Viscoelastic Testing in the Clinical Management of Subarachnoid Hemorrhage and Intracerebral Hemorrhage
Hvas CL, Hvas AM
Seminars in thrombosis and hemostasis. 2022
Subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) are both debilitating and life-threatening incidents calling for immediate action and treatment. This review focuses on the applicability of viscoelastic testing (rotational thromboelastometry or thromboelastography [TEG]) in the management of SAH and ICH. A systematic literature search was performed in PubMed and EMBASE. Studies including patients with SAH or ICH, in which viscoelastic testing was performed, were identified. In total, 24 studies were included for analysis, and further subdivided into studies on SAH patients investigated prior to stenting or coiling (n = 12), ICH patients (n = 8) and studies testing patients undergoing stenting or coiling, or ischemic stroke patients undergoing thrombolysis or thrombectomy and developing ICH as a complication (n = 5). SAH patients had increased clot firmness, and this was associated with a higher degree of early brain injury and higher Hunt-Hess score. SAH patients with delayed cerebral ischemia had higher clot firmness than patients not developing delayed cerebral ischemia. ICH patients showed accelerated clot formation and increased clot firmness in comparison to healthy controls. Patients with hematoma expansion had longer clot initiation and lower platelet aggregation than patients with no hematoma expansion. During stent procedures for SAH, adjustment of antiplatelet therapy according to TEG platelet mapping did not change prevalence of major bleeding, thromboembolic events, or functional outcome. Viscoelastic testing prior to thrombolysis showed conflicting results in predicting ICH as complication. In conclusion, viscoelastic testing suggests hypercoagulation following SAH and ICH. Further investigation of the predictive value of increased clot firmness in SAH seems relevant. In ICH, the prediction of hematoma expansion and ICH as a complication to thrombolysis might be clinically relevant.
Dynamic Hemostasis and Fibrinolysis Assays in Intensive Care COVID-19 Patients and Association with Thrombosis and Bleeding-A Systematic Review and a Cohort Study
Hvas CL, Larsen JB, Adelborg K, Christensen S, Hvas AM
Seminars in thrombosis and hemostasis. 2021
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Patients admitted to the intensive care unit (ICU) with coronavirus disease 2019 (COVID-19), the infectious pathology caused by severe acute respiratory syndrome coronavirus 2, have a high risk of thrombosis, though the precise mechanisms behind this remain unclarified. A systematic literature search in PubMed and EMBASE identified 18 prospective studies applying dynamic coagulation assays in ICU COVID-19 patients. Overall, these studies revealed normal or slightly reduced primary hemostasis, prolonged clot initiation, but increased clot firmness. Thrombin generation assay parameters generally were equivalent to the control groups or within reference range. Fibrinolysis assays showed increased clot resistance. Only six studies related their findings to clinical outcome. We also prospectively included 51 COVID-19 patients admitted to the ICU. Blood samples were examined on day 1, 3-4, and 7-8 with platelet function tests, rotational thromboelastometry (ROTEM), in vivo and ex vivo thrombin generation, and clot lysis assay. Data on thrombosis, bleeding, and mortality were recorded during 30 days. Primary hemostasis was comparable to healthy controls, but COVID-19 patients had longer ROTEM-clotting times and higher maximum clot firmness than healthy controls. Ex vivo thrombin generation was similar to that of healthy controls while in vivo thrombin generation markers, thrombin-antithrombin (TAT) complex, and prothrombin fragment 1 + 2 (F1 + 2) were higher in ICU COVID-19 patients than in healthy controls. Impaired fibrinolysis was present at all time points. TAT complex and F1 + 2 levels were significantly higher in patients developing thrombosis (n = 16) than in those without. In conclusion, only few previous studies employed dynamic hemostasis assays in COVID-19 ICU-patients and failed to reveal a clear association with development of thrombosis. In ICU COVID-19 patients, we confirmed normal platelet aggregation, while in vivo thrombin generation was increased and fibrinolysis decreased. Thrombosis may be driven by increased thrombin formation in vivo.
Patients admitted to intensive care unit with COVID-19 (18 studies).
Systematic review examining the haemostasis with a wide range of dynamic haemostasis assays including platelet aggregation, global whole blood coagulation, thrombin generation assays, and fibrinolysis assays.
The included studies revealed normal or slightly reduced primary haemostasis, prolonged clot initiation, but increased clot firmness. Thrombin generation assay parameters generally were equivalent to the control groups or within reference range. Fibrinolysis assays showed increased clot resistance. Only six studies related their findings to clinical outcome.
