Failure of the anticoagulant therapy and psychological distress : Still far from a bridge

Background: The procoagulant stress response reflects part of a beneficial adaptation of the organism to environmental threats, but a protracted procoagulant state generates a thrombotic risk. Atrial fibrillation (AF) is the most common arrhythmia in the general population. Patients with AF have a higher risk of thromboembolic events and stroke, therefore they are treated with long-term oral anticoagulant (OAC) therapy. The aim of this study is to evaluate if there is any association between psychological distress and clinically unexplained variations of the International Normalized Ratio (INR), that is the index used to monitor both thromboembolic and bleeding risk in the case of patients under OAC therapy. Methods: Fifty-eight patients (men = 27; women = 31; mean age = 74.98) were recruited. The sample was divided according to the recognition (or not) of the reason why the INR was subtherapeutic ( < 2) and classified as "Known Reasons" (KR = 32.8%) and "Unknown Reasons" (UR = 67.2%). Psychological assessment included the following dimensions: symptoms of anxiety and depression, perceived stress, emotional regulation strategies, and alexithymia. Results: Considering Mann-Whitney test results, no significant difference was found in the scores of anxiety, depression, stress, and emotional regulation strategies. With regard to alexithymia, UR patients are characterized by a moderate tendency to an outward-oriented thinking (r = 0.25). Conclusion: A clear role for the detected psychological factors in determining abnormal INR range in patients under OAC therapy could not be found. Further studies are needed to support our findings, if possible exploring factors other than psychological distress and the related emotion regulation strategies

ProCMD: a database and 3D web resource for protein C mutants

Background: Activated Protein C (ProC) is an anticoagulant plasma serine protease which also plays an important role in controlling inflammation and cell proliferation. Several mutations of the gene are associated with phenotypic functional deficiency of protein C, and with the risk of developing venous thrombosis. Structure prediction and computational analysis of the mutants have proven to be a valuable aid in understanding the molecular aspects of clinical thrombophilia. Results: We have built a specialized relational database and a search tool for natural mutants of protein C. It contains 195 entries that include 182 missense and 13 stop mutations. A menu driven search engine allows the user to retrieve stored information for each variant, that include genetic as well as structural data and a multiple alignment highlighting the substituted position. Molecular models of variants can be visualized with interactive tools; PDB coordinates of the models are also available for further analysis. Furthermore, an automatic modelling interface allows the user to generate multiple alignments and 3D models of new variants. Conclusion: ProCMD is an up-to-date interactive mutant database that integrates phenotypical descriptions with functional and structural data obtained by computational approaches. It will be useful in the research and clinical fields to help elucidate the chain of events leading from a molecular defect to the related disease. It is available for academics at the URL http://www.itb.cnr.it/procmd/

Levels of Soluble Endothelial Protein C Receptor Are Associated with CD4+ Changes in Maraviroc-Treated HIV-Infected Patients

BACKGROUND: Inflammation is a key feature of HIV infection and is correlated with long-term negative cardiovascular outcomes. Therapy-induced increases in CD4(+) cell counts can control inflammation, as shown by decreases of coagulation and inflammation markers during efficacious therapy. Maraviroc, a CCR5-antagonist, has resulted in larger increases in CD4(+) counts both in naïve and experienced subjects compared to traditional antiretroviral therapy. OBJECTIVES AND METHODS: To examine if a member of the protein C anticoagulant and anti-inflammatory pathway, and marker of coagulation and inflammation, the soluble endothelial protein C receptor, is modified by infection and therapy-related variables in patients treated with Maraviroc. Endothelial protein C receptor, together with other established markers of inflammation and coagulation (CRP, IL-6, D-dimer and soluble thrombomodulin) was studied in 43 patients on traditional antiretroviral therapy and in 45 on Maraviroc during 48 weeks of follow-up. RESULTS: Soluble endothelial protein C receptor was the only marker that could discriminate at least partially between patients with a good response to Maraviroc and patients who did not respond with an adequate increase in CD4(+) cell counts (more than 500 cells/µL by week 48). CONCLUSIONS: Elevated levels of soluble endothelial protein C receptor, a sensitive marker of endothelial damage, indicated a low level of inflammation and coagulation activation in Maraviroc treated patients not picked up by other widely used markers. Persistent elevated levels of this marker at 48 weeks from beginning of treatment with Maraviroc were related to a poor increase in CD4(+) cells

Atrial fibrillation and psychological factors : a systematic review

BACKGROUND: Psychological factors have been suggested to have an influence in Atrial Fibrillation (AF) onset, progression, severity and outcomes, but their role is unclear and mainly focused on anxiety and depression. METHODS: A systematic electronic search had been conducted to identify studies exploring different psychological factors in AF. The search retrieved 832 articles that were reviewed according to inclusion criteria: observational study with a control/comparison group; use of standardized and validated instruments for psychological assessment. Results were summarized qualitatively and quantitatively by effect size measure (Cohen's d and its 95% confidence interval). Cochrane Collaboration guidelines and the PRISMA Statement were adopted. RESULTS: Eight studies were included in the systematic review. Depression was the most studied construct/ but only one study showed a clear link with AF. The remaining studies showed small and non-significant (95% CI [-0.25-1.00]) differences between AF and controls, no differences in frequency of depression history (95% CI [-0.14-0.22]) or in case frequency (95% CI [-0.50-0.04]). Miscellaneous results were found as far as anxiety: AF patients showed higher levels when compared to healthy subjects (95% CI [2.05-2.95]), but findings were inconsistent when compared to other heart diseases. Considering personality and life-events preceding AF, we respectively found a large (95% CI [1.87-2.49]) and a moderate to large effect (95% CI [0.48-0.98]). DISCUSSION: The small number of studies does not allow to draw clear-cut conclusions on the involvement of psychological factors in AF. Promising lines of research are related to personality and adverse life-events, and to the increase of longitudinal design studies. Some methodological problems could be overcome by including clinical psychologists in the implementation of research protocols

Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time

The synthetic vasopressin derivative desmopressin (DDAVP) shortens a prolonged bleeding time (BT) in patients with uremia, congenital platelet dysfunction, and von Willebrand disease. To establish the limits of the clinical usefulness of DDAVP, a controlled randomized study was carried out in 53 patients and ten volunteers with different conditions that have in common a prolonged BT. DDAVP significantly shortened the BT in 21 cirrhotics (P less than .01), in eight patients with unclassified prolonged BT (P less than .05) and in ten volunteers taking the antiplatelet drugs aspirin (P less than .05) and ticlopidine. The BT changes were not statistically significant in 15 patients with severe thrombocytopenia nor in nine with congenital platelet dysfunction, even though a few patients with storage pool deficiency responded with a marked BT shortening. Our findings indicate that DDAVP might be given when biopsies or other surgical procedures must be carried out in patients with prolonged BT. However, the compound is often ineffective in patients with thrombocytopenia or congenital platelet dysfunction

Selective modulation of protein C affinity for EPCR and phospholipids by Gla domain mutation

Uniquely amongst vitamin K-dependent coagulation proteins, protein C interacts via its Gla domain both with a receptor, the endothelial cell protein C receptor (EPCR), and with phospholipids. We have studied naturally occurring and recombinant protein C Gla domain variants for soluble (s)EPCR binding, cell surface activation to activated protein C (APC) by the thrombin-thrombomodulin complex, and phospholipid dependent factor Va (FVa) inactivation by APC, to establish if these functions are concordant. Wild-type protein C binding to sEPCR was characterized with surface plasmon resonance to have an association rate constant of 5.23 x 10(5) m(-1).s(-1), a dissociation rate constant of 7.61 x 10(-2) s(-1) and equilibrium binding constant (K(D)) of 147 nm. It was activated by thrombin over endothelial cells with a K(m) of 213 nm and once activated to APC, rapidly inactivated FVa. Each of these interactions was dramatically reduced for variants causing gross Gla domain misfolding (R-1L, R-1C, E16D and E26K). Recombinant variants Q32A, V34A and D35A had essentially normal functions. However, R9H and H10Q/S11G/S12N/D23S/Q32E/N33D/H44Y (QGNSEDY) variants had slightly reduced (< twofold) binding to sEPCR, arising from an increased rate of dissociation, and increased K(m) (358 nm for QGNSEDY) for endothelial cell surface activation by thrombin. Interestingly, these variants had greatly reduced (R9H) or greatly enhanced (QGNSEDY) ability to inactivate FVa. Therefore, protein C binding to sEPCR and phospholipids is broadly dependent on correct Gla domain folding, but can be selectively influenced by judicious mutation

Alterations of hemostatic parameters in the early development of allogeneic hematopoietic stem cell transplantation-related complications

Thrombotic events are common and potentially fatal complications in patients receiving hematopoietic stem cell transplantation (HSCT). Early diagnosis is crucial but remains controversial. In this study, we investigated the early alterations of hemostatic parameters in allogeneic HSCT recipients and determined their potential diagnostic values in transplantation-related thrombotic complications and other post-HSCT events. Results from 107 patients with allogeneic HSCT showed higher levels of plasma plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and tissue-plasminogen activator (t-PA) and a lower level of plasma protein C after transplantation. No change was found for prothrombin time, antithrombin III, d-dimer, and activated partial thromboplastin time following HSCT. Transplantation-related complications (TRCs) in HSCT patients were defined as thrombotic (n = 8), acute graft-versus-host disease (aGVHD, n = 45), and infectious (n = 38). All patients with TRCs, especially the patients with thrombotic complications, presented significant increases in the mean and maximum levels of PAI-1 during the observation period. Similarly, a high maximum t-PA level was found in the thrombotic group. In contrast, apparent lower levels of mean and minimum protein C were observed in the TRC patients, especially in the aGVHD group. Therefore, the hemostatic imbalance in the early phase of HSCT, reflecting prothrombotic state and endothelial injury due to the conditioning therapy or TRCs, might be useful in the differential diagnosis of the thrombotic complication from other TRCs

Evolution of model proteins on a foldability landscape

We model the evolution of simple lattice proteins as a random walk in a fitness landscape, where the fitness represents the ability of the protein to fold. At higher selective pressure, the evolutionary trajectories are confined to neutral networks where the native structure is conserved and the dynamics are non self-averaging and nonexponential. The optimizability of the corresponding native structure has a strong effect on the size of these neutral networks and thus on the nature of the evolutionary process. Proteins 29:461–466, 1997. © 1997 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38527/1/6_ftp.pd