfluidics system and in vivo, while neutrophil depletion abolishes thrombus formation. Absence of PAD4 or PAD4 inhibition with GSK484 abrogates thrombus formation but not thrombocytopenia, suggesting they are induced by separate mechanisms. NETs markers and neutrophils undergoing NETosis are present in HIT patients. Our findings demonstrating the involvement of NETosis in thrombosis will modify the current concept of HIT pathogenesis and may lead to new therapeutic strategies