SciCombinator

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Concept: Factor XII

28

In order to develop a promising substitute for heparin, N-succinyl chitosan (NSC) was chemically modified by sulfating agent N(SO(3)Na)(3), which were synthesized with sodium bisulfite and sodium nitrite in aqueous solution. The N-succinyl chitosan sulfates (NSCS) products were characterized by infrared spectroscopy (FT-IR) and (13)C NMR. The degree of substitution (DS) of NSCS depended on the ratio of sulfating agent to N-succinyl chitosan, reaction temperature, reaction time and pH of sulfation agent. N-succinyl chitosan sulfates with DS of 1.97 were obtained under optimal conditions. The in vitro coagulation assay of NSCS was determined by activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) assays. The results showed that NSCS obviously prolonged APTT. The anticoagulant activity strongly depended on DS, molecular weight (M(w)) and concentration of NSCS. The anticoagulant activity of NSCS promoted with the increase of DS and concentration, and NSCS exhibited the best anticoagulant activity with the M(w) of 1.37×10(4).

Concepts: Spectroscopy, Concentration, Chemistry, Warfarin, Heparin, Factor XII, Prothrombin time, Partial thromboplastin time

26

The CS5100 analyzer (Sysmex) was validated for the determination of routine coagulation parameters. This fully automated coagulation analyzer uses multiple wavelength technology to perform coagulation (e.g., activated partial thromboplastin time - APTT, prothrombin time - PT, fibrinogen - FBG), chromogenic (e.g., antithrombin - AT) and immunological (e.g., D-dimers - DDi) assays.

Concepts: Coagulation, Warfarin, Blood tests, Factor XII, Thrombin, Prothrombin time, Disseminated intravascular coagulation, Partial thromboplastin time

25

Marine algae are important sources of phycocolloids like agar, carrageenans and alginates used in industrial applications. Algal polysaccharides have emerged as an important class of bioactive products showing interesting properties. The aim of our study was to evaluate the potential uses as anticoagulant drugs of algal sulphate polysaccharides extracted from Ulva fasciata (Chlorophyta) and Agardhiella subulata (Rhodophyta) collected in Ganzirri Lake (Cape Peloro Lagoon, north-eastern Sicily, Italy). Toxicity of algal extracts through trypan blue test and anticoagulant action measured by activated partial thromboplastin time (APTT), prothrombin time (PT) test has been evaluated. Algal extracts showed to prolong the PT and APTT during the coagulation cascade and to avoid the blood coagulation of samples. Furthermore, the algal extracts lack toxic effects towards cellular metabolism and their productions are relatively at low cost. This permits to consider the algae as the biological source of the future.

Concepts: Algae, Coagulation, Warfarin, Toxicity, Factor XII, Prothrombin time, Partial thromboplastin time, Seaweed

23

The plasma contact system sits atop the intrinsic coagulation cascade and plasma kallikrein-kinin pathway, and in vivo its activation contributes, respectively, to coagulation and inflammation mainly via two downstream pathways. This system has been widely investigated, its activation mechanisms by negatively charged surfaces and the interactions within its components, factor XII, prekallikrein and high molecular weight kininogen are well understood at the biochemical level. However, as most of the activators that have been discovered by in vitro experiments are exogenous, the physiological activators and roles of the contact system have remained unclear and controversial. In the last two decades, several physiological activators have been identified, and a better understanding of its roles and its connection with other signaling pathways has been obtained from in vivo studies. In this article, we present an overview of the contact pathway with a focus on the activation mechanisms, natural stimuli, possible physiological roles, potential risks of its excessive activation, remaining questions and future prospects.

Concepts: Electric charge, Molecule, Coagulation, In vivo, In vitro, Factor XII, Coagulation system, High-molecular-weight kininogen

7

A substantial fraction of all American healthcare expenditures are potentially wasted, and practices that are not evidence-based could contribute to such waste. We sought to characterize whether Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) tests of preoperative patients are used in a way unsupported by evidence and potentially wasteful.

