Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery.

BACKGROUND: Right ventricular failure (RVF) is a leading driver of morbidity and death after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy. METHODS: In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and death at 30 days, 90 days, and 1 year after surgery. RESULTS: Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, -6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes. CONCLUSIONS: Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03081052.

Heparins May Not Be the Optimal Anticoagulants for Sepsis and Sepsis-Associated Disseminated Intravascular Coagulation.

Historically, heparin has had the longest historical use as an anticoagulant and continues this day to be the primary therapeutic option for preventing thrombosis and thromboembolism in critically ill hospitalized patients. Heparin is also used to treat sepsis and sepsis-associated disseminated intravascular coagulation (DIC) in various countries. However, the efficacy and safety of heparin for this indication remains controversial, as adequately powered randomized clinical studies have not demonstrated as yet a survival benefit in sepsis and sepsis-associated DIC, despite meta-analyses and propensity analyses reporting improved outcomes without increasing bleeding risk. Further, activated protein C and recombinant thrombomodulin showed greater improvements in outcomes compared with heparin, although these effects were inconclusive. In summary, further research is warranted, despite the ongoing clinical use of heparin for sepsis and sepsis-associated DIC. Based on Japanese guidelines, antithrombin or recombinant thrombomodulin may be a preferable choice if they are accessible.

Andexanet alfa or prothrombin complex concentrate for acute reversal of oral factor Xa inhibitors: monitoring of antidote effects.

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.

Antithrombin supplementation attenuates heparin resistance in plasma spiked with Gla-domainless factor Xa S195A in vitro.

BACKGROUND: Andexanet alfa is a Gla-domainless mutant (S195A) factor Xa (GDXa) approved for acute reversal of oral factor Xa inhibitors. Cardiac surgery patients exposed to andexanet before cardiopulmonary bypass often exhibit severe heparin resistance. There is a paucity of data on the effectiveness and optimal dosage of antithrombin use in this setting. The objective of this study was to evaluate the in vitro effect of increased heparin with antithrombin levels on attenuating heparin resistance induced by GDXa. METHODS: Heparinised normal pooled plasma and cardiopulmonary bypass plasma were spiked with GDXa 4 µM. Tissue factor-activated thrombin generation was used to assess heparin reversal effects of GDXa and restoration of anticoagulation with additional heparin with and without antithrombin. Serum thrombin-antithrombin complex, antithrombin activity, and tissue factor pathway inhibitor were also measured in tissue factor-activated, recalcified cardiopulmonary bypass plasma spiked with GDXa. RESULTS: In normal pooled plasma, GDXa-induced heparin reversal was mitigated by maintaining a high heparin concentration (12 U ml-1) and supplementing antithrombin (1.5-4.5 µM) based on peak and velocity of thrombin generation. Heparin reversal by GDXa was also demonstrated in cardiopulmonary bypass plasma, but supplementing both heparin (8 U ml-1) and antithrombin (3 µM) attenuated GDXa-induced changes in peak and velocity of thrombin generation by 72.5% and 72.2%, respectively. High heparin and antithrombin levels attenuated thrombin-antithrombin complex formation in tissue factor-activated, GDXa-spiked cardiopulmonary bypass plasma by 85.7%, but tissue factor pathway inhibitor remained depleted compared with control cardiopulmonary bypass plasma. CONCLUSIONS: Simultaneous supplementation of heparin and antithrombin mitigate GDXa-induced heparin resistance by compensating for the loss of tissue factor pathway inhibitor.

Droxidopa or Atomoxetine for Refractory Hypotension in Critically Ill Cardiothoracic Surgery Patients.

