Changes in the hematobiochemical, acid-base and blood gas elements as well as biomarkers of inflammation and bone metabolism in donkeys (Equus asinus) with acute bleeding.

Background: Acute hemorrhage is fatal in equines with a complication of severe hypovolemic shock that causes a sudden death in such cases. Aim: This study was designed to report the influences of acute bleeding in conscious non-sedated donkeys (Equus asinus) on the hematobiochemical variables, acid-base, blood gas elements, and markers of inflammation and bone metabolism. Methods: Eight healthy donkeys were used where a total of 900 ml of whole blood was collected. Five blood samples were collected from each animal: just before collection of blood (T0); (2) 30 (T1), 60 (T2), 120 (T3), and 240 minutes (T4) later. The blood panels including total white blood cells, lymphocytes, neutrophils, red blood cell counts (RBCs), HCT, hemoglobin (Hg), and RBCs indices were measured. Biochemical parameters and electrolytes were evaluated. The activity of aspartate aminotransferase (AST), creatine kinase (CK), and γ-glutamyl transferase (GGT) were also determined. Complete acid-base and blood gas panels were assessed. Serum amyloid A (SAA), haptoglobin (Hp), osteocalcin (OC), bone alkaline phosphatase (b-ALP), and pyridinoline cross-links (PYD) were measured. Results: The RBCs, Hg, and HCT increased significantly at points T1, T2, and T3 compared to T0. The concentrations of total proteins and albumin decreased significantly at points T3 and T4. The blood urea nitrogen concentrations increased significantly at T4. Creatinine concentrations increased significantly at T2 and T3. The AST, GGT, and CK decreased significantly. On the other hand, glucose increased significantly at T3 and T4. The pH decreased significantly at points T1, T2, T3, and T4. The PCO2 increased significantly at T3 and T4. The BE, HCO3, and TCO2 values decreased significantly at T2, T3, and T4. Contrary, the AG increased significantly at points T3 and T4. The potassium increased significantly at T1-T4 and chloride decreased significantly at T3 and T4. Lactate showed significant increases at T1-T4. The SAA, Hp, OC, b-ALP, and PYD did not differ significantly at T1-T4. Conclusion: In conscious non-sedated donkeys, induced bleeding resulted in significant changes in the hematobiochemical elements, the acid-base status, and blood gas and electrolyte parameters. However, it did not change the markers of inflammation and bone metabolism.

Bleeding risk in hemophilia A and B carriers: comparison of factor levels determined using chronometric and chromogenic assays.

BACKGROUND: Predicting the bleeding risk in hemophilia A and B carriers (HAC, HBC) is challenging. OBJECTIVE: The objectives of this study were to describe the bleeding phenotype in HAC and HBC using the standardized Tosetto bleeding score (BS); to determine whether the BS correlates better with factor levels measured with a chromogenic assay than with factor levels measured with chronometric and thrombin generation assays; and to compare the results in HAC and HBC. METHODS: This ambispective, noninterventional study included obligate and sporadic HAC and HBC followed at a hemophilia treatment center between 1995 and 2019. RESULTS AND CONCLUSION: The median BS (3, range 0-21 vs. 3.5, range 0-15, P  = ns, respectively) and the abnormal BS rate (35.6% vs. 38.2%, P  = ns) were not significantly different in 104 HAC and 34 HBC (mean age: 38 years, 6-80 years). However, some differences were identified. The risk of factor deficiency was higher in HBC than HAC. Specifically, Factor VIII activity (FVIII):C/Factor IX activity (FIX):C level was low (<40 IU/dl) in 18.3% (chronometric assay) and 17.5% (chromogenic assay) of HAC and in 47% and 72.2% of HBC ( P  < 0.001). Moreover, the FIX:C level thresholds of 39.5 IU/dl (chronometric assay) and of 33.5 IU/dl (chromogenic assay) were associated with very good sensitivity (92% and 100%, respectively) and specificity (80% for both) for bleeding risk prediction in HBC. Conversely, no FVIII:C level threshold could be identified for HAC, probably due to FVIII:C level variations throughout life.

