The perioperative management of treatment with anticoagulants and platelet aggregation inhibitors.

BACKGROUND: When giving anticoagulants and inhibitors of platelet aggregation either prophylactically or therapeutically, physicians face the challenge of protecting patients from thromboembolic events without inducing harmful bleeding. Especially in the perioperative period, the use of these drugs requires a carefully balanced evaluation of their risks and benefits. Moreover, the choice of drug is difficult, because many different substances have been approved for clinical use. METHOD: We selectively searched for relevant publications that appeared from 2003 to February 2013, with particular consideration of the guidelines of the European Society of Cardiology, the Association of Scientific Medical Societies in Germany (AWMF), the American College of Cardiology, and the American Heart Association. RESULTS: Vitamin K antagonists (VKA), low molecular weight heparins, and fondaparinux are the established anticoagulants. The past few years have seen the introduction of orally administered selective inhibitors of the clotting factors IIa (dabigatran) and Xa (rivaroxaban, apixaban). The timing of perioperative interruption of anticoagulation is based on pharmacokinetic considerations rather than on evidence from clinical trials. Recent studies have shown that substituting short-acting anticoagulants for VKA before a procedure increases the risk of bleeding without lowering the risk of periprocedural thromboembolic events. The therapeutic spectrum of acetylsalicylic acid and clopidogrel has been broadened by the newer platelet aggregation inhibitors prasugrel and ticagrelor. Patients with drug eluting stents should be treated with dual platelet inhibition for 12 months because of the risk of in-stent thrombosis. CONCLUSION: Anticoagulants and platelet aggregation inhibitors are commonly used drugs, but the evidence for their perioperative management is limited. The risks of thrombosis and of hemorrhage must be balanced against each other in the individual case. Anticoagulation need not be stopped for minor procedures.

Multiple electrode whole blood aggregometry, PFA-100, and in vivo bleeding time for the point-of-care assessment of aspirin-induced platelet dysfunction in the preoperative setting.

BACKGROUND: Acquired platelet dysfunction due to aspirin ingestion may increase bleeding tendency during surgery. Thus, we examined the diagnostic accuracy of in vivo bleeding time (BT) and 2 platelet function assays for the preoperative assessment of a residual antiplatelet effect in patients treated with aspirin. METHODS: Consecutive patients scheduled for surgery were prospectively enrolled in this study. The patients' last aspirin ingestion had occurred within the previous 48 hours before blood sampling in the "full aspirin effect" group, between 48 and 96 hours before in the "variable aspirin effect" group, and >96 hours before in the "recovered aspirin effect" group. The control group had not taken any aspirin. Multiple electrode aggregometry, platelet function analyzer (PFA)-100, and in vivo BT were performed to assess the effects of aspirin. One-way analysis of variance on ranks with a post hoc multiple-comparison procedure (Dunn) was used to detect differences among the groups. Categorical data were compared using the z test. Receiver operating characteristic (ROC) curves were created to determine the diagnostic accuracy of the platelet function assays investigated. The area under the ROC curve (AUC), sensitivity, and specificity of the assays were calculated. The level of statistical significance was set at P < 0.05. RESULTS: Three hundred ninety-four patients were included in the analysis (133 control and 261 aspirin-treated patients). All 3 methods were able to detect the antiplatelet effect of aspirin in the full aspirin effect group. Furthermore, no difference in the measurement values between the recovered aspirin effect and control group was found, irrespective of the assay performed. Measurement values in the variable aspirin effect group were different from those of the control group in the ASPItest using multiple electrode aggregometry and COL-EPI using PFA-100 but not in BT. ROC analysis showed the highest diagnostic accuracy in excluding the residual aspirin effect in the ASPItest (AUC 0.81, P < 0.001), followed by COL-EPI (AUC 0.78, P < 0.001) and BT (AUC 0.56, P = 0.05). The cutoff value of 53 U in the ASPItest excluded the effect of aspirin with a sensitivity of 88% and specificity of 71%. CONCLUSIONS: The full therapeutic antiplatelet effects of aspirin can be expected within 48 hours of the patient's last aspirin ingestion. Platelet function recovered in our study if aspirin cessation occurred >96 hours (4 days) before; thus, in these patients, preoperative platelet function testing is not useful. To quantify any residual aspirin effect in patients who ceased their intake of aspirin between 48 and 96 hours before surgery, the ASPItest might have the highest diagnostic accuracy.

