The Pathophysiology and Management of Hemorrhagic Shock in the Polytrauma Patient.

The recognition and management of life-threatening hemorrhage in the polytrauma patient poses several challenges to prehospital rescue personnel and hospital providers. First, identification of acute blood loss and the magnitude of lost volume after torso injury may not be readily apparent in the field. Because of the expression of highly effective physiological mechanisms that compensate for a sudden decrease in circulatory volume, a polytrauma patient with a significant blood loss may appear normal during examination by first responders. Consequently, for every polytrauma victim with a significant mechanism of injury we assume substantial blood loss has occurred and life-threatening hemorrhage is progressing until we can prove the contrary. Second, a decision to begin damage control resuscitation (DCR), a costly, highly complex, and potentially dangerous intervention must often be reached with little time and without sufficient clinical information about the intended recipient. Whether to begin DCR in the prehospital phase remains controversial. Furthermore, DCR executed imperfectly has the potential to worsen serious derangements including acidosis, coagulopathy, and profound homeostatic imbalances that DCR is designed to correct. Additionally, transfusion of large amounts of homologous blood during DCR potentially disrupts immune and inflammatory systems, which may induce severe systemic autoinflammatory disease in the aftermath of DCR. Third, controversy remains over the composition of components that are transfused during DCR. For practical reasons, unmatched liquid plasma or freeze-dried plasma is transfused now more commonly than ABO-matched fresh frozen plasma. Low-titer type O whole blood may prove safer than red cell components, although maintaining an inventory of whole blood for possible massive transfusion during DCR creates significant challenges for blood banks. Lastly, as the primary principle of management of life-threatening hemorrhage is surgical or angiographic control of bleeding, DCR must not eclipse these definitive interventions.

Optimizing transfusion strategies in damage control resuscitation: current insights.

From clinical and laboratory studies of specific coagulation defects induced by injury, damage control resuscitation (DCR) emerged as the most effective management strategy for hemorrhagic shock. DCR of the trauma patient who has sustained massive blood loss consists of 1) hemorrhage control; 2) permissive hypotension; and 3) the prevention and correction of trauma-induced coagulopathies, referred to collectively here as acute coagulopathy of trauma (ACOT). Trauma patients with ACOT have higher transfusion requirements, may eventually require massive transfusion, and are at higher risk of exsanguinating. Distinct impairments in the hemostatic system associated with trauma include acquired quantitative and qualitative platelet defects, hypocoagulable and hypercoagulable states, and dysregulation of the fibrinolytic system giving rise to hyperfibrinolysis or a phenomenon referred to as fibrinolytic shutdown. Furthermore, ACOT is a component of a systemic host defense dysregulation syndrome that bears several phenotypic features comparable with other acute systemic physiological insults such as sepsis, myocardial infarction, and postcardiac arrest syndrome. Progress in the science of resuscitation has been continuing at an accelerated rate, and clinicians who manage catastrophic blood loss may be incompletely informed of important advances that pertain to DCR. Therefore, we review recent findings that further characterize the pathophysiology of ACOT and describe the application of this new information to optimization of resuscitation strategies for the patient in hemorrhagic shock.

Clot dynamics and mortality: The MA-R ratio.

INTRODUCTION: The coagulopathy of trauma, illustrated by a short R-time, is common and well understood. The physiology behind this may be early thrombin burst with rapid clot formation. Rapid consumption of fibrinogen, however, may result in weak clot and substrate depletion, resulting in low MA. While these characteristics are interesting, utilizing thromboelastography (TEG) to identify those at risk of subsequent bleeding diathesis, especially in those who do not demonstrate early signs of physiologic derangement, is challenging. We have developed a novel ratio utilizing TEG values to describe patients at specific risk of traumatic coagulopathy. The purpose of this study was to create a single TEG value, which would reflect both the hypercoagulability and hypocoagulability of TIC. We hypothesized that this ratio, at admission, would be indicative of TIC and predictive of both blood product transfusion volumes and subsequent mortality. METHODS: Patients admitted via the highest activation criteria at one of two Level I trauma centers were included if they received at least 1 unit of packed red blood cells in the first 24 hours of admission. The admission TEG was collected, and a ratio was calculated by dividing the MA by the R-time (MA-R). MA-R quartiles were developed, and multivariable logistic regression was utilized to determine odds of mortality. RESULTS: Three hundred thirty patients with admission TEG were included. In all patients, median age was 35 years (interquartile range, 25-54 years), Injury Severity Score (ISS) was 20 (interquartile range, 13-29), 76% were male, and 43% had penetrating trauma. The MA-R groups were based on quartiles. Multivariable analysis, controlling for mechanism of injury, ISS, and admission pH, showed that increasing ratios were associated with decreased odds of death. The lowest MA-R ratios were also significantly associated with higher ISS, higher rates of blunt injury, and higher plasma utilization without a significant difference in packed red blood cell administration. CONCLUSIONS: Patients with the lowest MA-R ratios demonstrated the highest mortality rates. This novel ratio may prove highly useful to predict at-risk patients early, when other physiologic indicators are absent. The mechanism driving this finding may rest in fibrinogen depletion, resulting in weak clot. Patients with low MA-R ratios may benefit from earlier resuscitation with cryoprecipitate, rather than the traditional use of plasma found in current massive transfusion protocols. LEVELS OF EVIDENCE: Prognostic study, Level I.

