scholarly journals Personalized modulation of coagulation factors using a thrombin dynamics model to treat trauma-induced coagulopathy

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Damon E. Ghetmiri ◽  
Mitchell J. Cohen ◽  
Amor A. Menezes
Keyword(s):  
Trauma Patient ◽  
Protein Interactions ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Superior Performance ◽  
Patient Specific ◽  
Blood Protein ◽  
Dynamics Model ◽  
Coagulation Management ◽  
Trauma Induced Coagulopathy

AbstractCurrent trauma-induced coagulopathy resuscitation protocols use slow laboratory measurements, rules-of-thumb, and clinician gestalt to administer large volumes of uncharacterized, non-tailored blood products. These one-size-fits-all treatment approaches have high mortality. Here, we provide significant evidence that trauma patient survival 24 h after hospital admission occurs if and only if blood protein coagulation factor concentrations equilibrate at a normal value, either from inadvertent plasma-based modulation or from innate compensation. This result motivates quantitatively guiding trauma patient coagulation factor levels while accounting for protein interactions. Toward such treatment, we develop a Goal-oriented Coagulation Management (GCM) algorithm, a personalized and automated ordered sequence of operations to compute and specify coagulation factor concentrations that rectify clotting. This novel GCM algorithm also integrates new control-oriented advancements that we make in this work: an improvement of a prior thrombin dynamics model that captures the coagulation process to control, a use of rapidly-measurable concentrations to help predict patient state, and an accounting of patient-specific effects and limitations when adding coagulation factors to remedy coagulopathy. Validation of the GCM algorithm’s guidance shows superior performance over clinical practice in attaining normal coagulation factor concentrations and normal clotting profiles simultaneously.

Coagulation management in major trauma

2006 ◽  
Vol 26 (S 02) ◽  
pp. S50-S55 ◽  
Author(s):  
H. Schoechl
Keyword(s):  
Blood Loss ◽  
Major Trauma ◽  
Damage Control ◽  
Coagulation Factor ◽  
Damage Control Surgery ◽  
Coagulation Factors ◽  
Conclusive Evidence ◽  
Trauma Patients ◽  
Coagulation Management ◽  
Haemostatic Agents

SummaryBleeding is a common problem in major trauma. Coagulopathy could be detected in approximately 25% of all trauma patients on arrival in the emergency room. The reasons for that are blood loss, dilution of the remaining coagulation factors by fluids not containing coagulation factors, consumption of coagulation factors and hyperfibrinolysis. Hypothermia and acidosis are also well described contributors of coagulopathy.Diagnosis of coagulation abnormalities should be based on clinical judgement. Standard coagulation tests are universally available, but there is some evidence, that those tests are not predictive for transfusion requirement. Thrombelastography/ metry is a promising technology which not only shows the initiation of the coagulation process but also the dynamic of clot formation and the clot firmness. It is the golden standard for the diagnosis of hyperfibrinolysis. To restore adequate haemostasis an aggressive treatment of hypothermia and acidosis is essential. The concept of damage control surgery and permissive hypotension in server bleeding patients could reduce the whole amount of blood loss.For coagulation factor replacement therapy fresh frozen plasma, PCC, fibrinogen concentrates and cryoprecipitate could be used. Haematocrit should be maintained in the range of 30% and platelet count should not drop below 50 000/μl. In some circumstances haemostatic agents such as DDAVP, antifibrinolytics and rFVIIa could be helpful, even there is no conclusive evidence for the use of these drugs in severe trauma patients.

scholarly journals Management of Coagulopathy in Bleeding Patients

2021 ◽  
Vol 11 (1) ◽  
pp. 1
Author(s):  
Stefan Hofer ◽  
Christoph J. Schlimp ◽  
Sebastian Casu ◽  
Elisavet Grouzi
Keyword(s):  
Early Recognition ◽  
Point Of Care ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Coagulation Factor ◽  
Blood Gas Analysis ◽  
Coagulation Factors ◽  
Gas Analysis ◽  
Coagulation Management ◽  
Reversal Agents

