key: cord-0827254-t0e6xp5d
authors: Fabbro, Michael; Patel, Prakash A.; Henderson, Reney A; Bolliger, Daniel; Tanaka, Kenichi A.; Mazzeffi, Michael A.
title: Coagulation and Transfusion Updates from 2021
date: 2022-04-06
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2022.03.042
sha: 801021b9c8a95b1b0824f67f286daad3e2ad8343
doc_id: 827254
cord_uid: t0e6xp5d

2021 and the COVID 19 pandemic have brought unprecedented blood shortages worldwide. These deficits have propelled national efforts to reduce blood usage, including limiting elective services and accelerating Patient Blood Management (PBM) initiatives. A host of research dedicated to blood usage and management within cardiac surgery has continued to emerge. The intent of this review is to highlight this past year's research pertaining to Patient Blood Management and COVID-19 related coagulation changes.

their respective guidelines. 2, 3 In 2021 a strong endorsement statement for following PBM guidelines was put forth by the ASA PBM Committee in light of pandemic driven blood deficits. 4 A recent survey published by the Society for Cardiothoracic Anesthesiologists (SCA) members in Anesthesia and Analgesia highlighted new widespread implementation of these recommendations. 5 As high utilizers of blood products, cardiac anesthesiologists are at the forefront of blood conservation measures. There are many components to PBM and updates on important topics within PBM will be highlighted in this review. COVID-19 related updates will also be highlighted.

At present time, point-of-care testing for coagulation is highly recommended in all PBM [hPa] for Quantra ® , and dynes/cm 2 converted to hPa for TEG ® 5000). 6 Notably, only a single channel kaolin test was used on TEG ® , and no other tests such as functional fibrinogen and rapidTEG ® were included. Despite these limitations, their study provided clinically pertinent information in terms of data exchangeability and application. First, clotting time values were recorded within 5 minutes on Quantra ® , 12 minutes earlier than kaolin TEG ® reaction time. Whole blood clot strengths between the two devices overall correlated well (r=0. 84 ), but TEG ® clot strength (in hPa) was numerically lower than that of Quantra ® . The authors also compared TEG ® clot strength with platelet-specific and fibrinspecific clot strengths of Quantra ® , but these comparisons should have been done using TEG ® functional fibrinogen. The newer version of TEG ® 6s is a cartridge-based system, and 4 separate tests are performed simultaneously: kaolin, kaolin plus heparinase, rapidTEG ® , and functional fibrinogen. At present, rapidTEG ® does not report reaction time. The reference range of functional fibrinogen differs from Quantra ® or FIBTEM on ROTEM ® (Instrumentation Laboratory, Bedford, MA). 7 

In a pilot, prospective randomized trial (PRT), Karkouti, et al. compared 4 factor prothrombin complex concentrate (Octaplex ® ; Octapharma AG, Lachen, Switzerland) and fresh frozen plasma (FFP) transfusion in post-cardiopulmonary bypass (CPB) patients with serious bleeding at 2 Canadian teaching hospitals. 9 EXTEM clotting time over 90 seconds or international normalized ratio (INR) >1.5 was used as an indication for an investigational medical product (IMP: PCC or FFP). IMP was dosed at 25 international unit (IU) per kg for prothrombin complex concentrate (PCC), and 12.5 ml/kg for FFP. The primary endpoints were the need for any additional hemostatic therapies, cumulative amounts of allogeneic blood component units following the use of IMP, and avoidance of red blood cell (RBC) transfusion. 131 patients were randomized, and in the final analysis, 101 subjects were included in the analysis (n=54 in PCC, and n=47 in FP group). The demographic data show that their patients were at median age of 66-67, and the majority were White (56.4%) and Asian (21.7%) with a mean BMI of 23-24 kg/m 2 . CPB time was long (mean, 166-172 min), and non-elective surgical cases were included (20.4% in PCC vs. 31.9% in FFP group). EXTEM data were not reported from the trial, but the transfusion algorithm was similar to the one used in the previous study on hemostasis testing after CPB. 10 The initial intervention occurred at 1.0-1.2 hours from the end of CPB, and the second IMP was utilized in 9.3% in PCC group, and 19.1% in FFP group (P=0.25). The use of VCT guided PCC administration resulted in numerically lower allogeneic blood component usage including FFP units, and 24-hour chest tube drainage compared to the FFP group. In addition, reexploration for bleeding, and rFVIIa usage trended lower in PCC group. This study did not suggest increased adverse event rates from PCC administration, and median days of hospitalization were reduced in PCC group (9.3 days vs. 12.3 days in FFP group). Taken together, Karkouti, et al.' s data supported the role of VCT in the selection of post-CPB hemostatic intervention. Notably, EXTEM utilizes tissue factor (TF) as an activator, but other automated devices, TEG ® 6s and Quantra ® do not currently offer TF-based clotting time measurements.

Further clinical validation studies are required to determine if kaolin-activated clotting time can be effectively used to titrate PCC.

The pandemic has drawn major attention to thromboinflammation because both arterial and venous thromboses have been reported in the presence of elevated cytokines in severe COVID-19. 11 Plasma fibrinogen and D-dimer are frequently tested in COVID-19 patients, and increased D-dimer level has been considered as a prognostic marker of disease progression and mortality. 12 There has been increasing interest in testing for impaired fibrinolysis in critically-ill patients using VCT devices, given the tests ability to track clot growth and clot dissolution over time. VCT has been used to diagnose accelerated fibrinolysis using lysis index or maximum lysis (ML) in liver transplantation and severe trauma. Several investigators observed impaired fibrinolysis on TEG ® or ROTEM ® in severe COVID-19 associated with thrombotic events and proposed to use VCT to diagnose delayed fibrinolysis coined, "fibrinolysis shutdown".

