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At present, little is known about the clearance of platelet-derived microparticles (PMP) in human blood, as due to ethical considerations infusion experiments with labeled microparticles are delicate. Therefore, we investigated the kinetics of PMP, which are abundantly present in apheresis platelet concentrates (PC), following platelet transfusion in severe thrombocytopenic patients ( n == 11). PMP were double-stained with annexin V and cell-specific antibodies (anti-CD61, anti-CD63 or anti-CD62P, respectively) and detected by flow cytometry before and after transfusion of a single PC at fixed time intervals. Upon transfusion, the plasma levels of MP binding annexin V (2.5-fold), PMP (CD61++; 2.9-fold), and PMP from activated platelets (CD63++; 1.9-fold) or P-selectin (2.5-fold) increased immediately. The plasma levels of MP decreased with a half life of 5.8 hours (annexin V; 95%% CI: 1.8--18.3) and 5.3 hours (CD61; 95%% CI: 2.0--14.2). This is the first report in which the half life time of transfused PMP has been investigated in humans. [ABSTRACT FROM AUTHOR]

Microparticles (MP) are membrane vesicles with thrombogenic and immunomodulatory properties. We determined MP subgroups from resting platelets, activated platelets and endothelial cells in donors and apheresis platelet concentrates (PC). MP were double stained with annexin V and CD61 (platelet-derived MP; PMP), P-selectin or CD63 (MP from activated platelets) and CD144 plus E-selectin (endothelial cell-derived MP; EMP) and detected by flow cytometry in platelet donors ( n = 36) and apheresis PC ( n = 11; Trima™). PC contained MP, mainly from resting platelets [93% (90-95)], and minor fractions of PMP from activated platelets [P-selectin or CD63; 4·8% (3·2-7·7) and 2·6% (2·0-4·0)]. Compared to donors, levels of annexin V+ MP, PMP, P-selectin and CD63 MP were 1·7-, 2·3-, 8·6- and 3·1-fold higher in PC (all P < 0·05). During storage (1-5 days), levels of annexin V+ MP and PMP did not increase, although small increases in the fraction of P-selectin or CD63 MP occurred (both P < 0·05). PC also contained EMP, which were 2·6- to 3·7-fold enriched in PC compared to donors ( P < 0·05). Transfusion of apheresis PC also results in transfusion of HLA-carrying PMP and EMP. This might counteract the aim of reducing transfused HLA load by leucodepletion. The increases in PMP exposing P-selectin or CD63 reflect mild platelet activation during storage. We conclude that in leucodepleted platelet apheresis using fluidized particle bed technology, MP are harvested mainly from the donor by apheresis. Improvement in apheresis technology might reduce MP load. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) as potent antigen-presenting cells (APC) and T cells as effector cells play an essential role in the pathophysiology of both graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactions after transplantation. Therefore, we determined the kinetics of DC and T-cell chimerism establishment after allogeneic hematopoietic cell transplantation (AHCT) in a group of 144 patients, using fluorescence-activated cell sorting (FACS) or magnetic cell sorting (MACS) followed by FISH or STR-PCR analysis for chimerism evaluation. In all, three cell lines investigated (CD3 + T cells, CD11c + DC1 and CD123 + DC2), we found a rapid and consistent establishment of complete donor chimerism (CDC) in over 70% of all patients during the first 6 weeks after AHCT. The rate of patients with CDC increased significantly over time within the first year after transplantation. A related donor (P = 0.004) as well as an underlying lymphatic leukemia (P = 0.03) were found to be significantly associated with development of MC in T cells. No significant correlation between DC or T cell chimerism and GvHD or relapse was detected. Our results thus demonstrate a fast and stable CDC in DC1, DC2 and T cells after AHCT that continuously increases over time in nearly all patients. [ABSTRACT FROM AUTHOR]