Early recognition of coagulopathy is necessary for its prompt correction and successful management. Novel approaches, such as point-of-care testing (POC) and administration of coagulation factor concentrates (CFCs), aim to tailor the haemostatic therapy to each patient and thus reduce the risks of over- or under-transfusion. CFCs are an effective alternative to ratio-based transfusion therapies for the correction of different types of coagulopathies. In case of major bleeding or urgent surgery in patients treated with vitamin K antagonist anticoagulants, prothrombin complex concentrate (PCC) can effectively reverse the effects of the anticoagulant drug. Evidence for PCC effectiveness in the treatment of direct oral anticoagulants-associated bleeding is also increasing and PCC is recommended in guidelines as an alternative to specific reversal agents. In trauma-induced coagulopathy, fibrinogen concentrate is the preferred first-line treatment for hypofibrinogenaemia. Goal-directed coagulation management algorithms based on POC results provide guidance on how to adjust the treatment to the needs of the patient. When POC is not available, concentrate-based management can be guided by other parameters, such as blood gas analysis, thus providing an important alternative. Overall, tailored haemostatic therapies offer a more targeted approach to increase the concentration of coagulation factors in bleeding patients than traditional transfusion protocols.

scholarly journals Characterization and visualization of murine coagulation factor VIII-producing cells in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morisada Hayakawa ◽  
Asuka Sakata ◽  
Hiroko Hayakawa ◽  
Hikari Matsumoto ◽  
Takafumi Hiramoto ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Factor Viii ◽  
Fluorescent Protein ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Genetically Engineered ◽  
Coagulation Factor Viii ◽  
Liver Sinusoidal Endothelial Cells ◽  
Genetically Engineered Mice

AbstractCoagulation factors are produced from hepatocytes, whereas production of coagulation factor VIII (FVIII) from primary tissues and cell species is still controversial. Here, we tried to characterize primary FVIII-producing organ and cell species using genetically engineered mice, in which enhanced green fluorescent protein (EGFP) was expressed instead of the F8 gene. EGFP-positive FVIII-producing cells existed only in thin sinusoidal layer of the liver and characterized as CD31high, CD146high, and lymphatic vascular endothelial hyaluronan receptor 1 (Lyve1)+. EGFP-positive cells can be clearly distinguished from lymphatic endothelial cells in the expression profile of the podoplanin− and C-type lectin-like receptor-2 (CLEC-2)+. In embryogenesis, EGFP-positive cells began to emerge at E14.5 and subsequently increased according to liver maturation. Furthermore, plasma FVIII could be abolished by crossing F8 conditional deficient mice with Lyve1-Cre mice. In conclusion, in mice, FVIII is only produced from endothelial cells exhibiting CD31high, CD146high, Lyve1+, CLEC-2+, and podoplanin− in liver sinusoidal endothelial cells.

EXPRESSION IN ONTOGENESIS OF HUMAN BLOOD COAGULATION FACTORS

1987 ◽  
Author(s):  
H J Hassan ◽  
A Leonardi ◽  
C Chelucci ◽  
R Guerriero ◽  
P M Mannucci ◽  
...  
Keyword(s):  
Blood Coagulation ◽  
Protein C ◽  
Antithrombin Iii ◽  
Liver Homogenate ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Adult Liver ◽  
Blood Coagulation Factors ◽  
Guanidine Isothiocyanate

