Kyou-Sup Han

Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial

BACKGROUNDnBone-marrow stem-cell transplantation has been shown to improve cardiac function in patients with myocardial infarction. We examined the feasibility and efficacy of granulocyte-colony stimulating factor (G-CSF) therapy and subsequent intracoronary infusion of collected peripheral blood stem-cells (PBSCs) in such patients.nnnMETHODSnWe prospectively randomised 27 patients with myocardial infarction who underwent coronary stenting for the culprit lesion of infarction into three groups; cell infusion (n=10), G-CSF alone (n=10), and control group (n=7). Changes in left ventricular systolic function and perfusion were assessed after 6 months. By December, 2003, seven patients from the cell infusion group, three from the G-CSF group, and one from the control group had been assessed.nnnFINDINGSnG-CSF injection and intracoronary infusion of the mobilised PBSC did not aggravate inflammation and ischaemia during the periprocedural period. Exercise capacity (mean treadmill exercise time: 450 s [SD 178] at baseline vs 578 s [168] at 6 months follow-up, p=0.004), myocardial perfusion (perfusion defect 11.6% [9.6] vs 5.3% [5.0], p=0.020) and systolic function (left ventricular ejection fraction 48.7% [8.3] vs 55.1% [7.4], p=0.005) improved significantly in patients who received cell infusion. However, we noted an unexpectedly high rate of in-stent restenosis at culprit lesion in patients who received G-CSF, and therefore we stopped enrollment.nnnINTERPRETATIONnG-CSF therapy with intracoronary infusion of PBSC showed improved cardiac function, and promoted angiogenesis in patients with myocardial infarction. However, aggravation of restenosis could be a serious problem. In future studies with G-CSF based stem-cell therapy, patients should be carefully monitored for unexpected effects.

Differential Effect of Intracoronary Infusion of Mobilized Peripheral Blood Stem Cells by Granulocyte Colony–Stimulating Factor on Left Ventricular Function and Remodeling in Patients With Acute Myocardial Infarction Versus Old Myocardial Infarction The MAGIC Cell-3-DES Randomized, Controlled Trial

Background— The efficacy of intracoronary infusion of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) has not been compared between patients with acute (AMI) versus old myocardial infarction (OMI). In addition, the potential risk of restenosis associated with G-CSF–based stem cell therapy has not been evaluated in the setting of drug eluting stent (DES) implantation. Methods and Results— We randomly allocated 96 patients with myocardial infarction who underwent coronary revascularization with DES for the culprit lesion into 4 groups. Eighty-two patients completed 6-month follow-up; AMI cell infusion (n=25), AMI control (n=25), OMI cell infusion (n=16), and OMI control group (n=16). In cell infusion groups, PBSCs were mobilized by G-CSF for 3 days and delivered to infarcted myocardium via intracoronary infusion. The AMI cell infusion group showed a significant additive improvement in left ventricular ejection fraction (LVEF) and remodeling compared with controls (change of LVEF: +5.1±9.1% versus −0.2±8.6%, P<0.05; change of end-systolic volume: −5.4±17.0 mL versus 6.5±21.9 mL, P<0.05). In OMI patients, however, there was no significant change of LVEF and ventricular remodeling in spite of significant improvement of coronary flow reserve after cell infusion. G-CSF–based cell therapy did not aggravate neointimal growth with DES implantation. Conclusions— Intracoronary infusion of mobilized PBSCs with G-CSF improves LVEF and remodeling in patients with AMI but is less definite in patients with OMI. G-CSF–based stem cell therapy with DES implantation is both feasible and safe, eliminating any potential for restenosis.

