Temporal Transitions in Fibrinolysis after Trauma: Adverse Outcome Is Principally Related to Late Hypofibrinolysis.

BACKGROUND: The relationship between late clinical outcomes after injury and early dynamic changes between fibrinolytic states is not fully understood. The authors hypothesized that temporal transitions in fibrinolysis states using rotational thromboelastometry (ROTEM) would aid stratification of adverse late clinical outcomes and improve understanding of how tranexamic acid modulates the fibrinolytic response and impacts mortality. METHODS: The authors conducted a secondary analysis of previously collected data from trauma patients enrolled into an ongoing prospective cohort study (International Standard Randomised Controlled Trial Number [ISRCTN] 12962642) at a major trauma center in the United Kingdom. ROTEM was performed on admission and at 24 h with patients retrospectively grouped into three fibrinolysis categories: tissue factor-activated ROTEM maximum lysis of less than 5% (low); tissue factor-activated ROTEM maximum lysis of 5 to 15% (normal); or tissue factor-activated ROTEM maximum lysis of more than 15% (high). Primary outcomes were multiorgan dysfunction syndrome and 28-day mortality. RESULTS: Seven-hundred thirty-one patients were included: 299 (41%) were treated with tranexamic acid and 432 (59%) were untreated. Two different cohorts with low-maximum lysis at 24 h were identified: (1) severe brain injury and (2) admission shock and hemorrhage. Multiple organ dysfunction syndrome was greatest in those with low-maximum lysis on admission and at 24 h, and late mortality was four times higher than in patients who remained normal during the first 24 h (7 of 42 [17%] vs. 9 of 223 [4%]; P = 0.029). Patients that transitioned to or remained in low-maximum lysis had increased odds of organ dysfunction (5.43 [95% CI, 1.43 to 20.61] and 4.85 [95% CI, 1.83 to 12.83], respectively). Tranexamic acid abolished ROTEM hyperfibrinolysis (high) on admission, increased the frequency of persistent low-maximum lysis (67 of 195 [34%]) vs. 8 of 79 [10%]; P = 0.002), and was associated with reduced early mortality (28 of 195 [14%] vs. 23 of 79 [29%]; P = 0.015). No increase in late deaths, regardless of fibrinolysis transition patterns, was observed. CONCLUSIONS: Adverse late outcomes are more closely related to 24-h maximum lysis, irrespective of admission levels. Tranexamic acid alters early fibrinolysis transition patterns, but late mortality in patients with low-maximum lysis at 24 h is not increased.

ADAMTS13 testing update: Focus on laboratory aspects of difficult thrombotic thrombocytopenic purpura diagnoses and effects of new therapies.

TTP is a life-threatening disorder diagnosed using a combination of clinical information and laboratory results. ADAMTS13 activity and antibody testing represent a major advance in the field, but results can sometimes be difficult to interpret due to technical aspects of the tests and characteristics of the causative antibodies in acquired TTP. Genetic testing for ADAMTS13 mutations is also now available to assist with the diagnosis of inherited TTP. This review will focus on ADAMTS13 testing and will highlight patient and laboratory aspects that can lead to diagnostic difficulty. The effects of TTP therapies on test results will also be discussed.

Current Practice and Clinical Utility of Thrombophilia Testing in Hospitalized Patients with Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Testing for thrombophilic disorders is often performed in patients after cryptogenic ischemic stroke in an attempt to identify a hematologic explanation for the event. However, the role of commonly tested thrombophilias in ischemic stroke is poorly defined. There is limited evidence to quantify how these disorders affect ischemic stroke risk and testing practices are highly variable. METHODS: Retrospective evaluation of thrombophilia testing practices and clinical outcomes was performed in hospitalized patients with acute ischemic stroke (n = 1898) at a large academic hospital over a two-year period. Variables assessed included testing components, timing of testing, number of abnormal results, and frequency of change in clinical management prompted by abnormal results. A provider survey was also performed to assess perceptions of current testing practices and provider understanding of testing indications. RESULTS: Thrombophilia testing was performed in 190 (10%) patients admitted for acute ischemic stroke. Of those tested, 137 (72.1%) had at least one abnormal result, but this decreased to 37.4% when elevated factor VIII activity was excluded. An abnormal result prompted initiation of anticoagulation in only 4 patients (2%). The provider survey indicated that all providers (100%) were selecting thrombophilia tests using a pre-existing order set and were interested in additional education on testing indications and interpretation. Comparison to similar studies at other institutions revealed significant variation in testing practices, and a small proportion of patients in which testing prompted a change in management (1-8%). CONCLUSIONS: Thrombophilia testing is frequently obtained in hospitalized patients with acute ischemic stroke, yet testing only changed management in 2% of patients. Efforts to improve provider education and the stewardship of testing are needed to ensure appropriate evaluation and treatment of patients with acute ischemic stroke.