We have analyzed the expression of several blood coagulation factors (IX, VIII, X, fibrinogen chains) and inhibitors (antithrombin III, protein C) in human embryonic and fetal livers, obtained from legal abortions at 6-11 week post-conception. The age was established by morphologic staging and particularly crown-rump lenght measurement.Total cellular RNA was isolated from partially purified hepatocytes or total liver homogenate using the guanidine isothiocyanate method. Poly(A)+ RNA was selected by oligodT cellulose chromatography. The size and the number of the embryonic and fetal transcripts are equivalent to those observed in adult liver, as evaluated by Northern blot analysis of total or poly(A)+ RNA hybridized to human cDNA probes.The level of coagulation factor transcripts in embryonic and fetal liver was evaluated by dot hybridization of total RNA (0.5-10 ug), as compared to RNA extracted from normal adult liver biopsies. The expression of blood coagulation factors in embryos is generally reduced for all factors, but at a different degree. In 5-11 wk liver, the level of factor IX is 5-10% of that observed in adults, while fibrinogen, protein C, antithrombin III RNA level rises from 25 to 50% and factor X is expressed at a level comparable to that observed in adult liver.We conclude that during these stages of development blood coagulation factors are expressed according to three different time, curves, possibly due to the effect of different types of regulatory mechanisms.

Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo

2004 ◽  
Vol 92 (09) ◽  
pp. 503-508 ◽  
Author(s):  
Hans-Ulrich Pauer ◽  
Thomas Renné ◽  
Bernhard Hemmerlein ◽  
Tobias Legler ◽  
Saskia Fritzlar ◽  
...  
Keyword(s):  
Fetal Loss ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Mendelian Inheritance ◽  
Biological Role ◽  
Factor Xii ◽  
Wild Type ◽  
Contact Phase ◽  
Health And Disease

SummaryTo analyze the biological role of factor XII (FXII, Hageman Factor) in vivo, we generated mice deficient for FXII using a gene targeting approach on two distinct genetic backgrounds, i.e. mixed C57Bl/6J X 129X1/SvJ and inbred 129X1/SvJ. Homozygous FXII knockout (FXII-/-) mice showed no FXII plasma activity and had a markedly prolonged activated partial thromboplastin time (aPTT). In contrast, coagulation factors XI, VIII, IX, X,VII,V, II and fibrinogen did not differ between FXII-/- mice and their wild-type littermates. Heterozygous matings segregated according to the Mendelian inheritance indicating that FXII deficiency does not increase fetal loss. Furthermore, matings of FXII-/- males and FXII-/females resulted in normal litter sizes demonstrating that total FXII deficiency in FXII-/females does not affect pregnancy outcome. Also, gross and histological anatomy of FXII-/mice was indistinguishable from that of their wild-type littermates on both genetic backgrounds. Thus it appears that deficiency of murine FXII does not cause thrombophilia or impaired fibrinolysis in vivo. These results indicate that FXII deficiency does not affect hemostasis in vivo and we anticipate that the FXII-/mice will be helpful to elucidate the biological role(s) of FXII in health and disease.

scholarly journals An Explainable Multi-Modal Neural Network Architecture for Predicting Epilepsy Comorbidities Based on Administrative Claims Data

2020 ◽  
Author(s):  
Thomas Linden ◽  
Johann de Jong ◽  
Chao Lu ◽  
Victor Kiri ◽  
Kathrin Haeffs ◽  
...  
Keyword(s):  
Neural Network ◽  
Network Architecture ◽  
Claims Data ◽  
Health Claims ◽  
Superior Performance ◽  
Patient Specific ◽  
Administrative Claims ◽  
Theoretic Approach ◽  
Neural Network Architecture ◽  
Health Claims Data

1AbstractEpilepsy is a complex brain disorder characterized by repetitive seizure events. Epilepsy patients often suffer from various and severe physical and psychological co-morbidities (e.g. anxiety, migraine, stroke, etc.). While general comorbidity prevalences and incidences can be estimated from epidemiological data, such an approach does not take into account that actual patient specific risks can depend on various individual factors, including medication. This motivates to develop a machine learning approach for predicting risks of future comorbidities for the individual epilepsy patient.In this work we use inpatient and outpatient administrative health claims data of around 19,500 US epilepsy patients. We suggest a dedicated multi-modal neural network architecture (Deep personalized LOngitudinal convolutional RIsk model - DeepLORI) to predict the time dependent risk of six common comorbidities of epilepsy patients. We demonstrate superior performance of DeepLORI in a comparison with several existing methods Moreover, we show that DeepLORI based predictions can be interpreted on the level of individual patients. Using a game theoretic approach, we identify relevant features in DeepLORI models and demonstrate that model predictions are explainable in the light of existing knowledge about the disease. Finally, we validate the model on independent data from around 97,000 patients, showing good generalization and stable prediction performance over time.

