Clot Growth Research Articles

The hemostasis system in children with hereditary spherocytosis

IntroductionPatients with hereditary spherocytosis (HS) are characterized by having an increased risk for thrombosis. An early manifestation of thrombotic complications can occur even in childhood, especially after surgery. Hypercoagulability can be associated with hemolytic crises. AimThe aim of this study was to investigate the hemostatic state in children with HS using global hemostasis assays. MethodsThe hemostatic status of 62 children (38 boys and 24 girls; age range: 0.5 to 17 years) with HS during and without hemolytic crisis was assessed using clotting times (APTT, TT, and PR), fibrinogen and D-dimer levels, and global hemostasis, thromboelastography (TEG) and thrombodynamics (TD) assays. One hundred and two healthy children undergoing annual medical examination were enrolled as a control group. ResultsTEG and TD parameters were increased in the children with HS compared to the control group (60 ± 5 mm vs. 53 ± 4 mm, p < 0.05 for TEG maximum amplitude; 28 ± 3 μm/min vs. 24 ± 2 μm/min, p < 0.05 for TD clot growth rate), while APTT, TT and PR were not significantly different between the two groups. Patients with HS were divided into 2 groups: those during hemolytic crisis (28 patients) and those without hemolytic crisis (34 patients). TEG and TD parameters were increased in those during hemolytic crisis compared to the steady state HS group (62 ± 5 mm vs. 57 ± 4 mm, p < 0.05 for TEG maximum amplitude; 31 ± 4 μm/min vs. 26 ± 3 μm/min, p < 0.05 for TD clot growth rate). The D-dimer levels were increased in 4 HS patients, for whom the activation of blood clotting was noted. Fibrinogen levels were decreased in patients with HS compared to the control group (2.1 ± 0.4 mg/ml vs. 2.6 ± 0.4 mg/ml, p < 0.05). Other tests were within the reference ranges for both groups. ConclusionsThe global hemostasis tests TEG and TD revealed hypercoagulability in patients with HS. More dramatic changes were observed in patients experiencing a hemolytic crisis.

Thrombodynamic correlates of catatonia severity in children with autism

To study a correlation between the values of thrombodynamics parameters of hypercoagulation measured by the thrombodynamics test and the severity of catatonia in children with infantile psychosis in childhood autism (F84.02). Twenty-four patients (22 boys and 2 girls) aged from 3 to 13 years, were studied. The severity of catatonia was determined by BFCRS. A thrombodynamic test was performed in platelet-free plasma using the analyzer T-2 Thrombodynamics Device (Hemacore LLC, Russia). Thrombodynamic (TD) parameters of clot growth rates from the activator (V, Vi and Vst) were statistically significantly higher than normal values. Similar results were obtained for Clot Size at 30 min (CS, μm): Tlag and D values were within normal limits. The values of Time of appearance of spontaneous clots (Tsp min) were less than the lower limit values for the norm (30 min). Correlation analysis showed that the severity of catatonia is positively correlated with the initial clot growth rate (Vi) (p=0.009) and negatively with Tsp (p=0.002). With an increase in the time of appearance of spontaneous clots (due to a decrease in the procoagulant activity of platelet microparticles in the plasma of patients), the severity of catatonia in children with ASD decreases. The results suggest that normalizing plasma and platelet hemostasis is important for increasing the effectiveness of treatment of patients with ASD with catatonia.

Existence of pulses for a reaction-diffusion system of blood coagulation in flow.

A reaction-diffusion system describing blood coagulation in flow is studied. We prove the existence of stationary solutions provided that the speed of the travelling wave problem for the limiting value of the velocity is positive. The implications to the problem of clot growth are discussed.

Thrombodynamic method of evaluation of some hemostatic parametersin healthy pregnant women and in women with preeclampsia