A lower fibrinogen threshold does not lead to increased bleeding risk in patients receiving therapeutic plasma exchange: A prospective single-center analysis.

BACKGROUND: Plasma exchange (PLEX) therapy is indicated for several disorders. The 5% albumin is often used as a sole replacement fluid during most PLEX. However, each 1.0 plasma volume exchange depletes coagulation factors by ~65%. Although most coagulation factors recover to hemostatic levels within 24 h post-PLEX, fibrinogen requires 48-72 h to recover. Fibrinogen is the key coagulation protein for hemostasis. Therefore, fibrinogen is often monitored during the acute course of PLEX, and plasma is supplemented to prevent bleeding if fibrinogen is <100 mg/dL. STUDY DESIGN AND METHODS: We conducted a prospective, single-center, observational study to evaluate bleeding risk in adults who received an acute course of PLEX with a fibrinogen level of 80-100 mg/dL without plasma supplementation during the procedure or before central venous catheter removal. The study group was compared to patients with plasma fibrinogen >100 mg/dL. RESULTS: Among the 275 patients who received 1406 PLEXes, 62 patients (23%) who underwent 323 PLEXes met the inclusion criteria, and only 2 (3%) patients had bleeding while on oral anticoagulants. In contrast, out of 275 patients, 143 (52%) with fibrinogen levels >100 mg/dL received 751 PLEX treatments, and bleeding occurred in 2 (1%) while on low-molecular-weight heparin. CONCLUSIONS: Our findings suggest that a pre-procedure fibrinogen threshold of 80-100 mg/dL without plasma supplementation does not increase bleeding risk unless patients were on anticoagulation.

Multicenter evaluation of the hemostatic activity of emicizumab in patients with severe hemophilia A.

BACKGROUND: Emicizumab has been approved for the prophylaxis of patients with hemophilia A with or without inhibitors. However, spontaneous and trauma-induced breakthrough bleeds have been reported in patients on emicizumab prophylaxis, and no laboratory assay has been validated to evaluate the hemostatic activity of emicizumab. OBJECTIVES: The thrombin generation assay (TGA) could be a surrogate marker of the hemostatic efficacy of emicizumab. The correlation between TGA and the methods used to measure emicizumab blood concentration was evaluated in this study. METHODS: TGA was modified by the use of a trigger reagent combining a very low concentration of tissue factor and activated factor (F)XI. Emicizumab quantification was performed by 3 methods: the modified 1-step FVIII assay and 2 methods based on liquid chromatography and mass spectrometry (LC-MS). RESULTS: Using tissue factor/activated FXI-triggered TGA and platelet-poor plasma, a relationship was observed between the area under the thrombin generation curve (endogenous thrombin potential [ETP]) and the clinical response of patients to emicizumab. The ultrastructure of fibrin clots was consistent with ETP results and showed that emicizumab had a hemostatic activity equivalent to 20 to 30 IU/dL of FVIII. Finally, pharmacokinetic/pharmacodynamic analyses showed no correlation between ETP and LC-MS nor with modified 1-stage FVIII assay, but a statistically significant correlation between the LC-MS methods and the time-to-peak results of the TGA. CONCLUSION: Using a modified TGA, this study showed that patients who experienced breakthrough bleeds while on emicizumab had a lower thrombin-generating capacity compared with others with good clinical response to emicizumab.

Relationship between plasma tissue Factor Pathway Inhibitor (TFPI) levels, thrombin generation and clinical risk of bleeding in patients with severe haemophilia A or B.

INTRODUCTION: Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor (TFPI) level. AIM: To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency. METHODS: Data on bleeding episodes retrospectively recorded during follow-up visits over 5-10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet-poor plasma (PPP) and platelet-rich plasma (PRP) using calibrated automated tomography (CAT). RESULTS: Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two-fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was ≤ 4.9 $ \le 4.9$ , AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR. CONCLUSION: In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment.

Biomarkers of bleeding and venous thromboembolism in patients with acute leukemia.