OBJECTIVE: To evaluate the effects of droxidopa or atomoxetine on intravenous (IV) vasoactive agent discontinuation in cardiothoracic intensive care unit (ICU) patients with hypotension refractory to midodrine. DESIGN: Single-center, retrospective cohort study. SETTING: Tertiary- and quaternary-care university teaching hospital. PARTICIPANTS: Included patients who received at least 4 consecutive doses of droxidopa or atomoxetine and remained on concurrent midodrine. Patients were excluded if they received study medication before admission, had clinical deterioration after study medication initiation requiring additional vasoactives/escalation of IV vasoactive dosage for at least 12 hours, had a diagnosis of hepatorenal syndrome, were prisoners, or were pregnant. INTERVENTIONS: Droxidopa, atomoxetine, or both. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was time to discontinuation of IV vasoactive agents after initiation of study medication, analyzed using a Kaplan-Meier estimate with the Wilcoxon method, censoring death within 24 hours of the last dose of study medication. No adjustment for repetitive analyses was made, as the analysis was hypothesis-generating. Of the 72 charts reviewed, 45 patients met inclusion criteria (18 atomoxetine, 17 droxidopa, and 10 both). There were no differences in median time to discontinuation of IV vasoactive agents (21.9 days v 8.0 days v 13.9 days, respectively; p = 0.259) or ICU or hospital length of stay between groups. A higher percentage of patients who survived to hospital discharge received both study medications or droxidopa alone (90% v 76.5%) than atomoxetine alone (44.4%, p = 0.028). CONCLUSIONS: Droxidopa and atomoxetine are oral vasoactive agents with potential mechanisms to facilitate IV vasopressor weaning for patients in the ICU with hypotension refractory to midodrine, but further prospective research is needed.

Management of patients on antithrombotic therapy with severe infections: a joint clinical consensus statement of the ESC Working Group on Thrombosis, the ESC Working Group on Atherosclerosis and Vascular Biology, and the International Society on Thrombosis and Haemostasis.

Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combinations, require integrated clinical counselling among coagulation, infectious disease, and cardiology specialists, due to sepsis-induced coagulopathy that frequently occurs. Bacterial and viral pathogens constitute an increasing threat to global public health, especially for patients with ongoing antithrombotic treatment who have a high risk of thrombotic recurrences and high susceptibility to severe infections with increased morbidity and mortality. Similarly, sepsis survivors are at increased risk for major vascular events. Coagulopathy, which often complicates severe infections, is associated with a high mortality and obligates clinicians to adjust antithrombotic drug type and dosing to avoid bleeding while preventing thrombotic complications. This clinical consensus statement reviews the best available evidence to provide expert opinion and statements on the management of patients hospitalized for severe bacterial or viral infections with a pre-existing indication for antithrombotic therapy (single or combined), in whom sepsis-induced coagulopathy is often observed. Balancing the risk of thrombosis and bleeding in these patients and preventing infections with vaccines, if available, are crucial to prevent events or improve outcomes and prognosis.

Platelet Activation and Thrombosis in COVID-19.

Although thrombosis frequently occurs in infectious diseases, the coagulopathy associated with COVID-19 has unique characteristics. Compared with bacterial sepsis, COVID-19-associated coagulopathy presents with minimal changes in platelet counts, normal prothrombin times, and increased D-dimer and fibrinogen levels. These differences can be explained by the distinct pathophysiology of the thromboinflammatory responses. In sepsis-induced coagulopathy, leukocytes are primarily responsible for the coagulopathy by expressing tissue factor, releasing neutrophil extracellular traps, multiple procoagulant substances, and systemic endothelial injury that is often associated with vasoplegia and shock. In COVID-19-associated coagulopathy, platelet activation is a major driver of inflammation/thrombogenesis and von Willebrand factor and platelet factor 4 are deeply involved in the pathogenesis. Although the initial responses are localized to the lung, they can spread systemically if the disease is severe. Since the platelets play major roles, arterial thrombosis is not uncommon in COVID-19. Despite platelet activation, platelet count is usually normal at presentation, but sensitive biomarkers including von Willebrand factor activity, soluble P-selectin, and soluble C-type lectin-like receptor-2 are elevated, and they increase as the disease progresses. Although the role of antiplatelet therapy is still unproven, current studies are ongoing to determine its potential effects.

