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Hypercoagulability is an increasingly recognized complication of SARS-CoV-2 infection. As such, anticoagulation has become part and parcel of comprehensive COVID-19 management. However, several uncertainties exist in this area, including the appropriate type and dose of heparin. In addition, special patient populations, including those with high body mass index and renal impairment, require special consideration. Although the current evidence is still insufficient, we provide a pragmatic approach to anticoagulation in COVID-19, but stress the need for further trials in this area., (© 2020 International Society on Thrombosis and Haemostasis.)

Hypercoagulability can occur after severe tissue injury, that is likely related to tissue factor exposure and impaired endothelial release of tissue plasminogen activator (tPA). In contrast, when shock and hypoperfusion occur, activation of the protein C pathway and endothelial tPA release induce a shift from a procoagulant to a hypocoagulable and hyperfibrinolytic state with a high risk of bleeding. Both thrombotic and bleeding phenotypes are associated with increased mortality and are influenced by the extent and severity of tissue injury and degree of hemorrhagic shock. Response to trauma is a complex, dynamic process in which risk can shift from bleeding to thrombosis depending on the injury pattern, hemostatic treatment, individual responses, genetic predisposition, and comorbidities. Based on this body of knowledge, we will review and consider future directions for the management of severely injured trauma patients.

Background/objectives: Prothrombin complex concentrates (PCC) are increasingly administered off-label in the United States to treat bleeding in cardiovascular surgical patients and carry the potential risk for acquired thromboembolic side-effects after surgery. Therefore, we hypothesized that the use of low-dose 3-factor (3F) PCC (20-30 IU/kg), as part of a transfusion algorithm, reduces bleeding without increasing postoperative thrombotic/thromboembolic complications., Materials/methods: After IRB approval, we retrospectively analysed 114 consecutive, complex cardiovascular surgical patients (age > 18 years), between February 2014 and June 2015, that received low-dose 3F-PCC (Profilnine ® ), of which seven patients met established exclusion criteria. PCC was dosed according to an institutional perioperative algorithm. Allogeneic transfusions were recorded before and after PCC administration (n = 107). The incidence of postoperative thromboembolic events was determined within 30 days of surgery, and Factor II levels were measured in a subset of patients (n = 20) as a quality control measure to avoid excessive PCC dosing., Results: Total allogeneic blood product transfusion reached a mean of 12·4 ± 9·9 units before PCC and 5·0 ± 6·3 units after PCC administration (P < 0·001). The mean PCC dose was 15·8 ± 7·1 IU/kg. Four patients (3·8%) each experienced an ischaemic stroke on postoperative day 1, 2, 4 and 27. Seven patients (6·5%) had acquired venous thromboembolic disease within 10 days of surgery. Median factor II level after transfusion algorithm adherence and PCC administration was 87%., Conclusions: 3F-PCC use for refractory bleeding after cardiovascular surgery resulted in reduced transfusion of allogeneic blood and blood products. Adherence to this algorithmic approach was associated with an acceptable incidence of postoperative thrombotic/thromboembolic complications., (© 2019 International Society of Blood Transfusion.)

Background: Retrospective studies suggested that storage age of RBCs is associated with inflammation and thromboembolism. The Red Cell Storage Duration Study (RECESS) trial randomized subjects undergoing complex cardiac surgery to receive RBCs stored for shorter versus longer periods, and no difference was seen in the primary outcome of change in multiple organ dysfunction score., Study Design and Methods: In the current study, 90 subjects from the RECESS trial were studied intensively using a range of hemostasis, immunologic, and nitric oxide parameters. Samples were collected before transfusion and on Days 2, 6, 28, and 180 after transfusion., Results: Of 71 parameters tested, only 4 showed a significant difference after transfusion between study arms: CD8+ T-cell interferon-γ secretion and the concentration of extracellular vesicles bearing the B-cell marker CD19 were higher, and plasma endothelial growth factor levels were lower in recipients of fresh versus aged RBCs. Plasma interleukin-6 was higher at Day 2 and lower at Days 6 and 28 in recipients of fresh versus aged RBCs. Multiple parameters showed significant modulation after surgery and transfusion. Most analytes that changed after surgery did not differ based on transfusion status. Several extracellular vesicle markers, including two associated with platelets (CD41a and CD62P), decreased in transfused patients more than in those who underwent surgery without transfusion., Conclusions: Transfusion of fresh versus aged RBCs does not result in substantial changes in hemostasis, immune, or nitric oxide parameters. It is possible that transfusion modulates the level of platelet-derived extracellular vesicles, which will require study of patients randomly assigned to receipt of transfusion to define., (© 2019 AABB.)

