Ferritin Levels on Hospital Admission Predict Hypoxic-Ischemic Encephalopathy in Patients After Out-of-Hospital Cardiac Arrest: A Prospective Observational Single-Center Study.

AIM: Out-of-hospital cardiac arrest (OHCA) is a major health concern in Western societies. Poor outcome after OHCA is determined by the extent of hypoxic-ischemic encephalopathy (HIE). Dysregulation of iron metabolism has prognostic relevance in patients with ischemic stroke and sepsis. The aim of this study was to determine whether serum iron parameters help to estimate outcomes after OHCA. METHODS: In this prospective single-center study, 70 adult OHCA patients were analyzed. Serum ferritin, iron, transferrin (TRF), and TRF saturation (TRFS) were measured in blood samples drawn on day 0 (admission), day 2, day 4, and 6 months after the return of spontaneous circulation (ROSC). The association of 4 iron parameters with in-hospital mortality, neurological outcome (cerebral performance category [CPC]), and HIE was investigated by receiver operating characteristics and multivariate regression analyses. RESULTS: OHCA subjects displayed significantly increased serum ferritin levels on day 0 and lowered iron, TRF, and TRFS on days 2 and 4 after ROSC, as compared to concentrations measured at a 6-month follow-up. Iron parameters were not associated with in-hospital mortality or neurological outcomes according to the CPC. Ferritin on admission was an independent predictor of features of HIE on cranial computed tomography and death due to HIE. CONCLUSION: OHCA is associated with alterations in iron metabolism that persist for several days after ROSC. Ferritin on admission can help to predict HIE.

Flagellin-Induced Immune Response in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Pathogen-associated molecular patterns (PAMPs) are involved in the pathogenesis of septic cardiomyopathy through a toll-like receptor (TLR)-mediated immune response. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can reflect the innate immune abilities of cardiomyocytes. Therefore, hiPSC-CMs may provide an attractive tool with which to study PAMP-induced alterations in cardiomyocytes. HiPSC-CMs from two different healthy donors were exposed to the PAMP flagellin (FLA) at different doses and exposure times. Alterations in the expression levels of distinct inflammation-associated cytokines, intracellular inflammation pathways including TLR5 downstream signaling, reactive oxygen species levels and surface antigen composition were assessed using PCR, ELISA and FACS techniques. Higher doses of flagellin increased the expression levels of inflammation-associated cytokines like TNFα (p < 0.01) and downstream signaling molecules like caspase-8 (p < 0.05). TLR5 expression (p < 0.01) and TLR5 fluorescence proportion (p < 0.05) increased in hiPSC-CMs after prolonged FLA exposure. FLA-induced innate immune response processes in cardiomyocytes might be detectable with an hiPSC-CMs-based in vitro model.

Elevated lipoprotein(a) levels and homozygous human platelet antigen 1b (HPA-1b) genotype are risk factors for intrauterine growth restriction (IUGR).

The risk of premature manifestation of cardiovascular disease is higher in women after a maternal placental syndrome, especially with a history of fetal IUGR. Aim of the study was to assess hereditary risk factors for arterial thrombosis as risk factors for IUGR. 183 women with fetal IUGR birth weight below the 10th percentile for gestational age and 300 control women were evaluated using a case-control design. In 121 of the 183 women, the newborns' birth weight was below the 5th percentile for gestational age. A risk association could be shown for homozygous human platelet antigen 1b genotype (OR 3.2, P = 0.038) in women with a history for a newborn's birth weight below the 5th percentile. Elevated levels of lipoprotein(a) (>0.7 g/l [95 % percentile], OR 2.9, P = 0.048) also represent a risk association in the same group of subjects. So did elevated levels of lipoprotein(a) (>0.7 g/l [95 % percentile], OR 3.4, P = 0.015) in women with a history for a newborn's birth weight below the 10th percentile. Risk factors of arterial thrombosis such as platelet receptor genotypes associated with platelet thrombogenicity and elevated levels of lipoprotein(a) might be of importance in the pathogenesis of IUGR.

Highly efficient lentiviral transduction of phenotypically and genotypically characterized endothelial progenitor cells from adult peripheral blood.

Postnatal vasculogenesis has been implicated as an important mechanism for neovascularization via bone marrow-derived endothelial progenitor cells (EPCs) circulating in peripheral blood. In preparation of the utilization of EPCs in clinical protocols, we have generated blood-derived EPCs according to two established protocols by culturing either nonadherent mononuclear cells on fibronectin or adherent mononuclear cells on collagen. To explore the feasibility of these EPCs for their potential clinical use as target cells for genetic transduction to enhance their thromboresistance, newly designed retroviral and lentiviral gene ontology expression vectors were tested. Whereas cell clusters derived from the nonadherent cells demonstrated an only limited proliferative potential, cell colonies derived from collagen-adherent cells expanded more than a million-fold. Characterization of the exponentially growing cells by surface antigen and gene expression profiling revealed a consistently strong expression of characteristic endothelial markers, whereas expression of leukocyte markers was gradually lost. Using a single-step transduction protocol, we were able to achieve gene transfer efficiency of up to 99%. Our results suggest that the generated blood-derived EPC population might be attractive target cells for tissue engineering and gene therapy protocols due to their well defined phenotype, extensive proliferative potential, and efficient genetic transducibility, three important qualities that need to be defined prior to any clinical use.

The G1691A mutation of the factor V gene (factor V Leiden) and the G20210A mutation of the prothrombin gene as risk factors in thrombotic microangiopathies.