What Role Does Microthrombosis Play in Long COVID?

Soon after the outbreak of coronavirus disease 2019 (COVID-19), unexplained sustained fatigue, cognitive disturbance, and muscle ache/weakness were reported in patients who had recovered from acute COVID-19 infection. This abnormal condition has been recognized as "long COVID (postacute sequelae of COVID-19 [PASC])" with a prevalence estimated to be from 10 to 20% of convalescent patients. Although the pathophysiology of PASC has been studied, the exact mechanism remains obscure. Microclots in circulation can represent one of the possible causes of PASC. Although hypercoagulability and thrombosis are critical mechanisms of acute COVID-19, recent studies have reported that thromboinflammation continues in some patients, even after the virus has cleared. Viral spike proteins and RNA can be detected months after patients have recovered, findings that may be responsible for persistent thromboinflammation and the development of microclots. Despite this theory, long-term results of anticoagulation, antiplatelet therapy, and vascular endothelial protection are inconsistent, and could not always show beneficial treatment effects. In summary, PASC reflects a heterogeneous condition, and microclots cannot explain all the presenting symptoms. After clarification of the pathomechanisms of each symptom, a symptom- or biomarker-based stratified approach should be considered for future studies.

Perioperative Considerations in Management of the Severely Bleeding Coagulopathic Patient.

Inherited and acquired coagulopathy are frequently associated with major bleeding in severe trauma, cardiac surgery with cardiopulmonary bypass, and postpartum hemorrhage. Perioperative management is multifactorial and includes preoperative optimization and discontinuation of anticoagulants and antiplatelet therapy in elective procedures. Prophylactic or therapeutic use of antifibrinolytic agents is strongly recommended in guidelines and has been shown to reduce bleeding and need for allogeneic blood administration. In the context of bleeding induced by anticoagulants and/or antiplatelet therapy, reversal strategies should be considered when available. Targeted goal-directed therapy using viscoelastic point-of-care monitoring is increasingly used to guide the administration of coagulation factors and allogenic blood products. In addition, damage control surgery, which includes tamponade of large wound areas, leaving surgical fields open, and other temporary maneuvers, should be considered when bleeding is refractory to hemostatic measures.

Epinephrine-induced Effects on Cerebral Microcirculation and Oxygenation Dynamics Using Multimodal Monitoring and Functional Photoacoustic Microscopy.

BACKGROUND: The administration of epinephrine after severe refractory hypotension, shock, or cardiac arrest restores systemic blood flow and major vessel perfusion but may worsen cerebral microvascular perfusion and oxygen delivery through vasoconstriction. The authors hypothesized that epinephrine induces significant microvascular constriction in the brain, with increased severity after repetitive dosing and in the aged brain, eventually leading to tissue hypoxia. METHODS: The authors investigated the effects of intravenous epinephrine administration in healthy young and aged C57Bl/6 mice on cerebral microvascular blood flow and oxygen delivery using multimodal in vivo imaging, including functional photoacoustic microscopy, brain tissue oxygen sensing, and follow-up histologic assessment. RESULTS: The authors report three main findings. First, after epinephrine administration, microvessels exhibited severe immediate vasoconstriction (57 ± 6% of baseline at 6 min, P < 0.0001, n = 6) that outlasted the concurrent increase in arterial blood pressure, while larger vessels demonstrated an initial increase in flow (108 ± 6% of baseline at 6 min, P = 0.02, n = 6). Second, oxyhemoglobin decreased significantly within cerebral vessels with a more pronounced effect in smaller vessels (microvessels to 69 ± 8% of baseline at 6 min, P < 0.0001, n = 6). Third, oxyhemoglobin desaturation did not indicate brain hypoxia; on the contrary, brain tissue oxygen increased after epinephrine application (from 31 ± 11 mmHg at baseline to 56 ± 12 mmHg, 80% increase, P = 0.01, n = 12). In the aged brains, microvascular constriction was less prominent yet slower to recover compared to young brains, but tissue oxygenation was increased, confirming relative hyperoxia. CONCLUSIONS: Intravenous application of epinephrine induced marked cerebral microvascular constriction, intravascular hemoglobin desaturation, and paradoxically, an increase in brain tissue oxygen levels, likely due to reduced transit time heterogeneity.

