A multi-constituent model for assessing the effect of impeller shroud on the thrombosis potential of a centrifugal blood pump.

Centrifugal blood pumps can be used for treating heart failure patients. However, pump thrombosis has remained one of the complications that trouble clinical treatment. This study analyzed the effect of impeller shroud on the thrombosis risk of the blood pump, and predicted areas prone to thrombosis. Multi-constituent transport equations were presented, considering mechanical activation and biochemical activation. It was found that activated platelets concentration can increase with shear stress and adenosine diphosphate(ADP) concentration increasing, and the highest risk of thrombosis inside the blood pump was under extracorporeal membrane oxygenation (ECMO) mode. Under the same condition, ADP concentration and thrombosis index of semi-shroud impeller can increase by 7.3% and 7.2% compared to the closed-shroud impeller. The main reason for the increase in thrombosis risk was owing to elevated scalar shear stress and more coagulation promoting factor-ADP released. The regions with higher thrombosis potential were in the center hole, top and bottom clearance. As a novelty, the findings revealed that impeller shroud can influence mechanical and biochemical activation factors. It is useful for identifying potential risk regions of thrombus formation based on relative comparisons.

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Red Blood Cell Morphodynamics in Patients with Polycythemia Vera and Stroke.

Polycythemia vera (PV) is a Ph-negative myeloproliferative neoplasm (MPN) which is characterized by erythrocytosis and a high incidence of thrombotic complications, including stroke. The study aimed to evaluate red blood cell (RBC) morphodynamic properties in PV patients and their possible association with stroke. We enrolled 48 patients with PV in this cross-sectional study, 13 of which have a history of ischemic stroke. The control group consisted of 90 healthy subjects. RBC deformability and aggregation analysis were performed using a laser-assisted optical rotational red cell analyzer. The following parameters were calculated: aggregation amplitude (Amp), RBC rouleaux formation time constant (Tf), time of formation of three-dimensional aggregates (Ts), aggregation index (AI), rate of complete disaggregation (y-dis), and the maximal elongation of RBC (EImax). Statistical analysis was performed with the R programming language. There were significant differences in RBCs morphodynamics features between patients with PV and the control group. Lower EImax (0.47 (0.44; 0.51) vs. 0.51 (0.47; 0.54), p < 0.001) and γ-dis (100 (100; 140) vs. 140 (106; 188) s-1, p < 0.001) along with higher amplitude (10.1 (8.6; 12.2) vs. 7.7 (6.6; 9.2), p < 0.001) was seen in patients with PV compared with control. A statistically significant difference between PV patients with and without stroke in aggregation amplitude was found (p = 0.03). A logistic regression model for stroke was built based on RBC morphodynamics which performed reasonably well (p = 0.01). RBC alterations may be associated with overt cerebrovascular disease in PV, suggesting a possible link between erythrocyte morphodynamics and increased risk of stroke.

Microrheological disorders in patients with polycythemia vera suffered acute ischemic stroke.

The relevance of the study is determined by the fact that the combination of cerebrovascular disorders and myeloproliferative diseases requires the search for a predictive biomarker to improve outcomes. The aim of this article was to explore the meanings of microrheological disorders in patients with polycythemia vera (PV) who suffered an acute ischemic stroke (AIS). The study was carried out at the Research center of Neurology. We studied microrheological properties in 181 patients (aged 42-75 years). From the AIS developed in 68 (38%) patients with PV; 59 (32%) patients with AIS were without PV; 54 (30%) patients with PV did not suffer AIS. Microrheological disorders, first of all, the red blood cells (RBC) deformability correlated to AIS severity and its features in comorbid patients. The RBC deformability was dependent on the allelic load of the V617F mutation in the JAK2 gene. Additionally, it was found that RBC deformability perform diagnostic value in the acute phase of ischemic stroke as well as get predictive value for thrombotic complications development within 2 years after AIS in such patients. We suppose that in patients with PV an ischemic stroke and thrombosis would directly depend on the success of PV treatment. In turn, RBC deformability is applicable for some predictive models to late thrombosis development.

Neutrophil extracellular traps in feline cardiogenic arterial thrombi: a pilot study.