The non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban, and rivaroxaban, which inhibit coagulation factor Xa. Although clinical studies of NOACs were conducted without antidotes, patient outcomes with major bleeding when receiving NOACs were no worse than those in patients treated with a vitamin K antagonist. Nonetheless, in patients with life-threatening bleeding or requiring urgent surgery, the capacity for rapid NOAC reversal is likely to increase patient safety. Three NOAC reversal agents are in various stages of development: idarucizumab, a specific reversal agent for dabigatran; andexanet alfa, which reverses factor Xa inhibitors; and ciraparantag, which is purported to reverse all NOACs. Idarucizumab is licensed in many countries, andexanet is under consideration by regulatory agencies, and ciraparantag is undergoing phase III evaluation. In the absence of licensed reversal agents for the oral factor Xa inhibitors, prothrombin complex concentrates are often used in patients taking these agents who present with life-threatening bleeding. In this Review, we summarize the approved indications for the NOACs, outline how to measure their anticoagulant effects, describe the mechanism of action of the reversal strategies, assess the preclinical and clinical data supporting their use, provide guidance on potential indications for reversal, and offer a management approach for patients treated with NOACs who present with serious bleeding or require urgent surgery.

Prothrombin complex concentrates (PCCs) contain vitamin K-dependent clotting factors (II, VII, IX, and X) and are marketed as 3 or 4 factor-PCC formulations depending on the concentrations of factor VII. PCCs rapidly restore deficient coagulation factor concentrations to achieve hemostasis, but like with all procoagulants, the effect is balanced against thromboembolic risk. The latter is dependent on both the dose of PCCs and the individual patient prothrombotic predisposition. PCCs are approved by the US Food and Drug Administration for the reversal of vitamin K antagonists in the setting of coagulopathy or bleeding and, therefore, can be administered when urgent surgery is required in patients taking warfarin. However, there is growing experience with the off-label use of PCCs to treat patients with surgical coagulopathic bleeding. Despite their increasing use, there are limited prospective data related to the safety, efficacy, and dosing of PCCs for this indication. PCC administration in the perioperative setting may be tailored to the individual patient based on the laboratory and clinical variables, including point-of-care coagulation testing, to balance hemostatic benefits while minimizing the prothrombotic risk. Importantly, in patients with perioperative bleeding, other considerations should include treating additional sources of coagulopathy such as hypofibrinogenemia, thrombocytopenia, and platelet disorders or surgical sources of bleeding. Thromboembolic risk from excessive PCC dosing may be present well into the postoperative period after hemostasis is achieved owing to the relatively long half-life of prothrombin (factor II, 60-72 hours). The integration of PCCs into comprehensive perioperative coagulation treatment algorithms for refractory bleeding is increasingly reported, but further studies are needed to better evaluate the safe and effective administration of these factor concentrates.

Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.

Idarucizumab, a Fab fragment directed against dabigatran, produced rapid and complete reversal of the anticoagulation effect of dabigatran in animals and in healthy volunteers. The Study of the REVERSal Effects of Idarucizumab in Patients on Active Dabigatran (RE-VERSE AD™) is a global phase 3 prospective cohort study aimed at investigating idarucizumab in dabigatran-treated patients who present with uncontrollable or life-threatening bleeding, and in those requiring urgent surgery or intervention. We describe the rationale for, and design of the trial (clinicaltrials.gov NCT02104947).

The use of extracorporeal circulation requires anticoagulation to maintain blood fluidity throughout the circuit, and to prevent thrombotic complications. Additionally, adequate suppression of hemostatic activation avoids the unnecessary consumption of coagulation factors caused by the contact of blood with foreign surfaces. Cardiopulmonary bypass represents the greatest challenge in this regard, necessitating profound levels of anticoagulation during its conduct, but also quick, efficient reversal of this state once the surgical procedure is completed. Although extracorporeal circulation has been around for more than half a century, many questions remain regarding how to best achieve anticoagulation for it. Although unfractionated heparin is the predominant agent used for cardiopulmonary bypass, the amount required and how best to monitor its effects are still unresolved. This review discusses the use of heparin, novel anticoagulants, and the monitoring of anticoagulation during the conduct of cardiopulmonary bypass., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Total thrombus formation velocity calculated using amplitude parameters obtained at different times could be used to estimate the amplification and the propagation phases observed during coagulation processes, and therefore might be useful to predict postoperative hemostatic products administration in pediatric patients., Methods: We retrospectively analyzed data from 49 children <3 months of age who underwent cardiac surgery. Children ≤1 month of age routinely received fresh frozen plasma during bypass while children >1 month of age did not. The EXTEM parameters were used to calculate velocity curves using amplitudes obtained at different times, the area under the curve called total thrombus formation and the maximum rate of thrombus formation. These parameters were compared between children who received fresh frozen plasma and those who did not. Receiver operating characteristics curves were used to define variables that could be used to predict postoperative fresh frozen plasma transfusion., Results: Total thrombus formation and maximum rate of thrombus formation significantly increased in children who received fresh frozen plasma compared to those who did not. Both total thrombus formation and maximum rate of thrombus formation have a better specificity to predict postoperative fresh frozen plasma transfusion compared to clotting time or maximal clot firmness., Conclusion: Based on this descriptive study, dynamic ROTEM(®) parameters of total thrombus formation could be used to estimate the amplification and the propagation phases of coagulation in children. These parameters might be used in further well-designed study to predict the need for hemostatic products in children undergoing cardiac surgery with cardiopulmonary bypass., (© 2015 John Wiley & Sons Ltd.)