scholarly journals Cryo-EM structures of human coagulation factors V and Va

Blood ◽  
2021 ◽  
Author(s):  
Eliza A Ruben ◽  
Michael J Rau ◽  
James Fitzpatrick ◽  
Enrico Di Cera
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Proteolytic Processing ◽  
Coagulation Cascade ◽  
Factor V ◽  
Prothrombinase Complex ◽  
A2 Domain

Coagulation factor V is the precursor of factor Va that, together with factor Xa, Ca2+ and phospholipids, defines the prothrombinase complex and activates prothrombin in the penultimate step of the coagulation cascade. Here we present cryo-EM structures of human factors V and Va at atomic (3.3 Å) and near-atomic (4.4 Å) resolution, respectively. The structure of fV reveals the entire A1-A2-B-A3-C1-C2 assembly but with a surprisingly disordered B domain. The C1 and C2 domains provide a platform for interaction with phospholipid membranes and support the A1 and A3 domains, with the A2 domain sitting on top of them. The B domain is highly dynamic and visible only for short segments connecting to the A2 and A3 domains. The A2 domain reveals all sites of proteolytic processing by thrombin and activated protein C, a partially buried epitope for binding factor Xa and fully exposed epitopes for binding activated protein C and prothrombin. Removal of the B domain and activation to fVa exposes the sites of cleavage by activated protein C at R306 and R506 and produces increased disorder in the A1-A2-A3-C1-C2 assembly, especially in the C-terminal acidic portion of the A2 domain responsible for prothrombin binding. Ordering of this region and full exposure of the factor Xa epitope emerge as a necessary step for the assembly of the prothrombin-prothrombinase complex. These structures offer molecular context for the function of factors V and Va and pioneer the analysis of coagulation factors by cryo-EM.

MEDICAL PREVENTION OF POST-TRANSFUSION COMPLICATIONS AFTER TRANSFUSION THERAPY APPLIED IN CASE OF SEVERE OBSTETRIC BLOOD LOSS

2020 ◽  
Vol 4 (2) ◽  
pp. 1048-1056
Author(s):  
F.N. Karpenko ◽  
◽  
A.V. Novik ◽  
E.D. Rasyuk ◽  
V.V. Pasyukov ◽  
...  
Keyword(s):  
Blood Loss ◽  
Emergency Obstetric Care ◽  
Coagulation Factor ◽  
Obstetric Care ◽  
Coagulation Factors ◽  
Blood Components ◽  
Obstetric Hemorrhage ◽  
Transfusion Therapy ◽  
Modern Approach ◽  
Golden Hour

The article presents an analysis of the modern approach to the treatment of acute obstetric hemorrhage. Some features of the preparation of leukodepleted and pathogen-reduced blood components are shown and indications for use in severe obstetric blood loss are determined. It has been shown that the pathogen reduction of blood components leads to a decrease the level of coagulation factors (coagulation factor VIII, fibrinogen in fresh frozen plasma) by 20-30 %, the activity and number of platelets by 15-20 % in platelet concentrate, does not affect the morphological usefulness of platelets. A "package" of blood components for the provision of emergency transfusion therapy for obstetric bleeding has been calculated. The need for a given quantity of blood components was determined – 2.3 "packages" per 1000 births. The proposed "emergency obstetric care packages" and the organization of their centralized delivery to medical healthcare organizations ensure a high degree of readiness of the blood service to comply with the "golden hour" rule for treating acute severe obstetric hemorrhage and minimize post-transfusion reactions and complications when using them. Pathogen-reduced blood components are expensive. Therefore, their use in clinical practice is indicated for the decreed contingents of recipients: for organ and tissue transplantation, in neonatology, oncohematology and for recipients with “multiple transfusions of blood, its components”, in cardiac surgery and obstetric practice.

