[Diagnostic and therapeutic management of patients receiving antithrombotic drugs: what to heed?].
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Biomedical subjects
Publications and source records attributed to M Spannagl.
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Acquired, perioperative coagulopathy often develops due to acute bleeding. In the case of primarily healthy patients with normal bone marrow and liver functions, a lack of coagulation factors initiates coagulopathy before secondary thrombopenia arises. Replacement of coagulation factors can be performed by infusion of fresh plasma (single donor or pooled plasma) or concentrates of clotting factors. Fresh plasma as well as concentrates of clotting factors available in German-speaking countries are of high quality and fulfil all safety standards. Undesirable side-effects due to transmission of infections and immunological reactions are--in all probability--more uncommon for virus-inactivated plasma and clotting factors than for single donor plasma. In contrast, thromboembolic complications are unlikely when using fresh frozen plasma, because it contains a balanced ratio of pro-coagulatory and anti-coagulatory factors. For virus-inactivated pooled plasma and concentrates of clotting factors, sporadic reports of thromboembolic events have been published. Concentrates of clotting factors can be stored easily and are rapidly prepared for use. In contrast, fresh frozen plasma has to be thawed before application leading to a significant delay in the schedule. During activated hemostasis, the half-life of clotting factors is significantly reduced in comparison to a stable physiological situation. In the case of perioperative coagulopathy higher dosages of fresh plasma and clotting factors than those recommended in published guidelines are often necessary for successful treatment. When using fresh plasma for coagulation therapy the resulting volume load must be considered. In conclusion, a modern concept of perioperative coagulation management should include fresh plasma as well as concentrates of clotting factors. The anesthetist should be familiar with the available components and be able to consider and adapt them to the individual situation.
An adequate supply of blood components for patients depends on the population's willingness to donate blood as well as on a well-organized blood donation system. In order to ensure the blood supply, a high expenditure is necessary. The article at hand describes two areas of the use of blood and blood products. First, it considers the application of factor concentrates in haemophiliacs (approximately 3000-4000 patients are regularly in need of treatment). For the German statutory health insurance, the estimated yearly expenses for factor concentrates is approx. 450 million Euros, the average costs per patient and year and per treatment center range between 40,903 and 117,597 Euros. The costs for an immune tolerance therapy (ITT) for patients with inhibitors are estimated to be between 70,300 and 3,800,000 Euros for children, depending on the length of the therapy and the degree of severity. In the second part of the article, the authors outline the status quo of the economic evaluation of cellular blood products and present the results of a German cross-sectional survey on the use of erythrocytes in orthopaedic surgery. Within the scope of this hemotherapy study, the transfusion rates vary considerably within the participating treatment centers [elective hip joint replacement (THR): 17 and 94%]. The average blood loss also differs significantly. Comparing the treatment centers, the calculated blood loss during THR shows considerable differences (median blood loss in treatment center with lowest/treatment center with highest blood loss: 883 ml/2,975 ml). The acceptance of low intraoperative hemoglobin values in the clinics is high and diverse. These differences in transfusion procedures between the treatment centers clearly show the need to take effective action in the area of quality assurance in order to make the most of the existent savings potential. Transparency of treatment processes is a necessary condition for an economic assessment and for optimal resource allocation.
Cardiovascular disease is the leading cause for mortality and morbidity in the western world. Arterial thrombosis has multiple origins and may present with different clinical presentations such as acute coronary syndromes, stroke, and peripheral embolization. Furthermore, thrombotic complications may occur during percutaneous interventions. The underlying causes range from atherosclerosis with plaque rupture or erosion, embolization, stasis and hypercoagulable states. Thrombotic complications lead to activation of the intrinsic coagulation system and to platelet aggregation. Despite the development of effective platelet inhibitors, there is still the need for an optimal anticoagulation regimen. While unfractionated heparin is the most commonly used antithrombotic agent, which has major inherent limitations. Direct thrombin inhibitors and anti factor Xa agents are agents which may overcome the limitation of unfractionated heparin. The potential advantages of these new compounds are discussed on the basis of available clinical data in patients with coronary artery disease.
Global tests of haemostasis represent several reaction steps in the physiologic process of clotting. The proportion of plasma or whole blood in the test mixture of a global test is significantly higher than in clotting factor tests. Accordingly, the influence of preanalytical variables is strong, e.g. underlying diseases or drug effects. Strict adherence to preanalytical requirements is of utmost importance. Apart form the standardized reporting of the thromboplastin time (prothrombin time) as International Normalized Ratio (INR), results are generally not comparable when generated by using different reagents or instrumentation. Multiple potential influencing factors have to be considered when interpreting the results. Only laboratory requests precisely derived from the clinical situation can yield clinically relevant conclusions.