Inflammation, coagulation, and cellular injury in heat-induced shock.

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.

The antithrombin activity recovery after substitution therapy is associated with improved 28-day mortality in patients with sepsis-associated disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a common and critical complication in sepsis. Antithrombin activity, which is considered a biomarker for disease severity, was measured in septic DIC treated with antithrombin concentrates in this study. METHODS: We conducted a retrospective analysis of post-marketing survey data that included 1,800 patients with sepsis-associated DIC and antithrombin activity of 70% or less who were treated with antithrombin concentrates. The changes in sequential organ failure assessment (SOFA) score, DIC score, and antithrombin activity were sequentially assessed. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed to evaluate the performance of antithrombin activity to assess 28-day survival. Furthermore, the relationship between post-treatment antithrombin activity and survival was examined by Logistic regression analysis. RESULTS: Sex, baseline SOFA score, baseline antithrombin activities, and the presence of pneumonia and soft tissue infection were significantly associated with 28-day mortality. The area under the curve for mortality was 0.639 for post-treatment antithrombin activity, and higher than those of baseline- and delta antithrombin activities. Logistic regression analysis revealed that higher post-treatment antithrombin activity was associated with better 28-day survival. When post-treatment antithrombin activity was more than 80%, the estimated survival was 88.2%. Whereas, the survival was 74.4% when the antithrombin activity was 80% or less (P < 0.0001). However, the relationship between post-treatment antithrombin activity and 28-day survival was considerably different between patients who recovered from DIC by Day 6 compared to those who did not. Similarly, the estimated 28-day survival, based on antithrombin activity, varied among patients with high and low SOFA scores, and the calculation needs to be adjusted based on the severity of the condition. CONCLUSIONS: Post-treatment antithrombin activity measurement was helpful in estimating the 28-day survival in patients with sepsis-associated DIC. However, patient outcomes vary considerably depending on factors that include baseline SOFA score, age, and baseline antithrombin activity. These variables play a substantial role in determining patient prognosis and should be considered when evaluating and interpreting the results.

Renal Dysfunction and Arrhythmia Association in Patients Receiving Milrinone After Cardiac Surgery.

OBJECTIVE: The altered pharmacokinetics of milrinone in renal impairment could result in an increased risk of cardiac arrhythmias. This study aimed to determine if there is an association between new-onset arrhythmias and renal impairment after cardiac surgery following milrinone administration. DESIGN: A retrospective cohort study. SETTING: A single-center tertiary care hospital. PARTICIPANTS: Adult patients who received a milrinone infusion in the intensive care unit (ICU) setting after coronary artery bypass graft, valvuloplasty, annuloplasty, or a combination of these surgeries from July 1, 2014 to July 1, 2021. Renal impairment was defined using a creatinine clearance <60 mL/min, calculated using the Cockcroft-Gault equation. INTERVENTIONS: Patients received a weight-based continuous intravenous infusion of milrinone. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the presence of new arrhythmias after the initial administration of a weight-based continuous intravenous infusion of milrinone postcardiac surgery. Of the 197 patients who met inclusion, there was no difference in the presence of new arrhythmias (42.9% v 40.3%, p = 0.76) or in the time to first new arrhythmia from milrinone initiation in those with renal impairment compared to those without renal impairment (29.1 hours v 33.3 hours, p = 0.54). Patients with renal impairment had a longer hospital stay than patients without renal impairment (17.5 days v 13.9 days, p = 0.016). Arrhythmia type, length of ICU stay, ICU mortality, and hospital mortality were not different between the cohorts. CONCLUSIONS: There was no association between new arrhythmias, milrinone, and renal impairment in patients postcardiac surgery.