Neutrophil to lymphocyte ratio for preoperative diagnosis of uterine sarcomas: A case-matched comparison

BACKGROUNDnUterine sarcomas are rare among all uterine malignancies, and frequently misdiagnosed as benign uterine diseases such as leiomyoma and adenomyosis because of lack of feasible tools for the preoperative diagnosis. Although some studies have suggested the role of serum CA-125 levels for the preoperative diagnosis, the efficacy is controversial. Since malignancy is known to be associated with systemic inflammation which leads to hematological alteration, we compared the efficacy for the preoperative diagnosis of uterine sarcomas between the neutrophil to lymphocyte ratio (NLR) and serum CA-125 levels using a case-match comparison.nnnMETHODSnFrom November 2004 to December 2008, 55 patients with carcinosarcoma (n=21), leiomyosarcoma (n=20) and endometrial stromal sarcoma (n=14) were matched to 330 patients with leiomyoma (n=165) and adenomyosis (n=165) in terms of age at diagnosis, body mass index and uterine volume.nnnRESULTSnThe receiver operating characteristic curve showed the best cut-off values of the NLR (>or=2.12) and serum CA-125 levels (>or=27.5U/ml) for the preoperative diagnosis of uterine sarcomas, demonstrating that the NLR was more powerful for the preoperative diagnosis of uterine sarcomas than serum CA-125 levels (sensitivity, 74.5% vs. 52.3%; specificity, 70.3% vs. 50.5%; positive predictive value, 29.5% vs. 15.1%; negative predictive value, 94.3% vs. 86.5%; accuracy, 60.6% vs. 49.6%; p<0.05). Furthermore, the NLR reflected recurrence and progression more accurately than serum CA-125 levels in patients with uterine sarcomas.nnnCONCLUSIONSnThese findings suggest that the NLR may be more useful than serum CA-125 levels as a cost-effective tool for the preoperative diagnosis in patients with uterine sarcomas.

Accuracy of Platelet Counting by Automated Hematologic Analyzers in Acute Leukemia and Disseminated Intravascular Coagulation Potential Effects of Platelet Activation

Platelet counting in patients with acute leukemia or disseminated intravascular coagulation (DIC) may have a risk for erroneous counts owing to the presence of nonplatelet particles or platelet activation. We evaluated automated platelet counting methods using the Abbott Cell-Dyn Sapphire (Abbott Diagnostics, Santa Clara, CA), Sysmex XE-2100 (Sysmex, Kobe, Japan), ADVIA 2120 (Siemens Diagnostics, Tarrytown, NY), and Beckman Coulter LH 750 (Beckman Coulter, Miami, FL) compared with the international reference method (IRM). Automated platelet counting methods were inaccurate compared with the IRM, without evidence of interfering nonplatelet particles. It is interesting that platelet activation markers were associated with DIC severity and erroneous platelet counting, suggesting that platelet activation is a potential source of inaccuracy. Furthermore, the artifactual in vitro platelet activation induced a high degree of intermethod variation in platelet counts. The inaccuracy of automated platelet counts increased the risk for misdiagnosis of DIC. More attention needs to be given to the accuracy of platelet counts, especially in clinical conditions with florid platelet activation.

Surface Expression of Neutrophil CXCR4 is Down-Modulated by Bacterial Endotoxin

The chemokine receptor CXCR4 and its unique ligand, stromal-derived factor 1 (SDF-1), play critical roles in the retention of hematopoietic cells within bone marrow and in their mobilization into the circulation. Surface CXCR4 down-regulation in hematopoietic cells is associated with a loss of retention of the cells in bone marrow. Lipopolysaccharide (LPS), commonly referred to as endotoxin, induces neutrophilia in vivo, but the mechanism of mobilization related to neutrophilia has not been fully clarified. We show that LPS reduces CXCR4 surface expression in a dose- and time-dependent manner in neutrophils and monocytes, but not in lymphocytes. Polymyxin B neutralization of LPS in culture supernatants still induced this down-modulation, and LPS-stimulated neutrophils released interferon γ and interleukin 1β. These results provide evidence that CXCR4 down-regulation can be attributed to soluble factors released by neutrophils upon LPS treatment. Moreover, LPS treatment increased CXCR4 messenger RNA in neutrophils, suggesting that the down-regulation of surface CXCR4 is caused by a posttranslational mechanism, and the chemotactic migration of neutrophils in response to SDF-1 was reduced by LPS pretreatment.Thus, the present study has shown that by down-regulating neutrophil CXCR4 expression and attenuating neutrophil responsiveness to SDF-1, LPS can mobilize neutrophils from bone marrow to the peripheral blood through reducing neutrophil retention in bone marrow.

