The influence of antithrombin substitution on heparin sensitivity and activation of hemostasis during coronary artery bypass graft surgery: a dose-finding study.

BACKGROUND: Cardiopulmonary bypass is associated with a high degree of hemostatic system activation. Supplementation of antithrombin (AT) may attenuate this activation and increase a patient's susceptibility to heparin. However, the appropriate dosage of AT has not been defined. We sought to determine the dosage of AT concentrate necessary to achieve >100% AT activity at the end of cardiac surgery and the influence of AT on heparin sensitivity. METHODS: Forty-one patients were included. Thirty consecutive patients undergoing primary coronary artery bypass graft surgery with cardiopulmonary bypass were assigned to 3 groups of increasing dosages of AT concentrate. Eleven additional patients served as controls. AT activity and molecular markers of thrombin generation were determined, and heparin sensitivity was calculated. RESULTS: A median amount of 36.5 U (19.0; 42.8), 47.0 U (41.3; 61.6), and 50.0 U (47.4; 66.6) AT concentrate/kilogram body weight in the low, medium, and high AT group, respectively, was administered. At the end of surgery, AT activity with substitution was 84% (77; 111), 110% (92; 120), and 104% (97; 120) (median [25th; 75th percentile]), respectively, compared with 63% (49; 79) in controls (P < 0.05 all substitution groups versus control). Heparin sensitivity increased from 1.29 (1.17; 1.66) s/U heparin/kg in the control group to 2.02 (1.43; 3.65), 2.56 (1.52; 3.64), 1.72 (1.24; 2.66) s/U heparin/kg in the groups with substitution (P < 0.05 all substitution groups versus control). Compared with preoperative values, AT activity decreased during the postoperative period in all patients with a nadir on postoperative day 3 (P < 0.05 compared with baseline except for the medium AT group). Corresponding to this decrease, an increase in prothrombin fragment 1+2 and d-dimer could be observed postoperatively. DISCUSSION: High dosages of AT were required to preserve physiologic AT activity during coronary artery bypass graft surgery and to significantly enhance heparin sensitivity, respectively. However, a significant decrease in AT activity, accompanied by high levels of thrombin generation, was encountered up to 5 days postoperatively.

Review article: unexpected bleeding in the operating room: the role of acquired von Willebrand disease.

Acquired von Willebrand disease (AvWD) is a rare bleeding disorder that occurs in association with a variety of underlying disorders and can lead to unforeseen bleeding in surgical patients. Cardiovascular as well as malignant and immunological diseases may be associated with AvWD, and several pathophysiological mechanisms have been proposed. von Willebrand factor (vWF) is a plasma glycoprotein that mediates platelet adhesion to subendothelial collagen and causes platelet aggregation under high shear stress. Additionally, vWF acts as a specific carrier for coagulation factor VIII (FVIII) in the plasma. AvWD results from a reduced rate of vWF synthesis, an increased rate of vWF removal, or a final generation of lower-molecular-weight, less active subunits or multimers. In contrast to inherited von Willebrand disease patients, who are characterized by lifelong bleeding episodes, AvWD patients present with a sudden onset of bleeding symptoms, which can induce acute bleeding episodes during critical surgical procedures. Typically, no family history of bleeding is found. The clinical visualization of AvWD is similar to that of the hereditary form with mucocutaneous bleeding and increased perioperative bleeding, ranging from mild to severe bleeding. Laboratory evaluation of AvWD is mainly based on the measurement of vWF activity and antigens as well as on the multimeric analysis of vWF. A variety of therapeutic approaches have been used depending on the underlying disease and pathophysiological mechanisms. Treatment options to control acute hemorrhages or to prevent bleeding complications during surgery include desmopressin, FVIII/vWF concentrates, high-dose IV immunoglobulins, and plasma exchange. Because the half-life of vWF is reduced in AvWD, high doses of FVIII/vWF concentrates administered at frequent intervals may be necessary during bleeding episodes. In cases of unresponsiveness to standard therapy, recombinant activated factor VIIa may be an alternative option. However, the most effective therapy is the resolution of the underlying disease. In the present review, we focus on the current understanding of AvWD, outlining the associated disorders, underlying pathophysiological mechanisms, and possible treatment options.