1: 1 Transfusion strategies are right for the wrong reasons.

BACKGROUND: Early assessment of clot function identifies coagulopathies after injury. Abnormalities include a hypercoagulable state from excess thrombin generation, as well as an acquired coagulopathy. Efforts to address coagulopathy have resulted in earlier, aggressive use of plasma emphasizing 1:1 resuscitation. The purpose of this study was to describe coagulopathies in varying hemorrhagic profiles from a cohort of injured patients. METHODS: All injured patients who received at least one unit of packed red blood cells (PRBC) in the first 24 hours of admission from September 2013 to May 2015 were eligible for inclusion. Group-Based Trajectory Modeling, using volume of transfusion over time, was used to identify specific hemorrhagic phenotypes. The thromboelastography profile of each subgroup was characterized and group features were compared. RESULTS: Four hemorrhagic profiles were identified among 330 patients-minimal (MIN, group 1); patients with large PRBC requirements later in the hospital course (LH, group 2); massive PRBC usage (MH, group 3), and PRBC transfusion limited to shortly after injury (EH, group 4). All groups had an R-time shorter than the normal range (3.2-3.5, p = NS). Patients in group 3 had longer K-times (1.8 vs. 1.2-1.3, p < 0.05), significantly flatter α-angles (66.7 vs. 70.4-72.8, p < 0.05), and significantly weaker clot strength (MA 54.6 vs. 62.3-63.6, p < 0.05). Group 3 had greater physiologic derangements at admission and worse overall outcomes. CONCLUSION: Hemorrhagic profiles suggest a rapid onset of clot formation in all subgroups but significantly suppressed thrombin burst and diminished clot strength in the most injured. Patients are both hypercoagulable, with early and precipitous clot formation, and also have a demonstrable hypocoagulability. The exact cause of traumatic hypocoagulability is likely multifactorial. Goal-directed resuscitation, as early as institution of the massive transfusion protocol, may be more effective in resuscitating the most coagulopathic patients. LEVEL OF EVIDENCE: Prognostic study, level III.

Damage Control Resuscitation for Catastrophic Bleeding.

The timely recognition of shock secondary to hemorrhage from severe facial trauma or as a complication of complex oral and maxillofacial surgery presents formidable challenges. Specific hemostatic disorders are induced by hemorrhage and several extreme homeostatic imbalances may appear during or after resuscitation. Damage control resuscitation has evolved from massive transfusion to a more complex therapeutic paradigm that includes hemodynamic resuscitation, hemostatic resuscitation, and homeostatic resuscitation. Definitive control of bleeding is the principal objective of any comprehensive resuscitation scheme for hemorrhagic shock.

Damage control resuscitation.

The early recognition and management of hemorrhage shock are among the most difficult tasks challenging the clinician during primary assessment of the acutely bleeding patient. Often with little time, within a chaotic setting, and without sufficient clinical data, a decision must be reached to begin transfusion of blood components in massive amounts. The practice of massive transfusion has advanced considerably and is now a more complete and, arguably, more effective process. This new therapeutic paradigm, referred to as damage control resuscitation (DCR), differs considerably in many important respects from previous management strategies for catastrophic blood loss. We review several important elements of DCR including immediate correction of specific coagulopathies induced by hemorrhage and management of several extreme homeostatic imbalances that may appear in the aftermath of resuscitation. We also emphasize that the foremost objective in managing exsanguinating hemorrhage is always expedient and definitive control of the source of bleeding.

