thromboplastin and Blood-Loss--Surgical

Excessive bleeding is a major concern in scar debridement and grafting procedures. TT-173 is a new topical hemostatic agent based on recombinant human tissue factor that has shown promising results in patients who underwent tooth extraction. EHTIC study sought to evaluate the efficacy and safety of TT-173 to reduce the bleeding in donor sites of skin grafting procedures.. EHTIC study was a phase II, randomized, parallel, double blind, placebo controlled trial. Patients received TT-173 (n=38) or placebo (n=33) sprayed over donor site after graft harvest. Time to hemostasis and incidence of adverse events were recorded. Systemic absorption of the product and its immunogenicity were also measured during the follow up of the subjects.. Treatment with TT-173 significantly reduced the bleeding time from 7 to 3min (Log-Rank p<0.0001). Moreover, bleeding stopped within the 10min of evaluation period in all the patients that received TT-173. In contrast, 24.24% of patients from placebo group required additional measures to arrest hemorrhage (Fisher p=0.0013). Product related adverse events, systemic absorption into blood stream, interferences with the healing of the donor site or immunogenic reaction against TT-173 were not observed.. The new hemostatic agent TT-173 has proven efficacious and safe to reduce the bleeding from donor site. This study paves the way for further investigation of the product as topical hemostatic treatment in plastic surgery and other surgical indications.

Topics: Adult; Blood Loss, Surgical; Burns; Double-Blind Method; Female; Hemostatics; Humans; Male; Middle Aged; Recombinant Proteins; Skin Transplantation; Thromboplastin; Treatment Outcome; Wounds and Injuries

Heparinization requires monitoring, but optimal methods for measuring the anticoagulant effects of heparin remain to be determined. We compared prothrombinase-induced clotting time (PiCT) and two chromogenic anti-factor Xa activity (anti-Xa) assays in monitoring high-dose heparinization during cardiopulmonary by-pass (CPB). Heparin effects were serially measured with PiCT and two anti-Xa assays in 100 patients. Antithrombin and protein C activities were measured preoperatively, and antithrombin activity was measured during CPB. Activation of coagulation was assessed with measurements of prothrombin fragment F1+2, soluble fibrin complexes, and D-dimer before, during, and after CPB. During CPB mean ranges of PiCT and of anti-Xa heparin levels measured with (anti-Xa A) and without (anti-Xa B) dextran sulfate and antithrombin supplementation were 5.0-5.2, 4.7-5.0, and 4.5-4.9 IU/ml, respectively. There was poor agreement between PiCT and anti-Xa and between the two anti-Xa assays (r = 0.32-0.65 and broad limits of agreement). Patients with low preoperative antithrombin or protein C levels had lower PiCT (p = 0.028 and p = 0.01) and anti-Xa A (both p<0.001) levels during CPB than others. Patients with the lowest heparin activities during CPB (lowest deciles of PiCT and anti-Xa A) had higher subsequent F1+2 after CPB (p = 0.002 and p = 0.02), and patients with high heparin levels required fewer transfusions of packed red blood cells than others. In conclusion, in the challenging setting of CPB there is poor agreement between anti-Xa assays and PiCT. However, coagulation-based PiCT could provide an alternative to the chromogenic anti-Xa assays. Higher heparin levels during CPB were confirmed to associate with reduced transfusion requirements.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Blood Loss, Surgical; Cardiopulmonary Bypass; Chromogenic Compounds; Coronary Artery Bypass; Coronary Artery Disease; Drug Monitoring; Erythrocyte Transfusion; Factor Xa; Factor Xa Inhibitors; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Male; Middle Aged; Monitoring, Intraoperative; Peptide Fragments; Prospective Studies; Protein C; Prothrombin; Thromboplastin

Topics: Administration, Topical; Animals; Blood Loss, Surgical; Disease Models, Animal; Female; Hemostasis, Surgical; Hemostatics; Hepatectomy; Humans; Liver; Male; Rats; Recombinant Proteins; Swine; Thromboplastin