Normovolemic modified ultrafiltration is associated with better preserved platelet function and less postoperative blood loss in patients undergoing complex cardiac surgery: a randomized and controlled study.

OBJECTIVE: The purpose of the investigation was to study the impact of normovolemic modified ultrafiltration (N-MUF) on hemostasis and perioperative blood loss. METHODS: Fifty patients scheduled for elective complex cardiac surgery were enrolled in this prospective, randomized, and controlled study. Patients were randomized into a control group (n = 25) or an N-MUF group (n = 25). N-MUF was performed using a BC140plus Filter (Maquet Cardiopulmonary AG, Hirrlingen, Germany) in the N-MUF group. Blood samples were taken before (T1) and 30 minutes after (T2) N-MUF in the N-MUF group and at corresponding time points in the control group. Platelet function analyses (TRAPtest, ASPItest, ADPtest) using multiple electrode aggregometry (Multiplate, Dynabyte, Munich, Germany), thrombelastometry (ROTEM, Pentapharm GmbH, Munich, Germany), and conventional laboratory coagulation analyses were performed at each time point. Intraoperative and postoperative transfusion requirements, hemostatic therapy, and blood loss were recorded. RESULTS: There were no significant group differences in demographic or surgical data. At T1, platelet aggregation revealed no significant group differences in the TRAPtest, ASPItest, or ADPtest. Platelet aggregation at T2 was significantly higher in the N-MUF group compared with the control group in the TRAPtest (65 [50/87] U vs 44 [28/51]; P < .001), the ASPItest (52 [36/69] U vs 22 [8/47] U; P = .001), or the ADPtest (39 [28/51] U vs 28 [19/39] U; P = .009). The postoperative chest tube blood loss was significantly lower in the N-MUF at 24 hours (890 [500/1100] mL vs 1075 [800/1413] mL in the N-MUF group vs the control group; P = .039) and 48 hours (900 [550/1350] mL vs 1400 [900/1750] mL; P = .026) postoperatively. Conventional laboratory coagulation analyses and thrombelastometric parameters did not differ within the groups at T1 or T2. CONCLUSIONS: N-MUF improved general platelet aggregation and reduced postoperative blood loss in a significant manner. However, performing N-MUF did not result in less postoperative transfusion requirements.

Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate.

INTRODUCTION: The appropriate strategy for trauma-induced coagulopathy management is under debate. We report the treatment of major trauma using mainly coagulation factor concentrates. METHODS: This retrospective analysis included trauma patients who received >or= 5 units of red blood cell concentrate within 24 hours. Coagulation management was guided by thromboelastometry (ROTEM). Fibrinogen concentrate was given as first-line haemostatic therapy when maximum clot firmness (MCF) measured by FibTEM (fibrin-based test) was <10 mm. Prothrombin complex concentrate (PCC) was given in case of recent coumarin intake or clotting time measured by extrinsic activation test (EXTEM) >1.5 times normal. Lack of improvement in EXTEM MCF after fibrinogen concentrate administration was an indication for platelet concentrate. The observed mortality was compared with the mortality predicted by the trauma injury severity score (TRISS) and by the revised injury severity classification (RISC) score. RESULTS: Of 131 patients included, 128 received fibrinogen concentrate as first-line therapy, 98 additionally received PCC, while 3 patients with recent coumarin intake received only PCC. Twelve patients received FFP and 29 received platelet concentrate. The observed mortality was 24.4%, lower than the TRISS mortality of 33.7% (P = 0.032) and the RISC mortality of 28.7% (P > 0.05). After excluding 17 patients with traumatic brain injury, the difference in mortality was 14% observed versus 27.8% predicted by TRISS (P = 0.0018) and 24.3% predicted by RISC (P = 0.014). CONCLUSIONS: ROTEM-guided haemostatic therapy, with fibrinogen concentrate as first-line haemostatic therapy and additional PCC, was goal-directed and fast. A favourable survival rate was observed. Prospective, randomized trials to investigate this therapeutic alternative further appear warranted.