Hypothesis/aims of study. During pregnancy, hypercoagulation develops and fibrinolysis is inhibited. These changes are particularly pronounced in pregnancy complicated by preeclampsia. The existing techniques to evaluate hemostasis are rather laborious and do not provide a complete information of the volume and density of the fibrin clot. We aimed to conduct comparative studies of the state of the hemostasis system by conventional test-tube and thrombodynamic methods in healthy non-pregnant women and in pregnant women who are suffering and are not suffering from preeclampsia.&#x0D; Study design, materials, and methods. We examined 40 pregnant women aged 17–33 years (mean age 24.3 ± 3.2 years) at the gestational age of 35–39 weeks. In 18 women, pregnancy was complicated by preeclampsia. The control group consisted of 35 healthy women (mean age 25.1 ± 2.6 years). The thrombodynamic characteristics of the clot were evaluated using the T-2 Thrombodynamics Recorder device (GemaKor Ltd., Russia) using the following parameters: Tlag, clot growth delay; Vi, initial growth rate; Vs, steady growth rate; D, clot density; C30, the size of the main clot in the 30th minute.&#x0D; Results. When evaluating the hemostasis system by the thrombodynamic method in healthy pregnant women and in women with preeclampsia compared with non-pregnant women, the onset time of clot formation was significantly reduced, the initial and steady rate of the clot appearance, as well as the clot density and the clot size being increased.&#x0D; Conclusion. The method for evaluating thrombodynamic properties of the blood clot is objective and visual way to estimate hemostasis. It complements the coagulogram indices and gives a clear view of the hemostasis system.

Computational Modeling and Microfluidics Reveal Characteristic Patterns of Regulation of Clot Structure and Mechanics By Tissue Factor Localization

The growth of a blood clot is initiated by tissue factor (TF) exposure and is expected to depend on TF localization (i.e., its level and spatial distribution). We sought to understand how the structural and mechanical properties of clots under flow are shaped by simultaneously varying the surface density of TF and its area of exposure. We used a microfluidic device harboring thrombogenic surfaces that differed in length and TF surface density. We perfused human whole blood through this device and continually measured platelet deposition, thrombin formation, and fibrin accumulation by means of fluorescence microscopy. Using our recently developed, detailed mathematical model of spatial clot growth under flow, we performed computational simulations to gain insights into the connection between the structure of a clot and its mechanical properties, such as resistance to blood flow and flow axial velocity.We detected a non-additive, synergistic influence of the thrombogenic surface length and TF surface density on bulk thrombin and fibrin generation. We found that thrombogenic surface length and TF density controlled not only bulk accumulation, but also the occlusivity of the deposited platelet mass, as well as clot resistance to flow. The extent of this control depended on the blood flow velocity. An increase in the TF surface density resulted in condition-dependent differential acceleration of platelet deposition, thrombin formation, and fibrin accumulation. The viscous resistance of the clot was characterized by spatial variations and was higher in the inner clot region. Notably, despite variations in the intraclot structure, variations in the intraclot flow velocity were minor compared to the abrupt decrease in flow velocity at the boundary of the platelet deposition domain.Our analysis revealed characteristic patterns that describe how the shape, size, internal structure, and viscous resistance of a clot depend on the surface density of TF and its area of exposure. Taken together, our results suggest that the structure and mechanics of a growing clot are correlated, but can differ in their regulation by the distinct aspects of TF localization. These findings provide new insights into how initiating signals can temporally and spatially affect thrombus growth under flow. DISCLAIMERThe opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army or of the U.S. Department of Defense. This abstract has been approved for public release with unlimited distribution. DisclosuresNo relevant conflicts of interest to declare.

Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

Blood coagulation is a delicately regulated space- and time-dependent process that leads to the formation of fibrin clots preventing blood loss upon vascular injury. The sensitivity of the coagulation network was previously investigated without accounting for transport processes. To investigate its sensitivity to coagulation factor deficiencies in a spatial reaction-diffusion system, we combined an in vitro experimental design with a computational systems biology model. Clot formation in platelet-free plasma supplemented with phospholipids was activated with identical amounts of tissue factor (TF) either homogeneously distributed (concentration 5 pM, homogeneous model) or immobilized on the surface (surface density 100 pmole/m2, spatially heterogeneous model). Fibrin clot growth and thrombin concentration dynamic in space were observed using video microscopy in plasma of healthy donors or patients with deficiencies in factors (F) II, FV, FVII, FVIII, FIX, FX, or FXI. In the spatially heterogeneous model, near-activator thrombin generation was decreased in FV-, FVII-, and FX-deficient plasma. In the homogeneous model, clotting was not registered in these samples. The simulation and experiment data showed that the coagulation threshold depended on the TF concentration. Our data indicate that the velocity of spatial clot propagation correlates linearly with the concentration of thrombin at the clot wave front but not with the overall thrombin wave amplitude. Spatial clot growth in normal plasma at early stages was neither reaction nor diffusion limited but became diffusion limited later. In contrast, clot growth was always diffusion limited in FV-, FVII-, and FX-deficient plasma and reaction limited in FVIII-, FIX-, and FXI-deficient plasma. We conclude that robustness of the spatially heterogeneous coagulation system was achieved because of the combination of 1) a local high TF surface density that overcomes activation thresholds, 2) diffusion control being shared between different active factors, and 3) an early saturated stimulus-response dependence of fibrin clot formation by thrombin.

