Optimizing management of replacement fluids for therapeutic plasma exchange: Use of an automated mathematical model to predict post-procedure fibrinogen and antithrombin levels in high-risk patients.

BACKGROUND: Therapeutic plasma exchange (TPE) utilizes an extracorporeal circuit to remove pathologic proteins causing serious illness. When processing a patient's entire blood volume through an extracorporeal circuit, proteins responsible for maintaining hemostatic system homeostasis can reach critically low levels if replacement fluid types and volumes are not carefully titrated, which may increase complications. METHODS: The charts from 27 patients undergoing 46 TPE procedures were reviewed to evaluate the accuracy of our predictive mathematical model, utilizing the following patient information: weight, hematocrit, pre- and post-TPE factor levels (fibrinogen, n = 46, and antithrombin, n = 23), process volume and volumes of fluids (eg, plasma, albumin, and normal saline) administered during TPE and adverse events during and after TPE. RESULTS: Altogether, 25% of patients experienced minor adverse events that resolved spontaneously or with management. There were no bleeding or thrombotic complications. The mean difference between predicted and measured post-TPE fibrinogen concentrations was -0.29 mg/dL (SD ±23.0, range -59 to 37), while percent difference between measured and predicted fibrinogen concentration was 0.94% (SD ±10.8, range of -22 to 19). The mean difference between predicted and measured post-TPE antithrombin concentrations were 0.89% activity (SD ±10.0, range -23 to 14), while mean percent difference between predicted and measured antithrombin concentrations was 3.87% (SD ±14.5, range -25 to 38). CONCLUSIONS: Our model reliably predicts post-TPE fibrinogen and antithrombin concentrations, and may help optimize patient management and attenuate complications.

Acute graft-versus-host disease following lung transplantation in a patient with a novel TERT mutation.

Familial pulmonary fibrosis is associated with loss-of-function mutations in telomerase reverse transcriptase (TERT) and short telomeres. Interstitial lung diseases have become the leading indication for lung transplantation in the USA, and recent data indicate that pathogenic mutations in telomerase may cause unfavourable outcomes following lung transplantation. Although a rare occurrence, solid organ transplant recipients who develop acute graft-versus-host disease (GVHD) have very poor survival. This case report describes the detection of a novel mutation in TERT in a patient who had lung transplantation for familial pulmonary fibrosis and died from complications of acute GVHD.

Finding a common definition of heparin resistance in adult cardiac surgery: communication from the ISTH SSC subcommittee on perioperative and critical care thrombosis and hemostasis.

Ensuring adequate anticoagulation for patients requiring cardiac surgery and cardiopulmonary bypass (CPB) is important due to the adverse consequences of inadequate anticoagulation with respect to bleeding and thrombosis. When target anticoagulation is not achieved with typical doses, the term heparin resistance is routinely used despite the lack of uniform diagnostic criteria. Prior reports and guidance documents that define heparin resistance in patients requiring CPB and guidance documents remain variable based on the lack of standardized criteria. As a result, we conducted a review of clinical trials and reports to evaluate the various heparin resistance definitions employed in this clinical setting and to identify potential standards for future clinical trials and clinical management. In addition, we also aimed to characterize the differences in the reported incidence of heparin resistance in the adult cardiac surgical literature based on the variability of both target-activated clotting (ACT) values and unfractionated heparin doses. Our findings suggest that the most extensively reported ACT target for CPB is 480 seconds or higher. Although most publications define heparin resistance as a failure to achieve this target after a weight-based dose of either 400 U/kg or 500 U/kg of heparin, a standardized definition would be useful to guide future clinical trials and help improve clinical management. We propose the inability to obtain an ACT target for CPB of 480 seconds or more after 500 U/kg as a standardized definition for heparin resistance in this setting.

Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery.