It is important to recognize that a small fibrinolysis-like pattern on TEG ® /ROTEM ® can be platelet-mediated clot retraction, therefore, if fibrinolysis is occurring in a whole blood sample, lysis patterns should be observed in both native and platelet-inhibited channels (e.g., EXTEM and FIBTEM). Indeed, FIBTEM is more sensitive to fibrinolysis induced by tissue plasminogen activator (tPA). 13 A small case series by Creel-Bulos, et al. reported "fibrinolysis shutdown" in 25 COVID-19 patients. 14 EXTEM-ML below 3.5% was used as a cut-off for the shutdown, and 11 of 25 (44%) met this criterion with a median ML of 1.0%. These patients frequently had venous thromboembolism (8 of 11) and their D-dimers trended higher than those in non-shutdown cases (median, 5,215 vs. 1,431 ng/ml; P=0.11). Platelet counts and fibrinogen levels were similar between the shutdown and non-shutdown cases. As previously pointed out by Dr. Ton Lisman, "fibrinolysis shutdown" based on a single TEG ® /ROTEM ® trace is likely a misnomer, and elevated D-dimers suggest that fibrinolysis is occurring in vivo. 15 The half-life of tissue plasminogen activator (tPA) is 5-10 minutes, and localized fibrinolysis cannot be reflected in a systemic blood sample on TEG ® /ROTEM ® . 16 Creel-Bulos et al. did not report FIBTEM-ML(%) in their series, which would have been a better test given its higher sensitivity to tPA. 13 Emphasizing this point, an observational series of hospitalized patients with COVID-19 (n = 543) and those without (n = 288), by Thangaraju et al. simultaneously assessed thrombin generation triggered by tissue factor, and plasmin generation triggered by exogenous tPA. The investigators found that both rate and peak thrombin generation were significantly elevated in plasma from COVID patients older than 65 years compared to non-COVID samples. 17 Conversely, plasmin generation rate and peak level were significantly decreased in plasma from older COVID patients. Reduced plasmin generation was also found in plasma from COVID patients less than 65 years. Overall plasmin generation peak and rate were decreased by 9% and 18%, respectively, between COVID and non-COVID plasma samples (P< 0.0001). In contrast to standard TEG ® /ROTEM ® tests that only account for circulating tPA, plasmin generation utilizes exogenously added tPA (0.7 µg/ml). To address this gap in existing VCT devices, a new VCT system, ClotPro (enicor GmnH, Munich, Germany) introduced a tPA test utilizing exogenous tPA (0.65 µg/ml). Bachler et al. recently reported a case series of 20 critically ill COVID patients compared to 60 healthy volunteers. 18 Lysis time (LT) is used as a main endpoint of TPA test, and is defined as a duration to achieve a 50% reduction in maximum clot firmness (MCF). Prolonged LT over 393 seconds was considered impaired fibrinolysis based on their local reference range.

The median LT (25-75% range) was increased by more than 2-fold in COVID patients compared to healthy subjects: 508 (365-827) vs. 210 (186-261) seconds (P<0.01). D-dimer levels trended lower in patients with prolonged LT, but a statistical significance was not reached. The study was not designed to assess any associations between impaired fibrinolysis and clinical outcomes, including thromboembolism and mortality. However, a tPA challenge test can be applied to other VCT platforms, 19 and it may better delineate impaired fibrinolysis that underlies thromboinflammation. Further studies are warranted to assess the clinical utility of a tPA challenge test in guiding the use of fibrinolysis modulators in critical illness.

The use of factor concentrates in cardiac surgery remain an important area of investigation for managing certain preoperative anticoagulants, as well as treating post-bypass coagulopathy. The advantages of these potent agents are well-established in terms of targeted factor replacement without the volume overload. Not surprisingly, recommendations for the use of factor concentrates for both drug-induced and non-drug-induced bleeding are increasingly present in PBM guidelines. 2 Numerous ongoing investigations continue to determine efficacy and safety profiles. In the past year several studies have contributed a great deal of information to our current knowledge of concentrates such as PCC and fibrinogen concentrates.

Despite the growing off-label uses of PCC, the FDA-approved indication for warfarin reversal remains the only indication for 4-factor PCC administration. 20 Given that warfarin reversal with PCC, rather than FFP, has been the preferred approach for several years, more recent investigations have instead focused on dosing strategies for reversal. Current recommendations use a variable-dose based on the patient's INR and range from 25 to 50 Units/kg. 21 Advocates for fixed-dosing of 4-factor PCC argue that a fixed dose allows for a faster preparation time, lower dosing and fewer adverse events. A recent meta-analysis of 10 studies that included 988 patients compared the two approaches for warfarin reversal. 21 The results found that the time required for goal INR (mean 191 minutes vs 206 minutes, p=0.509) and the rate of thromboembolic events was similar between the two groups, with the fixed-dose 4factor PCC group having a lower cumulative dose (mean 1360.4 Units vs 2028.9 Units, p<0.001) and faster time to administration (68 minutes vs 87.75 minutes, p<0.001). 21 Asides from warfarin reversal, off-label use of PCCs in cardiac surgery for the management of direct oral anticoagulants remains an option when specific reversal agents (idarucizumab or andexanet alfa) are not available. 2, 22, 23 While PCC is recommended as an alternative in this situation, it should be acknowledged that an effective response may be variable. 2 Use in managing bleeding due to oral Factor Xa inhibitors (e.g., rivaroxaban or apixaban) often gets more attention over dabigatran-related bleeding. While this is primarily due to the cost of andexanet alfa, it is also a preferred option in certain cardiac surgery cases because of concern for heparin resistance caused by early andexanet alfa administration. 24 This was recently demonstrated in an ablation case where the patient was given andexanet alfa due to apixaban-related bleeding. Unfortunately, emergent cardiac surgery was needed to address the cardiac injury, and the patient was unable to achieve an adequate activated clotting time (ACT), which led to visible thrombi in the operating field and in the bypass circuit. 25 Additional concern with andexanet alfa in the cardiac surgery population, even when the drug is given after bypass, is the potential need to return to bypass, which would again lead to a similar heparin resistant state. Therefore, the use of high-dose 4-factor PCCs (as high as 50 Units/kg) has been proposed as a reasonable option for Factor Xa inhibitor reversal. However, a recent investigation looking at lower dose PCC (25 Units/kg) found a similar hemostatic effectiveness rate when compared to high-dose PCC (50 Units/kg). 26 Unfortunately, there is limited data that directly compares PCC to andexanet alfa in the cardiac surgery population, but outcomes of direct comparisons in non-cardiac settings can likely be extrapolated to cardiac patients. A retrospective comparison of andexanet alfa and 4-factor PCC for bleeding due to Factor Xa inhibitors demonstrated similar outcomes in terms of effective hemostasis (p=0.7) without a difference in thromboembolic events (p=0.99) and mortality (p=0.39). 27 Another recent comparison in intracranial hemorrhage patients also found no difference between the two options in terms of imaging stability, functional outcome, or thromboembolic events. 28 Finally, a larger meta-analysis (andexanet alfa: 438 patients; PCC: 1,278 patients) also revealed similar effectiveness for treating Factor Xa inhibitor-associated bleeding, while also demonstrating a trend towards greater thromboembolic events in the andexanet alfa group. 29 Given these findings and the implications on potential cost savings, randomized controlled trials comparing andexanet alfa and 4-factor PCC are warranted to determine the optimal choice for Factor Xa inhibitors in cardiac surgery.