In Vitro Treatment of Extracorporeal Membrane Oxygenation Coagulopathy with Recombinant von Willebrand Factor or Lyophilized Platelets.

OBJECTIVES: The objective was to compare primary hemostasis between adult ECMO patients and cardiac surgical patients before heparinization and cardiopulmonary bypass. Furthermore, the authors explored whether in vitro treatment of ECMO patient blood samples with recombinant von Willebrand Factor (vWF) or lyophilized platelets improved primary hemostasis in vitro. DESIGN: Prospective cohort study. SETTING: Single academic medical center. PARTICIPANTS: Ten cardiac surgical patients and 8 adult ECMO patients. INTERVENTIONS: Cardiac surgical patients and ECMO patients had blood samples collected, and in vitro platelet thrombus formation was assessed using the ATLAS PST device. The ECMO patients had platelet thrombus formation evaluated at baseline and after in vitro treatment with recombinant vWF or lyophilized platelets, whereas cardiac surgical patients had a single blood sample obtained before heparinization and cardiopulmonary bypass run. MEASUREMENTS AND MAIN RESULTS: Median maximum force (39.7 v 260.2 nN) and thrombus area (0.05 v 0.11) at 5 minutes were lower in untreated ECMO patient samples compared with cardiac surgical patients (p = 0.008 and p < 0.001, respectively). The ECMO patient samples treated with recombinant vWF demonstrated an increase in both platelet maximum force (median value of 222.1 v 39.7 nN) (p = 0.01) and platelet thrombus area (median value of 0.16 v 0.05; p = 0.001). The ECMO patient samples treated with lyophilized platelets demonstrated no increase in platelet maximum force (median value of 193.3 v 39.7 nN; p = 0.18); however, there was a significant increase in platelet thrombus area (median value of 0.13 v 0.05; p = 0.04). CONCLUSIONS: Recombinant vWF and lyophilized platelets may help to restore primary hemostasis in ECMO patients. Future studies should further evaluate the safety and efficacy of these potential therapeutics in ECMO patients.

Direct oral anticoagulants and their antagonists in perioperative practice.

PURPOSE OF REVIEW: Review management strategies for patients receiving nonvitamin K direct-acting oral anticoagulants (DOACs). RECENT FINDINGS: Updated clinical trials and guidelines continue to further define optimal management for patients on DOACs requiring emergency surgery or procedural interventions. In addition, specific bleeding management strategies that include either specific or nonspecific antagonists are becoming available. SUMMARY: Most currently used DOACs are factor Xa inhibitors and should be stopped for 24-48 h for elective surgical procedures in patients at risk for bleeding and potentially longer for dabigatran, depending on renal function. Idarucizumab, a specific dabigatran reversal agent, has been studied in surgical patients and is currently approved for use. For Xa inhibitors apixaban and rivaroxaban, although andexanet alfa is approved for medical bleeds, it is not approved for surgical patients, has a short duration of effect, and costs $12 500 per gram. When managing DOAC-treated patients requiring emergency surgery, when stopping the DOAC and delaying surgery is not feasible, standard approaches should include hemostatic, hemodynamic, and transfusional support. Due to higher risk associated with therapeutic agents used to manage DOAC-related bleeding, increasing data supports the potential off-label use of prothrombin complex concentrate (PCC).

Recognizing Vaccine-Induced Immune Thrombotic Thrombocytopenia.