OBJECTIVES: The aim of this study was to investigate the spatial distribution of neutrophil extracellular traps (NETs) in cardiogenic arterial thromboembolism (CATE). Specifically, we aimed to examine the related structural features of NETs in feline arterial thrombi in relation to their arterial locations. METHODS: Paraffin-embedded aortic bifurcations from nine cats with hypertrophic cardiomyopathy (four with CATE and five without) were deparaffinized, and NETs were identified by immunodetection based on colocalization of cell-free DNA, citrullinated histone H3 and neutrophil elastase. The distribution of NETs in thrombi within the aortic bifurcations and common iliac arteries (CIAs) was compared based on their proximity to the descending aorta (proximal, mid, distal). Ten random fields per section were captured at × 10 and × 20 magnification for each section of the clot and analyzed. RESULTS: The distributions of NETs in thrombi within the aortic bifurcation and CIAs were found to differ in relation to their assigned zones (proximal, mid, distal; P = 0.04); NETs were concentrated mostly in the proximal region in the aortic bifurcations (47.56%, interquartile range [IQR] 14.07-77.95) and CIAs (44.69%, IQR 24.65-85.28), compared with the distal regions (2.69%, IQR 0.10-50.04 [P = 0.027]; 7.08%, IQR 1.27-59.33 [P = 0.02]). CONCLUSIONS AND RELEVANCE: The variation in NET distribution within arterial thrombi may shed light on the pathogenesis of thrombus growth. This may be due to possible neutrophil entrapment or variations in shear stress.

Interplay between coagulation and inflammation in cancer: Limitations and therapeutic opportunities.

Advances in understanding the molecular mechanisms of tumor progression have achieved impressive progress in the treatment of cancer and so-called immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Indeed, antibody-based drugs blocking immune escape of tumor cells by modulation of T cell responses are increasingly utilized for a wide range of tumor entities. Nonetheless, response rates remain limited, and the development of secondary resistance is a common problem. In addition, by increasing the immune response a variety of severe side effects are provoked. Next to autoimmune responses, activation of the complement system and skin toxicity, an increased incidence for thrombotic complications has been observed associated with an increased mortality rate. Based on this, it can be postulated that the interplay of coagulation with inflammation in the tumor microenvironment is relevant for each step in the tumor life cycle. This review focuses on the coagulation as central player fostering mechanisms associated with tumor progression. Thus, a better understanding of the molecular pathways involved in the complex interaction of circulating tumor cells, the plasmatic coagulation and immune cells may help to improve therapeutic concepts reducing mortality and morbidity associated with cancer.

MPN and thrombosis was hard enough . . . now there's COVID-19 thrombosis too.

Both myeloproliferative neoplasms (MPNs) and coronavirus disease 2019 (COVID-19) are characterized by an intrinsic thrombotic risk. Little is known about the incidence and the outcome of thrombotic events in patients with MPN infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but common mechanisms of coagulation activation, typical of both disorders, suggest that these patients can be at particularly high risk. To define the best thromboprophylaxis and treatment regimens in both MPN and COVID-19, individual- and disease-specific thrombotic risk factors, bleeding risk, and concomitant specific treatments need to be considered. In this case-based review, an individualized approach is presented in a case of SARS-CoV-2 infection occurring in a man with polycythemia vera (PV). A primary anticoagulant thromboprophylaxis strategy and adjustment of his PV treatment were implemented. However, during the hospital stay, he experienced pulmonary embolism and therapeutic anticoagulation had to be set. Then his condition improved, and discharge was planned. Postdischarge decisions had to be made about the type and duration of venous thromboembolism treatment as well as the management of PV-specific drugs. The steps of our decisions and recommendations are presented.

Platelet Function, Role in Thrombosis, Inflammation, and Consequences in Chronic Myeloproliferative Disorders.

Platelets are conventionally defined as playing a vital role in homeostasis and thrombosis. This role has over the years transformed as knowledge regarding platelets has expanded to include inflammation, cancer progression, and metastasis. Upon platelet activation and subsequent aggregation, platelets release a host of various factors, including numerous pro-inflammatory factors. These pro-inflammatory factors are recruiters and activators of leukocytes, aiding in platelets' immune regulating function and inflammatory function. These various platelet functions are interrelated; activation of the inflammatory function results in thrombosis and, moreover, in various disease conditions, can result in worsened or chronic pathogenesis, including cancer. The role and contribution of platelets in a multitude of pathophysiological events during hemostasis, thrombosis, inflammation, cancer progression, and metastasis is an important focus for ongoing research. Platelet activation as discussed here is present in all platelet functionalities and can result in a multitude of factors and signaling pathways being activated. The cross-talk between inflammation, cancer, and platelets is therefore an ideal target for research and treatment strategies through antiplatelet therapy. Despite the knowledge implicating platelets in these mentioned processes, there is, nevertheless, limited literature available on the involvement and impact of platelets in many diseases, including myeloproliferative neoplasms. The extensive role platelets play in the processes discussed here is irrefutable, yet we do not fully understand the complete interrelation and extent of these processes.

Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment.

Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10-50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (>90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs.

Indoleamine 2,3-dioxygenase-1, a Novel Therapeutic Target for Post-Vascular Injury Thrombosis in CKD.

BACKGROUND: CKD, characterized by retained uremic solutes, is a strong and independent risk factor for thrombosis after vascular procedures . Urem ic solutes such as indoxyl sulfate (IS) and kynurenine (Kyn) mediate prothrombotic effect through tissue factor (TF). IS and Kyn biogenesis depends on multiple enzymes, with therapeutic implications unexplored. We examined the role of indoleamine 2,3-dioxygenase-1 (IDO-1), a rate-limiting enzyme of kynurenine biogenesis, in CKD-associated thrombosis after vascular injury. METHODS: IDO-1 expression in mice and human vessels was examined. IDO-1-/- mice, IDO-1 inhibitors, an adenine-induced CKD, and carotid artery injury models were used. RESULTS: Both global IDO-1-/- CKD mice and IDO-1 inhibitor in wild-type CKD mice showed reduced blood Kyn levels, TF expression in their arteries, and thrombogenicity compared with respective controls. Several advanced IDO-1 inhibitors downregulated TF expression in primary human aortic vascular smooth muscle cells specifically in response to uremic serum. Further mechanistic probing of arteries from an IS-specific mouse model, and CKD mice, showed upregulation of IDO-1 protein, which was due to inhibition of its polyubiquitination and degradation by IS in vascular smooth muscle cells. In two cohorts of patients with advanced CKD, blood IDO-1 activity was significantly higher in sera of study participants who subsequently developed thrombosis after endovascular interventions or vascular surgery. CONCLUSION: Leveraging genetic and pharmacologic manipulation in experimental models and data from human studies implicate IS as an inducer of IDO-1 and a perpetuator of the thrombotic milieu and supports IDO-1 as an antithrombotic target in CKD.

Computational modeling of blood component transport related to coronary artery thrombosis in Kawasaki disease.

Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case-mechanical or biochemical-could help define improved strategies for thrombosis prevention tailored for each patient.

Thrombo-Inflammation: A Focus on NTPDase1/CD39.

There is increasing evidence for a link between inflammation and thrombosis. Following tissue injury, vascular endothelium becomes activated, losing its antithrombotic properties whereas inflammatory mediators build up a prothrombotic environment. Platelets are the first elements to be activated following endothelial damage; they participate in physiological haemostasis, but also in inflammatory and thrombotic events occurring in an injured tissue. While physiological haemostasis develops rapidly to prevent excessive blood loss in the endothelium activated by inflammation, hypoxia or by altered blood flow, thrombosis develops slowly. Activated platelets release the content of their granules, including ATP and ADP released from their dense granules. Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 dephosphorylates ATP to ADP and to AMP, which in turn, is hydrolysed to adenosine by ecto-5'-nucleotidase (CD73). NTPDase1/CD39 has emerged has an important molecule in the vasculature and on platelet surfaces; it limits thrombotic events and contributes to maintain the antithrombotic properties of endothelium. The aim of the present review is to provide an overview of platelets as cellular elements interfacing haemostasis and inflammation, with a particular focus on the emerging role of NTPDase1/CD39 in controlling both processes.

Thromboinflammation Supports Complement Activation in Cancer Patients With COVID-19.

Background: COVID-19 pathology is associated with exuberant inflammation, vascular damage, and activation of coagulation. In addition, complement activation has been described and is linked to disease pathology. However, few studies have been conducted in cancer patients. Objective: This study examined complement activation in response to COVID-19 in the setting of cancer associated thromboinflammation. Methods: Markers of complement activation (C3a, C5a, sC5b-9) and complement inhibitors (Factor H, C1-Inhibitor) were evaluated in plasma of cancer patients with (n=43) and without (n=43) COVID-19 and stratified based on elevated plasma D-dimer levels (>1.0 µg/ml FEU). Markers of vascular endothelial cell dysfunction and platelet activation (ICAM-1, thrombomodulin, P-selectin) as well as systemic inflammation (pentraxin-3, serum amyloid A, soluble urokinase plasminogen activator receptor) were analyzed to further evaluate the inflammatory response. Results: Increases in circulating markers of endothelial cell dysfunction, platelet activation, and systemic inflammation were noted in cancer patients with COVID-19. In contrast, complement activation increased in cancer patients with COVID-19 and elevated D-dimers. This was accompanied by decreased C1-Inhibitor levels in patients with D-dimers > 5 ug/ml FEU. Conclusion: Complement activation in cancer patients with COVID-19 is significantly increased in the setting of thromboinflammation. These findings support a link between coagulation and complement cascades in the setting of inflammation.