The value of PCC administration for non-drug-induced bleeding, such as coagulopathy after cardiopulmonary bypass, is becoming increasingly recognized. PBM guidelines in cardiac surgery from 2021 now state that PCC is a reasonable option over FFP as first-line therapy for refractory coagulopathy in select situations (Class IIA recommendation; Level of evidence B). 2 A small, randomized trial comparing PCC and FFP for bleeding within 24 hours of cardiac surgery found that a PCC dose of 1000 to 1500 Units was as effective as 4 to 5 Units of FFP in terms of correcting coagulation abnormalities. 30 These findings are especially meaningful given the differences in total volume being administered. The previously mentioned trial comparing VCT guided PCC administration versus FFP administration also favored PCC use, with 24-hour cumulative allogeneic transfusion being lower in the PCC group, and differences in RBC transfusion being statistically significant (1.5 Units vs 4.0 Units, p=0.05). 9 An additional observational investigation in post-cardiac surgery bleeding compared 415 patients who received either PCC only (n=72) or FFP only (n=343). 31 Primary outcome assessment included RBC and platelet transfusion needs in the first 24 hours after bypass. The analysis demonstrated that each unit of FFP was associated with an increase in odds of RBC and platelet transfusion, while each 500 Units of PCC was associated with a decrease in odds of RBC and platelet transfusion. As with other studies, adverse events were again similar between the two groups.

Continued research with larger randomized studies, although challenging, are still needed in this patient population to further determine efficacy and safety. 32 Despite the above data suggesting no significant thrombotic complications with PCC, there remains hesitancy in utilizing PCC for coagulopathy during cases of mechanical circulatory support. This past year has provided some additional insight into the use of PCC for left ventricular assist device (LVAD) implantation or exchange. A retrospective analysis of 160 LVAD cases found that PCC use decreased the need for intraoperative transfusion when compared to no PCC; however, this difference did not reach statistical significance. Similarly, there was a non-significant trend towards higher LVAD pump thrombosis with PCC (2.6% vs 0.8%, p=0.98). 33 In another retrospective investigation of activated PCC (factor eight inhibitor bypassing activity; FEIBA) for post-LVAD coagulopathy, FEIBA use was associated with no increase in 14-day thrombotic outcomes (11.0% vs 7.6%, p=0.343) or mortality rate (3.7% vs 1.3%, p=0.179). 34 While the authors suggest a favorable risk-benefit profile for FEIBA use in LVAD surgery, they acknowledge that future studies are still required to fully assess the safety profile.

The impact of cardiopulmonary bypass on dilution, consumption, and loss of coagulation factors, including fibrinogen, is well-known. 35 Fibrinogen levels may decrease by as much as 50%, and concentrations below 200 mg/dL may be associated with impaired hemostasis. 35, 36 Restoration of adequate fibrinogen levels with fibrinogen concentrates in this situation remains off-label in the United States. While rare in cardiac surgery, an on-label indication was recently reported in a young woman with congenital afibrinogenemia undergoing pulmonary thromboendarterectomy with deep hypothermic circulatory arrest. 37 Given the higher use for acquired (rather than congenital) hypofibrinogenemia, ongoing investigation over the past year on the efficacy and safety of fibrinogen concentrates in cardiac surgery continues.

Since the results of a 2019 randomized trial comparing fibrinogen concentrates to cryoprecipitate demonstrated non-inferiority for fibrinogen replacement after cardiac surgery, the arguments for fibrinogen concentrates over cryoprecipitate have strengthened. 36, 38 These arguments are further supported by the fact that fibrinogen concentrate use did not result in a significantly higher rate of thromboembolic events. 38 Advantages of fibrinogen concentrates include greater dose predictability given the known fibrinogen content, lower risk of viral transmission, and rapid reconstitution. Concerns with fibrinogen concentrates, asides from higher cost, include lower efficacy in more complex cardiac cases where fibrinogen supplementation alone may not be sufficient to restore hemostasis. 36 Despite this concern, recent clinical practice guidelines in critically ill patients have recommended empiric use of fibrinogen concentrates in cardiac surgery patients with non-massive bleeding. 39 Either a fixed dose of 2 to 4 grams or dose titration based on rotational thromboelastometry (FIBTEM) is suggested.

While fibrinogen supplementation may be required for acquired hypofibrinogenemia, simultaneous replacement of other factors after certain cardiac cases may also be needed as mentioned above. A recent single-center investigation combining fibrinogen concentrates and PCC was performed in patients undergoing surgery for congenital heart disease. 40 This combination was well-tolerated and allowed for adequate hemostasis when compared to standard treatment with FFP alone. Another study examined the value of adding Factor XIII concentrates to fibrinogen concentrates in treating coagulopathy. 41 There is low level of evidence to support the use of Factor XIII concentrates alone, but perhaps there would be benefit with a combined approach for improved clot formation and stability. Unfortunately, this in vitro analysis demonstrated no value of a combined approach as determined by thromboelastometry parameters. 41 Another area of interest over the past year has included assessment of different fibrinogen concentrate formulations. While fibrinogen is the primary clotting factor, currently available products differ based on the manufacturing process and content. 42 An in vitro study recently compared three commercially available fibrinogen concentrates by supplementing 2.5 g fibrinogen per 70 kg of body weight to postoperative blood collected from 23 cardiac surgery patients. Clot strength was improved in all three formulations as assessed by viscoelastic testing; however, there were notable differences between the concentrates when looking at changes in clot formation time and maximum clot firmness (p<0.001). 42 As fibrinogen concentrate use continues to rise in cardiac surgery, these findings may impact the product of choice as well as dosing.