BACKGROUND: Coagulopathy and associated bleeding and deep vein thrombosis (DVT) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated. OBJECTIVES: To evaluate the associations between biomarker levels and bleeding and DVT in acute leukemia patients. METHODS: We examined plasma levels of activators, inhibitors, and biomarkers of the coagulation and fibrinolytic pathways in patients aged ≥18 years with newly diagnosed acute leukemia compared with those of normal controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and DVT in acute leukemia patients. The study included 358 patients with acute leukemia (29 with acute promyelocytic leukemia [APL], 253 with non-APL acute myeloid leukemia, and 76 with acute lymphoblastic leukemia) and 30 normal controls. RESULTS: Patients with acute leukemia had higher levels of extracellular vesicle tissue factor (EVTF) activity, phosphatidylserine-positive extracellular vesicles, plasminogen activator inhibitor-1, plasmin-antiplasmin complexes, and cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared with normal controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among acute leukemia patients. There were 41 bleeding and 23 DVT events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (subdistribution hazard ratio, 2.30; 95% CI, 0.99-5.31), whereas high levels of plasminogen activator inhibitor-1 were associated with increased risk of DVT (subdistribution hazard ratio, 3.00; 95% CI, 0.95-9.47) in these patients. CONCLUSION: Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and DVT.

The feasibility of introducing a whole blood component for traumatic haemorrhage in the UK.

BACKGROUND: The interest in re-introducing whole blood (WB) transfusion for the management of traumatic major haemorrhage is increasing. However, due to the current leucodepletion filters used in the UK a WB component was not readily available. Instead, an alternative but similar component, leucocyte depleted red cell and plasma (LD-RCP), which provided a unique experience in assessing the feasibility of a WB component was used whilst a WB component was being manufactured. STUDY DESIGN AND METHODS: Between November 2018 and October 2020, LD-RCP replaced RBC as standard of care for all trauma patients with major haemorrhage in London. The aims of the study were to assess (a) deliverability, (b) component wastage and (c) safety. RESULTS: Over the study period a total of 1208 LD-RCP units were delivered, of which 96.5% were delivered 'On Time In Full' (OTIF). Of the 1208 units, 733 (60.68%) were transfused and 475 (39.3%) units were wasted. Component wastage reduced significantly throughout the study (p = 0.001). A total of 177 patients had a blood group recorded, 86 were group O and 91 were non-group O. There was no statistically significantly difference between haemoglobin (p = 0.422), or bilirubin levels (p = 0.084) between group O and non-group O patients. DISCUSSION: It was feasible for NHS Blood and Transplant to deliver LD-RCP on time in full, however component wastage was high due to short shelf life and limited use of the component. Low titre group O LD-RCP units were not associated with clinical evidence of haemolysis.

Evaluation of soluble P-selectin as a predictive biomarker in acute symptomatic pulmonary embolism: Insights from a prospective observational study.

BACKGROUND: Soluble P-selectin (sP-selectin) has been proposed as a potential biomarker for venous thromboembolism (VTE) diagnosis with interesting results. However, its role in predicting early mortality in pulmonary embolism (PE) remains unexplored. METHODS: This observational, prospective, single-center study enrolled consecutive patients aged 18 or older with confirmed acute symptomatic PE and no prior anticoagulation. The study aims to assess the prognostic capacity of sP-selectin measured at the time of PE diagnosis for short-term mortality and major bleeding. RESULTS: A total of 196 patients, with a mean age of 69.1 years (SD 17), were included, of whom 52.6% were male. Within 30 days, 9.7% of patients (n = 19) died, and 5.1% (n = 10) suffered major bleeding. PE risk stratification revealed 4.6% (n = 9) with high-risk PE, 34.7% (n = 68) with intermediate-high-risk PE, 38.3% (n = 75) with intermediate-low-risk PE, and 22.5% (n = 44) with low-risk PE according to the European Society of Cardiology score. Mean plasma sP-selectin levels were comparable between survivors and non-survivors (489.7 ng/mL ±63 vs. 497.3 ng/mL ±51; p = .9). The ROC curve for 30-day all-cause mortality and major bleeding yielded an AUC of 0.49 (95% CI 0.36-0.63) and 0.46 (95% CI 0.24-0.68), respectively. Multivariate and survival analyses were precluded due to lack of significance. CONCLUSIONS: sP-selectin was not useful for predicting short-term mortality or major bleeding in patients with acute symptomatic pulmonary embolism. Further studies are required to clarify the role of sP-selectin in VTE, particularly in prognosticating PE outcomes.