Neutrophil extracellular traps in patients with liver cirrhosis and hepatocellular carcinoma.

Neutrophil extracellular traps (NETs) are web-like structures consisting of DNA, histones and granule proteins, released from neutrophils in thrombus formation, inflammation, and cancer. We asked if plasma levels of the NET markers myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit)-DNA, are elevated in liver cirrhosis and hepatocellular carcinoma (HCC) and if the levels correlate with clinical parameters. MPO-DNA, H3Cit-DNA, and thrombin-antithrombin (TAT) complex, as a marker of coagulation activity, were measured using ELISA in plasma from 82 patients with HCC, 95 patients with cirrhosis and 50 healthy controls. Correlations were made to clinical parameters and laboratory data and patients were followed for a median of 22.5 months regarding thrombosis development. H3Cit-DNA was significantly (p < 0.01) elevated in plasma from cirrhosis (66.4 ng/mL) and HCC (63.8 ng/mL) patients compared to healthy controls (31.8 ng/mL). TAT levels showed similar pattern (3.1, 3.7, and 0.0 µg/mL respectively, p < 0.01). MPO-DNA was significantly (p < 0.01) elevated in cirrhosis patients (0.53 O.D.) as compared to controls (0.33 O.D.). Levels of MPO-DNA and H3Cit-DNA correlated positively with Child-Pugh and MELD score. TAT was increased in all Child-Pugh and MELD groups. In multivariable logistic regression, Child B and C liver cirrhosis were independent predictors of elevated H3Cit-DNA in plasma. Levels of MPO-DNA and H3Cit-DNA were similar in patients with or without history of thrombosis, or thrombus formation during follow-up. In conclusion, plasma markers of NET formation are elevated in liver cirrhosis and correlate to the degree of liver dysfunction in patients with liver cirrhosis and/or HCC. The presence of HCC did not further increase the plasma levels of NET markers as compared to patients with cirrhosis only.

Concern About the Adverse Effects of Thrombocytopenia and Thrombosis After Adenovirus-Vectored COVID-19 Vaccination.

Since the outbreak of Covid-19 in December, 2019, scientists worldwide have been committed to developing COVID-19 vaccines. Only when most people have immunity to SARS-CoV-2, COVID-19 can reduce even wholly overcome. So far, nine kinds of COVID-19 vaccines have passed the phase III clinical trials and have approved for use. At the same time, adverse reactions after COVID-19 vaccination have also reported. This paper focuses on the adverse effects of thrombosis and thrombocytopenia caused by the COVID-19 vaccine, especially the adenovirus-vector vaccine from AstraZeneca and Pfizer, and discusses its mechanism and possible countermeasures.

Roxadustat Does Not Affect Platelet Production, Activation, and Thrombosis Formation.

Objective: Roxadustat is a new medication for the treatment of renal anemia. EPO (erythropoietin)-the current treatment standard-has been reported to enhance platelet activation and production. However, to date, the effect of roxadustat on platelets is unclear. To address this deficiency, herein, we have evaluated the effect of roxadustat on platelet production and function. Approach and Results: We performed several mouse platelet functional assays in the presence/absence of in vitro and in vivo roxadustat treatment. Both healthy and 5/6 nephrectomized mice were utilized. The effect of roxadustat on platelet function of healthy volunteers and chronic kidney disease patients was also evaluated. For platelet production, megakaryocyte maturation and proplatelet formation were assayed in vitro. Peripheral platelet and bone marrow megakaryocyte counts were also determined. We found that roxadustat could not stimulate washed platelets directly, and platelet aggregation, spreading, clot retraction, and P-selectin/JON/A exposure were similar with or without in vitro or in vivo roxadustat treatment among both healthy and 5/6 nephrectomized mice. In vivo mouse thrombosis models were additionally performed, and no differences were detected between the vehicle and roxadustat treatment groups. EPO, which was considered a positive control in the present study, promoted platelet function and production as reported previously. Megakaryocyte maturation and proplatelet formation were also not significantly different between control mice and those treated with roxadustat. After receiving roxadustat for 14 days, no difference in the peripheral platelet count was observed in the mice. Conclusions: Administration of roxadustat has no significant impact on platelet production and function.

