Assessing Factor V Antigen and Degradation Products in Burn and Trauma Patients.

Introduction: Proposed mechanisms of acute traumatic coagulopathy (ATC) include decreased clotting potential due to factor consumption and proteolytic inactivation of factor V (FV) and activated factor V (FVa) by activated protein C (aPC). The role of FV/FVa depletion or inactivation in burn-induced coagulopathy is not well characterized. This study evaluates FV dynamics following burn and nonburn trauma.

Inhalation Injury Is Associated With Endotheliopathy and Abnormal Fibrinolytic Phenotypes in Burn Patients: A Cohort Study.

Burn injury is associated with endothelial dysfunction and coagulopathy and concomitant inhalation injury (IHI) increases morbidity and mortality. The aim of this work is to identify associations between IHI, coagulation homeostasis, vascular endothelium, and clinical outcomes in burn patients. One hundred and twelve patients presenting to a regional burn center were included in this retrospective cohort study.

Circulating Syndecan-1 and Tissue Factor Pathway Inhibitor, Biomarkers of Endothelial Dysfunction, Predict Mortality in Burn Patients.

Objective: The aim of this study is to evaluate the association between burn injury and admission plasma levels of Syndecan-1 (SDC-1) and Tissue Factor Pathway Inhibitor (TFPI), and their ability to predict 30-day mortality.

Background: SDC-1 and TFPI are expressed by vascular endothelium and shed into the plasma as biomarkers of endothelial damage. Admission plasma biomarker levels have been associated with morbidity and mortality in trauma patients, but this has not been well characterized in burn patients.

Factor Xa Inhibition Reduces Coagulation Activity but Not Inflammation Among People With HIV: A Randomized Clinical Trial.

Background: Coagulation activity among persons with HIV is associated with end-organ disease risk, but the pathogenesis is not well characterized. We tested a hypothesis that hypercoagulation contributes to disease risk, in part, via upregulation of inflammation.

Methods: Treatment effects of edoxaban (30 mg), a direct factor Xa inhibitor, vs placebo were investigated in a randomized, double-blind crossover trial among participants with HIV and viral suppression and D-dimer levels ≥100 ng/mL.

Variation in platelet expression of FcγRIIa after myocardial infarction.

FcγRIIa amplifies platelet activation and greater platelet expression of FcγRIIa identifies patients at greater risk of subsequent cardiovascular events. Thus, platelet expression of FcγRIIa may be useful to guide therapy. Because platelet function tests are impacted by preparative procedures and substantial intra-individual variability, we examined the impact of these factors on platelet expression of FcγRIIa in blood from healthy subjects and in patients after myocardial infarction (MI).

Utilizing Plasma Composition Data to Help Determine Procoagulant Dynamics in Patients with Thermal Injury: A Computational Assessment.

Introduction: The development of methods that generate individualized assessments of the procoagulant potential of burn patients could improve their treatment. Beyond its role as an essential intermediate in the formation of thrombin, factor (F)Xa has systemic effects as an agonist to inflammatory processes. In this study, we use a computational model to study the FXa dynamics underlying tissue factor-initiated thrombin generation in a small cohort of burn patients.

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus.

Background: Effective HIV treatment with antiretroviral therapy has prolonged survival and shifted causes of death to non-AIDS illnesses such as cardiovascular disease. We have shown that inflammation and HIV viral load associate with pro- and anticoagulant factor imbalances resulting in increased thrombin generation when mathematically modeled. We explore the hypothesis that factor compositional imbalance, corresponding to increased in silico thrombin generation, predicts mortality among HIV+ persons.

Assessment of Coagulation Homeostasis in Blunt, Penetrating, and Thermal Trauma: Guidance for a Multicenter Systems Biology Approach.

Introduction: Provisioning care for traumatically injured patients makes conducting research very proximal to injury difficult. These studies also inherently have regulatory barriers to overcome. Here we outline a protocol for acute-phase enrollment of traumatically injured patients into a prospective observational clinical trial with precise and comprehensive sample acquisition in support of a systems biology approach to a research study.

Hemodilution and Endothelial Cell Regulation of Whole Blood Coagulation.

Background: Beyond localized damage to the circulatory system and surrounding tissue, trauma stresses endothelial cells throughout the vasculature, potentially leading to hemorrhagic or thrombotic complications away from the injury site.

Objective: Use a whole blood endothelial cell model to define the effects of crystalloid fluid therapy on protein C pathway regulation of tissue factor-initiated coagulation.

Methods: Tissue factor-initiated coagulation was studied in the presence of EA.

Reference ranges for rotational thromboelastometry in male Sprague Dawley rats.

Background: A functional coagulation assay was used to investigate the extrinsic pathway of coagulation on citrated whole blood samples from healthy adult male Sprague Dawley rats using the mini cup and pin system.

Methods: Reference values for coagulation parameters from forty-three animals were calculated using data obtained from the ROTEM® hemostasis analyzer with the EXTEM test.

Results: The following ranges, presented as the 2.

Probing the Dynamics of Clot-Bound Thrombin at Venous Shear Rates.

In closed system models of fibrin formation, exosite-mediated thrombin binding to fibrin contributes to clot stability and is resistant to inhibition by antithrombin/heparin while still susceptible to small, active-site inhibitors. Each molecule of fibrin can bind ∼1.6 thrombin molecules at low-affinity binding sites (K = 2.

In-depth analysis of clotting dynamics in burn patients.