Contributions of procoagulants and anticoagulants to the international normalized ratio and thrombin generation assay in patients treated with warfarin: Potential role of protein Z as a powerful determinant of coagulation assays

BACKGROUNDnThe effects of warfarin are measured with the international normalized ratio (INR). However, the thrombin generation assay (TGA) may offer more information about global coagulation. We analyzed the monitoring performance of the TGA and INR and investigated the impact of procoagulants (fibrinogen, factor (F)II, FVII, FIX, and FX) and anticoagulants (proteins C, S, and Z) on them.nnnMETHODSnThe TGA was performed on a calibrated automated thrombogram, producing lag time, endogenous thrombin potential (ETP), and peak thrombin in 239 patients treated with warfarin. Pro- and anticoagulant levels were also measured.nnnRESULTSnThe INR was significantly and inversely correlated with ETP. The therapeutic range of ETP comparable to an INR range of 2.0-3.0 was 290.1-494.6. ETP showed comparable performance to the INR as a warfarin-monitoring parameter with respect to clinical complication rate. The median levels of FII, FVII, FIX, and FX and proteins C and Z tended to decrease gradually with increasing anticoagulation intensity according to the INR or ETP. Of note, protein Z levels decreased dramatically with increasing anticoagulation status. INRs were significantly determined by FII, FVII, and protein Z. ETP was significantly dependent on FVII, and proteins C and Z concentration. Protein Z significantly reduced the total amount of thrombin generation and prolonged PT value in vitro.nnnCONCLUSIONSnThe INR and ETP exhibit similar efficacy for warfarin monitoring according to the clinical complication rate. Protein Z is considered to be a significant determinant of INR and ETP in patients on warfarin therapy.

Coagulation Proteins Influencing Global Coagulation Assays in Cirrhosis: Hypercoagulability in Cirrhosis Assessed by Thrombomodulin-Induced Thrombin Generation Assay

Background. Liver disease is accompanied by profound hemostatic disturbances. We investigated the influences of pro- and anticoagulation factors on global coagulation tests including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin generation assay (TGA) in cirrhosis. We also investigated whether cirrhotic patients exhibit hypo- or hypercoagulability using the TGA. Methods. The TGA was performed on a calibrated automated thrombogram, given lag time, endogenous thrombin potential (ETP), and peak thrombin in 156 cirrhotic patients and 73 controls. Results. PT was determined according to the factor (F) II, FV, FVII, FIX, and protein C levels. We observed that aPTT was dependent on FII, FIX, and FX levels. The ETP was dependent on FII, antithrombin, and protein C with 5u2009pM tissue factor (TF) stimulation, and FIX and protein C at 1u2009pM TF. The ETP ratio with 1u2009pM TF increased significantly in cirrhosis, indicating hypercoagulability, whereas that with 5u2009pM TF did not increase in cirrhosis. Conclusion. PT and the TGA are sensitive to protein C levels. Even with prolonged PT, the TGA can detect hypercoagulability in cirrhosis. Further studies should evaluate global coagulation status in cirrhosis patients using the newly devised TGA system.

Neutrophil and monocyte activation markers have prognostic impact in disseminated intravascular coagulation: in vitro effect of thrombin on monocyte CD163 shedding.