Direct oral anticoagulants (DOACs) are approved for multiple thromboembolic disorders and provide advantages over existing agents. As with all anticoagulants, management protocols for the eventuality of bleeding are important. Randomized phase III studies generally show that DOACs have a similar risk of clinically relevant bleeding compared with standard anticoagulants, with reductions in major bleeding in some cases. This may be particularly important in patients with atrial fibrillation, for whom the rate of intracranial hemorrhage was approximately halved with DOACs compared with warfarin. Conversely, the risk of gastrointestinal bleeding may be increased. Specific patient characteristics, such as renal impairment, comedications, and particular aspects of each drug, including the proportion eliminated by the kidneys, must be taken into account when assessing the risk of bleeding. Although routine coagulation monitoring of DOACs is not required, it may be useful under some circumstances. Of the traditional clotting assays, a sensitive and calibrated prothrombin time may be useful for detecting the presence or absence of clinically relevant factor Xa inhibitor concentrations (rivaroxaban or apixaban), but specific anti-factor Xa assays can measure drug levels quantitatively. For dabigatran, the results of an activated partial thromboplastin time test may exclude a clinically relevant pharmacodynamic effect, but a calibrated dilute thrombin time assay can be used for quantification of drug levels. In the event of mild or moderate bleeding, normal hemostatic support measures are recommended. For life-threatening bleeding, use of nonspecific prohemostatic agents may be considered, although clinical evidence is scarce. Specific antidotes are in development., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Hereditary angioedema (HAE) is a rare, autosomal dominant disease in which C1 esterase inhibitor (C1 INH) is deficient or dysfunctional. Package inserts for nanofiltered C1 esterase inhibitor (C1 INH-nf) products contain warnings about thrombotic events. The objective of this study was to evaluate the effect of C1 INH-nf on hemostatic activation, clot formation, and thrombin generation. Ten healthy volunteers provided blood samples for thromboelastometry using the ROTEM system. Platelet-poor samples were prepared for thrombin generation studies. C1 INH-nf was added to samples at final concentrations of 0.14, 0.7, 1.4, 2.8, and 7.0 U/ml. Recombinant factor VIIa and prothrombin complex concentrate were used as procoagulant controls, and antithrombin and desirudin were used as anticoagulant controls. C1 INH-nf had no procoagulant effect on hemostasis based on thromboelastometry, regardless of the final concentration or activating reagent used (P > 0.05 for all comparisons of C1 INH-nf versus negative control). C1 INH-nf 2.8 and 7.0 U/ml concentrations had a statistically significant anticoagulant effect on maximum clot firmness (P < 0.05 for all comparisons of C1 INH-nf versus negative control), with a magnitude similar to that observed with desirudin. C1 INH-nf had no effect on thrombin generation lag time, peak thrombin generation, or thrombin generation rate, regardless of the final concentration or activating reagent used (P < 0.05 for all comparisons of C1 INH-nf versus negative controls). We found no evidence of a procoagulant effect of C1 INH-nf when studied ex vivo at concentrations up to 10-fold higher than those achieved with clinical dosing in patients with HAE.

Introduction: Prasugrel is a thienopyridyl P2Y12 antagonist with potent antiplatelet effects. At present, little is known about its effects on thrombin generation or what strategies may emergently reverse its anticoagulant effects. In the current study we evaluated whether recombinant activated factor VII may reverse prasugrel induced effects and increase thrombin generation in an in vitro model., Methods: The effect of prasugrel active metabolite, PAM (R-138727), was evaluated on platelet aggregation, thrombin generation, and rotational thromboelastometry parameters using blood from 20 healthy volunteers. Additionally, we evaluated the effects of adenosine diphosphate (ADP) and recombinant activated factor VII on restoring these parameters towards baseline values., Results: PAM reduced maximum platelet aggregation and led to platelet disaggregation. It also decreased peak thrombin, increased lag time, and increased time to peak thrombin. Treatment with recombinant activated factor VII restored all three parameters of thrombin generation towards baseline. ADP decreased lag time and time to peak thrombin, but had no effect on peak thrombin. When recombinant activated factor VII and ADP were combined they had a greater effect on thrombin parameters than either drug alone. PAM also increased thromboelastometric clotting time and clot formation time, but had no effect on maximum clot firmness. Treatment with either recombinant activated factor VII or ADP restored these values towards baseline., Conclusions: Recombinant activated factor VII restores thrombin generation in the presence of PAM. In patients taking prasugrel with life-threatening refractory bleeding it has the potential to be a useful therapeutic approach. Additional clinical studies are needed to validate our findings., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Severe trauma is associated with bleeding, coagulopathy, and transfusion of blood and blood products, all contributing to higher rates of morbidity and mortality. The aim of this review is to focus on point-of-care devices to monitor coagulation in trauma. Close monitoring of bleeding and coagulation as well as platelet function in trauma patients allows goal-directed transfusion and an optimization of the patient's coagulation, reduces the exposure to blood products, reduces costs, and probably improves clinical outcome. Noninvasive hemoglobin measurements are not to be used in trauma patients due to a lack in specificity and sensitivity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose of Review: Coagulopathy in an ICU setting is multifactorial, but newer anticoagulation agents are the potentially contributing causes. Critically ill patients may suffer from disorders because of surgery or trauma, in addition to acquired causes including antiplatelet agents and the new oral anticoagulants. An understanding of the coagulopathy, hemostatic considerations, and therapeutic approaches is important when managing these patients., Recent Findings: All anticoagulation agents may contribute to coagulopathy in critically ill patients. Options for management include hemodialysis, transfusion of blood products, and prohemostatic drugs. Recombinant and purified coagulation therapies are also now available in most countries that provide clinicians with specific agents to treat targeted deficiencies., Summary: Coagulopathy occurs in ICU patients because of multiple factors including anticoagulants, dilution, fibrinolysis, and factor consumption. Therapeutic prohemostatic pharmacologic approaches, in addition to standard transfusion therapy, need to be considered in managing coagulopathy in the ICU setting.