Postoperative bleeding and venous thromboembolism in colorectal cancer patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a systematic review and meta-analysis
Lundbech M, Krag AE, Iversen LH, Hvas AM
International journal of colorectal disease. 2021
PURPOSE Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival for selected patients with peritoneal metastases from colorectal cancer. Previous studies report conflicting rates of postoperative bleeding and venous thromboembolism (VTE) after CRS + HIPEC. The aim of the present study was to systematically review the literature and to estimate the overall 30-day incidence of postoperative bleeding and the overall 90-day incidence of VTE after CRS + HIPEC. METHODS Studies were identified in PubMed, Embase, and Web of Science on 29 April 2021. Data were extracted for a qualitative synthesis and to estimate an overall mean incidence in the meta-analysis. RESULTS Fourteen studies with a total of 3268 patients were included in the systematic review. Postoperative bleeding incidence rates within 30 days ranged from 1.7 to 8.3% with an overall 30-day postoperative bleeding incidence with [95% CI] at 4.2 [2.6;6.2]%. VTE incidence rates within 90 days ranged from 0.2 to 13.6% with an overall 90-day VTE incidence with [95% CI] at 2.7 [1;5.2]% after CRS + HIPEC. CONCLUSION This systematic review and meta-analysis indicate a low risk for postoperative bleeding within 30 days and VTE within 90 days after CRS + HIPEC for peritoneal metastases from colorectal cancer.
Efficacy and Safety of Antifibrinolytic Drugs in Pediatric Surgery: A Systematic Review
Hovgesen NT, Larsen JB, Fenger-Eriksen C, Hansen AK, Hvas AM
Seminars in thrombosis and hemostasis. 2021;47(5):538-568
Antifibrinolytic drugs are used to reduce blood loss and subsequent transfusions during surgery and following trauma, but the optimal dosing regimen in the pediatric population is still unresolved. The aim of this systematic review was to evaluate efficacy and safety of antifibrinolytic drugs in pediatric surgery and trauma to determine the optimal dosing regimen. A literature search was performed in PubMed, Embase, Cochrane, and Web of Science on May 3, 2020. We included randomized controlled studies investigating the effect of tranexamic acid (TXA), aprotinin, and epsilon-aminocaproic acid, in terms of reducing blood loss, blood transfusions, reoperations, and rebleeds in pediatric patients aged 0 to 18 years undergoing cardiac surgery, noncardiac surgery, or trauma. Fifty randomized controlled trials (RCTs) were included; 28 RCTs investigated cardiac surgery and 22 investigated noncardiac surgery. No RCTs regarding trauma met the inclusion criteria. All antifibrinolytic drugs reduced postoperative blood loss and transfusions when used in pediatric surgery. The dosing regimen varied between studies, but similar effect sizes were found in terms of reduced blood loss regardless of the cumulative dose used. Few studies found adverse events, and no difference in incidence or type of adverse events was seen between the antifibrinolytic and the placebo group. In conclusion, use of antifibrinolytics is efficient and safe in children undergoing surgery. We propose TXA as the drug of choice based on its level of evidence and safety profile; we recommend a dosing regimen composed of a loading dose of 10 to 15 mg/kg prior to surgery followed by 1 to 5 mg/kg/h as continuous infusion throughout surgery.
Effect of Remote Ischemic Conditioning on Bleeding Complications in Surgery: A Systematic Review and Meta-Analysis
Krag AE, Hvas CL, Kiil BJ, Hvas AM
Seminars in thrombosis and hemostasis. 2021
Remote ischemic conditioning (RIC) is administered with an inflatable tourniquet by inducing brief, alternating cycles of limb ischemia and reperfusion. RIC possibly impacts the hemostatic system, and the intervention has been tested as protective therapy against ischemia-reperfusion injury and thrombotic complications in cardiac surgery and other surgical procedures. In the present systematic review, we aimed to investigate the effect of RIC on intraoperative and postoperative bleeding complications in meta-analyses of randomized controlled trials including adult patients undergoing surgery. A systematic search was performed on November 7, 2020 in PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Randomized controlled trials comparing RIC versus no RIC in adult patients undergoing surgery that reported bleeding outcomes in English publications were included. Effect estimates with 95% confidence intervals were calculated using the random-effects model for intraoperative and postoperative bleeding outcomes. Thirty-two randomized controlled trials with 3,804 patients were eligible for inclusion. RIC did not affect intraoperative bleeding volume (nine trials; 392 RIC patients, 399 controls) with the effect estimate -0.95 [-9.90; 7.99] mL (p = 0.83). RIC significantly reduced postoperative drainage volume (seven trials; 367 RIC patients, 365 controls) with mean difference -83.6 [-134.9; -32.4] mL (p = 0.001). The risk of re-operation for bleeding was reduced in the RIC group (16 trials; 838 RIC patients, 839 controls), albeit not significantly, with the relative risk 0.65 [0.39; 1.09] (p = 0.10). In conclusion, RIC reduced postoperative bleeding measured by postoperative drainage volume in this meta-analysis of adult patients undergoing surgery.