Carbon monoxide inhibits the anticoagulant activity of phospholipase A2 purified from Crotalus adamanteus venom.

Snake venom contains a myriad of classes of enzyme which have been investigated for medicinal and toxinological purposes, including phospholipase A2 (PLA2), which is responsible for anticoagulant, myotoxic and neurotoxic effects. Given the importance of PLA2, the purposes of the present investigation were to characterize the coagulation kinetic behavior of a PLA2 purified from Crotalus adamanteus venom (Ca-PLA2) in human plasma with thrombelastography and determine if carbon monoxide could inhibit its activity. Coagulation kinetics were determined in human plasma with a range of Ca-PLA2 activity (0-2U/ml) via thrombelastography. Then, using carbon monoxide releasing molecule-2 or its inactivated molecule (0 or 100µM), the vulnerability of Ca-PLA2 activity to carbon monoxide mediated inhibition was assessed. Lastly, the inhibitory response of Ca-PLA2 activity to exposure to carbon monoxide releasing molecule-2 (0-100µM) was determined. Ca-PLA2 activity degraded the velocity of clot growth and clot strength in an activity dependent, exponential manner. Carbon monoxide inhibited Ca-PLA2 activity in a concentration dependent fashion, with loss of detectable activity at 100µM of carbon monoxide releasing molecule-2. These findings, while preliminary, open the possibility that other PLA2 contained in snake venom with multiple toxicities (e.g., myotoxin, neurotoxin) may be heme bearing and CO-inhibitable, which have profound potential basic and clinical science implications.

Technical Indicators to Evaluate the Degree of Large Clot Formation Inside the Membrane Fiber Bundle of an Oxygenator in an In Vitro Setup.

The most common technical complication during ECMO is clot formation. A large clot inside a membrane oxygenator reduces effective membrane surface area and therefore gas transfer capabilities, and restricts blood flow through the device, resulting in an increased membrane oxygenator pressure drop (dpMO). The reasons for thrombotic events are manifold and highly patient specific. Thrombus formation inside the oxygenator during ECMO is usually unpredictable and remains an unsolved problem. Clot sizes and positions are well documented in literature for the Maquet Quadrox-i Adult oxygenator based on CT data extracted from devices after patient treatment. Based on this data, the present study was designed to investigate the effects of large clots on purely technical parameters, for example, dpMO and gas transfer. Therefore, medical grade silicone was injected into the fiber bundle of the devices to replicate large clot positions and sizes. A total of six devices were tested in vitro with silicone clot volumes of 0, 30, 40, 50, 65, and 85mL in accordance with ISO 7199. Gas transfer was measured by sampling blood pre and post device, as well as by sampling the exhaust gas at the devices' outlet at blood flow rates of 0.5, 2.5, and 5.0L/min. Pre and post device pressure was monitored to calculate the dpMO at the different blood flow rates. The dpMO was found to be a reliable parameter to indicate a large clot only in already advanced "clotting stages." The CO2 concentration in the exhaust gas, however, was found to be sensitive to even small clot sizes and at low blood flows. Exhaust gas CO2 concentration can be monitored continuously and without any risks for the patient during ECMO therapy to provide additional information on the endurance of the oxygenator. This may help detect a clot formation and growth inside a membrane oxygenator during ECMO even if the increase in dpMO remains moderate.

Impaired platelet activity and hypercoagulation in healthy term and moderately preterm newborns during the early neonatal period.

Preterm newborns are at thrombohemorrhagic risk during the early neonatal period. Taking into account the lack of informative tools for the laboratory diagnosis of hemostasis disorders in newborns, our goal was to determine the baseline values of thrombodynamics and platelet functional activity in healthy term and moderately preterm newborns during the early neonatal period future potential clinical use of these tests. Coagulation was assessed using an integral assay of thrombodynamics and standard coagulation assays, and platelet functional activity was estimated by flow cytometry. Hypercoagulation of newborns, represented by a significantly higher clot growth velocity and the presence of spontaneous clots in the thrombodynamics, was combined with platelet hypoactivity. Granule release, phosphatidylserine exposure, and the ability to change shape upon activation were decreased in the platelets of moderately preterm newborns. The platelet function remained at the same level over the first four days of life, whereas the hypercoagulation became less pronounced. The hemostasis of newborns is characterized by hypercoagulation combined with reduced platelet functional activity. Moderately preterm and term newborns do not differ in the parameters of coagulation, while some of the functional responses of platelets are lower in moderately preterm newborns than in term.