scholarly journals Multimodal deep representation learning for protein interaction identification and protein family classification

2019 ◽  
Vol 20 (S16) ◽  
Author(s):  
Da Zhang ◽  
Mansur Kabuka
Keyword(s):  
Protein Interactions ◽  
Protein Sequence ◽  
Representation Learning ◽  
Superior Performance ◽  
Sequence Information ◽  
Protein Protein Interactions ◽  
Learning Framework ◽  
Topological Features ◽  
Ppi Networks ◽  
Ppi Prediction

Abstract Background Protein-protein interactions(PPIs) engage in dynamic pathological and biological procedures constantly in our life. Thus, it is crucial to comprehend the PPIs thoroughly such that we are able to illuminate the disease occurrence, achieve the optimal drug-target therapeutic effect and describe the protein complex structures. However, compared to the protein sequences obtainable from various species and organisms, the number of revealed protein-protein interactions is relatively limited. To address this dilemma, lots of research endeavor have investigated in it to facilitate the discovery of novel PPIs. Among these methods, PPI prediction techniques that merely rely on protein sequence data are more widespread than other methods which require extensive biological domain knowledge. Results In this paper, we propose a multi-modal deep representation learning structure by incorporating protein physicochemical features with the graph topological features from the PPI networks. Specifically, our method not only bears in mind the protein sequence information but also discerns the topological representations for each protein node in the PPI networks. In our paper, we construct a stacked auto-encoder architecture together with a continuous bag-of-words (CBOW) model based on generated metapaths to study the PPI predictions. Following by that, we utilize the supervised deep neural networks to identify the PPIs and classify the protein families. The PPI prediction accuracy for eight species ranged from 96.76% to 99.77%, which signifies that our multi-modal deep representation learning framework achieves superior performance compared to other computational methods. Conclusion To the best of our knowledge, this is the first multi-modal deep representation learning framework for examining the PPI networks.

scholarly journals In vivo effects of human granulocyte neutral proteases on blood coagulation in green monkeys (cercopithecus aetiops)

1977 ◽  
Author(s):  
R. Egbring ◽  
M. Gramse ◽  
N. Heimburger ◽  
K. Havemann
Keyword(s):  
Proteolytic Enzymes ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Fibrinogen Concentration ◽  
Α2 Macroglobulin ◽  
In Vivo Effects ◽  
Neutral Proteases ◽  
Green Monkeys

Two neutral proteases (elastase-1ike = ELP, and chymotrypsin-like = CLP) derived from human PMN in highly purified form inactivate in vitro humanisolated coagulation factors (Thromb. Res. 6, 315, 1975). These effects can be observed also in human plasma, despite its high antiprotease capacity. (Blood February 1977).ELP and CLP (both free of endotoxin) were infused into green monkeys either separate or in combination to investigate a possible role of these proteolytic enzymes also in vivo. Activity of coagulation factors I - XIII and antiprotease potential has been followed for a 24 hour period in short intervals.A loss of activity of coagulation factor II, V, VIII, IX, X and XIII could be demonstrated. Fibrinogen concentration decreased and fibrinogen split products could be detected. In two-dimensional immunelectrophoresis α1-antitrypsin-ELP and α2-macroglobulin-ELP-complexes were demonstrable for about 6 hours after protease infusion. Bleeding complication occurred after injection of both enzymes.The results indicate a direct proteolysis of coagulation factors by PMN neutral proteases in vivo.We suggest that similar conditions are present in patients with acute leukemia or septicemia.

Sign in / Sign up

Export Citation Format

Share Document