Summary:Veno-occlusive disease (VOD) is one of the most serious complications following hematopoietic stem cell transplantation (HSCT) and is associated with a high mortality. We conducted a large trial on the clinical significance of protein C (PC) and procollagen III peptide (PNPIII) levels, which have been described as possible diagnostic markers of VOD. In total, 350 patients undergoing allogeneic HSCT were included. PC and PNPIII levels were analyzed prior to conditioning and weekly until 8 weeks after the HSCT. Signs of VOD and other transplantation-related complications (graft-versus-host disease (GVHD), toxicity, microangiopathic hemolytic anemia, infection) were recorded weekly throughout the trial. Patients showed a significant drop of the PC levels in VOD (70.3 vs 96.3%, P<0.001) and with increasing severity of aGVHD. Steroids increased the PC levels (69.4% vs 109.4%, P<0.001). The highest PNPIII levels were registered in patients with VOD (mean 6.3 IU/ml). Patients with aGVHD showed an elevation of PNPIII, especially patients with hepatic aGVHD. PC levels during conditioning do not predict VOD (98.5 vs 76.5%, NS). Although PC and PNPIII may play a role in the pathogenesis of VOD they cannot discriminate between complications with jaundice and are only of limited help in the differential diagnosis of VOD.Bone Marrow Transplantation (2005) 36, 631–637. doi:10.1038/sj.bmt.1705114; published online 1 August 2005 [ABSTRACT FROM AUTHOR]

Background: Successful pregnancies require fine tuning of fibrinolytic activities in order to secure fibrin polymerization and stabilization of the placental basal plate as well as to prevent excess fibrin deposition in placental vessels and intervillous spaces. Fibrinolysis is tightly regulated by plasminogen activator inhibitor-1 (PAI-1). Endothelial PAI-1 synthesis is induced by angiotensin II, which is generated by angiotensin I-converting enzyme (ACE).Methods: We studied the ACE deletion (D)/insertion (I) polymorphism and the PAI-1 4G/5G polymorphism in women with recurrent spontaneous miscarriages (RM). Both polymorphisms have been shown to be associated with ACE and PAI-1 expression levels respectively. A study group of 184 patients with a history of two or more consecutive unexplained spontaneous miscarriages was compared with a control group of 127 patients with uneventful term deliveries and no history of miscarriages.Results: Our findings show: (i) homozygosity for the D allele of the ACE gene, which results in elevated PAI-1 concentrations and hypofibrinolysis, is associated with an elevated risk of RM; (ii) the combination of the D/D genotype with two 4G alleles of the PAI-1 promoter, which further increases PAI-1 plasma levels, is significantly more frequent in RM patients compared with controls.Conclusions: Based on these results, we recommend the incorporation of these two polymorphisms into the spectrum of thrombophilic mutations which should be analysed in individuals with recurrent spontaneous miscarriages. Patients homozygous for both the ACE D and PAI-1 4G alleles may benefit from the application of low molecular weight heparin as early as possible in the pregnancy in order to prevent uteroplacental microthromboses. [ABSTRACT FROM AUTHOR]

Presents a study which observed blood platelet count of patients after undergoing allogeneic hematopoietic stem cell transplantation. Information on the patients and methods; Results of the study; Discussion of findings.

Studies the impact of antithymocyte globulin on short-term toxicity after allogeneic stem cell transplantation. Information on the patients; Methodology; Results of the study.

The conditioning regimen preceding hematopoietic stem cell transplantation (HSCT) causes a rapid decrease in the platelet count and signs of disseminated intravascular coagulation, possibly indicating platelet activation. As impacts during the conditioning regimen may predict later transplantation-associated complications, we investigated changes in platelet membrane glycoproteins (GP) and the liberation of microparticles. Platelet receptors and granules of 49 patients undergoing HSCT were evaluated by flow cytometric analysis before and after the different phases of the conditioning regimen [chemotherapy, total body irradiation (TBI), therapy with antithymocyte globulin (ATG)] and final transplantation. Following chemotherapy a high surface expression of CD62P, a low mepacrine staining, and a reduced surface expression of CD42b (part of the GP Ib/V/IX complex) were found, indicating an irreversible activation of platelets. In addition, elevated levels of circulating microparticles were observed, which may reinforce the thrombosis risk in these patients. Treatment with ATG leads to an elevated surface expression of PAC-1 epitopes, which are neoepitopes appearing after activation of GP IIb/IIIa. However, a significant degranulation was not detectable, which may be the consequence of inhibitory influences on platelets during ATG-induced cytokine release syndrome. TBI and transplantation itself had no influence on platelets. This study was able to demonstrate activating effects on platelets by certain phases of the conditioning regimen in patients receiving HSCT. Chemotherapy, in particular, leads to a strong and irreversible platelet activation and a generation of microparticles, which may cause an increased thrombosis risk. Our findings underline the impact of platelets on the pathogenesis of hemostatic complications during HSCT. [ABSTRACT FROM AUTHOR]