Thromboelastometric prediction of mortality using the kinetics of clot growth in critically ill septic patients.

: Sepsis induces alterations in blood coagulation which are associated with mortality. Using rotational thromboelastometry (ROTEM), these states are often characterized by changes in parameters representing terminal clot lysis. However, the ROTEM changes are often subtle, making them difficult to recognize and interpret. The objective of this study is to evaluate a new ROTEM clot velocity parameter representing clot formation kinetics in septic ICU patients. We hypothesized that this time-based parameter was significantly different in critically ill septic survivors vs. nonsurvivors. This retrospective observational study included severe sepsis and septic shock patients having a minimum of two organ dysfunctions by Sequential Organ Failure Assessment criteria (study group), and a control group of healthy adults without infection . ROTEM with EXTEM activation was performed in all groups. The time from maximal clot formation velocity to zero velocity, representing the latter portion of time during active clot formation prior to achieving maximal clot firmness (t-AUCi) was calculated along with other ROTEM parameters and compared between septic survivors, nonsurvivors and healthy controls. A total of 76 septic patients, of which 26.3%, survived, were included in the study group, and 26 healthy control individuals were included in the control group. t-AUCi correlated with terminal clot lysis (P < 0.001), and was significantly prolonged in septic nonsurvivors compared with survivors and healthy controls (P < 0.001). t-AUCi also differentiated nonsurvivors vs. survivors among those patients having similar ROTEM lysis indices. t-AUCi was useful to differentiate critically ill septic patients, and could be useful to identify septic patients with high-risk of ICU mortality.

A computational thrombus formation model: application to an idealized two-dimensional aneurysm treated with bare metal coils.

Cardiovascular implantable devices alter the biofluid dynamics and biochemistry of the blood in which they are placed. These perturbations can lead to thrombus formation which may or may not be desired, depending on the application. In this work, a computational model is developed that couples biofluid dynamics and biochemistry to predict the clotting response of blood to such devices. The model consists of 28 advection-diffusion-reaction partial differential equations to track proteins in the blood involved in clotting and utilizes boundary flux terms to model the initiation of the intrinsic clotting pathway at thrombogenic device surfaces. We use this model to simulate the transient clot growth within a 2D idealized bifurcation aneurysm filled with various distributions of bare metal coils with similar packing densities. The clot model predicts initial clot formation to occur in areas along coil surfaces where flow is minimal and where time-averaged shear rates are the smallest. Among the six coil-filled aneurysm cases simulated, maximum thrombus occlusion ranged between 80.8 and 92.2% of the post-treatment aneurysm volume and was achieved 325-450s after treatment. With further refinement and validation, the computational clotting model will be a valuable engineering tool for evaluating and comparing the relative performance of cardiovascular implantable devices.

Relationship Between Haemostasis Parameters and Anxiety Under Examination Stress: A Pilot Study.

This work aims to clarify how blood coagulation parameters reflect mild stress response in males and females. Healthy student volunteers of both sexes were used in this pilot study. A new global sensitive assay of haemostasis, spatial thrombodynamics, along with conventional coagulometry approach were used to evaluate of blood coagulation parameters. Psychodiagnostics scales (according to Spielberger and Taylor) are employed to evaluate anxiety as stress-induced response. We have selected exam stress, which despite being a mild stressor may nevertheless cause somatic disorders. We provide the first evidence of a statistically significant increase in initial clot growth velocity in women, but not men, in response to exam stress. The exam situation produces higher situational anxiety in female volunteers, and so they express remarkable stress-induced haemostatic responses, including plasma- and platelet-based changes. In contrast, male volunteers do not express pronounced stress-induced changes in haemostasis, and only display a decrease in plateletcrit value and an increase in prothrombin time. Mild form of stress (exam) induces changes in some blood coagulation parameters. A statistically significant remarkable increase in Vinit value and some other plasma- and platelet-based parameters has been seen in female students (but not male ones) under exam stress.