Monocyte and neutrophil activation occur during microvascular disturbance of disseminated intravascular coagulation (DIC). This study investigated the diagnostic and prognostic value of circulating neutrophil elastase (NE) and neutrophil volume distribution width (NDW) as neutrophil activation markers and circulating soluble CD163 (sCD163) and monocyte volume distribution width (MDW) as monocyte activation markers in 168 patients suspected of having DIC. The sCD163 provided significant diagnostic value. The prognostic value of sCD163 was comparable to that of D-dimer, but was dependent on other coagulation markers. In vitro, thrombin significantly induced sCD163 from monocytes upregulated with IL-10 or dexamethasone. NDW was an independent and powerful prognostic marker. MDW and NE did not provide diagnostic and prognostic power. Excessive thrombin during ongoing DIC induces florid secretion of CD163; sCD163 might therefore be a potential diagnostic and prognostic marker for DIC. NDW, a convenient parameter measured by an automated hematology analyzer, may be an independent prognostic parameter for DIC.

Association between red blood cell storage duration and clinical outcome in patients undergoing off-pump coronary artery bypass surgery: a retrospective study

BackgroundProlonged storage of red blood cells (RBCs) leads to fundamental changes in both the RBCs and the storage media. We retrospectively evaluated the relationship between the RBC age and in-hospital and long-term postoperative outcomes in patients undergoing off-pump coronary artery bypass.MethodsThe electronic medical records of 1,072 OPCAB patients were reviewed and information on the transfused RBCs and clinical data were collected. The effects of RBCs age (mean age, oldest age of transfused RBCs, any RBCs older than 14xa0days) on various in-hospital postoperative complications and long-term major adverse cardiovascular and cerebral events over a mean follow-up of 31xa0months were investigated. Correlations between RBCs age and duration of intubation, intensive care unit, or hospital stay, and base excess at the first postoperative morning were also analyzed.ResultsAfter adjusting for confounders, there was no relationship between the RBCs age and in-hospital and long-term clinical outcomes except for postoperative wound complications. A significant linear trend was observed between the oldest age quartiles of transfused RBCs and the postoperative wound complications (quartile 1 vs. 2, 3 and 4: OR, 8.92, 12.01 and 13.79, respectively; P for trendu2009=u20090.009). The oldest transfused RBCs showed significant relationships with a first postoperative day negative base excess (Pu2009=u20090.021), postoperative wound complications (Pu2009=u20090.001), and length of hospital stay (Pu2009=u20090.008).ConclusionsIn patients undergoing off-pump coronary artery bypass, the oldest age of transfused RBCs were associated with a postoperative negative base excess, increased wound complications, and a longer hospital stay, but not with the other in-hospital or long-term outcomes.

Impact of cytokine gene polymorphisms on risk and treatment outcomes of aplastic anemia.

Autoreactive cytotoxic T cells play a key role in the pathogenesis of aplastic anemia (AA) by myelosuppressive cytokines including interferon-gamma, tumor necrosis factor alpha, and transforming growth factor beta. The purpose of this study is to determine which single nucleotide polymorphisms (SNPs) in cytokine genes were relevant to AA risk and whether the relevant SNPs were associated with response to immunosuppressive therapy (IST). Among 84 screened patients, 80 patients confirmed as having acquired AA, and 84 age- and sex-matched healthy controls were analyzed consecutively. We genotyped ten polymorphisms in three cytokine genes (IFNG, TNF, and TGFB1) and FAS gene. We assessed the association between polymorphisms and AA risk, and the association between polymorphisms and response to IST in three genetic models (dominant, recessive, and additive). The IFNG −2,353 T allele (dominant model, ORu2009=u20090.43, pu2009=u2009.012) and TCA haplotype (dominant model, ORu2009=u20090.50, pu2009=u2009.038) were significantly associated with the development of AA. In addition, this relevant IFNG −2,353 T allele and TCA haplotype were related to the response of IST (dominant model, ORu2009=u20090.076, pu2009=u2009.034). Concerning TGFB1, although its polymorphisms are not related to AA susceptibility, P10L T allele (recessive model, ORu2009=u20090.18, pu2009=u2009.038) and CT haplotype (dominant model, ORu2009=u20095.68, pu2009=u2009.038) were associated with response to IST. This exploratory study concurred with prior studies indicating that polymorphisms in IFNG are related to AA susceptibility. In addition, it was found that polymorphisms in IFNG and TGFB1 are associated with response to IST.