Concepts: European Union, Medical signs, Blood tests, Factor XII, Prothrombin time, Partial thromboplastin time, Waste

6

Vascular abnormalities and inflammation are found in many Alzheimer’s disease (AD) patients, but whether these changes play a causative role in AD is not clear. The factor XII-initiated contact system can trigger both vascular pathology and inflammation and is activated in AD patients and AD mice. We have investigated the role of the contact system in AD pathogenesis. Cleavage of high molecular weight kininogen (HK), a marker for the inflammatory arm of the contact system, is increased in a mouse model of AD, and this cleavage is temporally correlated with the onset of brain inflammation. Depletion of FXII in AD mice inhibited HK cleavage in plasma and reduced neuroinflammation, fibrinogen deposition, and neurodegeneration in the brain. Moreover, FXII-depleted AD mice showed better cognitive function than untreated AD mice. These results indicate that the FXII-mediated contact system activation contributes to AD pathogenesis, and therefore this system may offer novel targets for AD treatment.

Concepts: Inflammation, Psychology, Brain, Coagulation, Cognition, Neurology, Mind, Factor XII

5

The PT/INR (prothrombin time/international normalized ratio) and aPTT (activated partial thromboplastin time) were tests developed in the early 20th century for specific and unique indications. Despite this, they are often ordered together routinely. The objective of this study was to determine if a multimodal intervention could reduce PT/INR and aPTT testing in the emergency department (ED). This was a prospective multi-pronged quality improvement study at St. Michael’s Hospital. The initiative involved stakeholder engagement, uncoupling of PT/INR and aPTT testing, teaching, and most importantly a revision to the ED order panels. After changes to order panels, weekly rates of PT/INR and aPTT testing per 100 ED patients decreased (17.2 vs 38.4, rate ratio=0.45 (95% CI 0.43-0.47), p<0.001; 16.6 vs 37.8, rate ratio=0.44 (95% CI 0.42-0.46), p<0.001, respectively). Rate of creatinine testing per 100 ED patients, our internal control, increased during the same period (54.0 vs 49.7, rate ratio=1.09 (95% CI 1.06-1.12); p<0.0001) while the weekly rate per 100 ED patients receiving blood transfusions slightly decreased (0.5 vs 0.7, rate ratio=0.66 (95% CI 0.49-0.87), p=0.0034). We found that a simple process change to order panels was associated with meaningful reductions in coagulation testing without obvious adverse effects.

Concepts: HIV, Blood, Hospital, 20th century, Factor XII, Prothrombin time, Partial thromboplastin time

5

Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.

Concepts: Immune system, Central nervous system, Antibody, Blood, Coagulation, Immunology, Multiple sclerosis, Factor XII

4

Coagulation screening prior to surgery is performed routinely worldwide to identify patients at risk of bleeding during the procedure. Evidence from medical and surgical literature suggests that the activated partial thromboplastin time (aPTT) alone is suitable for predicting individual bleeding risk during surgery and it is current practice in our hospital to measure this parameter.

Concepts: Medicine, Hospital, Surgery, Physician, Al-Andalus, Factor XII, Prothrombin time, Partial thromboplastin time

4

Hereditary angioedema type III (HAEIII) is a rare inherited swelling disorder that is associated with point mutations in the gene encoding the plasma protease factor XII (FXII). Here, we demonstrate that HAEIII-associated mutant FXII, derived either from HAEIII patients or recombinantly produced, is defective in mucin-type Thr309-linked glycosylation. Loss of glycosylation led to increased contact-mediated autoactivation of zymogen FXII, resulting in excessive activation of the bradykinin-forming kallikrein-kinin pathway. In contrast, both FXII-driven coagulation and the ability of C1-esterase inhibitor to bind and inhibit activated FXII were not affected by the mutation. Intravital laser-scanning microscopy revealed that, compared with control animals, both F12-/- mice reconstituted with recombinant mutant forms of FXII and humanized HAEIII mouse models with inducible liver-specific expression of Thr309Lys-mutated FXII exhibited increased contact-driven microvascular leakage. An FXII-neutralizing antibody abolished bradykinin generation in HAEIII patient plasma and blunted edema in HAEIII mice. Together, the results of this study characterize the mechanism of HAEIII and establish FXII inhibition as a potential therapeutic strategy to interfere with excessive vascular leakage in HAEIII and potentially alleviate edema due to other causes.

Concepts: Gene, Mutation, Coagulation, Angioedema, Hereditary angioedema, Factor XII, Bradykinin, Serpin