A point-of-care assessment of the effects of desmopressin on impaired platelet function using multiple electrode whole-blood aggregometry in patients after cardiac surgery.

BACKGROUND: Blood loss after cardiac surgery can be caused by acquired platelet dysfunction after cardiopulmonary bypass. Monitoring of platelet function is clinically important for the identification of patients experiencing such platelet dysfunction. 1-Deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP) has been shown to augment platelet function and to reduce blood loss in patients with platelet dysfunction. In this study, we examined the feasibility of whole blood multiple electrode aggregometry (MEA) for the detection of cardiopulmonary bypass-induced platelet dysfunction and investigated its ability to monitor DDAVP treatment. METHODS: Fifty-eight consecutive patients with blood loss exceeding 150 mL/h in the first 2 consecutive hours after cardiac surgery were screened for suspected isolated platelet dysfunction. Twenty-two patients had suspected isolated platelet dysfunction and were enrolled in the study. Platelet dysfunction was assumed if conventional coagulation analyses (platelet count, activated partial thromboplastin time, international normalized ratio, and fibrinogen) did not show abnormal values as defined for transfusion of allogenic blood products, and no surgical cause of bleeding was suspected. Eleven patients received 0.3 microg/kg DDAVP, and 11 patients received no therapy in a nonrandomized manner. MEA was performed after stimulation with thrombin receptor-activating peptide (TRAPtest, 32 microM), adenosine diphosphate (ADPtest, 6.4 microM), and arachidonic acid (ASPItest, 0.5 mM) before and 2 hours after intervention. Conventional laboratory variables were recorded. The Mann-Whitney test was used to detect differences between the groups, and the Wilcoxon test was used to detect differences before and after intervention. RESULTS: All enrolled patients showed platelet dysfunction that manifested as impaired platelet aggregation in MEA before intervention. After the intervention, platelet function improved in the DDAVP group (49 U [30/72 U], median [25th/75th percentile] postintervention vs 15 U [8/21 U] preintervention for the ASPItest [P < 0.001]; 35 U [24/54 U] vs 14 U [7/28 U] for the ADPtest [P = 0.002]; and 85 U [66/115 U] vs 64 U [26/88 U] for the TRAPtest [P = 0.007]). In contrast, MEA remained unchanged in the control group (22 U [10/50 U] postintervention vs 33 U [14/57 U] preintervention for the ASPItest [P = 0.175]; 17 U [12/20 U] vs 14 U [10/28 U] for the ADPtest [P = 0.147]; and 65 U [41/89 U] vs 57 U [30/91 U] for the TRAPtest [P = 0.123]). CONCLUSIONS: Impaired platelet function after cardiac surgery can be assessed at the bedside using MEA. The effect of DDAVP on impaired platelet function can also be detected as significant improvement in platelet aggregation to all activators. This device might be helpful for the identification of patients who may benefit from DDAVP therapy.

In vitro inhibition of factor XIII retards clot formation, reduces clot firmness, and increases fibrinolytic effects in whole blood.