Background: The activated clotting time (ACT) is widely used for monitoring heparin anticoagulation during cardiac surgery. Celite-based ACT values are prolonged when aprotinin is administered. MDCO-2010, a novel serine protease inhibitor, is currently being evaluated as a possible alternative to aprotinin. Therefore, we evaluated the in vitro effects of this novel agent on ACT values using 3 different point-of-care instruments with kaolin or celite as an activator., Methods: The study was performed in 2 parts. In the first part, blood samples were obtained from 15 healthy volunteers. Samples were pipetted into small Eppendorf tubes and 2 concentrations of the MDCO-2010 (100 and 500 nM, final concentration) alone or with heparin (1.2 or 2.4 U/mL) were added. ACTs were measured using Helena (celite), Hemochron (kaolin), and Medtronic (kaolin) devices. In the second part of the study, blood samples were obtained intraoperatively, at 5 time points, from 15 patients undergoing cardiopulmonary bypass. MDCO-2010 at a final concentration of 100 or 500 nM was added and ACT testing was performed as before. Additional coagulation tests included prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin, prothrombin, and anti-Xa levels., Results: Addition of MDCO-2010 concentration-dependently prolonged ACTs in volunteers' and patients' blood samples regardless of the ACT activator or device used. In volunteer samples (no heparin) and in patient samples (baseline and intensive care unit) percent changes in ACTs due to MDCO-2010 were on average 3.1 ± 1.8 times higher (95% confidence interval 2.6-3.6; P < 0.001) for the celite-based Helena device compared with either Hemochron or Medtronic devices., Conclusion: MDCO-2010 causes less ACT prolongation with kaolin than with celite activation.

Background: Coagulopathy after cardiopulmonary bypass (CPB) is caused by multiple perturbations in cellular and humoral elements of coagulation. A timely and comprehensive method to evaluate hemostasis would be helpful in the management of bleeding patients after CPB. The assessment of whole blood coagulation using rotation thromboelastometry (ROTEM) was compared to coagulation tests routinely performed during cardiac surgery., Study Design and Methods: Blood was obtained from 26 patients undergoing CPB surgery at baseline, at 60 minutes on CPB, at the end of CPB, and on admission to intensive care unit. ROTEM tests (extrinsically activated [EXTEM], intrinsically activated [INTEM], specific clot formation [FIBTEM]), prothrombin time, activated partial thromboplastin time, platelet (PLT) count, fibrinogen, prothrombin level, antithrombin level, and thrombin generation (TG) measurement were performed., Results: We observed strong correlations between FIBTEM-amplitude at 10 minutes (A10) and fibrinogen level (r=0.87; p<0.001) and between EXTEM/ INTEM-A10 variables and PLT count (r=0.72 and 0.67, respectively; p<0.001). Receiver operating characteristic analysis demonstrated that EXTEM-A10 and INTEM-A10 are predictive of thrombocytopenia below 80×10(9)/L (area under the curve [AUC], 0.83 and 0.82, respectively), and FIBTEM-A10 was highly predictive of fibrinogen level below 200 mg/dL (AUC, 0.96). There were only weak correlations found between TG peak and clot formation time of EXTEM or INTEM (r=0.30 and 0.29, respectively; p<0.05)., Conclusion: ROTEM variables demonstrated clinically relevant correlations with PLT counts and fibrinogen levels. In particular, decreasing levels of fibrinogen can be quickly determined (<15-20 min) using FIBTEM., (© 2011 American Association of Blood Banks.)