Hemostasis and Fibrinolysis following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review on Additional Knowledge from Dynamic Assays and Potential Treatment Targets
Hvas CL, Hvas AM
Seminars in thrombosis and hemostasis. 2021
Mortality after aneurysmal subarachnoid hemorrhage (aSAH) is augmented by rebleeding and delayed cerebral ischemia (DCI). A range of assays evaluating the dynamic process of blood coagulation, from activation of clotting factors to fibrinolysis, has emerged and a comprehensive review of hemostasis and fibrinolysis following aSAH may reveal targets of treatment. We conducted a systematic review of existing literature assessing coagulation and fibrinolysis following aSAH, but prior to treatment. PubMed, Embase, and Web of Science were searched on November 18, 2020, without time boundaries. In total, 45 original studies were eventually incorporated into this systematic review, divided into studies presenting data only from conventional or quantitative assays (n = 22) and studies employing dynamic assays (n = 23). Data from conventional or quantitative assays indicated increased platelet activation, whereas dynamic assays detected platelet dysfunction possibly related to an increased risk of rebleeding. Secondary hemostasis was activated in conventional, quantitative, and dynamic assays and this was related to poor neurological outcome and mortality. Studies systematically investigating fibrinolysis were sparse. Measurements from conventional or quantitative assays, as well as dynamic fibrinolysis assays, revealed conflicting results with normal or increased lysis and changes were not associated with outcome. In conclusion, dynamic assays were able to detect reduced platelet function, not revealed by conventional or quantitative assays. Activation of secondary hemostasis was found in both dynamic and nondynamic assays, while changes in fibrinolysis were not convincingly demonstrable in either dynamic or conventional or quantitative assays. Hence, from a mechanistic point of view, desmopressin to prevent rebleeding and heparin to prevent DCI may hold potential as therapeutic options. As changes in fibrinolysis were not convincingly demonstrated and not related to outcome, the use of tranexamic acid prior to aneurysm closure is not supported by this review.
Hyperfibrinolysis in Patients with Solid Malignant Neoplasms: A Systematic Review
Winther-Larsen A, Sandfeld-Paulsen B, Hvas AM
Seminars in thrombosis and hemostasis. 2020
Solid malignant neoplasms have the capability of disturbing the fibrinolytic system, leading to primary hyperfibrinolysis, a paraneoplastic syndrome that potentially results in severe bleeding. Yet, the full extent of primary hyperfibrinolysis in solid malignant neoplasms is unknown. Thus, the purpose of this study was to systematically review the current literature regarding clinical manifestations, biochemical diagnosis, and treatment of primary hyperfibrinolysis in patients with solid malignant neoplasms. The review was performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases PubMed, Embase, Scopus, and Web of Science were searched on December 5, 2019, without time limits. Studies were included if they comprised at least one biochemical marker of fibrinolysis in addition to fibrinogen degradation products such as D-dimer, and furthermore included a correlation between biochemical marker and clinical outcome. In total, 12 studies were included. All studies were case reports including a total of 21 patients. Prostate cancer was the most frequently represented cancer type (76%), and the majority of cancer patients had metastatic disease (81%). Spontaneous bleeding was the clinical presentation in the majority of patients (76%), and the most frequently localization for the bleedings was subcutaneous. Antifibrinolytic agents were the most commonly used treatment and ceased bleedings in 80% of patients. Three patients died of uncontrolled bleedings. In conclusion, primary hyperfibrinolysis induced by solid malignant neoplasms is a rare but potentially life-threatening condition that should be considered, especially in patients with metastatic disease presenting with serious, spontaneous subcutaneous bleedings. A standardized diagnostic strategy is strongly needed.