Enhanced thrombin generation after cardiopulmonary bypass surgery.

BACKGROUND: Thrombin generation has a key role in the pathophysiology of hemostasis. Research has focused on the intraoperative course of hemostasis, while little is known about postoperative hemostatic activation. Thrombin generation assays quantify the potential for thrombin generation ex vivo and may be useful for determining hypercoagulability. The thrombin dynamics test (TDT) assesses the initial kinetics of thrombin formation. We hypothesized that there would be an increase in thrombin generation as well as thrombin capacity after cardiac surgery. METHODS: Two hundred twenty patients undergoing primary coronary artery bypass grafting or aortic valve replacement (AVR) surgery were prospectively enrolled. Patients undergoing AVR received warfarin beginning on the second postoperative day. In addition to prothrombin fragment (F(1+2)), TDT, d-dimer, and troponin T were assessed. Blood samples were obtained preoperatively, at the end of the operation, 4 hours postoperatively, and the morning of postoperative days (PODs) 1, 3, and 5. The primary end point was the change of thrombin dynamics on POD 1. RESULTS: In all patients, F(1+2) peaked at the end of the operation and remained significantly elevated until POD 5. Compared with baseline and after an initial decrease, TDT was found to be significantly elevated on POD 1. After coronary artery bypass graft, TDT remained significantly elevated, whereas in AVR patients with warfarin treatment, TDT was significantly reduced on PODs 3 and 5. CONCLUSIONS: After cardiac surgery, thrombin generation continues, accompanied by a high thrombin-generating capacity and elevated fibrinogen levels. This constellation suggests a marked procoagulopathic state in the postoperative period with the potential to aggravate the risk of thromboembolic complications. Warfarin treatment after AVR significantly reduced thrombin-generating capacity.

Monitoring of direct anticoagulants.

In recent years, new anticoagulants directly targeting individual components of the coagulation cascade have been developed. Although there is no need for routine coagulation monitoring with most of these agents, there are several clinical situations where a specific coagulation test should be available. Global coagulation tests react very sensitive to direct thrombin inhibitors or factor Xa inhibitors. However, with most agents, the effects on activated partial thromboplastin time (APTT) and prothrombin time (PT) are not linear and heterogeneous with respect to different reagents. In contrast, chromogenic assays show a good correlation to the pharmacokinetic of a specific agent.

A standardized treatment regimen for patients with severe haemophilia A undergoing orthopaedic or trauma surgery: a single centre experience.

Recommendations on the administration of clotting factor concentrates in patients with severe haemophilia undergoing surgery are usually determined by monitoring target clotting factor levels. In this retrospective cohort study, we enrolled patients with severe haemophilia A who underwent major orthopaedic or trauma surgery. We wanted to evaluate the feasibility and the safety of a standardized medical treatment procedure. Further on, we wanted to assess whether our standardized treatment regimen enables surgical procedures in certain situations in which measuring clotting factor VIII (FVIII) activity is not available. We created a standardized medical treatment procedure that included a medical protocol and close cooperation with the Haemophilic Treatment Centre. Thirteen surgical procedures in nine patients were examined. The feasibility and safety of this standardized treatment concept were assessed by identifying perioperative complications and by means of a questionnaire. Depending on the surgery, the amount of FVIII administered within the first 10 days ranged between 653 and 1027 units/kg body weight. No allogeneic blood transfusion was required. The measurement of FVIII activity was performed repeatedly in five patients. In all patients activated partial thromboplastin time monitoring was performed during the hospital stays. The surgeons and patients were satisfied with our treatment concept and adhered to the medical regimen protocol. By means of a detailed, standardized medical protocol and by ensuring close cooperation between the patient, the surgeons and the Haemophilic Treatment Centre, we could show that elective and emergency operations can be safely performed even in situations in which FVIII activity could not be monitored.

