Circulating platelet-derived microparticles are associated with atherothrombotic events: a marker for vulnerable blood.
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Biomarkers↗
Biomedical subjects
Shosaku Nomura
Publications and source records attributed to Shosaku Nomura.
Elevation of soluble interleukin-2 receptor in patients with non-small cell lung cancer treated with gefitinib.
PURPOSE: We previously reported that plasma thromboxan B(2), soluble P-selectin, and serum regulated on activation, normal T-cell expressed and secreted (RANTES) were elevated after gefitinib treatment. We hypothesized that gefitinib could activate T-lymphocytes via activated platelets, and so we measured serum levels of soluble interleukin-2 receptor (sIL-2R) in patients medicated with gefitinib. METHODS: Twenty-one patients with non-small cell lung cancer (NSCLC) were entered into this study. All patients received gefitinib over 2 weeks without severe adverse effects. Blood samples were withdrawn from all patients before and after the administration of gefitinib and plasma soluble P-selectin, serum RANTES, and serum sIL-2R were measured by enzyme-linked immunosolvent assay. In addition, we carried out the basic study of the interleukin-2 receptor (IL-2R) expression on CD4(+) lymphocytes by RANTES. RESULTS: Plasma soluble P-selectin, serum RANTES, and serum sIL-2R levels increased significantly in patients receiving gefitinib treatment for 1 and 2 weeks. RANTES did not induce the expression of IL-2R on CD4(+) lymphocyte. However, the anti-CD3 monoclonal antibody-induced expression of IL-2R was enhanced by the addition of RANTES. CONCLUSION: Our finding indicated that lymphocytes were activated by gefitinib treatment. We think that sIL-2R elevation after gefitinib administration may be a factor positively effecting patients with NSCLC. It is deemed possible that the effect of gefitinib is induced not only by its blocking of the tyrosine kinase of epidermal growth factor receptor but also by antitumor immunity via its activation of T-cells.
Adult↗
Elevation of monocyte-derived microparticles in patients with diabetic retinopathy.
Diabetic retinopathy is associated with microvascular damage and capillary occlusions which are common features of the microangiopathy in diabetes. Monocyte-derived microparticles (MDMPs) are released from activated monocytes and enhance the procoagulant activity, and also activate adhesion reactions. These are key events in the development of capillary occlusion. The MDMPs level in the blood, and platelet activation markers (platelet-derived microparticles (PDMPs), CD62P and CD63) were measured by flow cytometry in 72 diabetic patients. The plasma levels of intracellular adhesion molecule-1 (ICAM-1) and P-selectin were analyzed by ELISA. The level of MDMPs was significantly correlated with the levels of PDMPs (r=0.52, P<0.001), CD62P (r=0.37, P=0.001), CD63 (r=0.31 and P=0.007), P-selectin (r=0.38, P=0.001), and ICAM-1 (r=0.31, P=0.009). The MDMPs level increased with the progression of the diabetic retinopathy: 81+/-14/10(4)platelets (plts) in patients without retinopathy (n=10); 88+/-8/10(4)plts with mild or moderate non-proliferative diabetic retinopathy (NPDR, n=12); 95+/-8/10(4)plts with severe NPDR (n=24); and 112+/-9/10(4)plts with proliferative diabetic retinopathy (PDR) (n=26). The MDMPs level in patients with areas of capillary occlusion (123+/-10/10(4)plts, n=25) was significantly higher than that in patients without areas of capillary occlusion (84+/-5/10(4)plts, n=25; P=0.0008). These correlations suggest that increased levels of MDMPs may accelerate the progression of diabetic retinopathy.
Adult↗
Burkitt lymphoma of the uterus in a human T lymphotropic virus type-1 carrier.
A 71-year-old Japanese woman who was seropositive for T-lymphotropic virus type-1 (HTLV-1) developed primary Burkitt lymphoma of the uterus. CT showed marked enlargement of the uterine body. Chromosomal abnormalities were detected in biopsied cells, and most showed the t (8; 14) (q24; q32) translocation. Fluorescence in situ hybridization (FISH) with a dual-color stain for IgH/C-MYC fusion showed 99% positively. Biopsies from abdominal operation were diagnosed as Burkitt lymphoma. Treatment was started with intensive chemotherapy according to a protocol for Burkitt lymphoma and mature-B cell leukemia. Two regimens were done with four courses with rituximab. Treatment response was fast, with a documented and lasting first complete remission on CT and laboratory markers after the 4 cycle treatment.
