Patients with coronavirus disease 2019 (COVID-19) frequently experience a coagulopathy associated with a high incidence of thrombotic events leading to poor outcomes. Here, biomarkers of coagulation ...(such as D-dimer, fibrinogen, platelet count), inflammation (such as interleukin-6), and immunity (such as lymphocyte count) as well as clinical scoring systems (such as sequential organ failure assessment SOFA, International Society on Thrombosis and Hemostasis disseminated intravascular coagulation ISTH DIC, and sepsis-induced coagulopathy SIC score) can be helpful in predicting clinical course, need for hospital resources (such as intensive care unit ICU beds, intubation and ventilator therapy, and extracorporeal membrane oxygenation ECMO) and patient’s outcome in patients with COVID-19. However, therapeutic options are actually limited to unspecific supportive therapy. Whether viscoelastic testing can provide additional value in predicting clinical course, need for hospital resources and patient’s outcome or in guiding anticoagulation in COVID-19–associated coagulopathy is still incompletely understood and currently under investigation (eg, in the rotational thromboelastometry analysis and standard coagulation tests in hospitalized patients with COVID-19 ROHOCO study). This article summarizes what we know already about COVID-19–associated coagulopathy and—perhaps even more importantly—characterizes important knowledge gaps.
Rotational thromboelastometry (ROTEM) is a point-of-care viscoelastic method and enables to assess viscoelastic profiles of whole blood in various clinical settings. ROTEM-guided bleeding management ...has become an essential part of patient blood management (PBM) which is an important concept in improving patient safety. Here, ROTEM testing and hemostatic interventions should be linked by evidence-based, setting-specific algorithms adapted to the specific patient population of the hospitals and the local availability of hemostatic interventions. Accordingly, ROTEM-guided algorithms implement the concept of personalized or precision medicine in perioperative bleeding management ('theranostic' approach). ROTEM-guided PBM has been shown to be effective in reducing bleeding, transfusion requirements, complication rates, and health care costs. Accordingly, several randomized-controlled trials, meta-analyses, and health technology assessments provided evidence that using ROTEM-guided algorithms in bleeding patients resulted in improved patient's safety and outcomes including perioperative morbidity and mortality. However, the implementation of ROTEM in the PBM concept requires adequate technical and interpretation training, education and logistics, as well as interdisciplinary communication and collaboration.
Hypothermia and acidosis were reported to influence coagulopathy in different clinical settings. We evaluated whole blood coagulation to determine the effects of hypothermia and/or acidosis on ...hemostasis.
Whole blood samples (3.000 microL) from 10 healthy volunteers (2 female, 8 male) were acidified by adding 40 microL of hydrochloric acid of increasing molarity to achieve a blood pH (alpha-stat) between 7.0 and 7.37, and coagulation was analyzed by rotational thromboelastometry after an incubation period of 30 min using both intrinsically (InTEM) and extrinsically (ExTEM) activated assays. To assess temperature-dependent effects, all tests were performed at blood/thromboelastometer temperatures of 30, 33, 36, and 39 degrees C, respectively. An additional extrinsically activated test with addition of cytochalasin D was performed to examine clot formation without platelet contribution.
Hypothermia at a normal pH produced an increased coagulation time ExTEM: 65 s +/- 3.6 (36 degrees C) vs 85 +/- 4 (30 degrees C), P < 0.001; coagulation time, InTEM: 181 s +/- 10 (36 degrees C) vs 226 +/- 9, P < 0.001 and clot formation time ExTEM: 105 s +/- 5 (36 degrees C) vs 187 +/- 6 (30 degrees C), P < 0.001; clot formation time InTEM: 101 s +/- 5 (36 degrees C) vs 175 +/- 7, P < 0.001, as well as decreased alpha angle ExTEM: 65.6 +/- 1.8 (36 degrees C) vs 58 +/- 1.1, P < 0.01, P < 0.01; InTEM: 70.5 +/- 1.8 (36 degrees C) vs 60.2 +/- 1.5, P < 0.001. Maximum clot firmness was significantly impaired only in InTEM assays 56.9 mm +/- 0.9 (36 degrees C) vs 52.7 +/- 0.9, P < 0.05. In contrast, acidosis per se had no significant effects during normothermia. Acidosis amplified the effects of hypothermia, and synergistically impaired clotting times, alpha angle, and decreased maximum clot firmness, again in both extrinsically and intrinsically activated assays. Formation of a fibrin clot tested after abolition of platelet function by cytochalasin D was not impaired. Clot lysis decreased under hypothermic and/or acidotic conditions, but increased with hyperthermia.