Effect of Tranexamic Acid on Coagulation and Fibrin Clot Properties in Children Undergoing Craniofacial Surgery
Fenger-Eriksen C, Lindholm AD, Krogh L, Hell T, Berger M, Hermann M, Fries D, Juul N, Rasmussen M, Hvas AM
Thrombosis and haemostasis. 2020
OBJECTIVE Craniosynostosis surgery in small children is very often associated with a high blood loss. Tranexamic acid (TXA) reduces blood loss during this procedure, although the potential underlying coagulopathy in these children is not known in detail. Objective was to determine the nature of any coagulopathy found during and after craniosynostosis surgery and to characterize the effect of TXA on fibrin clot formation, clot strength, and fibrinolysis. MATERIALS AND METHODS Thirty children received either TXA (bolus dose of 10 mg/kg followed by 8 hours continuous infusion of 3 mg/kg/h) or placebo. Dynamic whole blood clot formation assessed by thromboelastometry, platelet count, dynamic thrombin generation/thrombin-antithrombin, clot lysis assay, and fibrinogen/factor XIII (FXIII) levels were measured. Additionally, clot structure was investigated by real-time live confocal microscopy and topical data analysis. RESULTS Increased ability of thrombin generation was observed together with a tendency toward shortened activated partial thromboplastin time and clotting time. Postoperative maximum clot firmness was higher among children receiving TXA. FXIII decreased significantly during surgery in both groups.Resistance toward tissue plasminogen activator-induced fibrinolysis was higher in children that received TXA, as evidenced by topical data analysis and by a significant longer lysis time. Fibrinogen levels were higher in the TXA group at 24 hours. CONCLUSION A significant coagulopathy mainly characterized by changes in clot stability and not parameters of thrombin generation was reported. Tranexamic acid improved clot strength and reduced fibrinolysis, thereby avoiding reduction in fibrinogen levels.
Effect of tranexamic acid on markers of inflammation in children undergoing craniofacial surgery
Fenger-Eriksen C, Rasmussen M, Juul N, Krog J, Hvas AM
Acta anaesthesiologica Scandinavica. 2020
BACKGROUND Tranexamic acid (TXA) reduces blood loss and transfusion requirements during craniosynostosis surgery in small children. Possible interaction from TXA on the inflammatory system is unknown. OBJECTIVE To evaluate the effect of TXA on a wide range of inflammatory markers in children receiving TXA in a randomized, blinded and placebo controlled study design. METHODS Thirty children undergoing craniosynostosis surgery with significant blood loss received TXA (bolus dose of 10 mg kg(-1) followed by 8 hours continuous infusion of 3 mg kg(-1) h(-1) ) or placebo in a randomized, double-blinded study design. Using a new proximity extension assays employing a panel of inflammatory biomarkers samples was used for analysis of blood samples obtained preoperatively, 4h and 24 h after operation. RESULTS Ninety-two inflammatory parameters were measured. TXA did not affect any of the measured parameters as compared with placebo. Among 34 of the 92 pro- and antiinflammatory parameters investigated changes were observed between preoperative, 4 h or 24 h respectively, reflecting immune activation during surgical stress. CONCLUSION TXA administration in a low-dose regimen including bolus followed by 8h infusion during craniosynostosis surgery did not change any of 92 inflammatory markers as compared with placebo.
Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial
Fenger-Eriksen C, D'Amore Lindholm A, Norholt SE, von Oettingen G, Tarpgaard M, Krogh L, Juul N, Hvas AM, Rasmussen M
British journal of anaesthesia. 2019
BACKGROUND Tranexamic acid (TXA) reduces intraoperative blood loss and transfusion during paediatric craniosynostosis surgery. Additional reduction of postoperative blood loss may further reduce exposure to allogeneic blood products. We studied the effect of combined intra- and postoperative TXA treatment on postoperative blood loss in children. METHODS Thirty children admitted for craniosynostosis surgery were randomised to combined intra- and postoperative TXA treatment or placebo. The primary endpoint was postoperative blood loss. Secondary endpoints included total blood loss, transfusion requirements, and clot stability evaluated by tissue plasminogen activator-stimulated clot lysis assay. RESULTS TXA reduced postoperative blood loss by 18 ml kg(-1) (95% confidence interval 8.9) and total blood loss from a mean of (standard deviation [SD]; 20) ml kg(-1) to 28 (14) ml kg(-1) (P<0.001). Intraoperative red blood cell (RBC) and fresh frozen plasma (FFP) transfusions were reduced in the treatment group from RBC 14.0 (5.2) ml kg(-1) to 8.2 (5.1) ml kg(-1) (P=0.01) and from FFP 13.0 (6.3) ml kg(-1) to 7.8 (5.9) ml kg(-1) (P=0.03). Postoperative RBC transfusion median was 5 (inter-quartile range [IQR] 0-6) ml kg(-1) in the placebo group and 0 (0-5.7) ml kg(-1) in the TXA group. Resistance to lysis was higher in the treatment group (P<0.001). CONCLUSIONS Combined intra- and postoperative tranexamic acid treatment reduced postoperative and overall blood loss and transfusion requirements. Improved clot stability represents a possible mechanism for blood loss reduction.