Background: Studies associating coagulopathic changes with burn injury have relied on limited tests such as partial thromboplastin time (PTT) and international normalized ratio (INR). Understanding the clotting dynamics and associated risk factors after burn injury could influence management. This work aimed to identify real-time changes in coagulation after burn injury not indicated by PTT or INR alone.

Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency.

Whole genome sequencing of an individual completely devoid of plasma- and platelet-derived factor V (FV) identified 167 variants in his F5 gene including previously identified and damaging missense mutations at rs6027 and Leu90Ser. Because the administration of fresh frozen plasma (FFP) prevents gastrointestinal bleeding in this individual, its effects on his plasma- and platelet-derived FV concentrations were assessed. The patient's plasma FV levels peaked by 2 hours following FFP administration and were undetectable 96 hours later.

Global assays of hemostasis.

Purpose Of Review: There exists an imbalance between our understanding of the physiology of the blood coagulation process and the translation of this understanding into useful assays for clinical application. As technology advances, the capabilities for merging the two areas have become more attainable. Global assays have advanced our understanding of the dynamics of the blood coagulation process beyond end point assays and are at the forefront of implementation in the clinic.

Developing individualized coagulation profiling of disease risk: thrombin generation dynamic models of the pro and anticoagulant balance.

Global assays and computational models have advanced research into the realm of individualized profiling of hemostatic states. This brief review will describe one computational approach which utilizes an integrated method that evaluates the dynamics of thrombin generation by defining interactions of the pro and anticoagulant proteins, enzymes and cofactors based upon individualized concentrations of select factors. This plasma composition based computational modeling can provide a mechanism based bridge between empirical global assays of coagulation and individualized risk prediction.

Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer.

While platelets are well known to play a central role in hemostasis and thrombosis, there is emerging experimental evidence to suggest that they also mediate tumor cell growth, dissemination, and angiogenesis. An increase in platelet number (thrombocytosis) and activity is seen in patients with a wide spectrum of malignancies, and the former is correlated with a decrease in overall survival and poorer prognosis. Preclinical data suggest that circulating tumor cell partnerships with platelets in the blood facilitate tumor metastases through direct interactions and secreted bioactive proteins.

Thrombin generation and fibrin clot formation under hypothermic conditions: an in vitro evaluation of tissue factor initiated whole blood coagulation.

Background: Despite trauma-induced hypothermic coagulopathy being familiar in the clinical setting, empirical experimentation concerning this phenomenon is lacking. In this study, we investigated the effects of hypothermia on thrombin generation, clot formation, and global hemostatic functions in an in vitro environment using a whole blood model and thromboelastography, which can recapitulate hypothermia.

Methods: Blood was collected from healthy individuals through venipuncture and treated with corn trypsin inhibitor, to block the contact pathway.

Modeling thrombin generation: plasma composition based approach.

Thrombin has multiple functions in blood coagulation and its regulation is central to maintaining the balance between hemorrhage and thrombosis. Empirical and computational methods that capture thrombin generation can provide advancements to current clinical screening of the hemostatic balance at the level of the individual. In any individual, procoagulant and anticoagulant factor levels together act to generate a unique coagulation phenotype (net balance) that is reflective of the sum of its developmental, environmental, genetic, nutritional and pharmacological influences.

Depletion of systemic concentrations of coagulation factors in blood from patients with atherosclerotic vascular disease.

Objective: Thrombosis complicating the rupture of an atherosclerotic plaque can lead to arterial occlusion. Tissue factor, a membrane-bound glycoprotein, is expressed to a greater extent in atherosclerotic plaques and may be a key mediator of microthrombosis and macrothrombosis. This pilot study was designed to determine whether the angiographic presence or the extent of atherosclerosis was correlated with the activity of coagulation factors in blood.

From principle to practice: bridging the gap in patient profiling.

The standard clinical coagulation assays, activated partial thromboplastin time (aPTT) and prothrombin time (PT) cannot predict thrombotic or bleeding risk. Since thrombin generation is central to haemorrhage control and when unregulated, is the likely cause of thrombosis, thrombin generation assays (TGA) have gained acceptance as "global assays" of haemostasis. These assays generate an enormous amount of data including four key thrombin parameters (lag time, maximum rate, peak and total thrombin) that may change to varying degrees over time in longitudinal studies.

The prothrombotic phenotypes in familial protein C deficiency are differentiated by computational modeling of thrombin generation.

The underlying cause of thrombosis in a large protein C (PC) deficient Vermont kindred appears to be multicausal and not explained by PC deficiency alone. We evaluated the contribution of coagulation factors to thrombin generation in this population utilizing a mathematical model that incorporates a mechanistic description of the PC pathway. Thrombin generation profiles for each individual were generated with and without the contribution of the PC pathway.

Tissue factor-dependent thrombin generation across pregnancy.

Objective: Normal pregnancy results in a prothrombotic state. Studies that have investigated the capacity of pregnant women to generate thrombin are limited. Our aim was to evaluate thrombin generation longitudinally from the preconception period, through pregnancy, and after pregnancy.

Defining the boundaries of normal thrombin generation: investigations into hemostasis.

In terms of its soluble precursors, the coagulation proteome varies quantitatively among apparently healthy individuals. The significance of this variability remains obscure, in part because it is the backdrop against which the hemostatic consequences of more dramatic composition differences are studied. In this study we have defined the consequences of normal range variation of components of the coagulation proteome by using a mechanism-based computational approach that translates coagulation factor concentration data into a representation of an individual's thrombin generation potential.