In this in vitro study, hypothermia produced coagulation changes that were worsened by acidosis whereas acidosis without hypothermia has no significant effect on coagulation, as studied by thromboelastometry. This effect was mediated by the inhibition of coagulation factors and platelet function. Thus, thromboelastometry performed at 37 degrees C overestimated integrity of coagulation during hypothermia in particular in combination with acidosis.
Most centres use fresh frozen plasma (FFP) based protocols to prevent or treat haemostatic disturbances during liver transplantation. In the present study, we used a rotational thrombelastometry ...(ROTEM™, TEM, Munich, Germany) guided haemostasis management with fibrinogen concentrates, prothrombin complex concentrates (PCC), platelet concentrates and tranexamic acid without FFP usage and determined the effect on 30 day mortality.
Retrospective data analysis with 372 consecutive adult liver transplant patients performed between 2007 and 2011.
Thrombelastometry guided coagulation management resulted in a transfusion rate for fibrinogen concentrates in 50.2%, PCC in 18.8%, platelet concentrates in 21.2%, tranexamic acid in 4.5%, and red blood cell concentrates in 59.4%. 30 day mortality for the whole cohort was 14.2%. The univariate analyses indicated that nonsurvivors received significantly more fibrinogen concentrates, PCC, red blood cell concentrates, platelet concentrates, and infusion volume, and had a higher MELD score. However, association with mortality was weak as evidenced by receiver operating characteristic curve analyses. Further univariate analyses demonstrated, that up to 8 g of fibrinogen did not increase mortality compared to patients not receiving the coagulation factor. Multivariate analysis demonstrated that platelet concentrates (p = 0.0002, OR 1.87 per unit), infused volume (p = 0.0004, OR = 1.13 per litre), and MELD score (p = 0.024; OR 1.039) are independent predictors for mortality. Fibrinogen concentrates, PCC, and red blood cell concentrates were ruled out as independent risk factors.
ROTEM™ guided substitution with fibrinogen concentrates and PCC does not negatively affect mortality after liver transplantation, while the well-known deleterious effect associated with platelet concentrates was confirmed.
Management of Hemorrhage in Cardiothoracic Surgery Görlinger, Klaus, MD; Shore-Lesserson, Linda, MD; Dirkmann, Daniel, MD ...
Journal of cardiothoracic and vascular anesthesia,
08/2013, Letnik:
27, Številka:
4
Journal Article
Recenzirano
Bleeding is an important issue in cardiothoracic surgery, and about 20% of all blood products are transfused in this clinical setting worldwide. Transfusion practices, however, are highly variable ...among different hospitals and more than 25% of allogeneic blood transfusions have been considered inappropriate. Furthermore, both bleeding and allogeneic blood transfusion are associated with increased morbidity, mortality, and hospital costs. In the past decades, several attempts have been made to find a universal hemostatic agent to ensure hemostasis during and after cardiothoracic surgery. Most drugs studied in this context have either failed to reduce bleeding and transfusion requirements or were associated with severe adverse events, such as acute renal failure or thrombotic/thromboembolic events and, in some cases, increased mortality. Therefore, an individualized goal-directed hemostatic therapy (“theranostic” approach) seems to be more appropriate to stop bleeding in this complex clinical setting. The use of point-of-care (POC) transfusion and coagulation management algorithms guided by viscoelastic tests such as thromboelastometry/thromboelastography in combination with POC platelet function tests such as whole blood impedance aggregometry, and based on first-line therapy with fibrinogen and prothrombin complex concentrate have been associated with reduced allogeneic blood transfusion requirements, reduced incidence of thrombotic/thromboembolic and transfusion-related adverse events, and improved outcomes in cardiac surgery. This article reviews the current literature dealing with the management of hemorrhage in cardiothoracic surgery based on POC diagnostics and with specific coagulation factor concentrates and its impact on transfusion requirements and patients’ outcomes.