Elaborate measures for donor selection and the production of clotting factor concentrates have led to a high safety standard of these products. A multimodal approach to eliminate unwanted contents has been established by strict screening of possible donors and various inactivation procedures within the production process. The systematic registration of adverse events shows very few allergic and nonallergic reactions to plasma derived clotting factor concentrates. In none of the registered cases transmission of infections could be verified. The worldwide registration of such adverse events is not yet sufficiently established, since adequate structures are lacking in some countries. According to estimates, far less than half of occurring adverse events are registered in Germany. A European solution in the form of an official register is about to be introduced.
During acute and severe perioperative bleeding a coagulopathy due to depletion, consumption and dilution of clotting factors and thrombocytes may occur. Diagnosis and therapy of such a coagulopathy should take place immediately. We report two cases of acute coagulopathy during perioperative bleeding and massive transfusion, which were treated successfully by administration of high dose fibrinogen concentrate. Diagnosis and treatment control were performed by thrombelastography.
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In recent years point-of-care testing (POCT) has seen wider applications in the clinical management of surgical and critically ill patients. The available methods for haemostasis analysis include simple-to-handle tests for the assessment of plasmatic coagulation, platelet function tests and the more complex visco-elastic assays. The main advantage of POCT is the fast availability of the results allowing a targeted management of haemostasis disorders. The benefits and risks of POCT depend on the urgency of the analysis, the turn-around time of the laboratory tests, the availability of motivated staff at the point-of-care and the expected haemostatic alterations. An underestimated aspect of POCT is the importance of established quality management procedures. For this purpose control materials based on plasma or artificial fluids are being applied. In spite of often higher costs we appraise the use of POC analysis in many settings as justified because of the gain of time and the overall better process quality, i.e. targeted haemostasis therapy instead of consecutive application of different therapeutic options.
BACKGROUND: During the physiological course of pregnancy maternal peripheral vascular resistance decreases. Using the Doppler technique, the decreasing resistance and disappearance of the early diastolic notch in the arterial uterine perfusion can be observed. These changes in the Doppler flow velocity wave form are caused by the trophoblast invasion in which the spiral arteries loose their musculoelastic structure of the arterial wall. The aim of this study was to investigate whether maternal systemic alteration in the Doppler flow velocity waveform and Pulsatility Index (PI) could be monitored at the cubital artery during normal pregnancy. METHODS AND RESULTS: Forty-five patients were investigated in a prospective study in 4-6-week intervals for Dopplersonographic evaluation of the two uterine arteries and the right cubital artery; 20 of the patients were also investigated after delivery. The presence or absence of the early diastolic reverse flow of the cubital artery was analyzed. Furthermore, the PI was calculated for all vessels. With increasing duration of gestation, the reverse flow of the cubital artery disappeared. During the course of gestation a significant decrease in the PI of the cubital artery was observed in addition to a significantly decreased PI of the uterine arteries. The PI of the placental and nonplacental uterine arteries showed a significant correlation to the PI of the cubital artery. CONCLUSIONS: This study demonstrates systemical changes in arterial resistance correlating to those of the uterine arteries during the course of physiological pregnancy.
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Recently, discussions have focused on the question of whether acquired APC resistance (APCsr) is a clue to the observed association between risk of venous thromboembolism (VTE) and OC use especially with the so-called third-generation OCs. It seems plausible that abnormalities in an extrinsic-based APCsr reflect an increased risk of VTE in women, but this has not yet been properly studied. The objective of our study was to determine whether there was an association of extrinsic APC resistance with VTE risk in a case-control study. Sixty-seven women with confirmed VTE diagnosis were consecutively recruited in primary health care settings, interviewed and blood samples were taken at least 6 months after VTE. Cases were age-matched to 290 population controls. Extrinsic APC resistance was measured as normalized APC ratio (APCsr). The effect of APC on tissue factor-initiated thrombin generation was measured in plasma using alpha2-macroglobulin attached thrombin activity as an endpoint. The extrinsic APCsr was significantly associated with factor V Leiden (FVL) mutation, both in the cases and in the controls. Also, in the women using OC, significantly higher values of APCsr were observed, which confirms the results of other studies. We did not identify a significant association between the extrinsic APCsr and VTE in women not using OC who are non-carriers of factor V Leiden using different approaches: comparison of medians, analyses with unconditional logistic regression using various cut-points of the APCsr distribution, and the comparison between the highest and the lowest quartile of APCsr. With all attempts, the risk estimates were close to unity. In conclusion, we were not able to find evidence for any association of extrinsic APCsr with VTE in women who were not using OCs and non-carriers of FVL.