Impact of Tissue Factor Localization on Blood Clot Structure and Resistance under Venous Shear

The structure and growth of a blood clot depend on the localization of tissue factor (TF), which can trigger clotting during the hemostatic process or promote thrombosis when exposed to blood under pathological conditions. We sought to understand how the growth, structure, and mechanical properties of clots under flow are shaped by the simultaneously varying TF surface density and its exposure area. We used an eight-channel microfluidic device equipped with a 20- or 100-μm-long collagen surface patterned with lipidated TF of surface densities ∼0.1 and ∼2 molecules/μm2. Human whole blood was perfused at venous shear, and clot growth was continually measured. Using our recently developed computational model of clot formation, we performed simulations to gain insights into the clot’s structure and its resistance to blood flow. An increase in TF exposure area resulted not only in accelerated bulk platelet, thrombin, and fibrin accumulation, but also in increased height of the platelet mass and increased clot resistance to flow. Moreover, increasing the TF surface density or exposure area enhanced platelet deposition by approximately twofold, and thrombin and fibrin generation by greater than threefold, thereby increasing both clot size and its viscous resistance. Finally, TF effects on blood flow occlusion were more pronounced for the longer thrombogenic surface than for the shorter one. Our results suggest that TF surface density and its exposure area can independently enhance both the clot’s occlusivity and its resistance to blood flow. These findings provide, to our knowledge, new insights into how TF affects thrombus growth in time and space under flow.

A role of insomnia in the development of silent cerebral infarctions

To investigate the relationship between insomnia, hemostatic abnormalities and silent cerebral infarctions. A complex study of 76 male patients, aged 40-85, with vascular risk factors was carried out. Magnetic resonance imaging (MRI) data was used to verify presence of silent cerebral infarctions; the presence and severity of insomnia were determined using questionnaires and polysomnography. Laboratory diagnosis included a complete assessment of hemostatic system with thrombodynamics test. Patients were divided into 2 groups according the MRI data. The 1st group included 20 men with less than 4 silent cerebral infarctions, the 2nd group 56 men with multiple silent cerebral infarctions - from 5 to 25. Chronic insomnia was diagnosed in 35 (46%) of patients, more frequently in the second group (25% and 54% respectively, p<0.05). The group of patients with multiple silent infarctions demonstrated a loss of sleep efficiency and hypercoagulation with an increased rate of clot growth in thrombodynamics test. Correlation analysis confirmed the dependence between sleep efficiency and quantity of vascular sites, sleep efficiency and clot growth rate. The more severe plasma haemostasis disorder in patients with multiple silent infarctions and relation between insomnia severity and plasma haemostasis activation suggest that insomnia can be an additional risk factor of arteriole thrombosis.

Thrombodynamic parameters of hypercoagulability in patients with affective disorder and schizophrenia in a state of exacerbation

To detect coagulability impairment of blood plasma in patients with schizophrenia or affective disease in a state of exacerbation using a thrombodynamics test. The study included 46 women, 32 with attack-like/shift-like/or continuous schizophrenia (ICD-10: F20.00, F20.01, F20.02), 7 with schizotypal disorder (ICD-10: F21.3-21.4) and 7 with affective disorder (ICD-10: F32.00, F32.3). Thrombodynamics tests were performed on T-2 thrombodynamics analyzer ('Hemacore LLC', Moscow, Russia). For the first time, it was shown that in the patient population (n=46), the thrombodynamic parameters of the blood clot growth rate [initial velocity (Vi), steady-state velocity (Vst) and spontaneous clots adjusted velocity (V)] and clot size at 30 minute of thrombodynamics (Clot Size, CS) were significantly higher than normal values. The mean appearance of spontaneous clots (Tsp) was significantly lower than 30 minutes (p<0.0001) which indicated a rapid, spontaneous clots formation. The mean value of clot lag time (Tlag) and clot density (Density, D) did not differ significantly from normal values. The number of changed thrombodynamic parameters decreased in the following sequence: schizophrenia with different types of courses > schizotypal disorder>affective disorder. This is in good agreement with the fact that the course of affective disorders is more favorable than that in schizophrenia. The thrombodynamics test has a good potential for introduction into medicine to detect hypercoagulability and increased risks of thrombotic complications in patients, as well as to control for normalization of hemostasis with antiaggregant or anticoagulant drugs. Thrombodynamics makes it possible to identify a tendency to hypercoagulable states at an early stage, when other methods are still not sensitive enough. The study identified the hypercoagulability in patients with schizophrenia and affective disorders.