OBJECTIVE: The purpose of this report is to describe the clinical use of antithrombin III concentrate in 53 patients who were found, in the operating room before cardiopulmonary bypass, to be heparin resistant. METHOD: Resistance to heparin was determined to be present when greater than 600 U/kg body weight of heparin failed to prolong the kaolin-activated clotting time to more than 600 seconds in 53 aprotinin-treated patients. Blood samples were obtained for subsequent antithrombin III activity determination. Patients were then administered 500 U of antithrombin III concentrate, and the activated clotting time was remeasured. If the activated clotting time remained less than 600 seconds, a second 500-U dose was given. RESULTS: Of the 53 patients, 45 (85%) had subnormal measured antithrombin III activity, and the mean plasma antithrombin III activity level for the entire group was 67% (normal 80%-120%). Administration of antithrombin III concentrate (500 U in 45 patients and 1000 U in 8 patients) resulted in prolongation of the mean activated clotting time from 492 to 789 seconds without additional heparin. The mean heparin dose response increased from 36.5 to 69.3 s x U(-1) x mL(-1) with antithrombin III treatment. Only one patient did not achieve the target activated clotting time, despite administration of greater than 600 U/kg heparin and 1000 U of antithrombin III concentrate, and was treated with fresh-frozen plasma. CONCLUSIONS: On the basis of the criterion used in this report, most of the patients defined as being heparin resistant had subnormal plasma antithrombin III activity. Treatment with antithrombin III concentrate resulted in potentiation of the heparin effect to meet predetermined activated clotting time thresholds and allow for cardiopulmonary bypass.

Coronary artery bypass grafting in 2 thrombophilic patients with protein s deficiency.

In this report, we review 2 cases of coronary revascularization in patients with a diagnosis of coronary artery disease and preoperative protein S deficiency, an established hypercoagulable condition. In an attempt to normalize protein S levels, fresh frozen plasma was used as the priming fluid for the cardiopulmonary bypass circuit before the initiation of extracorporeal circulation. On the basis of a low risk of bleeding and the theoretical risk of thrombosis, neither patient received intraoperative antifibrinolytic treatment nor did they develop perioperative thrombotic complications.

The occurrence of antibodies to heparin-platelet factor 4 in cardiac and thoracic surgical patients receiving desirudin or heparin for postoperative venous thrombosis prophylaxis.

INTRODUCTION: This randomized, exploratory study compared the incidence of heparin-dependent antibodies associated with subcutaneous (SC) desirudin or heparin given for deep-vein thrombosis prophylaxis following cardiac and thoracic surgery. MATERIALS AND METHODS: Adult patients scheduled for elective cardiac or thoracic surgery received desirudin 15 mg SC twice daily or unfractionated heparin 5000 units SC thrice daily. Duration of thrombosis prophylaxis was determined by the treating physician. Primary outcome measure was the incidence of new antibody formation directed against platelet factor 4 (PF4)/heparin complex. Secondary outcomes included bleeding and thrombotic complications. Blood was tested for anti-PF4/heparin antibodies at baseline, after surgery prior to study drug administration, postdrug day (PDD) 2, PDD 7, and at 1 month. Doppler studies were done before discharge. RESULTS: Of 120 patients, 61 received desirudin, 59 received heparin. New PF4/heparin antibodies occurred in 10.2% and 13.6% of desirudin- and heparin-treated patients, respectively. Among desirudin patients with no heparin exposure, none (0/36) developed PF4/heparin antibodies versus 17.1% with heparin exposure. Incidence of deep venous thrombosis was 4.9% and 3.4% in the desirudin and heparin groups, respectively. Two heparin-group patients developed pulmonary embolism. Two patients per group had bleeding events; no patients required re-exploration for bleeding complications. Median chest tube output was similar with desirudin (900 mL) and heparin (692 mL) as was blood transfusion requirements of more than 2 units (5/61, desirudin; 2/59 heparin). CONCLUSIONS: The incidence of thrombotic events was low in both groups. There were no safety concerns, and desirudin was not associated with anti-PF4/heparin antibodies.