Protease-activated receptor-1 contributes to cardiac remodeling and hypertrophy.

BACKGROUND: Protease-activated receptor-1 (PAR-1) is the high-affinity receptor for the coagulation protease thrombin. It is expressed by a variety of cell types in the heart, including cardiomyocytes and cardiac fibroblasts. We have shown that tissue factor (TF) and thrombin contribute to infarct size after cardiac ischemia-reperfusion (I/R) injury. Moreover, in vitro studies have shown that PAR-1 signaling induces hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. The purpose of the present study was to investigate the role of PAR-1 in infarction, cardiac remodeling, and hypertrophy after I/R injury. In addition, we analyzed the effect of overexpression of PAR-1 on cardiomyocytes. METHODS AND RESULTS: We found that PAR-1 deficiency reduced dilation of the left ventricle and reduced impairment of left ventricular function 2 weeks after I/R injury. Activation of ERK1/2 was increased in injured PAR-1(-/-) mice compared with wild-type mice; however, PAR-1 deficiency did not affect infarct size. Cardiomyocyte-specific overexpression of PAR-1 in mice induced eccentric hypertrophy (increased left ventricular dimension and normal left ventricular wall thickness) and dilated cardiomyopathy. Deletion of the TF gene in cardiomyocytes reduced the eccentric hypertrophy in mice overexpressing PAR-1. CONCLUSIONS: Our results demonstrate that PAR-1 contributes to cardiac remodeling and hypertrophy. Moreover, overexpression of PAR-1 on cardiomyocytes induced eccentric hypertrophy. Inhibition of PAR-1 after myocardial infarction may represent a novel therapy to reduce hypertrophy and heart failure in humans.

Toll-like receptor 4 mediates lung ischemia-reperfusion injury.

BACKGROUND: We have previously reported that nuclear factor (NF)-kappaB activation and inflammatory cytokine expression were involved in the development of lung ischemia-reperfusion injury (LIRI). Because Toll-like receptor 4 (TLR4) activates NF-kappaB-dependent transcription of inflammatory cytokine genes during myocardial ischemia-reperfusion injury, we examined whether absence of TLR4 in TLR4-deficient mice protects against LIRI. METHODS: Left lungs of wild-type (C57BL/6J) mice or TLR4-null (TLR4-/-) mice were made ischemic for 60 minutes and then reperfused for 180 minutes. Response to injury was quantified by tissue myeloperoxidase activity, vascular permeability ([125I]-bovine serum albumin extravasation), and leukocyte and inflammatory mediator accumulation in bronchoalveolar lavage expression. Lung homogenates were also analyzed for activation of mitogen-activated protein kinases and nuclear translocation of the transcription factors NF-kappaB and activator protein-1. RESULTS: After LIRI, lungs from TLR4-/- mice demonstrated a 52.4% reduction in vascular permeability (p = 0.001), a 52.6% reduction in lung myeloperoxidase activity (p = 0.006), and a marked reduction in bronchoalveolar lavage leukocyte accumulation when compared with lungs from wild-type mice. The TLR4-/- mice lungs, subjected to LIRI, also demonstrated marked reductions in amounts of several proinflammatory cytokines/chemokines in bronchoalveolar lavage samples. Phosphorylation of c-Jun NH2-terminal kinase, and activation of NF-kappaB and activator protein-1 were also significantly reduced in homogenates of lungs from TLR4-/- mice injured by ischemia and reperfusion (p < 0.05). CONCLUSIONS: These data suggest that TLR4 plays a role in LIRI. Thus, TLR4 may be a potential therapeutic target to minimize ischemic-reperfusion-induced tissue damage and organ dysfunction.

Inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury.