BACKGROUND: Thrombelastography has received renewed interest in the perioperative setting. The main determinants of thrombelastographic results are coagulation factor concentrations (various zymogens and fibrinogen) and platelet count; thus, platelet inhibition renders these assays mainly coagulation factor dependent. Assays with and without platelet inhibition are thus increasingly used to trigger and monitor replacement therapy with blood products. In this study, we evaluated the effect of factor XIII inhibition and additional glycoprotein (GP) IIb/IIIa blockade on (platelet-inhibited) whole blood thrombelastography and whether a modified routine assay (using factor XIII antibody) can be used to detect factor XIII deficiency. METHODS: Normal whole blood was incubated with increasing amounts of a nonspecific antibody, an anti-GPIIb/IIIa antibody, or a neutralizing anti-factor XIII antibody; samples were analyzed with a tissue factor-activated and platelet-inhibited whole blood thrombelastographic assay. Clotting time, clot formation time, maximum clot firmness, and clot lysis at 60 min were evaluated in triplicate. Also, 25 whole blood routine samples were evaluated for factor XIII deficiency using a new thrombelastographic assay incorporating a factor XIII antibody and using a standard factor XIII assay for comparison. RESULTS: Although GPIIb/IIIa inhibition did not alter the results of the platelet-inhibited whole blood thrombelastography, factor XIII inhibition significantly reduced maximum clot firmness (P = 0.020) and increased clot formation time (P = 0.025) and clot lysis (P = 0.007), leaving clotting time unchanged; a ceiling effect seemed to be present with increasing antibody concentrations in whole blood (but not plasma). The thrombelastographic assay for factor XIII deficiency (<70% activity) had a 90% sensitivity and negative predictive value (area under receiver operating characteristic curve 0.803, P = 0.0015); for a deficiency <60%, sensitivity and negative predictive value were 100% (area under receiver operating characteristic curve 0.84, P = 0.0037). CONCLUSION: Factor XIII has significant impact on platelet-inhibited activated whole blood thrombelastography. This phenomenon should be considered when interpreting thrombelastographic results in the bleeding patient, especially when the results trigger procoagulant therapy. Antibody-mediated factor XIII inhibition can be used to establish thrombelastography-based assays to detect factor XIII deficiency.

Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry.

BACKGROUND: The aim of this study was to diagnose hyperfibrinolysis (HF) and its pattern using thrombelastometry and to correlate the diagnosis with mortality. Furthermore, routine laboratory based and the rotational thrombelastometry analyzer (ROTEM)-derived variables were also correlated with survival. METHODS: Severe trauma patients showing HF in ROTEM were consecutively enrolled in the study. Three different HF patterns were compared: fulminant breakdown within 30 minutes, intermediate HF of 30 to 60 minutes, and late HF after 60 minutes. Injury severity score (ISS), hemodynamics, hemoglobin, hematocrit, platelet count (PC), fibrinogen, and ROTEM variables at admission were analyzed. The observed mortality was compared with the predicted trauma and injury severity score mortality. RESULTS: Thirty-three patients were diagnosed with HF. The mean ISS was 47 +/- 14. Fulminant, intermediate, or late HF (n = 11 each group) resulted in 100%, 91%, or 73% mortality, respectively, with the best prognosis for late HF (p = 0.0031). The actual overall mortality of HF (88%) exceeded the predicted trauma and injury severity score mortality (70%) (p = 0.039). Lower PC (123 +/- 53 vs. 193 +/- 91; p = 0.034), ROTEM prolonged clot formation time [CFT, 359 (140/632) vs. 82 (14/190); p = 0.042], and lower platelet contribution to maximum clot firmness [MCF(EXTEM) - MCF(FIBTEM), 34 (20/40) vs. 46 (40/53); p = 0.026] were associated with increased mortality. CONCLUSION: ROTEM-based diagnosis of HF predicted outcome. Further independent predictors of death were combination of HF with hemorrhagic shock, low PC, and prolonged CFT in ROTEM. ROTEM-based point of care testing in the emergency room is thus able to identify prognostic factors such as prolonged CFT and low platelet contribution to clot firmness (MCF(EX) - MCF(FIB)) earlier than standard laboratory-based monitoring.