2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.

BACKGROUND: Practice guidelines reflect published literature. Because of the ever changing literature base, it is necessary to update and revise guideline recommendations from time to time. The Society of Thoracic Surgeons recommends review and possible update of previously published guidelines at least every three years. This summary is an update of the blood conservation guideline published in 2007. METHODS: The search methods used in the current version differ compared to the previously published guideline. Literature searches were conducted using standardized MeSH terms from the National Library of Medicine PUBMED database list of search terms. The following terms comprised the standard baseline search terms for all topics and were connected with the logical 'OR' connector--Extracorporeal circulation (MeSH number E04.292), cardiovascular surgical procedures (MeSH number E04.100), and vascular diseases (MeSH number C14.907). Use of these broad search terms allowed specific topics to be added to the search with the logical 'AND' connector. RESULTS: In this 2011 guideline update, areas of major revision include: 1) management of dual anti-platelet therapy before operation, 2) use of drugs that augment red blood cell volume or limit blood loss, 3) use of blood derivatives including fresh frozen plasma, Factor XIII, leukoreduced red blood cells, platelet plasmapheresis, recombinant Factor VII, antithrombin III, and Factor IX concentrates, 4) changes in management of blood salvage, 5) use of minimally invasive procedures to limit perioperative bleeding and blood transfusion, 6) recommendations for blood conservation related to extracorporeal membrane oxygenation and cardiopulmonary perfusion, 7) use of topical hemostatic agents, and 8) new insights into the value of team interventions in blood management. CONCLUSIONS: Much has changed since the previously published 2007 STS blood management guidelines and this document contains new and revised recommendations.

The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: Extracorporeal photopheresis (ECP) has been used to treat acute and chronic rejection after solid organ transplantation. However, data supporting the use of ECP for bronchiolitis obliterans syndrome (BOS) after lung transplantation are limited. METHODS: We retrospectively analyzed the efficacy and safety of ECP for progressive BOS at our institution. Between January 1, 2000, and December 31, 2007, 60 lung allograft recipients were treated with ECP for progressive BOS. RESULTS: During the 6-month period before the initiation of ECP, the average rate of decline in forced expiratory volume in 1 second (FEV(1)) was -116.0 ml/month, but the slope decreased to -28.9 ml/month during the 6-month period after the initiation of ECP, and the mean difference in the rate of decline was 87.1 ml/month (95% confidence interval, 57.3-116.9; p < 0.0001). The FEV(1) improved in 25.0% of patients after the initiation of ECP, with a mean increase of 20.1 ml/month. CONCLUSIONS: ECP is associated with a reduction in the rate of decline in lung function associated with progressive BOS.

Use of activated recombinant factor VII for severe coagulopathy post ventricular assist device or orthotopic heart transplant.

BACKGROUND: Ventricular assist devices(VAD) implantation/removal is a complex surgical procedure with perioperative bleeding complications occurring in nearly half of the cases. Recombinant activated factor VII (rFVIIa) has been used off-label to control severe hemorrhage in surgery and trauma. We report here our experience with rFVIIa as a rescue therapy to achieve hemostasis in patients undergoing orthotopic heart transplant (OHT) and/or VAD implantation. METHODS: A retrospective review was conducted from Jan 03 to Aug 05 for patients who received rFVIIa for the management of intractable bleeding unresponsive to standard hemostatic blood component therapy. Blood loss and the quantity of blood products, prior to, and for at least 12 hours after, administration of rFVIIa were recorded. RESULTS: Mean patient age was 53, (38-64 yrs), mean dose of rFVIIa administered was 78.3 microg/kg (24-189 microg/kg) in 1-3 doses. All patients received the drug either intraoperatively or within 6 hours of arrival in ICU. Mean transfusion requirements and blood loss were significantly reduced after rFVIIa administration (PRBC's; 16.9 +/- 13.3 to 7.1 +/- 6.9 units, FFP; 13.1 +/- 8.2 to 4.1 +/- 4.9 units, platelets; 4.0 +/- 2.8 to 2.1 +/- 2.2 units, p < 0.04 for all). 5 patients expired including 3 with thromboembolic cause. One patient developed a lower extremity arterial thrombus, and another deep vein thrombosis. CONCLUSION: In this review, there was a significant decrease in transfusion requirement and blood loss after rFVIIa administration. Although, 5/17 developed thromboembolic complications, these patients may have been at higher risk based on the multiple modality therapy used to manage intractable bleeding. Nevertheless, the exact role of rFVIIa with respect to development of thromboembolic complications cannot be clearly determined. Further investigation is needed to determine rFVIIa's safety and its effectiveness in improving postoperative morbidity and mortality.