To investigate endothelial cell alterations in BMT recipients developing acute graft-versus-host disease (aGVHD) we determined levels of the endothelial cell markers von Willebrand factor (VWF) and thrombomodulin (TM) in 57 patients undergoing BMT. Before conditioning VWF and TM levels did not differ significantly between transplant recipients who later developed no or mild (grade I) aGVHD (group A, allogeneic n = 22, autologous n = 7; VWF 136.0 ± 44.1%; TM 29.5 ± 18.0 ng/ml), and those with moderate or severe (grade II or III) aGVHD (group B, n = 28; VWF 142.2 ± 37.6%; TM 35.2 ± 20.1 ng/ml). A first significant rise of both VWF and TM levels was noted after conditioning (day 0) both in group A (VWF 197.0 ± 113.3%; P < 0.001; tm 39.3 ± 23.3 ng/ml; P < 0.01) as well as in group b (vwf 201.7 ± 53.3%; P < 0.0001; tm 43.5 ± 23.5 ng/ml; P < 0.05). subgroup analysis of autografted patients revealed no significant increase after conditioning in these patients. at the time of engraftment and onset of agvhd (day 21), when vwf and tm levels within the groups were significantly elevated as compared with baseline (day -8) levels, group b patients (62.7 ± 38.5 ng/ml) had significantly higher (P < 0.01) tm levels than patients of group a (37.4 ± 19.6 ng/ml). this significant elevation also persisted at the end of the investigational period (day 28; group b: 56.0 ± 37.6 ng/ml; group a: 38.2 ± 23.7 ng/ml; P < 0.01). an elevation of endothelial cell markers is found in the course of bmt, particularly after conditioning and at the time of engraftment. this increase is pronounced in patients with agvhd suggesting not only epithelial cell but also endothelial cell injury during agvhd. [ABSTRACT FROM AUTHOR]

Plasminogen activator inhibitor 1 (PAI-1) and aminopropeptide of type III procollagen (PIIINP) have been described as markers of hepatic veno-occlusive disease (VOD) after bone marrow transplantation (BMT). We determined these parameters in two patients undergoing BMT and subsequent liver transplantation due to VOD. Previously normal PAI-1 levels (maximum 30.0 ng/ml in patient 1, 23.7 ng/ml in patient 2) were elevated for the first time in both patients at the time of clinically diagnosed VOD on days 40 and 20, respectively (patient 1: 317.5 ng/ml; patient 2: 317.2 ng/ml). Levels remained elevated until liver transplantation was performed on days 79 and 41, respectively. Baseline levels (day -8) of aminopropeptide of type III collagen (patient 1: 4.44 μ g/l; patient 2: 8.1 μ g/l) peaked at the time of BMT in both patients (155.0 μ g/l and 108.3 μ g/l). After an intermittent decrease at the time of discharge on day 32, a second elevation was observed in patient 1 when she was readmitted and presented with typical signs of VOD on day 40. In patient 2, PIIINP levels remained high until VOD was diagnosed (day 20) and liver transplantation was performed. After liver transplantation, PAI-1 levels normalized in both patients and PIIINP levels declined. Both patients died due to infectious complications and multiorgan failure on days 141 and 101, respectively. Whereas the early rise of PIIINP did not correlate with the clinical onset of VOD, the results emphasise the relevance of PAI-1 for diagnosing VOD. [ABSTRACT FROM AUTHOR]

Capillary leak syndrome (CLS) is a severe complication after bone marrow transplantation (BMT). To investigate whether there is a pathogenetic role of the complement system, we monitored the levels of the terminal complement complex C5b-9 (TCC) and C3a-desArg as indicators of an activation of the complement system and the inhibitor of the classical pathway of the complement cascade, C1 inhibitor (C1-INH), in 48 bone marrow transplant recipients from 1 week before to 5 weeks after transplantation. Capillary leak syndrome developed in 7 out of 48 patients between days 1 and 12 after BMT. Complement activation as indicated by TCC levels was more pronounced in patients with CLS (n = 7) from day -8 to +28 (p < 0.05; day -1) and the elevation of TCC levels lasted longer in CLS patients (peak day 21) than in patients without this complication (peak day 7). Mean C3a-desArg levels were highest in patients with CLS reaching a peak at day 7. During the early posttransplant period a significant elevation of C1-INH levels (p < 0.01 and p < 0.05 respectively) compared with baseline levels (day -8) was found in patients with and without CLS, which was more pronounced in those patients with CLS (p < 0.05). Although we could not observe an absolute C1-INH deficiency as compared to healthy individuals our data support the presence of a relative deficiency of the inhibitor which might explain the reported beneficial effects of C1-INH substitution in BMT related CLS. [ABSTRACT FROM AUTHOR]