OBJECTIVES: Vaccine-induced immune thrombotic thrombocytopenia is an unexpected consequence of the coronavirus disease 2019 pandemic era. We reviewed the pathogenesis, clinical presentation, diagnosis, and treatment of this rare side effect. DATA SOURCES: Online search of published medical literature through PubMed, Scopus, Web of Science, and Google Scholar using the terms "COVID-19," "vaccine," "thrombosis" was performed. STUDY SELECTION: Articles were chosen for inclusion based on their relevance to coronavirus disease 2019, vaccine, and thrombosis. DATA SYNTHESIS: Vaccine-induced immune thrombotic thrombocytopenia manifests most often as unusual thromboses (cerebral venous sinus thrombosis, splanchnic vein thrombosis) but sometimes also "usual" thromboses (arterial stroke, pulmonary embolism, deep-vein thrombosis), with oftentimes severe thrombocytopenia, that becomes clinically evident 5-30 days after adenovirus-vectored coronavirus disease 2019 vaccine administration. Most patients have disseminated intravascular coagulation. These features are the result of vaccine-triggered formation of anti-platelet factor 4 immunoglobulin G that activate platelets, clinically mimicking autoimmune heparin-induced thrombocytopenia. Early recognition based on thrombosis (sometimes, hemorrhage), thrombocytopenia, and d-dimer elevation within the day 5-30 postvaccine "window" is important given treatment with high-dose IV immunoglobulin plus nonheparin anticoagulation. CONCLUSIONS: Vaccine-induced immune thrombotic thrombocytopenia is a serious complication of vaccination that is not feasible to anticipate or prevent. When the patient presents with sustained headache, neurologic symptoms/signs, abdominal pain, dyspnea, or limb pain/swelling beginning 5-30 days post vaccination, platelet count and d-dimer must be measured, and imaging for thrombosis performed. Confirmation of vaccine-induced immune thrombotic thrombocytopenia diagnosis should be ordered (platelet factor 4/polyanion enzyme-linked immunosorbent assay; platelet factor 4-enhanced platelet activation testing) as treatment is initiated (nonheparin anticoagulation, IV immunoglobulin).

Disseminated Intravascular Coagulation: The Past, Present, and Future Considerations.

Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no "one-size-fits-all criteria." Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC.

COVID-19 and its implications for thrombosis and anticoagulation.

Severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019 (COVID-19)-induced infection can be associated with a coagulopathy, findings consistent with infection-induced inflammatory changes as observed in patients with disseminated intravascular coagulopathy (DIC). The lack of prior immunity to COVID-19 has resulted in large numbers of infected patients across the globe and uncertainty regarding management of the complications that arise in the course of this viral illness. The lungs are the target organ for COVID-19; patients develop acute lung injury that can progress to respiratory failure, although multiorgan failure can also occur. The initial coagulopathy of COVID-19 presents with prominent elevation of D-dimer and fibrin/fibrinogen-degradation products, whereas abnormalities in prothrombin time, partial thromboplastin time, and platelet counts are relatively uncommon in initial presentations. Coagulation test screening, including the measurement of D-dimer and fibrinogen levels, is suggested. COVID-19-associated coagulopathy should be managed as it would be for any critically ill patient, following the established practice of using thromboembolic prophylaxis for critically ill hospitalized patients, and standard supportive care measures for those with sepsis-induced coagulopathy or DIC. Although D-dimer, sepsis physiology, and consumptive coagulopathy are indicators of mortality, current data do not suggest the use of full-intensity anticoagulation doses unless otherwise clinically indicated. Even though there is an associated coagulopathy with COVID-19, bleeding manifestations, even in those with DIC, have not been reported. If bleeding does occur, standard guidelines for the management of DIC and bleeding should be followed.

The risk of thromboembolic events with early intravenous 2- and 4-g bolus dosing of tranexamic acid compared to placebo in patients with severe traumatic bleeding: A secondary analysis of a randomized, double-blind, placebo-controlled, single-center trial.