Fibrinolysis as a Causative Mechanism for Bleeding Complications on Extracorporeal Membrane Oxygenation: A Pilot Observational Prospective Study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is associated with a high risk of bleeding complications. The specific impact of ECMO on fibrinolysis remains unexplored. The objective of the current pilot observational prospective study was to investigate the longitudinal dynamics of fibrinolytic markers-i.e., changes over time-in the context of bleeding events in patients on ECMO. METHODS: Longitudinal dynamics of contact phase components (kininogen and bradykinin) and fibrinolysis markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1], their complexes [tPA•PAI-1], plasmin-antiplasmin complexes, plasminogen, and D-dimer) were measured in patients undergoing venovenous and venoarterial ECMO, before implantation, at 0, 6, and 12 h after implantation, and daily thereafter. RESULTS: The cohort consisted of 30 patients (214 ECMO days). The concentrations of tPA, D-dimer, plasmin-antiplasmin complexes, PAI-1, and tPA•PAI-1 complexes were increased, whereas plasminogen decreased compared to normal values. A noteworthy divergence was observed between hemorrhagic and nonhemorrhagic patients: in bleeding patients, D-dimer, plasmin-antiplasmin, tPA, PAI-1, and tPA•PAI-1 followed an increasing kinetics before hemorrhage and then decreased to their baseline level; conversely, nonbleeding patients showed a decreasing kinetics in these markers. Also, D-dimer and tPA followed an increasing kinetics in bleeding patients compared to nonbleeding patients (median values for D-dimer dynamics: 1,080 vs. -440 ng/ml, P = 0.05; tPA dynamics: 0.130 vs. 0.100 nM, P = 0.038), and both markers significantly increased the day before hemorrhage. A tPA concentration above 0.304 nM was associated with bleeding events (odds ratio, 4.92; 95% CI, 1.01 to 24.08; P = 0.049). CONCLUSIONS: Contact activation induces fibrinolysis in ECMO patients, especially in patients experiencing bleeding. This finding supports the role of this mechanism as a possible causal factor for hemorrhages during ECMO and open new avenues for novel therapeutic perspectives.

Analyzing and modeling massive transfusion strategies and the role of fibrinogen-How much is the patient actually receiving?

BACKGROUND: Hemorrhage is a leading cause of preventable death in trauma, cardiac surgery, liver transplant, and childbirth. While emphasis on protocolization and ratio of blood product transfusion improves ability to treat hemorrhage rapidly, tools to facilitate understanding of the overall content of a specific transfusion strategy are lacking. Medical modeling can provide insights into where deficits in treatment could arise and key areas for clinical study. By using a transfusion model to gain insight into the aggregate content of massive transfusion protocols (MTPs), clinicians can optimize protocols and create opportunities for future studies of precision transfusion medicine in hemorrhage treatment. METHODS: The transfusion model describes the individual round and aggregate content provided by four rounds of MTP, illustrating that the total content of blood elements and coagulation factor changes over time, independent of the patient's condition. The configurable model calculates the aggregate hematocrit, platelet concentration, percent volume plasma, total grams and concentration of citrate, percent volume anticoagulant and additive solution, and concentration of clotting factors: fibrinogen, factor XIII, factor VIII, and von Willebrand factor, provided by the MTP strategy. RESULTS: Transfusion strategies based on a 1:1:1 or whole blood foundation provide between 13.7 and 17.2 L of blood products over four rounds. Content of strategies varies widely across all measurements based on base strategy and addition of concentrated sources of fibrinogen and other key clotting factors. DISCUSSION: Differences observed between modeled transfusion strategies provide key insights into potential opportunities to provide patients with precision transfusion strategy.