Anemia in CPB patients continues to be an important topic for investigators in cardiac surgery. 2, 43, 44 The risk of intraoperative RBC transfusion and increased postoperative morbidity and mortality persists in anemic cardiac surgery patients. [43] [44] [45] Recent evidence, however, has shown that hemoglobin thresholds for increased risk may vary between men and women and between younger and older patients. 45, 46, [47] [48] [49] Combined with evidence suggesting RBC transfusion may not eliminate the risk of organ dysfunction and is associated with impaired outcomes, transfusion best practices remain elusive. 2, 43, 50, 51 Contributing to uncertainty, two large randomized controlled trials (RCT) in cardiac surgery did not show an impaired outcome with a more liberal transfusion strategy compared to a restrictive regimen. 47, 48 Adding even more confounders, a recent large retrospective analysis in healthcare data from >700,000 patients showed that non-white ethnicity was associated with increased rates of blood transfusion. 52 The authors suggested potential bias related to physicians and providers may account for these differences. 52 Considerable debate around transfusion practices persist.

This debate was highlighted in a recently published survey among United States cardiac anesthesiologists which demonstrated that around 30% accept a hemoglobin value < 7.0 g/dL as a RBC transfusion trigger. 5 This transfusion trigger is distinctly lower than the thresholds investigated in two key transfusion trials, TRICS-III and TITRe-2. 47, 48 It is also below the threshold of 7.0 to 8.0 g/dL used in most studies for the restrictive transfusion groups. 53 It is also in spite of some to the suggested benefits of a more liberal transfusion strategy. 47, 48 Taken as a whole, recent survey data suggests an increased adoption of low transfusion triggers in cardiac surgery based controversial evidence.

Alternatively, the use of physiological triggers of adequate tissue oxygenation could potentially address some of these controversies. 43, 54 In a recent RCT, patients admitted to intensive care units after cardiac surgery with a postoperative hemoglobin <9.0 g/dL were randomized to receive either a transfusion with one RBC unit (control group) or a transfusion only if the central venous oxygen saturation (ScvO2) was <70% (study group). 55 The study group received less RBC transfusions without increasing in-hospital morbidity or mortality. 55 This study does show that RBC transfusion triggers using physiological parameters in combination with hemoglobin values reduce overall transfusions. One key limitation to this study however, is that the transfusion trigger of 9.0 g/dL was higher than the recommended thresholds in the recent clinical guidelines, 2 .

Institutional and national PBM programs continue to work to address these variations in transfusion practices. At the foundation of these efforts is conserving the patient's own blood reserves in the perioperative period. The PBM definition has recently been updated, now focusing on a patient-centered, systematic, and evidence-based approach to improve patient outcome by using the different PBM tools as a bundle. 56 In addition, the clinical practice guidelines on PBM have been updated in the last year. 2 These consensus recommendations were recently supported by a retrospective propensity-score matching analysis including nearly 8,000 patients undergoing cardiac surgery at a large Chinese center. This study showed that a comprehensive blood conservation program during adult on-pump cardiac surgery was effective to reduce the transfusion of RBC without adversely affecting outcome. 49 An additional key component to PBM is optimizing the patient's own blood reserves before surgery. This approach was assessed in a retrospective Canadian cohort study including 532 patients referred to an outpatient blood conservation clinic before cardiac surgery. 57 The authors found that the preoperative treatment with iron and erythropoietin significantly increased hemoglobin values. Based on their analyses, intravenous iron at a dose of at least 600 mg and erythropoietin alfa at doses of at least 80,000 units were necessary to increase hemoglobin values. 57 This study highlighted two major problems in current preoperative PBM programs: First, the number of eligible patients is limited given that the roughly 530 included patients were recruited over a time period of about 10 years. Second, the high doses of iron and erythropoiesis-stimulating agents required for hemoglobin optimization might question the cost-effectiveness. Therefore, PBM practices should be introduced after critical and potentially individual assessment. 58 In agreement, a recently published large network meta-analysis including 393 randomized trials with nearly 55,000 enrolled patients found a reduction in exposure to RBC by about 40% by multiple PBM means but no statistically significant treatment effect in respect to mortality and major morbidity. 59 However, this meta-analysis was criticized by many experts given conflicting evidence demonstrating PBM programs reduce RBC transfusion and improve quality of care in patients undergoing cardiac surgery. 53,56 60, 61 The key recommendation related to CPB and anticoagulation management encourages individualized heparin and protamine doses. This guidance is supported by level II evidence; however, a paucity of information is included regarding "individualized" doses. Heparin concentration monitoring is potentially one way to individualize doses, but previous consensus statements published by the SCA point out that support for these monitors is lacking. 62 In consideration of this, Activated Clotting Times and lack any formal support. 62 The authors did however find that the compartmental modeling group received statistically less protamine. Investigations supporting ratios below 1:1 have also been published in the past. 64 More studies are still needed to elucidate optimal protamine dosing strategies to limit both under and over dosing. In consideration of Miles et al work, and other studies it seems likely lower ratios of protamine to heparin are more important that dose calculation methods.

Other important work on anticoagulation management in 2021 focused on Heparin-Induced Thrombocytopenia (HIT) patients undergoing cardiac surgery. Several guideline statements provided direction for managing this patient group, and a complete review can be found in the Journal of Cardiothoracic and Vascular Anesthesia. 65 In summary, the consensus is to wait until HIT is resolved and move forward using heparin. In those urgent/emergent situations alternative anticoagulants are supported, and if possible plasmapheresis may be considered. Authors from Duke presented safety data in 2021 for intraoperative therapeutic plasma exchange in 24 HIT patients. 66 Preoperative antibody titers were only available in about half of these patients and postoperative titers were demonstrably lower. Some patients did have postoperative thrombotic events; however, many patients were high risk advanced heart failure patients. Concerns around this technique may be warranted when considering data presented by Brown et al, where mortality following cardiac surgery was significantly higher in patients that developed HIT. 67 Interestingly mortality was not different among HIT patients with thrombotic events and those without.

In summary, anticoagulation management advances in 2021 focused on important areas that still trouble cardiac anesthesiologists today including "individualized" heparin and protamine dosing and HIT management within cardiac surgery. In the face of extreme national blood shortages these efforts and all PBM related activities have never been more important.

In 2021, several mechanistic studies shed light on the pathophysiology of coagulopathy that occurs during extracorporeal membrane oxygenation (ECMO). In a study that included 20 veno-arterial (VA) ECMO patients and 10 veno-venous (VV) ECMO patients, the authors obtained blood samples from ECMO patients on day 1, day 3, and after ECMO decannulation.