Genotype and laboratory and clinical phenotypes of protein s deficiency.

The diagnosis of thrombophilia caused by protein S deficiency remains difficult. From 2005 to 2010, we documented 135 patients with suspected hereditary protein S deficiency for whom mutational analysis of the PROS1 gene had been performed by direct double-stranded sequencing of the amplified 15 exons including splice sites. Multiplex ligation-dependent probe amplification was performed on 12 of 15 exons in cases with no mutation found but a large deletion in the PROS1 gene was suspected. Mutations were identified in 49 patients, 9 by familial screening. Altogether, 17 new and 11 previously described mutations of PROS1 were identified among the 49 patients. After the exclusion of acquired protein S deficiency due to pregnancy or hormonal contraceptives, there remained only 1 case with protein S activity levels less than 40% that could not be explained by sequence variations or deletions in the examined regions of the PROS1 gene. After the exclusion of conditions associated with acquired protein S deficiency, persistently low protein S activity levels are highly indicative of a genetic alteration in PROS1. We observed a clear correlation between the laboratory phenotype and the type of mutation.

Hemophilia A in cardiac operations: a model of reduced thrombin generation.

Patients with hemophilia A have a congenital defect in thrombin generation. Only limited data are available on the substitution regimens in hemophilia A patients during and after cardiac operations. There are no data on heparinization of these patients during cardiopulmonary bypass. Whereas most case reports suggest factor VIII replacement in combination with standard heparinization to achieve near-normal physiologic factor VIII activity, we describe the successful management of a hemophilic A patient using a low-level factor VIII replacement combined with a reduced heparin dosage during cardiopulmonary bypass. This approach facilitated adequate anticoagulation and minimized the amount of factor VIII treatment necessary without compromising bleeding control.

Postoperative changes in procoagulant factors after major surgery.

Surgical patients are primarily at an increased risk of perioperative bleeding; however, after surgery, these patients develop hypercoagulability that favors thrombotic events. Currently, the time course of postoperative coagulation is not well characterized. Thus, the aim of the present study was to provide a detailed description of the changes in procoagulant factors in patients after major surgery and to evaluate coagulation tests based on their ability to detect hypercoagulability. Fifty-one consecutive patients undergoing different types of major surgery were analyzed. Blood samples were taken preoperatively and on postoperative days (PODs) 1, 2, 3, and 6. In addition to prothrombin time (PT) and activated partial thromboplastin time (aPTT), all PT-dependent and aPTT-dependent clotting factors, von Willebrand factor (vWF), and fibrinogen were obtained, and thrombelastometry and multiplate electrode aggregometry (MEA) were performed. On POD 1, the majority of clotting factors, including factors II, VII, X, XI, and XII, showed a significant decrease from baseline. Factors II, X, XI, and XII remained significantly reduced until POD 3. In contrast, starting on POD 2, fibrinogen, factor VIII, and vWF continuously increased. No relevant changes were found for PT or aPTT. Thrombelastometry revealed a continuous increase in clot firmness, and MEA demonstrated an increase in platelet aggregation on POD 6. However, absolute values remained within normal ranges, and only serial measurements showed hypercoagulation. Beginning on POD 2 after major surgery, significant hypercoagulability developed in patients. However, clinically used global coagulation tests and point-of-care devices did not reliably reflect the hypercoagulatory state.

Observational study of fibrinogen concentrate in massive hemorrhage: evaluation of a multicenter register.