Total knee arthroplasty is associated with blood loss during the intervention and may require allogenic blood transfusion. Treatments such as tranexamic acid and fibrin sealants improved the bleeding control in several clinical trials, but the hemorrhage associated with the intervention is still significant. Thus far, very few studies have evaluated hemostatic treatments in animal models of total knee arthroplasty. This work describes a sheep model of bleeding associated with total knee arthroplasty and investigates a new class of hemostatic treatment based on recombinant tissue factor.. Sheep were treated with the anticoagulant heparin, and the joint was accessed by a paramedial incision. Ligaments and menisci were eliminated and femoral condyles and tibia plateau were sectioned exposing the trabecular bone. An intra-articular drain was used to recover and quantify the blood loss during the 90-min period after treatment. The efficacy of one milligram and three milligrams of TT-173 was evaluated and compared with tranexamic acid. The occurrence of analytical alterations and systemic absorption was also investigated.. Treatment with TT-173 reduced the blood loss in comparison with control or tranexamic acid. No significant differences were observed between the two doses evaluated. Moreover, a dose of six milligrams of TT-173 did not induce any clinical or analytical alteration, and significant systemic absorption was not observed.. Data obtained strongly suggest that TT-173 could be useful in reducing the blood loss associated with total knee arthroplasty and without safety concerns derived from the systemic absorption of the product.

Topics: Animals; Anticoagulants; Antifibrinolytic Agents; Arthroplasty, Replacement, Knee; Blood Loss, Surgical; Drainage; Female; Hemostatics; Heparin; Male; Sheep; Thromboplastin; Tranexamic Acid

Nutritional deficiencies and use of antiepileptic drugs can lead to alterations in the hematological status of children with cerebral palsy (CP), which may increase the risk of intraoperative or postoperative hematological complications. In this retrospective study, we evaluated the preoperative routine blood tests of CP patients with different levels of walking ability, who were scheduled to undergo orthopedic procedures.. Hemoglobin level, hematocrit, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red cell distribution width, white blood cell count, platelet count, prothrombin time, activated partial thromboplastin time, and plasma fibrinogen concentration were compared between 62 consecutive CP patients [28 girls, 34 boys; mean age 8.8 years (range 2-16 years)] and 130 consecutive orthopedic patients as control [64 girls, 66 boys; mean age 9.2 years (range 2-16 years)] who did not have any skeletal, cranial, thoracic, abdominal or major soft tissue injuries, or any other infectious, metabolic, hematological or malignant tumor disorders.. CP and control groups were similar with regard to the above-mentioned hematological parameters. In the CP group, no difference was found between Gross Motor Function Classification System for Cerebral Palsy (GMFCS) level I/II patients and GMFCS level III/IV patients in terms of these hematological parameters.. Preoperative blood tests results of pediatric CP patients, walking with or without any supportive devices and undergoing orthopedic interventions, are similar to those of other orthopedic patients. Advanced preoperative hematological tests can only be recommended for CP patients with abnormal blood test results.

Topics: Adolescent; Blood Loss, Surgical; Cerebral Palsy; Child; Child, Preschool; Female; Fibrinogen; Follow-Up Studies; Hematologic Tests; Humans; Male; Orthopedic Procedures; Postoperative Hemorrhage; Preoperative Period; Prognosis; Retrospective Studies; Thromboplastin

Tissue factor (TF) antagonists targeting the factor VII (FVII) binding domain have been shown to interrupt acute vascular thrombus formation without impairing haemostasis in non-human primates. In this study, we evaluate whether a human/mouse chimeric monoclonal antibody (ALT-836, formerly known as Sunol-cH36) blocking the factor X/factor IX (FX/FIX) binding site of tissue factor could achieve similar clinical benefits in an arterial thrombosis model induced by surgical endarterectomy in chimpanzees. In this model, sequential surgical endarterectomies on right and left superficial femoral arteries were performed 30 days apart in five chimpanzees. A bolus (1 mg/kg) of ALT-836 was injected intravenously immediately preceding the restoration of flow in the endarterectomised femoral artery. Pre-surgical labelling of autologous platelets using (111)In-Oxine and post-surgical gamma camera imaging of (111)In-platelet deposition at endarterectomy sites was performed. The manipulated arterial segments were harvested for patency analysis 30 days following surgery. The results indicate that ALT-836 was highly effective at reducing acute vascular thrombosis, with no significant variations in surgical blood loss and template-bleeding time in the treated group compared to the control animals. These data suggest that ALT-836 is an effective and safe antithrombotic agent in preventing TF-initiated vascular thrombogenesis without compromising haemostasis.

Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Binding Sites; Blood Coagulation; Blood Loss, Surgical; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Endarterectomy; Factor IX; Factor VIIa; Factor X; Female; Femoral Artery; Fibrinolytic Agents; Hemorrhage; Humans; Injections, Intravenous; Mice; Mice, Inbred BALB C; Pan troglodytes; Radionuclide Imaging; Recombinant Fusion Proteins; Thromboplastin; Thrombosis

Recombinant activated factor VII was used in a dose of 30 to 140 mcgr/kg in 35 cardiosurgical patients during intra- and postoperative periods complicated by massive uncontrolled (5 to 25 ml/min) bleeding of non-surgical origin. Basing on the analysis of changes in the hemostasis system parameters, the mechanism of action of the preparation may be presented as follows: recombinant fVIIa forms a complex with TF at the site of lesion; the formation of TF-fVIIa complex leads to the appearance of small amount of synthesized thrombin on the membrane of TF-containing cells, which, in turn, activates thrombocytes at the site of lesion; thrombocytes excrete phosphatidylserine, which serves as a matrix for further thrombin formation. FXIII is expressed from a granules ofthrombocytes and gets activated. FXIII binds with a specific receptor on platelets' membrane. It remains active as enzyme and participates in the formation of a firm fibrin plug at the site of lesion. Besides, substances with pro- and antifibrinolytic activity, antiheparin factor 4 and fibronectin are released from alpha granules. Factors IXa, VIIIa, and Va effectively "attach" to the surface of activated thrombocytes, and the forming of IXa-VIIIa complex leads to further activation of factor X, which, together with factor 3 expression, facilitates further local thrombin generation.

Topics: Blood Loss, Surgical; Blood Platelets; Dose-Response Relationship, Drug; Factor VIIa; Factor XIII; Follow-Up Studies; Hemostasis; Humans; Infusions, Intravenous; Intraoperative Care; Partial Thromboplastin Time; Postoperative Care; Postoperative Hemorrhage; Thromboplastin; Treatment Outcome

Orthopaedic surgery involves extensive dissection of connective and richly vascularised tissues rich in tissue factor (TF). It was, therefore, of interest to quantify the amount of TF antigen and activity in postoperatively drained, unwashed wound blood collected for the purpose of autologous transfusion. In nine young patients subjected to surgery for idiopathic thoracic scoliosis, samples were drawn postoperatively from collected shed blood, a pulmonary artery catheter and a radial arterial cannula prior to, during and after reinfusion of shed blood (10 ml/kg body weight), and analysed for TF antigen and activity. Preoperative arterial control samples contained 128 pg/ml TF antigen compared with 40 pg/ml postoperatively. During reinfusion of drained blood, arterial TF concentration rose to 96 pg/ml and dropped to 64 pg/ml after infusion. Arterial and mixed venous blood did not differ significantly in TF levels. Serum from drained blood contained high concentrations of TF antigen (773 pg/ml), but no TF activity was detected. It is concluded that the high concentrations of TF antigen in serum from postoperatively drained blood collected for autologous transfusion are devoid of procoagulant activity. The TF antigen in plasma of drained blood is suggested to be a soluble, proteolysed TF-apoprotein or a TF complex inactivated by the TF pathway inhibitor (TFPI).