The rapid Bethesda assay is equivalent to the standard Bethesda assay for detection of factor IX inhibitors in patients with severe haemophilia B.

INTRODUCTION: The time-dependent nature of factor VIII (FVIII) inhibitors is well described, and the standard FVIII Bethesda assay used to measure inhibitors incorporates a 2-hour incubation. Despite case reports and reviews describing the immediate-acting nature of factor IX (FIX) inhibitors, many coagulation laboratories continue to use a traditional prolonged incubation for FIX Bethesda assays. To our knowledge, a comprehensive evaluation of the FIX Bethesda assay without incubation has not been reported. AIM: The goal of this study was to evaluate the performance of a rapid FIX Bethesda (ie no incubation) compared with the standard Bethesda assay (2-hour incubation). METHODS: The analysis used a Bethesda assay configured for either immediate testing or a 2-hour incubation. Samples from 14 haemophilia B patients with inhibitors and 9 non-human controls were tested. RESULTS: The two assays yielded similar performance overall. The average per cent difference in inhibitor titre between the rapid and standard FIX Bethesda assay was -3% (range -15% to +13%; P = .175) for patient samples and -2% (range -17% to +14%; P = .376) for controls. CONCLUSION: The rapid Bethesda assay showed good agreement with the standard Bethesda assay for determination of inhibitor levels in patients with severe haemophilia B. The rapid assay allows for faster assessment of inhibitors in patients with severe haemophilia B and has the potential to improve the ability of the coagulation laboratory to perform testing from a logistical viewpoint. Further studies involving larger numbers of patients would be important to confirm our findings.

Clustered interventions to reduce inappropriate duplicate laboratory tests in an Irish tertiary hospital.

BACKGROUND: There is increasing emphasis on understanding the rate, and avoidable costs, of inappropriate laboratory testing in hospitals, especially associated with duplication of tests following transfer of patients from one hospital to another. While studies of inappropriate testing have been reported previously, there are no published data relevant to Ireland. AIMS: To determine the baseline rate of inappropriate testing for a subset of clinical parameters, specifically, full blood counts (FBC), biochemistry profiles (Bio) and coagulation (Coag) screens for geriatric patients transferring to and from University Hospital Limerick (UHL). Prospective pilot-scale implementation of five clustered interventions, and assessment of their effect. METHODS: Baseline testing levels were determined between October 2013 and January 2014. A patient survey was conducted to evaluate patient awareness of the blood tests they underwent. Five interventions were trialed sequentially each month between January and May 2014. These included: educational poster, intern training, presentations and communication to consultants; automated prompt in the Lab Information Technology system; highlighting of patient survey results to medical staff; inclusion of laboratory test details on patient transfer document; patient booklet promoting empowerment. Impact was assessed by determining rates of inappropriate laboratory testing monthly, and associated actual cost reductions were calculated. RESULTS: Approximately two-thirds of geriatric inpatients were unaware of why they underwent blood tests. Baseline numbers of inappropriate duplicate FBCs, Bio profiles and Coag tests were 758, 749 and 268 respectively for patients transferring to and from UHL. Following the interventions, these numbers dropped to 85, 84 and 0, respectively. CONCLUSION: The interventions resulted in sustained reduction in rates of inappropriate testing by May 2014. Extrapolated cost reductions exceed two million Euro annually. The most effective intervention involved staff education.

Hemodilution on Cardiopulmonary Bypass: Thromboelastography Patterns and Coagulation-Related Outcomes.