The incidence of bleeding and thrombo-embolic complications in patients undergoing mechanical circulatory support therapy remains high and is associated with bad outcomes and increased costs. The ...need for anticoagulation and anti-platelet therapy varies widely between different pulsatile and non-pulsatile ventricular-assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) systems. Therefore, a unique anticoagulation protocol cannot be recommended. Notably, most thrombo-embolic complications occur despite values of conventional coagulation tests being within the targeted range. This is due to the fact that conventional coagulation tests such as international normalised ratio (INR), activated partial thromboplastin time (aPTT) and platelet count cannot detect hyper- or hypofibrinolysis, hypercoagulability due to tissue factor expression on circulating cells or increased clot firmness, and platelet aggregation as well as response to anti-platelet drugs. By contrast, point-of-care (POC) whole blood viscoelastic tests (thromboelastometry/-graphy) and platelet function tests (impedance or turbidimetric aggregometry) reflect in detail the haemostatic status of patients undergoing mechanical circulatory support therapy and the efficacy of their anticoagulation and antiaggregation therapy. Therefore, monitoring of haemostasis using POC thromboelastometry/-graphy and platelet function analysis is recommended during mechanical circulatory support therapy to reduce the risk of bleeding and thrombo-embolic complications. Notably, these haemostatic tests should be performed repeatedly during mechanical circulatory support therapy since thrombin generation, clot firmness and platelet response may change significantly over time with a high inter- and intra-individual variability. Furthermore, coagulation management can be hampered in non-pulsatile VADs by acquired von Willebrand syndrome, and in general by acquired factor XIII deficiency as well as by heparin-induced thrombocytopenia. In addition, POC testing can be used in bleeding patients to guide calculated goal-directed therapy with allogeneic blood products, haemostatic drugs and coagulation factor concentrates to optimise the haemostasis and to minimise transfusion requirements, transfusion-associated adverse events and to avoid thrombo-embolic complications, as well. However, coagulation management in patients undergoing mechanical circulatory support therapy is somehow like navigating between Scylla and Charybdis, and development of protocols based on POC testing seems to be beneficial.
Since inadequate heparin anticoagulation and insufficient reversal can result in complications during cardiopulmonary bypass (CPB) surgery, heparin anticoagulation monitoring by point-of-care (POC) ...activated clotting time (ACT) measurements is essential for CPB initiation, maintainance, and anticoagulant reversal. However, concerns exist regarding reproducibility of ACT assays and comparability of devices.
We evaluated the agreement of ACT assays using four parallel measurements performed on two commonly used devices each (i.e., two Hemochron Signature Elite (Hemochron) and two Abbott i-STAT (i-STAT) devices, respectively). Blood samples from 30 patients undergoing cardiac surgery on CPB were assayed at specified steps (baseline, after heparin administration, after protamine administration) with four parallel measurements (two of each device type) using commercial Kaolin activated assays provided by the respective manufactures. Measurements were compared between identical and different device types using linear regression, Bland-Altman analyses, and calculation of Cohen's kappa coefficient.
Parallel i-STAT ACTs demonstrated a good linear correlation (r = 0.985). Bias, as determined by Bland-Altman analysis, was low (- 3.8 s; 95% limits of agreement (LOA): - 77.8 -70.2 s), and Cohen's Kappa demonstrated good agreement (kappa = 0.809). Hemochron derived ACTs demonstrated worse linear correlation (r = 0.782), larger bias with considerably broader LOA (- 13.14 s; 95%LOA:-316.3-290 s), and lesser concordance between parallel assays (kappa = 0.554). Although demonstrating a fair linear correlation (r = 0.815), parallel measurements on different ACT-devices showed large bias (-20s; 95% LOA: - 290-250 s) and little concordance (kappa = 0.368). Overall, disconcordant results according to clinically predefined target values were more frequent with the Hemochron than i-STAT. Furthermore, while discrepancies in ACT between two parallel iSTAT assays showed little or no clinical relevance, deviations from parallel Hemochron assays and iSTAT versus Hemochron measurements revealed marked and sometimes clinically critical deviations.
Currently used ACT point-of-care devices cannot be used interchangeably. Furthermore, our data question the reliability of the Hemochron in assessing adequacy of heparin anticoagulation monitoring for CPB.
The mechanisms of trauma induced coagulopathy (TIC) are considered multifactorial. Amongst others, however, shedding of the endothelial glycocalyx resulting in increased concentrations of glycocalyx ...fragments in plasma might also play a role. Thus, we hypothesized that shedded glycocalyx components affect coagulation and may act as humoral mediators of TIC.
To investigate effects of heparan sulfate, chondroitin sulfate, syndecan-1, versican, and thrombomodulin we added these fragments to in vitro assays of whole blood from healthy volunteers to yield concentrations observed in trauma patients. Platelet function, whole blood coagulation, and fibrinolysis were measured by standard coagulation tests, impedance aggregometry (IA), and viscoelastic tests (VET). To assess dose-response relationships, we performed IA with increasing concentrations of versican and VET with increasing concentrations of thrombomodulin.
Intrinsically activated clotting times (i.e., activated partial thromboplastin time and intrinsically activated VET with and without heparinase) were unaffected by any glycocalyx fragment. Thrombomodulin, however, significantly and dose-dependently diminished fibrinolysis as assessed by VET with exogenously added rt-PA, and increased rt-PA-induced lysis Indices after 30 (up to 108% of control, p < 0,0001), 45 (up to 368% of control, p < 0,0001), and 60 min (up to 950% of control, p < 0,0001) in VET. Versican impaired platelet aggregation in response to arachidonic acid (up to - 37,6%, p < 0,0001), ADP (up to - 14,5%, p < 0,0001), and collagen (up to - 31,8%, p < 0,0001) in a dose-dependent manner, but did not affect TRAP-6 induced platelet aggregation. Clotting time in extrinsically activated VET was shortened by heparan sulfate (- 7,2%, p = 0,024), chondroitin sulfate (- 11,6%, p = 0,016), versican (- 13%, p = 0,012%), and when combined (- 7,2%, p = 0,007).