They also obtained samples from 10 healthy volunteers and 15 patients with coronary artery disease. The authors analyzed the density of multiple platelet surface receptors at baseline and in response to different agonists. The main study findings were that ECMO patients had reduced activation of GPIIbIIIa in response to agonists including adenosine diphosphate (ADP) and thrombin receptor agonist protein (TRAP) and lower surface GPVI and GP1bα density, when compared to controls. These defects in adhesion and aggregation receptors may contribute to the severe bleeding that occurs in many ECMO patients. 68 Another study of 39 ECMO patients (17 VA and 22 VV) highlighted important differences in the coagulation profiles of VA and VV ECMO patients. In this study, patients had blood samples obtained every 48 hours during the first week on ECMO and every week after until the time of decannulation. VA ECMO patients had lower platelet counts, lower fibrinogen, lower antithrombin III activity, and comparable acquired von Willebrand syndrome, when compared to VV ECMO patients. 69 The heparin dose required to obtain target activated partial thromboplastin time (aPTT) was approximately one-third in VA ECMO patients, when compared to VV ECMO patients, perhaps because of lower procoagulant factor acitivity. 69 Tissue factor pathway inhibitor (TFPI) is an endogenous anticoagulant that inhibits Factor Xa and Factor VIIa. Systemic heparinization is known to increase TFPI levels, as heparin displaces TFPI from endothelial cell surfaces and increases TFPI release from endothelial cells. 70 In a study of 20 VA ECMO patients, the authors found that TFPI levels were increased approximately 2-fold compared to control plasma. 71 Increased TFPI levels correlated with increased tissue factor triggered lag time on calibrated automated thrombin generation assay. 71 These findings suggest that ECMO patients who receive systemic heparinization may have slowed tissue factor triggered thrombin generation, in part, because of elevated TFPI levels.

There are continued efforts to develop new anticoagulants for ECMO patients. In an animal model, a group from Duke University tested a ribonucleic acid (RNA)-based aptamer to Factor IXa (DTRI-178). The authors compared anticoagulation adequacy and surgical bleeding in pigs treated with DTRI-178 against pigs treated with intravenous heparin. After running the ECMO circuits for 12 hours, the authors examined oxygenators under microscopy and found minimal clot burden in both groups (<2% of oxygenator surface). 72 Further, the authors found that there was less surgical bleeding (at cannulation sites) in the group of pigs treated with DTRI-178. 72 In a second animal study that used rabbits, an ECMO circuit which was impregnated with poly-carboxybetaine (PCB) was combined with a Factor XIIa inhibitor (FXII900), and outcomes were compared against systemic heparin. 73 Pharmacologic shutdown of Factor XIIa in combination with a PCB circuit led to minimal macroscopic clot formation at 60 minutes and low fibrinopeptide A levels, suggesting minimal fibrin formation. 73 The importance of factor XII in the pathophysiology of thrombosis during ECMO was further highlighted in an observational study, which showed that increased Factor XII activity was associated with thrombosis during ECMO (OR=3.0 for every tertile increase in Factor XII activity). 74 Anticoagulation with heparin versus direct thrombin inhibitors (DTIs) remains a controversial topic in adult ECMO. In 2021, there were several studies comparing DTIs versus heparin. In a propensity matched cohort study from a major European ECMO center, the authors found that bleeding rates were similar between patients anticoagulated with heparin and argatroban; however argatroban was more expensive. 75 Interestingly, patients who received argatroban had higher platelets counts at the time of ECMO decannulation (141 vs.

included over 300 patients from 13 studies, the authors similarly found that patients anticoagulated with argatroban had comparable bleeding and thrombosis rates when compared to patients who were treated with heparin. 76 In a large single-center observational study (N=422), the authors compared patients who were anticoagulated with heparin versus those anticoagulated with bivalirudin. 77 They found lower mortality in patients who received bivalirudin (OR=0.39) and also a lower transfusion rate during the first 24 hours in pediatric ECMO patients treated with bivalirudin (OR=0.28). 77 Patients who received heparin had a 12% incidence of heparin induced thrombocytopenia, which is higher than in prior studies. 77 Although intriguing, this study had multiple limitations including a lack of adjustment for confounding by year of treatment. 78 In the early study period, heparin was preferentially used and there was a shift to bivalirudin over time. It is likely that ECMO practices and patient blood management improved in the authors' center over time, and this coincided with the change from heparin to bivalirudin. 78 Another noteworthy study related to anticoagulation during ECMO is a systematic review from Willems et al. where anti-Xa monitoring was compared with activated clotting time (ACT) and aPTT monitoring in over 2,000 patients who received heparin anticoagulation. In this study, patients who had anti-Xa monitoring had 51% lower odds of having a bleeding complication during ECMO (OR=0.49) and also significantly lower mortality (OR=0.61). 79 There was no significant difference in thrombosis between the two groups. 79 

Several interesting studies were published in 2021 describing coagulation changes in patients with ventricular assist devices (VADs). In a study of 39 patients with left ventricular assist devices (LVADs), the authors compared platelet surface receptor expression in patients with and without coagulopathic bleeding (N=19 and N=20 respectively). In the study, the authors found that patients with coagulopathic bleeding had approximately 25% lower expression of surface GP1bα, lower levels of ADP-stimulated P selectin and platelet endothelial cell adhesion molecule-1 (PECAM-1), and greater markers of oxidative stress. 80 They concluded that these platelet abnormalities might contribute to the coagulopathic bleeding in LVAD patients. 80 In a second study, the authors explored the potential impact of circulating plateletderived microparticles (PMPs) on thrombotic risk in 43 LVAD patients. In this study, there were eight patients who developed a thrombotic complication and they had higher levels of PMPs and thrombin generation. 81 Mean PMP levels more than doubled after LVAD implantation compared to baseline. 81 In patients with thrombotic complications, PMPs were approximately two-fold higher and this correlated with higher thrombin generation. 81 The authors concluded that PMP measurement might allow for improved risk stratification in LVAD patients. 81 Of note, PMPs rose relatively quickly after LVAD implantation, and remained relatively stable over the first year.