Increased Thrombogenicity in Chronic Renal Failure in a Rat Model Induced by 5/6 Ablation/Infarction.

PurposeAbnormalities in hemostasis and coagulation have been suggested in chronic renal failure (CRF). In this study, we compared processes of thrombus formation between rats with CRF and those with normal kidney function.Materials and MethodsCRF was induced by 5/6 ablation/infarction of the kidneys in Sprague-Dawley rats, and surviving rats after 4 weeks were used. Ferric chloride (FeCl3)-induced thrombosis in the carotid artery was induced to assess thrombus formation. Whole blood clot formation was evaluated using rotational thromboelastometry (ROTEM). Platelet aggregation was assessed with impedance platelet aggregometry.ResultsFeCl3-induced thrombus formation was initiated faster in the CRF group than in the control group (13.2±1.1 sec vs. 17.8±1.0 sec, p=0.027). On histological examination, the maximal diameters of thrombi were larger in the CRF group than in the control group (394.2±201.1 µm vs. 114.0±145.1 µm, p=0.039). In extrinsic pathway ROTEM, the CRF group showed faster clot initiation (clotting time, 59.0±7.3 sec vs. 72.8±5.0 sec, p=0.032) and increased clot growth kinetics (α angle, 84.8±0.2° vs. 82.0±0.6°, p=0.008), compared to the control group. Maximal platelet aggregation rate was higher in the CRF group than in the control group (58.2±0.2% vs. 44.6±1.2%, p=0.006).ConclusionOur study demonstrated that thrombogenicity is increased in rats with CRF. An activated extrinsic coagulation pathway may play an important role in increasing thrombogenicity in CRF.

Thrombodynamics, a new global coagulation test: Measurement of heparin efficiency

The actual coagulation status may be reliably measured using only highly sensitive global functional tests; however, they are not numerous and all of them have disadvantages. Thrombodynamics (TD), a novel global coagulation test, is sensitive to hypo- and hypercoagulable states. The main properties of this test were investigated, and its capabilities for hemostasis analysis were verified through pharmacodynamic monitoring of the most widely used anticoagulants, heparins. The anticoagulant effects in the plasma of donors (n = 20) and patients after hip replacement (n = 20) spiked with unfractionated heparin or enoxaparin were measured in vitro to eliminate the influence of pharmacokinetic factors. Sensitivity for heparins was compared for activated partial thromboplastin time, thrombin generation tests and TD. TD was shown to reliably characterize the pharmacodynamics of any heparin in the entire range of its prophylactic and therapeutic concentrations. Inter-individual variability for the anticoagulant action of heparins was also calculated using the TD data. This variability did not differ between the investigated groups and did not exceed 12% and 20% for the stationary clot growth rate in the presence of unfractionated heparin and enoxaparin, respectively. That finding was in accordance with the values determined earlier using the thrombin generation test. The study results showed that TD has advantages over the other global methods of coagulation analysis. These advantages are good standardization, high reproducibility, independence of the parameter values from patient age and gender, and a narrower parameter distribution in a normal population. These results indicate that TD is a promising universal assessment method that improves the quality of hemostasis analysis because it more reliably detects deviations from the parameters' reference values.

Initiation of reaction–diffusion waves of blood coagulation

Formation of blood clot in response to the vessel damage is triggered by the complex network of biochemical reactions of the coagulation cascade. The process of clot growth can be modeled as a traveling wave solution of the bistable reaction–diffusion system. The critical value of the initial condition which leads to convergence of the solution to the traveling wave corresponds to the pulse solution of the corresponding stationary problem. In the current study we prove the existence of the pulse solution for the stationary problem in the model of the main reactions of the blood coagulation cascade using the Leray–Schauder method.