BACKGROUND: Screening for the risk of thromboembolism (TE) due to tranexamic acid (TXA) in patients with severe traumatic injury has not been performed in randomized clinical trials. Our objective was to determine if TXA dose was independently-associated with thromboembolism. STUDY DESIGN AND METHODS: This is a secondary analysis of a single-center, double-blinded, randomized controlled trial comparing placebo to a 2-g or 4-g intravenous TXA bolus dose in trauma patients with severe injury. We used multivariable discrete-time Cox regression models to identify associations with risk for thromboembolic events within 30 days post-enrollment. Event curves were created using discrete-time Cox regression. RESULTS: There were 50 patients in the placebo group, 49 in the 2-g, and 50 in the 4-g TXA group. In adjusted analyses for thromboembolism, a 2-g dose of TXA had an hazard ratio (HR, 95% confidence interval [CI]) of 3.20 (1.12-9.11) (p = .029), and a 4-g dose of TXA had an HR (95% CI) of 5.33 (1.94-14.63) (p = .001). Event curves demonstrated a higher probability of thromboembolism for both doses of TXA compared to placebo. Other parameters independently associated with thromboembolism include time from injury to TXA administration, body mass index, and total blood products transfused. DISCUSSION: In patients with severe traumatic injury, there was a dose-dependent increase in the risk of at least one thromboembolic event with TXA. TXA should not be withheld, but thromboembolism screening should be considered for patients receiving a dose of at least 2-g TXA intravenously for traumatic hemorrhage.

Suppression of Fibrinolysis and Hypercoagulability, Severity of Hypoxemia, and Mortality in COVID-19 Patients: A Retrospective Cohort Study.

BACKGROUND: COVID-19 causes hypercoagulability, but the association between coagulopathy and hypoxemia in critically ill patients has not been thoroughly explored. This study hypothesized that severity of coagulopathy would be associated with acute respiratory distress syndrome severity, major thrombotic events, and mortality in patients requiring intensive care unit-level care. METHODS: Viscoelastic testing by rotational thromboelastometry and coagulation factor biomarker analyses were performed in this prospective observational cohort study of critically ill COVID-19 patients from April 2020 to October 2020. Statistical analyses were performed to identify significant coagulopathic biomarkers such as fibrinolysis-inhibiting plasminogen activator inhibitor 1 and their associations with clinical outcomes such as mortality, extracorporeal membrane oxygenation requirement, occurrence of major thrombotic events, and severity of hypoxemia (arterial partial pressure of oxygen/fraction of inspired oxygen categorized into mild, moderate, and severe per the Berlin criteria). RESULTS: In total, 53 of 55 (96%) of the cohort required mechanical ventilation and 9 of 55 (16%) required extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation-naïve patients demonstrated lysis indices at 30 min indicative of fibrinolytic suppression on rotational thromboelastometry. Survivors demonstrated fewer procoagulate acute phase reactants, such as microparticle-bound tissue factor levels (odds ratio, 0.14 [0.02, 0.99]; P = 0.049). Those who did not experience significant bleeding events had smaller changes in ADAMTS13 levels compared to those who did (odds ratio, 0.05 [0, 0.7]; P = 0.026). Elevations in plasminogen activator inhibitor 1 (odds ratio, 1.95 [1.21, 3.14]; P = 0.006), d-dimer (odds ratio, 3.52 [0.99, 12.48]; P = 0.05), and factor VIII (no clot, 1.15 ± 0.28 vs. clot, 1.42 ± 0.31; P = 0.003) were also demonstrated in extracorporeal membrane oxygenation-naïve patients who experienced major thrombotic events. Plasminogen activator inhibitor 1 levels were significantly elevated during periods of severe compared to mild and moderate acute respiratory distress syndrome (severe, 44.2 ± 14.9 ng/ml vs. mild, 31.8 ± 14.7 ng/ml and moderate, 33.1 ± 15.9 ng/ml; P = 0.029 and 0.039, respectively). CONCLUSIONS: Increased inflammatory and procoagulant markers such as plasminogen activator inhibitor 1, microparticle-bound tissue factor, and von Willebrand factor levels are associated with severe hypoxemia and major thrombotic events, implicating fibrinolytic suppression in the microcirculatory system and subsequent micro- and macrovascular thrombosis in severe COVID-19.