Gastrointestinal (GI) bleeding has historically been a major problem for continuous-axial flow LVAD patients. In a case series of eight patients with a Heartware HVAD, the authors reported on the use of tamoxifen to reduce major GI bleeding. 82 Tamoxifen has been used to treat hereditary telangioectasia and is thought to modulate (upregulate) transforming growth factor (TGF)-beta signaling, which reduces abnormal angiogenesis and potentially augments vascular repair. Tamoxifen may also reduce vascular endothelial growth factor (VEGF) release from platelets.

Acquired von Willebrand syndrome (VWS) is a well described complication in patients with durable LVADs; however, there are relatively few studies in patients with percutaneous catheter mounted axial-flow VADs (i.e. Impellas). In a study of 60 patients with cathetermounted VADs (20 right ventricular and 40 left ventricular) the authors found that acquired VWS occurred in 88% of patients with left ventricular support, while only 58% of patients with right ventricular support developed acquired VWS. 83 They hypothesized that lower pressures and lower shear stress with an RVAD may explain these findings. 83 In the study, over 50% of patients had major bleeding with a median of 3 days of support. 83 Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat major depression and anxiety. SSRIs also have mild anti-platelet effects and increase bleeding risk in patients with cardiovascular disease who are taking anti-platelet drugs. 84 In a study of 100 patients with a durable VAD (mostly Heartmate 3), the authors had an overall 36% hospital readmission rate for major bleeding. 85 After stratifying by SSRI use, the authors found that patients who were taking SSRIs were more commonly readmitted for major bleeding (46% vs. 15%, HR=2.3, P=0.004). 85 The authors concluded that SSRI use in VAD patients may be associated with significant bleeding risk and should be further evaluated in prospective randomized studies. Also, patients who take SSRIs may need to have their anticoagulation regiment altered to reduce bleeding risk.

Aspirin is the most commonly used anti-platelet drug in patients with a durable VAD. In a small cohort study of 28 VAD patients, aspirin's anti-platelet effects were assessed over time using aggregometry (Aspirin Verify Now Platelet Reactivity). In this study, the authors found that only 7% of patients were aspirin resistant in the immediate perioperative period, however, approximately one-third of patients were aspirin resistant at three and six months. 86 They concluded that a tailored approach to anti-platelet therapy may be needed, rather than a "onesize fits all" approach. Most patients who received an increase in their aspirin dose achieved an adequate response, suggesting that tailored monitoring and therapy has the potential to reduce complications.

Antiplatelet drugs, as either single antiplatelet therapy (SAPT) or combined with aspirin (ASA) as dual antiplatelet therapy (DAPT) remain commonplace for antithrombotic prevention in cardiac patients. Efforts investigating best practices regarding perioperative continuation of therapy continued in 2021. Current guidelines and evidence support the continuation of ASA perioperatively to reduce early postoperative thrombotic events and mortality after coronary artery bypass grafting surgery (CABG). 87 P<0.001), and CVA (HR, 0.5 8; 95% CI, 0.46-0.74; P<0.001) 6 months postoperatively without increasing incidence of major bleeding. 92 These findings are in spite of current recommendations are to discontinue P2Y 12 receptor inhibitors ticagrelor, clopidogrel, and prasugrel at 3 days, 5 days, and 7 days, respectively, prior to surgery. 87, 93 One key application of these findings is in patients with recent intracardiac stents, where interruption of therapy may be harmful. Alternatively, bridging with intravenous antiplatelet agents has been proposed, but lacks evidence at this time. Lastly, new antiplatelet drugs are currently being developed to decrease bleeding risk while maintaining antithrombotic benefits. Selatogrel is a novel P2Y 12 receptor inhibitor that can be administered subcutaneously. When used in patients with AMI, Selatogrel averaged a platelet reacting unit (PRU) with VerifyNow  of 9 and 51 in 15 min without bleeding complications, showing promise for earlier intervention for ACS. 94 Additional novel antiplatelet drugs are directed at different platelet receptors to limit platelet inhibition such as PAR 1 & 4, GPVI ligand, and protein disulfide isomerase. One such GPVI ligand is Revacept which competitively binds to GPVI expressed by exposed collagen preventing collagen-induced platelet activation. 95 With the continued development of novel antiplatelet drugs, clinicians will be presented with new challenges to assess platelet function to determine associated bleeding risks.

Platelet function testing (PFT) is increasingly used to reduce surgical waiting times and tailor antiplatelet therapy regimens. These tests also being incorporated into transfusion algorithms. Light transmission aggregometry (LTA) is the gold standard for PFT but due to its lack of standardized values, prolonged processing, and need for a specialized technician its clinical use is limited. Currently used PFTs are Platelet Function Analyzer 100 (PFA-100  ), Quantra  , Multiplate  , VerifyNow  , and TEG  Platelet mapping. Widespread adoption of these devices has been limited by cost and conflicting evidence.

Of these devices, Quantra  is the newest point-of-care coagulation analyzer. The automated cartridge tests whole blood clot function, and can provide platelet-specific information represented by platelet contribution to clot stiffness (PCS). In a recent prospective cohort study in cardiac surgical patients, Quantra  was shown to have a correlation of (r=0. 71) to platelet count and (r=0.67) and to more the more established PFT, Multiplate  . 96 In light of this, the Quantra  system may be a promising viscoelastic monitor to assess platelet count and platelet function.

TEG  Platelet Mapping (Haemonetics, Braintree, MA) which uses Activator F (reptilase and activated factor XIII) mixed with either ADP and AA to initiate platelet activation and fibrinogen polymerization has been of interest, but extensive processing has limited its application. Newer cartridge-based TEG  6s has improved this limitation, and more research is needed on this newer platform. 97 A recent study in 10 healthy volunteers did compare MEA, VerifyNow  , and TEG  6s while titrating ticagrelor to effective concentrations (EC) of 10%, 50%, and 90%. TEG  6s was able to distinguish all drug zones (<EC10, EC10-50, EC50-90, >EC90) while VerifyNow  and MEA could only distinguish three and two drug zones respectively. 98 

Emphasizing the potential impact of perioperative PFT, Nakashima et al. performed a randomized non-inferiority trial in CABG patients on DAPT and surgical planning with either standard treatment (5-7 days waiting period) or using MEA ADP 46U. After randomization 95 patients were stratified into each study group resulting in an 85h (50h vs 135h; p < 0.001) reduction in waiting time from surgical indication to surgical approval to proceed, 24h (112h vs 136h; p <0.001) reduction in surgical indication to the beginning of the procedure, and 58h (297h [IQR 256-412] vs 355h [IQR 307-447]; p=0.009) reduction in total hospital stay in the interventional group compared with the control group. 99 Overall this resulted in a 6.4% (p =0.014) decrease in median hospital expenses in the interventional group without an increase in 24h chest tube drainage.