Modeling of the effects of IL-17 and TNF-α on endothelial cells and thrombus growth

Rheumatoid and psoriatic arthritis are chronic inflammatory diseases, with massive increase of cardiovascular events (CVE), and contribution of the cytokines TNF-α and IL-17. Chronic inflammation inside the joint membrane or synovium results from the activation of fibroblasts/synoviocytes, and leads to the release of cytokines from monocytes (Tumor Necrosis Factor or TNF) and from T lymphocytes (Interleukin-17 or IL-17). At the systemic level, the very same cytokines affect endothelial cells and vessel wall. We have previously shown [1,2] that IL-17 and TNF-α, specifically when combined, increase procoagulation, decrease anticoagulation and increase platelet aggregation, leading to thrombosis. These results are the basis for the models of interactions between IL-17 and TNF, and genes expressed by activated endothelial cells. This work is devoted to mathematical modeling and numerical simulations of blood coagulation and clot growth under the influence of IL-17 and TNF-α. We show that they can provoke thrombosis, leading to the complete or partial occlusion of blood vessels. The regimes of blood coagulation and conditions of occlusion are investigated in numerical simulations and in approximate analytical models. The results of mathematical modeling allow us to predict thrombosis development for an individual patient.

Thromboelastometry Velocity Curve Predicts Blood Product Transfusion and Mortality Within the First 24 Hours in Severely Injured Trauma Patients

SESSION TITLE: Hematology/Oncology in the ICU SESSION TYPE: Original Investigation Slide PRESENTED ON: Monday, October 30, 2017 at 04:30 PM - 05:30 PM PURPOSE: The processes leading to uncontrolled bleeding after trauma are complex and heterogeneous. Thrombin generation (TG) is pivotal for an adequate hemostatic response but burdensome to assess in emergency settings. Instead, thromboelastometry (TEM), is an increasingly used point of care test for trauma patients care. TEM estimates the first derivative of the clot growth velocity curve (V-curve), which has a remarkable similarity with the endogenous thrombin potential trace and is highly correlated to TG determination by thrombin/antithrombin complex. TEM V-curve describes the maximum speed of clot formation (MaxV), the time to reach MaxV (MaxV-t) and the area under the curve (AUC). The study objective is to evaluate whether the TEM V-curve parameters (MaxV, MaxV-t, and AUC) can predict blood transfusion and mortality in the first 24h post-injury in adult trauma patients. METHODS: Retrospective cohort study of severely injured patients admitted to a Level I Trauma Center. Severity was defined as any abbreviated Injury Score (AIS) >2. Demographic data including mortality, conventional coagulation tests, rotational thromboelastometry on admission, and the total amount of blood products transfused in the first 24h were collected. With a linear regression model, we examined the effect of the V-curve parameters and the total number of blood products in 24h, adjusting for systolic pressure (SBP), temperature, injury severity score (ISS), base excess (BE), hemoglobin(HB), INR, fibrinogen, aPTT, and platelets levels. With a logistic regression model, we assessed the effect of V-curve parameters in 24h mortality, adjusting for age, AIS head, ISS, and BE. RESULTS: 550 patients were included with median ISS 19 and a median age of 43 years. The maximum speed of clot formation (MaxV) was associated with the number of units of blood product transfused in 24h of injury; for every unit decrease in MaxV (mm/min) there was an average increase of 0.7U transfused in 24h (95%CI 0.29-1.13, p= <0.0001) after adjusting for SBP, temperature, ISS, BE, hemoglobin, INR, fibrinogen, aPTT, platelets levels at admission, and the other V-curve parameters (MaxV-t, AUC). Other parameters affecting 24h blood transfusion were SBP (p= <0.0001), AUC (p= 0.037), BE (p= <0.0001). Time to reach MaxV (MaxV-t) not associated with blood transfusion. In a logistic regression model, MaxV was was associated with 24h mortality (OR 1.3, 95%CI 1.12-1.51, p= 0.0005) after adjusting for age, AIS head, ISS, and BE. Also, age(p= 0.0068), traumatic brain injury(p= 0.0027), and BE(p= 0.0033) were associated with 24h mortality. CONCLUSIONS: Our study is among the first to demonstrate an association between the TEM V-curve and clinical outcomes in trauma. Reductions in MaxV were associated with increased transfusion requirements and mortality in the initial 24h following injury, adding to the understanding of early trauma coagulopathy, that the velocity of clot growth rather than the total amount of thrombin impacts the clinical consequences significantly. CLINICAL IMPLICATIONS: TEM V-curve parameters evaluate the hemostatic potential, understanding the thrombin generation and clot formation dynamics in trauma patients with significant hemorrhage are crucial for developing adequate hemostatic strategies. DISCLOSURE: The following authors have nothing to disclose: Johana Gomez Builes, Sandro Rizoli, Andrew Baker No Product/Research Disclosure Information