Objective: The authors hypothesized that various hemostatic products may differently affect viscoelastic clot formation depending on their respective procoagulant activity and fibrinogen content., Design: In vitro coagulopathy modeling using warfarin-treated plasma (international normalized ratio, 2.8-3.8) and fibrinogen-deficient plasma evaluated by rotational thromboelastometry (ROTEM; Pentapharm, Munich, Germany)., Setting: A university laboratory., Intervention: Different volumes of cryoprecipitate, fresh frozen plasma (FFP), fibrinogen concentrate, and platelet concentrate were mixed with each abnormal plasma to simulate the in vivo transfusions of 250 mL to 1,000 mL. Three thromboelastometric variables that reflect the rate and extent of clot growth were measured: (1) coagulation time (CT), (2) angle, and (3) maximal clot firmness (MCF)., Measurements and Main Results: In warfarin-treated plasma, the addition of FFP, cryoprecipitate, and platelets led to a dose-dependent improvement of CT and angle, whereas MCF increased with cryoprecipitate or platelets only. The addition of fibrinogen concentrate improved MCF and angle but not CT. In fibrinogen-deficient plasma, the addition of cryoprecipitate, platelets, and fibrinogen concentrate led to a dose-dependent improvement of ROTEM variables, whereas the addition of FFP resulted in significantly longer CT and lower MCF values compared with other hemostatic products. The addition of platelets in the presence of cytochalasin D (a platelet inhibitor) resulted in improvements of ROTEM variables that were similar to when FFP was added to warfarin-treated and fibrinogen-deficient plasma., Conclusions: Cryoprecipitate supports clot formation on ROTEM more efficiently than FFP because of the high fibrinogen content. Improved ROTEM variables after platelet addition are presumably caused by increased interaction among thrombin-activated platelets and fibrinogen., (Copyright 2010 Elsevier Inc. All rights reserved.)

Perioperative bleeding is a major challenge particularly because of increasing clinical use of potent antithrombotic drugs. Understanding current concepts of coagulation is important in determining the preoperative bleeding risk of patients, and in managing hemostatic therapy perioperatively. The serine protease thrombin plays pivotal roles in the activation of additional serine protease zymogens (inactive enzymatic precursors), cofactors, and cell-surface receptors. Thrombin generation is closely regulated to locally achieve rapid hemostasis after injury without causing uncontrolled systemic thrombosis. During surgery, there are major disturbances in coagulation and inflammatory systems because of hemorrhage/hemodilution, blood transfusion, and surgical stresses. Postoperative bleeding often requires allogeneic blood transfusions, which support thrombin generation and hemostasis. However, procoagulant activity and inflammation are increased postoperatively; thus, antithrombotic therapy may be required to prevent perioperative thrombotic complications. There have been significant advances in the management of perioperative hemostasis and thrombosis because of the introduction of novel hemostatic and antithrombotic drugs. However, a limitation of current treatment is that conventional clotting tests do not reflect the entire physiological processes of coagulation making optimal pharmacologic therapy difficult. Understanding the in vivo regulatory mechanisms and pharmacologic modulation of thrombin generation may help control bleeding without potentially increasing prothrombotic risks. In this review, we focus on the regulatory mechanisms of hemostasis and thrombin generation using multiple, simplified models of coagulation.

Despite improvements in surgical techniques, the risk for perioperative bleeding remains significant. Transfusion of allogeneic red blood cells, platelets, and hemostatic factors remains the mainstay of current therapy strategy for management of perioperative bleeding. Transfusions significantly contribute to perioperative adverse events. Pharmacologic strategies to prevent or decrease perioperative bleeding are also important therapeutic approaches to reduce the need for allogeneic transfusions. This article discusses systemic pharmacologic prohemostatic agents (aprotinin, lysine analogues, protamine, desmopressin, and recombinant factor VIIa).

Background: Antithrombin (AT) levels decrease during cardiopulmonary bypass (CPB), particularly when combined with deep hypothermic circulatory arrest (DHCA). Low AT levels might lead to imbalance of pro- and anticoagulant factors promoting systemic thrombotic events. We hypothesized that low levels of AT might lead to increased in vitro thrombin generation when procoagulant factors are added to the patient's plasma after CPB., Methods: Blood samples were obtained before heparinization and after separation from CPB from five patients undergoing cardiac surgery with DHCA. AT levels were determined by chromogenic assay and expressed as a percent of normal activity. The balance between procoagulant and anticoagulant elements was manipulated in the patients' plasma by adding normal donor plasma, AT-deficient plasma, or purified AT. The Thrombinoscope system was used to evaluate thrombin generation with and without AT supplementation., Results: AT levels (median, range) were 82.0% (71.0, 109) and 37.0% (34.0, 41.0) of normal before and after separation from CPB, respectively (P < 0.05). Peak thrombin generation (median, range) was 56.6 nM (42.1, 61.0) in plasma after CPB, and it remained at 61.1 nM (54.9, 64.5) when a donor plasma with normal AT (105%) was added. When AT-deficient plasma was added to the patient's plasma, peak thrombin generation (median, range) was increased from 56.6 nM (42.0, 61.0) to 117 nM (95.0, 188) (P < 0.05 versus control). After the addition of purified AT, the peak thrombin generation was reduced to 12.2 nM (9.0, 29.3) (P < 0.05 versus control)., Conclusion: Plasma AT activity is severely decreased after CPB with DHCA. Our data suggest that the administration of coagulation factor components without AT repletion may lead to excessive thrombin generation, which clinically, may potentially lead to a hypercoagulable state.