Comparison of the effects between MPL and JAK2V617F on thrombosis and peripheral blood cell counts in patients with essential thrombocythemia: a meta-analysis.

To assess the effects between MPL and JAK2V617F on the thrombosis risk and peripheral blood cell counts in patients with essential thrombocythemia (ET), we identified eligible studies from PubMed, Embase, and the Cochrane Library. Seven studies were ultimately included in this meta-analysis. All studies reported the peripheral blood cell counts of ET patients, and three of them reported the eligible thrombotic events. In comparing the effect of MPL versus JAK2V617F on thrombosis, 1257 ET patients (73 MPL + and 1184 JAK2V617F +) were included. MPL-positive (MPL +) ET patients had a higher risk of thrombosis than JAK2V617F-positive (JAK2V617F +) ET patients [RR = 1.80 (1.08-3.01), P = 0.025]. And 3453 ET patients (138 MPL + and 3315 JAK2V617F +) were included in the comparison of peripheral blood cell counts. Platelet counts of MPL + ET patients were higher than that of JAK2V617F + ET patients [WMD = 81.18 (31.77-130.60), P = 0.001]. MPL + ET patients had lower hemoglobin [WMD = - 11.66 (- 14.32 to - 9.00), P = 0.000] and white blood cell counts [WMD = - 1.01 (- 1.47 to - 0.56), P = 0.000] than JAK2V617F + ET patients. These findings indicate that the MPL mutation is a high-risk factor for thrombosis in ET patients, and it may be rational to include MPL mutation in the revised IPSET as a criterion for thrombosis prediction scores. And given the differences in peripheral blood, it is necessary to further study whether MPL + ET patients differ from JAK2V617F + ET patients in bleeding and survival.

Critical traumatic brain injury is associated with worse coagulopathy.

OBJECTIVES: As thromboelastography (TEG) becomes the standard of care in patients with hemorrhagic shock (HS), an association between concomitant traumatic brain injury (TBI) and coagulopathy by TEG parameters is not well understood and is thus investigated. METHODS: Retrospective analysis of trauma registry data at a single level 1 trauma center of 772 patients admitted with head Abbreviated Injury Scale (AIS) score of 3 and TEG studies between 2014 and 2017. Patients were stratified to moderate-severe TBI by head AIS scores of 3 and 4 (435 patients) and critical TBI by head AIS score of 5 (328 patients). Hemorrhagic shock was defined by base deficit of 4 or shock index of 0.9. Statistical analysis with unpaired t tests compared patients with critical TBI with patients with moderate-severe TBI, and patients were grouped by presence or absence of HS. A comparison of TBI data with conventional coagulation studies was also evaluated. RESULTS: In the setting of HS, critical TBI versus moderate-severe TBI was associated with longer R time (p = 0.004), longer K time (p < 0.05), less acute angle (p = 0.001), and lower clot strength and stability (maximum amplitude [MA]) (p = 0.01). Worse TBI did not correlate with increased fibrinolysis by clot lysis measured by the percentage decrease in amplitude at 30 minutes after MA (p = 0.3). Prothrombin time and international normalized ratio failed to demonstrate more severe coagulopathy, while partial thromboplastin time was found to correlate with severity of TBI (p = 0.01). In patients with critical TBI, the presence of HS correlated with a statistically significant worsening of all parameters (p < 0.05) except for clot lysis measured by the percentage decrease in amplitude at 30 minutes after MA (LY-30). CONCLUSION: Thromboelastography demonstrates that, with and without hemorrhagic shock, critical TBI correlates with a significant worsening of traumatic coagulopathy in comparison with moderate/severe TBI. In HS, critical TBI correlates with impaired clot initiation, impaired clot kinetics, and impaired platelet-associated clot strength and stability versus parameters found in moderate-severe TBI. Hemorrhagic shock correlates with worse traumatic coagulopathy in all evaluated patient groups with TBI. Conventional coagulation studies underestimate TBI-associated coagulopathy. Traumatic brain injury-associated coagulopathy is not associated with fibrinolysis. LEVEL OF EVIDENCE: Prognostic/epidemiological, level IV; prognostic/epidemiological, level III.