BACKGROUND: We previously reported that the functional mutation of Toll-like receptor 4 (TLR4) in C3H/HeJ mice subjected to myocardial ischemia-reperfusion (MI/R) injury resulted in an attenuation of myocardial infarction size. To investigate the ligand-activating TLR4 during MI/R injury, we evaluated the effect of eritoran, a specific TLR4 antagonist, on MI/R injury, with the goal of defining better therapeutic options for MI/R injury. METHODS AND RESULTS: C57BL/6 mice received eritoran (5 mg/kg) intravenously 10 minutes before 30 minutes of in situ of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. Infarct size was measured using triphenyltetrazoliumchloride staining. A c-Jun NH(2)-terminal kinase (JNK) activation was determined by Western blotting, nuclear factor (NF)-kappaB activity was detected by gel-shift assay, and cytokine expression was measured by ribonuclease protection assay. Mice treated with eritoran developed significantly smaller infarcts when compared with mice treated with vehicle alone (21.0+/-6.4% versus 30.9+/-13.9%; P=0.041). Eritoran pretreatment resulted in a reduction in JNK phosphorylation (eritoran versus vehicle: 3.98+/-0.81 versus 7.01+/-2.21-fold increase; P=0.020), less nuclear NF-kappaB translocation (2.70+/-0.35 versus 7.75+/-0.60-fold increase; P=0.00007), and a decrease in cytokine expression (P<0.05). CONCLUSIONS: We conclude that inhibition of TLR4 with eritoran in an in situ murine model significantly reduces MI/R injury and markers of an inflammatory response.

Sacral resection and reconstruction for tumors and tumor-like conditions.

Sacrectomy is intended to resect aggressive local and life-threatening disease. Reconstruction can be difficult. This article reports on the use of sacrectomy for tumor and tumor-like conditions. Procedures included 9 partial, 7 subtotal, 7 hemi-, and 4 total sacrectomies. Of 22 patients with primary malignant disease, 64% were alive without evidence of disease. The local recurrence rate was 27%. Thirty-two percent developed metastatic disease and 32% died from progressive disease. The complication rate was 33%. Tumor control was achieved in 73%. Postoperative complications occurred in 33%. Sacral resection remains a challenging operation.

Specific inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates vascular proliferation in monocrotaline-induced pulmonary hypertension in rats.

OBJECTIVES: p38 mitogen-activated protein kinase is associated with many clinical entities characterized by inflammation. We postulated that inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates inflammation and the development of pulmonary hypertension in monocrotaline-treated rats. METHODS: Rats were divided into 4 groups: (1) the control group (daily 0.9% saline), (2) the FR group (daily FR167653, 2 mg . kg(-1) . d(-1)), (3) the MCT group (daily 0.9% saline the day after a single monocrotaline dose, 60 mg/kg), and (4) the MCT+FR group (daily FR167653, 2 mg . kg(-1) . d(-1), the day after a single MCT dose). Body weight, pulmonary artery pressure, and morphometric changes of the pulmonary artery with the histopathologic method were observed weekly for 4 weeks. Also, p38 mitogen-activated protein kinase activity and inflammatory cytokine expression in the lung were measured. RESULTS: Four weeks after monocrotaline administration, mean pulmonary artery pressure in the MCT+FR group was lower than in the MCT group (MCT+FR vs MCT: 24.7 +/- 1.9 vs 36.5 +/- 2.1 mm Hg; P < .05). In morphometric analysis the percentage of medial wall thickness and the percentage of muscularization in the MCT+FR group were reduced compared with those in the MCT group after 4 weeks (P < .05); however, the number of macrophages was not significantly different. p38 mitogen-activated protein kinase activity was significantly attenuated in the MCT+FR group compared with in the MCT group (7.2 +/- 0.52 vs 2.1 +/- 0.23 fold-increase, P < .05, at 1 week). Although mRNA levels of tumor necrosis factor alpha and interleukin 1beta were reduced in the MCT+FR group compared with in the MCT group (tumor necrosis factor alpha: 1.18 +/- 0.36 vs 3.05 +/- 1.12 fold-increase, P < .05, at 2 weeks; interleukin 1beta: 2.2 +/- 0.34 vs 4.4 +/- 1.09 fold-increase, P < .05, at 1 week), FR167653 did not suppress increased monocyte chemotactic protein 1 mRNA expression induced by monocrotaline (3.2 +/- 0.62 vs 3.1 +/- 0.42 fold-increase, at 1 week). CONCLUSION: FR167653 significantly attenuates the expression of inflammatory cytokines, ultimately preventing the progression of pulmonary hypertension. These results suggest that p38 mitogen-activated protein kinase might play a central role in the molecular events that underlie the development and progression of pulmonary hypertension.

FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injury.