Increased platelet to red blood cell transfusion ratio associated with acute kidney injury in children with life-threatening bleeding.

INTRODUCTION: Transfusion may increase the risk of organ failure through immunomodulatory effects. The primary objective of this study was to assess for patient or transfusion-related factors that are independently associated with the risk of acute kidney injury (AKI) and acute respiratory distress syndrome (ARDS) in a cohort of children with life-threatening bleeding from all etiologies. METHODS: In a secondary analysis of the prospective observational massive transfusion in children (MATIC) study, multivariable logistic regression was performed in an adjusted analysis to determine if blood product ratios or deficits were independently associated with AKI or ARDS in children with life-threatening bleeding. RESULTS: There were 449 children included with a median (interquartile range, IQR) age of 7.3 years (1.7-14.7). Within 5 days of the life-threatening bleeding event, AKI occurred in 18.5% and ARDS occurred in 20.3% of the subjects. Every 10% increase in the platelet to red blood cell transfusion ratio is independently associated with a 12.7% increase in the odds of AKI (adjusted odds ratio 1.127; 95% confidence interval 1.025-1.239; p-value .013). Subjects with operative or medical etiologies were independently associated with an increased risk of AKI compared to those with traumatic injury. No transfusion-related variables were independently associated with the risk of developing ARDS. CONCLUSION: The use of increased platelet to red blood cell transfusion ratios in children with life-threatening bleeding of any etiology may increase the risk of AKI but not ARDS. Prospective trials are needed to determine if increased platelet use in this cohort increases the risk of AKI to examine possible mechanisms.

Prolonged coagulation times in severe fever with thrombocytopenia syndrome virus infection, the indicators of heparin-like effect and increased haemorrhagic risk.

Prolonged coagulation times, such as activated partial thromboplastin time (APTT) and thrombin time (TT), are common in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV) and have been confirmed to be related to patient's poor outcome by previous studies. To find out the reason for prolonged coagulation time in patients with SFTSV infection, and whether it predicts haemorrhagic risk or not. Seventy-eight consecutive patients with confirmed SFTSV infection were enrolled in this prospective, single-centre, observational study. Several global and specific coagulation parameters of these patients on admission were detected, and the haemorrhagic events during hospitalization and their outcomes were recorded. Most of the enrolled patients had prolonged APTT (82.1%) and TT (80.8%), normal prothrombin time (83.3%) and intrinsic coagulation factors above haemostatic levels (97.4%). The heparin-like effect was confirmed by a protamine neutralization test and anti-Xa activity detection in most patients. Interestingly, the APTT and TT results were significantly positively correlated with the levels of endothelial markers and viral load, respectively. The APTT was independently associated with the haemorrhage of patients. The prolonged APTT and TT of SFTS patients may mainly be attributed to endogenous heparinoids and are associated with increased haemorrhagic risk.

ISTH bleeding assessment tool and platelet function analyzer in children with mild inherited platelet function disorders.

OBJECTIVES: To evaluate the diagnostic performance of platelet function analyzer (PFA) and The International Society on Thrombosis and Hemostasis bleeding-assessment-tool (ISTH-BAT) in detecting mild inherited platelet function disorders (IPFDs) in children with suspected bleeding disorders. METHODS: Prospective single-center diagnostic study including consecutive patients <18 years with suspected bleeding disorder and performing a standardized workup for platelet function defects including ISTH-BAT, PFA, platelet aggregation testing, blood smear-based immunofluorescence, and next-generation sequencing-based genetic screening for IPFDs. RESULTS: We studied 97 patients, of which 34 von Willebrand disease (VWD, 22 type-1, 11 type-2), 29 IPFDs (including delta-/alpha-storage pool disease, Glanzmann thrombasthenia, Hermansky-Pudlak syndrome) and 34 with no diagnosis. In a model combining PFA-adenosine diphosphate (ADP), PFA-epinephrine (EPI), and ISTH-BAT overall performance to diagnose IPFDs was low with area under the curves of 0.56 (95% CI 0.44, 0.69) compared with 0.84 (95% CI 0.76, 0.92) for VWD. Correlation of PFA-EPI/-ADP and ISTH-BAT was low with 0.25/0.39 Spearman's correlation coefficients. PFA were significantly prolonged in patients with VWD and Glanzmann thrombasthenia. ISTH-BAT-scores were only positive in severe bleeding disorders, but not in children with mild IPFDs or VWD. CONCLUSION: Neither ISTH-BAT nor PFA or the combination of both help diagnosing mild IPFDs in children. PFA is suited to exclude severe IPFDs or VWD and is in this regard superior to ISTH-BAT in children.

Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH.

In many patients referred with significant bleeding phenotype, laboratory testing fails to define any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this patient cohort poses significant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool. Patients with increased bleeding assessment tool scores should progress to hemostasis laboratory testing. To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment. In some laboratories, additional specialized hemostasis testing may be performed to identify other rare causes of bleeding. We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology. Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical significance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions.

How to investigate mild to moderate bleeding disorders and bleeding disorder of unknown cause.

A bleeding tendency is one of the most common complaints observed by hematologists. It is challenging to differentiate a clinically insignificant bleeding from a bleeding phenotype that requires hemostatic evaluation and medical intervention. A thorough review of personal and familial history, objective assessment of bleeding severity using a bleeding assessment tool, and a focused physical examination are critical to correctly identifying suspected patients with mild to moderate bleeding disorders (MBDs). A basic laboratory work-up should be performed in all patients referred for a bleeding tendency. If a hemostatic abnormality is found such as evidence of von Willebrand disease, a platelet function disorder, or a coagulation factor deficiency, more extensive testing should be performed to further characterize the bleeding disorder. Conversely, if all results are normal the patient is considered to have bleeding disorder of unknown cause (BDUC). For patients with BDUC, further evaluation may include non-routine testing to look for rare bleeding disorders not detected by routine hemostasis tests, such as thrombomodulin-associated coagulopathy, tissue factor pathway inhibitor-related bleeding disorder, hyperfibrinolytic-bleeding disorders or impaired tissue factor production. In this review, we summarize the stepwise diagnostic procedure in MBDs and provide some insights into the biological features of BDUC.

Association of dysglycaemia with persistent infarct core iron in patients with acute ST-segment elevation myocardial infarction.

BACKGROUND: Dysglycaemia increases the risk of myocardial infarction and subsequent recurrent cardiovascular events. However, the role of dysglycaemia in ischemia/reperfusion injury with development of irreversible myocardial tissue alterations remains poorly understood. In this study we aimed to investigate the association of ongoing dysglycaemia with persistence of infarct core iron and their longitudinal changes over time in patients undergoing primary percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI). METHODS: We analyzed 348 STEMI patients treated with primary PCI between 2016 and 2021 that were included in the prospective MARINA-STEMI study (NCT04113356). Peripheral venous blood samples for glucose and glycated hemoglobin (HbA1c) measurements were drawn on admission and 4 months after STEMI. Cardiac magnetic resonance (CMR) imaging including T2 * mapping for infarct core iron assessment was performed at both time points. Associations of dysglycaemia with persistent infarct core iron and iron resolution at 4 months were calculated using multivariable regression analysis. RESULTS: Intramyocardial hemorrhage was observed in 147 (42%) patients at baseline. Of these, 89 (61%) had persistent infarct core iron 4 months after infarction with increasing rates across HbA1c levels (<5.7%: 33%, ≥5.7: 79%). Persistent infarct core iron was independently associated with ongoing dysglycaemia defined by HbA1c at 4 months (OR: 7.87 [95% CI: 2.60-23.78]; p < 0.001), after adjustment for patient characteristics and CMR parameters. The independent association was present even after exclusion of patients with diabetes (pre- and newly diagnosed, n = 16). CONCLUSIONS: In STEMI patients treated with primary PCI, ongoing dysglycaemia defined by HbA1c is independently associated with persistent infarct core iron and a lower likelihood of iron resolution. These findings suggest a potential association between ongoing dysglycaemia and persistent infarct core iron, which warrants further investigation for therapeutic implications.

