thromboplastin and Shock--Traumatic

The initiation of coagulation in trauma is thought to originate from exposed tissue factor (TF); recent data have led to the alternative hypothesis that damage-associated molecular patterns may contribute to postinjury coagulation. In acute traumatic coagulopathy, aberrant coagulation is mediated via the activated protein C (aPC) pathway; the upstream regulators of this process and its relation to TF remain uncharacterized. To examine the role of the TF pathway in mediating acute traumatic coagulopathy, we used specific antibody blockades in an established murine model of traumatic hemorrhagic shock, hypothesizing that both coagulation activation after injury and aPC-mediated coagulopathy are driven by TF via thrombin.. Mice underwent an established model of trauma and hemorrhage and were subjected to either sham (vascular cannulation) or trauma-hemorrhage (cannulation, laparotomy, shock to mean arterial pressure of 35 mm Hg); they were monitored for 60 minutes before sacrifice. Mice in each group were pretreated with either targeted anti-TF antibody to block the TF pathway or hirudin for specific blockade of thrombin. Plasma was assayed for thrombin-antithrombin (TAT) and aPC by enzyme-linked immunosorbent assay.. Compared with controls, trauma-hemorrhage mice treated with anti-TF antibody had significantly reduced levels of TAT (2.3 ng/mL vs. 5.7 ng/mL, p = 0.016) and corresponding decreases in aPC (16.3 ng/mL vs. 31.6 ng/mL, p = 0.034), with reductions to levels seen in sham mice. Direct inhibition of thrombin yielded similar results, with reduction in aPC to levels below those seen in sham mice.. In this study, blockade of the TF pathway led to the attenuation of both thrombin production and aPC activation observed in traumatic shock. Specific thrombin inhibition achieved similar results, indicating that aPC-related coagulopathy is mediated via thrombin activated by the TF pathway. The near-complete blockade of TAT and aPC observed in this model argues for a dominant role of the TF-thrombin pathway in both coagulation activation after injury and traumatic coagulopathy.

Topics: Animals; Blood Coagulation Disorders; Enzyme-Linked Immunosorbent Assay; Hirudins; Male; Mice; Mice, Inbred C57BL; Protein C; Shock, Hemorrhagic; Shock, Traumatic; Thrombin; Thromboplastin; Wounds and Injuries

We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIC.. We made a prospective study of 57 trauma patients, including 30 patients with DIC and 27 patients without DIC. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction.. Patients with DIC showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIC. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIC in comparison with controls and non-DIC patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIC patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIC patients. Almost all ACoTS patients overlapped with the DIC patients. The changes in the measured variables in ACoTS patients coincided with those in DIC patients.. Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIC with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed.

Topics: Acute Disease; Adult; Antithrombins; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Prothrombin; Shock, Traumatic; Thrombin; Thromboplastin

Tissue factor (TF) is the primary cellular initiator of the coagulation protease cascade and serves as a cell surface receptor and a specific cofactor for plasma factors VII/VIIa. Because there is evidence that TF is regulated by a P-selectin dependent gene, we examined TF mRNA expression in the lungs during murine traumatic shock in the presence and absence of recombinant soluble P-selectin glycoprotein ligand-1 (rsPSGL.Ig) by using ribonuclease protection assays. Moreover, we studied the level of TF mRNA expression in mice with their P-selectin gene deleted (P-selectin -/-). Our data show that TF mRNA was significantly increased (+143%; P < 0.001) in the lungs 2 h after trauma compared with control rats subjected to sham trauma, which exhibited reduced TF mRNA expression (-34%; P < 0.001) after systemic administration of rsPSGL.Ig. The expression of TF mRNA was also significantly decreased (-29%; P < 0.05) in the lungs of P-selectin -/- mice compared with wild-type control C57B16 mice. The present results provide evidence for a P-selectin-dependent mechanism that enhances TF gene expression in traumatic shock. The major support for this mechanism is that either blockade of P-selectin by rsPSGL.Ig or deletion of the P-selectin gene leads to significant decreases in TF mRNA expression in the lung. These results are consistent with the concept that TF interacting with P-selectin may play a significant role in the pathophysiology of trauma.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Gene Expression Regulation; Immunoconjugates; Lung; Male; Membrane Glycoproteins; Mice; Mice, Knockout; P-Selectin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Shock, Traumatic; Thromboplastin

Tissue factor (TF) is a cell-surface glycoprotein responsible for initiating the extrinsic pathway of coagulation that has been shown to have a role in the pathophysiology of sepsis and reperfusion injury. The purpose of this study was to investigate TF expression in vital organs and to determine possible regulatory mechanisms of TF expression in the lung during traumatic shock in rats.. Noble-Collip drum trauma was induced in anesthetized Sprague-Dawley rats. Anesthetized rats without trauma served as controls. TF activity was measured in plasma and lung tissue. TF messenger RNA (mRNA) was measured in the lung, liver, and small intestine using ribonuclease protection assays. Electromobility shift assays were used to quantify binding of nuclear extracts from lung to TF-specific consensus domains for transcription factors NF-kappaB and AP-1.. TF activity in plasma increased up to 14-fold and +232% in the lung (P < 0.001 for plasma and lung) 2 h after trauma. TF mRNA level was significantly increased in the lungs (P < 0.01), small intestine (P < 0.01), and liver (P < 0.05) 1 h after trauma compared to sham-operated control rats. TF mRNA expression continued to increase in the lungs and the liver (both, P < 0.001) 2 h after trauma TF sequence-specific complex binding to AP-1 and NF-kappaB domains was enhanced in the lungs of trauma rats (+395%, P < 0.001 and +168%, P < 0.001, respectively).. These results suggest that TF may play an important role in the pathophysiology of severe trauma and that regulatory elements AP-1 and NF-kappaB may be involved in the regulation of TF mRNA expression in traumatic shock.

Topics: Animals; Autoradiography; Blood Pressure; Cell Nucleus; Cytoplasm; Electrophoresis, Polyacrylamide Gel; Intestine, Small; Liver; Lung; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Ribonucleases; RNA, Messenger; Shock, Traumatic; Thromboplastin; Transcription Factor AP-1

The antithrombin III-heparin complex was isolated from albino rat and human blood. The non-enzymatic fibrinolytic activity of the complex during anticoagulation system activation was higher, as compared to analogous activity in normal conditions or in depressed function of anticoagulation system.

Topics: Animals; Antithrombin III; Child; Child, Preschool; Fibrinolysis; Heparin; Humans; Rats; Shock, Traumatic; Thrombin; Thromboplastin; Time Factors

Topics: Adult; Aged; Blood Coagulation Disorders; Blood Gas Analysis; Blood Platelets; Blood Transfusion; Cell Aggregation; Embolism, Fat; Factor V; Factor VIII; Female; Femoral Fractures; Fibrinogen; Humans; Hydrogen-Ion Concentration; Hypoxia; Intracranial Embolism and Thrombosis; Male; Middle Aged; Pelvic Bones; Prothrombin Time; Pulmonary Embolism; Shock, Traumatic; Thromboplastin; Tibial Fractures

Topics: Blood Coagulation Disorders; Blood Flow Velocity; Blood Transfusion; Fibrinogen; Humans; Prothrombin Time; Shock, Traumatic; Thromboembolism; Thromboplastin

Topics: Animals; Brain; Burns; Carbon Isotopes; Heparin; Injections; Injections, Intraperitoneal; Mice; Mortality; Muscles; Pharmacology; Radiometry; Research; Shock, Traumatic; Skin; Sodium; Sodium Chloride; Sodium, Dietary; Thromboplastin; Tissue Extracts; Tourniquets; Toxicology