OBJECTIVE: Hemodilution has been associated with both hypocoagulability and hypercoagulability in studies based on thromboelastography (TEG). Severe hemodilution during cardiopulmonary bypass (CPB) is a risk factor for morbidity in cardiac surgery. This study investigated the effects of different degrees of hemodilution with CPB on post-CPB TEG parameters and coagulation-related outcomes. DESIGN: Retrospective cohort study. SETTING: University research hospital. PARTICIPANTS: The study comprised 793 cardiac surgery patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The patient population was divided into low (LH), moderate (MH), and severe (SH) hemodilution groups based on the hemodilution degree on CPB. Differences in TEG parameters and coagulation-related outcomes were assessed. Patients with SH experienced significantly (p = 0.019) prolonged clotting times (median r-time 6.1 min, interquartile range 5.1-7.4 min) with respect to patients with MH (median r-time 5.8 min, interquartile range 4.8-7 min) and LH (median r-time 5.9 min, interquartile range 4.8-7.2 min). Clot firmness was significantly (p = 0.001) lower in patients with SH (median maximum amplitude 63 mm, interquartile range 57-68 mm) compared with patients with MH (median maximum amplitude 65 mm, interquartile range 61-71 mm) and LH (median maximum amplitude 67 mm, interquartile range 62-74 mm). Patients with SH had higher chest drain blood loss and required more fresh frozen plasma and platelet concentrate transfusions than did patients with MH or LH. Postoperative thromboembolic complications were significantly (p = 0.006) more common in patients with SH (2.6%) than in patients with MH (0%) or LH (0.4%). CONCLUSIONS: SH on CPB is associated with hypocoagulation, bleeding, and thrombosis-associated worse outcomes.

Defensive Medicine Among Plastic and Aesthetic Surgeons in Israel.

BACKGROUND: Defensive medicine (DM) includes medical practices that are aimed at avoiding liability rather than benefitting the patient. DM has not been well characterized among plastic surgeons. OBJECTIVES: The authors examined the extents of intended and unintended DM among members of the Israeli Society of Plastic and Aesthetic Surgery (ISPAS) and identified risk factors for DM. METHODS: A total of 108 ISPAS members were asked to complete a questionnaire that addressed physician attitudes toward DM and intended or unintended DM practices. RESULTS: Seventy-eight surgeons (72.2% response rate) returned the questionnaire, although some questionnaires were returned incomplete. Forty respondents acknowledged practicing DM (ie, DM group), and 33 respondents did not (ie, non-DM group). There were no between-group differences in gender, years of practice, or number of previous litigations. Thirty-one percent of respondents in the DM group indicated that they avoid certain surgical procedures, compared with 6% of respondents in the non-DM group (P = .008). In private practice, 66.2% of respondents stated that they obtain written informed consent twice before surgery, and 100% request preoperative blood-coagulation testing. In contrast, 40% and 74% of respondents in public practice, respectively, acknowledged these behaviors (for consent, P = .027; for testing, P = .0059). Sixty-three percent of respondents prescribe antibiotics for more than 24 hours postoperatively, and this practice was slightly more common in the DM group (34 prescribe antibiotics vs 21 in the non-DM group; P = .079). CONCLUSIONS: DM is highly integrated into the daily medical practices of plastic surgeons in Israel.

The changing face of hemostasis testing in modern laboratories: consolidation, automation, and beyond.

The reality of laboratory diagnostics as a whole, and hemostasis testing in particular, is evolving under new paradigms of efficiency. The driving forces of health care and laboratory diagnostics in the third millennium are mainly represented by macro- and microeconomics. In a world with limited resources, shattered by an unprecedented economic crisis, laboratory diagnostics is undergoing a substantial reorganization, with emergence of new models under the imperative of terms, such as bedside testing, consolidation, and networking. The paradigms under which these changes are being developed include a variety of environment, preanalytical, technological, professional, and health-care aspects. The maintenance of continued quality is indeed the major challenge to be faced in the foreseeable future. In fact, some challenges prepotently emerge during a consolidation process, which basically involve delayed testing, centrifugation, transportation, and stability of the specimens, as well as the potential mismatch of sample matrix. This article is aimed to provide an overview of the current economic scenario of laboratory diagnostics and discuss the changing face of hemostasis testing in modern laboratories, providing a synthetic overview about potential drawbacks of actualized solutions.