Preoperative use of enoxaparin increases the risk of postoperative bleeding and re-exploration in cardiac surgery patients.

OBJECTIVE: The purpose of this study was to investigate if the preoperative use of new platelet inhibitors and low-molecular-weight heparins may contribute to bleeding after cardiac surgery. DESIGN: Retrospective data review. SETTING: University teaching hospital. PARTICIPANTS: One hundred eleven patients divided in 5 groups. INTERVENTIONS: Patients were grouped according to preoperative antithrombotic regimen: group 1, control, no agents (n=55); group 2, clopidogrel (n=9); group 3, enoxaparin (n=17); group 4, any GP IIb/IIIa inhibitor (n=14); and group 5, any drug combination (n=15). Data included cumulative mediastinal chest tube drainage, allogeneic blood transfusions, total blood donor exposures, and re-exploration. MEASUREMENTS AND MAIN RESULTS: Use of any drug (groups 2-5) resulted in greater total blood transfusions and donor exposure (p=0.0003) than control, especially red cells (p=0.002) and platelets (p=0.006). A greater percentage of patients on enoxaparin required mediastinal re-exploration for nonsurgical bleeding versus control (3/17 v 0/55, p=0.001). The use of enoxaparin was associated with significantly higher chest tube output after the first 24 hours postoperatively (p=0.048). CONCLUSION: Newer antithrombotic agents were associated with greater transfusion rates and total donor exposures. Enoxaparin use was associated with greater overall blood loss and with higher incidence of mediastinal re-exploration. The relative risk-benefit ratio of reduced periprocedure morbidity versus increased bleeding complications has yet to be determined.

A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass.

BACKGROUND: The study evaluated the efficacy of recombinant human antithrombin (rhAT) for restoring heparin responsiveness in heparin resistant patients undergoing cardiac surgery. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing cardiac surgery with cardiopulmonary bypass. Heparin resistance was diagnosed when the activated clotting time was less than 480 s after 400 U/kg heparin. Fifty-four heparin-resistant patients were randomized. One cohort received 75 U/kg rhAT, and the other received normal saline. If the activated clotting time remained less than 480 s, this was considered treatment failure, and 2 units fresh frozen plasma was transfused. Patients were monitored for adverse events. RESULTS: Only 19% of patients in the rhAT group received fresh frozen plasma, compared with 81% of patients in the placebo group (P < 0.001). During their hospitalization, 48% of patients in the rhAT group received fresh frozen plasma, compared with 85% of patients in the placebo group (P = 0.009). Patients in the placebo group required higher heparin doses (P < 0.005) for anticoagulation. There was no increase in serious adverse events associated with rhAT. There was increased blood loss 12 h postoperatively (P = 0.05) with a trend toward increased 24-h bleeding in the rhAT group (P = 0.06). There was no difference between the groups in blood and platelet transfusions. CONCLUSION: Treatment with 75 U/kg rhAT is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation in the majority of heparin-resistant patients. Treating heparin-resistant patients with rhAT may decrease the requirement for heparin and fresh frozen plasma.