More evidence supporting PFT ability to stratify bleeding risk also emerged this past

year. In a prospective trial of 416 patients undergoing an elective isolated CABG, MEA-ADP and MEA-AA were conducted preoperatively for each patient. MEA-ADP 50U was found to be 82.4% sensitive and 40% specific for bleeding > 1000ml. Additionally MEA-ADP 50U correlated with a statistically significant increase in total transfusion (20%), RBC (15%), PLT (35%), and cryoprecipitate (10%). 100 These findings are similar to the results of previous studies 101 Larger metanalysis have been conflicting on the ability of PFT to reduce transfusion and predict bleeding. 102, 103 

Unlike other viruses, COVID-19 causes an increase in platelet consumption and apoptosis mediated by IgG antibodies via the Fc IIA receptor on the platelet surface. 104 To account for this antiplatelet or anticoagulant therapy has been recommended for COVID-19 patients to improve outcomes. Analysis of approximately 8,000 COVID-19 patients presenting for hospitalization were enrolled into a registry to observe the effects of antiplatelet therapy. showed an increased incidence of bleeding complications (48% vs 2% p=0.0001), surgical re-exploration (35% vs 2% p=0.0001), and transfusions (74% vs 30% p=0.0006) compared to the control group. 106 These findings are a consideration as COVID-19 related surgical policies evolve.

In summary, 2021 brought many important updates regarding coagulation management, transfusion medicine and point-of-care testing. Some of these updates focused on timely problems including blood shortages and the COVID-19 pandemic. A number of clinical problems were highlighted that continue to require ongoing investigations for clarity. Future updates will hopefully address some of these questions.

Effects of the COVID-19 pandemic on supply and use of blood for transfusion

STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management

Practice guidelines for perioperative blood management: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*

American Society of Anesthesiologists

Blood Conservation and Hemostasis in Cardiac Surgery: A Survey of Practice Variation and Adoption of Evidence-Based Guidelines

Comparison of the Quantra QPlus System With Thromboelastography in Cardiac Surgery

Comparison of Thrombelastography-Derived Fibrinogen Values at Rewarming and Following Cardiopulmonary Bypass in Cardiac Surgery Patients

The effectiveness of different functional fibrinogen polymerization assays in eliminating platelet contribution to clot strength in thromboelastometry

Comparison of 4-factor prothrombin complex concentrate with frozen plasma for management of hemorrhage during and after cardiac surgery: a randomized pilot trial

Point-of-Care Hemostatic Testing in Cardiac Surgery: A Stepped-Wedge Clustered Randomized Controlled Trial

COVID-19 Associated Hypercoagulability: Manifestations, Mechanisms, and Management

D-dimer, disease severity, and deaths (3D-study) in patients with COVID-19: a systematic review and meta-analysis of 100 studies

Comparison between thrombelastography and thromboelastometry in hyperfibrinolysis detection during adult liver transplantation

Fibrinolysis Shutdown and Thrombosis in a COVID-19 ICU

Fibrinolytic Shutdown in COVID-19 Is Likely a Misnomer

Thromboelastometry and D-Dimer Elevation in Coronavirus-2019

The Impact of Age and BMI on the VWF/ADAMTS13 Axis and Simultaneous Thrombin and Plasmin Generation in Hospitalized COVID-19 Patients

Impaired fibrinolysis in critically ill COVID-19 patients

Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis

Clinical utilization of four-factor prothrombin complex concentrate: a retrospective single center study

Efficacy and safety of the fixed-dose versus variable-dose of 4-PCC for vitamin K antagonist reversal: a comprehensive systematic review and meta-analysis. Cardiovasc Drugs Ther

Emergency cardiac surgery for patients on NOACs in the NOAC era -Perspective

A European consensus statement on the use of four-factor prothrombin complex concentrate for cardiac and non-cardiac surgical patients

Andexanet alfa-induced heparin resistance: when anticoagulation really remains reversed

Successful antithrombin administration in andexanet alfa-associated heparin resistance

Comparison of high-and low-dose 4-factor prothrombin complex concentrate for the emergent reversal of oral Factor Xa inhibitors

Retrospective comparison of andexanet alfa and 4-factor prothrombin complex for reversal of factor Xainhibitor related bleeding

Andexanet alfa versus 4-factor prothrombin complex concentrate for reversal of factor Xa inhibitors in intracranial hemorrhage

Andexanet alfa or prothrombin complex concentrate for factor Xa inhibitor reversal in acute major bleeding: a systematic review and meta-analysis

Impact of prothrombin complex concentrate and fresh frozen plasma on correction of haemostatic abnormalities in bleeding patients undergoing cardiac surgery (PROPHESY trial results)

The association of prothrombin complex concentrates with postoperative outcomes in cardiac surgery: an observational substudy of the FIBRES randomized controlled trial

Out of control: why randomized trials of factor concentrates are so elusive

Intraoperative prothrombin complex concentrate administration and outcomes in patients undergoing left ventricular assist device implantation

The use of factor eight inhibitor bypass activity (FEIBA) for the treatment of perioperative hemorrhage in left ventricular assist device implantation

Fibrinogen and bleeding in adult cardiac surgery: a review of the literature

Pro-Con debate: fibrinogen concentrate or cryoprecipitate for treatment of acquired hypofibrinogenemia in cardiac surgical patients

Pulmonary thromboendarterectomy requiring cardiopulmonary bypass and deep hypothermic circulatory arrest in a patient with congenital afibrinogenemia

Effect of fibrinogen concentrate vs cryoprecipitate on blood component transfusion after cardiac surgery: the FIBRES randomized clinical trial

Transfusion strategies in bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine

Administration of fibrinogen concentrate combined with prothrombin complex maintains hemostasis in children undergoing congenital heart repair (a long-term propensity score-matched study)

Combined administration of fibrinogen and Factor XIII concentrate does not improve dilutional coagulopathy superiorly than sole fibrinogen therapy: results of an in-vitro thrombelastographic study