Growth Differentiation Factor-15 and Clinical Outcomes in Lower Extremity Artery Disease.

AIM: Lower extremity artery disease (LEAD) is an increasingly common health problem that is associated with high mortality due to thrombotic and bleeding events. Growth differentiation factor-15 (GDF15), a stress-response cytokine belonging to the transforming growth factor-beta superfamily, is associated with cardiovascular disease and its outcomes. The aim of the present study was to examine the effect of serum GDF15 levels on clinical outcomes in patients with LEAD. METHODS: We measured serum GDF15 levels in 200 patients with LEAD before their initial endovascular therapy. The primary endpoint was the all-cause mortality rate. The secondary endpoints, on the other hand, were thrombotic and bleeding events, such as cerebral infarction, acute coronary syndrome, acute limb ischemia, and Bleeding Academic Research Consortium types 3 and 5. RESULTS: The serum GDF15 levels increased with advancing Fontaine class. Kaplan-Meier analysis revealed that the high-GDF15 group (≥ 2,275 pg/mL) had higher rates of all-cause deaths and thrombotic and bleeding events than the low-GDF15 group (＜2,275 pg/mL). Multivariate Cox proportional-hazards regression analysis revealed that GDF15 was an independent predictor of all-cause mortality and thrombotic and bleeding events after adjusting for confounding risk factors. When the ABC-AF-bleeding score was substituted for GDF15, similar results were obtained. CONCLUSION: Serum GDF15 levels were associated with all-cause mortality and thrombotic and bleeding events in patients with LEAD. Serum GDF15 is a potentially useful marker of clinical outcomes, specifically for tracking thrombotic and bleeding events in patients with LEAD.

Retrospective study of clinical settings, indications and consequences of measurement of direct oral anticoagulant plasma levels in Northern Tasmania, Australia.

BACKGROUND: Routine monitoring of direct oral anticoagulant (DOAC) levels is not recommended but may be useful in certain clinical situations. There is a knowledge gap regarding the clinical use of DOAC levels in Australian hospitals. AIMS: To evaluate the clinical settings, indications and changes to anticoagulant management associated with DOAC levels in a tertiary hospital in Northern Tasmania, Australia. METHODS: Patients with one or more DOAC levels (dabigatran, rivaroxaban or apixaban) requested between January 2017 and December 2022 were identified. Retrospective chart review was performed to evaluate the clinical settings, indications, adequacy of request information and changes to clinical management associated with the measurement of DOAC levels. RESULTS: One hundred and twenty-nine DOAC measurements (54 rivaroxaban, 66 apixaban and nine dabigatran) were performed in 98 patients between January 2017 and December 2022. Annual requests for DOAC levels increased significantly between 2017 and 2019 and remained stable between 2020 and 2021 but declined in 2022. Overall, the most common indication for a DOAC level was renal impairment, followed by bleeding and recurrent thrombosis. Approximately 25% of requests were for acute bleeding with a reversal/haemostatic agent given in 45% of patients, while 10% were prior to urgent surgery. Measurement of DOAC levels was associated with a change in management in 50% of cases. 10% of requests did not specify anticoagulant history. CONCLUSION: Trends in requests for DOAC levels have changed over time. Clinician education regarding the importance of providing specific anticoagulant history is essential. Future prospective studies investigating the clinical utility of DOAC levels in different clinical settings are needed.

Fibrinogen levels in severe trauma: A preliminary comparison of Clauss Fibrinogen, ROTEM Sigma, ROTEM Delta and TEG 6s assays from the FEISTY pilot randomised clinical trial.