Topics: Adolescent; Adult; Blood Loss, Surgical; Blood Transfusion, Autologous; Female; Humans; Male; Orthopedics; Thromboplastin

Multiple stimuli converge in cardiopulmonary bypass to create a tremendous prothrombotic stimulus. The ideal anticoagulant for cardiopulmonary bypass should selectively target only the intravascular stimuli, thereby eliminating pathologic clotting in the bypass circuit while preserving hemostasis in the thoracic cavity. We propose the inhibition of factor IX as such a targeted anticoagulant strategy.. We prepared an inhibitor of activated factor IX and applied it to a primate model of cardiopulmonary bypass to confirm the anticoagulant efficacy of activated factor IX in this setting and to assess more subtle markers of thrombin generation, macrophage procoagulant activity, and cellular tissue factor expression. Seven baboons that received activated factor IX (460 microg/kg) and 7 that received heparin (300 IU/kg) and protamine underwent cardiopulmonary bypass for 90 minutes and were followed after the operation for 3 hours.. Analysis of plasma factor IX activity demonstrated adequate inhibition (<20%) of factor IX throughout cardiopulmonary bypass. Activated factor IX-treated baboons demonstrated similar circuit patency to heparin-treated baboons but had significantly diminished intraoperative blood loss. Preservation of extravascular hemostasis was further demonstrated in activated factor IX-treated animals by (1) significantly increased levels of thrombin-antithrombin III complex and prothrombin activation peptide (F1+2) without intravascular thrombosis, (2) significantly greater macrophage procoagulant activity in pericardial-derived monocytes, and (3) immunohistochemical evidence of tissue factor expression in pericardial mesothelial cells and macrophages.. Anticoagulation with activated factor IX allows for intravascular anticoagulation with maintenance of extravascular hemostasis. These findings suggest activated factor IX as an agent that not only exemplifies a targeted approach to selective anticoagulation in cardiac surgery but also further characterizes the procoagulant milieu during cardiopulmonary bypass.

Topics: Animals; Anticoagulants; Blood Coagulation Tests; Blood Loss, Surgical; Cardiopulmonary Bypass; Factor IX; Factor IXa; Heparin; Humans; Macrophages; Microscopy, Electron, Scanning; Papio; Surface Properties; Thrombin; Thrombophilia; Thromboplastin

Coagulation during cardiopulmonary bypass (CPB) traditionally has been attributed to activation of the contact system of plasma proteins and the intrinsic coagulation pathway by blood contact with negatively charged surfaces not lined by endothelium. Recent studies have focused on the possible role of the extrinsic coagulation pathway during cardiac surgery. We postulated that the wound activates the extrinsic coagulation pathway during CPB by producing procoagulant cells and enzymes that enter the general circulation.. Blood samples taken from 20 consenting patients who had elective cardiac surgery were assayed for peripheral blood mononuclear cell tissue factor (TF) expression, plasma F1.2, and factor VII and VIIa concentrations. Peripheral blood mononuclear cell TF expression increased in the perfusate after the surgical incision and after CPB was started and in monocytes that adhered to the perfusion circuit. TF on circulating monocytes, however, did not continue to rise during CPB. Peripheral blood mononuclear cell TF was elevated in cells isolated directly from blood in the pericardial cavity and was twice that detected in simultaneous samples from the perfusate (P < .05). F1.2 levels were highest in pericardial blood and increased progressively during CPB. Plasma factor VIIa concentrations, corrected for hemodilution, and ratios of factor VIIa to factor VII were highest in pericardial samples (P < .05) and increased progressively during and immediately after CPB. Pericardial biopsies obtained before and after CPB in 7 patients did not show TF expression by mesothelial cells.. These data provide direct evidence of TF expression, activation of the extrinsic coagulation pathway, and thrombin formation in the surgical wound. Addition of pericardial blood to the perfusate and expression of TF by both circulating and adherent monocytes strongly promote thrombus formation during open heart surgery.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; Blood Coagulation; Blood Loss, Surgical; Cardiopulmonary Bypass; Factor VII; Factor VIIa; Humans; Middle Aged; Monocytes; Peptide Fragments; Pericardium; Prothrombin; Thromboplastin; Thrombosis