Glycocalyx components exert distinct inhibitory effects on platelet function, coagulation, and fibrinolysis. These data do not support a 'heparin-like auto-anticoagulation' by shed glycosaminoglycans but suggest a possible role of versican in trauma-induced thrombocytopathy and of thrombomodulin in trauma-associated impairment of endogenous fibrinolysis.
Hyperosmolar therapy with either mannitol or hypertonic saline (HTS) is commonly used in the treatment of intracranial hypertension (ICH). In vitro data indicate that both mannitol and HTS affect ...coagulation and platelet function in dogs. The aim of this study was to compare the effects of 20% mannitol and 7.2% HTS on whole blood coagulation using rotational thromboelastometry (ROTEM®) and platelet function using a platelet function analyzer (PFA®) in dogs with suspected ICH. Thirty client-owned dogs with suspected ICH needing osmotherapy were randomized to receive either 20% mannitol (5 ml/kg IV over 15 min) or 7.2% HTS (4 ml/kg IV over 5 min). ROTEM® (EXTEM® and FIBTEM® assays) and PFA® analyses (collagen/ADP cartridges) were performed before (T
), as well as 5 (T
), 60 (T
) and 120 (T
) minutes after administration of HTS or mannitol. Data at T
, T
and T
were analyzed as a percentage of values at T
for comparison between groups, and as absolute values for comparison between time points, respectively.
No significant difference was found between the groups for the percentage change of any parameter at any time point except for FIBTEM® clotting time. Within each group, no significant difference was found between time points for any parameter except for FIBTEM® clotting time in the HTS group, and EXTEM® and FIBTEM® maximum clot firmness in the mannitol group. Median ROTEM® values lay within institutional reference intervals in both groups at all time points, whereas median PFA® values were above the reference intervals at T
(both groups) and T
(HTS group).
Using currently recommended doses, mannitol and HTS do not differ in their effects on whole blood coagulation and platelet function in dogs with suspected ICH. Moreover, no relevant impairment of whole blood coagulation was found following treatment with either solution, whereas a short-lived impairment of platelet function was found after both solutions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Blood transfusion is associated with increased morbidity and mortality. We developed and implemented an algorithm for coagulation management in cardiovascular surgery based on first-line ...administration of coagulation factor concentrates combined with point-of-care thromboelastometry/impedance aggregometry.
In a retrospective cohort study including 3,865 patients, we analyzed the incidence of intraoperative allogeneic blood transfusions (primary endpoints) before and after algorithm implementation.
Following algorithm implementation, the incidence of any allogeneic blood transfusion (52.5 vs. 42.2%; P < 0.0001), packed red blood cells (49.7 vs. 40.4%; P < 0.0001), and fresh frozen plasma (19.4 vs. 1.1%; P < 0.0001) decreased, whereas platelet transfusion increased (10.1 vs. 13.0%; P = 0.0041). Yearly transfusion of packed red blood cells (3,276 vs. 2,959 units; P < 0.0001) and fresh frozen plasma (1986 vs. 102 units; P < 0.0001) decreased, as did the median number of packed red blood cells and fresh frozen plasma per patient. The incidence of fibrinogen concentrate (3.73 vs. 10.01%; P < 0.0001) and prothrombin complex concentrate administration (4.42 vs. 8.9%; P < 0.0001) increased, as did their amount administered per year (179 vs. 702 g; P = 0.0008 and 162 × 10³ U vs. 388 × 10³ U; P = 0.0184, respectively). Despite a switch from aprotinin to tranexamic acid, an increase in use of dual antiplatelet therapy (2.7 vs. 13.7%; P < 0.0001), patients' age, proportion of females, emergency cases, and more complex surgery, the incidence of massive transfusion (≥10 units packed red blood cells), (2.5 vs. 1.26%; P = 0.0057) and unplanned reexploration (4.19 vs. 2.24%; P = 0.0007) decreased. Composite thrombotic/thromboembolic events (3.19 vs. 1.77%; P = 0.0115) decreased, but in-hospital mortality did not change (5.24 vs. 5.22%; P = 0.98).
First-line administration of coagulation factor concentrates combined with point-of-care testing was associated with decreased incidence of blood transfusion and thrombotic/thromboembolic events.
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