OBJECTIVE: During myocardial ischemia-reperfusion injury, p38 mitogen-activated protein kinase is activated. We examined the effect of a highly specific inhibitor of p38 mitogen-activated protein kinase, FR167653, in an experimental model of regional myocardial ischemia-reperfusion. METHODS: CD-1 mice received FR167653 intraperitoneally 24 hours before 30 minutes of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. The p38 mitogen-activated protein kinase activation and kinase activity were determined by Western blotting with monoclonal antibodies for the phosphorylated from of p38 mitogen-activated protein kinase or its substrate, activating transcription factor 2. Nuclear factor kappaB activity was measured by detecting translocation of nuclear factor kappaB to the nucleus. The expression of inflammatory cytokines was measured by ribonuclease protection assay. RESULTS: Pretreatment of mice with FR167653 before myocardial ischemia-reperfusion resulted in a reduction in p38 mitogen-activated protein kinase phosphorylation (P =.018), an inhibition of p38 mitogen-activated protein kinase activity (P =.047), a smaller amount of nuclear factor kappaB (P =.001), and a decrease in the expression of inflammatory cytokines (tumor necrosis factor alpha: P =.023, interleukin 1beta: P =.038, monocyte chemotactic protein 1: P =.0001) in the heart and the development of a significantly smaller infarct (P =.0069) relative to hearts from mice treated with vehicle alone. Activation of c-Jun N-terminal kinase and extracellular signal-regulated kinase were observed after myocardial ischemia-reperfusion without inhibition by FR167653. CONCLUSION: We conclude that FR167653 selectively inhibits p38 mitogen-activated protein kinase activation and activity during regional myocardial ischemia-reperfusion injury and efficaciously reduces infarct size (by 73.6%). Thus p38 mitogen-activated protein kinase inhibition may have a role in the treatment of myocardial ischemia-reperfusion.

Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart.

BACKGROUND: Restoration of blood flow to the ischemic heart may paradoxically exacerbate tissue injury (ischemia/reperfusion injury). Toll-like receptor 4, expressed on several cell types, including cardiomyocytes, is a mediator of the host inflammatory response to infection. Because ischemia/reperfusion injury is characterized by an acute inflammatory reaction, we investigated toll-like receptor 4 activation in a murine model of regional myocardial ischemia/reperfusion injury. We used C3H/HeJ mice, which express a nonfunctional toll-like receptor 4, to assess the pertinence of this receptor to tissue injury after reperfusion of ischemic myocardium. METHODS: Wild-type mice (C3H/HeN) or toll-like receptor 4 mutant mice (C3H/HeJ) were subjected to 60 minutes of regional myocardial ischemia followed by 2 hours of reperfusion. At the end of reperfusion, the area at risk and the myocardial infarct size were measured as the end point of myocardial ischemia/reperfusion injury. Myocardial mitogen-activated protein kinase activation was measured by Western blotting, and nuclear translocation of nuclear factor-kappaB and activator protein-1 was determined by electrophoretic mobility shift assay. Ischemia/reperfusion-injured myocardium was also assessed by ribonuclease protection assay for expression of inflammatory mediators (tumor necrosis factor-alpha, interleukin-1beta, monocyte chemotactic factor-1, and interleukin-6). RESULTS: The area at risk was similar for all groups after myocardial ischemia/reperfusion injury. There was a 40% reduction in infarct size (as a percentage of the area at risk) in C3H/HeJ mice compared with C3H/HeN mice (P =.001). Within the myocardium, significant activation of c-Jun N-terminal kinase, p38, and extracellular signal-regulated kinase was observed in both strains after ischemia and during reperfusion as compared with an absence of mitogen-activated protein kinase activation during sham operations; however, c-Jun N-terminal kinase activity, but not p38 or extracellular signal-regulated kinase activity, was significantly reduced in C3H/HeJ mice (P <.05). In both groups, nuclear factor-kappaB and activator protein-1 nuclear translocation occurred in the myocardium during myocardial ischemia/reperfusion injury, but, by densitometric analysis, nuclear translocation of nuclear factor-kappaB and activator protein-1 was significantly decreased in C3H/HeJ mice compared with C3H/HeN mice. Interleukin-1beta, monocyte chemotactic factor-1, and interleukin-6 were detectable in reperfused ischemic myocardium but were not detected in sham-operated myocardium; the expression of each of these mediators was significantly decreased in the myocardial tissue of C3H/HeJ mice when compared with expression in the control C3H/HeN mouse strain. CONCLUSIONS: Our data suggest that toll-like receptor 4 may mediate, at least in part, myocardial ischemia/reperfusion injury. Inhibition of toll-like receptor 4 activation may be a potential therapeutic target to attenuate ischemia/reperfusion-induced tissue damage in the clinical setting.