OBJECTIVE: To describe the relationships between different methods of measuring functional fibrinogen levels in severely injured, bleeding trauma patients across multiple timepoints during hospitalisation. METHODS: In 100 adult trauma patients enrolled in the FEISTY pilot randomised clinical trial at four tertiary trauma centres in Australia, blood samples were collected prospectively. Consistency of agreement was calculated, comparing functional fibrinogen levels measured by four methods - ROTEM® Delta and Sigma FIBTEM A5, TEG® 6s CFF MA, and gold-standard Clauss Fibrinogen. RESULTS: Comparing the ROTEM® Delta and new-generation ROTEM® Sigma machine, consistency of agreement for FIBTEM A5, measured by calculating intraclass correlation coefficients (ICCs), was ≥0.73 across all analysed timepoints, with mean differences (Sigma minus Delta) of 0.10-3.57 mm. Corresponding values comparing the ROTEM® Sigma FIBTEM A5 and TEG® 6s CFF MA were ICC = 0.55-0.82 and ICC = 4.69-7.97 (CFF MA minus A5). Comparing ROTEM® Sigma FIBTEM A5 and Clauss Fibrinogen Analysis (CFA), among statistically significant simple linear regression models, R2 was 0.25-0.67, and comparing TEG® 6s CFF MA and CFA (CFA) 0.65-0.82, although not all differences were significant with the latter comparison. Relationships across all timepoints combined were Clauss Fibrinogen (CF) (g/L) = 0.21𝑥 + 0.004 (where 𝑥 = ROTEM® Sigma FIBTEM A5 in mm) and (g/L) = 0.16𝑥 - 0.06 (where 𝑥 = TEG® 6s CFF MA in mm). CONCLUSIONS: The present study revealed acceptable agreement between four different assays measuring functional fibrinogen, with current- and previous-generation ROTEM® machines (Sigma, Delta) performing similarly measuring functional fibrinogen via FIBTEM assay. This suggests that haemostatic resuscitation algorithms designed for the ROTEM® Delta can be applied to the ROTEM® Sigma to guide fibrinogen replacement.

Ethnic Differences in Thrombotic Profiles of Acute Coronary Syndrome Patients and Relationship to Cardiovascular Outcomes: A Comparison of East Asian and White subjects.

BACKGROUND: East Asians (EAs), compared to white Caucasians (W), have a lower risk of ischemic heart disease and a higher risk of bleeding with antithrombotic medications. The underlying mechanisms are incompletely understood. OBJECTIVES: We sought to compare thrombotic profiles of EA and W patients with myocardial infarction (MI) and relate these to cardiovascular outcomes. METHODS: In a prospective study in the United Kingdom and Korea, blood samples from patients (n = 515) with ST- or non-ST-elevation MI (STEMI and NSTEMI) were assessed using the Global Thrombosis Test, measuring thrombotic occlusion (OT) and endogenous fibrinolysis (lysis time [LT]). Patients were followed for 1 year for major adverse cardiovascular events (MACE) and bleeding. RESULTS: EA patients showed reduced OT (longer OT) compared to W (646 seconds [470-818] vs. 436 seconds [320-580], p < 0.001), with similar LT. In STEMI, OT (588 seconds [440-759] vs. 361 seconds [274-462], p < 0.001) and LT (1,854 seconds [1,389-2,729] vs. 1,338 seconds [1,104-1,788], p < 0.001) were longer in EA than W. In NSTEMI, OT was longer (OT: 734 seconds [541-866] vs. 580 seconds [474-712], p < 0.001) and LT shorter (1519 seconds [1,058-2,508] vs. 1,898 seconds [1,614-2,806], p = 0.004) in EA than W patients. MACE was more frequent in W than EA (6.3 vs. 1.9%, p = 0.014) and bleeding infrequent. While OT was unrelated, LT was a strong independent predictor of MACE event after adjustment for risk factors (hazard ratio: 3.70, 95% confidence interval: 1.43-9.57, p = 0.007), predominantly in W patients, and more so in STEMI than NSTEMI patients. CONCLUSION: EA patients exhibit different global thrombotic profiles to W, associated with a lower rate of cardiovascular events.