A comparison of the in vitro effects of three fibrinogen concentrates on clot strength in blood samples from cardiac surgery patients

Preoperative anaemia in cardiac surgery: preoperative assessment, treatment and outcome

Preoperative anaemia and outcome after elective cardiac surgery: a Dutch national registry analysis

Critical Preoperative Hemoglobin Value to Predict Anemia-Related Complications After Cardiac Surgery

Sex-Specific Associations Between Preoperative Anemia and Postoperative Clinical Outcomes in Patients Undergoing Cardiac Surgery

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery

Liberal or restrictive transfusion after cardiac surgery

Quality Management of a Comprehensive Blood Conservation Program During Cardiopulmonary Bypass

Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation

Liberal Red Blood Cell Transfusion Strategy in Patients With Acute Myocardial Infarction and Anemia: A Systematic Review and Meta-Analysis

Non-White Race/Ethnicity and Female Sex Are Associated with Increased Allogeneic Red Blood Cell Transfusion in Cardiac Surgery Patients

Transfusion thresholds for guiding red blood cell transfusion

RBC Transfusion Triggers: Is There Anything New

Individualised or liberal red blood cell transfusion after cardiac surgery: a randomised controlled trial

A Global Definition of Patient Blood Management

Determining Optimal Treatment to Correct Preoperative Anemia and Reduce Perioperative Allogeneic Blood Transfusions in Cardiac Surgery: A Retrospective Cohort Study

Controversies in the Clinical Practice of Patient Blood Management

Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: a network metaanalysis

Guidelines for Conduct of Cardiopulmonary Bypass

EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery

Clinical Practice Guidelines: Anticoagulation during Cardiopulmonary Bypass

A comparative analysis of four activated clotting time measurement devices in cardiac surgery with cardiopulmonary bypass

Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial

Heparin-induced Thrombocytopenia: Perioperative Diagnosis and Management

Clinical outcomes of cardiac surgery patients undergoing therapeutic plasma exchange for heparin-induced thrombocytopenia

Outcomes With Heparin-Induced Thrombocytopenia After Cardiac Surgery. The Annals of thoracic surgery

Early platelet dysfunction in patients receiving extracorporeal membrane oxygenation is associated with mortality

Hemostasis, coagulation and thrombin in venoarterial and venovenous extracorporeal membrane oxygenation: the HECTIC study

Heparin induces synthesis and secretion of tissue factor pathway inhibitor from endothelial cells in vitro

Tissue Factor Pathway Inhibitor Levels During Veno-Arterial Extracorporeal Membrane Oxygenation in Adults

Aptamer-based factor IXa inhibition preserves hemostasis and prevents thrombosis in a piglet model of ECMO

Combination of polycarboxybetaine coating and factor XII inhibitor reduces clot formation while preserving normal tissue coagulation during extracorporeal life support

Prevalence and Clinical Impact of Reduced Coagulation Factor XII Activity in Patients Receiving Extracorporeal Membrane Oxygenation

Argatroban versus heparin in patients without heparin-induced thrombocytopenia during venovenous extracorporeal membrane oxygenation: a propensity-score matched study

Argatroban Anticoagulation for Adult Extracorporeal Membrane Oxygenation: A Systematic Review

Comparison of Bivalirudin Versus Heparin for Maintenance Systemic Anticoagulation During Adult and Pediatric Extracorporeal Membrane Oxygenation

Bivalirudin Superior to Heparin for Extracorporeal Membrane Oxygenation: Not So Fast

Anti-Xa versus time-guided anticoagulation strategies in extracorporeal membrane oxygenation: a systematic review and meta-analysis

Device-induced platelet dysfunction in patients after left ventricular assist device implantation

Thromboembolic Events in Patients With Left Ventricular Assist Devices Are Related to Microparticle-Induced Coagulation

Novel Use of Tamoxifen to Reduce Recurrent Gastrointestinal Bleeding in Patients with Left Ventricular Assist Devices

Role of acquired von Willebrand syndrome in the development of bleeding complications in patients treated with

Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction

Serotonergic antidepressants and hospitalization for bleeding in patients supported with a continuous flow left ventricular assist device

Evaluation of aspirin platelet inhibition in left ventricular assist device population

STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management

The use of preoperative aspirin in cardiac surgery: A systematic review and meta-analysis

Timing Strategy of Preoperative Aspirin and Its Impact on Early Outcomes in Patients Undergoing Coronary Artery Bypass Grafting: A Propensity Score Matching Analysis

Aspirin Resistance Incidence and Associations Between Aspirin Effect and Outcomes in Cardiac Surgery

Platelet Activity Measured by VerifyNow® Aspirin Sensitivity Test Identifies Coronary Artery Bypass Surgery Patients at Increased Risk for Postoperative Bleeding and Transfusion

Dual Antiplatelet Therapy with Clopidogrel and Aspirin Versus Aspirin Monotherapy in Patients Undergoing Coronary Artery Bypass Graft Surgery

Perioperative Guidelines on Antiplatelet and Anticoagulant Agents: 2022 Update

Subcutaneous Selatogrel Inhibits Platelet Aggregation in Patients With Acute Myocardial Infarction

Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease: The Randomized, Double-blind, Placebo-Controlled ISAR-PLASTER Phase 2 Trial

A Comparative Study of SEER Sonorheometry Versus Standard Coagulation Tests, Rotational Thromboelastometry, and Multiple Electrode Aggregometry in Cardiac Surgery

Viscoelastic Coagulation Testing: Use and Current Limitations in Perioperative Decision-making

Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition

Platelet Reactivity in Patients With Acute Coronary Syndromes Awaiting Surgical Revascularization

The routine use of platelet function tests in elective coronary artery bypass grafting: A prospective observational trial

Platelet function after cardiac surgery and its association with severe postoperative bleeding: the PLATFORM study

The role of point-of-care platelet function testing in predicting postoperative bleeding following cardiac surgery: a systematic review and meta-analysis

Implementation of Perioperative Point-of-Care Platelet Function Analyses Reduces Transfusion Requirements in Cardiac Surgery: A Retrospective Cohort Study

Platelets and COVID-19

Antiplatelet therapy and outcome in COVID-19: the Health Outcome Predictive Evaluation Registry

Bleeding Complications in Patients With Perioperative COVID-19 Infection Undergoing Cardiac Surgery: A Single-Center Matched Case-Control Study