Aged↗
Role of platelet-derived chemokines (RANTES and ENA-78) after stem cell transplantation.
Stem cell transplantation (SCT) is being used for hematopoietic reconstitution following high-dose chemotherapy for malignancy. Some patients seem to have an imbalance of the immune response after SCT and cytokines are known to regulate this response. Recently, platelets have been shown to contain members of the chemokine family, suggesting a role of platelets as inflammatory cells. We measured and compared levels of platelet activation markers, chemokines, and soluble factors in patients undergoing SCT. IL-8 and GROalpha exhibited a significant elevation in the early phase (1 or 2 weeks) after SCT; this trend was marked after autologous SCT. Furthermore, these levels significantly and positively correlated with the change in G-CSF. In contrast, ENA-78 exhibited a significant elevation in the later phase (3 or 4 weeks) after SCT. In addition, its level negatively correlated with the change in G-CSF. Soluble CD40 ligand and platelet-derived microparticles significantly increased after both auto- and allo-SCT. In addition, ENA-78 positively correlated with the level of platelet-derived microparticles. The increase of RANTES seems to be related to platelet activation, since RANTES was in the dynamic phase similar to soluble CD40 ligand and platelet-derived microparticles. RANTES exhibited changes similar to IL-6, TNFalpha, and soluble IL-2 receptors, which are GVHD markers. Thus, the platelet-derived chemokines ENA-78 and RANTES exhibited particular changes after SCT. Our results suggest that ENA-78 play a role in hematopoietic conditions in which G-CSF is not involved, and RANTES generation after allo-SCT relates to GVHD.
Blood Platelets↗
Effect of valsartan on monocyte/endothelial cell activation markers and adiponectin in hypertensive patients with type 2 diabetes mellitus.
Angiotensin II receptor blockade has been shown to have a beneficial effect on the angiopathies of hypertension and hyperglycemia in patients with type 2 diabetes. However, the effect of angiotensin II receptor blockade on monocyte and endothelial cell adhesion markers in type 2 diabetes is poorly understood. We investigated the effects of valsartan on these markers in 53 hypertensive patients with and without type 2 diabetes mellitus. Levels of monocyte activation markers (soluble CD14: 2.1+/-0.9 vs. 3.3+/-1.4 microg/ml, p<0.01; monocyte chemotactic peptide: 392+/-94 vs. 489+/-114 pg/ml, p<0.05; and monocyte-derived microparticles: 264+/-98 vs. 511+/-128/microL, p<0.01) and endothelial cell activation markers (soluble E-selectin: 41+/-11 vs. 61+/-20 ng/ml, p<0.001; and soluble vascular cell adhesion molecule-1: 478+/-82 vs. 584+/-101 ng/ml, p<0.01) were significantly increased in hypertensive patients with type 2 diabetes compared to normotensive controls. In addition, the concentrations of adiponectin were significantly decreased in patients with type 2 diabetes (8.1+/-3.1 vs. 5.2+/-2.5 microg/ml, p<0.01). Regardless of the presence of diabetic complications, both systolic and diastolic blood pressures significantly decreased after valsartan administration (valsartan 80 mg/day for 8 weeks). Monocyte and endothelial cell activation markers were decreased significantly in patients with type 2 diabetes after valsartan treatment, but not in non-type 2 diabetic patients. In addition, valsartan alleviated hypoadiponectinemia in hypertensive patients with diabetes (before vs. after: 5.2+/-2.5 vs. 7.6+/-2.7 microg/ml, p<0.001) but did not increase adiponectin levels in the non-diabetic hypertensive group, for which the average adiponectin level was normal prior to treatment. These results suggest angiotensin II receptor blockade (valsartan) may be beneficial as an anti-atherosclerotic therapy in patients with type 2 diabetes in addition to its anti-hypertensive action.
Aged↗
Fiberoptic bronchoscopy induces platelet activation.