In acute hemorrhage, a critical decrease in fibrinogen often induces acquired coagulopathy. Fibrinogen concentrate has been used to supplement fibrinogen during massive hemorrhage. However, there are limited data on the utilization of fibrinogen concentrate in this setting. This prospective, multicenter observational study analyzed clinical treatment with fibrinogen concentrate in acute bleeding. A prospective multicenter web-based register was developed to document closed cases of massive hemorrhage treated with fibrinogen concentrate perioperatively. Anonymized data including the cause and kinetics of the bleeding, coagulation parameters, coagulation therapy, clinical effects and adverse events were recorded. Two hundred and twenty-three cases entered between September 2008 and August 2009 were eligible for analysis. According to patient needs, additional common blood and coagulation products were administered. Fibrinogen substitution by fibrinogen concentrate and fresh frozen plasma (FFP) was initiated at a median blood loss of 2.0 l and plasma fibrinogen of 1.45 g/l. After a median dose of 12.0 g fibrinogen (4 g in fibrinogen concentrate and 8 g in FFP), plasma fibrinogen rose to 2.19 g/l at the end of surgery; corresponding to a median increment of 0.045 g/l per gram of fibrinogen administered. After substitution, 6% of patients had supra-physiological plasma fibrinogen levels. Three percent of patients sustained thromboembolic complications perioperatively. Logistic regression analysis showed positive correlation of postoperative plasma fibrinogen and survival (P < 0.05). Clinical application of fibrinogen concentrate in bleeding patients is included within a multimodal therapeutic concept. High levels of fibrinogen are necessary in order to reach therapeutic goals. In bleeding patients, higher plasma fibrinogen might be associated with higher rates of survival.

Perioperative haemostatic management of Glanzmann thrombasthenia for abdominal surgery.

Glanzmann thrombasthenia is a rare congenital platelet disorder characterized by spontaneous mucocutaneous bleeding and severe bleeding complications during major surgery. This report centres on the perioperative haemostatic management of a patient with Glanzmann thrombasthenia undergoing elective major abdominal surgery. The treatment regimen was based mainly on recombinant activated factor VII, fibrinogen, and factor XIII, reducing platelet transfusion to a minimum. No red blood cell transfusions were needed perioperatively. For haemostatic monitoring, routine laboratory tests were sufficient.

Fast-track cardiac anesthesia: efficacy and safety of remifentanil versus sufentanil.

OBJECTIVE: The purpose of this study was to compare the safety and efficacy of fast-track cardiac anesthesia with remifentanil (group R) versus sufentanil (group S). DESIGN: Prospective, single-blinded, randomized study. SETTING: University hospital. PARTICIPANTS: One hundred twenty patients undergoing coronary artery bypass graft surgery and/or cardiac valve surgery. INTERVENTIONS: After routine standardized anesthesia induction, anesthesia was maintained with isoflurane (0.4-0.8 vol%) together with either remifentanil (group R) (1 microg/kg/min) or sufentanil (group S) (1 microg/kg for induction, 0.5 microg/kg for skin incision, and then 0.02 microg/kg/min). After surgery, which included cardiopulmonary bypass in all cases, postoperative sedation was achieved in both groups with propofol until the patient was deemed ready for extubation. Additionally, patients in group R received remifentanil, 0.25 microg/kg/min. MEASUREMENTS AND MAIN RESULTS: Recovery profile in group R patients was faster (p < 0.05), with a median time interval between end of surgery and eligibility for extubation of 295 minutes versus 375 minutes. Time from end of surgery to being eligible for discharge from intensive care unit was similar in both groups, with 22.9 hours in group R versus 26.3 hour in group S. Remifentanil provided a better protection against intraoperative stimuli at skin incision and maximal sternal spread (p < 0.05). The incidence of adverse events was comparable in both groups. Postoperative pain scores during the first hour of weaning were higher in group R (p < 0.05). CONCLUSIONS: Remifentanil for fast-track cardiac anesthesia provided safe and stable operating conditions and facilitated earlier tracheal extubation. However, postoperative pain management should be planned carefully.