Purpose: The authors analyzed the coagulation data of patients who underwent on-pump coronary artery bypass graft (CABG) or off-pump coronary artery bypass surgery (OPCAB) in a randomized prospective trial., Methods: CABG and OPCAB patients received heparin anticoagulation at 400 U x kg(-1), and 180 U x kg(-1) plus 3000 U every 30 min, respectively. In addition, OPCAB patients received a rectal aspirin, 650 mg, during the procedure. Perioperative coagulation test results (platelet count, fibrinogen, prothrombin time, partial thromboplastin time [PTT], activated clotting time [ACT], and thromboelastography [TEG; Haemoscope] were collected from CABG (n = 99) and OPCAB (n = 98) patients. Residual heparin activity after protamine was measured, using an anti-activated factor X (Xa) assay, in 10 patients from each group., Results: Our study showed that the current anticoagulation regimen in the OPCAB patients achieved a peak ACT of 445 +/- 73 s, and it preserved platelet counts and fibrinogen levels. A residual heparin effect was detected, with residual anti-Xa heparin activity of 0.2 U x ml(-1) up to 2 h after surgery in the OPCAB group. Despite the residual anticoagulation, the OPCAB group had a similar TEG index of native blood, postoperative chest tube drainage, and non-erythrocyte transfusion rate as compared with the CABG group., Conclusion: We have shown that the heparin anticoagulation regimen in OPCAB patients does not lead to an immediate hypercoagulable state. Total doses of heparin and protamine were lower in the OPCAB group compared with the CABG group, and there was a residual heparin effect on TEG and PTT in the early postoperative period in the OPCAB group.

Heparin is the current mainstay drug for anticoagulation during cardiac surgery, but it requires normal levels of antithrombin (AT) for optimal anticoagulation. Heparin anticoagulation may be less effective in cardiac surgical patients because of decreased AT levels due to the prolonged heparin therapy. Therefore, other anticoagulants that would work well in AT deficient patients may be more desirable. One such agent currently being evaluated is Intimatan, which catalyzes heparin cofactor II (HCII) dependent inhibition of thrombin. In the current in vitro study we examined the effects of Intimatan (20 microg/ml), heparin (0.25 U/ml), or both drugs in combination on thrombin generation in plasma with decreasing levels of AT, HCII or both cofactors, using a novel method based on the continuous measurement of thrombin generation. For the study, we collected blood samples from healthy volunteers, isolated platelet poor plasma by centrifugation and mixed it with AT, HCII, or AT-HCII deficient plasma samples to achieve different levels of AT, HCII and AT-HCII. Thrombin generation was inhibited equally well with heparin or Intimatan when the level of their respective cofactors was within the normal range. With decreasing levels of AT or HCII, heparin and Intimatan became less effective in thrombin inhibition, respectively. With the absence of both cofactors, neither agent alone or in combination had any effect on thrombin generation. We conclude that Intimatan may be an effective adjunct to heparin therapy under low AT conditions.

This study in vitro comprehensively assessed reversal of the anticoagulant effects of rivaroxaban, an oral factor Xa inhibitor, using andexanet alfa and various prothrombin complex concentrate (PCC) products in a battery of tests. In static coagulation assays, andexanet alpha outperformed PCCs except for activated PCC being more effective in standard coagulation times. However, in a flow chamber model mimicking arterial shear, both andexanet alpha and high-concentration PCC restored fibrin formation, but not platelet adhesion. In the Russell's viper venom test and anti-Xa assay, only andexanet alpha could be tested for efficacy. The antidote effects of andexanet alpha and PCCs in restoring coagulation can be qualitatively or selectively demonstrated using in vitro coagulation tests. [ABSTRACT FROM AUTHOR]

This document is a comment on an article about sepsis-induced coagulopathy. The authors discuss the role of fibrinogen, an acute-phase protein, in sepsis. While elevated fibrinogen levels in sepsis patients can contribute to immunothrombosis and enhance immune responses, they can also lead to a hypercoagulable state and disseminated intravascular coagulation (DIC). The authors highlight the challenges in interpreting fibrinogen levels and platelet count in sepsis-induced DIC and emphasize the importance of monitoring hemostasis markers for effective diagnosis and treatment. [Extracted from the article]