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Bronchoscopy↗
Platelet-derived chemokine RANTES may be a sign of restenosis after percutaneous coronary intervention in patients with stable angina pectoris.
Inflammation plays a pathogenic role in the development of restenosis after percutaneous coronary intervention (PCI). We measured and compared the ratio of elevated levels of regulated on activation normally T-cell expressed and secreted (RANTES), monocytic chemotactic peptide-1 (MCP-1), soluble (s) P-selectin and sL-selectin after PCI. Plasma levels of chemokines and soluble markers were measured before, 1, 3 and 7 days after PCI in 52 patients (43 males and nine females, aged 63 +/- 10 years) who underwent PCI and who had repeated angiograms at a 6-month follow-up. Restenosis occurred in 16 (31%) patients. A significant and time-dependent increase in sL-selectin was observed in the restenosis group. However, there were no significant differences in MCP-1 levels with or without restenosis. sP-selectin levels in the restenosis group exhibited a transient elevation at 3 days after PCI. RANTES levels were no different at baseline between patients with or without restenosis. However, a significant and time-dependent decrease in RANTES levels were observed in the non-restenosis group, and patients with restenosis compared with patients without restenosis had a statistically significant ratio of elevated levels of RANTES. These findings suggest that restenosis development after PCI in patients with effort angina pectoris may involve leukocyte activation at an early period after PCI. In addition, platelet-derived chemokine RANTES may be a sign of restenosis after PCI in patients with stable angina pectoris.
Aged↗
Aspirin reduces adverse effects of gefitinib.
We measured serum levels of soluble (s) P-selectin and thromboxane B2 (TxB2) in patients with lung cancer treated with gefitinib, and investigated the effect of low-dose aspirin on some adverse effects of gefitinib. The serum levels of sP-selectin and TxB2 increased significantly in all patients who received gefitinib for 2 weeks. Forty patients were recruited, and 28 received gefitinib without low-dose aspirin (Group 1) and 12 were co-administered low-dose aspirin (Group 2). In Group 2, the frequency of adverse events, skin rash and diarrhea was evidently reduced by the low-dose aspirin therapy, despite having shown no remarkable change in gefitinib responsiveness between both groups. In one of the 12 patients in Group 2, aspirin therapy was suspended due to the occurrence of nasal bleeding. Four days after treatment suspension, she developed a skin lesion in her finger. However, the skin lesion improved after re-administration of aspirin without any other medications. After treatment, TxB2 significantly decreased, but not sP-selectin. These results suggest that one of the mechanisms causing gefitinib-related adverse effects depends on platelet activation. Administration of gefitinib with low-dose aspirin to lung cancer patients may prevent the development of gefitinib-related complications.
Adult↗
Control of hepatic veno-occlusive disease with an antithrombin-III concentrate-based therapy.
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Antithrombin III↗
Gefitinib has the potential of activating cell immunity against malignant cells.
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Antineoplastic Agents↗
Long-term treatment with nifedipine modulates procoagulant marker and C-C chemokine in hypertensive patients with type 2 diabetes mellitus.
In type 2 diabetes mellitus, there is increased risk of nephropathy and cardiovascular complications and the incidence of renal failure increases in advanced stages of the disease. Nifedipine, a dihydropyridine-type calcium antagonist, improves endothelial function in hypercholesterolemia by enhancing nitric oxide function, and increases endothelial nitric oxide bioavailability by antioxidative mechanisms. We administered nifedipine, 50 mg/day, to the hypertensive patients for 12 months. There were no other changes in any of the patient's pharmacologic regimen during nifedipine treatment. Clinical and biochemical data obtained before and after nifedipine administration were compared. All markers were measured by ELISA. The levels of platelet activation markers (CD62P, CD63, PAC-1, and Annexin V), microparticles (PDMP and MDMP), RANTES and soluble adhesion markers (sP-selectin and sVCAM-1) differed in the control group and the hypertension group. The levels of these markers were also different in hypertensive patients with and without type 2 diabetes but were unchanged in patients without diabetes in comparison to the control group. However, the concentrations of MDMPs, chemokines, and soluble adhesion markers in hypertensive patients without type 2 diabetes decreased significantly following nifedipine treatment, although the level of RANTES was unchanged. Systolic blood pressure correlated with CD62P, CD63, annexin V, and RANTES levels, and diastolic blood pressure with CD62P and annexin V levels. The effect of nifedipine on platelet activation markers and C-C chemokines in the present study indicates potential effectiveness of calcium antagonist therapy for hypertensive patients with type 2 diabetes.