Guidelines and alternatives for neuraxial anesthesia and venous thromboembolism prophylaxis in major orthopedic surgery.

Neuraxial anesthesia during major orthopedic surgery, combined with venous thromboembolism prophylaxis, is generally safe and well tolerated, with potential benefits over general anesthesia. The risk of spinal/epidural hematoma, a rare but very serious complication, can be minimized by careful patient selection and attention to anesthetic technique. This risk is further reduced with the use of peripheral nerve blocks in place of neuraxial anesthesia.

Recombinant human transgenic antithrombin in cardiac surgery: a dose-finding study.

BACKGROUND: Acquired antithrombin III (AT) deficiency may render heparin less effective during cardiac surgery and cardiopulmonary bypass (CPB). The authors examined the pharmacodynamics and optimal dose of recombinant human AT (rh-AT) needed to maintain normal AT activity during CPB, optimize the anticoagulant response to heparin, and attenuate excessive activation of the hemostatic system in patients undergoing coronary artery bypass grafting. METHODS: Thirty-six patients scheduled to undergo elective primary coronary artery bypass grafting and who had received heparin for 12 h or more before surgery were enrolled in the study. Ten cohorts of three patients each received rh-AT in doses of 10, 25, 50, 75, 100, 125, 175, or 200 U/kg, a cohort of six patients received 150 U/kg of rh-AT, and a control group of six patients received placebo. RESULTS: Antithrombin III activity exceeded 600 U/dl before CPB at the highest dose (200 U/kg). Doses of 75 U/kg rh-AT normalized AT activity to 100 U/dl during CPB. Activated clotting times during CPB were significantly (P < 0.0001) greater in patients who received rh-AT (844 +/- 191 s) compared with placebo patients (531 +/- 180 s). Significant (P = 0.001) inverse relations were observed between rh-AT dose and both fibrin monomer (r = -0.51) and D-dimer (r = -0.51) concentrations. No appreciable adverse events were observed with any rh-AT doses used in the study. CONCLUSIONS: Supplementation of native AT with transgenically produced protein (rh-AT) in cardiac surgical patients was well tolerated and resulted in higher activated clotting times during CPB and decreased levels of fibrin monomer and D-dimer.

The influence of crystalloid and colloid replacement solutions in acute normovolemic hemodilution: a preliminary survey of hemostatic markers.

Acute normovolemic hemodilution (ANH), in which blood for autologous use is collected immediately before the onset of surgical blood loss, is a recommended autologous blood procurement technique for blood conservation. Both crystalloid and colloid replacement fluids have been used to maintain normovolemia during ANH, but few data are available to justify the use of a particular replacement fluid. Therefore, we designed a prospective, randomized study to determine if the replacement fluid choice affects various coagulation variables and perioperative blood loss. Forty adult patients, ASA physical status 1-3, scheduled for ANH during radical prostatectomy were randomly assigned to one of four replacement fluid groups: (a) Ringer's lactate, (b) 5% albumin, (c) 6% dextran 70 (DEX), or (d) 6% hetastarch (HES). After the induction of a standardized general anesthetic, all patients underwent ANH to a final hemoglobin level of 9 g/dL. Complete blood count, prothrombin time, partial thromboplastin time, fibrinogen, factors V and VIII levels, bleeding time, and thromboelastography (TEG measurements were obtained at similar time points in the procedure. When compared with baseline, activated partial thromboplastin time decreased and factor VIII levels increased in the postanesthesia care unit in both the Ringer's lactate and 5% albumin groups. The DEX and HES groups demonstrated a decrease in TEG maximum amplitude between preoperative and postanesthesia care unit measurements and TEG alpha (angle) was decreased from baseline in the DEX group. The changes in factor VIII, activated partial thromboplastin time, and TEG measurements indicate that HES and DEX may attenuate the hypercoagulability related to surgery.