Whole blood multiple electrode aggregometry is a reliable point-of-care test of aspirin-induced platelet dysfunction.

BACKGROUND: Aspirin is one of the most commonly ingested over-the-counter drugs. In addition to its analgesic and antiinflammatory actions, it also potently inhibits platelet aggregation. Evaluation of aspirin-induced platelet dysfunction is relevant in various clinical situations, including during complex surgeries with high bleeding risk in individuals who have ingested aspirin. In this study, we examined the suitability of multiple electrode aggregometry (MEA) for time course assessment of the antiplatelet effects of a single oral dose of 500 mg aspirin. We also determined the applicability of this method in the point-of-care (POC) setting by comparing the results of the test after different time intervals after blood sampling. METHOD: Twenty-four adult volunteers were enrolled in the study. After blood drawing at baseline, 500 mg aspirin was administered to all volunteers. Blood samples were taken at 4, 24, 56, 80, and 124 h after aspirin ingestion. At each time point, measurements were performed immediately and 30 and 60 min after drawing blood. Whole blood MEA was performed after stimulation with thrombin receptor activating peptide (TRAPtest, 32 microM) and arachidonic acid (ASPItest, 0.5 mM). Repeated measurement analysis of variance with a Bonferroni correction for multiple comparisons was performed to detect differences between time points. Assay imprecision was determined by calculating the coefficient of variation. The level of statistical significance was set to P < 0.05. RESULTS: Platelet aggregation by ASPItest was markedly decreased 4 h after aspirin intake. From the second day after aspirin intake, ASPItest values recovered with high interindividual variability, and 5 days after aspirin intake, ASPItest values did not differ significantly from baseline. TRAP-induced platelet aggregation (TRAPtest) showed no systematic changes during the study period. The resting time of the sample did not affect TRAPtest or ASPItest values. The coefficients of variation were 10% for the ASPItest and 7% for the TRAPtest. CONCLUSIONS: MEA reliably detected the effects of aspirin. Notably, 500 mg aspirin caused complete inhibition of arachidonic acid-induced platelet aggregation for 2 days in all volunteers. Aggregation returned to baseline values with a wide interindividual variation in time course by day 5. No resting time for the blood sample was required for ASPItest or TRAPtest. These assays can be implemented as real POC tests. The reproducibility of the assays studied here is within the range of modern POC analyzers.

[Hemostasis management in multiple trauma patients--value of near-patient diagnostic methods]. / Hämostaseologisches Management beim Polytrauma--Stellenwert der patientennahen diagnostischen Methoden.

Massively transfused multiple trauma patients commonly develop a complex coagulopathy which needs immediate treatment. Near-patient diagnostic methods are available for the management of this coagulopathy and for the guidance of the therapeutic options with blood products and haemostatic drugs: conventional laboratory analysis methods adapted to the point-of-care (POC) situation (blood gas analysis, point of care PT, APTT and platelet count), and the complex whole blood methods used for near-patient coagulation monitoring (thromboelastometry and platelet function analysis). Based on the new Guidelines of the German Medical Association for the use of blood and plasma derivates, interventions with blood products and haemostatic drugs in multiple trauma patients are suggested. The diagnostic value of near-patient methods for coagulation monitoring is discussed.

[Platelet function analysis with point-of-care methods]. / Messung der Thrombozytenfunktion mit Point-of-Care-Methoden.