Aged↗
5-HT2A receptor antagonist increases circulating adiponectin in patients with type 2 diabetes.
We compared the levels of plasma adiponectin, platelet activation markers (P-selectin, CD63, PAC-1, annexin V, and platelet-derived microparticles), and endothelial injury markers (soluble E-selectin and soluble vascular cell adhesion molecule-1) in 53 patients with type 2 diabetes mellitus to investigate potential contributions to diabetic vascular complications. In addition, we administered serotonin antagonist (sarpogrelate hydrochloride) to type 2 diabetes patients who had increased soluble E-selectin levels. The concentrations of platelet activation markers and endothelial injury markers in diabetic patients were significantly higher than those in normal subjects. However, levels of adiponectin were lower in type 2 diabetes patients than in control subjects. A total of 32 patients had high-soluble E-selectin levels (soluble E-selectin >or= 62 ng/ml); a subset of patients that also had significant elevation of platelet activation and endothelial injury markers compared with patients without high soluble E-selectin. In addition, both platelet-P-selectin and platelet-derived microparticle levels negatively correlated with the adiponectin level. Patients with high soluble E-selectin exhibited significant improvement of all markers after sarpogrelate hydrochloride treatment. These findings suggest that there is a link between vascular change in type 2 diabetes and activated platelets, endothelial dysfunction, and an adiponectin abnormality.
Adiponectin↗
Gefitinib affects functions of platelets and blood vessels via changes in prostanoids balance.
Prostaglandins (PGs) and thromboxane (TX) produced by cyclooxygenase (COX) have a great influence on vascular systems and platelet functions. The serum levels of epidermal growth factor (EGF) and PGs were measured in patients with lung cancer treated with gefitinib, and the influence of EGF on platelet aggregation was investigated. Twenty patients were investigated. The serum level of TXB(2) increased significantly in all patients who received gefitinib for 2 weeks (before vs. after = 94.1 +/- 47.3 vs. 190.9 +/- 54.3, p<0.01). TXB(2) also increased significantly in responders without concurrent chemotherapy (before vs. after = 79.3 +/- 35.5 vs. 194.5 +/- 58.1, p<0.05), but not in non-responders (before vs. after = 106. 5 +/- 65.8 vs. 162.2 +/- 52.8, N.S.). PG 6-keto F1alpha and PGE(2) did not exhibit significant changes. Furthermore, EGF showed no significant change (after vs. before = 234 +/- 35 vs. 276 +/- 72, N.S.). Although there was no correlation between the levels of EGF and TXB(2) (N.S.), the PG 6-keto F2alpha/TXB(2) ratio decreased significantly (before vs. after = 0.054 +/- 0.018 vs 0.033 +/- 0.015, p<0.05). The secondary platelet aggregation observed after high-dose adenosine diphosphate stimulation was inhibited after a 1-minute preincubation with EGF. Platelet aggregation in patients after gefitinib administration tended to accelerate and secondary aggregation was observed after low-dose adenosine diphosphate stimulation. We conclude that careful observation is needed for patients with chronic obstructive pulmonary disease, pulmonary fibrosis, and thromboembolic diseases receiving gefitinib. Furthermore, measurement of prostanoids may be a good predictor of the beneficial and adverse effects. Moreover, the combination of gefitinib with a COX inhibitor that regulates TXA(2)/PGI(2) balance should be evaluated.
Adult↗
Significance of alpha(IIb)beta(3) in subacute stent thrombosis after percutaneous coronary intervention.