HSP70.1 and -70.3 are required for late-phase protection induced by ischemic preconditioning of mouse hearts.

We investigated the role of inducible heat shock proteins 70.1 and 70.3 (HSP70.1 and HSP70.3, respectively) in myocardial ischemic preconditioning (IP) in mice. Wild-type (WT) mice and HSP70.1- and HSP70.3-null [HSP70.1/3(-/-)] mice were subjected to IP and examined 24 h later during the late phase of protection. IP significantly increased steady-state levels of HSP70.1 and HSP70.3 mRNA and expression of inducible HSP70 protein in WT myocardium. To assess protection against tissue injury, mice were subjected to 30 min of regional ischemia and 3 h of reperfusion. In WT mice, IP reduced infarct size by 43% compared with sham IP-treated mice. In contrast, IP did not reduce infarct size in HSP70.1/3(-/-) mice. Absence of inducible HSP70.1 and HSP70.3 had no effect, however, on classical or early-phase protection produced by IP, which significantly reduced infarct size in HSP70.1/3(-/-) mice. We conclude that inducible HSP70.1 and HSP70.3 are required for late-phase protection against infarction following IP in mice.

Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury.

Reperfusion of the ischemic heart is necessary to prevent irreversible injury of the myocardium, which leads to permanent organ dysfunction. However, reperfusion in itself leads to myocardial ischemia/reperfusion (I/R) injury, which is characterized by an acute inflammatory response mediated by activated inflammatory cells, chemokines, cytokines, and adhesion molecules. The molecular mechanisms of myocardial I/R injury are not completely known. Tissue factor (TF) and thrombin, two potent procoagulant and proinflammatory mediators, are recognized to play significant roles in myocardial I/R injury. To investigate the role of TF and thrombin in myocardial I/R injury, we used rabbit and murine in situ coronary artery ligation models. Increased TF mRNA, antigen, and activity were found in ischemic cardiomyocytes. Administration of an inhibitory antirabbit TF monoclonal antibody before or during the onset of ischemia resulted in a significant reduction in infarct size. Functional inhibition of thrombin with hirudin also reduced the infarct size. However, defibrinogenating rabbits with ancrod had no effect on infarct size, suggesting a requirement of thrombin generation but not fibrin deposition in myocardial I/R injury.

Nuclear factor kappaB mediates a procoagulant response in monocytes during extracorporeal circulation.

OBJECTIVE: The objective of this study was to examine the mechanism of procoagulant activity and inhibition in whole blood during extracorporeal circulation. METHODS: In this study we examine the development of procoagulant activity and monocyte activation in heparinized whole blood passing through a closed circuit consisting of a pump and silicone envelope membrane oxygenator for 6 hours. RESULTS: Anaphylatoxins, C3a and C5a, determined by means of enzyme-linked immunosorbant assay, appeared in the blood within 30 minutes of circulation. Circulated blood developed a marked potential for coagulation demonstrated in a 1-step clotting assay that reached maximal activity by 4 hours of circulation. This procoagulant activity was neutralized by anti-tissue factor antibody, suggesting a prominent role for the extrinsic pathway in pump-induced intravascular coagulation. Isolation of monocytes from circulated blood revealed that tissue factor expression is upregulated on the cell surface. Furthermore, we observed nuclear factor kappaB nuclear translocation in monocytes from blood passing through the circuit, suggesting that tissue factor expression was due to monocyte stimulation and transcriptional activation of the tissue factor gene. Tissue factor expression resulted in an approximately 30-fold increase in thrombin generation. Monocyte nuclear factor kappaB activation, monocyte tissue factor expression, thrombin generation, and the procoagulant activity of blood in extracorporeal circulation were all blocked by the proteasome inhibitor MG132. CONCLUSIONS: We conclude that intravascular tissue factor expression during extracorporeal circulation of blood is due to nuclear factor kappaB-mediated activation of monocytes (possibly by complement), which can be controlled pharmacologically.