Technological advances in the hemostasis laboratory.

Automation is conventionally defined as the use of machines, control systems, and information technologies to optimize productivity. Although automation is now commonplace in several areas of diagnostic testing, especially in clinical chemistry and immunochemistry, the concept of extending this process to hemostasis testing has only recently been advanced. The leading drawbacks are still represented by the almost unique biological matrix because citrated plasma can only be used for clotting assays and few other notable exceptions, and by the highly specific pretreatment of samples, which is particularly distinct to other test systems. Despite these important limitations, a certain degree of automation is also now embracing hemostasis testing. The more relevant developments include the growing integration of routine hemostasis analyzers with track line systems and workcells, the development of specific instrumentation tools to enhance reliability of testing (i.e., signal detection with different technologies to increase test panels, plasma indices for preanalytical check of interfering substances, failure patterns sensors for identifying insufficient volume, clots or bubbles, cap-piercing for enhancing operator safety, automatic reflex testing, automatic redilution of samples, and laser barcode readers), preanalytical features (e.g., positive identification, automatic systems for tube(s) labeling, transillumination devices), and postphlebotomy tools (pneumatic tube systems for reducing turnaround time, sample transport boxes for ensuring stability of specimens, monitoring systems for identifying unsuitable conditions of transport). Regardless of these important innovations, coagulation/hemostasis testing still requires specific technical and clinical expertise, not only in terms of measurement procedures but also for interpreting and then appropriately utilizing the derived information. Thus, additional and special caution has to be used when designing projects of automation that include coagulation/hemostasis testing because peculiar and particular requirements must be taken into account.

Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives.

Hemophilia is a bleeding disorder that afflicts about 1 in 5000 males. Treatment relies upon replacement of the deficient factor, and response to treatment both in clinical research and practice is based upon subjective parameters such as pain and joint mobility. Existing laboratory assays quantify the amount of factor in plasma, which is useful diagnostically and prognostically. However, these assays are limited in their ability to fully evaluate the patient's clot-forming capability. Newer assays, known as global assays, provide a far more detailed view of thrombin generation and clot formation and have been studied in hemophilia for about 10 years. They have the potential to offer a more objective measure of both the hemophilic phenotype as well as the response to treatment. In particular, in patients who develop inhibitors to deficient clotting factors and in whom bypassing agents are required for hemostasis, these assays offer the opportunity to determine the laboratory response to these interventions where traditional coagulation assays cannot. In this article we review the existing literature and discuss several controversial issues surrounding the assays. Last, a vision of future clinical uses of these assays is briefly described.

Prospective longitudinal study of thromboelastography and standard hemostatic laboratory tests in healthy women during normal pregnancy.

BACKGROUND: Hemostatic disorders are common in obstetric complications. Thromboelastography (TEG®) simultaneously measures coagulation and fibrinolysis within 10 to 20 minutes. Our primary aim in this prospective longitudinal study was to obtain knowledge about physiological changes in TEG® variables during normal pregnancy and 8 weeks postpartum. The secondary aims were to compare TEG® variables during pregnancy with TEG® variables 8 weeks postpartum and gestational weeks 10 to 15 and to correlate TEG® variables to standard laboratory analyses. METHODS: Blood samples were collected from 45 healthy pregnant women at gestational weeks 10 to 15, 20 to 22, 28 to 30, and 38 to 40, and at 8 weeks postpartum. The following TEG® analyses were performed: time until start of clotting (TEG®-R), time until 20-mm clot firmness (TEG®-K), angle of clotting (TEG®-Angle), maximum amplitude (TEG®-MA), and lysis after 30 minutes (TEG®-LY30). Activated partial thromboplastin time, prothrombin time, soluble fibrin, antithrombin, D-dimer, and platelet count were analyzed. RESULTS: Compared to 8 weeks postpartum TEG®-R was at least 0.9 minutes shorter (upper limit 99% confidence intervals) until gestational weeks 28 to 30 and the mean reduction varied between 23%-26%. TEG®-K was at least 0.1 minutes shorter throughout pregnancy and the mean reduction varied between 18%-35%. TEG®-Angle was at least 2.5 degrees greater during pregnancy and the mean increase varied between 12%-20%. TEG®-MA was also at least 0.4 mm greater during pregnancy and the mean increase varied between 6%-8%. TEG®-LY30 was at least 0.03% lower during gestational weeks 28 to 30 and 38 to 40 and the mean reduction varied between 67%-73%. The routine coagulation laboratory values were within normal pregnant limits. There were no or weak correlations between TEG® and the laboratory variables. CONCLUSIONS: TEG® demonstrates increased coagulability and decreased fibrinolysis during pregnancy. There was a faster initiation of hemostasis, with a minor increase in clot strength. Fibrinolysis decreased during late pregnancy. Alternative cutoff limits for TEG® variables may be required during pregnancy. Standard hemostatic laboratory tests were as expected during pregnancy. Future studies are needed to ascertain whether viscoelastic methods are preferable to standard hemostatic tests for the diagnosis of coagulopathy during obstetric hemorrhage.