SUMMARY: Soluble P-selectin and whole blood aggregation (WBA) were measured after percutaneous coronary intervention in patients who then received antiplatelet therapy. One had subacute thrombosis on day 7. This patient's WBA exhibited time-dependent enhancement. In addition, the accentuation of WBA on day 3 was observed when anti-alpha(IIb)beta(3) antibody was added. The remaining 22 patients were divided according to WBA results on day 3 with anti-alpha(IIb)beta(3) antibody added (A group, WBA enhanced; B group, WBA did not enhance). WBA on day 3 was similar in the two groups. The ratio of WBA with and without anti-alpha(IIb)beta(3) antibody was higher in group A than in group B. A significant time-dependent increase of soluble P-selectin was observed in the A group. These results suggest that enhancement of WBA with anti-alpha(IIb)beta(3) antibody after percutaneous coronary intervention predicts subacute thrombosis.
Acute Disease↗
Is eradication therapy useful as the first line of treatment in Helicobacter pylori-positive idiopathic thrombocytopenic purpura? Analysis of 207 eradicated chronic ITP cases in Japan.
A retrospective study was performed to determine the prevalence of Helicobacter pylori (H pylori) infection, the effect of H pylori eradication on platelet counts, and the characteristic clinical features of chronic immune or idiopathic thrombocytopenic purpura (ITP) with H pylori infection. H pylori infection was found in 300 patients, a group that was significantly older (P < .005) and had more cases of hyperplastic megakaryocytes in the bone marrow (P = .01) than patients without H pylori infection. H pylori eradication therapy was performed in 207 H pylori-positive ITP cases, and the platelet count response was observed in 63% of the successful eradication group and in 33% of the unsuccessful eradication group (P < .005). In the successful group, the complete remission and partial remission rates were 23% and 42%, respectively, 12 months after eradication. In the majority of responders, the platelet count response occurred 1 month after eradication therapy, and the increased platelet count continued without ITP treatment for more than 12 months. H pylori eradication therapy was effective even in refractory cases, which were unresponsive to splenectomy. In conclusion, H pylori infection was involved in most ITP patients older than 40 years in Japan, and eradication therapy should be the first line of treatment in H pylori-positive ITP patients.
Adult↗
[Definition and mechanism of drug-induced thrombocytopenia].
Drug-induced thrombocytopenia is common, but most previous reports do not present evidence for drugs as a definite or probable cause of the thrombocytopenia. The important diagnostic issue is to distinguish between drug-induced thrombocytopenia and idiopathic thrombocytopenic purpura, because the latter diagnosis requires the exclusion of other causes of thrombocytopenia. Drug-induced thrombocytopenia includes at least three mechanisms, such as marrow suppression, immunological, and nonimmunological thrombocytopenia. In immunological thrombocytopenia, demonstration of drug-dependent antiplatelet antibodies was included as evidence confirming the causal role of a drug. However, there are no standard assays for drug-dependent antiplatelet antibodies, no standard criteria for distinguishing positive from negative results, and no data on the sensitivity and specificity of these assays based on clinical criteria for a causal relation. Nonimmunological thrombocytopenia includes heparin-dependent thrombocytopenia and thrombotic thrombocytopenic purpura.
Anticoagulants↗
[CD30-negative diffuse large B-cell lymphoma expressing ALK].
A 33-years-old man was diagnosed as having undifferentiated carcinoma presenting with right neck lymphadenopathy in December 2000. He obtained complete remission (CR) following chemotherapy, radiation and lymphadenectomy on the right neck. He had multiple para-aorta lymphadenopathy and splenomegaly in December 2001. An open-abdominal lymph node biopsy was performed from which a diagnosis of anaplastic large cell lymphoma was made. CR was achieved with biweekly CHOP, however, the patient suffered from a relapse twice. He underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from his HLA-matched sister while in non-CR in November 2002. Engraftment was achieved on day 14, and at the same time, complete chimerism was confirmed. Acute grade III graft-versus-host disease (GVHD) developed and was controlled with cyclosporine A and prednisolone. Extensive chronic GVHD was subsequently observed and required systemic immunosuppression. His condition returned to CR after the PBSCT and he sustained complete chimerism. He suddenly died of fulminant thrombotic microangiopathy seven months after the PBSCT. The tumor cells were ALK-positive, CD30-negative and JH rearrangement was detected, and were therefore classified as diffuse large B-cell lymphoma with expression of ALK according to the WHO classification, though they differed from this subtype in some points. Although this case was refractory for chemotherapy with a complex karyotype, the graft-versus-lymphoma effect might have contributed to the sustained CR following the PBSCT.
Adult↗