Background: The number of heatstroke victims hit record numbers in 2022 as global warming continues. In heat-induced injuries, circulatory shock is the most severe and deadly complication. This review aims to examine the mechanisms and potential approaches to heat-induced shock and the life-threatening complications of heatstroke. Methods: A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning heatstroke, shock, inflammation, coagulopathy, endothelial cell, cell death, and heat shock proteins. Results: Dehydration and heat-induced cardiomyopathy were reported as the major causes of heat-induced shock, although other heat-induced injuries are also involved in the pathogenesis of circulatory shock. In addition to dehydration, the blood volume decreases considerably due to the increased vascular permeability as a consequence of endothelial damage. Systemic inflammation is induced by factors that include elevated cytokine and chemokine levels, dysregulated coagulation/fibrinolytic responses, and the release of damage-associated molecular patterns (DAMPs) from necrotic cell death that cause distributive shock. The cytoprotective heat shock proteins can also facilitate circulatory disturbance under excess heat stress. Conclusions: Multiple mechanisms are involved in the pathogenesis of heat-induced shock. In addition to dehydration, heat stress-induced cardiomyopathy due to the thermal damage of mitochondria, upregulated inflammation via damage-associated molecular patterns released from oncotic cells, unbalanced coagulation/fibrinolysis, and endothelial damage are the major factors that are related to circulatory shock. [ABSTRACT FROM AUTHOR]

It is generally accepted that a coagulation/fibrinolysis disorder is involved in the pathogenesis of sepsis, and the association of disseminated intravascular coagulation (DIC) and poor outcomes have been reported. Based on these findings, recently released "Japanese Surviving Sepsis Campaign guidelines 2020" recommend the diagnosis of DIC and the application of anticoagulants for sepsis-associated DIC. Meanwhile, the updated "International Guidelines for the Management of Sepsis and Septic Shock 2021" did not mention coagulation abnormalities or DIC. Because management strategies continue to evolve to provide improved outcomes in sepsis, the role of adjunctive anticoagulant treatment should be included in subsequent international guidelines. [ABSTRACT FROM AUTHOR]

Disseminated intravascular coagulation (DIC) has been recognized as a deadly complication in sepsis, and its early recognition followed by appropriate management of the underlying infection are the current management strategies. The activation of coagulation, inflammation, and other pathways are fundamental host responses against infection but also produce injury to the host. Recent advances have helped define the critical roles of thrombus formation in overcoming infection. In addition to activation of coagulation induced by pathogens, other important pathways including damage-associated molecular patterns, neutrophil extracellular traps, extracellular vesicles, and glycocalyx damage are involved in the pathogenesis of sepsis-induced DIC. The hallmark of DIC is thrombosis in the microvasculature; however, sepsis-induced DIC is a laboratory diagnosis based on coagulation test results and clinical setting. Although simplified criteria were recently introduced, DIC should be distinguished from other similar conditions such as thrombotic microangiopathy and heparin-induced thrombocytopenia. In DIC, treating the underlying cause is crucial, and additional adjunct therapies including antithrombin, thrombomodulin, and heparins may have potential benefit, but evidence supporting their use in terms of improvement of clinically relevant outcomes continues to be debated. In this review, we introduce recent findings regarding the pathophysiology, diagnosis, and treatment of sepsis-induced DIC. In addition, we also discuss future potential therapeutic approaches regarding this complex, life-threatening complication. [ABSTRACT FROM AUTHOR]

Dabigatran is effective in decreasing the risk of ischaemic stroke in patients with atrial fibrillation. However, like all anticoagulants, it is associated with a risk of bleeding. In cases of trauma or emergency surgery, emergency reversal of dabigatran-induced anticoagulation may be required. A specific reversal agent for dabigatran, idarucizumab, has been approved by the US Food and Drug Administration. Alternative reversal agents are available, such as prothrombin complex concentrates (PCCs) and activated PCCs (aPCCs). In this review we evaluate the role of PCCs and aPCCs in the reversal of dabigatran anticoagulation and consider which tests are appropriate for monitoring coagulation in this setting. Pre-clinical studies, small clinical studies and case reports indicate that PCCs and aPCCs may be able to reverse dabigatran-induced anticoagulation in a dose-dependent manner. However, dosing based on coagulation parameters can be difficult because available assays may not provide adequate sensitivity and specificity for measuring anticoagulation induced by dabigatran or the countering effects of PCCs/aPCCs. In addition, PCCs or aPCCs can potentially provoke thromboembolic complications. Despite these limitations and the fact that PCCs and aPCCs are not yet licensed for dabigatran reversal, their use appears to be warranted in patients with life-threatening haemorrhage if idarucizumab is not available. [ABSTRACT FROM AUTHOR]

The article explores the well-known therapies and novel oral anticoagulants (OA) for the prevention of venous thromboembolism (VTE) in the perioperative and postoperative management of surgical patients. These new anticoagulants are believed to have the potential to enhance the efficacy, safety and ease of administration, and do not require routine coagulation monitoring. The most improved OA, like the direct factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran etexilate, were tested in the postoperative setting in patients undergoing surgery for total hip- or knee-replacement with encouraging results.