Factor V Leiden (FVL) mutation and prothrombin G20210A mutation are common hereditary risk factors for venous thrombosis. In the current study, 40 patients (mean age +/- standard deviation, 35 +/- 11 years) and 764 healthy control subjects (mean age +/- standard deviation, 37 +/- 14 years) were enrolled to assess the potential role of these mutations in the manifestation of thrombotic microangiopathies. Compared with controls, neither the heterozygous FVL mutation (7.5% vs 8.5%; P = 1) nor the heterozygous prothrombin mutation (2.5% vs 2.8%; P = 1) was more prevalent in the patients. The findings do not support a significant role of FVL and prothrombin mutations as risk factors for the manifestation of thrombotic microangiopathies. Thus, screening for these mutations does not allow the identification of individuals at increased risk for these rare thrombotic disorders.

Recombinant factor VIIa for the prophylaxis of perioperative hemorrhage in a patient with congenital factor XI deficiency undergoing brain tumor neurosurgery.

The authors report on the first successful use of recombinant activated factor VII for the prophylaxis of bleeding during brain tumor neurosurgery in a patient suffering from inherited factor XI deficiency. Using the agent, surgery was performed without any bleeding complications. In this setting, off-label use of recombinant activated factor VII appears to be a promising alternative for patients suffering from this rare hemostatic defect with hitherto limited therapeutic options.

No evidence for involvement of prothrombotic platelet receptor polymorphisms in acute coronary stent thrombosis.

Polymorphisms of receptors involved in platelet adhesion and aggregation modulate platelet thrombogenicity and were found to predispose to premature arterial thromboses in individuals at risk. In our current study, we assessed the potential relevance of prothrombotic platelet receptor polymorphisms for the pathogenesis of acute coronary stent thrombosis. Comparing the genotype prevalences of respective polymorphisms in patients with acute coronary stent thrombosis and healthy control subjects, our data do not indicate an increased risk of carriers of prothrombotic variants of platelet receptors for this complication. Other factors such as the remodelling process and antiplatelet medication appear to be more relevant in this clinical setting. Along with our findings, screening for respective polymorphisms for risk assessment prior to coronary stenting is not indicated.

Association of genotypes of thrombin-activatable fibrinolysis inhibitors with thrombotic microangiopathies--a pilot study.

BACKGROUND: Thrombotic microangiopathies are characterized by microvascular thrombosis, consequently leading to microangiopathic haemolytic anaemia, thrombocytopenia and organ dysfunction. Although recent research has elucidated the pathogenesis of these rare thrombotic disorders to some extent, the determinants contributing to the manifestation remain rather unclear in the majority of affected patients. METHOD: In the present pilot study, we used a case-control design, enrolling 40 patients [mean age (+/-SD) 35+/-11 years] with a history of thrombotic microangiopathy and 689 control subjects to evaluate the association of gene polymorphisms of the thrombin-activatable fibrinolysis inhibitor (TAFI) with the manifestation of these rare thrombotic disorders. These polymorphisms are major determinants of TAFI plasma levels that were found to modulate the onset of venous and arterial thrombosis. RESULTS: As a result of our study, the prevalence of the GG genotype (adjusted OR 2.58; 95% CI 0.9-6.1, P=0.044) and the G allele (adjusted OR 2.2; 95% CI 1.2-4.2, P=0.017) of the C1542G polymorphism was significantly higher in patients with a history of thrombotic microangiopathy compared with controls. A higher prevalence of the GG genotype of the TAFI G505A polymorphism was also observed, but this association was not statistically significant (adjusted OR 4.97, CI 0.7-36.7, P=0.12). Considering the established genotype-phenotype associations, our observation suggests that lower TAFI plasma levels are associated with an increased risk for the manifestation of thrombotic microangiopathies. A diminished inactivation of C3a and C5a-also known from haemolytic uraemic syndrome (HUS) associated with factor H deficiency-might be the most likely explanation. CONCLUSIONS: The results of our pilot study indicate that the GG genotype of the C1542G polymorphism of TAFI displays risk factors for the manifestation of thrombotic microangiopathies. Our observation provides a rationale to assess genotype-phenotype relations by determination of TAFI plasma levels in various stages of disease in patients suffering from these rare thrombotic disorders.

Amyloidosis and bleeding: pathophysiology, diagnosis, and therapy.

Amyloid diseases can be associated with potentially life-threatening hemorrhage. Pathogenetic factors contributing to the abnormal bleeding tendency in this setting are heterogeneous and depend on the type of amyloidosis and pattern of organ involvement. In patients with light-chain (AL) amyloidosis, acquired hemostatic abnormalities, including coagulation factor deficiencies, hyperfibrinolysis, and platelet dysfunction, can be regarded as the most important pathogenetic factors. In patients with other types of amyloidosis, acquired hemostatic defects are rare, and amyloid deposition has also been reported to be the main cause of abnormal bleeding manifestations. Amyloid angiopathy with increased fragility of blood vessels and impaired vasoconstriction may promote bleeding in this setting. Rupture of solid organs caused by amyloid deposition also was reported. Whereas therapeutic options in bleeding caused by local amyloid deposition are restricted to supportive measures and, in severe cases, surgery, acquired hemostatic defects may be treated according to the causative mechanism. In this review, we focus on bleeding risks in patients with amyloid diseases. Current concepts with regard to pathophysiology, diagnosis, and treatment are summarized and discussed.