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The extravascular localization of tissue factor (TF), the central initiator of coagulation, is thought to ensure that thrombus formation is prevented in the intact vessel. We observed that during a 5-min stimulation of human blood with collagen (type I), TF antigen appeared on the surface of platelets adhering to leukocytes. The rapidly presented intravascular TF was competent to start the coagulation cascade. The isolated platelets from healthy donors contained appreciable amounts of the TF protein, while no TF antigen was detected in the neutrophils and rapidly isolated monocytes. Direct interactions with the neutrophils and monocytes were apparently necessary to activate the platelet-associated TF. This was most likely mediated by inactivation of tissue factor pathway inhibitor through leukocyte elastase. In summary, the leukocyte-elicited activation of the platelet TF participates in the rapid initiation of coagulation by collagen.
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UNLABELLED: We evaluated the interaction of preoperative antithrombin (AT) activity and intraoperative response to heparin in cardiac surgery. Heparin anticoagulation is essential during cardiopulmonary bypass (CPB). Heparin itself has no anticoagulant properties, however it causes a conformational change of the physiologic plasma inhibitor AT that converts this slow-acting serine protease inhibitor into a fast acting one. Thus, adequate AT activity is a prerequisite for sufficient heparin anticoagulation. AT activity is reduced by long-term heparin therapy. This prospective, observational study investigated 1516 consecutive cardiac-surgical patients (1304 patients >1 yr (Group A) and 212 patients < or = 1 yr (Group I)). AT activity was measured the day before surgery by a chromogenic substrate assay. The celite-activated activated clotting time (ACT) was used to guide intraoperative heparin administration. Heparin sensitivity was calculated and the postoperative blood loss and perioperative blood requirement was recorded. Infant patients had significantly less preoperative AT activity compared with older patients: 84 (33)% vs 97 (17)%, median (interquartile range) (P < 0. 05). The subgroup of patients aged <1 mo (n = 64) demonstrated a preoperative AT activity of 56 (27)% as compared with 90 (23)% in infant patients between one month and one year (n = 148). In adult patients, preoperative AT activity depended predominantly on preoperative heparin treatment: 62% of the patients with an AT activity <80% were pretreated with heparin. Five minutes after heparin but before CPB the ACT was 587 (334) s in Group A patients with AT activity > or = 80%, and 516 (232) in patients with AT activity < or = 80% (P < 0.05). The target ACT of 480 s was achieved in 70% of patients with normal AT activity in Group A compared with only 54% of patients with AT activity <80% (P < 0.05). In Group A patients with decreased AT activity, 18% demonstrated an inadequate ACT response-defined as ACT <400 s-to the first bolus injection of heparin. In Group I, preoperative AT activity did not influence the ACT response (ACT 5 min after heparin: 846 [447] s in patients with AT activity > or = 80% vs 1000 [364] s in patients with decreased AT activity). The heparin sensitivity was 2.4 (1.1) s/unit heparin/kg compared with 1.5 (0.8) s/unit heparin/KG in group A (P < 0.05). These results suggest that preoperative diminished AT activity causes reduced response to heparin in adult but not in infant patients. Infant patients demonstrate a higher heparin sensitivity despite lower preoperative AT activity. Measurement of preoperative AT activity identifies adult patients at risk of reduced sensitivity to heparin. IMPLICATIONS: In patients less than one year of age, low antithrombin (AT) activity is caused by the immature coagulation system. Despite low AT activity, these young patients demonstrate a normal or increased response to heparin anticoagulation before cardiopulmonary bypass (CPB). In contrast, in patients older than one year of age and adult patients decreased preoperative AT activity is mainly caused by preoperative heparin therapy and causes insufficient response to heparin anticoagulation with a standard heparin dosage. Measurement of preoperative AT activity identifies patients at risk of inadequate anticoagulation during CPB.
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The antiplatelet action of acetylsalicylic acid is mostly used in vascular medicine. In the meantime two other classes of platelet inhibiting agents have been introduced. Thieopyridines (Ticlyridin, Clopidogrel) have been shown to inhibit ADP induced platelet aggregation with persistence of this effect for several days after withdrawal. The short acting intravenous Glycoprotein IIb/IIIa inhibitors considerably improved the management of acute coronacy syndrome. The above mentioned compounds may be applied in combination at least for some days, and heparins are given in addition. Mainly the bleeding complications are to be taken into account especially if patients have to undergo emergency interventions. Hemodialysis or platelet concentrates are recommended to antagonise the antiplatelet effects immediately.