Thrombin plays a central role in coagulation and haemostasis. Binding of thrombin to thrombomodulin generates activated protein C (APC), which exerts a negative feedback on thrombin formation. Aprotinin, a natural proteinase inhibitor is used extensively during cardiac surgery because this procedure is often associated with profound activation of coagulation and inflammatory pathways. Some in vitro evidences suggest that aprotinin inhibits APC, but the clinical relevance is unclear. The recombinant human soluble thrombomodulin (rhsTM)-modified thrombin generation (TG) assay was used to investigate the effects of aprotinin on APC in plasma samples obtained from healthy volunteers, aprotinin-treated cardiac surgical patients and in protein C (PC)-depleted plasma. Based on the results of in vitro TG assay, addition of rhsTM (0·75–3·0 μg/ml) to volunteer or patient platelet-poor plasma significantly reduced (70·8 ± 21·9 and 95·3% ± 4·6%, respectively) thrombin formation when compared with PC-depleted plasma (8·3% ± 5·2%). Aprotinin (100–200 KIU) caused a small, statistically insignificant decrease in the peak thrombin formation in normal and PC-deficient plasma (12·0 ± 6·1%). In cardiac surgical patients, levels of functional PC, factor II, antithrombin and platelet significantly decreased after cardiopulmonary bypass (CPB). Soluble thrombomodulin concentrations were increased after CPB (3·5 ± 2·2 to 5·0 ± 2·2 ng/ml), but they were still within the normal range for human plasma. Our results showed that, even though endogenous PC level is decreased after CPB, it retains its activity in the presence of thrombomodulin, and aprotinin has limited inhibitory effect on APC generation. [ABSTRACT FROM AUTHOR]

The author comments on a study on the use of tranexamic acid in trauma patients, published within the issue. He provides an overview of the study, which found that tranexamic acid reduces mortality. He argues that the study failed to show an antifibrinolytic effect of tranexamic. The author also claims that the study is a relevant example of the associations between coagulation, fibrinolysis, inflammation and clinical outcomes following tissue injury.

Anticoagulant therapy is challenging to modern surgical practice because it complicates risks of bleeding and the need for allogeneic blood transfusions. In an aging population, there is extensive use of antiplatelet agents, and patients present for operations receiving these agents. Hemostatic inhibitors are reviewed here, including anticoagulants, platelet inhibitors (clopidogrel), low-molecular-weight heparins, pentasaccharide (fondaparinux), and other factor Xa inhibitors. Agents used to manage bleeding, including aprotinin, lysine analogs, desmopressin, and recombinant factor VIIa, are discussed. [Copyright &y& Elsevier]

The diagnostic criteria of overt disseminated intravascular coagulation (DIC) were established by the International Society on Thrombosis and Haemostasis (ISTH) in 2001. Since then, DIC has long been associated with adverse outcomes. However, recent advances in sepsis shed light on the role of coagulation disorders in the progression of sepsis. Currently, inflammation and coagulation are recognized as the two drivers that promote organ dysfunction in sepsis and septic shock. The ISTH has published new diagnostic criteria for improved management, namely sepsis-induced coagulopathy (SIC), in 2017. SIC is a pragmatic scoring system composed of platelet count, prothrombin time, and organ dysfunction score to detect the early-stage of sepsis-associated DIC. Since overt DIC represents an uncompensated coagulation disorder, a two-step approach using SIC and overt DIC criteria is a novel strategy to evaluate the severity and manage this challenging complication. Although there is no globally agreed on anticoagulant therapy for DIC, the Japanese Surviving Sepsis Campaign Guidelines 2020 recommend using antithrombin and recombinant thrombomodulin for sepsis associated DIC. Since research in this area has been previously reported, an international collaborative study is necessary to develop future diagnostic tools and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran.Methods: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures.Results: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals.Conclusions: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .). [ABSTRACT FROM AUTHOR]

Background: DX-88 is a potent kallikrein inhibitor that is being studied for the treatment of hereditary angioedema (HAE) and represents a potential alternative to aprotinin in cardiac surgical patients. The current study was designed to evaluate in vitro effects of DX-88 on coagulation in comparison with aprotinin. Methods: Blood samples were obtained from consented 12 healthy volunteers. DX-88 or aprotinin was added to blood at 200 and 800 kallikrein inhibitory units (KIU) per milliliter for aprotinin, and at 1.1, 2.2, or 8.8 μg/ml for DX-88. Thromboelastography (TEG®) was performed using celite, kaolin, or tissue factor (TF) activation. Kaolin-based activated clotting times (ACTs) were measured at different heparin levels. The whole blood prothrombin time (PT)/PTT values were also measured. The endogenous thrombin generation was assessed with a fluorogenic assay using platelet-poor plasma (PPP). Results: With celite and kaolin activation of TEG, the reaction time was prolonged with DX-88 and aprotinin. With tissue factor activation, TEG parameters were not affected. DX-88 caused dose-dependent kaolin-ACT prolongation that was augmented by increasing doses of heparin. DX-88 or aprotinin had no significant effects on the PT values, but PTT values were dose-dependently prolonged. Both agents delayed the onset of thrombin generation when PTT reagent was used as a trigger, whereas no change was observed when tissue factor was used. Conclusion; We found that DX-88 delayed contact activator induced coagulation without affecting tissue factor mediated coagulation. For evaluation of coagulation during DX-88 therapy, the use of PT or tissue factor-activated TEG may be preferable. [Copyright &y& Elsevier]