Measurement of the new anticoagulants.

New oral anticoagulants are given at fixed daily doses without laboratory dose adjustment for prevention of venous thromboembolism following elective total knee- and hip replacement, for treatment and prevention of recurrent events of acute venous thromboembolism, and for prevention of embolic events in atrial fibrillation. However, it may be necessary to determine the anticoagulant effect of new oral anticoagulants in special patient populations such as in elderly, for renal impairment, before operation, bleeding or thrombotic episodes and to monitor self-compliance. Oral factor Xa and oral thrombin inhibitors influence dose dependently global and specific coagulation assays. Standardization of assays is currently undertaken. Determination of the new oral anticoagulants in serum samples would facilitate blood sampling and analysis from samples taken and stored for creatinine or other biochemical parameters. Point of care methods from plasma or urine for the new oral anticoagulants would improve patient care. First data demonstrate the feasibility of such assays in urine.

Perioperative point of care coagulation testing.

BACKGROUND: Conventional laboratory tests of blood coagulation yield only partial diagnostic information. "Point of care" (POC) devices are increasingly being used at the bedside perioperatively for rapid, detailed testing of hemostatic function and for treatment monitoring in patients with coagulopathies. In this review, we discuss the benefits and limitations of POC coagulation testing-in particular, its effects on the rate of perioperative transfusion of allogeneic blood products, on the frequency of other types of hemostatic treatment, and on the clinical outcome. METHODS: This article is based on a selective review of pertinent literature retrieved by a search in PubMed. RESULTS: The clinical value of preoperative POC screening for coagulopathies has not yet been examined in a prospective, randomized clinical trial. On the other hand, studies in patients with coagulopathies undergoing (mainly cardiac) surgery have shown that algorithm-based hemostatic treatment based on viscoelastic POC coagulation testing reduces both perioperative blood loss and the rate of transfusion of allogeneic blood products. None of the studies published to date had adequate power to reveal any independent effect of POC coagulation testing on perioperative morbidity or mortality. CONCLUSION: Despite certain limitations that must be borne in mind, POC techniques are a valuable means of testing various aspects of hemostasis rapidly and in detail. Their implementation in hemostatic treatment algorithms may reduce both the rate of transfusion of allogeneic blood products and the total cost of treatment for blood loss and coagulopathies. The putative effect of POC testing on perioperative morbidity and mortality has not yet been demonstrated.

Laboratory testing of anticoagulants: the present and the future.

This review provides an update on laboratory testing and monitoring for existing and emerging anticoagulants, starting with an overview of haemostasis and the routine coagulation tests currently employed within most haemostasis laboratories, including the prothrombin time (PT)/international normalised ratio (INR) and the activated partial thromboplastin time (APTT). Current anticoagulant therapy and laboratory monitoring is then discussed in terms of benefits and limitations, followed by a similar brief discussion of the new and emerging anticoagulants. The main focus, however, is laboratory testing related to vitamin K antagonists, heparin, lepirudin and the new agents dabigatran etexilate and rivaroxaban. Although the newer agents do not require laboratory monitoring, laboratory testing will occasionally be required, and pathology laboratories should become proactive in developing appropriate strategies. The tests most likely to fulfill this role are the ecarin clotting time (or chromogenic alternatives), and the chromogenic anti-Xa assay. Nevertheless, the dilute Russell viper venom time (dRVVT) assay may provide another alternative, and existing routine tests are also likely to be utilised for the foreseeable future, potentially also for laboratory testing of the new anticoagulants, albeit perhaps in modified form.

Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing's syndrome: results from a prospective study before and after surgery.

OBJECTIVES: To evaluate whether patients with Cushing's syndrome (CS) had i) changes in coagulative and fibrinolytic parameters associated with CS activity and ii) higher prevalence of venous thromboembolic events (VTE). DESIGN: Prospective study conducted on patients with CS evaluated at diagnosis and 12 months after surgery. PATIENTS AND METHODS: Forty patients with active CS (36 with Cushing's disease (CD) and 4 with an adrenal adenoma) were evaluated. Forty normal subjects and 70 patients with non-ACTH-secreting pituitary adenomas served as controls. All patients and controls underwent an assessment of coagulation and fibrinolysis indexes before and after surgery. RESULTS: CS patients at baseline had a hypercoagulative phenotype when compared with normal subjects (activated partial thromboplastin time (aPTT), fibrinogen, D-Dimer, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1 or SERPINE1), antithrombin III (ATIII or SERPINC1), P<0.0001, α(2) antiplasmin, P=0.0004, thrombin-antithrombin complex (TAT), P=0.01, factor IX (F9), P=0.03). Patients with still active disease after surgery had higher coagulative parameters than those in remission (VWF (P<0.0001), PAI-1 (P=0.004), TAT (P=0.0001), ATIII (P=0.0002) and α(2) antiplasmin (or SERPINF2; P=0.006)), whereas aPTT levels (P=0.007) were significantly reduced. VTE occurred in three patients with CD (7.5%): one had a pulmonary embolism and two patients had a deep venous thrombosis; no patients submitted to transsphenoidal surgery for non-Cushing's pituitary adenoma had VTE (P=0.04). CONCLUSIONS: Patients with CS have a procoagulative phenotype due to cortisol-associated changes in haemostatic and fibrinolytic markers, leading to increased incidence of VTE. Thromboprophylaxis seems to be appropriated in patients with active disease, particularly in the postoperative period.

Management and monitoring of anticoagulation for children undergoing cardiopulmonary bypass in cardiac surgery.

Cardiopulmonary bypass (CPB) creates a pro-coagulant state by causing platelet activation and inflammation leading to thrombin generation and platelet dysfunction. It is associated with severe derangements in normal homeostasis resulting in both thrombotic and hemorrhagic complications. This derangement is greater in children with congenital heart disease than in adults because of the immaturity of the coagulation system, hemodilution of coagulation factors, hyperreactive platelets, and in some patients, physiologic changes associated with cyanosis. During CPB, an appropriate amount of heparin is given with the goal of minimizing the risk of thrombosis and platelet activation and at the same time reducing the risk of bleeding from over anticoagulation. In young children, this balance is more difficult to achieve because of inherent characteristics of the hemostatic system in these patients. Historically, protocols for heparin dosing and monitoring in children have been adapted from adult protocols without re-validation for children. Extreme hemodilution of coagulation factors and platelets in young children affects the accuracy of anticoagulation monitoring in children. The activated clotting time does not correlate with plasma levels of heparin. In addition, recent studies suggest that children need larger doses of heparin than adults, because they have lower antithrombin levels, and they metabolize heparin more rapidly. Preliminary studies demonstrated that the use of individualized heparin and protamine monitoring and management in children is associated with reduced platelet activation and dysfunction and improved clinical outcomes. However, this review article clearly establishes that further studies are necessary to obtain evidence-based protocols for the proper management of anticoagulation of children undergoing cardiopulmonary bypass.

Physiology of hemostasis: with relevance to current and future laboratory testing.

This article briefly details the physiologic and interdependent mechanisms of vascular hemostasis, with an eye toward how the laboratory can assist in diagnosing and maintaining the balance of procoagulant and anticoagulant functions. These functions include determining characteristics of the blood vessel wall, platelet components and receptor-ligand interactions critical for hemostasis, the regulation of thrombin generation and its effects, and the complex fibrinolytic pathways that complete the coagulation cascade.