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Heat-related illness is becoming more problematic due to ongoing global warming. Heat-related injury causes systemic inflammation and coagulopathy, due to leukocyte, platelet, and vascular endothelial cell activation and injury. Hyperthermia directly modulates platelet function and can induce cellular damage. Meanwhile, heat also affects platelet function via activated coagulation, excess inflammation, production of cytokines, and heat shock proteins. Aberrant hyperthermia-induced interactions between leukocytes and endothelial cells are also involved in platelet regulation. Heat-induced coagulopathy commonly progresses to disseminated intravascular coagulation (DIC), leading to multiple organ failure and in some cases enhanced bleeding. Consequently, platelet count, prothrombin time, and DIC score are useful for evaluating the severity of heat-related illness in addition to other organ damage markers such as Glasgow Coma Scale, creatinine, and bilirubin. Despite the increasing risk, therapeutic modalities targeting platelets are limited and no established therapy exists. In this review, we summarize the current knowledge about the role of platelets in the pathogenesis, diagnosis, and management of heat-related illness.

COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI 2, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 μg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.

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

Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoingcardiac surgery may be especially vulnerable to the adverse effects of transfusion.

Bleeding is a significant complication of anticoagulant therapy. With the emergence of new oral anticoagulants (NOACs; ie, direct factor IIa or Xa inhibitors), this risk is further compounded by the lack of validated reversal strategies for these agents. Emerging postmarketing evidence suggests that the bleeding risks are in line with results observed in head-to-head clinical trials of NOACs versus traditional anticoagulants. Several guidelines have recommended the use of hemostatic agents for NOAC reversal in patients with life-threatening bleeding. Ultimately, adequately powered studies will be crucial for full assessment of the effectiveness and safety of any proposed reversal strategies

Internal mammary arteries (IMA) are routinely used for coronary artery bypass grafting (CABG), but can exhibit impairment of endothelium-dependent vascular relaxation. The use of radial artery (RA) grafts for CABG has been recently reintroduced. The long-term patency of these grafts may depend on the ability of these vessels to produce endotheliumderived nitric oxide (NO). We therefore sought to determine if the RA exhibits better endothelial function compared with IMA harvested from the same patient. Using the organ bath technique, vessels were preconstricted with the thromboxane A2 analogue (U46619) and exposed to increasing concentrations of either acetylcholine (ACh ), calcium ionophore A23187 (A23187), or nitroglycerin (NTG). We prepared the rubbed RA for comparison of between RA with and without endothelium on response to ACh relaxation. KCI and U46619 constricted RA (11.3ﾂｱ4.9g and 16.0ﾂｱ4.3g respectively) more than IMA(2.4ﾂｱ1.4g and 4.5ﾂｱ1.7 respectively). Both RA and IMA relaxed 100% of the preconstricted tension to NTG. ACh induced less relaxation in the IMA(28ﾂｱ24%) when compared with the RA(49ﾂｱ16%)(p, Acta medica Nagasakiensia. 2000, 45(3-4), p.33-37

The objective of this study was to characterize the bleeding, transfusion, and other outcomes of patients related to the timing of prasugrel or clopidogrel withdrawal before coronary artery bypass grafting (CABG).There is little evidence to guide clinical decision making regarding the use of prasugrel in patients who may need urgent or emergency CABG. Experience with performing CABG in the presence of clopidogrel has raised concern about perioperative bleeding complications that are unresolved.A subset of the TRITON-TIMI 38 study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38), in which patients with acute coronary syndrome were randomized to treatment with aspirin and either clopidogrel or prasugrel, underwent isolated CABG (N = 346). A supplemental case report form was designed and administered, and the data combined with the existing TRITON-TIMI 38 database. Baseline imbalances were corrected for using elements of the European System for Cardiac Operative Risk Evaluation and The Society of Thoracic Surgeons predictive algorithm.A significantly higher mean 12-h chest tube blood loss (655 ± 580 ml vs. 503 ± 378 ml; p = 0.050) was observed with prasugrel compared with clopidogrel, without significant differences in red blood cell transfusion (2.1 U vs. 1.7 U; p = 0.442) or the total donor exposure (4.4 U vs. 3.0 U; p = 0.463). All-cause mortality was significantly reduced with prasugrel (2.31%) compared with 8.67% with clopidogrel (adjusted odds ratio: 0.26; p = 0.025).Despite an increase in observed bleeding, platelet transfusion, and surgical re-exploration for bleeding, prasugrel was associated with a lower rate of death after CABG compared with clopidogrel.

The major therapeutic approach to systemic and pulmonary hypertension and vasospasm in cardiac surgery patients involves the use of parenteral agents that reverse systemic vasoconstriction and produce vasodilation. Potential pharmacologic approaches include 1) alpha1-adrenergic receptor blockers, ganglionic blockers, and calcium channel blockers; 2) central alpha2-adrenergic receptor agonists, dopamine1-adrenergic receptor agonists, potassium channel modulators, and vascular cyclic nucleotide stimulators; 3) phosphodiesterase enzyme inhibitors, and 4) angiotensin-converting enzyme inhibitors. Of the currently available intravenous vasoactive therapies, the mainstay agents are the nitrovasodilators and the dihydropyridine-type calcium channel blockers. The nitrovasodilators, a diverse group of drugs that achieve vascular relaxation by stimulating cyclic nucleotides and thereby releasing nitric oxide, include nitroglycerin and sodium nitroprusside. Although these drugs are useful, rapid development of tolerance is a drawback to nitroglycerin, while nitroprusside can cause coronary steal and increase intracranial pressure. Intravenous dihydropyridine-type calcium channel blockers inhibit mechanical responses of cardiac muscle and vascular smooth muscle by blocking inward calcium currents. Nicardipine is an arterial specific vasodilator. Treatment for vasospasm is usually empiric; pharmacologic options include nitroglycerin, but dihydropyridine calcium channel blockers and phosphodiesterase inhibitors should also be considered.

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

ObjectivesThe objective of this study was to characterize the bleeding, transfusion, and other outcomes of patients related to the timing of prasugrel or clopidogrel withdrawal before coronary artery bypass grafting (CABG).BackgroundThere is little evidence to guide clinical decision making regarding the use of prasugrel in patients who may need urgent or emergency CABG. Experience with performing CABG in the presence of clopidogrel has raised concern about perioperative bleeding complications that are unresolved.MethodsA subset of the TRITON–TIMI 38 study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38), in which patients with acute coronary syndrome were randomized to treatment with aspirin and either clopidogrel or prasugrel, underwent isolated CABG (N = 346). A supplemental case report form was designed and administered, and the data combined with the existing TRITON–TIMI 38 database. Baseline imbalances were corrected for using elements of the European System for Cardiac Operative Risk Evaluation and The Society of Thoracic Surgeons predictive algorithm.ResultsA significantly higher mean 12-h chest tube blood loss (655 ± 580 ml vs. 503 ± 378 ml; p = 0.050) was observed with prasugrel compared with clopidogrel, without significant differences in red blood cell transfusion (2.1 U vs. 1.7 U; p = 0.442) or the total donor exposure (4.4 U vs. 3.0 U; p = 0.463). All-cause mortality was significantly reduced with prasugrel (2.31%) compared with 8.67% with clopidogrel (adjusted odds ratio: 0.26; p = 0.025).ConclusionsDespite an increase in observed bleeding, platelet transfusion, and surgical re-exploration for bleeding, prasugrel was associated with a lower rate of death after CABG compared with clopidogrel. (A Comparison of Prasugrel [CS-747] and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention; NCT00097591)