BACKGROUND: More and more patients are treated with antiplatelet drugs today. In this context a sufficient inhibition of platelet aggregation, on the one hand, is of essential importance to the efficiency of prophylaxis of myocardial and cerebral infarction and to avoiding thrombosis of drug-eluting stents. On the other hand, this medication can result in an increased risk of perioperative bleeding. In both situations control of the efficiency of therapy or rather the assessment of the impairment of hemostasis is of vital importance. METHODS: Platelet function analyzer (PFA-100), multiple platelet function analyzer (Multiplate), and rotational thrombelastometry (ROTEM) are reliable and easy to use point-of-care (POC) devices. Since these three analyzers monitor different aspects of platelet function and have different limitations, the selection of the right test system depends on the right question. RESULTS: PFA-100 enables a sensitive detection of von Willebrand's syndrome. Multiplate is apt to control efficiency of platelet inhibiton with acetylsalicylic acid, clopidogrel and glycoprotein IIb/IIIa receptor antagonists. ROTEM analysis offers the opportunity to assess hemostasis as a holistic system. Thereby, ROTEM analysis particularly detects hyperfibrinolysis, heparin effects, and fibrinogen-platelet interaction. CONCLUSION: Due to their easy handling the described POC devices are applicable to perioperative coagulation management as well as during and after coronary intervention or to monitoring of platelet function in cardiologic practice. They enable a quick assessment of platelet function and an individually guided therapy.

[Neurological diseases in pregnancy: implications for anesthesia care - part 2]. / Die Schwangere mit neurologischen Begleiterkrankungen - Implikationen für das peripartale Anästhesiemanagement - Teil II.

In the parturient as well as in the pregnant patient with neurological disease, surgery is necessary more frequently than in healthy pregnants. Most pregnancies of these patients will result in a slightly increased rate for cesarean section. The focus of anesthesia care is mostly to avoid damage to the fetus, in some pathologies to protect the mother. Pregnancy itself may change the course of pre-existent chronic neurological diseases such as epileptic seizure, multiple sclerosis, or myasthenia gravis. Other diseases will have their onset predominantly in pregnancy such as back pain, nerve compression syndromes, some brain tumors or cerebrovascular events. Subarachnoidal hemorrhage and intracranial bleeding contribute to 65 % of maternal mortality. Finally, pregnancy induced conditions such as eclampsia and HELLP syndrome and its management are reviewed where the concerns for the nervous system have high relevance for anesthesiological management. Anesthesia care for the pregnant and the parturient presenting with a neurological disease requires 1.) expertise with neuroanesthesia and obstetric anesthesia care, 2.) accurate physical examination of the neurological system preoperatively, 3.) safe choice and conductance of the anesthesia technique (mostly regional anesthesia) 4.) avoidance of unfavorable drug effects for the fetus and the nervous system of the mother and 5.) intraoperative neuromonitoring together with the control of the fetal heart rate.

[Neurological diseases in pregnancy: implications for anesthesia care--Part 1]. / Die Schwangere mit neurologischen Begleiterkrankungen - Implikationen für das peripartale Anästhesiemanagement - Teil I.

In the parturient as well as in the pregnant patient with neurological disease, surgery is necessary more frequently than in healthy pregnants. Most pregnancies of these patients will result in a slightly increased rate for cesarean section. The focus of anesthesia care is mostly to avoid damage to the fetus, in some pathologies to protect the mother. Pregnancy itself may change the course of pre-existent chronic neurological diseases such as epileptic seizure, multiple sclerosis, or myasthenia gravis. Other diseases will have their onset predominantly in pregnancy such as back pain, nerve compression syndromes, some brain tumors or cerebrovascular events. Subarachnoidal hemorrhage and intracranial bleeding contribute to 65 % of maternal mortality. Finally, pregnancy induced conditions such as eclampsia and HELLP syndrome and its management are reviewed where the concerns for the nervous system have high relevance for anesthesiological management. Anesthesia care for the pregnant and the parturient presenting with a neurological disease requires 1.) expertise with neuroanesthesia and obstetric anesthesia care, 2.) accurate physical examination of the neurological system preoperatively, 3.) safe choice and conductance of the anesthesia technique (mostly regional anesthesia) 4.) avoidance of unfavorable drug effects for the fetus and the nervous system of the mother and 5.) intraoperative neuromonitoring together with the control of the fetal heart rate.